Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C@H:10]1[NH:15][C:14](=[O:16])[C@@H:13]([C@@H:17]([CH3:20])[CH2:18][CH3:19])[N:12]([CH:21]([C:32]2[C:33]([CH3:39])=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=2)[C:22]([NH:24][C:25]2C=CC=CC=2O)=[O:23])[C:11]1=[O:40].C(N1C=CN=C1)(N1C=CN=C1)=O.CN.O1CCCC1>ClCCl>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C@H:10]1[NH:15][C:14](=[O:16])[C@@H:13]([C@@H:17]([CH3:20])[CH2:18][CH3:19])[N:12]([C@H:21]([C:32]2[C:33]([CH3:39])=[N:34][C:35]([CH3:38])=[CH:36][CH:37]=2)[C:22]([NH:24][CH3:25])=[O:23])[C:11]1=[O:40]
Reactant: CC[C@H](C)[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1C(C(=O)Nc1ccccc1O)c1ccc(C)nc1C
Agent: CN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]1C(=O)N[C@H](C2Cc3ccccc3C2)C(=O)N1[C@@H](C(=O)NC)c1ccc(C)nc1C
Reaction time: 8 h

Procedure:
2-{(3R,6R)-3-(2,3-dihydro-1H-inden-2-yl)-6-[(1S)-1-methylpropyl]-2,5-dioxo-1-piperazinyl}-2-(2,6-dimethyl-3-pyridinyl)-N-(2-hydroxyphenyl)acetamide (intermediate 2) (0.400 g, 0.74 mmol) and 1,1′-carbonyldiimidazole (0.192 g, 1.18 mmol) in dry dichloromethane (10 mL) were stirred at room temperature under N2 for 7 hrs. The mixture was treated with a 2M solution of methylamine in tetrahydrofuran (1.849 mL, 3.70 mmol) and left to stand overnight at room temperature. The solvents were blown down under N2 and the residue was purified on a Redisep silica column (35 g) eluted with 0-10% methanol in ethyl acetate followed by further purification on a Kromasil KR100-10-C18 reverse-phase column eluted with aqueous acetonitrile (20-45% MeCN) containing 0.1% formic acid. This gave the title compound as a white lyophilisate (30%) after freeze-drying from 1,4-dioxane.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]2[N:8]=[C:9]([C:18]3[CH:19]=[N:20][C:21]([NH2:24])=[N:22][CH:23]=3)[N:10]=[C:11]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:6]=2[S:5][C:4]=1[CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(OC([NH:39][C:40]([CH3:45])([CH3:44])[C:41](O)=[O:42])=O)(C)(C)C.C(O)(C(F)(F)F)=O>>[NH2:39][C:40]([CH3:45])([CH3:44])[C:41]([N:29]1[CH2:30][CH2:31][N:26]([CH2:25][C:4]2[S:5][C:6]3[C:11]([N:12]4[CH2:13][CH2:14][O:15][CH2:16][CH2:17]4)=[N:10][C:9]([C:18]4[CH:19]=[N:20][C:21]([NH2:24])=[N:22][CH:23]=4)=[N:8][C:7]=3[C:3]=2[CH3:2])[CH2:27][CH2:28]1)=[O:42]
Reactant: Cc1c(CN2CCNCC2)sc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc12
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(CN2CCN(C(=O)C(C)(C)N)CC2)sc2c(N3CCOCC3)nc(-c3cnc(N)nc3)nc12
Yield: 80.3 %

Procedure:
Crude HCl salt of 5-(7-methyl-4-morpholino-6-(piperazin-1-ylmethyl)thieno[3,2-d]pyrimidin-2-yl)pyrimidin-2-amine (74 mg) was reacted with 70 mg 2-(tert-butoxycarbonylamino)-2-methylpropanoic acid via General Procedure B, treated with TFA and purified via reverse phase HPLC to yield 71.3 mg of 352 after reverse phase HPLC purification. MS (Q1) 512.3 (M)+
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[O:5][C:4](=[O:10])[CH:3]=1.[C:11](Cl)(=[O:15])[CH2:12][CH2:13][CH3:14]>FC(F)(F)C(O)=O>[C:11]([C:3]1[C:4](=[O:10])[O:5][C:6]([CH2:8][CH3:9])=[CH:7][C:2]=1[OH:1])(=[O:15])[CH2:12][CH2:13][CH3:14]
Reactant: CCCC(=O)Cl
Reactant: CCc1cc(O)cc(=O)o1
Solvent: O=C(O)C(F)(F)F
Product: CCCC(=O)c1c(O)cc(CC)oc1=O
Temperature: 90 °C
Yield: 64.5 %

Procedure:
According to the method of Douglas and Money (see: Can. J. Chem. 1968, 46, 695), 4-hydroxy-6-ethyl-2-pyrone (see: Hsung, et. al. Synthesis 2007, 749; 1.24 g, 8.85 mmol) was dissolved in trifluoroacetic acid (4 mL) in a pressure-safe vessel. Butyryl chloride (1.0 mL, 9.73 mmol) was added and the solution flushed with argon. The vessel was sealed and stirred in a 90° C. heating bath overnight. After cooling to room temperature, the solution was poured onto powdered sodium bicarbonate (9 g) before water (80 mL) was added carefully. Organics were extracted from the aqueous slurry with dichloromethane (3×80 mL), dried with magnesium sulfate, filtered, and concentrated. The crude product was purified by chromatography on silica gel with gradient elution (10→20% ether in hexanes) to afford 3-butyryl-6-ethyl-4-hydroxy-2-pyrone (1.20 g, 65%) as an oily solid. Used without further characterization.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:28])[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][N:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[CH2:31]([S:34](Cl)(=[O:36])=[O:35])[CH2:32][CH3:33]>N1C=CC=CC=1>[OH:22][C:21]1[C:20]2[C:15](=[N:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:13](=[O:28])[C:12]=1[C:7]1[NH:6][C:5]2[CH:29]=[CH:30][C:2]([NH:1][S:34]([CH2:31][CH2:32][CH3:33])(=[O:36])=[O:35])=[CH:3][C:4]=2[S:9](=[O:11])(=[O:10])[N:8]=1
Reactant: CCCS(=O)(=O)Cl
Reactant: CC(C)CCn1c(=O)c(C2=NS(=O)(=O)c3cc(N)ccc3N2)c(O)c2cccnc21
Solvent: c1ccncc1
Product: CCCS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(c1c(O)c3cccnc3n(CCC(C)C)c1=O)N2
Temperature: 120 °C
Yield: 11.2 %

Procedure:
To the product of Example 205 (21.5 g, 0.05 mmol) in pyridine (1 mL) was added 1-propanesulfonyl chloride (22.5 mL, 0.2 mmol). The reaction mixture was heated in a microwave reactor at 120° C. for 120 minutes. The reaction was cooled to 25° C. and concentrated under reduced pressure. The residue was triturated with water (1 mL), filtered, and washed with 1:1 hexane:ethyl acetate. The crude product was chromatographed on reverse phase HPLC eluting with 0.1% aqueous trifluoroacetic acid/methanol (90/10) to 0.1% aqueous trifluoroacetic acid/methanol (5/95) to give the title compound (3 mg, 11%). 1H NMR (300 MHz, DMSO-d6) δ 0.97 (m, 9 H) 1.57 (m, 2 H) 1.69 (m, 3 H) 3.17 (t, J=7.74 Hz, 2 H) 4.49 (t, J=7.74 Hz, 2 H) 7.50 (dd, J=7.91, 4.60 Hz, 1 H) 7.58 (dd, J=8.82, 2.57 Hz, 1 H) 7.64 (d, J=2.21 Hz, 1 H) 7.75 (d, J=8.82 Hz, 1 H) 8.56 (dd, J=7.72, 1.84 Hz, 1 H) 8.90 (dd, J=4.41, 1.84 Hz, 1 H) 10.35 (s, 1 H) 14.09 (s, 1 H). MS (ESI−) m/z 532 (M−H)−.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([C:13]3[CH:14]=[C:15]([CH2:19][CH2:20][CH2:21]OS(C)(=O)=O)[CH:16]=[CH:17][CH:18]=3)[CH:10]=[C:9]([N:27]3[CH2:32][CH2:31][N:30]([C:33]4[C:38]([C:39]([F:42])([F:41])[F:40])=[CH:37][CH:36]=[CH:35][N:34]=4)[CH2:29][CH2:28]3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:43][NH:44][CH3:45]>C1COCC1>[CH3:43][N:44]([CH3:45])[CH2:21][CH2:20][CH2:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([C:11]2[CH:10]=[C:9]([N:27]3[CH2:32][CH2:31][N:30]([C:33]4[C:38]([C:39]([F:42])([F:41])[F:40])=[CH:37][CH:36]=[CH:35][N:34]=4)[CH2:29][CH2:28]3)[N:8]=[C:7]([N:1]3[CH2:2][CH2:3][O:4][CH2:5][CH2:6]3)[N:12]=2)[CH:14]=1
Reactant: CS(=O)(=O)OCCCc1cccc(-c2cc(N3CCN(c4ncccc4C(F)(F)F)CC3)nc(N3CCOCC3)n2)c1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)CCCc1cccc(-c2cc(N3CCN(c4ncccc4C(F)(F)F)CC3)nc(N3CCOCC3)n2)c1

Procedure:
Dissolve the crude methanesulfonic acid 3-(3-{2-morpholin-4-yl-6-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrimidin-4-yl}-phenyl)-propyl ester obtained above in THF and heat with an excess of dimethylamine in a sealed tube at 55° C. Concentrate under reduced pressure and partition the residue between aqueous NaHCO3 and EtOAc. Dry the organic layer (Na2SO4) and concentrate under reduced pressure. Purify the residue using preparative plate TLC (MeOH/DCM eluent) to afford the title compound. 1H NMR (CDCl3): δ 1.17 (m, 2H), 2.27 (s, 6H), 2.37 (t, 2H), 2.72 (t, 2H), 3.40 (m, 4H), 3.80 (m, 8H), 3.87 (m, 4H), 6.37 (s, 1H), 7.03 (m, 1H), 7.25 (d, 1H, J=7.1 Hz), 7.35 (dd, 1H), 7.79 (m, 2H), 7.89 (d, 1H, J=7.87 Hz), 8.46 (d, 1H).
Reaction SMILES: Br[CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4]>C(O)(=O)C.[Zn]>[F:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][CH2:2][C:3]([O:5][CH3:6])=[O:4])=[CH:13][CH:12]=1
Reactant: COC(=O)C(Br)Cc1ccc(F)cc1
Agent: [Zn]
Solvent: CC(=O)O
Product: COC(=O)CCc1ccc(F)cc1
Reaction time: 0.5 h

Procedure:
Crude methyl 2-bromo-3-(4-fluorophenyl)propionate in acetic acid (330 ml) was stirred and treated with zinc dust (32.75 g) in portions over 30 minutes. The mixture was stirred for an additional 30 minutes and filtered, and the filter cake was washed with acetic acid. After the filtrate was evaporated the residue was partitioned between methylene chloride and water to give crude methyl 3-(4-fluorophenyl)propionate, which was refluxed with aqueous sodium hydroxide (400 ml, 10%) for 2 hrs, cooled, treated with decolorizing carbon, and filtered. The filtrate was acidified with 5 N HCl and filtered. The filter cake was washed extensively with water to give 3-(4-fluorophenyl)propionic acid (20.0 g) as colourless crystals, mp 90° C.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][C:26]([F:29])([F:28])[F:27])[CH:13]=[N:12]2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:30][C:31]1([CH3:43])[O:35][C@H:34]([CH2:36][N:37]2[CH:41]=[CH:40][C:39]([NH2:42])=[N:38]2)[CH2:33][O:32]1>>[CH:1]1([CH2:6][CH:7]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][C:26]([F:28])([F:27])[F:29])[CH:13]=[N:12]2)[C:8]([NH:42][C:39]2[CH:40]=[CH:41][N:37]([CH2:36][C@@H:34]3[CH2:33][O:32][C:31]([CH3:43])([CH3:30])[O:35]3)[N:38]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC1(C)OC[C@@H](Cn2ccc(N)n2)O1
Reactant: O=C(O)C(CC1CCCC1)n1ncc(Oc2ccccc2OC(F)(F)F)cc1=O
Product: CC1(C)OC[C@@H](Cn2ccc(NC(=O)C(CC3CCCC3)n3ncc(Oc4ccccc4OC(F)(F)F)cc3=O)n2)O1

Procedure:
Using the method described in Example 49, 3-cyclopentyl-2-[6-oxo-4-(2-trifluoromethoxy-phenoxy)-6H-pyridazin-1-yl]-propionic acid (Intermediate 76) and 1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-ylamine (Intermediate 4) afforded 3-cyclopentyl-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-2-[6-oxo-4-(2-trifluoromethoxy-phenoxy)-6H-pyridazin-1-yl]-propionamide as an off-white foam as a mixture of diastereomers (1.37 g, 96%).
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[CH:10][C:5]2[N:6]=[C:7]([SH:9])[NH:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:20][O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29]Br.O>CN(C)C=O>[CH3:20][O:21][C:22](=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][S:9][C:7]1[NH:8][C:4]2[CH:3]=[C:2]([CH3:1])[C:11]([CH3:12])=[CH:10][C:5]=2[N:6]=1
Reactant: COC(=O)c1ccccc1CBr
Reactant: Cc1cc2nc(S)[nH]c2cc1C
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccccc1CSc1nc2cc(C)c(C)cc2[nH]1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 89.5 %

Procedure:
To the resulting 5,6-dimethylbenzimidazole-2-thiol (89 mg, 0.50 mmol) in dimethylformamide (2 ml), triethylamine (84 μl, 0.6 mmol) and 2-bromomethyl benzoic acid methyl ester (137 mg, 0.6 mmol) were added. After the resulting solution was stirred at 80° C. for 1.5 hours, water was added, followed by extraction with ethyl acetate. After drying the ethyl acetate phase with anhydrous magnesium sulfate, it was concentrated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain the title compound (146 mg, yield 90%). The compound was confirmed by identification of molecular weight using LC-MS. Calculated M=326.11, measured (M+H)+=327.2
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C([O-])([O-])=O.[K+].[K+].[CH2:20](Br)[CH:21]=[CH2:22].O>CN(C=O)C>[NH2:11][C:8]1[CH:9]=[CH:10][C:2]([F:1])=[C:3]([CH:7]=1)[C:4]([O:6][CH2:22][CH:21]=[CH2:20])=[O:5]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1F
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1cc(N)ccc1F

Procedure:
2-Fluoro-5-nitrobenzoic acid (4.16 g, 22.5 mM) was dissolved in DMF (45 ml), and anhydrous K2CO3 (4.65 g, 33.7 mM) added with stirring. Allyl bromide (2.38 ml, 28.1 mM) was run in, the mixture was stirred for 18 hours at ambient temperature before being poured into water (450 ml) and extracted with diethyl ether (3×100 ml). The combined extracts were dried over MgSO4, and evaporated to give a yellow oil (5.4 g). The oil was purified by chromatography on silica, eluting with a mixture of ethyl acetate/hexane (12.5:87.5), to give allyl 2-fluoro-5-nitrobenzoate (4.64 g, 92%). Nmr (CDCl3): δ 4.89 (d, 2H); 5.30-5.50 (m, 2H); 5.90-6.10 (m, 1H); 7.32 (t, 1H); 8.38-8.46 (m, 1H); 8.86 (dd, 1H).
Reaction SMILES: [CH:1]1[C:6]([C:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)=[C:8]([Cl:10])[Cl:9])=[CH:5][CH:4]=[C:3]([Cl:18])[CH:2]=1.[Cl:19]Cl>O>[CH:16]1[C:11]([CH:7]([C:8]([Cl:19])([Cl:10])[Cl:9])[C:6]2[CH:5]=[CH:4][C:3]([Cl:18])=[CH:2][CH:1]=2)=[CH:12][CH:13]=[C:14]([Cl:17])[CH:15]=1
Reactant: ClC(Cl)=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Reactant: ClCl
Solvent: O
Product: Clc1ccc(C(c2ccc(Cl)cc2)C(Cl)(Cl)Cl)cc1

Procedure:
Onto the p,p'-DDE obtained in Stage (b) 100 ml water is added, the mixture heated to 80° C.-85° C. and chlorine gas added over a period of 8-11 hours, until the concentration of p,p'-DDE drops to 0.2%. The upper aqueous phase is separated to afford 410 g p,p'-DDT, which was used directly in the next stage.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([C:18]([C:20]3[C:28]4[CH:27]=[N:26][CH:25]=[N:24][C:23]=4[NH:22][CH:21]=3)=[O:19])[CH:17]=2)=[O:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:36][C:37]([O:39][CH3:40])=[O:38]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[C:16]([C:18]([C:20]3[C:28]4[CH:27]=[N:26][CH:25]=[N:24][C:23]=4[N:22]([CH2:36][C:37]([O:39][CH3:40])=[O:38])[CH:21]=3)=[O:19])[CH:15]=[N:14][CH:13]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: COC(=O)CBr
Reactant: O=C(Cc1ccc(Cl)cc1)Nc1cncc(C(=O)c2c[nH]c3ncncc23)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1cc(C(=O)c2cncc(NC(=O)Cc3ccc(Cl)cc3)c2)c2cncnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 120.3 %

Procedure:
To a stirred solution of 2-(4-chlorophenyl)-N-[5-(7H-pyrrolo[2,3-d]pyrimidin-5-ylcarbonyl)pyridin-3-yl]acetamide (Example 308, 250 mg, 0.638 mmol) in DMF (4 mL) was added Cs2CO3 (374 mg, 1.15 mmol) followed by methyl bromoacetate (73 uL, 0.766 mmol). The reaction was stirred at 25° C. for 3 hours and then quenched with water (10 mL) and extracted with EtOAc (3×10 mL). The organics were combined, washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo to give a pale yellow oil (356 mg) which solidified on standing. Purification by column chromatography on silica gel (gradient of 0-100% 90:10:1 DCM/MeOH/NH3 in DCM) gave the title compound as a pale yellow solid in 70% yield, 208 mg. 1HNMR (400 MHz, CDCl3) δ 3.78 (s, 2H), 3.81 (s, 3H), 5.15 (s, 2H), 7.29-7.41 (m, 4H), 7.51 (s, 1H), 7.88 (s, 1H), 8.46 (m, 1H), 8.78-8.82 (m, 2H), 9.04 (s, 1H), 9.65 (s, 1H). LCMS (System 4): Rt=2.07 min; m/z 464 [M+H]+.
Reaction SMILES: CCN(CC)CC.[C:8]([O:12][C:13](=[O:29])[N:14]=[C:15]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])N1C=CC=N1)([CH3:11])([CH3:10])[CH3:9].[NH2:30][CH2:31][C:32]1([C:35]2[O:39][C:38]([CH:40]3[CH2:46][CH2:45][C@@H:44]4[CH2:47][N:41]3[C:42](=[O:56])[N:43]4[O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[N:37][N:36]=2)[CH2:34][CH2:33]1>CO>[C:25]([O:24][C:22]([N:21]=[C:15]([NH:14][C:13]([O:12][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:29])[NH:30][CH2:31][C:32]1([C:35]2[O:39][C:38]([CH:40]3[CH2:46][CH2:45][C@@H:44]4[CH2:47][N:41]3[C:42](=[O:56])[N:43]4[O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[N:37][N:36]=2)[CH2:33][CH2:34]1)=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Reactant: NCC1(c2nnc(C3CC[C@@H]4CN3C(=O)N4OCc3ccccc3)o2)CC1
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)OC(=O)N=C(NCC1(c2nnc(C3CC[C@@H]4CN3C(=O)N4OCc3ccccc3)o2)CC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.5 %

Procedure:
Et3N (5 g, 0.05 mol) and tert-butyl(((tert-butoxycarbonyl)amino)(1H-pyrazol-1-yl)methylene)carbamate (5.5 g, 17.5 mmol) were added to a solution of (5R)-2-(5-(1-(aminomethyl)cyclopropyl)-1,3,4-oxadiazol-2-yl)-6-(benzyloxy)-1,6-diaza-bicyclo[3.2.1]octan-7-one (7 g, 0.017 mol) in CH3OH (500 mL). The mixture was stirred at rt for 4 hrs and then concentrated. The residue was purified by silica gel column chromatography (gradient elution 50 to 66% EtOAc/petroleum ether) to afford (5R)-2-(5-(1-(2,3-bis-(tert-butoxycarbonyl)-guanidinomethyl)cyclopropyl)-1,3,4-oxadiazol-2-yl)-6-(benzyloxy)-1,6-diaza-bicyclo[3.2.1]octan-7-one (9 g, 86%) as a white solid. ESI-MS (EI+, m/z): 612.3 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([N+:15]([O-])=O)=[C:9]2[C:4]=1[C:5]([CH3:18])=[CH:6][CH:7]=[N:8]2>[Ni]>[NH2:15][C:10]1[CH:11]=[C:12]([O:13][CH3:14])[C:3]([O:2][CH3:1])=[C:4]2[C:9]=1[N:8]=[CH:7][CH:6]=[C:5]2[CH3:18]
Reactant: COc1cc([N+](=O)[O-])c2nccc(C)c2c1OC
Agent: [Ni]
Product: COc1cc(N)c2nccc(C)c2c1OC
Yield: 84 %

Procedure:
The nitro compound was reduced catalytically in ethanol-dioxane with use of Raney nickel. An 84% yield of 8-amino-5,6-dimethoxy-4-methylquinoline resulted. It could be crystallized from cyclohexane or from benzene-petroleum ether mixture; mp 108°-110° (softening at 103°).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:10][O:11][CH2:12][C:13]2[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=2[C:15](OC)=[O:16])=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC>[C:27]([O:26][C:24](=[O:25])[NH:23][CH:9]([CH2:10][O:11][CH2:12][C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[CH2:15][OH:16])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: COC(=O)c1ccccc1COCC(Cc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)NC(COCc1ccccc1CO)Cc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
To a solution of compound 3g (5 g, 10 mmol) in dry ether (80 mL) was added slowly LiAlH4 (1M in THF, 15.7 mL, 15.7 mmol) at 0° C. The mixture was stirred at 0° C. for 30 min. Then the mixture was quenched with water (1 mL) under vigorous stirring. The precipitate was removed by filtration and the filtrate was concentrated in vacuo to give 3h as a white solid (4.3 g, 92% yield).
Reaction SMILES: [F-:1].[K+].CS(O[CH2:8][CH2:9][O:10][CH2:11][CH2:12][N:13]([C:23](=[O:25])[CH3:24])[C:14]1[CH:19]=[C:18]([CH3:20])[C:17]([Br:21])=[C:16]([CH3:22])[CH:15]=1)(=O)=O>C(OCC)(=O)C>[Br:21][C:17]1[C:18]([CH3:20])=[CH:19][C:14]([N:13]([CH2:12][CH2:11][O:10][CH2:9][CH2:8][F:1])[C:23](=[O:25])[CH3:24])=[CH:15][C:16]=1[CH3:22]
Reactant: [F-]
Reactant: CC(=O)N(CCOCCOS(C)(=O)=O)c1cc(C)c(Br)c(C)c1
Agent: [K+]
Solvent: CCOC(C)=O
Product: CC(=O)N(CCOCCF)c1cc(C)c(Br)c(C)c1
Yield: 69.7 %

Procedure:
Potassium fluoride (180 mg, 3.11 mmol) was added to a solution of 2-[2-[acetyl-(4-bromo-3,5-dimethyl-phenyl)amino]ethoxy]ethyl methanesulfonate (254 mg, 0.622 mmol) in PEG200 (2 ml), and the mixture was irradiated with microwaves at 100° C. for 10 minutes. The reaction solution was diluted with ethyl acetate, and the organic layer was sequentially washed with water and saturated brine and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give N-(4-bromo-3,5-dimethyl-phenyl)-N-[2-(2-fluoroethoxy)ethyl]acetamide (144 mg, 70%).
Reaction SMILES: [CH3:1][C:2]([CH3:23])([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[N:18]=[CH:17][N:16]=[C:15](Cl)[C:14]=2[N+:20]([O-])=O)[CH2:9][CH2:8]1)=[O:6])[CH3:3].C(N(CC)CC)C.[H][H]>[Pd].C(O)C>[CH3:3][C:2]([CH3:23])([O:4][C:5]([N:7]1[CH2:8][CH2:9][N:10]([C:13]2[N:18]=[CH:17][N:16]=[CH:15][C:14]=2[NH2:20])[CH2:11][CH2:12]1)=[O:6])[CH3:1]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc(Cl)c2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(c2ncncc2N)CC1

Procedure:
A mixture of 1-[1,1-dimethylethoxycarbonyl]-4-[4-chloro-5-nitro-6-pyrimidyl]piperazine (PREPARATION 23, 0.56 g) and triethylamine (0.3 ml) and palladium on carbon (5%, 0.13 g) in ethanol (100 ml) is charged with hydrogen gas (30 psi). After the theoretical amount of hydrogen gas is consumed, the catalyst is removed under reduced pressure. The filtrate is concentrated under reduced pressure to a foam which is diluted with an aqueous saturated solution of potassium carbonate and dichloromethane. The phases are separated and the organic phase is dried over sodium sulfate and concentrated to give to give the title compound, NMR (CDCl3) 1.49, 3.49, 3.29, 3.56, 7.98, and 8.39 δ.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[NH:12][C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].O1CC[CH2:24][CH2:23]1.C(OC(OCC)N(C)C)C>O>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[N:12]([CH2:23][CH3:24])[C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C1CCOC1
Reactant: O=c1[nH]c(=O)n(-c2cccc([N+](=O)[O-])c2)c2ccccc12
Agent: CCOC(OCC)N(C)C
Solvent: O
Product: CCn1c(=O)c2ccccc2n(-c2cccc([N+](=O)[O-])c2)c1=O

Procedure:
A mixture of 2.8 g of 1-(m-nitrophenyl)quinazoline-2,4(1H, 3H)-dione, 40 ml of dry tetrahydrofuran and 4.4 g of N,N-dimethylformamide diethyl acetal was refluxed for 6 hours. After the reaction was complete, the solvent was distilled off from the reaction mixture under reduced pressure. To the residue obtained was added water to precipitate a crude product, which was then recrystallized from methanol to produce 2.8 g of 1-(m-nitrophenyl)- 3-ethylquinazoline-2,4(1H, 3H)-dione as colorless prisms, melting at 193°-194° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:18]=2O)[C:16]#[N:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:18]1[C:15]([C:16]#[N:17])=[CH:14][N:13]=[CH:12][C:11]=1[C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1ccc(-c2cncc(C#N)c2O)cc1OC
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc(-c2cncc(C#N)c2Cl)cc1OC
Temperature: 25 °C
Yield: 91 %

Procedure:
A solution of 5-(3,4-dimethoxyphenyl)-4-hydroxynicotinonitrile (4 g, 15.7 mmol) in phosphorus oxychloride (POCl3, 25 mL) was heated at 125° C. for 1.5 h, then cooled to r.t. and poured into an ice/3 N sodium hydroxide (NaOH)/EtOAc mixture. The mixture was stirred and the layers separated. The organic layer was dried over magnesium sulfate (MgSO4), filtered and concentrated to give 4-chloro-5-(3,4-dimethoxyphenyl)nicotinonitrile (3.9 g, 91%) as a brown solid.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[O:11])=[CH:5][CH:4]=1.CCN(CC)CC.CS([Cl:29])(=O)=O>>[Cl:29][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[O:11])=[CH:5][CH:4]=1
Reactant: O=C(Nc1ccc(CO)cc1)c1ccccn1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(CCl)cc1)c1ccccn1
Yield: 95.1 %

Procedure:
Reaction of Pyridine-2-carboxylic acid (4-hydroxymethyl-phenyl)amide (342 mg, 1.50 mmol), Et3N (262 μL, 1.80 mmol), and methanesulfonylchloride (128 μL, 1.65 mmol) for 2 h at reflux gave the title compound (352 mg, 95%) as a red solid. 1H NMR (300 MHz, CDCl3) δ 4.61 (s, 2H), 7.45 (d, 2H, J=8.4 Hz), 7.50 (ddd, 1H, J=7.5, 4.5, 0.9 Hz), 7.80 (d, 2H, J=8.7 Hz), 7.92 (ddd, 1H, J=7.8, 7.8, 1.6 Hz), 8.63 (d, 1H, J=6.0 Hz), 10.08 (br s, 1H).