Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]([C:3]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]3[NH:13][CH:14]=[C:6]([C:7]=23)[CH2:5][N:4]=1)[NH2:2].C.[CH3:16][C:17]([CH3:19])=O>>[C:17](=[N:2][NH:1][C:3]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]3[NH:13][CH:14]=[C:6]([C:7]=23)[CH2:5][N:4]=1)([CH3:19])[CH3:16]
Reactant: NNC1=NCc2c[nH]c3cccc1c23
Reactant: CC(C)=O
Product: CC(C)=NNC1=NCc2c[nH]c3cccc1c23

Procedure:
5-Hydrazino-1,3-dihydropyrrolo[4,3,2-de]isoquinoline (4.5 g), described in Example 8, is boiled in acetone (ca. 50 ml) for 10 minutes. The reaction mixture is treated with charcoal, filtered and concentrated. Addition of ether-hexane gives a precipitate. The precipitate is recrystallized from benzenemethanol-ether to give the title compound, mp 200° - 201°C, νmaxnujol 3450, 3100, 1625, 1565, 1540 and 1510 cm-1.
Reaction SMILES: C([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+].Cl.[Cl:31]CCl>C(O)C.CC(C)=O>[ClH:31].[CH2:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[O:14][CH2:13][CH2:12][N:8]1[CH2:9][CH2:10][CH2:11][C@@H:6]([C:4]([OH:5])=[O:3])[CH2:7]1)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: ClCCl
Reactant: CCOC(=O)[C@@H]1CCCN(CCOc2ccccc2Cc2ccccc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CCO
Product: O=C(O)[C@@H]1CCCN(CCOc2ccccc2Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
The above ester (1.7 g, 4.6 mmol) was dissolved in ethanol (10 ml) and 4N sodium hydroxide (3.5 ml) was added. The mixture was stirred at ambient temperature for 5 h. Excess concentrated hydrochloric acid was added followed by dichloromethane (300 ml). The phases were separated and the organic phase was dried (Na2SO4). The solvent was evaporated in vacuo to give a foamy residue which was dissolved in acetone (15 ml). The solid which formed was isolated by filtration and dried to give 1.3 g of the title compound as a solid.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C@H:12]([NH:14][C:15]([C@@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:34])[C@@H:24]([NH:26][C:27](=[O:33])[C@@H:28]([OH:32])[CH:29]([CH3:31])[CH3:30])[CH3:25])[NH:18]3)=[O:16])[CH3:13])=[N:9]2)=[CH:4][CH:3]=1.[F:35][CH:36]([F:46])[O:37][CH2:38][C@@:39]([CH3:45])([CH:43]=[CH2:44])[C:40]([OH:42])=[O:41].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:35][CH:36]([F:46])[O:37][CH2:38][C@@:39]([CH3:45])(/[CH:43]=[CH:44]/[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C@H:12]([NH:14][C:15]([C@@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:34])[C@@H:24]([NH:26][C:27](=[O:33])[C@@H:28]([OH:32])[CH:29]([CH3:30])[CH3:31])[CH3:25])[NH:18]3)=[O:16])[CH3:13])=[N:9]2)=[CH:4][CH:3]=1)[C:40]([OH:42])=[O:41]
Reactant: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(Br)cc3n2)N1
Reactant: C=C[C@](C)(COC(F)F)C(=O)O
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(/C=C/[C@](C)(COC(F)F)C(=O)O)cc3n2)N1
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of (S)-1-[(S)-2-((S)-2-hydroxy-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid [(R)-1-(7-bromo-quinolin-2-yl)-ethyl]-amide (160 mg, 0.3 mmol), (R)-2-difluoromethoxymethyl-2-methyl-but-3-enoic acid (54 mg, 0.3 mmol), tri(o-tolyl)phosphine (18 mg, 0.06 mmol) and triethylamine (91 mg, 0.125 mL, 0.9 mmol) in 1,4-dioxane (6 mL) was stirred at 50° C. under nitrogen. Tris(dibenzylideneacetone)dipalladium(0) (27 mg, 0.03 mmol) was added and the reaction mixture was heated at reflux for 40 minutes. The reaction mixture was cooled to room temperature and the mixture was filtered through a hydrophobic frit and the filtrate was evaporated to afford crude (E)-(R)-2-difluoromethoxymethyl-4-{2-[(R)-1-({(S)-1-[(S)-2-((S)-2-hydroxy-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carbonyl}-amino)-ethyl]-quinolin-7-yl}-2-methyl-but-3-enoic acid (0.3 mmol) which was used in the next step. LCMS (m/z) 634.2 [M+H], Tr=2.04 min.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([OH:10])=O)[C:4](=[O:11])[N:3]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1C=NC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(CC)CC.[NH2:46][C:47]1[CH:52]=[CH:51][C:50]([OH:53])=[CH:49][CH:48]=1>CN(C=O)C>[OH:53][C:50]1[CH:51]=[CH:52][C:47]([NH:46][C:8]([C:5]2[C:4](=[O:11])[N:3]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:2]([CH3:1])[C:6]=2[CH3:7])=[O:10])=[CH:48][CH:49]=1
Reactant: Cc1c(C(=O)O)c(=O)n(-c2ccccc2)n1C
Reactant: Nc1ccc(O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2ccc(O)cc2)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 85 %

Procedure:
To a solution of 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (1.70 g, 7.35 mmol), HOAT (1.2 g, 8.82 mmol), and EDCI (1.68 g, 8.82 mmol) in DMF (40 mL) was added Et3N (2.6 mL, 18.38 mmol) drop wise. The solution was stirred at rt for 20 minutes, then a solution of 4-aminophenol (994 mg, 9.11 mmol) in DMF (6 mL) was added drop wise to the reaction system. The reaction was heated at 70° C. for 5 hours, then concentrated to 2 mL in vacuo, and diluted with water (50 mL). The precipitate was collected by filtration, washed with water (5 mL) and dried. The crude product was washed with DCM (20 mL) to give the title compound as a brown solid (2.02 g, 85%).
Reaction SMILES: [Li].[Br:2][C:3]1[CH:4]=[C:5]([C:14]([O-])=[CH:15][C:16](=O)[C:17]([O:19]CC)=[O:18])[CH:6]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:8]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C(C(O)=O)C=2)C=C(F)C=1.Cl.[F:47][C:48]1[CH:49]=[C:50]([NH:54][NH2:55])[CH:51]=[N:52][CH:53]=1>>[Br:2][C:3]1[CH:4]=[C:5]([C:14]2[N:54]([C:50]3[CH:51]=[N:52][CH:53]=[C:48]([F:47])[CH:49]=3)[N:55]=[C:16]([C:17]([OH:19])=[O:18])[CH:15]=2)[CH:6]=[C:7]([O:9][C:10]([F:11])([F:12])[F:13])[CH:8]=1
Reactant: NNc1cncc(F)c1
Reactant: CCOC(=O)C(=O)C=C([O-])c1cc(Br)cc(OC(F)(F)F)c1
Agent: Cl
Agent: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Agent: [Li]
Product: O=C(O)c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2cncc(F)c2)n1

Procedure:
500 mg (1.16 mmol) of the compound of Example 5A is reacted analogously to the synthesis of the compound of Example 20A with 265 mg (1.62 mmol) of 5-fluoropyridin-3-yl-hydrazine hydrochloride. After hydrolysis, 340 mg (66% of theory) of the title compound is obtained.
Reaction SMILES: Cl.Cl.[CH2:3]([C@:5]1([C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][N:20]=3)[CH2:15][CH2:14]2)=[O:12])[CH2:9][CH2:8][C@H:7]([NH2:10])[CH2:6]1)[CH3:4].[CH3:29][CH:30]1[C:35](=O)[CH2:34][CH2:33][O:32][CH2:31]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH2:3]([C@:5]1([C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][N:20]=3)[CH2:15][CH2:14]2)=[O:12])[CH2:9][CH2:8][C@H:7]([NH:10][CH:35]2[CH2:34][CH2:33][O:32][CH2:31][CH:30]2[CH3:29])[CH2:6]1)[CH3:4]
Reactant: CC1COCCC1=O
Reactant: CC[C@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)CC[C@H](N)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC[C@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)CC[C@H](NC2CCOCC2C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.6 %

Procedure:
To a solution of (1S,3S)-3-ethyl-3-(4-[4-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentanamine dihydrochloride (100 mg, 0.20 mmol), 3-methyltetrahydro-4H-pyran-4-one (96 mg, 0.71 mmol), and triethylamine (0.11 mL, 0.79 mmol) in methylene chloride (3 mL) was added sodium triacetoxyborohydride (96 mg, 0.45 mmol). After being stirred at room temperature overnight, the reaction was quenched with saturated NaHCO3 and extracted with methylene chloride three times. The combined organics were dried (MgSO4), filtered, concentrated, purified by flash column chromatography (NH4OH/MeOH/EtOAc) to yield the desired product (38 mg, 40%). MS calculated for C24H35F3N4O2: (M+H) 469.3; found 469.3.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:20]=[CH:19][C:9]2[N:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:11](=[O:13])[O:12][C:8]=2[CH:7]=1)(=[O:4])=[O:3].Cl.Cl[CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C([O-])([O-])=O.[K+].[K+]>CC#N>[O:28]1[CH2:29][CH2:30][N:25]([CH2:24][CH2:23][N:5]([C:6]2[CH:20]=[CH:19][C:9]3[N:10]([CH2:14][C:15]([O:17][CH3:18])=[O:16])[C:11](=[O:13])[O:12][C:8]=3[CH:7]=2)[S:2]([CH3:1])(=[O:3])=[O:4])[CH2:26][CH2:27]1
Reactant: COC(=O)Cn1c(=O)oc2cc(NS(C)(=O)=O)ccc21
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Cn1c(=O)oc2cc(N(CCN3CCOCC3)S(C)(=O)=O)ccc21
Temperature: 100 °C
Yield: 82.3 %

Procedure:
To a solution of methyl 2-(6-(methylsulfonamido)-2-oxobenzo[d]oxazol-3(2H)-yl)acetate (300 mg, 0.999 mmol) (prepared in an analogous manner as described in Example 24, Scheme 24, Steps 1, 2, 3) in CH3CN (15 ml), 4-(2-chloroethyl)morpholine hydrochloride (186 mg, 0.999 mmol) and K2CO3 (138 mg, 0.999 mmol) were added. The mixture was heated at 100° C. under microwaves irradiation for 1 hour. The solvent was removed under vacuum, and the residue was portioned between EtOAc and water. The organic phase was washed several times with brine and dried over sodium sulfate; the solvent was evaporated to dryness and the crude was purified by flash chromatography on silica gel (DCM/MeOH 98/2) to afford methyl 2-(6-(N-(2-morpholinoethyl)methylsulfonamido)-2-oxobenzo[d]oxazol-3(2H)-yl)acetate (340 mg, 0.822 mmol, 82% yield, MS/ESI+ 414.0 [MH]+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:43]([C:45]1[CH:54]=[C:53]2[C:48]([CH:49]=[C:50]([C:57]3[CH:58]=[C:59]([NH:64]/[C:65](/[NH2:68])=[N:66]/O)[CH:60]=[CH:61][C:62]=3[CH3:63])[C:51](=[O:56])[N:52]2[CH3:55])=[CH:47][N:46]=1)[CH3:44]>CN(C=O)C>[CH2:43]([C:45]1[CH:54]=[C:53]2[C:48]([CH:49]=[C:50]([C:57]3[CH:58]=[C:59]([NH:64][C:65]4[N:66]=[C:7]([C:2]5[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=5)[O:9][N:68]=4)[CH:60]=[CH:61][C:62]=3[CH3:63])[C:51](=[O:56])[N:52]2[CH3:55])=[CH:47][N:46]=1)[CH3:44]
Reactant: CCc1cc2c(cn1)cc(-c1cc(N/C(N)=N/O)ccc1C)c(=O)n2C
Reactant: O=C(O)c1ccccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCc1cc2c(cn1)cc(-c1cc(Nc3noc(-c4ccccn4)n3)ccc1C)c(=O)n2C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of picolinic acid (10 mg, 0.09 mmol) in DMF (1 mL) were added DIPEA (16 μL, 0.09 mmol) and HATU (33 mg, 0.09 mmol). After stirring at rt for 15 min, 17a (30 mg, 0.09 mmol) was added as a solution in DMF (0.5 mL). The reaction was stirred at rt until complete consumption of 17a was determined by LC/MS and then heated at 100° C. for 1 h. Subsequently the reaction was cooled to rt, filtered and purified by preparative LC/MS to give 7-ethyl-1-methyl-3-(2-methyl-5-(5-(pyridin-2-yl)-1,2,4-oxadiazol-3-ylamino)phenyl)-1,6-naphthyridin-2(1H)-one (A105). 1H NMR (400 MHz, d6-DMSO) δ 10.13 (s, 1H), 9.09 (s, 1H), 8.81 (s, 1H), 8.18 (d. J=8 Hz, 1H), 8.10 (m, 2H), 7.75 (s, 1H), 7.71 (m, 1H), 7.47 (d, J=8 Hz, 1H), 7.41 (s, 1H), 7.28 (d, J=8 Hz, 1H), 3.72 (s, 3H), 3.01 (q, J=7.6 Hz, 2H), 2.10 (s, 3H), 1.36 (t, J=7.6 Hz, 3H). MS m/z 439.3 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]=[C:27]([CH3:35])[CH:26]=3)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C@H:10]([C:36](O)=[O:37])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:39][OH:40]>>[OH:40][NH:39][C:36]([C@H:10]1[C@@H:11]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]=[C:27]([CH3:35])[CH:26]=3)=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1)=[O:37]
Reactant: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CN(C(=O)OC(C)(C)C)C[C@H]3C(=O)O)cc2)c2ccccc2n1
Reactant: NO
Product: Cc1cc(COc2ccc(S(=O)(=O)N[C@H]3CN(C(=O)OC(C)(C)C)C[C@H]3C(=O)NO)cc2)c2ccccc2n1
Yield: 81 %

Procedure:
According to the procedure of Example 17, Step 5, the reaction of 122 mg of cis-1-(tert-butoxycarbonyl)-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]pyrrolidine-3-carboxylic acid with hydroxylamine provided 104 mg (81% yield) of tert-butyl cis-3-[(hydroxyamino)carbonyl]-4-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}sulfonyl)amino]pyrrolidine-1-carboxylate. MS: 557.3 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([CH3:23])([NH2:22])[CH3:21])=[CH:15][C:14]=1[F:24].O>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[NH:22][C:20]([CH3:23])([CH3:21])[CH2:19][C:16]1[CH:17]=[CH:18][C:13]([Cl:12])=[C:14]([F:24])[CH:15]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: CC(C)(N)Cc1ccc(Cl)c(F)c1
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(Cc1ccc(Cl)c(F)c1)Nc1ccc([N+](=O)[O-])cc1Cl
Temperature: 90 °C
Reaction time: 38.5 h
Yield: 57.2 %

Procedure:
A mixture of 3-chloro-4-fluoro-1-nitrobenzene (421 mg, 2.40 mmol) and 1-(4-chloro-3-fluorophenyl)-2-methylpropan-2-amine (484 mg, 2.40 mmol) in DMSO (10 mL) was heated at 90° C. under N2 for 3 h. The mixture was cooled to rt and stirred at rt for 38.5 h. It was then heated and stirred further at 90° C. for 81.5 h. The mixture was cooled to rt and 80 mL of water was added. The resulting mixture was extracted with EtOAc (30 mL×3). The combined organic layers were dried over anhydrous Na2SO4 (10 g) and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/DCM (V/V)=20:1) to give the title compound as yellow oil (490 mg, 57.2%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:22]([NH:24][C@H:25]([C:38]([OH:40])=[O:39])[CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:23])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=O.[Na+].[C:46](=[O:53])([O:50][CH2:51]I)[S:47][CH2:48][CH3:49]>O.C(Cl)Cl>[C:46](=[O:53])([S:47][CH2:48][CH3:49])[O:50][CH2:51][O:39][C:38](=[O:40])[C@H:25]([CH2:26][CH2:27][CH2:28][CH2:29][NH:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[NH:24][C:22](=[O:23])[C@H:9]([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCSC(=O)OCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCSC(=O)OCOC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 90.8 %

Procedure:
To a mixture of dipeptide 51 (969 mg, 1.69 mmol) in H2O (3.25 mL) and CH2Cl2 (3.25 mL) was added NaHCO3 (294 mg, 3.50 mmol) and TBAHSO4 (572 mg, 1.69 mmol). After stirring for 15 min, S-ethyl O-iodomethyl carbonothioate (322 mg, 1.30 mmol) in CH2Cl2 (1 mL) was added. The biphasic reaction was stirred vigorously for 2.5 h and was diluted with water and CH2Cl2. The layers were separated, the organic layer was washed with H2O, 0.5 N HCl solution, saturated NaHCO3 solution, saturated NaCl solution, dried over MgSO4, filtered and concentrated to dryness. The crude product was triturated with Et2O and the solids were removed by filtration and rinsed with small portions of Et2O. After concentration, the combined filtrates were purified by flash chromatography on silica gel, using a gradient of 0-50% EtOAc in CH2Cl2 as eluent to provide compound 52 (818 mg, 91%) as a white foam. 1H NMR (400 MHz, CDCl3) δ 1.30-1.53 (m, 8H), 1.33 (t, J=7.4 Hz, 3H), 1.44 (s, 27H), 1.60-1.75 (m, 2H), 1.82-1.90 (m, 2H), 2.90 (q, J=7.4 Hz, 2H), 3.06-3.14 (m, 4H), 4.04-4.10 (m, 1H), 4.58-4.64 (m, 1H), 4.70 (bs, 2H), 5.18-5.21 (m, 1H), 5.78 (d, J=5.6 Hz, 1H), 5.90 (d, J=5.6 Hz, 1H) 6.67 (bd, J=6.8 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([S:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][C:16]=2[CH3:23])=[CH:9][C:8]=1[CH3:24])[CH3:2].[F:26][C:27]([F:36])([F:35])[C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[C:10]([S:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][NH:32][C:31]3[CH:33]=[CH:34][C:28]([C:27]([F:26])([F:35])[F:36])=[CH:29][CH:30]=3)=[CH:17][C:16]=2[CH3:23])=[CH:9][C:8]=1[CH3:24])[CH3:2]
Reactant: CCOC(=O)COc1cc(C)c(Sc2ccc(C=O)cc2C)cc1C
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)COc1cc(C)c(Sc2ccc(CNc3ccc(C(F)(F)F)cc3)cc2C)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
To a stirred solution of compound 21.4 (13.5 g, 37.7 mmol) in CHCl3 (135 mL) was successively added 4-(trifluoromethyl)aniline (6.07 g, 37.7 mmol) and AcOH (3.24 mL). After stirring at room temperature for 30 min, the reaction was cooled to 0° C., sodium triacetoxyborohydride (12.0 g, 56.6 mmol) was added, and the reaction was stirred at room temperature for 3 h. The reaction mixture was poured into 150 mL of ice-water and the product was extracted with 2×50 mL CHCl3. The organics were sequentially washed with 150 mL aqueous NaHCO3 and 150 mL brine, dried over MgSO4, and concentrated to a yellow oil, which was purified with flash chromatography (SiO2 gel 60 N, eluted with 10% EtOAc/hexanes—20% EtOAc/hexanes). The fractions containing the desired product were combined and concentrated to yield a colorless solid (18.7 g). 1H NMR (400 MHz) (CDCl3) δ 7.38 (2H, d, J=8.5 Hz); 7.20 (1H, s); 7.14 (1H, s); 6.97 (1H, d, J=8.1 Hz); 6.70-6.50 (4H, m); 4.66 (2H, s); 4.40-4.20 (5H, m); 2.38 (3H, s); 2.30 (3H, s); 2.22 (3H, s); 1.31 (3H, t, J=7.1 Hz).
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][N:14]3[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)=[C:9]([C:27]([F:30])([F:29])[F:28])[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[N:14]1([CH2:13][C:10]2[CH:11]=[CH:12][C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[CH:8][C:9]=2[C:27]([F:30])([F:29])[F:28])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(N3CCOCC3)cc2C(F)(F)F)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1cc(N2CCOCC2)ccc1CN1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
A 100 mL round-bottom flask was charged with tert-butyl 4-[[4-(morpholin-4-yl)-2-(trifluoromethyl)phenyl]methyl]piperazine-1-carboxylate (1.60 g, 3.73 mmol, 1.00 equiv), dichloromethane (10 mL). Trifluoroacetic acid (3.10 g, 27.2 mmol, 7.30 equiv) was added at 0° C. The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure to yield 1.00 g (81% yield) of 4-[4-(piperazin-1-ylmethyl)-3-(trifluoromethyl)phenyl]morpholine as yellow oil. LCMS (ESI, m/z): 330 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH:8]1([C:13]2[S:22][C:21]3[NH:20][C:19]4[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=4[NH:17][C:16](=S)[C:15]=3[N:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1>N1C=CC=CC=1>[CH:8]1([C:13]2[S:22][C:21]3[NH:20][C:19]4[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=4[N:17]=[C:16]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)[C:15]=3[N:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: S=C1Nc2ccccc2Nc2sc(C3CCCC3)nc21
Reactant: CN1CCNCC1
Solvent: c1ccncc1
Product: CN1CCN(C2=Nc3ccccc3Nc3sc(C4CCCC4)nc32)CC1
Temperature: 25 °C
Yield: 68 %

Procedure:
Combine N-methyl piperazine (0.264 g, 2.64 mmol) and 2-cyclopentyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo{f}azulene-10-thione (0.205 g, 0.66 mmol) in 7 ml of pyridine, and heat to reflux over night. Cool to room temperature, remove pyridine, the residue purify on silica gel using 2N ammonia in methanol/ dichloromethane (1:10) as the eluent to give 165 mg foam, which recrystallize in methanol to give 110 mg of title compound: Mass spectrum (electrospray) (m/e): C20H25N5S, Cacl. Mass (M): 367.18, Found: 368.18 (M+1); 1H NMR (400 MHz, CDCl3) δ ppm: 6.97–6.90 (m, 2H), 6.81 (dt, 1H, J=7.3 Hz, J=1.0 Hz), 6.55 (dd, 1H, J=7.8 Hz, J=1.5 Hz), 4.96 (br, 1H), 3.2–3.17 (m, 1H), 2.49–2.47 (m, 4H), 2.28 (s, 3H), 2.03–1.97 (m, 2H), 1.71–1.55 (m, 10H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([O:25]S(C2C=CC(C)=CC=2)(=O)=O)=[N:10][N:11]2[C:16]=1[C:15]([CH3:17])=[N:14][N:13]=[C:12]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[F:24].[CH3:36][N:37]1[C:41]([CH2:42]O)=[N:40][CH:39]=[N:38]1.[H-].[Na+].O>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([O:25][CH2:42][C:41]2[N:37]([CH3:36])[N:38]=[CH:39][N:40]=2)=[N:10][N:11]2[C:16]=1[C:15]([CH3:17])=[N:14][N:13]=[C:12]2[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[F:24]
Reactant: Cc1ccc(S(=O)(=O)Oc2nn3c(-c4ccccc4F)nnc(C)c3c2-c2ccccc2F)cc1
Reactant: Cn1ncnc1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nnc(-c2ccccc2F)n2nc(OCc3ncnn3C)c(-c3ccccc3F)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To toluene-4-sulfonic acid 3,7-bis(2-fluorophenyl)-4-methylpyrazolo[1,5-d][1,2,4]triazin-2-yl ester (200 mg, 0.407 mmol) and (2-methyl-2H-[1,2,4]triazol-3-yl)methanol (57.5 mg, 0.0509 mmol; prepared as described in EP-A-170073) in DMF (5 ml) was added sodium hydride (23.7 mg of a 60% dispersion in mineral oil; 0.593 mmol) and the mixture was stirred at room temperature for 30 min. Water (50 ml) was added, then the solvent was removed in vacuo, and the residue was purified by flash chromatography on silica gel eluting with 0 to 100% ethyl acetate in dichloromethane. 3,7-Bis(2-fluorophenyl)-4-methyl-2-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)pyrazolo[1,5-d][1,2,4]triazine was isolated as a gum, which solidified upon trituration under isohexane (75 mg). 1H NMR (400 MHz, CDCl3) δ 2.52 (3H, s), 3.73 (3H, s), 5.44 (1H, d, J=13 Hz), 5.49 (1H, d, J=13 Hz), 7.18-7.31 (3H, m), 7.36-7.46 (3H, m), 7.63 (1H, m), 7.78 (1H, m), 7.82 (1H, s); MS (ES+) m/e 434 [MH]+. Anal. Found C, 61.03; H, 4.08; N, 21.95%. C22H17F2N7O.0.1 C6H14 requires C, 61.41; H, 4.20; N, 22.18%.
Reaction SMILES: P(Cl)(Cl)(Cl)(Cl)Cl.[Cl:7][C:8]1[C:9]([C:23](=O)[NH:24][CH2:25][CH:26]=[CH2:27])=[C:10]2[C:15](=[CH:16][C:17]=1[Cl:18])[N:14]=[C:13]([O:19][CH3:20])[C:12]([O:21][CH3:22])=[N:11]2.[CH:29]([NH:31][NH2:32])=O.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:7][C:8]1[C:9]([C:23]2[N:24]([CH2:25][CH:26]=[CH2:27])[CH:29]=[N:31][N:32]=2)=[C:10]2[C:15](=[CH:16][C:17]=1[Cl:18])[N:14]=[C:13]([O:19][CH3:20])[C:12]([O:21][CH3:22])=[N:11]2
Reactant: NNC=O
Reactant: C=CCNC(=O)c1c(Cl)c(Cl)cc2nc(OC)c(OC)nc12
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=CCn1cnnc1-c1c(Cl)c(Cl)cc2nc(OC)c(OC)nc12
Yield: 10.4 %

Procedure:
Phosphorus pentachloride (0.67 g, 3.22 mmol) was added to a stirred suspension of 6,7-dichloro-2,3-dimethoxy-5-(N-allylcarbamoyl)quinoxaline (Preparation 18, 1.0 g, 2.93 mmol) in toluene (40 mL) at room temperature and then heated under reflux for 1 hour. After being cooled, formylhydrazine (0.585 g, 8.79 mmol) and triethylamine (0.592 g, 8.79 mmol) were added and the mixture heated under reflux for 1 hour. After being cooled, the mixture was partitioned between ethyl acetate (60 mL) and 10% w/w aqueous potassium carbonate solution (60 mL). The phases were separated and the aqueous phase extracted with ethyl acetate (2×40 mL). The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, by gradient elution using toluene:ethyl acetate (1:0 changing to 1:1, by volume) to afford 6,7-dichloro-2,3-dimethoxy-5-(4-allyl-4H-1,2,4-triazol-3-yl)quinoxaline (0.112 g, 10%) as a white solid, mp 206-208° C.