Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Cl)(Cl)Cl.C([NH:9][S:10]([C:13]1[S:14][C:15]([C:18]2[N:23]=[C:22]([NH:24][C:25]3[CH:29]=[C:28]([CH:30]4[CH2:32][CH2:31]4)[NH:27][N:26]=3)[C:21]([C:33]#[CH:34])=[C:20]([CH3:35])[N:19]=2)=[CH:16][CH:17]=1)(=[O:12])=[O:11])(C)(C)C>C(Cl)Cl>[CH:30]1([C:28]2[CH:29]=[C:25]([NH:24][C:22]3[C:21]([C:33]#[CH:34])=[C:20]([CH3:35])[N:19]=[C:18]([C:15]4[S:14][C:13]([S:10]([NH2:9])(=[O:12])=[O:11])=[CH:17][CH:16]=4)[N:23]=3)[NH:26][N:27]=2)[CH2:32][CH2:31]1
Reactant: C#Cc1c(C)nc(-c2ccc(S(=O)(=O)NC(C)(C)C)s2)nc1Nc1cc(C2CC2)[nH]n1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: C#Cc1c(C)nc(-c2ccc(S(N)(=O)=O)s2)nc1Nc1cc(C2CC2)n[nH]1
Reaction time: 0.5 h
Yield: 87.4 %

Procedure:
BCl3 (1 M in CH2Cl2, 2.5 mL, 2.5 mmol, 5 eq) was added to a stirred solution of N-tert-butyl-5-(4-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-ethynyl-6-methyl pyrimidin-2-yl)thiophene-2-sulfonamide (230 mg, 0.50 mmol, 1.0 eq) in CH2Cl2 (10 mL) at rt under nitrogen. The reaction mixture was stirred for 30 min and then quenched with aq. NaHCO3 in ice bath. The reaction mixture was extracted with ethyl acetate and washed with water, brine, dried and evaporated. The crude product was crystallized with THF/isopropanol to afford the title compound 5-(4-(3-cyclopropyl-1H-pyrazol-5-ylamino)-5-ethynyl-6-methylpyrimidin-2-yl)thiophene-2-sulfonamide (Compound 267) (175.0 mg, 87.5%). LC-MS (m/z)=401.1 [M+H]+. δ (400 MHz, DMSO-d6): 0.81-0.85 (m, 2H), 1.03-1.07 (m, 2H), 1.99-2.04 (m, 1H), 2.55 (s, 3H), 5.17 (s, 1H), 6.49 (s, 1H), 7.61 (d, J=3.6 Hz, 1H), 7.88 (s, 2H), 7.91 (d, J=3.6 Hz, 1H), 9.21 (s, 1H)
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH3:13][CH:14]1[CH2:18][NH:17][C:16](=[O:19])[CH2:15]1.C(=O)([O-])[O-].[K+].[K+].CNCCNC>[Cu]I.O.C1(C)C=CC=CC=1>[CH3:13][CH:14]1[CH2:18][N:17]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)[C:16](=[O:19])[CH2:15]1
Reactant: CC1CNC(=O)C1
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1ccc(N2CC(C)CC2=O)cc1
Yield: 76.3 %

Procedure:
To a mixture of ethyl 4-iodobenzoate (552 mg), 4-methylpyrrolidin-2-one (198 mg), potassium carbonate (536 mg) and copper(I) iodide (190 mg) were added toluene (2 mL) and N,N′-dimethylethylenediamine (215 μL), and the mixture was stirred with heating under reflux for 8 hr. The reaction mixture was cooled, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The obtained residue was purified by column chromatography (hexane:ethyl acetate) to give the title compound (377 mg).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:16]=[C:15]2[C:11]([CH:12]=[C:13]([C:17]3[C:18]([O:24][CH3:25])=[N:19][CH:20]=[CH:21][C:22]=3[I:23])[NH:14]2)=[CH:10][C:9]=1[O:26][CH3:27])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[I:23][C:22]1[CH:21]=[CH:20][N:19]=[C:18]([O:24][CH3:25])[C:17]=1[C:13]1[NH:14][C:15]2[C:11]([CH:12]=1)=[CH:10][C:9]([O:26][CH3:27])=[C:8]([NH2:7])[CH:16]=2
Reactant: COc1cc2cc(-c3c(I)ccnc3OC)[nH]c2cc1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc2cc(-c3c(I)ccnc3OC)[nH]c2cc1N
Yield: 84.3 %

Procedure:
A solution of [2-(4-iodo-2-methoxy-pyridin-3-yl)-5-methoxy-1H-indol-6-yl]-carbamic acid tert-butyl ester (250 mg, 0.51 mmol) in CH2Cl2 (5 mL) was added 2,2,2-trifluoroacetic acid (1 mL) at 25° C. The solution was heated to reflux for 3 h and then concentrated in vacuo and poured into water. The aqueous phase was extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over magnesium sulfate. Filtration followed by concentration in vacuo gave a brown solid. Flash chromatography (50/50 hexanes/ethyl acetate) afforded 2-(4-iodo-2-methoxy-pyridin-3-yl)-5-methoxy-1H-indol-6-ylamine (170 mg, 85%) as a white solid. MH+ 395.0.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]2[O:12][CH:13]=[C:14]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][N:28]4[CH:32]=[CH:31][N:30]=[C:29]4[CH2:33][CH2:34][C:35](O)=[O:36])=[CH:20][CH:19]=3)[N:15]=2)=[CH:5][CH:4]=1.[NH:40]1[CH2:44][CH2:43][CH2:42][CH2:41]1.P(C#N)(OCC)(OCC)=O>C(N(CC)CC)C>[F:38][C:2]([F:39])([F:1])[C:3]1[CH:4]=[CH:5][C:6](/[CH:9]=[CH:10]/[C:11]2[O:12][CH:13]=[C:14]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][CH2:27][N:28]4[CH:32]=[CH:31][N:30]=[C:29]4[CH2:33][CH2:34][C:35]([N:40]4[CH2:44][CH2:43][CH2:42][CH2:41]4)=[O:36])=[CH:20][CH:19]=3)[N:15]=2)=[CH:7][CH:8]=1
Reactant: C1CCNC1
Reactant: O=C(O)CCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Product: O=C(CCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1)N1CCCC1

Procedure:
Using 3-[1-[4-[4-[(2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazol-4-yl)methoxy]phenyl]butyl]-1H-imidazol-2-yl]propionic acid (200 mg), pyrrolidine (0.174 ml), diethyl cyanophosphate (0.303 ml) and triethylamine (0.310 ml), the same reaction as Example 5-(ii) was carried out to yield the titled compound (86 mg).
Reaction SMILES: Br[CH2:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([Li])CCC.[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20]([C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)=[O:21].O>C1COCC1.CCCCCCC.CCOC(C)=O.CCOCC>[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20]([C:22]1[S:23][CH:24]=[CH:25][CH:26]=1)([C:7]1[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=1)[OH:21]
Reactant: O=C(c1cccs1)c1cccs1
Reactant: BrCOc1ccccc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(C(O)(c2cccs2)c2cccs2)cc1

Procedure:
p-Bromo methoxybenzene (0.96 g, 5.2 mmol) was dissolved in THF (50 mL) and n-butyl lithium (2.08 mL, 2.5M in toluene) was added at -70° C. and stirred at this temperature for 10 minutes when the thienyl ketone (1.0 g 5.2 mmol) (see JACS 74: 1733-36 (1952), JCS 1956, 698-705 and Receuil 68: 24 (1949)) dissolved in THF (5 mL) was added. The temperature was allowed to rise gradually to room temperature over night. The mixture was hydrolysed with water (50 mL). Ether (150 mL) was added and the phases were separated, the aqueous phase was extracted with more ether (100 mL) and the combined organic phase was washed with water (70 mL), dried (MgSO4) and the solvent evaporated leaving a semi-crystalline black residue. The black residue was dissolved in hot heptane/EtOAc (3:1) and chromatographed on a column of alumina with heptane:EtOAc 3:1 as eluent. The product was isolated in a yield of 0.72 g (46.0%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].CS(O[CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28]1)(=O)=O>CN(C=O)C.C(OCC)(=O)C>[C:36]([O:35][C:33]([N:29]1[CH2:30][CH2:31][CH2:32][CH:27]([CH2:26][O:1][C:2]2[CH:3]=[C:4]([O:8][S:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=2)[CH2:28]1)=[O:34])([CH3:39])([CH3:37])[CH3:38]
Reactant: CC(C)(C)OC(=O)N1CCCC(COS(C)(=O)=O)C1
Reactant: O=S(=O)(Oc1cccc(O)c1)c1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(COc2cccc(OS(=O)(=O)c3ccccc3Cl)c2)C1
Reaction time: 0.17 h
Yield: 52.9 %

Procedure:
To a solution of 2-chlorobenzenesulfonic acid 3-hydroxyphenyl ester (570 mg, 2.0 mmol), as prepared in step d of Example 1, in DMF (8 mL) was added NaH (95%, 53 mg, 2.2 mmol). The reaction mixture was stirred under nitrogen for 10 min. N-(tert-Butoxycarbonyl)-3-piperidinemethanol methanesulfonate (586 mg, 2.0 mmol), as prepared in step b, was added and the reaction mixture was stirred at 40° C. under nitrogen overnight. The reaction mixture was diluted with ethyl acetate (150 mL), washed sequentially with saturated NaHCO3 (2×50 mL) and brine (2×50 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (2:1 hexane:ethyl acetate) to give the title compound as a colorless syrup (510 mg, 54%). 1H-NMR (300 MHz, CDCl3) δ 1.32 (m, 1H), 1.45 (s, 9H), 1.65-1.98 (m, 4H), 2.88 (m, 2H), 3.73 (m, 2H), 3.79 (d, 2H), 6.69 (m, 2H), 7.13 (t, 1H), 7.37 (t, 1H), 7.61 (m, 2H), 7.94 (d, 1H).
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=2[CH2:21][N:22]2[C@@H:26]([CH3:27])[C@@H:25]([C:28]3[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=3)[CH:31]=O)[O:24][C:23]2=[O:36])=[C:4]([O:37][CH3:38])[CH:3]=1.[CH3:39][NH2:40].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CC(O)=O>ClCCCl.C1COCC1>[F:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[CH:6][C:5]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][C:12]=2[CH2:21][N:22]2[C@@H:26]([CH3:27])[C@@H:25]([C:28]3[CH:35]=[CH:34][CH:33]=[C:30]([CH2:31][NH:40][CH3:39])[CH:29]=3)[O:24][C:23]2=[O:36])=[C:4]([O:37][CH3:38])[CH:3]=1
Reactant: CN
Reactant: COc1cc(F)c(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cccc(C=O)c2)[C@@H]1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CNCc1cccc([C@H]2OC(=O)N(Cc3cc(C(F)(F)F)ccc3-c3cc(C(C)C)c(F)cc3OC)[C@H]2C)c1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
To a solution of 3-((4S,5R)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-2-oxo-1,3-oxazolidin-5-yl)benzaldehyde (15 mg, 0.028 mmol) in 1,2-dichloroethane (1 mL) was added methylamine (1 mL of a 2.0 M solution in THF). The resulting mixture was treated with sodium triacetoxyborohydride (34.8 mg, 0.16 mmol) and AcOH (0.05 mL). The mixture was stirred under N2 at room temperature for 5 days. The reaction mixture was quenched with 1N NaOH and the aqueous layer was extracted with ether (3×15 mL). The ether extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (Si) to afford (4S,5R)-3-{[4′-fluoro-5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-5-{3-[(methylamino)methyl]phenyl}-1,3-oxazolidin-2-one. LCMS calc.=545.23; found=545.4 (M+1)+. 1H NMR (500 MHz, CDCl3, 1:1 mixture of atropisomers) δ 7.74 (s, 0.5H); 7.67 (s, 0.5H); 7.64 (s, 0.5H); 7.62 (s, 0.5H); 7.33 (m, 3H); 7.20 (s, 1H); 7.13 (s, 0.5H); 7.12 (s, 0.5H); 7.01 (d, J=8.4 Hz, 0.5H); 6.98 (d, J=8.5 Hz, 0.5H); 6.71 (d, J=2.9 Hz, 0.5H); 6.68 (d, J=2.8 Hz, 0.5H); 5.51 (d, J=8.1 Hz, 0.5H); 5.37 (d, J=8.0 Hz, 0.5H); 4.82 (d, J=15.9 Hz, 0.5H); 4.75 (d, J=15.9 Hz, 0.5H); 4.16 (d, J=15.9 Hz, 0.5H); 3.92 (d, J=15.9 Hz, 0.5H); 3.77 (m, 5.5H); 3.70 (t, J=6.6 Hz, 0.5H); 3.25-3.18 (m, 1H); 2.45 (s, 3H); 1.93 (br, s, 1H); 1.27 (m, 4.5H); 1.19 (d, J=6.9 Hz, 1.5H); 0.53 (d, J=6.5 Hz, 1.5H); 0.40 (d, J=6.5 Hz, 1.5H).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=1[C:29]([F:32])([F:31])[F:30]>>[F:30][C:29]([F:31])([F:32])[C:20]1[CH:21]=[C:22]([C:25]([F:28])([F:26])[F:27])[CH:23]=[CH:24][C:19]=1[CH2:18][NH:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3
Reactant: Nc1ccc2c(=O)[nH]c3ncccc3c2c1
Reactant: FC(F)(F)c1ccc(CBr)c(C(F)(F)F)c1
Product: O=c1[nH]c2ncccc2c2cc(NCc3ccc(C(F)(F)F)cc3C(F)(F)F)ccc12
Yield: 22.1 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 454 using 70 (121 mg, 0.57 mmol) and 1-(bromo-methyl)-2,4-bis(trifluoromethyl)benzene (176 mg, 0.57 mmol) to provide 455 (55 mg, 22% yield) as a white powder. LC-MS (M+H=438, obsd.=438). 1H NMR (400 MHz, DMSO-D6) δ 11.55 (s, 1H), 8.37 (m, 2H), 8.06 (dd, J=7.9, 13.0, 2H), 7.84 (d, J=8.5, 1H), 7.31 (m, 2H), 7.24 (dd, J=4.7, 7.9, 1H), 6.94 (dd, J=2.1, 8.8, 1H), 4.77 (d, J=5.7, 2H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][N:17]=3)[CH:12]=[C:11]([CH:19]=[C:20]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[C:21]#[N:22])[C:10]2=[O:29])=[CH:5][CH:4]=1.CC=C(C)C.B(Br)(Br)Br.ClCCl>C(Cl)(Cl)Cl.O>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][N:17]=3)[CH:12]=[C:11]([CH:19]=[C:20]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[C:21]#[N:22])[C:10]2=[O:29])=[CH:5][CH:4]=1
Reactant: COc1ccc(-n2c(=O)c(C=C(C#N)c3cccnc3)cc3cccnc32)cc1
Agent: BrB(Br)Br
Agent: CC=C(C)C
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: N#CC(=Cc1cc2cccnc2n(-c2ccc(O)cc2)c1=O)c1cccnc1
Temperature: -40 °C
Reaction time: 15 h
Yield: 8.7 %

Procedure:
2.5 g of 3-[1,2-dihydro-1-(4-methoxyphenyl)-2-oxo-1,8-naphthyridin-3-yl]-2-(3-pyridyl)prop-2-enenitrile, prepared in Example 82, are dissolved in 100 ml of chloroform stabilized with amylene. The yellow solution is cooled to -40° C. and 13.2 ml of a 1 M solution of BBr3 in dichloromethane (2 eq) are then added dropwise at this temperature, with stirring. The mixture is then left to warm up to room temperature and stirring is continued for 15 h. The reaction medium is hydrolyzed by the addition of 100 ml of water, after which the aqueous phase is separated off and extracted several times with dichloromethane. The precipitate which appears is filtered off, washed with acetone and dried to give 0.21 g of 3-[1,2-dihydro-1-(4-hydroxy- phenyl)-2-oxo-1,8-naphthyridin-3-yl]-2-(3-pyridyl)prop-2-enenitrile in the form of a yellow solid melting at >317° C. Yield 9%.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:5]=[C:4]([S:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([CH:25]3[CH2:27][CH2:26]3)=[O:24])=[CH:18][CH:17]=2)[N:3]=1.Cl.[CH:29]1([C:32]2([F:36])[CH2:35][NH:34][CH2:33]2)[CH2:31][CH2:30]1.CCN(C(C)C)C(C)C.ClCCl>O1CCOCC1>[CH:29]1([C:32]2([F:36])[CH2:35][N:34]([C:2]3[CH:7]=[C:6]([NH:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=4)[N:5]=[C:4]([S:15][C:16]4[CH:21]=[CH:20][C:19]([NH:22][C:23]([CH:25]5[CH2:27][CH2:26]5)=[O:24])=[CH:18][CH:17]=4)[N:3]=3)[CH2:33]2)[CH2:31][CH2:30]1
Reactant: O=C(Nc1ccc(Sc2nc(Cl)cc(Nc3ccccn3)n2)cc1)C1CC1
Reactant: FC1(C2CC2)CNC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Sc2nc(Nc3ccccn3)cc(N3CC(F)(C4CC4)C3)n2)cc1)C1CC1

Procedure:
Prepared according the procedure used for the synthesis of compound I-1, starting with N-(4-(4-Chloro-6-(pyridin-2-ylamino)pyrimidin-2-ylthio)phenyl)cyclopropane carboxamide (110 mg, 28 mmol), 3-cyclopropyl-3-fluoroazetidine hydrochloride (60 mg, 0.39 mmol), and DiPEA (0.15 mL, 0.9 mmol) in 1,4-dioxane. After column chromatography, the product containing fraction (TLC: SiO2, dichloromethane/7.5% 2-propanol, Rf=0.65; HPLC: 70/90% purity, Rf=8.813 minutes) was purified further by preparative HPLC to yield 4 mg after evaporation and lyophilization with a purity of 96+% (HPLC method B, Rf=5.841 minutes).
Reaction SMILES: [CH3:1][O:2][C:3](=[CH:7][CH:8]=[CH:9][C:10]1[S:11][C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=2[C:14]=1[CH3:15])[C:4]([O-:6])=[O:5].[CH2:20]1CCN2C(=NCCC2)CC1.C(OC(C)C)(C)C>C(Cl)Cl>[CH3:1][O:2]/[C:3](=[CH:7]/[CH:8]=[CH:9]/[C:10]1[S:11][C:12]2[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=2[C:14]=1[CH3:15])/[C:4]([O:6][CH3:20])=[O:5]
Reactant: C1CCC2=NCCCN2CC1
Reactant: COC(=CC=Cc1sc2ccccc2c1C)C(=O)[O-]
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Product: COC(=O)/C(=C\C=C\c1sc2ccccc2c1C)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 1 %

Procedure:
Methyl (2Z,4E)-2-(methoxy-5-(3-methylbenzothiophen-2-yl)-2,4-pentadienoate and methyl (2Z,4E)-2-(methoxy-5-(3-methylbenzothiophen-2-yl)-2,4-pentadienoate. A solution of (E)-3-[2-(3-methylbenzothiophen-2yl)]-2-propenal (1 g, 5 mmol) in CH2Cl2 (30 ml) under nitrogen was treated with methoxycarbonylmethyl-2-methoxy triphenylphosphonium bromide (4.45 g, 10 mmol) and DBU (1.5 ml, 10 mmol). The reaction mixture was stirred at room temperature for 2 hours, washed with 10% aqueous HCl (5 ml), saturated solution of NaHCO3 (5 ml) and brine (5 ml), dried over Na2SO4 and evaporated under vacuum. The residue was purified by chromatography on silicagel (hexane/EtOAc 7/3) to afford, after trituration with isopropyl ether, methyl (2Z,4E)-2-methoxy-5-)3-methylbenzothiophen-2-yl)-2,4-pentiadienoate (380 mg, 1.32 mmol, yield 26.3%), m.p.=106-107° C., and methyl (2E,4E)-2-methoxy-5-(methylbenzothiophen-2-yl)-2,4-pentadienoate, (13 mg, 0.050 mmol, yield 1.0%), m.p.=91-92° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][C:3]=1[C@:17]1([CH2:36][F:37])[CH2:22][C@@H:21]([C:23]([F:26])([F:25])[F:24])[O:20][C:19]([NH:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:18]1.OO.O.C([O-])(O)=[O:42].[Na+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:42])=[CH:4][C:3]=1[C@:17]1([CH2:36][F:37])[CH2:22][C@@H:21]([C:23]([F:24])([F:25])[F:26])[O:20][C:19]([NH:27][C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[N:18]1
Reactant: CC1(C)OB(c2ccc(F)c([C@]3(CF)C[C@@H](C(F)(F)F)OC(NC(=O)c4ccccc4)=N3)c2)OC1(C)C
Reactant: O=C([O-])O
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(NC1=N[C@](CF)(c2cc(O)ccc2F)C[C@@H](C(F)(F)F)O1)c1ccccc1
Reaction time: 16 h
Yield: 56 %

Procedure:
To a solution of N-((4S,6S)-4-(2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (4.16 g, 7.93 mmol) in THF (22.67 mL) at 0° C. was added hydrogen peroxide 30% in water (2.431 mL, 23.80 mmol). The reaction mixture was stirred at 0° C. to room temperature for 16 h. The reaction mixture was acidified to pH 5-7 by addition of saturated NaHCO3, and extracted with EtOAc (2×). The combined organics were washed with water and brine, dried and concentrated. The crude material was purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0-30% EtOAc in hexane, to provide N-((4S,6S)-4-(2-fluoro-5-hydroxyphenyl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (1.84 g, 4.44 mmol, 56.0% yield) as white foam. MS m/z=415 [M]+. Calculated for C19H15F5N2O3: 414.33.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[O:9]1[C:13]2([CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[O:12][CH2:11][CH2:10]1.CCN(C(C)C)C(C)C.O>CS(C)=O>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:16]2[CH2:17][CH2:18][C:13]3([O:12][CH2:11][CH2:10][O:9]3)[CH2:14][CH2:15]2)=[CH:6][CH:7]=1
Reactant: C1CC2(CCN1)OCCO2
Reactant: Clc1ccc(Cl)nn1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Clc1ccc(N2CCC3(CC2)OCCO3)nn1
Temperature: 80 °C

Procedure:
To a mixture of 3,6-dichloropyridazine (2.98 g, 20 mmol) in DMSO (10 mL) was added 1,4-dioxa-8-azaspiro[4.5]decane (3 g, 21 mmol) and DIPEA (4.18 mL, 24 mmol). The resulting mixture was heated at 80° C. for 4 h and was then poured into H2O (300 mL). The resulting solid was washed with H2O (10 mL×3) and hexane (10 mL×3) and then dried to yield 8-(6-chloropyridazin-3-yl)-1,4-dioxa-8-azaspiro[4.5]decane.
Reaction SMILES: [CH3:1][CH:2]1[N:7]([CH3:8])[CH2:6][C:5]2[S:9][CH:10]=[CH:11][C:4]=2[CH2:3]1.FC(F)(F)C([O-])=O.[Br-:19].[K+].BrBr>O>[Br:19][C:10]1[S:9][C:5]2[CH2:6][N:7]([CH3:8])[CH:2]([CH3:1])[CH2:3][C:4]=2[CH:11]=1
Reactant: [Br-]
Reactant: CC1Cc2ccsc2CN1C
Agent: BrBr
Agent: O=C([O-])C(F)(F)F
Agent: [K+]
Solvent: O
Product: CC1Cc2cc(Br)sc2CN1C
Temperature: 0 °C

Procedure:
1.0 g (3.6 mmol) 5,6-dimethyl-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine (as the trifluoroacetate salt) are dissolved in 60 ml of water and at the temperature of an ice bath combined with a solution of 1.0 g (8.5 mmol) potassium bromide and 182 μl (3.6 mmol) bromine in 20 ml of water. The mixture is stirred for 2.5 hours in the ice bath and then extracted twice with 100 ml ethyl acetate. The combined organic phases are washed with sat. sodium chloride solution, then dried on sodium sulphate and evaporated down i. vac. The crude product thus obtained is purified by chromatography on silica gel (eluant DCM/methanol 50:1).
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([C:8]([NH:10][NH:11][C:12]2[N:13]=[C:14]3[CH:20]=[CH:19][N:18]([S:21]([C:24]4[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=4)(=[O:23])=[O:22])[C:15]3=[N:16][CH:17]=2)=O)[CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1)[CH3:2].S(Cl)(Cl)=O.Cl.CCOCC>O1CCOCC1>[CH2:1]([C@H:3]1[CH2:4][NH:5][CH2:6][C@H:7]1[C:8]1[N:13]2[C:14]3[CH:20]=[CH:19][N:18]([S:21]([C:24]4[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=4)(=[O:23])=[O:22])[C:15]=3[N:16]=[CH:17][C:12]2=[N:11][N:10]=1)[CH3:2]
Reactant: CC[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1C(=O)NNc1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: CC[C@H]1CNC[C@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Temperature: 70 °C
Reaction time: 3 h
Yield: 87.3 %

Procedure:
To a solution of (cis)-tert-butyl 3-ethyl-4-(2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)hydrazinecarbonyl)pyrrolidine-1-carboxylate (9.4 g, 16.41 mmol) in 1,4-dioxane (150 mL), TEA (7.00 mL, 50.2 mmol) and thionyl chloride (1.80 mL, 24.6 mmol) were each added sequentially in one portion to the solution. The reaction was heated at about 70° C. for about 18 h. The solvent was removed under reduced pressure. A solution of HCl (4 M in 1,4-dioxane, 41.0 mL, 164 mmol) was added in one portion and the reaction was stirred for about 3 h. Et2O (100 mL) was added and the solid was filtered. The solids were combined with the mother liquor and the solvent was removed under reduced pressure. The solid was partially dissolved in EtOAc (650 mL) and washed with aqueous saturated NaHCO3 (150 mL). An emulsion formed and was fitered through Celite® washing with EtOAc. The solid on top of the Celite® layer was product. The solid was scraped off of the Celite® and dissoved in a solution of 10% MeOH in DCM (150 mL). The organic layer was washed with water (2×30 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate (4×150 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to afford 1-((cis)-4-ethylpyrrolidin-3-yl)-6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazine (5.88 g, 80%) as a brown foam: LC/MS (Table 1, Method a) Rt=1.55 min; MS m/z: 411 (M+H)+.
Reaction SMILES: [N:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([N:10]([CH3:12])[CH3:11])=[O:9])=[CH:6][N:5]=1)=[N+]=[N-].C(OCC)(=O)C>[Pd].CO>[NH2:1][C:4]1[CH:14]=[CH:13][C:7]([C:8]([N:10]([CH3:12])[CH3:11])=[O:9])=[CH:6][N:5]=1
Reactant: CN(C)C(=O)c1ccc(N=[N+]=[N-])nc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1ccc(N)nc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
In a 250 mL round-bottomed flask, 6-azido-N,N-dimethylnicotinamide (2.26 g, 11.8 mmol) was combined with ethyl acetate (50 ml) and methanol (30 ml) to give a yellow solution. 10% Pd/C (200 mg, 1.88 mmol) was added and the reaction mixture was evacuated and filled with H2 twice. The reaction mixture was stirred under balloon pressure of H2 at 25° C. for 17 h. The reaction mixture was filtered through celite and the filter cake was washed with MeOH. The filtrate was concentrated in vacuo and the cream colored solid was dried under vacuum at 45° C. for 3 hrs to give the title compound in quantitative yield. (M+H)+=166 m/e. 1H NMR (300 MHz, CHLOROFORM-d) δ: 8.21 (d, J=2.3 Hz, 1H), 7.59 (dd, J=8.3, 2.3 Hz, 1H), 6.50 (d, J=8.7 Hz, 1H), 4.69 (br. s., 2H), 3.08 (s, 6H).
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([O:23]C)[C:18]=2[O:25]C)=[CH:6][CH:5]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:25][C:18]1[C:19]([OH:23])=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:7]1[CH:6]=[CH:5][C:4]([C:3]([OH:27])=[O:2])=[CH:9][CH:8]=1
Reactant: COC(=O)c1ccc(OCCCCCCc2cccc(OC)c2OC)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(O)c1ccc(OCCCCCCc2cccc(O)c2O)cc1
Reaction time: 7 h
Yield: 42 %

Procedure:
To 0.80 g (2.2 mmol) of 4-[6-(2,3-dimethoxyphenyl)hexyloxy]benzoic acid methyl ester in 25 mL of methylene chloride stirred and cooled at -70° was added 8.0 mL of 1M boron tribromide in methylene chloride. The reaction mixture was stirred at -70° for 30 minutes and at -20° for 7 hours. Workup as in example 32 and recrystallization from ethyl acetate-hexane gave 0.30 g (42% yield), mp 170°-172° of 4-[6-(2,3-dihydroxyphenyl)hexyloxy]benzoic acid.