Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([CH2:7][NH:8][C:9]2[CH:13]=[CH:12][O:11][N:10]=2)=[CH:5][CH:4]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Br:26][C:27]1[C:32]([F:33])=[CH:31][C:30]([N:34]2[C:43]3[C:38](=[CH:39][C:40]([S:44](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:46])=[O:45])=[CH:41][CH:42]=3)[CH:37]=[CH:36][C:35]2=[O:59])=[C:29]([OH:60])[CH:28]=1.[Cl-].[NH4+]>C1COCC1.O.CC(C)=O>[Br:26][C:27]1[C:32]([F:33])=[CH:31][C:30]([N:34]2[C:43]3[C:38](=[CH:39][C:40]([S:44]([N:8]([C:9]4[CH:13]=[CH:12][O:11][N:10]=4)[CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:15][CH:14]=4)(=[O:45])=[O:46])=[CH:41][CH:42]=3)[CH:37]=[CH:36][C:35]2=[O:59])=[C:29]([OH:60])[CH:28]=1
Reactant: O=c1ccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc2n1-c1cc(F)c(Br)cc1O
Reactant: COc1ccc(CNc2ccon2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)=O
Product: COc1ccc(CN(c2ccon2)S(=O)(=O)c2ccc3c(ccc(=O)n3-c3cc(F)c(Br)cc3O)c2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of N-(4-methoxybenzyl)isoxazol-3-amine (3.37 g, 16.49 mmol) in THF (30.0 ml) was cooled to −78° C. LHMDS (15.74 ml, 15.74 mmol) was then added dropwise and the acetone/dryice bath was removed for 5 minutes. The solution was then returned to −78° C. and a solution of perfluorophenyl 1-(4-bromo-5-fluoro-2-hydroxyphenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonate (4.35 g, 7.50 mmol) in THF (30.0 ml) was added dropwise. The resulting solution was stirred for 4 hours warming to room temperature. Saturated ammonium chloride was added to the reaction mixture. The resulting mixture was transferred to a sep. funnel containing water and the aqueous layer was washed 3× with EtOAc. The organic layers were combined, dried with MgSO4, filtered and concentrated to an oil. The crude product was purified by ISCO MPLC (100% heptanes to 60% 3:1 EtOAc:EtOH). The product eluted at 50% 3:1 EtOAc:EtOH. m/z (ESI) 602.1 (M+1)±.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14](O)=[O:15])[CH:5]=[CH:4][C:3]1=2.CN(C=O)C.[NH2:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1.O>O=S(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]([NH:23][C:24]3[CH:25]=[CH:26][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:32][CH:33]=3)=[O:15])[CH:5]=[CH:4][C:3]1=2
Reactant: COC(=O)c1ccc(N)cc1
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)O)ccc21
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Solvent: O
Product: COC(=O)c1ccc(NC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 73.2 %

Procedure:
5,5,8,8-Tetramethyl-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid 2 (0.20 g, 0.86 mmol) was dissolved in SOCl2 (4.3 mL) at 0° C. A drop of DMF was added and the mixture was stirred for 0.5 h. The SOCl2 was removed under vacuum and the crude acid chloride was dissolved in pyridine (10 mL). Methyl 4-aminobenzoate (0.143 g, 0.947 mmol) and DMAP (0.010 mg, 0.086 mmol) were added and the mixture was heated at 60° C. for 2 h with stirring. The mixture was poured into H2O and the product was extracted with EtOAc; The organic layer was washed successively with HCl (2M), saturated NaHCO3, saturated NaCl, dried over MgSO4, filtrated to give after evaporation methyl 4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-carboxamido)benzoate 3 (0.23 g, 73% yield) as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:12]/[CH:13]=[CH:14]/[N+:15]([O-:17])=[O:16])=[C:7]([CH:11]=1)[C:8](O)=[O:9])[CH3:2].C([O-])(=O)C.[K+]>C(OC(=O)C)(=O)C>[CH2:1]([C:3]1[CH:11]=[C:7]2[C:6](=[CH:5][CH:4]=1)[N:12]=[CH:13][C:14]([N+:15]([O-:17])=[O:16])=[C:8]2[OH:9])[CH3:2]
Reactant: CCc1ccc(N/C=C/[N+](=O)[O-])c(C(=O)O)c1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Product: CCc1ccc2ncc([N+](=O)[O-])c(O)c2c1

Procedure:
The title compound is prepared in analogy to Example 19b starting from 11.2 g (47.4 mmol) of 5-ethyl-2-((E)-2-nitro-vinylamino)benzoic acid (Example 49c) and 5.58 g (56.8 mmol) potassium acetate in 50 ml acetic anhydride. mp: 308-310° C. (dec.); MS: 219 (M++1); HPLC: tret=12.48 min (Grad 3).
Reaction SMILES: [NH2:1][O:2][CH2:3][CH2:4][OH:5].[F:6][C:7]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:8]=1[NH:9][C:10]1[C:11]([C:18](O)=[O:19])=[CH:12][N:13]([CH3:17])[C:14](=[O:16])[CH:15]=1.C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>CO>[F:6][C:7]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:8]=1[NH:9][C:10]1[C:11]([C:18]([NH:1][O:2][CH2:3][CH2:4][OH:5])=[O:19])=[CH:12][N:13]([CH3:17])[C:14](=[O:16])[CH:15]=1
Reactant: Cc1ccc(Nc2cc(=O)n(C)cc2C(=O)O)c(F)c1
Reactant: NOCCO
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Product: Cc1ccc(Nc2cc(=O)n(C)cc2C(=O)NOCCO)c(F)c1
Yield: 61 %

Procedure:
2-(Aminooxy)ethanol, 4-(2-fluoro-4-methylanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxylic acid and DMT-MM were reacted in MeOH as outlined in example 33, step D. Further purification by flash chromatography on silica gel (EtOAc followed by 10% MeOH/CH2Cl2) gave 4-(2-fluoro-4-methylanilino)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide (61%) as a cream solid; m.p. (EtOAc/Hexane) 110-115° C. 1H NMR [400 MHz, (CD3)2SO] δ 11.62 (br s, 1H), 9.21 (br s, 1H), 8.11 (s, 1H), 7.31 (t, J=8.3 Hz, 1H), 7.17 (d, J=11.8 Hz, 1H), 7.06 (d, J=8.3 Hz, 1H), 5.38 (s, 1H), 4.75 (t, J=5.3 Hz, 1H), 3.91 (t, J=4.9 Hz, 2H), 3.62 (q, J=4.9 Hz, 2H), 3.35 (s, 3 H, obscured), 2.32 (s, 3H). LCMS (ACPI−) 334 (50%). Anal. Calcd for C16H18FN3O4.0.25 H2O: C, 56.6; H, 5.5; N, 12.4. Found C, 56.5; H, 5.5; N, 12.1.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:15]1[CH:24]=[C:23]2[C:18]([CH2:19][CH2:20][N:21](C(=O)C(F)(F)F)[CH2:22]2)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.C1(C)C=CC=CC=1>[F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([C:15]2[CH:24]=[C:23]3[C:18]([CH2:19][CH2:20][NH:21][CH2:22]3)=[CH:17][CH:16]=2)=[CH:5][CH:4]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: O=C(N1CCc2ccc(Br)cc2C1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: FC(F)(F)c1ccc(-c2ccc3c(c2)CNCC3)cc1
Yield: 44.4 %

Procedure:
4.63 g 4-(Trifluormethyl)phenylboronic acid was dissolved in 15 ml ethanol and added to a mixture of 5.0 g 1-(7-bromo-3,4-dihydro-1H-isoquinolin-2-yl)-2,2,2-trifluoro-ethanone in 150 ml toluene and 54 ml of a 2 molar sodium carbonate solution. The reaction mixture was degassed then 940 mg tetrakis(triphenylphosphine)palladium(0) was added and the mixture heated under reflux for two hours. The cooled reaction mixture was evaporated, the resulting residue was dissolved in 150 ml ethyl acetate and washed with 50 ml water and brine. The organic layer was dried over MgSO4 and the solvent removed in vacuo. The resulting crude material was purified by reversed phase HPLC to obtain 2.0 g 7-(4-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-isoquinoline as its trifluoroacetate salt.
Reaction SMILES: [ClH:1].[CH2:2]([N:5]([CH2:19][CH2:20][CH3:21])[C@H:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[O:16]C)[C@H:7]1[CH3:18])[CH:3]=[CH2:4].B(Br)(Br)Br.[NH4+].[OH-]>C(Cl)(Cl)Cl>[ClH:1].[CH2:2]([N:5]([CH2:19][CH2:20][CH3:21])[C@H:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][C:12]=2[OH:16])[C@H:7]1[CH3:18])[CH:3]=[CH2:4]
Reactant: C=CCN(CCC)[C@H]1CCc2c(OC)cccc2[C@H]1C
Agent: BrB(Br)Br
Agent: Cl
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Product: C=CCN(CCC)[C@H]1CCc2c(O)cccc2[C@H]1C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The intermediate cis-N-allyl-5-methoxy-1-methyl-2-(n-propylamino) tetralin hydrochloride (200 mg; 0.68 mmol) was dissolved in CHCl3 (2 ml) and added during 2 minutes to a well-stirred solution of BBr3 (1.10 g; 4.39 mmol) in CHCl3 (13 ml) maintained in the temperature range 23°-26° C. The stirring was continued for 15 minutes at 20° C. The reaction mixture was poured into a well-stirred mixture of ice (6 g) and concentrated NH4OH (1.5 ml). The two-phase system was kept at 0° for 30 minutes with continuous stirring. The system was separated and the organic phase was dried and evaporated. The desired oily product was precipitated as a hydrochloride salt and was recrystallized from CHCl3 /ether. Yield: 100 mg (50%) NMR (CDCl3), δ0.89 (t, 3H), δ1.20(d, 3H), δ3.53-0.60(m, 18H), δ4.96 (s, 1H phenolic), δ5.07 (m, 1H), δ5.31 (m, 1H), δ 6.02 (m, 1H), δ6.70 (m, 2H), δ7.10 (m, 1H), MS (70 eV) m/z 259 (45%), 161 (100%) 124 (79%).
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7]([CH:26]=O)=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:24][C:23]3[CH2:22][CH2:21][NH:20][C:19](=[O:25])[C:18]=3[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:29][OH:30].CO.C(Cl)Cl>CO.C([O-])(O)=O.[Na+]>[C:1]([NH:5][C:6]1[C:7](/[CH:26]=[N:29]/[OH:30])=[N:8][C:9]2[C:14]([N:15]=1)=[C:13]([C:16]1[NH:24][C:23]3[CH2:22][CH2:21][NH:20][C:19](=[O:25])[C:18]=3[CH:17]=1)[CH:12]=[CH:11][CH:10]=2)([CH3:3])([CH3:4])[CH3:2]
Reactant: NO
Reactant: CC(C)(C)Nc1nc2c(-c3cc4c([nH]3)CCNC4=O)cccc2nc1C=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)Nc1nc2c(-c3cc4c([nH]3)CCNC4=O)cccc2nc1/C=N/O
Temperature: 25 °C
Yield: 68.3 %

Procedure:
A solution of 3-(tert-butylamino)-5-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinoxaline-2-carbaldehyde (307b) (44.0 mg, 0.12 mmol), hydroxylamine hydrochloride (11.7 mg, 0.17 mmol), and TEA (0.024 mL, 0.17 mmol) in MeOH (5.0 mL) was stirred at 60° C. for 1.5 h. The reaction mixture was subsequently cooled to RT, diluted with saturated aq. NaHCO3 (20 mL), and extracted with 5% MeOH/DCM (2×30 mL). The combined extracts were sequentially washed with water (30 mL) and brine (20 mL), dried over Na2SO4, filtered, and concentrated onto silica gel. Chromatographic purification (silica gel, 0-100% EtOAc/hexanes, then 0-10% MeOH/DCM) furnished (E)-3-(tert-butylamino)-5-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinoxaline-2-carbaldehyde oxime (31.0 mg, 0.082 mmol, 68% yield) as an orange solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 12.34 (1H, br. s.), 11.86 (1H, br. s.), 8.34 (1H, s), 8.31 (1H, s), 7.91 (1H, dd, J=7.3, 1.1 Hz), 7.67 (1H, dd, J=8.0, 1.0 Hz), 7.40 (1H, t, J=7.8 Hz), 7.09 (1H, d, J=2.2 Hz), 6.95 (1H, br. s.), 3.43 (2H, td, J=6.8, 2.2 Hz), 2.86 (2H, t, J=6.8 Hz), 1.57 (9H, s). m/z (ESI, +ve) 379.1 (M+H)+.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([O:23]C)=[O:22])=[CH:18][C:17]4[CH:25]=[C:26]([O:29][CH3:30])[CH:27]=[CH:28][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl.P([O-])(O)(O)=O.[Na+]>C1COCC1.CO.CN(C=O)C>[C:34]([O:33][C:31]([C:11]1[CH:10]=[CH:9][C:8]2[C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:15]3[C:16]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:17]=4[CH:18]=[C:19]([C:21]([OH:23])=[O:22])[CH2:20][N:14]3[C:13]=2[CH:12]=1)=[O:32])([CH3:37])([CH3:35])[CH3:36]
Reactant: COC(=O)C1=Cc2cc(OC)ccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC(C)(C)C)cc3n2C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=P([O-])(O)O
Solvent: C1CCOC1
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C=C(C(=O)O)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)OC(C)(C)C)cc21
Temperature: 25 °C

Procedure:
Dissolve 10-(1,1-dimethylethyl) 6-methyl 13-cyclohexyl-3-(methyloxy)-7H-indolo[2,1-a][2]benzazepine-6,10-dicarboxylate (5.53 g, 11.02 mmol) in THF (70 ml) with heating, add DMF (20 ml) to maintain solubility, allow to cool to room temperature then add tetrabutylammonium hydroxide (33.1 ml, 33.1 mmol) 10M in methanol. Stir reaction at room temperature for 2 hrs then add 0.1N aqueous 0.1N hydrochloric acid to the reaction followed by 01M aqueous NaH2PO4. Separate phases, wash organic layer sequentially with 1.0N aqueous hydrochloric acid, 0.1M aqueous NaH2PO4. Back extract aqueous 1× using ethyl acetate. Combine ethyl acetate fractions and wash sequentially with 0.1M aqueous NaH2PO4 and brine. Dry over magnesium sulfate, filter and remove solvents in vacuo to yield a bright yellow solid. Dry product in vacuo at room temperature to give 5.2 μg (97%). 1H NMR (500 MHz, CHLOROFORM-D) δ ppm 1.12-1.28 (m, 2H) 1.28-1.45 (m, 2H) 1.46-1.60 (m, 2H) 1.63 (s, 9H) 1.66-1.96 (m, 4H) 1.96-2.16 (m, 3H) 2.76-2.84 (m, 1H) 3.91 (s, 3H) 4.18 (br.s., 1H) 5.66 (br.s, 1H) 7.00 (d, J=2.44 Hz, 1H) 7.10 (dd, J=8.55, 2.75 Hz, 1H) 7.53 (d, J=8.54 Hz, 1H) 7.65-7.71 (m, 1H) 7.82 (d, J=8.24 Hz, 1H) 7.93 (s, 1H) 8.22 (s, 1H). LC-MS retention time 1.47 min; 486 m/z (MH−). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Xterra MS 7u C18 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.
Reaction SMILES: Br[C:2]1[C:7]([CH2:8][NH:9][C:10]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=3[Cl:22])[N:13]=[N:12][N:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:23]([O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)[CH3:24]>>[Cl:22][C:16]1[C:17]([Cl:21])=[CH:18][CH:19]=[CH:20][C:15]=1[N:14]1[C:10]([NH:9][CH2:8][C:7]2[C:2]([C:29]3[CH:30]=[CH:31][C:26]([O:25][CH2:23][CH3:24])=[CH:27][CH:28]=3)=[N:3][CH:4]=[CH:5][CH:6]=2)=[N:11][N:12]=[N:13]1
Reactant: Clc1cccc(-n2nnnc2NCc2cccnc2Br)c1Cl
Reactant: CCOc1ccc(B(O)O)cc1
Product: CCOc1ccc(-c2ncccc2CNc2nnnn2-c2cccc(Cl)c2Cl)cc1
Yield: 6 %

Procedure:
Prepared in 6% yield from (2-bromo-pyridin-3-ylmethyl)-[1-(2,3-dichloro-phenyl)-1H-tetrazol-5-yl]-amine from Example 142C and 4-ethoxyphenylboronic acid according to the procedure described for Example 146. MS (ESI+) m/z 441.0 (M+H)+; 1H NMR (DMSO-d6) δ 1.36 (t, J=6.9 Hz, 3H), 4.09 (q, J=6.9 Hz, 2H), 4.53 (d, J=5.4 Hz, 2H), 7.01 (d, J=8.8 Hz, 2H), 7.34 (dd, J=7.8, 4.7 Hz, 1H), 7.51 (d, J=8.8 Hz, 2H), 7.61 (dd, J=8.1, 8.0 Hz, 1H), 7.67-7.74 (m, 2H), 7.81 (dd, J=7.8, 1.7 Hz, 1H), 7.94 (dd, J=8.1, 1.7 Hz, 1H), 8.53 (dd, J=4.6, 1.5 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:8]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]3([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:13]2=[O:26])[CH2:9][CH2:10]O)[CH:5]=[CH:6][CH:7]=1.C1(C)C(S(Cl)(=O)=O)=CC=CC=1.[N:38]1C=CC=C[CH:39]=1>C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@@H:8]([N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]3([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:13]2=[O:26])[CH2:9][CH2:10][NH:38][CH3:39])[CH:5]=[CH:6][CH:7]=1
Reactant: c1ccncc1
Reactant: O=C1N([C@@H](CCO)c2cccc(F)c2)c2ccccc2C12CCCCC2
Agent: Cc1ccccc1S(=O)(=O)Cl
Solvent: CCOC(C)=O
Product: CNCC[C@@H](c1cccc(F)c1)N1C(=O)C2(CCCCC2)c2ccccc21
Reaction time: 3 h

Procedure:
1′-[(1S)-1-(3-fluorophenyl)-3-hydroxypropyl]spiro[cyclohexane-1,3′-indol]-2′(1′H)-one (0.27 g, 0.76 mmol) was dissolved in pyridine (4 mL) and toluenesufonyl chloride (0.29 g, 2.0 mmol) was added. Stirred for 3 hours then the reaction mixture was diluted with ethyl acetate and washed with water, 2N hydrochloric acid, saturated copper sulfate, 2N hydrochloric acid, and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The crude product was immediately dissolved in methylamine (8M in ethanol, 30 mL) and stirred for 16 hours. The mixture was concentrated in vacuo and purified via chromatography (silica, 5% methanol saturated with ammonia in chloroform) to give 1′-[(1S)-1-(3-fluorophenyl)-3-(methylamino)propyl]spiro[cyclohexane-1.3′-indol]-2′(1′H)-one as a colorless oil (0.20 g). The freebase was dissolved in ether (5 mL) and treated with 1N hydrochloric acid in ether (0.55 mL, 1.0 equivalent). The white precipitate was collected and dried under vacuum to give 193 mg (63% over three steps) 1′-[(1S)-1-(3-fluorophenyl)-3-(methylamino)propyl]spiro[cyclohexane-1,3′-indol]-2′(1′H)-one hydrochloride.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:12]2[CH2:17][CH2:16][CH2:15][NH:14][N:13]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[CH3:18][C:19]1[N:20]=[C:21]([C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)[S:22][C:23]=1[C:24](Cl)=[O:25]>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:24]([C:23]3[S:22][C:21]([C:27]4[S:28][CH:29]=[CH:30][CH:31]=4)=[N:20][C:19]=3[CH3:18])=[O:25])[N:13]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc(C2=NNCCC2)ccc1OC
Reactant: Cc1nc(-c2cccs2)sc1C(=O)Cl
Product: CCOc1cc(C2=NN(C(=O)c3sc(-c4cccs4)nc3C)CCC2)ccc1OC
Yield: 78.7 %

Procedure:
Analogously to Example 2, reaction of 1.04 g of 3-(3-ethoxy-4-methoxyphenyl)-5,6-dihydro4H-pyridazine with 1.08 g of 4-methyl-2-thiophen-2-ylthiazole-5-carbonyl chloride (“CA”) gives the compound 1-[3-(3-ethoxy-4-methoxyphenyl)-5,6-dihydro-4H-pyridazin-1-yl]-1-(4-methyl-2-thiophen-2-ylthiazol-5-yl)methanone (1.54 g).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:33]3[N:34]=[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][N:36]4[CH:41]=3)[CH:31]=[CH:32][C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:33]3[N:34]=[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][N:36]4[CH:41]=3)[CH:31]=[CH:32][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2ccc(-c3cn4ccccc4n3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2ccc(-c3cn4ccccc4n3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[[2-n-propyl-6-(imidazo[1,2-a]pyridin-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:8])=[CH:5][C:6]=1[CH3:7].[Br:9]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:9][CH2:7][C:6]1[CH:5]=[C:4]([Cl:8])[S:3][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(Cl)sc1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1cc(CBr)c(Cl)s1
Yield: 91.1 %

Procedure:
To a stirred solution of 2,5-dichloro-3-methylthiophene (25.8 g, 154 mmol) in carbon tetrachloride (47 mL) was added N-bromosuccinimide (27.5 g, 154 mmol) and benzoyl peroxide (310 mg, 1.28 mmol). The mixture was heated at reflux temperature for 8 hours. After cooling, the insolubles were filtered off. The filtrate was washed with aqueous sodium sulfite solution, dried over MgSO4, and concentrated in vacuo. The residue was fractionally distilled under reduced pressure (bp 80° C., 0.5 mmHg) to give the subtitle compound (34.5 g, 91% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH2:20][C@H:21]([OH:23])[CH3:22])=[CH:16][CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.C(O[K])=O>C1COCC1.O.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH2:20][C@H:21]([OH:23])[CH3:22])=[CH:16][CH:17]=3)[N:12]=[CH:11][CH:10]=2)=[CH:24][CH:25]=1
Reactant: C[C@@H](O)COc1ccc2c(Oc3ccc([N+](=O)[O-])cc3)ccnc2c1
Agent: [Pd]
Agent: O=CO[K]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)COc1ccc2c(Oc3ccc(N)cc3)ccnc2c1
Temperature: 73 °C
Reaction time: 5 h
Yield: 76 %

Procedure:
To a suspension of (R)-1-((4-(4-nitrophenoxy)quinolin-7-yl)oxy)propan-2-ol (3.6 g, 10.6 mmol) and HCOOK (6.2 g, 74.1 mmol) in THF/H2O (33 mL/11 mL) was added a catalytic amount of 10% Pd/C (33 mg). After stirring at 73° C. for 5 hours, the reaction mixture was cooled to room temperature. The mixture was filtered through a celite pad and the filter cake was washed with DCM (50 mL). The organic phase was separated, dried over Na2SO4, and concentrated in vacuo. The residue was purified by a column chromatography on silica gel (EtOAc/PE=1:1) to give the title compound as a yellow solid (2.5 g, 76.2%).
Reaction SMILES: S1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.C(N(CC([O-])=O)CC(O)=O)CN(CC([O-])=O)CC(O)=O.[Na+].[Na+].[S:30]([O-:35])(O[O-])(=O)=[O:31].[K+].[K+].C([O-])(O)=O.[Na+]>C(#N)C.O>[O:31]=[S:30]1(=[O:35])[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1
Reactant: O=S(=O)([O-])O[O-]
Reactant: O=C1CCSCC1
Agent: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)O)CC(=O)O
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C1CCS(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.7 %

Procedure:
To a solution of tetrahydrothiopyran-4-one (400 mg) stirring in acetonitrile (5 ml) and Na2.EDTA (0.0004 M aq, 3 ml) was added potassium peroxymonosulphate (Oxone, 6.34 g) and NaHCO3 (2.69 g) in several aliquots over 30 minutes. The reaction mixture was stirred at room temperature for a further 2 hours, then diluted with water (40 ml), extracted into dichloromethane, and dried (MgSO4) to give 1,1-dioxo-tetrahydro-thiopyran-4-one (330 mg) as a white solid. To this compound (75 mg) stirring in anhydrous 1,2-dichloroethane (6 ml) was added 2-chloro-4-morpholin-4-yl-thienopyrimidine-6-yl methyl methylamine (150 mg, as previously prepared from 2-chloro-4-morpholin-4-yl-thienopyrimidine-6-carbaldehyde and methylamine under reductive amination conditions), followed by glacial acetic acid (31 μl) and sodium triacetoxy borohydride (138 mg). The reaction mixture was stirred for 24 hours at room temperature, and the product isolated by extraction into dichloromethane, followed by purification by flash chromatography to give (2-chloro-4-morpholin-4-yl-thienopyrimidine-6-ylmethyl)-(1,1-dioxo-hexahydro-thiopyran-4-yl)-methyl-amine (115 mg) as a yellow solid, which was used in a Suzuki coupling with 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indazole, to give, after flash silica purification the title compound (38 mg) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH2:8]Br)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1.C([O-])([O-])=O.[K+].[K+]>>[Br:1][C:2]1[C:7]([CH2:8][N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: c1c[nH]cn1
Reactant: BrCc1cccnc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Brc1ncccc1Cn1ccnc1

Procedure:
Synthesized from 5a (891 mg, 2.78 mmol), imidazole (658 mg, 5.56 mmol) and K2CO3 (1.92 g, 13.9 mmol) according to Method B. Yield: 375 mg, 1.41 mmol, 51%. 1H NMR (CDCl3, 500 MHz): δH (ppm): 5.23 (s, 2H), 6.96 (t, J=1.3 Hz, 1H), 7.07 (d, J=7.6 Hz, 1H) 7.15 (t, J=1.3 Hz, 1H), 7.24 (dd, J=7.6, 4.7 Hz, 1H), 7.66 (brs, 1H), 8.32 (dd, J=4.7, 1.9 Hz, 1H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=49.7, 119.3, 123.4, 130.0, 133.4, 136.6, 137.6, 142.0, 149.7; MS (ESI): m/z=239.10 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][CH2:24][CH3:25])[CH:11]=1)[CH3:2].[CH3:27][O:28][CH2:29][C:30]([OH:32])=O>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][C:13]=2[CH2:22][N:23]([CH2:24][CH3:25])[C:30](=[O:32])[CH2:29][O:28][CH3:27])[CH:11]=1)[CH3:2]
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cncc(CC(=O)OCC)c1
Reactant: COCC(=O)O
Product: CCOC(=O)Cc1cncc(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)COC)c1

Procedure:
[5-(2-Ethylaminomethyl-4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester and methoxyacetic acid were reacted as described in Example 8, Step 6 to provide [5-(2-{[N-ethyl-N-(2-methoxy-acetyl)-amino]-methyl}-4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester. The ester was hydrolyzed to the acid as described in Example 30, Step 2.