Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(F)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:16][C:17](=[N:51][C:52](=[O:59])[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[C:18]1[CH:23]=[CH:22][C:21]([NH:24][CH:25]([C:38]2[CH:43]=[C:42]([O:44][CH3:45])[CH:41]=[C:40]([O:46][CH2:47][CH2:48][OH:49])[C:39]=2[F:50])[C:26]2[NH:30][C:29](=[O:31])[N:28]([C:32]3[N:37]=[CH:36][CH:35]=[CH:34][N:33]=3)[N:27]=2)=[CH:20][CH:19]=1.C(O)(=O)[CH2:61][C:62](CC(O)=O)(C(O)=O)[OH:63].P([O-])([O-])(O)=O.[Na+].[Na+]>CN(C1C=CN=CC=1)C.C1COCC1.C(OCC)(=O)C.O.CN(C=O)C.ClCCl.C(O)(=O)C.C(N(CC)CC)C>[NH2:16][C:17](=[N:51][C:52](=[O:59])[C:53]1[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=1)[C:18]1[CH:23]=[CH:22][C:21]([NH:24][CH:25]([C:26]2[NH:30][C:29](=[O:31])[N:28]([C:32]3[N:33]=[CH:34][CH:35]=[CH:36][N:37]=3)[N:27]=2)[C:38]2[C:39]([F:50])=[C:40]([CH:41]=[C:42]([O:44][CH3:45])[CH:43]=2)[O:46][CH2:47][CH2:48][O:49][C:62](=[O:63])[CH3:61])=[CH:20][CH:19]=1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: COc1cc(OCCO)c(F)c(C(Nc2ccc(C(N)=NC(=O)c3ccccc3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Agent: CN(C)C(F)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: O
Product: COc1cc(OCCOC(C)=O)c(F)c(C(Nc2ccc(C(N)=NC(=O)c3ccccc3)cc2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Reaction time: 1 h

Procedure:
Under nitrogen atmosphere, triethylamine (6.97 mL) was added under ice-cooling to a mixture of acetic acid (601 mg), TFFH (2.64 g), and dichloromethane (50 mL), and the resulting mixture was stirred for 1 hour. To the resulting mixture, a mixture of N-[1-amino-1-(4-{[[2-fluoro-3-(2-hydroxyethoxy)-5-methoxyphenyl]-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]triazol-3-yl)methyl]amino}phenyl)methylidene]benzamide (Example 1a, 3 g), DMAP (5 mg), and DMF (50 mL) was added dropwise. After stirring the resulting mixture overnight at room temperature, the solvent in the mixture was distilled off under reduced pressure. The residue obtained was dissolved in a small amount of THF, and ethyl acetate (300 mL) and water (100 mL) were added to the resulting mixture. After a buffer (prepared by adding 37 mL of 0.1 M citric acid to 63 mL of 0.2 M disodium hydrogen phosphate) was added to the resulting mixture to adjust the pH to 6, the mixture was shaken, and the organic layer was collected. The organic layer was sequentially washed twice with water (100 mL) and with saturated aqueous sodium chloride solution (100 mL), and dried over anhydrous magnesium sulfate. The resulting mixture was filtered, and the filtrate obtained was concentrated under reduced pressure. The residue obtained was purified by NAM silica gel column chromatography (mixed solvent of methanol-ethyl acetate) to obtain the captioned compound (2.16 g).
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([NH2:30])=[CH:29][C:24]=2[O:23][CH2:22]1>COCCO>[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([NH:30][C:4]3[N:9]=[CH:8][C:7]4=[CH:10][CH:11]=[C:12]([C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=5[O:19][CH3:20])[N:6]4[N:5]=3)=[CH:29][C:24]=2[O:23][CH2:22]1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Reactant: Nc1ccc2c(c1)OCO2
Solvent: COCCO
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc4c(c3)OCO4)nn12
Temperature: 180 °C
Yield: 3.2 %

Procedure:
2-Methane sulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (67.0 mg, 0.000233 mol) and 1,3-Benzodioxol-5-ylamine (63.9 mg, 0.000466 mol) were dissolved in 2-Methoxyethanol (1.64 mL) and the reaction was heated at 180° C. until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 2.65 mg 1,3-Benzodioxol-5-yl-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-amine as a lyophilated powder. (M+H)=361.20. 1H NMR (400 MHz, DMSO, d6) δ 9.29 (s, 1H), 8.93 (s, 1H), 7.75 (d, 1H, J=7.07 Hz), 7.51 (s, 1H), 7.46 (m, 1H), 7.20 (m, 1H), 7.10 (m, 2H), 7.05 (s, 2H), 6.76 (d, 1H, J=8.34 Hz), 5.94 (s, 2H), 3.79 (s, 3H).
Reaction SMILES: [Na].[C:2]([SH:10])(=[S:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[K+].I[I-]I>O1CCCC1>[C:2]([S:10][S:10][C:2](=[S:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)(=[S:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: S=C(S)c1ccccc1
Agent: I[I-]I
Agent: [K+]
Agent: [Na]
Solvent: C1CCOC1
Product: S=C(SSC(=S)c1ccccc1)c1ccccc1

Procedure:
100 ml of a sodium salt solution of dithiobenzoic acid (0.15 mol) were added by drops to an 80 not iodine aqueous solution (0.1 mol) over 1 hour. After completing the reaction, the obtained product was dissolved in an organic solvent of tetrahydrofurane (THF) and washed with distillated water twice and dried over magnesium sulfate (MgSO4). The organic solvent was removed by vacuum evaporation. It was then recrystalized in ethanol to obtain dithiobenzoyl disulfide.
Reaction SMILES: F[C:2]1[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[N:13]1([CH2:19][CH2:20][NH2:21])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.CCOC(C)=O>CN(C=O)C>[N:13]1([CH2:19][CH2:20][NH:21][C:2]2[C:11]([F:12])=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COC(=O)c1cccc(F)c1F
Reactant: NCCN1CCCCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(F)c1NCCN1CCCCC1
Temperature: 100 °C
Yield: 63 %

Procedure:
Methyl 2,3-difluorobenzoate (0.816 g, 4.741 mmol) and 2-(piperidin-1-yl)ethanamine (2.7 mL, 18.93 mmol) were dissolved in DMF (15 mL) and heated in a microwave for 30 mins at 100° C. The reaction mixture was transferred to a separatory funnel with EtOAc (75 mL) the organics washed with 10 ml pure water. The layers were separated and the aqueous layer was extracted with EtOAc (2×50 mL). The crude material was purified by silica gel column chromatography eluting with EtOAc/Hexanes to give methyl 2-(2-(piperidin-1-yl)ethylamino)-3-fluorobenzoate (837 mg, 63%). LC/MS: 281.17 (M+1) Rt=1.63 min (10-90% 3/5 min (grad/run) with formic acid).
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]2[N:17]=[N:18][N:19]3[C:24]=2[C:23]2[CH:25]=[CH:26][NH:27][C:22]=2[N:21]=[CH:20]3)[CH2:12][CH2:11]1)(C(C)(C)C)(C)C.[Si](OCC1C=CC(C2N=NN3C=2C2C=CNC=2N=C3)=CC=1)(C(C)(C)C)(C)C>>[C:16]1([C@H:13]2[CH2:12][CH2:11][C@H:10]([CH2:9][OH:8])[CH2:15][CH2:14]2)[N:17]=[N:18][N:19]2[C:24]=1[C:23]1[CH:25]=[CH:26][NH:27][C:22]=1[N:21]=[CH:20]2
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CC[C@H](c2nnn3cnc4[nH]ccc4c23)CC1
Agent: CC(C)(C)[Si](C)(C)OCc1ccc(-c2nnn3cnc4[nH]ccc4c23)cc1
Product: OC[C@H]1CC[C@H](c2nnn3cnc4[nH]ccc4c23)CC1

Procedure:
The reactions in Synthetic Examplea 140 were carried out in substantially the same manners except that 1-(trans-4-{[(tert-butyldimethylsilyl)oxy]methyl}cyclohexyl)-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine obtained in Reference Synthetic Examplea 92 was used instead of 1-(4-{[(tert-butyldimethylsilyl)oxy]methyl}phenyl)-7H-pyrrolo[3,2-e][1,2,3]triazolo[1,5-c]pyrimidine to give the title compound as a pale yellow solid (2.05 g, yield 78%). (alternative to Synthetic Examplea 10).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[N:9]2)[CH:5]=[CH:4][C:3]=1[OH:17].O[CH:19]([C:23]1[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:24]=1)[CH2:20][CH2:21][CH3:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC=[N+]=[N-])=O)=NC([O-])=O>O1CCCC1>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[N:9]2)[CH:5]=[CH:4][C:3]=1[O:17][CH:19]([C:23]1[CH:33]=[CH:32][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:25][CH:24]=1)[CH2:20][CH2:21][CH3:22]
Reactant: Cc1cc(-n2cc(C(F)(F)F)cn2)ccc1O
Reactant: CCCC(O)c1ccc(C(=O)OCC)cc1
Agent: [N-]=[N+]=CCOC(=O)N=NC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC(Oc1ccc(-n2cc(C(F)(F)F)cn2)cc1C)c1ccc(C(=O)OCC)cc1
Reaction time: 17 h
Yield: 24.3 %

Procedure:
2-Methyl-4-(4-(trifluoromethyl)-1H-pyrazol-1-yl)phenol (200 mg, 0.83 mmol) was combined with ethyl 4-(1-hydroxybutyl)benzoate (see Intermediate 5) (19 mg, 0.87 mmol) and dissolved in anhydrous tetrahydrofuran (5 mL). Triphenylphosphine (347 mg, 1.3 mmol) was added at 0° under stirring followed by 0.83 ml of 1.5 M solution of diazoethyl azodicarboxylate (1.24 mmol). The reaction was stirred at room temperature as a yellow solution. At 17 hours, the reaction was concentrated and 10 ml of ethyl acetate and 5 ml of heptanes were added. Solid was filtered off and the mother liquor was loaded on silica gel. Chromatography on a silica gel column (gradient from 5% to 40% of ethyl acetate in heptane) gave the target product as a colorless glass (90 mg, 24%). MS (M+1): 447.2.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH3:9])=[C:6]([CH3:10])[N:5]=[C:4]([C:11]2[S:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[N:3]=1.[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([Br:27])=[C:22]([CH:26]=1)[C:23]([OH:25])=[O:24].Cl>O1CCOCC1.CC(O)=O>[Br:27][C:21]1[CH:20]=[CH:19][C:18]([NH:17][C:2]2[C:7]([CH2:8][CH3:9])=[C:6]([CH3:10])[N:5]=[C:4]([C:11]3[S:12][C:13]([Cl:16])=[CH:14][CH:15]=3)[N:3]=2)=[CH:26][C:22]=1[C:23]([OH:25])=[O:24]
Reactant: Nc1ccc(Br)c(C(=O)O)c1
Reactant: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CCc1c(C)nc(-c2ccc(Cl)s2)nc1Nc1ccc(Br)c(C(=O)O)c1
Temperature: 110 °C
Reaction time: 2 h
Yield: 77.3 %

Procedure:
A 18-mL vial was charged with 4-chloro-2-(5-chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidine (87 mg, 0.318 mmol, 1.05 eq.), 5-amino-2-bromo-benzoic acid (65 mg, 0.3 mmol, 1 eq.). AcOH (1 ml) and 4 N HCl in dioxane (5 drops). The resulting mixture was stirred under Ar at 110° C. for 2 hr. After cooling to rt, The volatile material was removed under reduced pressure and the residue was treated with dichloromethane to give the title compound (105 mg, 77% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([C:34]#[N:35])([CH2:20][C:21]([O:23][CH:24]1[CH:29]([CH:30]([CH3:32])[CH3:31])[CH2:28][CH2:27][CH:26]([CH3:33])[CH2:25]1)=[O:22])[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)=[O:38].C(=O)([O-])[O-].[K+].[K+].OO>O>[CH2:1]([O:8][C:9]([NH:11][C:12]([C:34](=[O:38])[NH2:35])([CH2:20][C:21]([O:23][CH:24]1[CH:29]([CH:30]([CH3:31])[CH3:32])[CH2:28][CH2:27][CH:26]([CH3:33])[CH2:25]1)=[O:22])[C:13]([O:15][C:16]([CH3:19])([CH3:17])[CH3:18])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CCC(C(C)C)C(OC(=O)CC(C#N)(NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)C1
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: O
Product: CC1CCC(C(C)C)C(OC(=O)CC(NC(=O)OCc2ccccc2)(C(N)=O)C(=O)OC(C)(C)C)C1
Reaction time: 6 h
Yield: 45.8 %

Procedure:
t-Butyl 2-benzyloxycarbonylamino-2-cyano-3-[(−)-menthyloxycarbonyl]propionate (2.00 g, 4.11 mmol) and acetone (10 ml) were mixed and an aqueous solution of potassium carbonate (566 mg, 5.34 mmol) in water (5.0 ml) was added thereto. Further, 30% aqueous hydrogen peroxide solution (1.6 ml) was added dropwise and the mixture was stirred for about 6 hours. When completion of the reaction was confirmed, water was added and the precipitated crystals were filtered, washed with sprayed water and hexane to give t-butyl 2-benzyloxycarbonylamino-2-carbamoyl-3-[(−)-menthyloxycarbonyl]propionate (950 mg, yield 45.8%) as a pale yellow crystal. Optical purity of (2R)-derivative was 7.4% d.e.
Reaction SMILES: [C:1](=S)=[S:2].[NH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[S:15][C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[N:4]([CH2:5][CH2:6][CH2:7][N:8]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=2[S:15][C:16]2[C:21]1=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:1]=[S:2]
Reactant: S=C=S
Reactant: NCCCN1c2ccccc2Sc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: S=C=NCCCN1c2ccccc2Sc2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 124.8 %

Procedure:
4.2 g of carbon disulfide was added dropwise to a solution of 12.8 g of 10-(3-aminopropyl)phenothiazine and 7.7 ml of triethylamine in 100 ml of tetrahydrofuran. After stirring the solution at room temperature for 2 hours, a solution of 11.3 g of dicyclohexylcarbodiimide in 20 ml of tetrahydrofuran was added dropwise thereto, and the reaction was conducted at room temperature for 5 hours. After removing solvents in vacuo, 50 ml of ethyl acetate was added to the residue, and the crystals precipitated were collected by filtration, and the filtrate was concentrated to obtain 18.6 g of the desired compound (oily).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH:12]=[C:13]([O:15]CC2C=CC=CC=2)[CH:14]=1)[CH2:5][C:6]([CH3:8])=[CH2:7]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:33])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:24]=[CH:25][C:26]([C:29]([F:31])([F:30])[F:32])=[CH:27][CH:28]=2)[CH:12]=[C:13]([OH:15])[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: C=C(C)CC(C(=O)OC)c1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(CC(C)C)c1cc(O)cc(-c2ccc(C(F)(F)F)cc2)c1
Reaction time: 48 h
Yield: 83.8 %

Procedure:
10% Pd/C (Aldrich cat no 205699, 0.30 g) was added to a stirred solution of 2-(5-benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pent-4-enoic acid methyl ester (2.71 g, 5.96 mmol) in MeOH (75 mL) at room temperature. Stirring was continued for 2 days under H2 (1 atm). Then the mixture was filtered through Celite, concentrated in vacuo to give the compound (1.83 g, 84%) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[O:15][C:14]([NH:16][C:17](=O)[C@@H:18]([NH:30]C(=O)OC(C)(C)C)[CH2:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[N:13][CH:12]=3)[CH:9]=2)[NH:4][N:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C(O)(C(F)(F)F)=O>>[NH2:30][C@@H:18]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:29])[F:28])=[CH:22][CH:21]=1)[CH2:17][NH:16][C:14]1[O:15][C:11]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[NH:4][N:3]=[C:2]3[CH3:1])=[CH:12][N:13]=1
Reactant: Cc1n[nH]c2ccc(-c3cnc(NC(=O)[C@H](Cc4ccc(C(F)(F)F)cc4)NC(=O)OC(C)(C)C)o3)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1n[nH]c2ccc(-c3cnc(NC[C@@H](N)Cc4ccc(C(F)(F)F)cc4)o3)cc12

Procedure:
The compound was synthesized by reducing tert-butyl(S)-1-(5-(3-methyl-1H-indazol-5-yl)oxazol-2-ylamino)-1-oxo-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate with LAH followed with a TFA treatment. LCMS (API-ES) m/z (%): 416 (100%, M++H); 1H NMR (400 MHz, MeOH-d4) δ ppm 6.31 (s, 1H) 6.12 (d, J=8.02 Hz, 2H) 5.91-6.03 (m, 4H) 5.75 (s, 1H) 2.27 (dd, J=7.14, 4.40 Hz, 1H) 2.07-2.15 (m, 1H) 1.97-2.07 (m, 1H) 1.56-1.64 (m, 1H) 1.54 (d, J=6.85 Hz, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:26])[C:6]1[CH:11]=[C:10]([CH3:12])[C:9](Br)=[C:8]([S:14]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=2[NH2:25])(=[O:16])=[O:15])[CH:7]=1>CN(C)C=O>[CH3:3][O:4][C:5]([C:6]1[CH:11]=[C:10]([CH3:12])[C:9]2[NH:25][C:19]3[C:20]([Cl:24])=[CH:21][CH:22]=[CH:23][C:18]=3[CH2:17][S:14](=[O:16])(=[O:15])[C:8]=2[CH:7]=1)=[O:26]
Reactant: COC(=O)c1cc(C)c(Br)c(S(=O)(=O)Cc2cccc(Cl)c2N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cccc(Cl)c1N2
Reaction time: 0.5 h

Procedure:
Sodium hydride (0.234 g, 5.07 mmol) was added in portions to a stirred solution of Example 37d (0.785 g, 1.69 mmol) in dry dimethylformamide (10 mL) at 0° C. The reaction mixture was stirred for 0.5 h. Excess sodium hydride was destroyed using methanol (5 mL). The reaction mixture was diluted with cold water (100 mL), the solid separated was filtered, crystallized using ethyl acetate/pet. ether 60-80° C. to obtain the title compound. Yield: 0.409 g, (64.10%); 1H NMR (DMSO-d6, 300 MHz): δ 2.65 (s, 3H, CH3), 3.90 (s, 3H, OCH3), 5.15 (s, 2H, CH2), 7.25 (t, 1H, Ar), 7.65 (d, 1H, Ar), 7.75 (d, 1H, Ar), 7.85 (s, 1H, NH), 8.05 (s, 1H, Ar), 8.35 (s, 1H, Ar); MS: m/e (EI) 351 (M+).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=3)[CH:8]=2)[N:3]=1.[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[C:23]([NH:1][C:2]1[N:11]=[C:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=3)[CH:8]=2)[N:3]=1)(=[O:25])[CH3:24]
Reactant: COc1ccc(-c2ccc3nc(N)nc(O)c3c2)cc1OC
Reactant: CC(=O)OC(C)=O
Product: COc1ccc(-c2ccc3nc(NC(C)=O)nc(O)c3c2)cc1OC
Yield: 90 %

Procedure:
A suspension of the crude 2-amino-6-(3,4-dimethoxyphenyl)-4-hydroxyquinazoline from example 5 (3.0 g, 10 mmol) in acetic anhydride (20 ml) was refluxed for 40 minutes. After concentration under reduced pressure, the residue was purified by silica gel flash chromatography, the mobile phase being a mixture of methanol and dichloromethane (in a ratio of 1:40), yielding the title compound as a white solid (3.05 g, yield: 90%) which was characterized by its mass spectrum as follows: MS (m/z): 340 ([M+H]+, 100).
Reaction SMILES: [OH:1][C:2]([CH3:19])([CH3:18])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[N:8]=[CH:7][C:6]=1[N+:15]([O-])=O>[Pt].C(O)(C)C>[OH:1][C:2]([CH3:19])([CH3:18])[CH2:3][NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[N:8]=[CH:7][C:6]=1[NH2:15]
Reactant: CC(C)(O)CNc1c([N+](=O)[O-])cnc2cccnc12
Agent: [Pt]
Solvent: CC(C)O
Product: CC(C)(O)CNc1c(N)cnc2cccnc12

Procedure:
N-(2-Hydroxy-2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine (44.12 g, 0.17 mol), 5% platinum on carbon (4.4 g) and isopropanol (890 mL) were combined in a Parr vessel and placed under hydrogen pressure (35 psi, 2.4×105 Pa) overnight. The reaction mixture was filtered through a layer of filtering agent. The layer of filtering agent was rinsed well with isopropanol. The filtrate was concentrated under reduced pressure to provide N4-(2-hydroxy-2-methylpropyl)[1,5]naphthyridin-3,4-diamine as a thick oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]([CH2:23][CH2:24][C:25]([NH:27][NH2:28])=[O:26])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:29](OCC)(OCC)(OCC)[CH3:30]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:14])=[O:15])[CH:11]([CH2:23][CH2:24][C:25]3[O:26][C:29]([CH3:30])=[N:28][N:27]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: Cc1ccc(S(=O)(=O)N2C(CCC(=O)NN)CCC2c2ccc(F)cc2)cc1
Product: Cc1ccc(S(=O)(=O)N2C(CCc3nnc(C)o3)CCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, light yellow oil, MS: m/e=430.2 (M+H+), was prepared in accordance with the general method of example 127 from (2RS,5SR)-3-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-propionic acid hydrazide and triethyl orthoacetate.
Reaction SMILES: CCN(C(C)C)C(C)C.[NH:10]([C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)=[S:13])[NH2:11].[CH2:27]([O:34][N:35]1[C:41](=[O:42])[N:40]2[CH2:43][C@H:36]1[CH2:37][CH2:38][C@H:39]2[C:44](O)=[O:45])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:27]([O:34][N:35]1[C:41](=[O:42])[N:40]2[CH2:43][C@H:36]1[CH2:37][CH2:38][C@H:39]2[C:44]([NH:11][NH:10][C:12]([N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)=[S:13])=[O:45])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=S)NN)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(C(=S)NNC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.3 %

Procedure:
DIPEA (1.75 mL, 10.8 mmol) was added to a solution of tert-butyl 4-(hydrazinecarbonothioyl)piperazine-1-carboxylate (0.95 g, 3.6 mmol), (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carboxylic acid (1.0 g, 3.6 mmol) and HATU (1.51 g, 3.98 mmol) in dry DMF (15 mL) and the resulting reaction mixture was stirred at rt for 1 h. The reaction mixture was quenched with water (10 mL), and extracted with EtOAc (3×). The combined organic layer was dried over Na2SO4, then concentrated and purified by silica gel column chromatography (1:50 MeOH/DCM) to afford tert-butyl 4-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)hydrazinecarbonothioyl)piperazine-1-carboxylate (0.92 g, 49%) as a light yellow solid. ESI-MS (EI+, m/z): 519.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:19])[CH2:13][CH2:14][S:15]C(=O)C)([CH3:4])([CH3:3])[CH3:2].N>>[C:1]([O:5][C:6](=[O:20])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12](=[O:19])[CH2:13][CH2:14][SH:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)SCCC(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Agent: N
Product: CC(C)(C)OC(=O)[C@@H]1CCCN1C(=O)CCS

Procedure:
The product from step b, 3-acetylthiopropanoyl-L-proline-t-butyl ester, 0.5 g, was mixed with 4.5 ml of 5.5N methanolic ammonia at room temperature under nitrogen for one hour. The solvent was then removed at 25° C. with a rotary evaporator. After the product was taken up in methanol and reevaporated twice more in the rotary evaporator, the clear oily residue was dissolved in ethyl ether, washed twice with 5% potassium bisulphate and once with saturated NaCl, dried over MgSO4 and filtered. Residual solvent was removed in vacuo to yield a clear oily product, migrating as a single spot on thin layer chromatography in three separate solvent systems.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6]1[C:11](=[O:12])[CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5].Cl.C(N(CC)CC)C.[CH2:21]([O:28][C:29](ON1C(=O)CCC1=O)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1.O.C(OCC)(=O)C>[CH2:2]([O:3][C:4]([C:6]1[CH2:7][N:8]([C:29]([O:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:30])[CH2:9][CH2:10][C:11]=1[OH:12])=[O:5])[CH3:1]
Reactant: CCOC(=O)C1CNCCC1=O
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=C(O)CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Yield: 98.9 %

Procedure:
To a solution of ethyl 4-piperidone-3-carboxylate hydrochloride (5 g, 24.05 mmol) in THF (70 mL) and water (35 mL) at 0° C., was added triethylamine (8.7 mL, 62.5 mmol), followed by N-(benzyloxycarbonyloxy)succinimide (7.79 g, 31.27 mmol). The reaction mixture was stirred and allowed to warm to room temperature. After 3 hours the reaction mixture was diluted with water (50 mL) and ethyl acetate (100 mL) added. The aqueous phase was extracted into ethyl acetate (2×100 mL). The organic phases were combined, washed with brine (50 mL), dried (MgSO4), and the solvent removed in vacuo. The crude product was purified by column chromatography on silica gel (eluent, ethyl acetate:pentane=1:5) to give 4-hydroxy-5,6-dihydro-2H-pyridine-1,3-dicarboxylic acid 1-benzyl ester 3-ethyl ester as a colorless oil (7.26 g, 94%). MS (EI) 305 (M+).