Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([CH2:11][C@H:12]([CH3:15])[CH2:13]I)[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[CH:18](=[C:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH2:19][CH2:20][CH3:21]>CCCCCCC.CCOC(C)=O>[CH:18](=[C:22]1[CH2:27][CH2:26][N:25]([CH2:13][C@@H:12]([CH3:15])[CH2:11][N:6]2[C:5]3[CH:16]=[CH:17][C:2]([F:1])=[CH:3][C:4]=3[O:9][CH2:8][C:7]2=[O:10])[CH2:24][CH2:23]1)[CH2:19][CH2:20][CH3:21]
Reactant: C[C@H](CI)CN1C(=O)COc2cc(F)ccc21
Reactant: CCCC=C1CCNCC1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCCC=C1CCN(C[C@@H](C)CN2C(=O)COc3cc(F)ccc32)CC1
Yield: 73 %

Procedure:
The compound (S)-7-Fluoro-4-(3-iodo-2-methylpropyl)-4H-benzo[1,4]oxazin-3-one (111MF20)-(0.515 g, 1.47 mmol) and 4-butylidenepiperidine (0.205 g, 1.47 mmol) were mixed according to GP16. CC (SiO2; Heptane/EtOAc 4:1-4) gave the title compound (111MF29) (0.393 g, 73%). 1H NMR (CDCl3) δ 7.17-7.12 (m, 1H), 6.74-6.69 (m, 2H), 5.15-5.11 (t, J=7.2 Hz, 1H), 4.61 (q, J=15.2 Hz, 2H), 4.04-3.92 (m, 2H), 2.48-2.40 (m, 2H), 2.32-2.13 (m, 9H), 1.96 (q, J=7.2 Hz, 2H), 1.38-1.30 (m, 2H), 0.91-0.86 (m, 6H); 13C NMR (CDCl3) δ 164.1, 158.9 (d, J=243.4 Hz), 146.5 (d, J=11.9 Hz), 136.1, 125.2 (d, J=3.0 Hz), 128.9, 116.2 (d, J=22.7 Hz), 109.0 (d, J=22.7 Hz), 105.2 (d, J=26.2 Hz), 67.8, 63.7, 56.5, 55.7, 54.6, 36.3, 29.3, 28.5, 23.3, 17.1, 13.9.
Reaction SMILES: [H-].[Na+].Br[C:4]1[CH:5]=[C:6]([CH:27]=[CH:28][N:29]=1)[C:7]([NH:9][C:10]1[S:11][C:12]2[C:18]([CH:19]3[CH2:24][O:23][CH2:22][CH2:21][O:20]3)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=2[N:14]=1)=[O:8].[OH:30][CH2:31][CH:32]1[CH2:34][CH2:33]1.C(Cl)(Cl)Cl>O1CCOCC1.CN(C=O)C>[CH:32]1([CH2:31][O:30][C:4]2[CH:5]=[C:6]([CH:27]=[CH:28][N:29]=2)[C:7]([NH:9][C:10]2[S:11][C:12]3[C:18]([CH:19]4[CH2:24][O:23][CH2:22][CH2:21][O:20]4)=[CH:17][CH:16]=[C:15]([O:25][CH3:26])[C:13]=3[N:14]=2)=[O:8])[CH2:34][CH2:33]1
Reactant: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: OCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2COCCO2)c2sc(NC(=O)c3ccnc(OCC4CC4)c3)nc12

Procedure:
From (+)-2-bromo-N-(7-[1,4]dioxan-2-yl-4-methoxy-benzothiazol-2-yl)-isonicotinamide sodium hydride and hydroxymethylcyclopropane in dioxane and DMF. [α]D20=+39.2° (c=1.02, CHCl3), ES-MS m/e (%): 442 (M+H+, 100).
Reaction SMILES: C12BC(CCC1)CCC2.[CH2:10]([N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][C@@H:18]1[CH:30]=[CH2:31])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.Br[C:53]1[CH:58]=[CH:57][N:56]=[CH:55][CH:54]=1.[OH-].[Na+]>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>[CH2:10]([N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][C@@H:18]1[CH2:30][CH2:31][C:53]1[CH:58]=[CH:57][N:56]=[CH:55][CH:54]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Brc1ccncc1
Reactant: C=C[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: B1C2CCCC1CCC2
Agent: Cl
Product: c1ccc(CN2CCN(Cc3ccccc3)[C@@H](CCc3ccncc3)C2)cc1
Yield: 56.4 %

Procedure:
Prepared by the method in Example 128, using 9-borabicyclo[3.3.1]nonane (71.4 mL, 35.7 mmol, 0.5 M in THF), (S)-1,4-dibenzyl-2-vinyl-piperazine (2.61 g, 8.92 mmol), triphenylphosphine (749 mg, 2.86 mmol), tetrakis(triphenylphosphine)palladium(0) (413 mg, 0.36 mmol), 4-bromopyridine hydrochloride (2.60 g, 13.4 mmol) and 3M NaOH (10.4 mL, 31.2 mmol) to give the title compound (1.87 g, 56%): mp 96–98° C.; mass spectrum (ion spray): m/z=372 (M+1). Analysis calculated for C25H29N3: C, 80.82; H, 7.87; N, 11.31. Found: C, 80.80; H, 7.99; N, 11.18.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[C:12]([F:17])[C:11]=1[F:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:19]([C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=1)[CH2:20][CH3:21].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[CH2:1]([O:9][C:10]1[CH:16]=[CH:15][C:13]([N:14]=[CH:26][C:25]2[CH:28]=[CH:29][C:22]([CH2:19][CH2:20][CH3:21])=[CH:23][CH:24]=2)=[C:12]([F:17])[C:11]=1[F:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCc1ccc(C=O)cc1
Reactant: CCCCCCCCOc1ccc(N)c(F)c1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCOc1ccc(N=Cc2ccc(CCC)cc2)c(F)c1F

Procedure:
A mixture of 0.1 mol of 4-octyloxy-2,3-difluoroaniline (prepared from the corresponding amide by a Hoffmann rearrangement), 0.1 mol of 0.1 mol of 4-propylbenzaldehyde, 0.01 mol of p-toluenesulfonic acid and 200 ml of toluene is heated at the boiling point for 2 hours using a water separator. Customary working up gives (4 -octyloxy-2,3-difluorophenyl)-4-propylbenzylideneamine.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH:5]([C:7]1[S:11][CH:10]=[C:9]([C:12]#[N:13])[CH:8]=1)=[O:6].O.Cl>CN(C=O)C>[NH:1]1[C:12]([C:9]2[CH:8]=[C:7]([CH:5]=[O:6])[S:11][CH:10]=2)=[N:13][N:3]=[N:2]1
Reactant: N#Cc1csc(C=O)c1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cc(-c2nnn[nH]2)cs1
Temperature: 25 °C
Yield: 20 %

Procedure:
Sodium azide (2.9 g, 44.6 mmol) and TEA hydrochloride (4.13 g, 30 mmol) were added to a solution of 5-formyl-thiophene-3-carbonitrile (2 g, 15 mmol, prepared according to Intern. application WO 02/26718) in DMF (50 ml). The solution was refluxed for 12 h. After cooling to RT, water was added and the solution was carefully acidified with HCl. The solution was extracted 3 times with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to yield the desired product as a brown solid (540 mg) which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:22][CH2:21][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([O:18]CC)=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:23][C@H:24]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH2:37][C:38]([O:40]C)=[O:39])=[CH:31][C:30]=2[N:42]2[CH:46]=[CH:45][C:44]([CH3:47])=[N:43]2)[C:25]([F:28])([F:27])[F:26])[N:3]=1.[Li+].[OH-]>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:22][CH2:21][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:23][C@H:24]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])=[CH:31][C:30]=2[N:42]2[CH:46]=[CH:45][C:44]([CH3:47])=[N:43]2)[C:25]([F:28])([F:27])[F:26])[N:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(CCCC(=O)OC)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1
Agent: [Li+]
Agent: [OH-]
Product: Cc1ccn(-c2cc(CCCC(=O)O)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)n1

Procedure:
Hydrolysis of (S)-ethyl 8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4-(4-methoxy-4-oxobutyl)-2-(3-methyl-1H-pyrazol-1-yl)phenyl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate was carried out using the LiOH general method providing the title compound as an off-white solid.
Reaction SMILES: Cl.[C:2]([C:6]1[S:10][C:9]([CH:11]2[CH2:16][CH:15]([C:17]([O:19][CH3:20])=[O:18])[CH2:14][CH2:13][NH:12]2)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.Cl[C:31]([O:33][CH3:34])=[O:32]>C(Cl)Cl>[C:2]([C:6]1[S:10][C:9]([CH:11]2[CH2:16][CH:15]([C:17]([O:19][CH3:20])=[O:18])[CH2:14][CH2:13][N:12]2[C:31]([O:33][CH3:34])=[O:32])=[CH:8][CH:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(c2ccc(C(C)(C)C)s2)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(c2ccc(C(C)(C)C)s2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
Methyl 2-(5-tert-butylthiophen-2-yl)piperidine-4-carboxylate hydrochloride (2.36 g, 7.42 mmol) and DIPEA (3.24 mL, 18.56 mmol) were dissolved in DCM (30 mL). Methyl chloroformate (0.690 mL, 8.91 mmol) was added and the reaction mixture stirred at room temperature for 1 h. DCM (170 mL) was added. The organic phase was washed with 0.1 M HCl (2×200 mL), satd NaHCO3 (200 mL), dried with a phase separator and evaporated in vacuo yielding dimethyl 2-(5-tert-butylthiophen-2-yl)piperidine-1,4-dicarboxylate (2.490 g, 99%) as a dark oil. MS m/z 340 (M+H)+
Reaction SMILES: N1C2C(=CC=CC=2)C=C1.C([N:17]1[C:29]2[C:28]([OH:30])=[C:27]3[N:31](C(OC(C)(C)C)=O)[C:32]4[CH:33]=[CH:34][C:35]([Br:38])=[CH:36][C:37]=4[C:26]3=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[C:21]([Br:46])[CH:22]=2)(OC(C)(C)C)=O.[CH3:47][O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53]O>>[Br:38][C:35]1[CH:36]=[C:37]2[C:32](=[CH:33][CH:34]=1)[NH:31][C:27]1[C:28]([O:30][CH2:53][CH2:52][O:51][CH2:50][CH2:49][O:48][CH3:47])=[C:29]3[NH:17][C:18]4[CH:19]=[CH:20][C:21]([Br:46])=[CH:22][C:23]=4[C:24]3=[CH:25][C:26]2=1
Reactant: COCCOCCO
Reactant: CC(C)(C)OC(=O)n1c2ccc(Br)cc2c2cc3c4cc(Br)ccc4n(C(=O)OC(C)(C)C)c3c(O)c21
Agent: c1ccc2[nH]ccc2c1
Product: COCCOCCOc1c2[nH]c3ccc(Br)cc3c2cc2c1[nH]c1ccc(Br)cc12

Procedure:
The title compound was prepared in a manner analogous to Example 28 except the starting indole is 5,7-diBOC-2,10-dibromo-6-hydroxyindolo[2,3-b]carbazole and the reagent is diethylene glycol monomethyl ether. 1H-NMR (400 MHz, CDCl3) δ ppm 8.74 (s, 1 H), 8.21 (d, J=2.0 Hz, 2 H), 7.50-7.26 (m, 4 H), 4.50-4.38 (m, 2 H), 3.88-3.73 (m, 6 H), 3.55 (s, 3 H); MS (ESI) m/z 531.0 (M−H)−
Reaction SMILES: C([NH:9][C:10]([NH:21][CH2:22][CH2:23][CH2:24][C:25]1[N:26]=[CH:27][NH:28][CH:29]=1)=[N:11][CH2:12][CH2:13][S:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=O)C1C=CC=CC=1>Cl>[NH:28]1[CH:29]=[C:25]([CH2:24][CH2:23][CH2:22][NH:21][C:10]([NH:11][CH2:12][CH2:13][S:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[NH:9])[N:26]=[CH:27]1
Reactant: O=C(NC(=NCCSc1ccccc1)NCCCc1c[nH]cn1)c1ccccc1
Agent: Cl
Product: N=C(NCCCc1c[nH]cn1)NCCSc1ccccc1

Procedure:
0.82 g (2 mmol) of N-benzoyl-N'-[3-(imidazol 4-yl) propyl]-N"-(2-phenylthioethyl)-guanidine are heated under reflux in 18% hydrochloric acid for 7 hours and then worked up by a method analogous to that of Example 58. 0.72 g (96%) of a dry, hygroscopic foam is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:25][CH2:26][CH3:27])[C:13]([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])[C:14]([O:16]CC)=[O:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:25][CH2:26][CH3:27])[C:13]([O:19][CH2:20][CH3:21])([O:22][CH2:23][CH3:24])[C:14]([OH:16])=[O:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC[C@H](NC(=O)OCc1ccccc1)C(OCC)(OCC)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCC[C@H](NC(=O)OCc1ccccc1)C(OCC)(OCC)C(=O)O
Reaction time: 24 h
Yield: 120 %

Procedure:
To ethyl ester of Example 21 (1.6 g, 3.3 mmol) in ethanol (33 mL) was added an aqueous NaOH solution (6.6 mL, 1M, 6.6 mmol) and the reaction was stirred for 24 h. pH was adjusted to pH=2 with 1N HCl and extraction with CH2Cl2 provided 1.4 g of the crude acid.
Reaction SMILES: [O:1]=[C:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:21](O)=[O:22])[NH:3]1.[CH3:24][C:25]([NH2:33])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:26]>>[CH3:24][C:25]([NH:33][C:21]([C@H:11]1[CH2:10][CH2:9][C@H:8]2[C@H:7]3[C@H:16]([CH2:15][CH2:14][C@:12]12[CH3:13])[C@:17]1([CH3:20])[C:4]([NH:3][C:2](=[O:1])[CH2:19][CH2:18]1)=[CH:5][CH2:6]3)=[O:22])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:26]
Reactant: CC(C)(N)c1ccccc1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4NC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)O
Product: CC(C)(NC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4NC(=O)CC[C@]4(C)[C@H]3CC[C@]12C)c1ccccc1
Yield: 68 %

Procedure:
The title compound was prepared in a yield of 68% in a similar manner to that described in Example 37 by reacting 3-oxo-4-azaandrost-5-ene-17β-carboxylic acid and 1-methyl-1-phenylethylamine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[C:9]([C:12]2[N:16]([CH:17]([CH3:19])[CH3:18])[N:15]=[N:14][N:13]=2)[CH2:10][OH:11])=[CH:4][CH:3]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[C:9]([C:12]2[N:16]([CH:17]([CH3:19])[CH3:18])[N:15]=[N:14][N:13]=2)[CH:10]=[O:11])=[CH:4][CH:3]=1
Reactant: CC(C)n1nnnc1C(CO)=C(c1ccc(F)cc1)c1ccc(F)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)n1nnnc1C(C=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Yield: 53.4 %

Procedure:
The allylic alcohol (0.96 g) prepared in Step C was dissolved in 45 mL of dry methylene chloride at room temperature and to this vigorousy stirred solution was added 0.64 g (2.96 mmoles) pyridinium chlorchromate in one single portion. After the reaction mixture was stirred for four hours an analytical TLC eluted once with 10% EtOAc in hexanes (v/v) and twice with 20% EtOAc in hexanes (v/v) showed one major product spot at Rf =0.22. The crude mixture was poured onto a bed of silica gel about 1/2 inches thick and eluted with 20% EtOAc in hexanes to give 0.51 g (53%) of the title compound. MS (CI): m/e=355 for (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7]2[C:16]3[C:11](=[C:12]([O:17][CH3:18])[CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([C:19]([O:21]CC)=O)[N:8]=2)=[N:2]1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([Mg]Br)=[CH:27][CH:26]=1>C1COCC1>[NH:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7]2[C:16]3[C:11](=[C:12]([O:17][CH3:18])[CH:13]=[CH:14][CH:15]=3)[N:10]=[C:9]([C:19]([C:28]3[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=3)=[O:21])[N:8]=2)=[N:2]1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CCOC(=O)c1nc(Nc2cc[nH]n2)c2cccc(OC)c2n1
Solvent: C1CCOC1
Product: COc1cccc2c(Nc3cc[nH]n3)nc(C(=O)c3ccc(F)cc3)nc12

Procedure:
To ethyl 4-(1H-pyrazol-3-ylamino)-8-methoxyquinazoline-2-carboxylate (200 mg, 0.64 mmol) in dry THF (8 mL) cooled to −40° C. was added dropwise over 2 min 1N 4-fluorophenylmagnesium bromide in THF (2.17 mL, 2.17 mmol). After 1.5 h the reaction mixture was quenched by addition of saturated aq ammonium chloride. The solution was concentrated and H2O was added. The precipitate was washed with water and diethyl ether to give (4-(1H-pyrazol-3-ylamino)-8-methoxyquinazolin-2-yl)(4-fluorophenyl)methanone as a yellow solid (74 mg, 87% purity by LC/MS) 1H NMR (300 MHz, DMSO-d6) δ ppm 3.94 (s, 3H) 6.75 (s, 1H) 7.35-7.41 (m, 3H) 7.58-7.65 (m, 2H) 8.07-8.12 (m, 2H) 8.2 (d, J=8.48 Hz, 1H) 10.64 (br. s., 1H) 12.51 (br. s., 1H) LC-MS (ESI) m/z 364 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][N:14]1[C:19]2[CH:20]=[C:21]([C:28]([N:30]([C@@H:34]3[CH2:39][CH2:38][CH2:37][N:36]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:35]3)[CH:31]([CH3:33])[CH3:32])=[O:29])[C:22]([C:24]([F:27])([F:26])[F:25])=[CH:23][C:18]=2[O:17][C:16]([CH3:52])([C:47]([O:49]CC)=[O:48])[C:15]1=[O:53])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:54](Br)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1.[H-].[Na+].[OH-].[Na+].S([O-])(O)(=O)=O.[K+]>CN(C)C(=O)C.O1CCCC1>[CH2:54]([N:11]([C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH2:12][CH2:13][N:14]1[C:19]2[CH:20]=[C:21]([C:28]([N:30]([C@@H:34]3[CH2:39][CH2:38][CH2:37][N:36]([C:40]([O:42][C:43]([CH3:46])([CH3:44])[CH3:45])=[O:41])[CH2:35]3)[CH:31]([CH3:33])[CH3:32])=[O:29])[C:22]([C:24]([F:26])([F:27])[F:25])=[CH:23][C:18]=2[O:17][C:16]([CH3:52])([C:47]([OH:49])=[O:48])[C:15]1=[O:53])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: CCOC(=O)C1(C)Oc2cc(C(F)(F)F)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc2N(CCNC(=O)OCc2ccccc2)C1=O
Reactant: BrCc1ccccc1
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: CC(C)N(C(=O)c1cc2c(cc1C(F)(F)F)OC(C)(C(=O)O)C(=O)N2CCN(Cc1ccccc1)C(=O)OCc1ccccc1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reaction time: 1 h

Procedure:
To a solution of ethyl 4-(2-{[(benzyloxy)carbonyl]amino}ethyl)-6-{[[(3R)-1-(tert-butoxycarbonyl)piperidin-3-yl](isopropyl)amino]carbonyl}-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylate (1.00 g) in N,N-dimethylacetamide (2.7 ml) was added at 0° C. benzyl bromide (0.794 ml), and sodium hydride (193 mg), and the mixture was stirred for one hour. To the reaction solution were added 2N-aqueous sodium hydroxide solution (5.36 ml) and tetrahydrofuran (5.0 ml), and the mixture was stirred at room temperature for one hour. To the reaction solution was added a 5% aqueous potassium hydrogen sulfate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform /methanol=100/3, containing 5% acetic acid) to give the title compound (0.800 g).
Reaction SMILES: [C:1]([C:3]1[C:4]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[N:5][O:6][N:7]=1)#[N:2].N[NH:16][C:17]([NH2:19])=[S:18].C([O-])(O)=O.[Na+]>C(O)(C(F)(F)F)=O>[NH2:19][C:17]1[S:18][C:1]([C:3]2[C:4]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[N:5][O:6][N:7]=2)=[N:2][N:16]=1
Reactant: N#Cc1nonc1NC(=O)C(F)(F)F
Reactant: NNC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Nc1nnc(-c2nonc2NC(=O)C(F)(F)F)s1
Yield: 51 %

Procedure:
To a suspension of N-(4-cyano-1,2,5-oxadiazol-3-yl)-2,2,2-trifluoroacetamide (0.10 g, 0.49 mmol) in 2 mL of TFA was added thiosemicarbazide (0.044 g, 0.49 mmol). The reaction mixture was poured into ice and neutralized with sat. NaHCO3 to pH=7. The aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layer was washed with NaCl and concentrated. Trituration with diethyl ether afforded the title compound as a beige solid (0.070 g, 51%). 1H NMR (DMSO, 500 MHz) δ 7.93 (s, 2H), 6.55 (s, 1H). Mass Spec. FIA MS 281.1(M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C@H:10]([NH:12][C:13]2[C:22]3[C:17](=[C:18]([C:23]([NH2:25])=[O:24])[CH:19]=[CH:20][CH:21]=3)[N:16]=[CH:15][N:14]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([C@H:10]([NH:12][C:13]2[C:22]3[C:17](=[C:18]([C:23]([NH2:25])=[O:24])[CH:19]=[CH:20][CH:21]=3)[N:16]=[CH:15][N:14]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1
Reactant: C[C@@H](Nc1ncnc2c(C(N)=O)cccc12)c1cccc([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: C[C@@H](Nc1ncnc2c(C(N)=O)cccc12)c1cccc(N)c1
Yield: 93 %

Procedure:
A suspension of 4-{[(1R)-1-(3-nitrophenyl)ethyl]amino}quinazoline-8-carboxamide (1.50 g, 4.45 mmol) in methanol (125 mL) was shaken for 3 h in a Parr vessel under 35 psi hydrogen pressure in the presence of 30 wt % palladium on carbon (600 mg). The material was filtered through Celite, concentrated to get the title compound in 93% yield.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][NH:13][C:14](=[O:24])[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([CH3:23])[CH:17]=1.O>N1C=CC=CC=1>[CH3:12][NH:13][C:14](=[O:24])[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])=[C:18]([CH3:23])[CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CNC(=O)Oc1ccc(N)c(C)c1
Solvent: O
Solvent: c1ccncc1
Product: CNC(=O)Oc1ccc(NS(=O)(=O)c2ccc(C)cc2)c(C)c1

Procedure:
p-Toluenesulfonyl chloride (2.1g., 0.011 mole) was added portionwise to a solution of 3-methyl-4-aminophenyl N-methylcarbamate (1.8g., 0.01 mole) in pyridine (15 ml.). An exotherm to about 45° C. resulted and warming was continued at 48° C. for a short time. An excess of water was added and upon stirring and cooling, the product crystallized. The filtered product (3.1g.) was recrystallized from ethanol/water to give material with m.p. 181°-83.5° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:7]=[C:8]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:9][NH:10][C:11]1[N:16]=[CH:15][C:14]([CH2:17]O)=[CH:13][CH:12]=1>C(Cl)Cl>[Cl:3][CH2:17][C:14]1[CH:13]=[CH:12][C:11]([NH:10][CH2:9][C:8]2[CH:19]=[CH:20][C:21]([Cl:22])=[C:6]([Cl:5])[CH:7]=2)=[N:16][CH:15]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(NCc2ccc(Cl)c(Cl)c2)nc1
Solvent: ClCCl
Product: ClCc1ccc(NCc2ccc(Cl)c(Cl)c2)nc1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Thionyl chloride (0.103 mL, 1.413 mmol) was added to a suspension of (6-((3,4-dichlorobenzyl)amino)pyridin-3-yl)methanol (0.1 g, 0.353 mmol) in DCM (3.5 mL) cooled to 0° C. The mixture was stirred for 18 h at room temperature. The resulting white suspension was concentrated to yield 5-(chloromethyl)-N-(3,4-dichlorobenzyl)pyridin-2-amine, used in the next step without purification. 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.05 (1H, dd, J=9.29, 2.01 Hz), 7.92-8.01 (1H, m), 7.54-7.65 (2H, m), 7.36 (1H, dt, J=8.28, 1.00 Hz), 7.04-7.23 (1H, m), 4.65 (1H, s), 4.61 (2H, d, J=2.76 Hz), 4.39 (1H, s). LCMS: R.T.=2.96; [M+H]+=301.02.
Reaction SMILES: [CH:1]1([C:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]([CH2:17][CH3:18])[C:9](=[O:19])[CH:8]([NH:20]C(OCC3C=CC=CC=3)=O)[N:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)=O.CO.[Pd]>[NH2:20][CH:8]1[N:7]=[C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]([CH2:17][CH3:18])[C:9]1=[O:19]
Reactant: CCN1C(=O)C(NC(=O)OCc2ccccc2)N=C(C2CCCC2)c2ccccc21
Agent: [Pd]
Solvent: CO
Solvent: O=CO
Product: CCN1C(=O)C(N)N=C(C2CCCC2)c2ccccc21

Procedure:
5-Cyclopentyl-1,3-dihydro-1-ethyl-3(R,S)[(benzyloxycarbonyl)amino]-2H-1,4-benzodiazepin-2-one (0.5 g, 1.23 mmol) was dissolved in formic acid/methanol (50 ml of a 4.5% (v/v) solution), and added, over 5 min, to a stirred suspension of 10% palladium on carbon (200 mg, 40% (w/w)) in formic acid/methanol (10 ml). After 10 min the catalyst was removed by filtration, washed with methanol and acetone and the flitrate concentrated. The residue was partitioned between ethyl acetate (100 ml) and 10% sodium carbonate solution (100 ml). The organic phase was separated, dried (Na2SO4) and evaporated to give a clear oil which was used without further purification.
Reaction SMILES: C[Al](C)C.[CH3:5][C:6]1([CH3:22])[NH:11][CH2:10][CH2:9][N:8]([C:12]2[S:16][C:15]([C:17]([O:19]CC)=O)=[CH:14][CH:13]=2)[CH2:7]1.Cl.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH2:34][O:35][C:36]2[CH:37]=[C:38]([NH2:41])[NH:39][N:40]=2)[CH:29]=[C:30]([O:32][CH3:33])[CH:31]=1.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[CH3:33][O:32][C:30]1[CH:29]=[C:28]([CH2:34][O:35][C:36]2[CH:37]=[C:38]([NH:41][C:17]([C:15]3[S:16][C:12]([N:8]4[CH2:9][CH2:10][NH:11][C:6]([CH3:5])([CH3:22])[CH2:7]4)=[CH:13][CH:14]=3)=[O:19])[NH:39][N:40]=2)[CH:27]=[C:26]([O:25][CH3:24])[CH:31]=1
Reactant: CCOC(=O)c1ccc(N2CCNC(C)(C)C2)s1
Reactant: COc1cc(COc2cc(N)[nH]n2)cc(OC)c1
Agent: C[Al](C)C
Agent: Cl
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1cc(COc2cc(NC(=O)c3ccc(N4CCNC(C)(C)C4)s3)[nH]n2)cc(OC)c1
Temperature: 65 °C
Reaction time: 5 h
Yield: 15.5 %

Procedure:
2M Trimethylaluminium (1.250 ml, 2.50 mmol) in toluene, was added dropwise to a stirred solution of ethyl 5-(3,3-dimethylpiperazin-1-yl)thiophene-2-carboxylate (0.268 g, 1 mmol) and 5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine hydrochloride (0.286 g, 1.00 mmol) in toluene (7.14 ml) at 65° C. under nitrogen. The reaction mixture was stirred and heated at 65° C. for 4 h then 50° C. for 18 h followed by 80° C. for 5 h. Ethyl acetate (5 mL) was added to the reaction mixture followed by a solution of potassium sodium tartrate (5 mL, 20% aqueous). More ethyl acetate (50 mL) and water (25 mL) was added and the mixture was filtered through celite. The filtrate was transferred to a separating funnel and the aqueous layer removed. The ethyl acetate layer was washed with saturated brine and then dried over magnesium sulphate. After filtration the solvent was evaporated to give the crude product as a yellow gum. The crude product was purified by preparative LCMS, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (0.073 g, 15.48%) as a white solid.