Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[CH3:21][O:22][CH2:23][CH2:24][NH2:25]>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:25][CH2:24][CH2:23][O:22][CH3:21])=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: COCCN
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: COCCNC(=O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 50 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (100 mg, 0.28 mmol) and 2-Methoxy ethylamine (25 mg, 0.32 mmol). The title compound was obtained as a solid (52 mg, 46% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.99 (2H, m), 8.95 (1H, m), 8.46 (1H, m), 3.39 (2H, m), 3.35 (2H, m), 3.24 (3H, s). MS m/z: 405.99, 407.99 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([CH:13]([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22])C1C=CC=CC=1.[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[OH:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([CH:13]([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: [H][H]
Reactant: CCOC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2C
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1nc2n(c(=O)c1O)CCOC2C
Yield: 95.6 %

Procedure:
Hydrogenolysis of intermediate 14, ethyl 3-benzyloxy-9-methyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxylate, (0.610 g, 1.77 mmol) in a mixture of ethyl acetate (75 ml) and ethanol (75 ml) at 25° C. over 10% palladium on activated carbon (0.20 g) under 1 atm of hydrogen for 2 h gave 0.430 g (95% yield) of the title ester as white crystals; mp 119–121° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ ppm: 1.46 (3H, t, J=7.1 Hz, CH3), 1.67 (3H, d, J=6.6 Hz, CH3), 3.90 (2H, m, CH2), 4.13–4.32 (2H, m, CH2), 4.51 (2H, m, OCH2), 4.70 (1H, q, J=6.6 Hz, CH), 10.7 (1H, broad, OH). Anal. Calcd for C11H14N2O5: C, 51.96; H, 5.55; N, 11.01. Found: C, 51.60; H, 5.61; N, 10.70.
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:58]1([N:63]2[CH2:68][CH2:67][N:66]([NH2:69])[CH2:65][CH2:64]2)[CH2:62][CH2:61][CH2:60][CH2:59]1>>[CH:1]1([N:7]2[CH2:13][C:12]([F:14])([F:15])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27]([NH:69][N:66]5[CH2:65][CH2:64][N:63]([CH:58]6[CH2:62][CH2:61][CH2:60][CH2:59]6)[CH2:68][CH2:67]5)=[O:29])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NN1CCN(C2CCCC2)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NN2CCN(C3CCCC3)CC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-N-cyclopentyl piperazine-4-amine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.11-1.92 (m, 18H) 2.93 (br. s., 4H) 3.31 (s, 3H) 3.93 (s, 3H) 4.06 (t, J=13.39 Hz, 2H) 4.44 (m, 1H) 7.41 (d, J=8.0 Hz, 1H) 7.43 (s, 1H) 7.90 (s, 1H) 8.21 (s, 1H) 8.27 (d, J=8.34 Hz, 1H) 9.37 (s, 1H). Melting point: 98-99° C. [M+H] calculated for C31H42F2N8O3, 613. found 613.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:39][C:40]1[CH:47]=[CH:46][CH:45]=[CH:44][C:41]=1[CH2:42][NH2:43]>>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:10]=[CH:11][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](=[O:21])[NH:43][CH2:42][C:41]3[CH:44]=[CH:45][CH:46]=[CH:47][C:40]=3[Br:39])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:13][CH:14]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Reactant: NCc1ccccc1Br
Product: CC(C)c1ccc2c(Nc3cc(C(=O)NCc4ccccc4Br)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1

Procedure:
According to the procedure in Example 385F, the title compound was prepared using 4-(4-tert-butoxycarbonylamino-phenylsulfanyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzoic acid (prepared in Example 385E) and o-bromobenzylamine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:13])[CH2:12][CH2:11][NH:10][CH2:9]2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:45][C:46]1[CH:51]=[CH:50][C:49]([C:52]2[C:56]([C:57](O)=[O:58])=[CH:55][O:54][N:53]=2)=[CH:48][CH:47]=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([OH:13])[CH2:12][CH2:11][N:10]([C:57]([C:56]3[C:52]([C:49]4[CH:50]=[CH:51][C:46]([CH3:45])=[CH:47][CH:48]=4)=[N:53][O:54][CH:55]=3)=[O:58])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2nocc2C(=O)O)cc1
Reactant: OC1(c2ccc(F)cc2)CCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2nocc2C(=O)N2CCC(O)(c3ccc(F)cc3)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
A solution of 3-(4-fluorophenyl)pyrrolidin-3-ol (9 mg, 0.039 mmol), TBTU (15 mg, 0.047 mmol, 1.2 equ.) and N-ethyl-N-isopropylpropan-2-amine (14 μL, 0.079 mmol, 2 equ.) in DMF (0.3 mL) was added to 3-(4-methylphenyl)isoxazole-4-carboxylic acid (8 mg, 0.039 mmol) and the reaction mixture was stirred at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents the product was dried in vacuum to yield the title compound (10 mg). MS (ESI, pos. ion) m/z calcd for C21H19FN2O3: 366.1380, found 366.1381.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][N:9]1[C:13]2[C:14]([CH3:26])=[CH:15][C:16]([NH:18]C(=O)OC(C)(C)C)=[CH:17][C:12]=2[O:11][C:10]1=[O:27]>C(Cl)Cl>[NH2:18][C:16]1[CH:15]=[C:14]([CH3:26])[C:13]2[N:9]([CH3:8])[C:10](=[O:27])[O:11][C:12]=2[CH:17]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)cc2oc(=O)n(C)c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(N)cc2oc(=O)n(C)c12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
500 μL (6.58 mmol) TFA were added to 500 mg (1.80 mmol) tert-butyl (3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazol-6-yl)-carbamate in 10 mL DCM and the mixture was stirred for 1.5 h at RT. Then the reaction mixture was evaporated down, the residue was made alkaline and extracted with DCM. The organic phase was dried on sodium sulphate, filtered and evaporated down.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5]2[CH:6]=[N:7][NH:8][C:9]=2[CH:10]=1.[H-].[Na+].[C:14]([Si:18](Cl)([CH3:20])[CH3:19])([CH3:17])([CH3:16])[CH3:15]>O1CCCC1>[Si:18]([O:11][C:4]1[CH:3]=[C:2]([F:1])[CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1cc(F)cc2[nH]ncc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1cc(F)cc2[nH]ncc12
Reaction time: 0.17 h

Procedure:
6-Fluoro-1H-indazol-4-ol (0.91 g) in tetrahydrofuran (20 mL) was treated with 60% sodium hydride (0.251 g). After 10 minutes, tert-butylchlorodimethylsilane (0.992 g) was added. The solution was stirred for 16 hours. The solvent was removed, and the residue was purified by flash column chromatography on silica gel to give the title compound.
Reaction SMILES: C([O:5][C:6]([C:8]1[N:12]=[C:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:10]([CH3:20])[N:9]=1)=[O:7])CCC.[OH-].[Na+].Cl>C(O)C>[CH2:13]([C:11]1[N:10]([CH3:20])[N:9]=[C:8]([C:6]([OH:7])=[O:5])[N:12]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCCCOC(=O)c1nc(Cc2ccccc2)n(C)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1nc(C(=O)O)nc1Cc1ccccc1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
5-Benzyl-1-methyl-1H-[1,2,4]triazole-3-carboxylic acid butyl ester (45 mg, 0.165 mmol) was dissolved in ethanol (2 ml), followed by addition of 6M sodium hydroxide aqueous solution (55 μl, 0.330 mmol). The reaction mixture was stirred at 80° C. for 18 h, then cooled to 23° C. and neutralized with 1M hydrochloric acid. Solvents were removed in vacuo. The crude mixture of title compound and NaCl was used without further purification for the next step. HPLC (method G) Rt=1.241 min.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].Br[C:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[N:12]=[C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[N:10]=1>CN(C=O)C>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:14][N:13]1[C:9]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[N:10][C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[N:12]1
Reactant: Fc1ccccc1Cn1nc(-c2ccccn2)nc1Br
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccccc1Cn1nc(-c2ccccn2)nc1-n1ccnc1
Reaction time: 0.17 h
Yield: 26.7 %

Procedure:
To a stirring suspension of imidazole (1.2 eq) in DMF was added sodium hydride (2 eq). The reaction generated gas and was stirred for 10 minutes. Then 2-(5-bromo-1-(2-fluorobenzyl)-1H-1,2,4-triazol-3-yl)pyridine (I-16) was added. The reaction was stirred at 100° C. for 12 hr. The reaction was quenched with brine, extracted with methylene chloride, dried over sodium sulfate and concentrated. The mixture was purified by SiO2 chromatography to afford 2-(1-(2-fluorobenzyl)-5-(1H-imidazol-1-yl)-1H-1,2,4-triazol-3-yl)pyridine as a solid in 26.7% yield.
Reaction SMILES: Br[C:2]1[C:3](=[O:35])[N:4]([CH2:19][C@H:20]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:5](=[O:18])[N:6]([CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])[C:7]=1[CH3:8].[F:36][C:37]1[C:42]([O:43][CH3:44])=[CH:41][CH:40]=[CH:39][C:38]=1B(O)O>CCO.COCCOC>[C:31]([O:30][C:28]([NH:27][C@H:20]([CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)[CH2:19][N:4]1[C:3](=[O:35])[C:2]([C:38]2[CH:39]=[CH:40][CH:41]=[C:42]([O:43][CH3:44])[C:37]=2[F:36])=[C:7]([CH3:8])[N:6]([CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])[C:5]1=[O:18])=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: Cc1c(Br)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)C2CCCCC2)c(=O)n1Cc1c(F)cccc1F
Reactant: COc1cccc(B(O)O)c1F
Solvent: CCO
Solvent: COCCOC
Product: COc1cccc(-c2c(C)n(Cc3c(F)cccc3F)c(=O)n(C[C@H](NC(=O)OC(C)(C)C)C3CCCCC3)c2=O)c1F
Temperature: 80 °C
Yield: 32.3 %

Procedure:
5-Bromo-3-[2(R)-tert-butoxycarbonylamino-2-cyclohexylethyl]-1-[2,6-difluorobenzyl]-6-methyl-pyrimidine-2,4(1H,3H)-dione 2b (1.0 g, 1.79 mmol) in bezene/EtOH/ethylene glycol dimethyl ether (20/2/22 mL) was added 2-fluoro-3-methoxyphenylboronic acid (382 mg, 2.24 mmol) and saturated Ba(OH)2/water (˜0.5 M, 15 mL). The reaction mixture was deoxygenated with N2 for 10 minutes, tetrakis(triphenylphosine) palladium (0) (208 mg, 0.18 mmol) was added and the reaction mixture was heated at 80° C. overnight under N2. The reaction mixture was partitioned between brine and EtOAc. The organic layer was dried (sodium sulfate), evaporated, and purified by flash chromatography (silica, 30% EtOAc/hexanes) to give compound 2c (348 mg, 32.3%). MS (CI) m/z 502.20 (MH+-Boc).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH2:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[O:25][CH2:26][CH2:27][CH2:28][CH2:29]Cl>CS(C)=O.O>[CH2:7]([NH:14][CH2:29][CH2:28][CH2:27][CH2:26][O:25][C:16]1[CH:17]=[CH:18][C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClCCCCOc1ccc2ccccc2c1
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: c1ccc(CNCCCCOc2ccc3ccccc3c2)cc1
Temperature: 150 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and benzylamine (0.34 ml, 0.003 mole) was taken in dry DMSO (40 ml). Now 4-(2-naphthyloxy)-1-chlorobutane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 150° C. for 5 hrs. and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-benzyl-[4-(naphthalen-2-yloxy)-butyl]amine, solid, m.p. 105° C., (yield 0.62 gm, 95.3%).
Reaction SMILES: [Br:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10].[CH2:11]([OH:13])[CH3:12]>>[CH2:11]([O:13][C:7]1[CH:2]=[C:3]([OH:9])[C:6]2[C:7](=[C:2]([Br:1])[C:3]([O:9][CH3:10])=[CH:4][CH:5]=2)[N:8]=1)[CH3:12]
Reactant: CCO
Reactant: COc1cccc(N)c1Br
Product: CCOc1cc(O)c2ccc(OC)c(Br)c2n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To 2-bromo-3-aminoanisole 2b4 (750 mg, 3.7 mmol, 1 eq) was added imidate 2g2 (0.73 g, 3.7 mmol, 1 eq) in ethanol (7 mL) under a N2 atmosphere. The mixture was stirred at RT. for 24 hrs at which point the reaction was concentrated and purified directly on a silica gel column (eluent: EtOAc/Hexanes (1:9)) to afford adduct 2o1 (1.12 g, 88%) as a pale yellow oil. MS: 344 (M+H)+ and 346 (MH+2)+.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=O)=[CH:3][CH:2]=1.[CH3:14][O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][C:17]=1[N:23]1[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]1>>[CH3:14][O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:11]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=[CH:2][CH:3]=2)=[O:13])=[CH:18][C:17]=1[N:23]1[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]1
Reactant: O=C(O)c1ccnc2ccccc12
Reactant: COc1ccc(N)cc1N1CCN(C)CC1
Product: COc1ccc(NC(=O)c2ccnc3ccccc23)cc1N1CCN(C)CC1

Procedure:
The title compound was prepared from quinoline-4-carboxylic acid and 4-methoxy-3-(4-methylpiperazin-1-yl)aniline (EP0533268A1) using a similar procedure to Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:14]([N:21]1[CH2:32][CH2:31][C:24]2([O:28][C:27](=[O:29])[O:26][C:25]2=[CH2:30])[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1(C)C(C)=CC=CC=1.CCCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]2[C:25]([OH:26])([CH3:30])[C:24]3([CH2:23][CH2:22][N:21]([CH2:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH2:32][CH2:31]3)[O:28][C:27]2=[O:29])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: C=C1OC(=O)OC12CCN(Cc1ccccc1)CC2
Reactant: COc1ccc(CCN)cc1OC
Solvent: CCCCCCC
Solvent: Cc1ccccc1C
Product: COc1ccc(CCN2C(=O)OC3(CCN(Cc4ccccc4)CC3)C2(C)O)cc1OC
Reaction time: 8 h
Yield: 94 %

Procedure:
19.9 g of 2-(3,4-dimethoxyphenyl)ethylamine are portionwise added to a solution of 25.9 g of 8-benzyl-4-methylene-2-oxo-1,3-dioxa-8-azaspiro[4,5]decane in 35 ml of anhydrous xylene under stirring. Meanwhile the temperature of the reaction mixture increases to 35° to 40° C. The reaction mixture is left to stand at room temperature overnight, then the crystalline reaction mixture is diluted with n-heptane and filtered. The solid precipitate obtained is recrystallized from ethanol to obtain the title compound in 94% yield, m.p.: 181°-183° C.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10](O)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[S:27]1[CH:31]=[CH:30][N:29]=[C:28]1[C:32]1[CH:37]=[CH:36][C:35]([CH2:38][N:39]([NH2:63])[CH2:40][C@H:41]([OH:62])[C@@H:42]([NH:50][C:51](=[O:61])[C@H:52]([CH:58]([CH3:60])[CH3:59])[NH:53][C:54]([O:56][CH3:57])=[O:55])[CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:34][CH:33]=1>CN(C=O)C>[CH3:59][CH:58]([C@H:52]([NH:53][C:54]([O:56][CH3:57])=[O:55])[C:51]([NH:50][C@H:42]([C@@H:41]([OH:62])[CH2:40][N:39]([NH:63][C:10]([C@@H:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[CH:7]([CH3:9])[CH3:8])=[O:11])[CH2:38][C:35]1[CH:34]=[CH:33][C:32]([C:28]2[S:27][CH:31]=[CH:30][N:29]=2)=[CH:37][CH:36]=1)[CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:61])[CH3:60]
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2nccs2)cc1)C(C)C
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-c2nccs2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)C)C(C)C

Procedure:
Analogously to Example 7, 140 mg (0.80 mmol) of N-methoxycarbonyl-(L)-valine, 288 mg (1.5 mmol) of EDC and 135 mg (1.0 mmol) of HOBT in 2.2 ml of DMF and 418 μl (3.0 mmol) of TEA are reacted with 0.5 mmol of 1-[4-(thiazol-2-yl)-phenyl]-4(S)-hydroxy-2-amino-5(S)-N-(N-methoxycarbonyl-(L)-valyl)amino-6-phenyl-2-azahexane in 4.5 ml of DMF to form the title compound: m.p: 207-210° C.; HPLC20-100 : tRet =13.8; FAB MS (M+H)+ =683.
Reaction SMILES: [NH2:1][C@H:2]1[C:11]2[C:6](=[C:7]([Br:16])[CH:8]=[C:9]([C:12]([F:15])([F:14])[F:13])[CH:10]=2)[NH:5][C@@H:4]([CH:17]2[CH2:19][CH2:18]2)[CH2:3]1.C(O)(=O)C.[F:24][C:25]([F:39])([F:38])[C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH:29]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:24][C:25]([F:38])([F:39])[C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([C:34]([F:37])([F:35])[F:36])[CH:33]=1)[CH2:29][NH:1][C@H:2]1[C:11]2[C:6](=[C:7]([Br:16])[CH:8]=[C:9]([C:12]([F:15])([F:13])[F:14])[CH:10]=2)[NH:5][C@@H:4]([CH:17]2[CH2:18][CH2:19]2)[CH2:3]1
Reactant: N[C@@H]1C[C@H](C2CC2)Nc2c(Br)cc(C(F)(F)F)cc21
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: FC(F)(F)c1cc(CN[C@@H]2C[C@H](C3CC3)Nc3c(Br)cc(C(F)(F)F)cc32)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.8 %

Procedure:
To a solution of cis-4-amino-8-bromo-2-cyclopropyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinoline (Example 100A) (250 mg, 0.75 mmol) in anhydrous dichloromethane (10 mL) was added acetic acid (112 mg, 1.90 mmol), followed by 3,5-bis(trifluoromethyl)benzaldehyde (180 mg, 0.75 mmol) and sodium triacetoxyborohydride (791 mg, 3.73 mmol). The reaction was stirred at room temperature for 5 h. The reaction mixture was then diluted with dichloromethane and washed with 1N NaOH. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo to afford the title crude product (420 mg) which was used without further purification. 1H NMR (CDCl3) δ 0.3 (m, 2H), 0.6 (m, 2H), 1.0 (m, 1H), 7.5 (s, 1H), 7.8 (s, 2H), 7.9 (s, 2H).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](=[O:33])(=[O:32])[NH:11][C:12]1[CH:31]=[CH:30][C:15]2[N:16]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:17]([CH2:19][CH2:20][CH3:21])=[N:18][C:14]=2[CH:13]=1.CCN(CC)CC>CO>[C:26]([O:25][C:23](=[O:24])[CH2:22][N:16]1[C:15]2[CH:30]=[CH:31][C:12]([N:11]3[C:3](=[O:2])[C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=4[S:10]3(=[O:33])=[O:32])=[CH:13][C:14]=2[N:18]=[C:17]1[CH2:19][CH2:20][CH3:21])([CH3:29])([CH3:28])[CH3:27]
Reactant: CCCc1nc2cc(NS(=O)(=O)c3ccccc3C(=O)OC)ccc2n1CC(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: CO
Product: CCCc1nc2cc(N3C(=O)c4ccccc4S3(=O)=O)ccc2n1CC(=O)OC(C)(C)C
Temperature: 110 °C

Procedure:
The product of step b.) (33 mg, 0.069 mmol) was stirred in methanol (2 mL) with Et3N (10 μL, 0.069 mmol) at 65° C. for two hours without change. The reaction was concentrated to dryness and redissolved in toluene (2 mL). Et3N (10 μL, 0.069 mmol) was added to the solution and the reaction was heated to 110° C. overnight. Additional Et3N (35 μL, 0.242 mmol) was added and the reaction was heated overnight to complete reaction. The reaction was then concentrated to give the sub-title compound that was used in crude form without purification. MS: ESI (positive): 456 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:42]=[CH:41][C:8]([C:9]([NH:11][C:12]2[C:13]([CH3:40])=[C:14]([C:18]3[N:23]=[C:22]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([CH2:31][CH2:32]OS(C)(=O)=O)=[CH:27][CH:26]=4)[C:21](=[O:38])[N:20]([CH3:39])[CH:19]=3)[CH:15]=[CH:16][CH:17]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:43][CH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1.O>C(#N)C>[C:1]([C:5]1[CH:42]=[CH:41][C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[N:23]=[C:22]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][NH:43][CH:44]5[CH2:49][CH2:48][O:47][CH2:46][CH2:45]5)=[CH:27][CH:26]=4)[C:21](=[O:38])[N:20]([CH3:39])[CH:19]=3)[C:13]=2[CH3:40])=[O:10])=[CH:7][CH:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: NC1CCOCC1
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cn(C)c(=O)c(Nc2ccc(CCOS(C)(=O)=O)cc2)n1
Solvent: O
Solvent: CC#N
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1cn(C)c(=O)c(Nc2ccc(CCNC3CCOCC3)cc2)n1
Temperature: 90 °C

Procedure:
Methanesulfonic acid 2-(4-{6-[3-(4-tert-butyl-benzoylamino)-2-methyl-phenyl]-4-methyl-3-oxo-3,4-dihydro-pyrazin-2-ylamino}-phenyl)-ethyl ester (3) (0.2 g; 0.34 mmol) was dissolved in acetonitrile (2 mL) and excess 4-aminotetrahydropyran (0.25 mL) was added. The reaction vessel was sealed and heated to 90° C. for 4 hr. Water (10 mL) was added to the reaction vessel and the reaction was extracted with EtOAc (3×25 mL). The EtOAc layers were pooled, washed with brine, dried over solid sodium sulfate and filtered. The filtrate was then adsorbed directly onto silica and chromatographed using methanol/CH2Cl2 (1:9) as eluent to provide 75 mg of 4-tert-butyl-N-[2-methyl-3-(4-methyl-5-oxo-6-{4-[2-(tetrahydro-pyran-4-ylamino)-ethyl]-phenylamino}-4,5-dihydro-pyrazin-2-yl)-phenyl]-benzamide (4) as a light tan solid. MS 594.33 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH2:12][CH:13]([OH:15])[CH3:14].CC(C)([O-])C.[K+].F[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N+:29]([O-:31])=[O:30]>C1COCC1>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH2:12][CH:13]([O:15][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N+:29]([O-:31])=[O:30])[CH3:14]
Reactant: Cc1ccc2ccccc2c1CC(C)O
Reactant: O=[N+]([O-])c1ccccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccc2ccccc2c1CC(C)Oc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.7 %

Procedure:
1-(2-Methyl-naphthalen-1-yl)-propan-2-ol (1.2 g, 6.0 mmol) was dissolved in freshly distilled THF (15 mL) in a round bottom flask fitted with a reflux condenser. Potassium tert-butoxide (739 mg, 6.60 mmol) was added and the reaction was stirred at room temperature for 30 minutes. 2-fluoronitrobenzene (0.70 mL, 6.60 mmol) was added via syringe. The reaction was stirred at vigorous reflux for 18 hours. The reaction mixture was allowed to cool to room temperature and then was concentrated. The residue was diluted with saturated aqueous NaHCO3 and was extracted three times with EtOAc. The organic extracts were combined, washed with brine, dried over Na2SO4, filtered through celite, and concentrated. The crude product was purified by flash chromatography (SiO2, 20% CH2Cl2-hexanes) to give 2-methyl-1-[2-(2-nitro-phenoxy)-propyl]-naphthalene (1.51 g, 4.72 mmol) in 79% yield as an oil that solidified on standing. 1H NMR (300 MHz) CDCl3 δ 8.03 (d, J=8.4 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.67 (m, 2H), 7.49 (m, 1H), 7.40 (m, 1H), 7.29 (m, 2H), 6.90 (m, 1H), 6.75 (d, J=8.6 Hz, 1H), 4.93 (m, 1H), 3.67 (dd, J=7.5, 14.5 Hz, 1H), 3.46 (dd, J=5.7, 14.4 Hz, 1H), 2.56 (s, 3H), 1.46 (d, J=6.0 Hz, 3H).