Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:30][CH:31]=[CH2:32])[C:9]([N:11]=[C:12](SC)[NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH:24]=[N:23][C:22]([CH3:25])=[N:21]3)=[C:16]([O:26][CH3:27])[CH:15]=2)=O)=[CH:4][CH:3]=1.[CH2:33]([NH:36][NH2:37])[CH:34]=[CH2:35]>>[CH2:33]([N:36]1[C:9]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:30][CH:31]=[CH2:32])=[N:11][C:12]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH:24]=[N:23][C:22]([CH3:25])=[N:21]3)=[C:16]([O:26][CH3:27])[CH:15]=2)=[N:37]1)[CH:34]=[CH2:35]
Reactant: C=CCNN
Reactant: C=CCC(C(=O)N=C(Nc1ccc(-n2cnc(C)n2)c(OC)c1)SC)c1ccc(F)cc1
Product: C=CCC(c1ccc(F)cc1)c1nc(Nc2ccc(-n3cnc(C)n3)c(OC)c2)nn1CC=C

Procedure:
Methyl N′-2-(4-fluorophenyl)pent-4-enoyl-N-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)carbamimidothioate (0.62 g, 1.367 mmol) was reacted with allylhydrazine (70% solution in water, 0.55 mL, 5.47 mmol) using a procedure analogous to Step B of Example 1 to provide 1-allyl-5-(1-(4-fluorophenyl)but-3-enyl)-N-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-1H-1,2,4-triazol-3-amine. The purified product was dissolved in 0.1% TFA/dichloromethane and reconcentrated to afford 1-allyl-5-(1-(4-fluorophenyl)but-3-enyl)-N-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-1H-1,2,4-triazol-3-amine, TFA salt (446 mg, 0.692 mmol, 51% yield) as a clear solid residue. LC-MS (M+H)+=560.3.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=[C:15]([CH3:31])[CH2:16][CH2:17][C:18]1[N:22]([CH2:23][CH2:24][C:25]#[N:26])[C:21]2[CH:27]=[CH:28][CH:29]=[CH:30][C:20]=2[N:19]=1.ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH:15]([CH3:31])[CH2:16][CH2:17][C:18]2[N:22]([CH2:23][CH2:24][C:25]#[N:26])[C:21]3[CH:27]=[CH:28][CH:29]=[CH:30][C:20]=3[N:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)CCc1nc2ccccc2n1CCC#N
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: CC(CCc1nc2ccccc2n1CCC#N)N1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 80.3 %

Procedure:
A mixture of 0.3 g of 4-benzyl-piperidine, 0.24 g of 3-[2-(3-oxo-butyl)-benzimidazol-1-yl]-propionitrile, 5 mL of 1,2-dichloroethane and 0.3 g of sodium triacetoxyborohydride was stirred at room temperature for 3 days. The reaction mixture was diluted with 50 mL chloroform and 10 mL saturated aqueous Na2CO3 and the layers separated. The aqueous layer was extracted with 2×25 mL of chloroform and the combined organic layers dried over magnesium sulfate and concentrated under reduced pressure. Low pressure chromatography eluting with a gradient of 80:20 ethyl acetate:methanol to 80:20:5 ethyl acetate:methanol:triethylamine gave 320 mg of 3-{2-[3-(4-benzyl-piperidin-1-yl)-butyl]-benzimidazol-1-yl}-propionitrile as a resin.
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].C[O-].[Na+].O.O.C([O-])(=O)C.[Zn+2:20].C([O-])(=O)C>CO>[Zn:20].[NH2:1][C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: [Zn+2]
Agent: CC(=O)[O-]
Agent: C[O-]
Agent: N[C@@H](CCC(=O)O)C(=O)O
Solvent: O
Solvent: CO
Product: [Zn]

Procedure:
L-glutamic acid (2.0 g, 13.6 mmol) was added to an MeOH solution of NaOMe (prepared with Na: 0.31 g, MeOH: 50 ml) at 0° C. and stirred. An MeOH solution (30 ml) of zinc acetate dihydrate (1.49 g) was then slowly dropwise added thereto. After refluxing and stirring for 5 hours, the precipitated crystal (in suspension) was recovered by filtration, washed with water, air dried, and then dried under a reduced pressure (5 mmHg, 80° C.).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=1>>[Cl:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([N+:9]([O-:11])=[O:10])[C:2]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=1
Reactant: Nc1ccc(CCO)cc1
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Product: O=[N+]([O-])c1cccc(Cl)c1Nc1ccc(CCO)cc1

Procedure:
The title compound was prepared according to the procedure described in step 3 of Example 1 from 2,3-dichloronitrobenzene and 4-aminophenylethyl alcohol.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][C:12]3[C:14]([N:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=2)=[CH:5][CH:4]=1)[CH3:2].Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[C:28]([N+:33]([O-:35])=[O:34])[CH:27]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][C:12]3[C:14]([N:18]4[CH2:19][CH2:20][N:21]([CH2:25][C:26]5[CH:31]=[CH:30][C:29]([F:32])=[C:28]([N+:33]([O-:35])=[O:34])[CH:27]=5)[CH2:22][CH2:23]4)=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(-c2nc3cccc(N4CCNCC4)c3[nH]2)cc1
Reactant: O=[N+]([O-])c1cc(CBr)ccc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1ccc(-c2nc3cccc(N4CCN(Cc5ccc(F)c([N+](=O)[O-])c5)CC4)c3[nH]2)cc1
Reaction time: 1 h
Yield: 33.8 %

Procedure:
2-(4-Ethyl-phenyl)-7-piperazin-1-yl-1H-benzoimidazole (200 mg, 0.65 mmol) and 4-bromomethyl-1-fluoro-2-nitro-benzene (152 mg, 0.65 mmol) were stirred together with DIEA (83 mg, 0.6.5 mmol) in DMF (4 ml) at room temperature. After 1 h, the reaction is complete and it was purified by HPLC Method E to yield the title product (100 mg (34%), 0.22 mmol). 1H NMR (DMSO-d6): δ=12.71 (s, 1H), 8.15 (m, 1H), 8.04 (d, J=8.2 Hz, 2H), 7.83 (m, 1H), 7.59 (m, 1H), 7.34 (d, J=8.2 Hz, 2H), 7.08 (m, 2H), 6.52 (dd, J=6.64, 1.94 Hz, 1H), 3.69 (s, 2H), 3.65 (bs, 4H), 2.75 (bs, 6H), 1.32 (t, J=7.6 Hz, 3H). Calculated mass=457.43, [M+H]+=458.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[CH3:18][NH:19][CH2:20][CH:21]([O:24][CH3:25])[O:22][CH3:23].C(N(CC)CC)C>C1C=CC=CC=1>[CH3:18][N:19]([CH2:20][CH:21]([O:24][CH3:25])[O:22][CH3:23])[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16]
Reactant: CNCC(OC)OC
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)cc([N+](=O)[O-])c1Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COC(CN(C)c1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-])OC
Reaction time: 1 h

Procedure:
4-Chloro-3,5-dinitrobenzotrifluoride (5.4 grams; 0.02 mole) dissolved in benzene was charged into a glass reaction vessel equipped with a mechanical stirrer and addition funnel. N-Methyl-N-2,2-dimethoxyethylamine (2,4 grams; 0.02 mole) and triethylamine (2.02 grams; 0.02 mole) both dissolved in benzene (50 ml) were then added dropwise with stirring. After the addition was completed stirring was continued for a period of 1 hour resulting in the formation of a precipitate. The reaction mixture was filtered to remove the acid acceptor salt and was chromatographed. The solution was then evaporated to yield a solid product. This solid was recrystallized from hexane to yield the desired product N-methyl-N-(2,2-dimethoxyethyl)-2,6-dinitro-4-trifluoroemethylaniline melting at 48° to 50° C.
Reaction SMILES: [Mg].[F:2][C:3]1[CH:4]=[C:5](Br)[CH:6]=[C:7]([F:9])[CH:8]=1.II.C([O:15][CH2:16][CH3:17])=O>CCOCC>[F:2][C:3]1[CH:4]=[C:5]([CH:16]([C:17]2[CH:4]=[C:3]([F:2])[CH:8]=[C:7]([F:9])[CH:6]=2)[OH:15])[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: CCOC=O
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: OC(c1cc(F)cc(F)c1)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 21 h

Procedure:
A mixture of 486 mg magnesium, 8 mL dry ether, a small amount of 3,5-difluoro-bromobenzene and some iodine was warmed to start the Grignard reaction. 2.38 mL 3,5-difluoro-bromobenzene in 40 mL dry ether were added dropwise and the mixture refluxed for one hour. 0.81 mL ethyl formate was added and the mixture stirred for 21 hours at room temperature. The reaction was quenched with 7 mL 1N hydrochloric acid, diluted with ethyl acetate and washed with water and brine. Evaporation of the solvents and chromatography of the residue afforded 1.56 g of a light yellow solid, m.p.: 62° C.; MS: 315 ([M+AcO]−).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH3:20])[C:7]([N:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]=[CH:10]1)=[O:8].[N-:21]=[N+:22]=[N-:23].C([N+](CCCC)(CCCC)CCCC)CCC>CC(C)=O>[N:21]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]([CH3:20])[C:7]([N:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:11]=[CH:10]1)=[O:8])=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: CN(CCCCCl)C(=O)n1cnc(-c2ccccc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC(C)=O
Product: CN(CCCCN=[N+]=[N-])C(=O)n1cnc(-c2ccccc2)c1
Temperature: 25 °C

Procedure:
Compound 47 (4.3) (1 mmol) was taken in anhydrous acetone (25 mL) and tetra-n-butylammonium azide (2 mmol) was added and the reaction was refluxed for 8 h. The reaction was cooled to RT and solvent was evaporated on Rotavapor to give a crude compound which on purification by Biotage SP1 provided pure N-(4-azidobutyl)-N-methyl-4-phenyl-1H-imidazole-1-carboxamide (48/4.4).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][C:4]=1[F:12])#[N:2].Cl[C:14]1[N:19]=[C:18]([NH:20][CH3:21])[N:17]=[C:16]([N:22]2[C@H:27]([CH2:28][CH3:29])[CH2:26][O:25][C@H:24]([C:30]([NH:32][CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[O:31])[CH2:23]2)[CH:15]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:14]2[N:19]=[C:18]([NH:20][CH3:21])[N:17]=[C:16]([N:22]3[C@H:27]([CH2:28][CH3:29])[CH2:26][O:25][C@H:24]([C:30]([NH:32][CH:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)=[O:31])[CH2:23]3)[CH:15]=2)=[CH:5][C:4]=1[F:12])#[N:2]
Reactant: CC[C@@H]1CO[C@H](C(=O)NC2CCCCC2)CN1c1cc(Cl)nc(NC)n1
Reactant: N#Cc1ccc(B(O)O)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC[C@@H]1CO[C@H](C(=O)NC2CCCCC2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(NC)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.9 %

Procedure:
(4-Cyano-3-fluorophenyl)boronic acid (0.261 g, 1.582 mmol) was added to a 20 mL microwave vessel followed by the addition of Pd(PPh3)4 (0.046 g, 0.040 mmol) and (2S,5R)-4-[6-chloro-2-(methylamino)-4-pyrimidinyl]-N-cyclohexyl-5-ethyl-2-morpholinecarboxamide (0.302 g, 0.791 mmol) dissolved in 1,4-dioxane (5 mL). Saturated aqueous NaHCO3 (2.5 mL) was added and the reaction was irradiated at 130° C. for 30 minutes. SiliaBond® Thiol (3.04 g, 3.96 mmol) was added to the reaction and it was stirred at room temperature for 2 hours and then filtered. The filtrate was then diluted with H2O and extracted with EtOAc (2×). The organics were dried and concentrated to afford the crude title compound (0.387 g) as a dark brown oil. LC-MS (ES) m/z=467 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:41]=[CH:40][C:6]2[N:7](COCC[Si](C)(C)C)[C:8]([CH:10]([O:30][CH3:31])[C:11]3[C:19]([O:20][CH3:21])=[CH:18][C:17]([CH3:22])=[C:16]4[C:12]=3[CH:13]=[CH:14][N:15]4C(OC(C)(C)C)=O)=[N:9][C:5]=2[CH:4]=1)#[N:2].COC1C=C2C(=C(C)C=1)N(C([O-])=O)C=C2>>[CH3:31][O:30][CH:10]([C:11]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([CH3:22])=[C:16]2[C:12]=1[CH:13]=[CH:14][NH:15]2)[C:8]1[NH:7][C:6]2[CH:40]=[CH:41][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[N:9]=1
Reactant: COc1cc(C)c2c(ccn2C(=O)OC(C)(C)C)c1C(OC)c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C
Agent: COc1cc(C)c2c(ccn2C(=O)[O-])c1
Product: COc1cc(C)c2[nH]ccc2c1C(OC)c1nc2cc(C#N)ccc2[nH]1

Procedure:
The title compound was synthesized from a mixture of (±)-tert-butyl 4-((5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(methoxy)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate and (±)-tert-butyl 4-((6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)methoxy)methyl)-5-methoxy-7-methyl-1H-indole-1-carboxylate as described in Example 24-B. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.91 (d, J=6.57 Hz, 1H) 10.92 (br. s., 1H) 7.91-7.97 (m) 7.88 (m) 7.55-7.66 (m, 1H) 7.42-7.54 (m, 1H) 7.18 (t, J=2.72 Hz, 1H) 6.78 (s, 1H) 6.24-6.30 (m, 2H) 3.80 (s, 3H) 3.33 (s, 3H) 2.46 (s, 3H). HRMS calcd. for C20H18N4O2 (M+H)+ 347.1429. found 347.1516.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([S:21](Cl)(=[O:23])=[O:22])=[CH:13][CH:12]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[N:25]([CH:28]([CH3:30])C)=[C:26]=[O:27]>C(N(CC)CC)C>[C:26]([N:25]1[CH2:28][CH2:30][CH:2]([NH:3][S:21]([C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]([NH:10][C:8](=[O:9])[C:7]3[CH:6]=[CH:5][CH:4]=[N:3][C:2]=3[CH3:1])=[CH:12][CH:13]=2)(=[O:23])=[O:22])[CH2:7][CH2:6]1)(=[O:27])[CH2:12][CH2:11][CH3:20]
Reactant: Cc1ncccc1C(=O)Nc1ccc(S(=O)(=O)Cl)c2ccccc12
Reactant: CC(C)N=C=O
Solvent: CCN(CC)CC
Product: CCCC(=O)N1CCC(NS(=O)(=O)c2ccc(NC(=O)c3cccnc3C)c3ccccc23)CC1

Procedure:
The title compound was prepared following the general procedure in Scheme 5, beginning with 4-[(2-methyl-pyridine-3-carbonyl)-amino]-naphthalene-1-sulfonyl chloride, and substituting butyryl chloride and triethylamine for 2-isocyanato-propane. 1H NMR (300 MHz, DMSO) δ 10.76 (s, 1H), 8.68 (d, 1H), 8.59 (d, 1H), 8.31 (d, 1H), 8.24 (d, 1H), 8.10 (d, 1H), 8.04 (d, 1H), 7.98 (d, 1H), 7.73 (m, 2H), 7.41 (m, 1H), 4.00 (d, 1H), 3.61 (d, 1H), 3.23 (m, 1H), 2.93 (t, 1H), 2.66 (s, 3H), 2.59 (m, 1H), 2.17 (t, 2H), 1.48 (m, 2H), 1.43 (m, 2H), 1.19 (m, 2H), 0.82 (m, 2H). LC/MS m/z 494 (M−H)−, 496 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14]([F:17])([F:16])[CH2:13][C@H:12]1[C:18]([NH2:21])=[N:19][OH:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]([C:26]#[C:27][C:28]([O:30][CH3:31])=[O:29])=[O:25]>C(Cl)(Cl)Cl>[CH3:22][O:23][C:24](=[O:25])[C:26]([O:20][N:19]=[C:18]([NH2:21])[C@@H:12]1[CH2:13][C:14]([F:17])([F:16])[CH2:15][N:11]1[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])=[CH:27][C:28]([O:30][CH3:31])=[O:29]
Reactant: NC(=NO)[C@@H]1CC(F)(F)CN1C(=O)OCc1ccccc1
Reactant: COC(=O)C#CC(=O)OC
Solvent: ClC(Cl)Cl
Product: COC(=O)C=C(ON=C(N)[C@@H]1CC(F)(F)CN1C(=O)OCc1ccccc1)C(=O)OC

Procedure:
A solution of benzyl-(2S)-2-[amino(hydroxyimino)methyl]-4,4-difluoropyrrolidine-1-carboxylate and dimethylacetylendicarboxylate (1.2 eq.) in chloroform was refluxed for 1 hour under nitrogen and the solution was concentrated. Residue was purified by flash chromatography on silica gel, (eluent: petroleum ether:ethyl acetate=7.5:2.5), to give the desired product as a 3:1 mixture of two isomers by 1H NMR.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]([O:32][CH2:33][CH3:34])([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[N:27]=[C:26](I)[N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][N:23]3[CH:29]([CH3:31])[CH3:30])=[CH:14][CH:13]=1)[PH2:10]=[O:11])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[Br-].[CH:36]1([Zn+])[CH2:40][CH2:39][CH2:38][CH2:37]1.O>CN(C=O)C>[CH2:1]([O:3][P:4]([C:9]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[N:27]=[C:26]([CH:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[N:25]=[C:24]3[C:20]=2[N:21]=[CH:22][N:23]3[CH:29]([CH3:31])[CH3:30])=[CH:14][CH:13]=1)([O:32][CH2:33][CH3:34])[PH2:10]=[O:11])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOC([PH2]=O)(c1ccc(Nc2nc(I)nc3c2ncn3C(C)C)cc1)P(=O)(OCC)OCC
Reactant: [Zn+]C1CCCC1
Agent: [Br-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC([PH2]=O)(c1ccc(Nc2nc(C3CCCC3)nc3c2ncn3C(C)C)cc1)P(=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To {ethoxy-[4-(2-iodo-9-isopropyl-9H-purin-6-ylamino)-phenyl]-phosphinoylmethyl}-phosphonic acid diethyl ester (0.30 g, 0.48 mmol) in DMF (3.9 mL) was added PdCl2(PPh3)4 (17 mg, 0.024 mmol) followed by cyclopentylzinc bromide (0.5M THF, 3.9 mL, 1.9 mmol). The mixture was stirred at rt for 1 h, poured into water and extracted with EtOAc. The combined extracts, were washed with water, sat'd NaCl, then dried over MgSO4 and filtered. The material was used without purification in the next reaction.
Reaction SMILES: [F:1][C:2]([F:42])([F:41])[C:3]1[CH:4]=[C:5]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1)[CH2:6][C:7]1[C:12]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:11][N:10]=[C:9]([NH:19][C@@H:20]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH3:31])[N:28]=3)[NH:23][C@H:22]([CH2:32][CH3:33])[CH2:21]2)[N:8]=1.[Cl:43][CH2:44][CH2:45][N:46]=[C:47]=[O:48].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:43][CH2:44][CH2:45][NH:46][C:47]([N:23]1[C:24]2[C:29](=[N:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C@@H:20]([NH:19][C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[C:3]([C:2]([F:1])([F:41])[F:42])[CH:36]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:34]=3)[C:12]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[CH:11][N:10]=2)[CH2:21][C@H:22]1[CH2:32][CH3:33])=[O:48]
Reactant: O=C=NCCCl
Reactant: CC[C@@H]1C[C@H](Nc2ncc(N3CCOCC3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)c2nc(OC)ccc2N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC[C@@H]1C[C@H](Nc2ncc(N3CCOCC3)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)c2nc(OC)ccc2N1C(=O)NCCCl
Temperature: 60 °C
Reaction time: 9 h
Yield: 90.6 %

Procedure:
(2R,4S)-4-{[3,5-Bis(trifluoromethyl)benzyl]-[5-(morpholin-4-yl)-pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-1,2,3,4-tetrahydro-[1,5]naphthyridine (150 mg) is dissolved in toluene (2.0 ml), and thereto is added 2-chloroethyl isocyanate (40 mg). The mixture is stirred at 60° C. for 9 hours under nitrogen flow. To the reaction mixture is added a saturated aqueous sodium hydrogen carbonate solution, the mixture is extracted with ethyl acetate. The organic layer is washed with saturated brine and dried over magnesium sulfate, then concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane:ethyl acetate=2:1→1:9) to give (2R,4S)-4-{[3,5-bis(trifluoromethyl)-benzyl]-[5-(morpholin-4-yl)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid (2-chloroethyl)amide (160 mg). MS (m/z): 702/704 [M+H]+.
Reaction SMILES: [CH:1]1([C:6]2[S:7][CH:8]=[C:9]([C:11]([O:13]CC)=[O:12])[N:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCC(C1SC=C(C(OCC)=O)N=1)CC>>[CH3:3][CH2:2][CH:1]([C:6]1[S:7][CH:8]=[C:9]([C:11]([OH:13])=[O:12])[N:10]=1)[CH2:5][CH3:4]
Reactant: CCOC(=O)c1csc(C2CCCC2)n1
Agent: CCOC(=O)c1csc(C(CC)CC)n1
Product: CCC(CC)c1nc(C(=O)O)cs1

Procedure:
Prepared by the method of Carboxylic Acid 2, step d using ethyl 2-(pentan-3-yl)thiazole-4-carboxylate [Carboxylic Acid 3, step c] (2.8 g) in place of ethyl 2-cyclopentylthiazole-4-carboxylate. Yield 2.3 g.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[K+].[C:11]([O:15][C:16]([N:18]1[CH2:28][CH2:27][CH2:26][CH:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].I[CH3:30]>O1CCCC1>[C:11]([O:15][C:16]([N:18]1[CH2:28][CH2:27][CH2:26][C:20]([CH3:30])([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:19]1)=[O:17])([CH3:12])([CH3:13])[CH3:14]
Reactant: CI
Reactant: CCOC(=O)C1CCCN(C(=O)OC(C)(C)C)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)CCCN(C(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 88.8 %

Procedure:
Potassium bis(trimethylsilyl)amide (1200 ml, 0.5M in toluene, 0.6 mol) was added to a 3-necked 3-l flask equipped with an overhead stirrer, followed by tetrahydrofuran (90 ml) and the solution was cooled to −78° C. Ethyl N-(t-butyloxycarbonyl)nipecotate (100 g, 0.39 mol) in tetrahydrofuran (90 ml) was added dropwise and the resulting solution allowed to age for 15 minutes. Iodomethane (37.4 ml, 85.2 g, 0.6 mol) was added dropwise to the stirred solution keeping the temperature below −70° C. The resulting mixture was stirred at room temperature overnight and was evaporated under reduced pressure. The residue was partitioned between ethyl acetate and water and the organic layer was washed with brine, dried (sodium sulphate) and evaporated to give a yellow oil. This was purified on a plug of silica using dichloromethane as eluant to afford the product (94 g, 90%) as a pale yellow oil.
Reaction SMILES: CC1(C)CCC2C(=CC=CC=2)N1.[CH2:13]([C:15]1([CH2:25][CH3:26])[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16]1)[CH3:14]>CCOC(C)=O.[Pd]>[CH2:25]([C:15]1([CH2:13][CH3:14])[CH2:24][CH2:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16]1)[CH3:26]
Reactant: CCC1(CC)C=Cc2ccccc2N1
Agent: [Pd]
Agent: CC1(C)CCc2ccccc2N1
Solvent: CCOC(C)=O
Product: CCC1(CC)CCc2ccccc2N1
Yield: 70.4 %

Procedure:
This compound was prepared in a manner similar to that described for 1,2,3,4-tetrahydro-2,2-dimethylquinoline (structure 18 of Scheme III, where R1 =R2 =Me) from 2,2-diethyl-1,2-dihydroquinoline (1.46 g, 7.80 mmol) and 10% Pd/C (146 mg, 10% by weight) in EtOAc (18.7 mL) to afford 1.04 g (70%) 2,2-diethyl-1,2,3,4-tetrahydroquinoline after flash chromatography (hexanes:EtOAc, 97:3). Data for 2,2-diethyl-1,2,3,4-tetrahydroquinoline: Rf 0.43 (24:1 hexanes:ethyl acetate); 1H NMR (400 MHz, CDCl3) 6.90-7.00 (m, 2H), 6.57 (td, J=7.3, 1.0, 1H), 6.46 (dd, J=8.4, 1.0, 1H), 3.63 (broad s, 1H), 2.72 (t, J=6.7, 2H), 1.69 (t, J=6.7,2H), 1.38-1.53 (m, 4H), 0.86 (t, J=7.4,6H).
Reaction SMILES: [CH3:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]3=[N:17][S:18](=[O:22])(=[O:21])[CH2:19][CH2:20][N:15]3[CH:14]=[CH:13][CH:12]=2)=[CH:7][CH:6]=1>C1COCC1.CO.[Pt](=O)=O>[CH3:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]2[C:16]3=[N:17][S:18](=[O:21])(=[O:22])[CH2:19][CH2:20][N:15]3[CH2:14][CH2:13][CH2:12]2)=[CH:9][CH:10]=1
Reactant: Cc1ccccc1Oc1ccc(C2=CC=CN3CCS(=O)(=O)N=C23)cc1
Agent: O=[Pt]=O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccccc1Oc1ccc(C2CCCN3CCS(=O)(=O)N=C23)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 50.7 %

Procedure:
Platinum(IV) oxide (30 mg) was added to a solution of 9-[4-(2-methylphenoxy)phenyl]-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (281 mg) in THF (dry) (150 ml) and MeOH (150 mL) and the mixture was stirred at 50° C. under hydrogen overnight. Activated carbon was added and the insoluble solid was removed by filtration through NH-silica gel/Celite pad (eluted with EtOAc). The filtrate was concentrated and the residue was crystallized from MeCN/IPE to give the title compound (144.1 mg) as colorless crystals.
Reaction SMILES: O[CH2:2][C:3]1[CH:31]=[CH:30][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:16]=[CH:17][C:18]([O:25][S:26]([CH3:29])(=[O:28])=[O:27])=[C:19]([CH:24]=3)[C:20]([O:22][CH3:23])=[O:21])[O:12][C:13]=2[CH3:14])=[C:5]([O:32][CH3:33])[CH:4]=1.C1(C)C=CC=CC=1.S(Cl)([Cl:43])=O>C(OCC)(=O)C>[Cl:43][CH2:2][C:3]1[CH:31]=[CH:30][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:16]=[CH:17][C:18]([O:25][S:26]([CH3:29])(=[O:28])=[O:27])=[C:19]([CH:24]=3)[C:20]([O:22][CH3:23])=[O:21])[O:12][C:13]=2[CH3:14])=[C:5]([O:32][CH3:33])[CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1cc(-c2nc(COc3ccc(CO)cc3OC)c(C)o2)ccc1OS(C)(=O)=O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(-c2nc(COc3ccc(CCl)cc3OC)c(C)o2)ccc1OS(C)(=O)=O
Yield: 67.4 %

Procedure:
To a mixture of methyl 5-{4-[(4-hydroxymethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-methanesulfonyloxybenzoate (0.20 g) and toluene (10 mL) was added thionyl chloride (0.055 g), and the mixture was heated under reflux for 1 hr. After concentration of the reaction mixture, ethyl acetate was added to the residue. The ethyl acetate layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated to give methyl 5-{4-[(4-chloromethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}-2-methanesulfonyloxybenzoate (0.14 g, yield 67%) as colorless crystals. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 146-147° C.