Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(=C)C[O:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[C:8]([O:10][CH3:11])=[O:9]>ClCCl>[OH:4][C:5]1[C:6]([CH2:8][C:7]([CH3:12])=[CH2:6])=[C:7]([CH:12]=[CH:13][C:14]=1[N+:15]([O-:17])=[O:16])[C:8]([O:10][CH3:11])=[O:9]
Reactant: C=C(C)COc1cc(C(=O)OC)ccc1[N+](=O)[O-]
Solvent: ClCCl
Product: C=C(C)Cc1c(C(=O)OC)ccc([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 115 %

Procedure:
Methyl 3-(2-methylallyloxy)-4-nitro-benzoate 4a (4.52 g, 18 mmol) was heated to 190° C. and stirred for 3 hours. The reaction mixture was cooled down to room temperature followed by the addition of 50 mL of dichloromethane. The reaction solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound methyl 3-hydroxy-2-(2-methylallyl)-4-nitro-benzoate 4b (2.60 g, yield: 57.7%) as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:6]([NH:17][C:18](=[O:36])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:21][CH:20]=2)[CH:5]=1)([O-])=O>C(O)C.O1CCCC1.[C].[Pd]>[NH2:1][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:6]([NH:17][C:18](=[O:36])[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:21][CH:20]=2)[CH:5]=1
Reactant: CCOC(=O)COc1ccc([N+](=O)[O-])cc1NC(=O)c1ccc(OCCCCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(N)cc1NC(=O)c1ccc(OCCCCc2ccccc2)cc1
Yield: 65.2 %

Procedure:
To a mixture of 2.81 g of ethyl 4-nitro-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetate obtained in Example 26 in 50 ml of ethanol-tetrahydrofuran (1:1) was added 0.5 g of 10% palladium-carbon. Catalytic reduction was performed at room temperature under normal pressure until absorption of hydrogen was discontinued. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The obtained crystals were washed with isopropyl alcohol to obtain 1.72 g of ethyl 4-amino-2-[p-(4-phenylbutoxy)benzamido]phenoxyacetate.
Reaction SMILES: [CH3:1][NH2:2].[CH:3]1([C@H:6]([NH:8][C:9]2[C:10]3[N:11]([CH:18]=[C:19]([C:21]4[O:22][C:23](SC)=[N:24][N:25]=4)[CH:20]=3)[N:12]=[CH:13][C:14]=2[C:15]([NH2:17])=[O:16])[CH3:7])[CH2:5][CH2:4]1>>[CH:3]1([C@H:6]([NH:8][C:9]2[C:10]3[N:11]([CH:18]=[C:19]([C:21]4[O:22][C:23]([NH:2][CH3:1])=[N:24][N:25]=4)[CH:20]=3)[N:12]=[CH:13][C:14]=2[C:15]([NH2:17])=[O:16])[CH3:7])[CH2:5][CH2:4]1
Reactant: CN
Reactant: CSc1nnc(-c2cc3c(N[C@H](C)C4CC4)c(C(N)=O)cnn3c2)o1
Product: CNc1nnc(-c2cc3c(N[C@H](C)C4CC4)c(C(N)=O)cnn3c2)o1
Temperature: 200 °C
Reaction time: 0.42 h
Yield: 50.5 %

Procedure:
Methylamine (2 mL, 16 mmol, 8.0M solution in ethanol) was added in one portion to (R)-4-(1-cyclopropylethylamino)-6-(5-(methylthio)-1,3,4-oxadiazol-2-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide (7 mg, 0.018 mmol). The resulting mixture was heated in the CEM microwave at 200° C. for 1 hour. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×250 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10 mM NH4OAc; Mobile Phase B: 95:5 acetonitrile:water with 10 mM NH4OAc; Gradient: 0-100% B over 25 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound (3.1 mg). 1H NMR (500 MHz, MeOD) δ 8.15 (s, 1H), 7.98 (d, J=1.5 Hz, 1H), 7.26 (d, J=2.0 Hz, 1H), 4.07-3.78 (m, 1H), 3.10 (s, 3H), 1.50-1.36 (m, 3H), 1.19-1.04 (m, 1H), 0.70-0.48 (m, 2H), 0.43-0.23 (m, 2H). HPLC (method H) retention time=1.04 min. M+H=341.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([O:13]C)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([OH:13])=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(=O)/C=C/c1cc(Cl)cc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)/C=C/c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (E)-methyl 3-(3,5-dichlorophenyl)acrylate (step 1) (2 g, 8.66 mmol) in THF (35 ml) was added 2M NaOH (12.98 ml, 26.0 mmol) and the reaction mixture was stirred at RT overnight. The solvent was removed under reduced pressure and the residue was dissolved in water and washed with EtOAc. The aqueous portion was acidified to pH 4 using 1M HCl and extracted with DCM. The organic portion was dried using a phase separating column and the solvent removed under reduced pressure to afford the title compound as a white solid;
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:17])[C:6]([C:15]#[N:16])=[C:7](O)[CH:8]([CH2:11][S:12][CH3:13])[CH2:9][CH3:10])[CH2:2][CH3:3].O=P(Cl)(Cl)Cl.C([N:25](CC)CC)C>C(Cl)Cl>[NH2:25]/[C:7](/[CH:8]([CH2:11][S:12][CH3:13])[CH2:9][CH3:10])=[C:6](/[C:15]#[N:16])\[C:5]([O:4][CH2:1][CH2:2][CH3:3])=[O:17]
Reactant: CCCOC(=O)C(C#N)=C(O)C(CC)CSC
Reactant: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCCOC(=O)/C(C#N)=C(\N)C(CC)CSC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
15 g (58.3 mmol) of n-propyl-2-cyano-3-hydroxy-4-[(methyl-sulfanyl)methyl]-2-hexenoate were dissolved in CH2Cl2, and 18 g (0.12 mmol) of POCl3 were added. At 0° C., 24 g (237 mmol) of triethylamine were then added dropwise, and the mixture was stirred at 25° C. for 2 h. The reaction solution was concentrated and the residue was dissolved in acetonitrile. At 0° C., 50 ml (650 mmol) of 25% strength ammonia solution were then added dropwise to this solution, and the mixture was stirred for 1 h.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][CH3:16].[H-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH2:9]([O:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:14][CH2:15][CH3:16])=[CH:12][CH:11]=1)[CH3:10]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCOc1ccc(C(=O)OCC)cc1
Yield: 90.8 %

Procedure:
(Scheme 1, Compound A) To a solution of ethyl 4-hydroxybenzoate (2.0 g, 12 mmol) and bromopropane (4.0 g, 32.8 mmol) in DMF (50 mL) was added NaH (60% in mineral oil, 0.80 g, 20.8 mmol). The resultant suspension was stirred at room temperature for 1.0 hour. The mixture was diluted with ethyl acetate (EtOAc) (300 mL), washed with H2O, and then was dried over Na2SO4. After filtration and concentration in vacuo, the residue was purified by flash chromatography (SiO2: EtOAc/Hexanes). This compound was obtained as a yellow oil (2.26 g, 10.9 mmol, 91% yield). 1H NMR (DMSO-d6) δ 7.89 (d, 2H, J=8.7 Hz), 7.00 (d, 2H, J=9.0 Hz), 4.24 (q, 2H, J=6.9 Hz), 3.98 (t, 2H, J=6.6 Hz), 1.72 (m, 2H), 1.29 (t, 3H, J=6.6 Hz), 0.97 (t, 3H, J=7.2 Hz); Anal. Calcd for C12H16O3.0.47C6H14: C, 71.54; H, 9.14; N, 0.00. Found: C, 71.57; H, 8.78; N, 0.00; Mass Spec.: 209.04 (MH+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]=[C:8]([Cl:19])[N:9]=[C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH2:20][CH2:21][C:22]([CH3:25])([OH:24])[CH3:23]>>[Cl:19][C:8]1[N:9]=[C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:11]2[N:12]=[C:3]([CH2:2][NH:20][CH2:21][C:22]([CH3:25])([OH:24])[CH3:23])[CH:4]=[CH:5][C:6]=2[N:7]=1
Reactant: CC(C)(O)CN
Reactant: Clc1nc(N2CCOCC2)c2nc(CBr)ccc2n1
Product: CC(C)(O)CNCc1ccc2nc(Cl)nc(N3CCOCC3)c2n1

Procedure:
4-(6-(Bromomethyl)-2-chloropyrido[3,2-d]pyrimidin-4-yl)morpholine 7 (0.3 g) was reacted with 1-amino-2-methylpropan-2-ol via General Procedure B to afford quantitative yield of 1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methylamino)-2-methylpropan-2-ol.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:62])[CH2:5][N:6]([C:8](=[O:61])[C@@H:9]([NH:25][C:26](=[O:60])[C@@H:27]([NH:52]C(OC(C)(C)C)=O)[CH2:28][CH2:29][CH2:30][NH:31]/[C:32](/[NH2:51])=[N:33]\[S:34]([C:37]1[C:38]([CH3:50])=[C:39]([CH3:49])[C:40]2[O:44][C:43]([CH3:46])([CH3:45])[CH2:42][C:41]=2[C:47]=1[CH3:48])(=[O:36])=[O:35])[CH2:10][N:11]([CH3:24])[S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22])(=[O:14])=[O:13])[CH3:7])[CH3:2].Cl>C(Cl)Cl.O1CCOCC1>[CH2:1]([O:3][C:4](=[O:62])[CH2:5][N:6]([C:8](=[O:61])[C@@H:9]([NH:25][C:26](=[O:60])[C@@H:27]([NH2:52])[CH2:28][CH2:29][CH2:30][NH:31]/[C:32](/[NH2:51])=[N:33]\[S:34]([C:37]1[C:38]([CH3:50])=[C:39]([CH3:49])[C:40]2[O:44][C:43]([CH3:45])([CH3:46])[CH2:42][C:41]=2[C:47]=1[CH3:48])(=[O:35])=[O:36])[CH2:10][N:11]([CH3:24])[S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22])(=[O:14])=[O:13])[CH3:7])[CH3:2]
Reactant: CCOC(=O)CN(C)C(=O)[C@H](CN(C)S(=O)(=O)c1ccccc1[N+](=O)[O-])NC(=O)[C@H](CCCN/C(N)=N\S(=O)(=O)c1c(C)c(C)c2c(c1C)CC(C)(C)O2)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOC(=O)CN(C)C(=O)[C@H](CN(C)S(=O)(=O)c1ccccc1[N+](=O)[O-])NC(=O)[C@@H](N)CCCN/C(N)=N\S(=O)(=O)c1c(C)c(C)c2c(c1C)CC(C)(C)O2
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
Compound E (7.4 g, 8.2 mmol) in DCM (24 mL) was treated with 4 M HCl in dioxane (24 mL) at ambient temperature. The reaction mixture was stirred at ambient temperature for 1 h. DCM and most of the dioxane were removed in vacuo to a total volume of ˜15 mL, and Et2O (300 mL) was added. Precipitated product was filtered off, washed with Et2O (150 mL) and hexane and finally dried in vacuo to afford compound F (6.34 g, 100% yield) as a cream solid. LC-MS [M+H] 811.4 (C34H50N8O11S2+H, calc: 811.94). Purity >95% (UV/254 nm). Compound F was used without further purification.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([C:13]1[CH:18]=[N:17][N:16]2[CH:19]=[C:20]([C:22]3[CH:23]=[N:24][N:25]([CH2:27][C:28](O)=[O:29])[CH:26]=3)[CH:21]=[C:15]2[C:14]=1[NH:31][C@H:32]1[C@@H:36]([CH3:37])[CH2:35][N:34]([C:38]2[CH:43]=[CH:42][C:41]([C:44]#[N:45])=[CH:40][N:39]=2)[CH2:33]1)(=[O:12])[NH2:11].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[F:71][C:72]1([F:76])[CH2:75][NH:74][CH2:73]1>>[C:44]([C:41]1[CH:42]=[CH:43][C:38]([N:34]2[CH2:35][C@H:36]([CH3:37])[C@H:32]([NH:31][C:14]3[C:15]4[N:16]([CH:19]=[C:20]([C:22]5[CH:23]=[N:24][N:25]([CH2:27][C:28]([N:74]6[CH2:75][C:72]([F:76])([F:71])[CH2:73]6)=[O:29])[CH:26]=5)[CH:21]=4)[N:17]=[CH:18][C:13]=3[C:10]([NH2:11])=[O:12])[CH2:33]2)=[N:39][CH:40]=1)#[N:45]
Reactant: FC1(F)CNC1
Reactant: C[C@H]1CN(c2ccc(C#N)cn2)C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3cnn(CC(=O)O)c3)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(c2ccc(C#N)cn2)C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3cnn(CC(=O)N4CC(F)(F)C4)c3)cc12
Reaction time: 2.5 h
Yield: 17.8 %

Procedure:
Hunig's base (0.014 mL, 0.079 mmol) was added to a stirred solution of crude 2-(4-(3-carbamoyl-4-(((3S,4S)-1-(5-cyanopyridin-2-yl)-4-methylpyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazin-6-yl)-1H-pyrazol-1-yl)acetic acid (20 mg, from Step 2) and HATU (20.05 mg, 0.053 mmol). After 2.5 h at room temperature, 3,3-difluoroazetidine hydrochloride (6.83 mg, 0.053 mmol) was added. After 40 min at room temperature, the reaction was complete. The crude material was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×200 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 5-100% B over 15 minutes, then a 7-minute hold at 100% B; Flow: 25 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to give the title compound (4.1 mg). 1H NMR (500 MHz, chloroform-d/methanol-d4) δ ppm 8.31 (br. s., 1H), 8.07 (s, 1H), 7.89 (s, 1H), 7.82 (s, 1H), 7.75 (d, J=1.5 Hz, 1H), 7.63 (dd, J=8.9, 1.5 Hz, 1H), 6.99 (d, J=1.5 Hz, 1H), 6.49 (d, J=8.9 Hz, 1H), 4.99-4.91 (m, 3H), 4.46 (t, J=11.9 Hz, 2H), 4.39 (t, J=11.9 Hz, 2H), 3.94 (br. s., 2H), 3.41 (br. s., 1H), 2.84 (br. s., 1H), 1.29 (d, J=6.9 Hz, 3H); MS (ES+) m/z: 561.1 (M+H); LC retention time: 1.24 min (analytical LCMS Method I).
Reaction SMILES: C[O:2][C:3]1[N:8]=[C:7]([O:9]C)[C:6]([C:11]2[O:15][C:14]([C:16](=[O:29])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:13][CH:12]=2)=[CH:5][N:4]=1>CCOC(C)=O>[C:23]1([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:16]([C:14]2[O:15][C:11]([C:6]3[C:7](=[O:9])[NH:8][C:3](=[O:2])[NH:4][CH:5]=3)=[CH:12][N:13]=2)=[O:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COc1ncc(-c2cnc(C(=O)CCCCCCc3ccccc3)o2)c(OC)n1
Solvent: CCOC(C)=O
Product: O=C(CCCCCCc1ccccc1)c1ncc(-c2c[nH]c(=O)[nH]c2=O)o1
Yield: 71.6 %

Procedure:
The title compound was prepared from 1-(5-(2,4-dimethoxypyrimidin-5-yl)oxazol-2-yl)-7-phenylheptan-1-one (15 mg, 0.038 mmol) following General Procedure H. Flash chromatography (EtOAc) yielded the title compound as a white solid (10 mg, 71%): 1H NMR (CDCl3, 400 MHz) δ 7.90 (s, 1H), 7.71 (s, 1H), 7.28-7.24 (m, 2H), 7.18-7.14 (m, 3H), 2.99 (t, J=7.5 Hz), 2.52 (t, 2H, J=7.8 Hz), 1.67 (quint, 2H, J=7.3 Hz), 1.55 (quint, 2H, J=7.4 Hz), 1.33-1.31 (m, 4H); 13C NMR (CDCl3, 100 MHz) δ 188.8, 160.9, 155.4, 150.6, 147.4, 142.5, 139.0, 128.2, 128.0, 126.0, 125.4, 102.6, 38.6, 35.6, 31.1, 28.8, 28.8, 23.8; MALDI-FTMS m/z 368.1613 (M+H+, C20H21N3O4, requires 368.1610).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7](N)=[C:8]([C:20]#[N:21])[C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:12][CH:11]=1)=[O:4].[I:23]CI.N(OCCC(C)C)=O>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([I:23])=[C:8]([C:20]#[N:21])[C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:12][CH:11]=1)=[O:4]
Reactant: ICI
Reactant: COC(=O)c1sc(N)c(C#N)c1-c1ccc(C(C)(C)C)cc1
Agent: CC(C)CCON=O
Solvent: CC#N
Product: COC(=O)c1sc(I)c(C#N)c1-c1ccc(C(C)(C)C)cc1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
Combine 5-amino-3-(4-tert-butyl-phenyl)-4-cyano-thiophene-2-carboxylic acid methyl ester (0.29 mmol) in acetonitrile and add diiodomethane (1.02 mmol) and iso-amyl nitrite (0.73 mmol) and heat to 100° C. After 15 minutes, cool the reaction slowly to room temperature and stir an additional 1 hour. Concentrate the reaction to a dark oil which is purified by radial chromatography on a 2000 micron silica plate eluting with 50/50 methylene chloride/hexane and then 100% methylene chloride. Concentrate desired fractions were to give the title compound. 1H NMR (400 MHz, CDCl3) δ 7.41 (m, 4H), 3.78 (s, 3H), 1.37 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16])\[CH3:7])[CH3:2].[Br:18]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:17])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[Cl:16])\[CH2:7][Br:18])[CH3:2]
Reactant: CCOC(=O)/C=C(\C)Oc1ccc(Cl)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)/C=C(\CBr)Oc1ccc(Cl)cc1Cl
Yield: 65.2 %

Procedure:
To a stirred mixture of (E)-3-(2,4-dichloro-phenoxy)-but-2-enoic acid ethyl ester (4.00 g, 0.015 mol) in carbon tetrachloride (25 mL) under a nitrogen atmosphere was added N-bromosuccinimide (2.32 g, 0.013 mol) and benzoyl peroxide (280 mg, 0.001 mol). Nitrogen gas was bubbled through the mixture for 5 min, and the resulting mixture was heated to reflux for 4 h. The reaction mixture was then placed in the refrigerator overnight. The solids formed were removed by filtration and the filtrate concentrated in vacuo. The crude product obtained was purified using flash column chromatography (silica gel (100-200 mesh), ethyl acetate/hexanes) to afford (E)-4-bromo-3-(2,4-dichloro-phenoxy)-but-2-enoic acid ethyl ester (3.00 g, 58%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([OH:6])=O.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.[I-].[CH2:49]([N+:53]1[N:57]=[C:56]([CH3:58])[S:55][C:54]=1[CH3:59])[CH2:50][CH2:51][CH3:52]>>[CH2:49]([N:53]1[N:57]=[C:56]([CH3:58])[S:55]/[C:54]/1=[CH:59]\[C:4]([C:3]1[CH:7]=[C:8]([C:11]([F:14])([F:13])[F:12])[CH:9]=[CH:10][C:2]=1[F:1])=[O:6])[CH2:50][CH2:51][CH3:52]
Reactant: CCCC[n+]1nc(C)sc1C
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)c1cc(C(F)(F)F)ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 2-fluoro-5-(trifluoromethyl)benzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.92 (t, 3 H) 1.26-1.37 (m, 2 H) 1.72-1.79 (m, 2 H) 2.50 (s, 3 H) 4.19 (t, 2 H) 6.47 (s, 1 H) 7.50-7.58 (m, 1 H) 7.87-7.93 (m, 1 H) 8.09-8.12 (m, 1 H); MS (ESI) m/z 361 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]1[C:10]2[C:5](=[C:6]([C:11]3[N:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=4)[C:21]#[N:22])[O:13][N:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[CH3:37][S:38]([CH:41]=[CH2:42])(=[O:40])=[O:39]>CC(N(C)C)=O>[CH:25]([O:24][C:19]1[CH:18]=[CH:17][C:16]([C:14]2[O:13][N:12]=[C:11]([C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:5]=3[CH2:4][CH2:3][C@H:2]4[NH:1][CH2:42][CH2:41][S:38]([CH3:37])(=[O:40])=[O:39])[N:15]=2)=[CH:23][C:20]=1[C:21]#[N:22])([CH3:27])[CH3:26]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4N)no2)cc1C#N
Reactant: C=CS(C)(=O)=O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4NCCS(C)(=O)=O)no2)cc1C#N
Temperature: 80 °C

Procedure:
To a solution of (R)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 49 (18 mg, 0.05 mmol) in DMA (0.5 mL) was added DIEA (87 μL, 0.5 mmol) and methylvinylsulfone (53 mg, 0.5 mmol). The reaction was heated to 80° C. for 24 h. The crude reaction mixture was purified by preparative HPLC to give (R)-2-isopropoxy-5-(3-(1-((2-(methylsulfonyl)ethyl)amino)-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)benzonitrile 125. LCMS-ESI (m/z) calculated for C24H26N4O4S: 466.2; found 467.1 [M+H]+, tR=2.58 min. 1H NMR (400 MHz, CDCl3) δ 8.41 (d, J=2.1 Hz, 1H), 8.32 (dd, J=8.9, 2.2 Hz, 1H), 8.07 (d, J=7.6 Hz, 1H), 7.47 (d, J=7.5 Hz, 1H), 7.37 (t, J=7.6 Hz, 1H), 7.10 (d, J=9.0 Hz, 1H), 4.77 (hept, J=6.1 Hz, 1H), 4.33 (t, J=6.7 Hz, 1H), 3.44 (ddd, J=17.5, 8.7, 4.8 Hz, 1H), 3.36-3.10 (m, 5H), 3.03 (s, 3H), 2.57-2.43 (m, 1H), 1.98-1.83 (m, 1H), 1.46 (d, J=6.1 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 173.04, 168.94, 162.76, 146.05, 143.49, 134.11, 133.92, 128.24, 127.03, 126.83, 123.28, 116.84, 115.33, 113.58, 103.88, 72.76, 63.05, 55.41, 42.42, 40.86, 32.98, 31.86, 21.75. Compound 126 was made in an analogous fashion.
Reaction SMILES: [Mg].C(I)C.C([C:7]1([OH:21])[CH2:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[S:10][C:9]2[S:18][CH:19]=[CH:20][C:8]1=2)C>CCOCC>[S:18]1[C:9]2[S:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[CH2:13][C:7](=[O:21])[C:8]=2[CH:20]=[CH:19]1
Reactant: CCC1(O)Cc2ccccc2Sc2sccc21
Agent: [Mg]
Solvent: CCOCC
Solvent: CCI
Product: O=C1Cc2ccccc2Sc2sccc21

Procedure:
From 4.9 g (0.2 mole) of magnesium, 31.2 g (0.2 mole) of ethyl iodide in abs. ether and 23.2 g (0.1 mole) of benzo[f]thieno[2,3-b]thiepin-4(5H)-one, there is obtained 4-ethyl-4,5-dihydro-benzo[f]thieno[2,3-b]thiepin-4-ol as an oily crude product.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:10](=[O:12])[NH:9][C:8](=[O:13])[N:7]([CH3:14])[C:6]=2[N:5]=[CH:4]1)[CH3:2].Br[CH2:16][CH2:17][CH2:18][P:19]([O:24][CH2:25][CH3:26])(=[O:23])[O:20][CH2:21][CH3:22]>>[CH2:1]([N:3]1[C:11]2[C:10](=[O:12])[N:9]([CH2:16][CH2:17][CH2:18][P:19](=[O:23])([O:24][CH2:25][CH3:26])[O:20][CH2:21][CH3:22])[C:8](=[O:13])[N:7]([CH3:14])[C:6]=2[N:5]=[CH:4]1)[CH3:2]
Reactant: CCOP(=O)(CCCBr)OCC
Reactant: CCn1cnc2c1c(=O)[nH]c(=O)n2C
Product: CCOP(=O)(CCCn1c(=O)c2c(ncn2CC)n(C)c1=O)OCC

Procedure:
The title substance was prepared from 0.041 mol of 7-ethyl-3-methyl-xanthine and 0.049 mol of diethyl 3-bromopropanephosphonate analogously to Example 32.
Reaction SMILES: [CH:1]([N:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:14]3[N:15]=[N:16][N:17]([C:20]4[C:21]([F:26])=[N:22][CH:23]=[CH:24][CH:25]=4)[C:18]=3[CH3:19])[CH:10]=2)[C:5]1=[O:27])([CH3:3])[CH3:2].[H][H]>[C].[Pd].C(O)C>[CH:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:14]3[N:15]=[N:16][N:17]([C:20]4[C:21]([F:26])=[N:22][CH:23]=[CH:24][CH:25]=4)[C:18]=3[CH3:19])[CH:10]=2)[C:5]1=[O:27])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: Cc1c(-c2ccc3c(=O)n(C(C)C)ccc3c2)nnn1-c1cccnc1F
Agent: [Pd]
Solvent: CCO
Product: Cc1c(-c2ccc3c(c2)CCN(C(C)C)C3=O)nnn1-c1cccnc1F
Yield: 69.6 %

Procedure:
30 mg of palladium carbon was added to 10 ml of ethanol solution with 10 mg of 4-(2-isopropyl-1-oxo-isoquinoline-6-yl)-1-(2-fluoropyridine-3-yl)-5-methyl-1H-[1,2,3]triazole, and hydrogen was added under 4 atm of hydrogen pressure. 8 hours later, the reaction solution was filtrated and after distilling out the solvents of the filtrate under reduced pressure, the residues were separated and purified by thin-layer chromatography (chloroform/methanol=10/1) to obtain 7 mg of the above compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl[CH:18]([C:24]([CH3:26])=[O:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C)C=O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH:18]([C:24](=[O:25])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(OC(=O)c1ccc(Cl)cc1)C(C)=O
Temperature: 80 °C
Yield: 94.3 %

Procedure:
A solution of 15.65 g (0.1 mol) of 4-chlorobenzoic acid in 20 ml of dimethylformamide was added dropwise to a stirred suspension of 5.3 g (0.05 mol) of anhydrous sodium carbonate in 80 ml of dimethylformamide. The suspension was heated at 80° C. for 1 hour and a solution of 16.46 g (0.1 mol) of ethyl 2-chloroacetoacetate in 10 ml of dimethylformamide was added. The suspension was heated at 80° C. for 6 hours and left to cool overnight. The solvent was removed by evaporation under reduced pressure and the residue was partitioned between 400 ml of water and 300 ml of diethyl ether. The organic phase was separated and washed twice with 300 ml of water. The organic phase was dried over magnesium sulphate, filtered and the solvent was removed by evaporation under reduced pressure to yield 26.86 g (94%) of ethyl 2-(4-chlorobenzoyloxy)-3-oxo-butyrate in the form of an oil which was homogeneous according to thin-layer chromatography.