Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11]3)[CH2:9][N:8]([C:19](=[O:40])[NH:20][C:21]3[S:22][C:23]([S:26][CH2:27][CH2:28][N:29]4C(=O)C5C(=CC=CC=5)C4=O)=[CH:24][N:25]=3)[C:5]2=[CH:6][CH:7]=1.O.NN>C(O)C>[NH2:29][CH2:28][CH2:27][S:26][C:23]1[S:22][C:21]([NH:20][C:19]([N:8]2[C:5]3[C:4](=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:10]3([CH2:14][CH2:13][N:12]([C:15]([O:17][CH3:18])=[O:16])[CH2:11]3)[CH2:9]2)=[O:40])=[N:25][CH:24]=1
Reactant: COC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(SCCN3C(=O)c4ccccc4C3=O)s1)c1ccc(Cl)cc12
Agent: NN
Solvent: O
Solvent: CCO
Product: COC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(SCCN)s1)c1ccc(Cl)cc12
Temperature: 90 °C
Reaction time: 3 h
Yield: 45.5 %

Procedure:
Methyl 5-chloro-1-((5-((2-(1,3-dioxoisoindolin-2-yl)ethyl)thio)thiazol-2-yl)carbamoyl)spiro[indoline-3,3′-pyrrolidine]-1′-carboxylate (56 mg, 0.094 mmol) was dissolved in ethanol (3 mL). Thereafter, hydrazine monohydrate (0.007 mL, 0.14 mmol) was added to the above obtained solution, and the thus obtained mixture was then stirred at 90° C. for 3 hours. Thereafter, insoluble matters were removed by filtration, and the reaction solution was then concentrated in vacuo. The obtained residue was purified by preparative thin-layer column chromatography (chloroform:saturated ammonium methanol=10:1) to obtain the captioned compound (20 mg, 46%) in the form of a white solid.
Reaction SMILES: [C:1]1([S:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14]([C@:17]([C@H:21]([C@@H:30]([C@@H:39]([CH2:41][O:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[OH:40])[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([OH:20])C=O)(=[O:16])C.[OH-].[Na+]>C1COCC1.CO>[C:8]1([S:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1.[CH2:23]([O:22][C@@H:21]([C@@H:30]([C@@H:39]([CH2:41][O:42][CH2:43][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[OH:40])[O:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C@@H:17]([OH:20])[CH:14]=[O:16])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(=O)[C@](O)(C=O)[C@@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](O)COCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Agent: c1ccc(Sc2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Product: O=C[C@H](O)[C@@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](O)COCc1ccccc1
Reaction time: 8 h
Yield: 93 %

Procedure:
To a solution of (CXII) (802 mg, 1.37 mmol) in 10 mL of THF is added MeOH (20 mL) and 12 drops of a saturated methanolic solution of NaOH. The reaction is stirred overnight then diluted with 150 mL of MeOH. Amberlite acidic resin is added and the reaction is stirred for 10 minutes. Litmus paper indicates that the pH is neutral and the resin is filtered off. The filtrate is concentrated in vacuo and the residue is purified by flash chromatography (20% EtOAc/petroleum ether to give 654 mg (93%) of the β sulfide (CXIII), and 49 mg (7%) of the a sulfide as white solids. Rf(β)=0.20 (15% EtOAc/petroleum ether) Rf(α)=0.13 (15% EtOAc/petroleum ether); 1H NMR (β) (CDCl3, 500 MHz) δ 7.25-7.63 (m, 20H), 4.87-4.98 (m, 3H), 4.55-4.68 (m, 4H), 3.85 (dd, J=11.0, 1.5 Hz, 1H), 3.79 (dd, J=10.5, 4.5 Hz, 1H), 3.63-3.68 (m, 2H), 3.54-3.60 (m, 2H), 2.50 (s, 1H, free OH); 13C NMR (β) (CDCl3, 500 MHz) δ 139.2, 139.0, 138.8, 133.6, 132.6, 129.7, 129.3, 129.2, 129.1, 128.8, 128.7, 128.5, 128.4, 128.3.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.C[O:16][B:17](OC)[O:18]C.[OH-].[Na+]>C1COCC1.CCCCCC>[CH3:9][S:8][C:5]1[CH:6]=[CH:7][C:2]([B:17]([OH:18])[OH:16])=[CH:3][CH:4]=1
Reactant: CSc1ccc(Br)cc1
Reactant: COB(OC)OC
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CSc1ccc(B(O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
Under nitrogen, a stirred solution of 30 g (150 mmol of 4-bromothioanisole (Aldrich) in 1500 mL of anhydrous THF at -78° C. was treated with 180 mmol of n-butyllithium in hexane. After 30 minutes, 51 mL (450 mmol) of trimethylborate was added neat and the reaction was allowed to warm to ambient temperature overnight. A solution of 300 mL of 10% NaOH was added and the mixture stirred vigorously for 1 hour. The solvent was removed in vacuo, the pH adjusted to 4-5, and the product collected by filtration. Repeated washings with hexane and water provided 21 g (83%) of 4-methylthiophenylboronic acid (21 in Synthetic Scheme VII when R5 =SCH3 and R3, R4, R6, and R7 =H) as a colorless solid: NMR (DHSO-d6) δ 2.47 (s, 3H), 7.20 (d, J=8 Hz, 2H), 7.71 (d, J=8 Hz, 2H), 7.96 (br s, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:36]=[CH:35][CH:34]=[CH:33][C:3]=1[O:4][C:5]1[CH2:9][N:8]([CH:10]([CH2:27][C:28]([F:31])([F:30])[F:29])[C:11]([NH:13][C:14]2[CH:18]=[CH:17][N:16]([CH2:19][C@@H:20]3[CH2:24][O:23]C(C)(C)[O:21]3)[N:15]=2)=[O:12])[C:7](=[O:32])[CH:6]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:1][C:2]1[CH:36]=[CH:35][CH:34]=[CH:33][C:3]=1[O:4][C:5]1[CH2:9][N:8]([CH:10]([CH2:27][C:28]([F:31])([F:29])[F:30])[C:11]([NH:13][C:14]2[CH:18]=[CH:17][N:16]([CH2:19][C@@H:20]([OH:21])[CH2:24][OH:23])[N:15]=2)=[O:12])[C:7](=[O:32])[CH:6]=1
Reactant: CC1(C)OC[C@@H](Cn2ccc(NC(=O)C(CC(F)(F)F)N3CC(Oc4ccccc4Cl)=CC3=O)n2)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: O=C(Nc1ccn(C[C@@H](O)CO)n1)C(CC(F)(F)F)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.5 %

Procedure:
In a round bottom flask was placed 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1-H-pyrazol-3-yl]-4,4,4-trifluoro-butyramide (164 mg, 0.31 mmol), methanol (5 mL) and p-toluenesulfonic acid monohydrate (15 mg). The mixture was stirred at 25° C. for 16 h and then concentrated in vacuo with silica gel (1.3 g). Purification by Biotage flash chromatography (Aspire column, 100% ethyl acetate to 5% methanol/ethyl acetate) afforded 2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-N-[1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-4,4,4-trifluoro-butyramide (116 mg, 77%) as a white foam: HR-ES-MS m/z calculated for C20H20N4O5ClF3 [M+H]+ 489.1147, observed 489.1148; 1H NMR (300 MHz, DMSO-d6) δ ppm 2.80-3.13 (m, 2H), 3.20-3.32 (m, 2H), 3.70-3.81 (m, 1H), 3.87 (dd, J=13.4, 7.5 Hz, 1H), 4.10 (dd, J=13.4, 3.9 Hz, 1H), 4.38 (s, 2H), 4.72 (t, J=5.6 Hz, 1H), 4.84 (s, 1H), 4.95 (d, J=5.4 Hz, 1H), 5.18 (dd, J=9.4, 3.9 Hz, 1H), 6.43 (d, J=2.1 Hz, 1H), 7.31-7.41 (m, 1H), 7.42-7.53 (m, 2H), 7.56 (d, J=2.1 Hz, 1H), 7.65 (d, J=8.2 Hz, 1H), 10.92 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:15])[N:12]([CH3:14])[N:13]=2)=[CH:4][CH:3]=1.Br[CH2:17][CH2:18][CH2:19][Cl:20].C([O-])([O-])=O.[K+].[K+]>CC#N>[Cl:20][CH2:19][CH2:18][CH2:17][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:15])[N:12]([CH3:14])[N:13]=2)=[CH:4][CH:3]=1
Reactant: ClCCCBr
Reactant: Cn1nc(-c2ccc(O)cc2)ccc1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cn1nc(-c2ccc(OCCCCl)cc2)ccc1=O

Procedure:
Phenol from step 3 (500 mg, 2.3 mmol), 3-bromo-1-chloropropane (720 mg, 4.6 mmol) and K2CO3 (950 mg) in CH3CN (25 mL) was stirred at reflux 20 h. The reaction was filtered and concentrated. The resulting oil was dissolved in Et2O, and washed with water, NaCl solution, dried (MgSO4) and concentrated. The product was triturated with Et2O-hexanes to yield 580 mg (91%) mp 186-187° C. 1H NMR (DMSO-d6) δ 2.2 (t, 2H), 3.7 (s, 3H), 3.8 (t, 2H), 4.15 (t, 2H), 7.0-7.1 (m, 3H), 7.8 (d, 2H), 8.0 (d, 1H). MS m/z=279 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:27]2[N:31]([CH3:32])[CH:30]=[N:29][CH:28]=2)[O:10][CH2:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[C:20]2[CH:25]=[CH:24][C:23](=[O:26])[NH:22][CH:21]=2)=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].[CH3:35][CH2:36][CH2:37]Br>CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:27]2[N:31]([CH3:32])[CH:30]=[N:29][CH:28]=2)[O:10][CH2:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=2[C:20]2[CH:25]=[CH:24][C:23](=[O:26])[N:22]([CH2:35][CH2:36][CH3:37])[CH:21]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Cn1cncc1C(OCc1ccc(C#N)cc1-c1ccc(=O)[nH]c1)c1ccc(C#N)cc1
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1cc(-c2cc(C#N)ccc2COC(c2ccc(C#N)cc2)c2cncn2C)ccc1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 35 %

Procedure:
A solution of Example 91F (27.3 mg, 0.0648 mmol) in DMF (2 mL) at 0° C. was treated with NaH (60%, 3.1 mg, 0.0777 mmol), stirred for 15 minutes, and treated with n-propyl bromide (11.8 μL, 0. 130 mmol). The mixture was slowly warmed to room temperature and stirred for about 18 hours. The mixture was quenched with saturated NH4Cl and extracted with ethyl acetate. The combined extracts were dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography with 10:0.2:0.02 to 10:1:0.1 ethyl acetate/methanol/NH4OH to provide 10.5 mg (35%) of the desired product. MS.(HR-FAB) m/z calculated: 464.2087 (M+H)+; observed: 464.2078 (M+H)+; 1H NMR (CDCl3) δ 7.67 (d, 1H), 7.59 (d, 1H), 7.53 (d, 1H), 7.47-7.44 (m, 3H), 7.26-7.24 (m, 3H), 6.96 (s, 1H), 6.60-6.58 (m, 1H), 5.58 (s, 1H), 4.50 (q, 2H), 3.86 (t, 2H), 3.33 (s, 3H), 1.80-1.74 (m, 2H), 0.94 (t, 3H).
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH2:11][CH2:10]1)=O)(C)(C)C>C(OCC)(=O)C>[ClH:1].[F:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:15][CH:12]2[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]2)=[CH:21][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2ccc(F)cc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Fc1ccc(CC2CCNCC2)cc1
Temperature: 25 °C

Procedure:
A solution of 4N hydrogen chloride in ethyl acetate (100 ml) was added to 1-tert-butoxycarbonyl-4-(4-fluorobenzyl)piperidine (39.9 g) and the solution was stirred for an hour at room temperature. The reaction mixture was concentrated under reduced pressure, then diethyl ether was added thereto. The resulting precipitate was collected by filtration, washed with diethyl ether, and dried under reduced pressure to give the title compound (30.1 g).
Reaction SMILES: Cl[C:2]([O:4][CH:5]([CH3:7])[CH3:6])=[O:3].N1C=CC=CC=1.[CH2:14]([OH:17])[CH2:15][OH:16]>C(Cl)Cl>[C:2](=[O:3])([O:4][CH:5]([CH3:7])[CH3:6])[O:16][CH2:15][CH2:14][OH:17]
Reactant: OCCO
Reactant: CC(C)OC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)OC(=O)OCCO
Temperature: 25 °C
Reaction time: 15 h
Yield: 42 %

Procedure:
To a stirred solution of isopropyl chloroformate (2 g, 0.016 mol.) in 10 mL of DCM at 0° C. under nitrogen atmosphere was added pyridine (3.8 mL, 0.048 mol) and then ethylene glycol (2.7 mL, 3 eq). The progress of the reaction was monitored by thin layer chromatography (TLC). After stirring for 15 hrs at room temperature. After removing the solvent under reduce pressure, the residue was purified by silica gel column chromatography to give 2-hydroxyethyl isopropyl carbonate as a colorless oil (0.5 g, 42% yield). 1HNMR (400 MHz, CDCl3): δ 1.22 (t, J=7.2 Hz, 3H); 2.94 (sbroad, 1H); 3.78 (t, J=4.4 Hz, 2H); 4.18 (t, J=4.4 Hz, 2H); 4.07 (q, J=7.2H, 2H).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:14]=[CH:13][C:8]2[S:9]C(=O)[O:11][C:7]=2[CH:6]=1)[CH:2]=[CH2:3].C1COCC1>[OH-].[Na+]>[CH2:1]([O:4][C:5]1[CH:14]=[CH:13][C:8]([SH:9])=[C:7]([OH:11])[CH:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1ccc2sc(=O)oc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=CCOc1ccc(S)c(O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-(Allyloxy)-1,3-benzoxathiol-2-one (48.3 g, 0.232 mol) was dissolved in aq. NaOH solution (2M, 300 ml) and THF (300 ml) to give a yellow solution which stirred at RT for 2 h. The THF was removed in vacuo, a small amount of precipitated starting material removed by filtration, and further starting material was removed by extraction of the aqueous phase into diethyl ether (3×300 ml). The aqueous phase was then acidified to pH 1 with cHCl (˜150 ml) with ice-cooling. Gas evolution was observed, and after 15 min, the title compound was obtained following extraction into diethyl ether (3×300 ml), drying over MgSO4 and concentration to a yellow oil (37.84 g, 0.18 mol).
Reaction SMILES: N[C:2]1[C:11]2[C:6](=[CH:7][C:8](OC)=[C:9](OC)[CH:10]=2)[N:5]=[C:4](N2CCNCC2)[N:3]=1.C(N(CC)CC)C>C(COC)OC>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:2]=[N:3][CH:4]=1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: c1ccc2ncncc2c1

Procedure:
In accordance with the foregoing reaction scheme, a 4-nitrophenylalkanoic acid (1) is reacted with phosphorous trichloride, such as by heating at reflux in a suitable solvent, to obtain the corresponding acid chloride (2). The latter is reacted with 4-amino-6,7-dimethoxy-2-(1-piperazinyl) quinazoline (3) and triethyl amine (TEA) in dimethoxy ethane (DME) to obtain the 4-amino-6,7-dimethoxy-2-[4-[4-nitrophenyl]-alkanoyl)-1-piperazinyl] quinazoline intermediate (4). The 4-nitrophenyl intermediate (4) is then subjected to catalytic hydrogenation, such as in the presence of a palladium-on-carbon (Pd/C) catalyst, to obtain the desired 4-aminophenyl product (5).
Reaction SMILES: [F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[I:9]N1C(=O)CCC1=O>CN(C=O)C>[F:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([I:9])[N:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Nc1cccnc1F
Solvent: CN(C)C=O
Product: Nc1ccc(I)nc1F
Reaction time: 8 h

Procedure:
To a solution of 2-fluoropyridin-3-amine (5.00 g, 44.60 mmol) in DMF (100 mL) was added N-iodosuccinimide (11.04 g, 49.06 mmol). The resulting mixture was stirred overnight. The reaction mixture was partitioned between EtOAc and water. The organic layer was dried with MgSO4 and concentrated. The residue was purified on silica eluted 0 to 50% EtOAc in Heptane. 2-fluoro-6-iodopyridin-3-amine was obtained as a dark tan solid (8.8674 g, 83%). To an ice cooled mixture of tert-Butyl nitrite (356.8 uL, 3.000 mmol) and Copper(II) bromide (536.0 mg, 2.400 mmol) in Acetonitrile (5 mL) was added 2-fluoro-6-iodopyridin-3-amine was obtained as a dark tan solid (476.0 mg, 2.000 mmol). The resulting mixture was stirred overnight allowing warming to room temperature. The mixture was filtered through Celite. The filtrated was concentrated. The residue was partitioned between Et2O and saturated NH4Cl. The organic layer was dried with MgSO4, and then concentrated. The residue was purified on silica eluted with 0 to 20% EtOAc in Heptane. 3-Bromo-2-fluoro-6-iodopyridine was obtained as a yellow solid (407.1 mg, 57%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH:19]3[CH:23]([O:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:22]([CH2:32][S:33][C:34]4[S:35][CH:36]=[CH:37][N:38]=4)[O:21][C:20]3=[O:39])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C[O:41]C1C=CC(C2C=CC(S(NC(C(OCC3C=CC=CC=3)C3OC3)C(OC)=O)(=O)=O)=CC=2)=CC=1.C1C=CC=CC=1.C(N(CC)CC)C.SC1SC=CN=1>C(OCC)(=O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][CH:19]([CH:23]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:22]([OH:41])[CH2:32][S:33][C:34]3[S:35][CH:36]=[CH:37][N:38]=3)[C:20]([OH:21])=[O:39])(=[O:16])=[O:17])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)C(NS(=O)(=O)c1ccc(-c2ccc(OC)cc2)cc1)C(OCc1ccccc1)C1CO1
Reactant: COc1ccc(-c2ccc(S(=O)(=O)NC3C(=O)OC(CSc4nccs4)C3OCc3ccccc3)cc2)cc1
Agent: Sc1nccs1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccc(S(=O)(=O)NC(C(=O)O)C(OCc3ccccc3)C(O)CSc3nccs3)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-[(4′-Methoxy[1,1′-biphenyl]-4-yl)sulfonyl]amino-2-oxo-4-phenylmethoxy-5-[[(2-thiazolyl)thio]methyl]-tetrahydrofuran: The methyl 2-[(4′-methoxy[1,1′-biphenyl]-4-yl)sulfonyl]amino-3-phenylmethoxy-4,5-epoxypentanoate 63e (285 mg, 0.558 mmol) is dissolved in benzene/triethylamine (2.5 mL, 0.101 mmol) and 2-mercaptothiazole (164 mg, 1.40 mmol) is added. The resulting mixture is then stirred at room temperature for four hours. The mixture is diluted with ethyl acetate and water and extracted with ethyl acetate (3 times). The organic layer is washed with water and brine, then dried over magnesium sulfate and concentrated to a clear oil. The crude material is adsorbed onto silica and purified over a silica column eluting with ethyl acetate/hexane (2/8) followed with ethyl acetate/hexane (1/1). Product fractions are combined and the solvent is removed in vacuo to give the desired product as a clear oil.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:7](=[O:18])[CH:6]3[CH2:19][O:20][CH2:21][CH2:22][N:5]3[C:4]=2[N:3]=1.[CH:23]1([NH:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33](B3OC(C)(C)C(C)(C)O3)=[CH:32][CH:31]=2)=[O:28])[CH2:25][CH2:24]1.C(=O)(O)[O-].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:23]1([NH:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([C:2]3[N:11]=[CH:10][C:9]4[N:8]([CH:12]5[CH2:17][CH2:16][O:15][CH2:14][CH2:13]5)[C:7](=[O:18])[CH:6]5[CH2:19][O:20][CH2:21][CH2:22][N:5]5[C:4]=4[N:3]=3)=[CH:32][CH:31]=2)=[O:28])[CH2:25][CH2:24]1
Reactant: O=C1C2COCCN2c2nc(Cl)ncc2N1C1CCOCC1
Reactant: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: O=C(Nc1ccc(-c2ncc3c(n2)N2CCOCC2C(=O)N3C2CCOCC2)cc1)NC1CC1
Temperature: 100 °C
Yield: 22.8 %

Procedure:
To a microwave reaction vial were added 2-chloro-5-(tetrahydro-2H-pyran-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (PREPARATION x55, 0.040 g, 0.123 mmol), 1-cyclopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (0.041 g, 0.135 mmol), and PdCl2(dppf) (0.018 g, 0.025 mmol) in saturated aq sodium bicarbonate (0.3 mL, 0.123 mmol) and dioxane (1.232 mL). The resulting suspension was heated by microwave irradiation at 100° C. for 1 hour, then filtered, and purified by preparatory HPLC using a 20-30% CH3CN gradient in H2O (with 0.05% TFA). The fractions were combined, concentrated in vacuo, and lyophilized to give the title compound as a white solid (13 mg, 23%). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.45-0.62 (m, 2H), 0.71-0.86 (m, 2H), 1.66-1.82 (m, 2H), 2.55-2.84 (m, 3H), 3.17-3.40 (m, 2H), 3.46-3.78 (m, 4H), 4.07 (td, J=12.19, 4.17 Hz, 3H), 4.30-4.46 (m, 2H), 4.55 (dd, J=10.61, 3.79 Hz, 1H), 4.96 (dd, J=13.64, 1.77 Hz, 2H), 7.67 (d, J=8.84 Hz, 2H), 8.01-8.26 (m, 3H); ESI-MS m/z [M+H]+ calc'd for C24H28N6O4, 465.2. found 465.4.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]#[N:8])=[C:5]([N+:9]([O-])=O)[C:4]([CH3:12])=[N:3]1>CO.[Ni]>[CH3:1][N:2]1[C:6]([C:7]#[N:8])=[C:5]([NH2:9])[C:4]([CH3:12])=[N:3]1
Reactant: Cc1nn(C)c(C#N)c1[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: Cc1nn(C)c(C#N)c1N

Procedure:
Two-hundred and seventy-two g of 1,3-dimethyl-4-nitro-5-cyano-pyrazole was subjected to catalytic hydrogenation in methanol using a Raney nickel catalyst. The catalyst was filtered away and the filtrate concentrated. The product solidified, mp 109°-111° C.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([C:8](OCC)=[O:9])[C:5](=[O:13])[C:4]2[CH:14]=[C:15]([CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[S:16][C:3]1=2.[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1>C1(C)C=CC=CC=1>[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:30][C:8]([C:6]2[C:5](=[O:13])[C:4]3[CH:14]=[C:15]([CH2:17][N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)[S:16][C:3]=3[N:2]([CH3:1])[CH:7]=2)=[O:9])=[CH:27][CH:26]=1
Reactant: NCc1ccc(F)cc1
Reactant: CCOC(=O)c1cn(C)c2sc(CN3CCOCC3)cc2c1=O
Solvent: Cc1ccccc1
Product: Cn1cc(C(=O)NCc2ccc(F)cc2)c(=O)c2cc(CN3CCOCC3)sc21
Yield: 50 %

Procedure:
A mixture of ethyl 7-methyl-2-(4-morpholinylmethyl)-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylate (0.300 g) from Preparation No. 4 and 4-fluorobenzylamine (1.02 mL) is stirred at 175° C. for 3 h. The reaction mixture is allowed to cool for several minutes and is then diluted with toluene (15 mL). The resulting off-white precipitate is filtered off and recrystallized from acetonitrile then ethanol to yield 0.184 g (50%) of the title compound as a white, crystalline solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33](=[O:54])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:45]=[CH:44][N:43]=[C:42]([CH2:46][O:47][CH:48]3[CH2:53][CH2:52][CH2:51][CH2:50][O:49]3)[CH:41]=2)[CH:35]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:18])([F:17])[F:19])[C:11]([C:20]([F:22])([F:23])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33](=[O:54])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[CH:45]=[CH:44][N:43]=[C:42]([CH2:46][O:47][CH:48]3[CH2:53][CH2:52][CH2:51][CH2:50][O:49]3)[CH:41]=2)[CH:35]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(COC3CCCCO3)c2)c1
Product: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccnc(COC3CCCCO3)c2)c1

Procedure:
The title compound was prepared from [2-amino-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J6) (374 mg, 1.0 mmol) and (RS)-3-oxo-3-{3-[2-(tetrahydro-pyran-2-yloxymethyl)-pyridin-4-yl]-phenyl}-propionic acid tert-butyl ester (Example K40) (412 mg, 1.0 mmol) according to the general procedure M. Obtained as a light brown solid (500 mg, 70%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].Br[CH2:9][CH2:10][CH2:11][Cl:12]>CC(C)=O>[Cl:12][CH2:11][CH2:10][CH2:9][N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: ClCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: ClCCCN1CCCC1
Yield: 56.6 %

Procedure:
Pyrrolidine (10 g, 0.14 mol), acetone (28 ml), 5M NaOH solution (21 ml) and 1-bromo-3-chloropropane (24.4 g, 0.15 mol) were stirred together under N2 for 8 hours. The organic layer was separated and concentrated in vacuo. The crude product was purified by vacuum distillation (b.p. 90° C./30 mbar) to give the title compound (11.7 g, 57%) as a colourless oil.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]=1[OH:17])(=[O:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:24](Br)[CH:25]=[CH2:26].CCOCC>CN(C=O)C>[C:1]([C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:7]=[CH:6][C:5]=1[O:17][CH2:26][CH:25]=[CH2:24])(=[O:3])[CH3:2]
Reactant: C=CCBr
Reactant: CC(=O)c1cc(Oc2ccccc2)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C=CCOc1ccc(Oc2ccccc2)cc1C(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Acetyl-4-phenoxyphenol (4.22 g, 18.5 mmol) and cesium carbonate (15.0 g, 46.0 mmol) are taken in DMF (50 mL) and treated with allyl bromide (2.24 g, 18.5 mmol). The mixture is stirred overnight at room temperature. Ether is added and the mixture is washed with saturated aqueous ammonium chloride solution. The organic phase is dried over magnesium sulfate and evaporated to give 2-acetyl-1-allyloxy-4-phenoxybenzene as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C1C(=O)N([Br:20])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:12][C:9]1[CH:10]=[CH:11][C:2]([F:1])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(C)ccc1F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(CBr)ccc1F

Procedure:
To a solution of methyl 2-fluoro-5-methylbenzoate (17.16 g, 102.1 mmol) in CCl4(250 mL) is added NBS (18.2 g, 102.1 mmol) and AIBN (0.83 g, 5.1 mmol), and the resulting solution is refluxed for 3 hours. After cooling, the mixture is filtered through celite, evaporated, and chromatographed (silica, 5 to 15% EtOAc/hexane) to yield methyl 5-bromomethyl-2-fluorobenzoate, as a white solid.