Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]C1C=C([N+]([O-])=O)C=CC=1C(Cl)=O.BrC1C=C(C=CC=1C)C(Cl)=O.FC1C=CC=C(F)C=1C(Cl)=O.Cl[C:37]1[CH:45]=[CH:44][C:43]([Cl:46])=[CH:42][C:38]=1[C:39]([Cl:41])=[O:40].ClC1C=C(C=C(Cl)C=1)C(Cl)=O.C1(C(Cl)=O)C2C(=CC=CC=2)C=CC=1>>[Cl:46][C:43]1[CH:42]=[C:38]([CH:37]=[CH:45][C:44]=1[Cl:1])[C:39]([Cl:41])=[O:40]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1Cl
Reactant: O=C(Cl)c1cc(Cl)ccc1Cl
Agent: Cc1ccc(C(=O)Cl)cc1Br
Agent: O=C(Cl)c1c(F)cccc1F
Agent: O=C(Cl)c1cc(Cl)cc(Cl)c1
Product: O=C(Cl)c1ccc(Cl)c(Cl)c1

Procedure:
Similarly, substituting 2-chloro-4-nitrobenzoyl chloride, 3-bromo-4-methylbenzoyl chloride, 2,6-difluorobenzoyl chloride, 2,5-dichlorobenzoyl chloride, 3,5-dichlorobenzoyl chloride or naphthoyl chloride, for 3,4-dichlorobenzoyl chloride, yields respectively: 2-chloro-4-nitrobenzoic acid, 2-(tert)-butylhydrazide; 3-bromo-4-methylbenzoic acid, 2-(tert)-butylhydrazide; mp 95°-97° C.; 2,5-dichlorobenzoic acid, 2-(tert)-butylhydrazide and 3,5-dichlorobenzoic acid, 2-(tert)-butylhydrazide, mp 163°-165° C.; 1-naphthoic acid, 2-(tert)-butylhydrazide mp 148°-150° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[CH:8][C:9]([F:12])=[N:10][CH:11]=1.C([N-]C(C)C)(C)C.[Li+].[I:21]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>C1COCC1.O>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]([I:21])[C:9]([F:12])=[N:10][CH:11]=1
Reactant: Fc1ccc(C2OCCO2)cn1
Reactant: II
Agent: CC(C)[N-]C(C)C
Agent: O=S([O-])([O-])=S
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Fc1ncc(C2OCCO2)cc1I
Reaction time: 3 h
Yield: 60.3 %

Procedure:
Cool a solution of 5-[1,3]dioxolan-2-yl-2-fluoro-pyridine (2.0 g, 11.8 mmol) in THF (20 mL) to −75° C. Add lithium diisopropylamide (2 M in THF, 6 mL, 12 mmol) over a period of 30 min. Stir the mixture for an additional 3 hours. Add iodine (3.0 g, 11.8 mmol, dissolved in 100 mL of THF). Stir for 2 hours after the addition is complete. Add water (100 mL) to the mixture and allow the temperature to rise to room temperature over 1 hour while stirring. Treat the mixture with saturated aqueous sodium thiosulfate solution (50 mL). Extract the solution with ether. Concentrate the solution in vacuo to a brown oil. Purify by column chromatography (hexane to 20% ethyl acetate in hexane) to afford the title compound (2.1 g, 60%) as a yellow oil. MS (ES) m/z 296 [M+1]+.
Reaction SMILES: B(Cl)(Cl)Cl.C1[O:26][C:25]2[CH:24]=[CH:23][C:9]([CH2:10][NH:11][C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=4)[N:15]=[CH:14][N:13]=3)=[CH:8][C:7]=2[O:6]1.CO>C(Cl)Cl.C(Cl)(Cl)Cl>[OH:6][C:7]1[CH:8]=[C:9]([CH:23]=[CH:24][C:25]=1[OH:26])[CH2:10][NH:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=2)[N:15]=[CH:14][N:13]=1
Reactant: Clc1ccc2ncnc(NCc3ccc4c(c3)OCO4)c2c1
Agent: ClB(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: Oc1ccc(CNc2ncnc3ccc(Cl)cc23)cc1O
Temperature: 25 °C
Yield: 79.6 %

Procedure:
40 ml of a 1.0 M solution of boron trichloride in methylene chloride was dropped into a solution of 2.00 g (6.37 mmol) of 4-(3,4-methylenedioxybenzyl)amino-6-chloroquinazoline in 150 ml of chloroform under stirring at room temperature. The obtained mixture was stirred at room temperature for 2 days, followed by the addition of methanol, and the obtained mixture was distilled under a reduced pressure to remove the solvent. This procedure was repeated twice. The crystals thus precipitated were washed with methanol and recrystallized from ethanol to give 1.53 g of the title compound as a yellow crystal.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([N:8]2[C:13](=[O:14])[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:30][CH2:31][CH3:32])[N:10]3[N:33]=[CH:34][N:35]=[C:9]23)[CH2:4][CH2:3]1.[N+](=[C:38]([CH2:44][CH:45]=[CH2:46])[C:39]([O:41][CH2:42][CH3:43])=[O:40])=[N-]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Rh+2].C([O-])(=O)C>[C:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:12]2[C:13](=[O:14])[N:8]([C@H:5]3[CH2:6][CH2:7][C@H:2]([O:1][CH:38]([CH2:44][CH:45]=[CH2:46])[C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:3][CH2:4]3)[C:9]3[N:10]([N:33]=[CH:34][N:35]=3)[C:11]=2[CH2:30][CH2:31][CH3:32])=[CH:17][CH:18]=1)#[N:29]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ncnn12
Reactant: C=CCC(=[N+]=[N-])C(=O)OCC
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: C=CCC(O[C@H]1CC[C@H](n2c(=O)c(Cc3ccc(-c4ccccc4C#N)cc3)c(CCC)n3ncnc32)CC1)C(=O)OCC
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
A mixture of 4′-{[4-(trans-4-hydroxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (1.8 g), rhodium(II) acetate (dimer) (0.018 g) and toluene (20 mL) was heated to 80° C. under an argon atmosphere, a solution of ethyl 2-diazopent-4-enoate (3.7 g) in toluene (20 mL) was added dropwise, and the mixture was stirred at 80° C. for 10 min. A solution of ethyl 2-diazopent-4-enoate (3.7 g) in toluene (10 mL) was further added, and the mixture was stirred at 80° C. for 10 min. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.98 g, 41%).
Reaction SMILES: C([O:3][C:4](=[O:19])[C:5]1([CH3:18])[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)C.[OH-].[Na+]>C1COCC1.C(O)C.OS([O-])(=O)=O.[K+]>[C:14]([O:13][C:11]([N:8]1[CH2:9][CH2:10][C:5]([CH3:18])([C:4]([OH:19])=[O:3])[CH2:6][CH2:7]1)=[O:12])([CH3:17])([CH3:15])[CH3:16]
Reactant: CCOC(=O)C1(C)CCN(C(=O)OC(C)(C)C)CC1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C)(C(=O)O)CC1
Yield: 26.5 %

Procedure:
To a stirring solution of N-tert-butoxycarbonyl-4-methyl-isonipecotic acid ethyl ester (17.4 mmol, 4.73 g) in THF (50 mL) and ethanol (50 mL) was added 50% NaOH (50 mL) and the mixture heated to reflux overnight. The reaction was diluted with 10% KHSO4 (600 mL) and cone. H2 SO4 (5 mL) and extracted with ethyl acetate (2×250 mL). The organic layers were combined, washed with water (500 mL) and brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was triturated with diethyl ether:hexanes and filtered to give 1.12 g of an orange solid. The filtrates were evaporated to give 2.71 g of the title compound as an orange solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][CH:28]([CH2:30][C@H:31]([OH:35])[C:32](O)=[O:33])[CH3:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[CH:16]2[CH2:21][CH2:20][N:19]([C:32](=[O:33])[C@@H:31]([OH:35])[CH2:30][CH:28]([CH3:29])[CH3:27])[CH2:18][CH2:17]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C[C@H](O)C(=O)O
Reactant: CC(C)=CCN(c1ccc(OCc2ccccc2)cc1)C1CCNCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)=CCN(c1ccc(OCc2ccccc2)cc1)C1CCN(C(=O)[C@@H](O)CC(C)C)CC1
Reaction time: 3 h
Yield: 49.1 %

Procedure:
(4-Benzyloxy-phenyl)-(3-methyl-but-2-enyl)-piperidin-4-yl-amine (Ic) (0.89 g, 2.54 mmol) was dissolved in DMF (17 mL) and treated with N,N-diisopropyletbylamine (1.77 mL, 10.17 mmol), L-2-hydroxyisocaproic acid (0.34 g, 2.54 mmol), and HBTU (0.96 g, 2.54 mmol). The reaction was stirred for 3 hours, then diluted with EtOAc (200 mL), washed with saturated bicarbonate solution and brine, dried over Na2SO4, and concentrated. The residue was chromatographed on silica gel eluting with 4% MeOH/CH2Cl2 to give 0.58 g (49%) of the desired product.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:10]2[CH2:11][CH:12]([CH2:14][O:15]S(C3C=CC(C)=CC=3)(=O)=O)[O:13][C:9]=2[CH:8]=[C:7]([C:26](=[O:34])[NH:27][C:28]2[CH:32]=[CH:31][N:30]([CH3:33])[N:29]=2)[CH:6]=1)([CH3:3])[CH3:2].[CH3:35][CH2:36][O-].[Na+]>CCO>[CH3:33][N:30]1[CH:31]=[CH:32][C:28]([NH:27][C:26]([C:7]2[CH:6]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[C:10]3[CH2:11][CH:12]([CH2:14][O:15][CH2:35][CH3:36])[O:13][C:9]=3[CH:8]=2)=[O:34])=[N:29]1
Reactant: CC[O-]
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3c(OC(C)C)cc(C(=O)Nc4ccn(C)n4)cc3O2)cc1
Agent: [Na+]
Solvent: CCO
Product: CCOCC1Cc2c(OC(C)C)cc(C(=O)Nc3ccn(C)n3)cc2O1
Temperature: 50 °C
Yield: 36 %

Procedure:
To a solution of toluene-4-sulfonic acid 4-isopropoxy-6-(1-methyl-1H-pyrazol-3-ylcarbamoyl)-2,3-dihydro-benzofuran-2-ylmethyl ester (216a) (84 mg, 0.17 mmol) in anhydrous EtOH (2 mL) was added NaOEt (1.5 mL, 21% wt). The mixture was heated at 50° C. for 4 hr, then quenched with H2O and extracted with 3×EtOAc. The organic layers were washed with 2×H2O, dried over Na2SO4, and concentrated. The residue was purified by reverse phase HPLC to give a white glass (22 mg, 36% yield). 1H NMR (400 MHz, CDCl3) δ 8.99 (s, 1 H) 7.20-7.34 (m, 1 H) 7.02 (s, 1 H) 6.86 (dd, J=13.26, 1.64 Hz, 2 H) 4.92-5.09 (m, 1 H) 4.57-4.69 (m, 1 H) 3.78 (s, 3 H) 3.63-3.72 (m, 1 H) 3.54-3.62 (m, 3 H) 3.22 (dd, J=16.42, 9.60 Hz, 1 H) 2.92 (dd, J=16.29, 7.45 Hz, 1 H) 1.34 (dd, J=5.81, 1.77 Hz, 6 H) 1.23 (t, J=7.07 Hz, 3 H); LCMS for C19H25N3O4 m/z 360.20 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].Br[CH:13]([CH2:18][CH2:19][Br:20])[C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O>[CH3:17][O:16][C:14](=[O:15])[CH:13]([O:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([F:1])[CH:3]=1)[CH2:18][CH2:19][Br:20]
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Reactant: COC(=O)C(Br)CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(CCBr)Oc1ccc([N+](=O)[O-])c(F)c1
Reaction time: 3 h
Yield: 64 %

Procedure:
To the solution of 5.5 g (35.0 mmol) 3-fluoro-4-nitrophenol in 55 mL N,N-dimethylformamide, 11.8 g (45.5 mmol) methyl 2,4-dibromobutyrate and 6.3 g (45.5 mmol) potassium carbonate were added. After stirring for 3 h the reaction mixture was poured on ethyl acetate and 1 M aqueous hydrochloric acid and extracted. The organic phases were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by column chromatography on silica gel using an MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane:ethyl acetate (1:0 to 1:1 v/v) to afford the title compound as a light yellow oil (64%) which was pure enough to be used in the next step.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][CH:10]=2)[C:5]([N+:18]([O-])=O)=[CH:4][CH:3]=1>CO.[Pd]>[NH2:18][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][OH:17])=[CH:11][CH:10]=2)=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=1
Reactant: Cc1ccc([N+](=O)[O-])c(Nc2ccc(CCO)cc2)n1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(N)c(Nc2ccc(CCO)cc2)n1
Reaction time: 2 h
Yield: 92.4 %

Procedure:
To a solution of 2-{4-[(6-methyl-3-nitro-2-pyridinyl)amino]phenyl}ethanol (step 1, 4.6 g, 16.9 mmol) in methanol (100 mL) was added 10% Pd-C (300 mg). The resulting mixture was stirred for 2 h under hydrogen atmosphere. The mixture was filtered through a pad of Celite and the filtrate was concentrated. The residue was purified by flash column chromatography eluting with hexane/ethyl acetate (gradient elution from 1:2 to 1:5) to afford 3.8 g (92%) of the title compound as yellow solids: 1H-NMR (CDCl3) δ 7.10-7.16 (4H, m), 6.91 (1H, d, J=8.4 Hz), 6.70 (1H, d, J=8.4 Hz), 6.19 (1H, s), 3.83 (2H, t, J=6.4 Hz), 2.81 (2H, t, J=6.4 Hz), 2.35 (3H, s).
Reaction SMILES: Cl.[CH2:2]([S:9][C:10]([CH3:14])([CH3:13])[CH:11]=[O:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:16]/[C:17](=[CH:22]\[CH3:23])/[C:18](OC)=[O:19].[Cl-].[NH4+]>C1COCC1.[Zn]>[CH2:2]([S:9][C:10]([CH:11]1[O:12][C:18](=[O:19])[C:17](=[CH2:16])[CH:22]1[CH3:23])([CH3:14])[CH3:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C=O)SCc1ccccc1
Reactant: C/C=C(\CBr)C(=O)OC
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=C1C(=O)OC(C(C)(C)SCc2ccccc2)C1C
Temperature: 25 °C

Procedure:
To a stirred suspension of zinc dust (0.77 g) activated with hydrochloric acid in THF (20 ml), 2-benzylthio-2-methylpropionaldehyde (2.00 g) dissolved in THF (10 ml) and methyl 2-bromomethylcrotonate (2.19 g) dissolved in THF (10 ml) were added dropwise in the order named at about 30° C. under nitrogen atmosphere and ultrasonic irradiation. The mixture was stirred over night at room temperature. Saturated aqueous ammonium chloride solution was added to the mixture and the mixture was filtered by celite. A reaction product was extracted with ethyl acetate from the filtrate. The organic layer was washed with 1N hydrochloric acid, water and then saturated sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The oily residue was purified and separated by silica gel column chromatography to give the each titled compound.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:25]=[CH:24][C:13]([C:14]([NH:16][CH:17]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:15])=[C:12]([Cl:26])[CH:11]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][CH2:9][C:10]1[CH:25]=[CH:24][C:13]([C:14]([NH:16][CH:17]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:15])=[C:12]([Cl:26])[CH:11]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)NC2CCCCCC2)c(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCc1ccc(C(=O)NC2CCCCCC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.9 %

Procedure:
Dissolve 4-tert-butoxycarbonylaminomethyl-2-chloro-N-cycloheptyl-benzamide (624 mg, 1.6 mmol) in dichloromethane (30 mL) then add trifluoroacetic acid (2 mL). Stir the solution at room temperature under a nitrogen atmosphere for 1 h. Concentrate the mixture in vacuo. Purify the crude mixture by SCX chromatography to obtain the desired intermediate (395 mg, 85%). MS (ES+) m/z: 281.2 (M+H)+.
Reaction SMILES: O[CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:3]1=2.O.O.[C:23]1([S:29]([O-:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Na+].FC(F)(F)C(OC(=O)C(F)(F)F)=O>>[C:23]1([S:29]([CH:2]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[CH2:6][O:5][C:4]3[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:3]2=3)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1ccc2c(c1)C(O)c1ccccc1CO2
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Product: COC(=O)c1ccc2c(c1)C(S(=O)(=O)c1ccccc1)c1ccccc1CO2

Procedure:
Compound b, 10 g, 15 g of sodium benzenesulfinate dihydrate and 25 ml of trifluoroacetic anhydride were treated in a manner similar to Example 109 to give 14.3 g of the objective compound.
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([Cl:11])[S:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]=1.Cl.[C:15]12([NH2:25])[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH2:16]1)[CH2:22]2.C(N(CC)CC)C.C>C(O)C.[OH-].[Na+]>[C:15]12([NH:25][C:2]3[NH:7][C:6]4[CH:8]=[C:9]([Cl:11])[S:10][C:5]=4[S:4](=[O:13])(=[O:12])[N:3]=3)[CH2:22][CH:21]3[CH2:20][CH:19]([CH2:18][CH:17]([CH2:23]3)[CH2:16]1)[CH2:24]2
Reactant: O=S1(=O)N=C(Cl)Nc2cc(Cl)sc21
Reactant: NC12CC3CC(CC(C3)C1)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=S1(=O)N=C(NC23CC4CC(CC(C4)C2)C3)Nc2cc(Cl)sc21
Temperature: 120 °C
Reaction time: 41 h
Yield: 11 %

Procedure:
A mixture of 3,6-dichloro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide (1.0 g, 3.9 mmol), 1-adamantanamine hydrochloride (1.46 g, 7.8 mmol) and triethylamine (1.1 ml, 7.8 mmol) in ethanol (6 ml) was stirred for 41 h at 120° C. in a sealed flask. The cooled solution was concentrated in vacuo and the residue was stirred with water (50 ml) followed by adjustment to pH <2 with 4M hydrochloric acid. The resulting dark mass was isolated by decantation and then partly dissolved in hot 1N sodium hydroxide (50 ml) followed by treatment with decolourising charcoal. After filtration, the solution was acidified to pH <2 and the precipitate was filtered off and recrystallised from ethanol to give 160 mg (11%) of the title compound as a beige solid; mp 339-340° C.; 1H-NMR (DMSO-d6): δ1.64 (br s, 6H), 2.02 (br s, 6H), 2.06 (br s, 3H), 6.67 (br s, 1H), 7.10 (s, 1H), 10.55 (br s, 1H); MS: m/e 371/373 (M+); (C15H18ClN3O2S2) calc C, 48.44; H, 4.88; N, 11.30; found C, 48.27; H, 4.85; N, 11.15.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].[CH2:15]([O:17][C:18]([C:20]1([NH2:30])[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([F:29])[CH:26]=2)[CH2:21]1)=[O:19])[CH3:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH2:15]([O:17][C:18]([C:20]1([NH:30][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[C:13]([CH3:14])[C:5]=2[O:4][CH:1]([CH3:2])[CH3:3])[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([F:29])[CH:26]=2)[CH2:21]1)=[O:19])[CH3:16]
Reactant: CCOC(=O)C1(N)Cc2ccc(F)cc2C1
Reactant: Cc1cccc(C(=O)O)c1OC(C)C
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: CCOC(=O)C1(NC(=O)c2cccc(C)c2OC(C)C)Cc2ccc(F)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.2 %

Procedure:
To a solution of 2-isopropoxy-3-methyl-benzoic acid (400 mg, 2.06 mmol), 2-amino-5-fluoro-indan-2-carboxylic acid ethyl ester (554 mg, 2.47 mmol), HATU 1.17 g, 3.09 mmol) in anhydrous DMF (10 mL) is added DIPEA (511 μL, 3.09 mmol). The resulting solution is stirred at RT overnight. After the removal of DMF in vacuo, the residue is dissolved in EtOAc (100 mL) and washed with water (1×10 mL) and brine (2×10 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (120 g silica gel, gradient elution: 5%-50% EtOAc in heptane) to give a pure product (96) as white solid (709 mg, 86%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8](/[CH:21]=[CH:22]/[C:23]([O:25][CH3:26])=[O:24])[CH:9]=[CH:10][C:11]=1B1OC(C)(C)C(C)(C)O1)[CH2:2][CH2:3][CH3:4].Br[C:28]1[N:33]=[C:32]([N:34]([CH3:44])[C:35]([NH:37][C:38]2C=[CH:42][CH:41]=[CH:40][CH:39]=2)=[O:36])[CH:31]=[CH:30][CH:29]=1>CN(C)C=O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:5][C:6]1[CH:7]=[C:8](/[CH:21]=[CH:22]/[C:23]([O:25][CH3:26])=[O:24])[CH:9]=[CH:10][C:11]=1[C:28]1[CH:29]=[CH:30][CH:31]=[C:32]([N:34]([CH3:44])[C:35]([NH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[O:36])[N:33]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1cc(/C=C/C(=O)OC)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: CN(C(=O)Nc1ccccc1)c1cccc(Br)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: CN(C)C=O
Product: CCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C/C(=O)OC)cc2OCCCC)n1
Temperature: 90 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
496 mg of methyl(E)-3-[3-butoxy-4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)phenyl]acrylate are dissolved in 5 mL of dimethylformamide and 1 mL of 2N potassium phosphate solution. 350 mg of 1-(6-bromopyrid-2-yl)-1-methyl-3-phenylurea are added, along with 5 mg of palladium acetate and 16 mg of dicyclohexylbiphenylphosphine. The mixture is stirred for 3 hours at 90° C. and is then hydrolyzed and extracted with ethyl acetate. After evaporation of the solvents and chromatography on silica gel (eluent=7/3 heptane/ethyl acetate), 430 mg of methyl (E)-3-{3-butoxy-4-[6-(1-methyl-3-pentylureido)pyrid-2-yl]phenyl}acrylate are obtained. Yield=82%.
Reaction SMILES: [C:1]([BH3-])#[N:2].[Na+].Cl.CN.[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[C:15](=[O:21])[CH2:14][CH:13]2[CH2:22][CH:23]=O>CO>[CH3:8][O:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[C:15](=[O:21])[CH2:14][CH:13]2[CH2:22][CH2:23][NH:2][CH3:1]
Reactant: COc1ccc2c(c1)C(CC=O)CC(=O)N2C
Reactant: [BH3-]C#N
Agent: CN
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CNCCC1CC(=O)N(C)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 19 h

Procedure:
Sodium cyanoborohydride (1.2 g) was added to a solution of 10.0 g of methylamine hydrochloride and 4.6 g of 1,2,3,4-tetrahydro-6-methoxy-1-methyl-2-oxo-4-quinolineacetaldehyde in 142 ml of methanol. The solution was stirred at room temperature for 19 hours, quenched with 10% hydrochloric acid solution and extracted with ethyl acetate. The aqueous layer was basified with potassium hydroxide and the product extracted into ethyl acetate. The combined organic layers were washed with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated to an oil. Column chromatography on silica gel (elution with triethylamine-methanol-ethyl acetate) afforded 3,4-dihydro-6-methoxy-1-methyl-4-[2-(methylamino)ethyl]-2(1H)-quinolinone as a solid. To a solution of the amine in methanol was added ethereal hydrochloric acid to pH 1. The solvent was removed, and the residue recrystallized from isopropanol-diethyl ether to afford the hydrochloride salt, m.p. 175°-177° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.[Br:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[C:31]([C:36]([F:39])([F:38])[F:37])[CH:30]=1>C(OCC)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:15])[NH:33][C:32]1[CH:34]=[CH:35][C:29]([Br:28])=[CH:30][C:31]=1[C:36]([F:39])([F:37])[F:38])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccc(Br)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)Nc1ccc(Br)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (4 g, 18.6 mmol) was dissolved in 200 mL dry diethyl ether under Ar, cooled in an ice water bath, added dry pyridine (9 mL, 111 mmol) followed by the dropwise addition of oxalyl chloride (4.8 mL, 54 mmol). A precipitate forms immediately. The reaction was stirred vigorously at 0° C. for one hour, then at ambient temperature for one hour. Added 100 mL diethyl ether, filtered off solids washing with diethyl ether. Concentrated the filtrates to an off white oil. Redissolved (2 g, 8.5 mmol) oil in 40 mL dry DCM under Ar, cooled to 0° C., added 2.8 mL pyridine followed by 4-bromo-2-trifluoromethylaniline (2.05 g, 8.6 mmol). The reaction was allowed to warm to ambient temperature, stirred overnight then concentrated. Redissolved in 100 mL EtOAc, washed with 1 N HCl (3×50 mL), brine (100 mL), dried with MgSO4, filtered and concentrated to yield title compound. (1.98 g, 53%) APCI (AP−): 435.0, 437.0 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:10]C(OC)=O)=[N:6][C:7]=1[O:8][CH3:9].C([O-])(O)=[O:16].[Na+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:10][OH:16])=[N:6][C:7]=1[O:8][CH3:9]
Reactant: COC(=O)Cc1ccc(Br)c(OC)n1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COc1nc(CO)ccc1Br

Procedure:
step d—A solution of 52c (0.060 g), 5% aq. NaHCO3 (2 mL) and MeOH (2 mL) was heated at reflux for 2 h. The reaction mixture was partitioned between H2O and EtOAc and the combined EtOAc extracts were dried, filtered and evaporated in vacuo. The crude product was purified by SiO2 chromatography eluting with 25% EtOAc/hexane to afford 50a.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)([O-:3])=[O:2].[Cl:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][C:28]=1[F:29]>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:25]4[CH:26]=[CH:27][C:28]([F:29])=[C:23]([Cl:22])[CH:24]=4)=[CH:17][C:15]=3[N:16]=2)[C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: COc1ccc([N+](=O)[O-])cc1-c1nc2cc(Br)ccc2o1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Product: COc1ccc([N+](=O)[O-])cc1-c1nc2cc(-c3ccc(F)c(Cl)c3)ccc2o1

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-6-methoxyphenyl)-5-bromobenzoxazole (400 mg, 1.14 mmol) and 3-chloro-4-fluorophenylboronic acid (299 mg, 1.71 mmol) the subtitle compound was obtained (277 mg, 47%). The product was used directly in the next step without purification