Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(C1N=CC2NC3C(C=2C=1C)=C(C=O)C=CC=3)=O)C.[N+](CC)([O-])=O.[CH2:27]([O:29][C:30]([C:32]1[N:33]=[CH:34][C:35]2[NH:36][C:37]3[C:42]([C:43]=2[C:44]=1[CH3:45])=[C:41]([CH:46]=[C:47]([N+:49]([O-])=O)[CH3:48])[CH:40]=[CH:39][CH:38]=3)=[O:31])[CH3:28]>>[CH2:27]([O:29][C:30]([C:32]1[N:33]=[CH:34][C:35]2[NH:36][C:37]3[C:42]([C:43]=2[C:44]=1[CH3:45])=[C:41]([CH2:46][CH:47]([NH2:49])[CH3:48])[CH:40]=[CH:39][CH:38]=3)=[O:31])[CH3:28]
Reactant: CCOC(=O)c1ncc2[nH]c3cccc(C=C(C)[N+](=O)[O-])c3c2c1C
Agent: CCOC(=O)c1ncc2[nH]c3cccc(C=O)c3c2c1C
Solvent: CC[N+](=O)[O-]
Product: CCOC(=O)c1ncc2[nH]c3cccc(CC(C)N)c3c2c1C

Procedure:
The production takes places analogously to example 9 by condensation of 5-formyl-4-methyl-beta-carboline-3-carboxylic acid ethyl ester with nitroethane and hydrogenation of the resulting 4-methyl-5-(2-nitropropenyl)-beta-carboline-3-carboxylic acid ethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[F:12])[N:8]=[C:7]([CH3:13])[CH:6]=[CH:5]2.C([N-]C(C)C)(C)C.[Li+].[CH2:22]([O:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36]Cl)=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[CH2:22]([O:29][C:30]1[CH:31]=[CH:32][C:33]([CH2:36][CH2:13][C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][C:11]([F:12])=[C:2]([F:1])[CH:3]=3)[N:8]=2)=[CH:34][CH:35]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Cc1ccc2cc(F)c(F)cc2n1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Fc1cc2ccc(CCc3ccc(OCc4ccccc4)cc3)nc2cc1F
Temperature: -10 °C

Procedure:
A solution of 8.9 g (49.6 mmol) of the product from Example 1, step 3 in 90 ml THF is cooled at −50° C. 28.6 ml (57.2 mmol) of a 2M solution of lithium diisopropylamide are added and the solution is allowed to heat to −10° C. After 15′ stirring at this temperature the deep colored solution is again cooled to −50° C. A solution of 11.6 g (49.8 mmol) of 1-benzyloxy-4-chloromethyl-benzene in 60 ml THF is dropped into the cooled solution. The system is allowed to heat to room temperature and stirred overnight. The solvent is evaporated and the residue that solidifies on cooling is stirred with ethyl ether and filtered. The residue is filtered through SiO2 eluting with dichloromethane. The yield is 3.75 g (20%).
Reaction SMILES: [C:1]([C:3]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH2:18][CH3:19])(=[O:17])=[O:16])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2].[CH3:20][C:21](C)([O-])[CH3:22].[K+].C(Br)C#C>>[C:1]([C:3]1[N:7]([CH2:22][C:21]#[CH:20])[C:6]([C:8]2[CH:9]=[CH:10][C:11]([NH:14][S:15]([CH2:18][CH3:19])(=[O:17])=[O:16])=[CH:12][CH:13]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CCS(=O)(=O)Nc1ccc(-c2ccc(C#N)[nH]2)cc1
Reactant: CC(C)(C)[O-]
Agent: C#CCBr
Agent: [K+]
Product: C#CCn1c(C#N)ccc1-c1ccc(NS(=O)(=O)CC)cc1
Yield: 6.3 %

Procedure:
N-[4-(5-cyano-1H-pyrrol-2-yl)phenyl]ethanesulfonamide (0.150 g, 0.54 mmol) was alkylated according to the procedure of Example 40 using potassium tert-butoxide (1.08 mL of a 1M solution, 1.08 mmol) and propargyl bromide (80% in toluene, 0.055 mL, 0.50 mmol) to afford the title compound (0.10 g, 6.3%).
Reaction SMILES: [C:1]1([CH2:11][CH:12]([CH2:16][C:17](=[O:27])[NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13](O)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:28][C@H:29]([C:36]([NH:38][C@H:39]([CH2:44][OH:45])[CH2:40][CH:41]([CH3:43])[CH3:42])=[O:37])[CH2:30][C:31]1[N:35]=[CH:34][NH:33][CH:32]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(N(CC)CC)C>[C:1]1([CH2:11][CH:12]([CH2:16][C:17](=[O:27])[NH:18][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:13]([NH:28][C@H:29]([C:36]([NH:38][C@H:39]([CH2:44][OH:45])[CH2:40][CH:41]([CH3:43])[CH3:42])=[O:37])[CH2:30][C:31]2[N:35]=[CH:34][NH:33][CH:32]=2)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(CC(Cc1cccc2ccccc12)C(=O)O)NCCc1ccccc1
Reactant: CC(C)C[C@@H](CO)NC(=O)[C@@H](N)Cc1c[nH]cn1
Agent: O=C([O-])O
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](CO)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C(CC(=O)NCCc1ccccc1)Cc1cccc2ccccc12
Reaction time: 8 h
Yield: 22 %

Procedure:
To a solution of 121 mg of (±)-2-(1-naphthylmethyl)-3-(phenethylcarbamoyl)propionic acid and 200 mg of L-histidyl-L-leucinol.2p-toluenesulfonic acid salt in 5 ml of N,N-dimethylformamide were successively added 0.09 ml of diphenylphosphoryl azide and 0.15 ml of triethylamine while ice-cooling, and the mixture was stirred overnight. To the reaction mixture was added a 5% aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by preparative silica gel thin layer chromatography (developing solvent: lower layer of chloroform/methanol/water=8/3/1 by volume) to obtain 44 mg of N-[2-(1-naphthylmethyl)-3-(phenethylcarbamoyl)propionyl]-L-histidyl-L-leucinol (isomer A) and 75 mg of isomer B as a white powder, respectively.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][N:3]1[C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:21])[C:18]([OH:20])=[O:19])=[CH:13][CH:12]=1.C(N(CC)CC)C.Br[CH:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:32](=[O:33])[O:31]1>C(Cl)(Cl)Cl>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][N:3]1[C:11]1[CH:16]=[CH:15][C:14]([CH:17]([CH3:21])[C:18]([O:20][CH:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:32](=[O:33])[O:31]2)=[O:19])=[CH:13][CH:12]=1
Reactant: CC(C(=O)O)c1ccc(N2Cc3ccccc3C2=O)cc1
Reactant: O=C1OC(Br)c2ccccc21
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C(=O)OC1OC(=O)c2ccccc21)c1ccc(N2Cc3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 75 %

Procedure:
To a solution of 8.4 g of 2-[4-(1-oxo-2-isoindolinyl)phenyl]propionic acid in 40 ml of chloroform and 3.4 of triethylamine is added a solution of 6.2 g of 3-bromophthalide in 20 ml of chloroform. The solution thus obtained is stirred 24 hours at room temperature, the organic phase is washed with an aqueous solution of sodium bicarbonate, then with water and finally it is dried on anhydrous sodium sulfate and evaporated to dryness to yield the phthalidyl 2-[4-(1-oxo-2-isoindolinyl)phenyl]propionate; yield 75%.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[N:10]2)[CH:6]=[CH:5][N:4]=1.ClNC(=O)CCC(N)=O.O.[CH:28]1([NH2:34])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>CN1C(=O)CCC1>[N:9]1([C:7]2[CH:6]=[CH:5][N:4]=[C:3]([NH:34][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[N:8]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[N:10]1
Reactant: CSc1nccc(-n2nnc3ccccc32)n1
Reactant: NC1CCCCC1
Agent: NC(=O)CCC(=O)NCl
Solvent: CN1CCCC1=O
Solvent: O
Product: c1ccc2c(c1)nnn2-c1ccnc(NC2CCCCC2)n1
Temperature: 130 °C
Reaction time: 0.12 h

Procedure:
To a solution of 1-(2-methylsulfanyl-pyrimidin-4-yl)-1H-benzotriazole (376 mg, 1.5 mmol) in 4 mL of NMP were added N-chlorosuccinamide (250 mg, 1.9 mmol) and 0.5 mL of water. The mixture was placed in an oil bath at 130° C. for 5-10 minutes, cyclohexylamine (450 mg, 5 mmol) was then added and the reaction mixture was stirred in an oil bath at 130° C. for 30 minutes. The cooled reaction mixture was partitioned between water (40 mL) and EtOAc (40 mL). The organic layer was separated and washed twice with water (40 mL), then dried over Na2SO4, filtered and the solvent removed under reduced pressure. The crude residue was purified by flash chromatography and recrystallized from CH2Cl2/EtOAc to give (4-benzotriazol-1-yl-pyrimidin-2-yl)-cyclohexyl-amine as a white short-needle crystalline solid (255 mg, 56% yield). mp=202.0-204.0° C.; MS=295 (M+H)+.
Reaction SMILES: [CH2:1]=O.[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH3:36])=[C:8]([NH:10][C:11]([C:13]2[N:14]=[CH:15][NH:16][C:17]=2[C:18]([NH:20][C:21]2[NH:25][C:24]3[CH:26]=[C:27]([N:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)[CH:28]=[CH:29][C:23]=3[N:22]=2)=[O:19])=[O:12])[CH:9]=1.[Na]>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH3:36])=[C:8]([NH:10][C:11]([C:13]2[N:14]=[CH:15][NH:16][C:17]=2[C:18]([NH:20][C:21]2[NH:22][C:23]3[CH:29]=[CH:28][C:27]([N:30]4[CH2:31][CH2:32][N:33]([CH3:1])[CH2:34][CH2:35]4)=[CH:26][C:24]=3[N:25]=2)=[O:19])=[O:12])[CH:9]=1
Reactant: C=O
Reactant: Cc1ccc(Cl)cc1NC(=O)c1nc[nH]c1C(=O)Nc1nc2ccc(N3CCNCC3)cc2[nH]1
Agent: [Na]
Solvent: CN(C)C=O
Product: Cc1ccc(Cl)cc1NC(=O)c1nc[nH]c1C(=O)Nc1nc2cc(N3CCN(C)CC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A round-bottom flask was charged with paraformaldehyde (2.0 mmol) and N4-(5-chloro-2-methylphenyl)-N5-(6-(piperazin-1-yl)-1H-benzo[d]imidazol-2-yl)-1H-imidazole-4,5-dicarboxamide (0.2 mmol), anhydrous DMF (5 mL) and sodium triacetoxybrohydride (1.0 mmol). The reaction mixture was stirred at room temperature overnight. The solution was concentrated under reduced pressure and purified by preparative scale —HPLC (aqueous ammonium acetate/acetonitrile) to give N4-(5-chloro-2-methylphenyl)-N5-[5-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-imidazole-4,5-dicarboxamide. 1H-NMR (400 MHz, MeOH-d4): δ 8.15 (s, 1H), 7.92 (s, 1H), 7.38 (d, 3H), 7.24 (s, 1H), 7.18-7.14 (m, 2H), 6.96 (dd, 1H), 3.35-3.25 (m, 4H), 3.00-2.90 (m, 4H), 2.57 (s, 3H), 2.40 (s, 3H). MS (EI): 493 (MH+).
Reaction SMILES: [I-].[CH2:2]([N+:6]1[C:10]([CH3:11])=[C:9]([CH3:12])[S:8][C:7]=1[CH3:13])[CH2:3][CH2:4][CH3:5].[O:14]1[C:18]2[CH:19]=[CH:20][C:21]([C:23](Cl)=[O:24])=[CH:22][C:17]=2[O:16][CH2:15]1>CN(C1C=CN=CC=1)C>[O:14]1[C:18]2[CH:19]=[CH:20][C:21]([C:23](=[O:24])/[CH:13]=[C:7]3\[S:8][C:9]([CH3:12])=[C:10]([CH3:11])[N:6]\3[CH2:2][CH2:3][CH2:4][CH3:5])=[CH:22][C:17]=2[O:16][CH2:15]1
Reactant: CCCC[n+]1c(C)sc(C)c1C
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Agent: CN(C)c1ccncc1
Agent: [I-]
Product: CCCCN1C(C)=C(C)S/C1=C\C(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 3-butyl-2,4,5-trimethylthiazol-3-ium iodide (48 mg in 0.5 mL DMA, 0.16 mmol, 1 equiv.) was added, followed by TEA (38 mg in 0.5 mL DMA, 0.37 mmol, 2.4 equiv.) and the solution went black. DMAP (2 mg in 0.5 mL DMA, 0.016 mmol, 0.1 equiv) was added next, followed by benzo[d][1,3]dioxole-5-carbonyl chloride (0.9 mL of 0.2M in DMA, 1.2 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 0.93 (t, 3 H) 1.34-1.44 (m, 2 H) 1.58-1.68 (m, 2 H) 2.16 (s, 3 H) 2.20 (s, 3 H) 4.02-4.09 (m, 2 H) 6.08 (s, 2 H) 6.48 (s, 1 H) 6.93-6.99 (m, 1 H) 7.47-7.48 (m, 1 H) 7.49-7.54 (m, 1 H); MS (ESI) m/z 332 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[C:11]1[CH:16]=[CH:15][N:14]([CH3:17])[CH2:13][CH:12]=1.[CH:28]([Sn](CCCC)(CCCC)CCCC)=[CH2:29].C(OCC)(=O)C>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:28]([C:2]1[CH:3]=[C:4]([O:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH2:16]1)=[CH2:29]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CN1C=CC(c2c[nH]c3c(Br)cc(OS(=O)(=O)c4ccccc4)cc23)=CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=Cc1cc(OS(=O)(=O)c2ccccc2)cc2c(C3CCN(C)CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of benzenesulfonic acid 7-bromo-3-(1-methylpyridin-4-yl)-1H-indol-5-yl ester and Pd (PPh3)4 (0.2 eq.) in dry toluene was degassed and then treated with vinyl tributyltin (1.1 eq.). Heat the reaction mixture to reflux. After 5 hours, cool to room temperature, pour into ethyl acetate, wash with brine, dry the organic layer over Na2SO4, and concentrate. Purify to give the title compound.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:4][CH2:3]1.[CH3:17][Li].[NH4+].[Cl-]>O1CCCC1.CCOCC>[OH:1][C:2]1([CH3:17])[CH2:3][CH2:4][CH:5]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH2:6][CH2:7]1
Reactant: CC(C)(C)OC(=O)NCC1CCC(=O)CC1
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC1(O)CCC(CNC(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 1.2 h

Procedure:
To a vigorous stirring solution of tert-butyl (4-oxocyclohexyl)methylcarbamate (1.7 g) in tetrahydrofuran (40 mL) at −78° C. was dropwise added 1.6 M methyllithium (14.02 mL) in ether. After completion of the addition, the mixture was stirred at −78° C. for 1.2 hours and poured into a cold aqueous NH4Cl solution. The resulting mixture was extracted with dichloromethane (3×100 mL) and the organic layer was dried over Na2SO4, filtered and concentrated. The residue was dissolved in dichloromethane and loaded onto an Analogix purification system, eluted with 0-50% ethyl acetate in dichloromethane to provide the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[S:20][C:19]([NH:21][C:22](=[O:36])[C:23]([NH:26][C:27](=[O:35])[C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)([CH3:25])[CH3:24])=[N:18][C:17]=2[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:34][C:31]1[CH:30]=[CH:29][C:28]([C:27]([NH:26][C:23]([CH3:25])([C:22](=[O:36])[NH:21][C:19]2[S:20][C:16]([C:14]([N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[O:15])=[C:17]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:18]=2)[CH3:24])=[O:35])=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2sc(NC(=O)C(C)(C)NC(=O)c3ccc(F)cc3)nc2-c2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(NC(=O)c1ccc(F)cc1)C(=O)Nc1nc(-c2ccccc2)c(C(=O)N2CCNCC2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-{2-[2-(4-Fluoro-benzoylamino)-2-methyl-propionylamino]-4-phenyl-thiazole-5-carbonyl}-piperazine-1-carboxylic acid tert-butyl ester (120 mg) and TFA (3 mL) in dichloromethane (3 mL) was stirred at RT for 1 h. The mixture was concentrated, and the residue was partitioned between ethyl acetate and aq. K2CO3. The organic extract was dried over MgSO4 and concentrated. The residue was taken up in dichloromethane-methanol (3:1 v/v), and 2 M HCl (in ether, 100 uL) was added. The mixture was stirred at RT for 10 min and concentrated to give hydrochloride salt of the title compound. LCMS method A, retention time 1.0 min. m/z 496.1 (M+H+).
Reaction SMILES: C[Mg+].[Br-].[OH:4][C:5]1[C:6]([C:11]([OH:13])=O)=[N:7][CH:8]=[CH:9][CH:10]=1.[CH2:14](N(CC)CC)C.C(OC)=O.Cl>C1COCC1>[OH:4][C:5]1[C:6]([C:11](=[O:13])[CH3:14])=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)c1ncccc1O
Agent: C[Mg+]
Agent: Cl
Agent: [Br-]
Solvent: COC=O
Solvent: C1CCOC1
Product: CC(=O)c1ncccc1O
Temperature: 60 °C
Reaction time: 2 h
Yield: 26.5 %

Procedure:
A solution of MeMgBr (390 mL of 1.4 M in toluene/THF (75:25), 540 mmol) was heated at 60° C. and a solution of 3-hydroxypyridine-2-carboxylic acid (15 g, 110 mmol) and triethylamine (15 mL, 110 mmol) in THF (75 mL) was added dropwise over 3 hours. The resulting mixture was then stirred for 2 hours at 60° C. The reaction mixture was cooled on an ice/brine bath and methyl formate (13 mL, 220 mmol) was added keeping the internal temperature below 20° C. The reaction mixture was then acidified to pH 5-6 with 1M aqueous HCl, and the layers were separated, and the aqueous layer was extracted with ethyl acetate (3×). The organic phases were combined, washed with brine, dried over sodium sulfate and evaporated to dryness to afford 1-(3-hydroxypyridin-2-yl)ethanone (4.0 g, 27%). ESI-MS m/z calc. 137.1. found 138.3 (M+1)+; Retention time: 0.62 minutes (3 min run).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:4]=[C:5]([OH:35])[CH:6]=[CH:7][C:8]=2[N:9]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][N:28]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:23][CH:24]=2)[C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1.C[OH:37]>C(O)(C)C>[CH3:1][C:2]1[C:3]2[CH:4]=[C:5]([OH:35])[CH:6]=[CH:7][C:8]=2[N:9]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)=[CH:21][CH:20]=2)[C:10]=1[C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1.[CH3:27][C:26]([OH:37])=[O:25]
Reactant: CO
Agent: Cc1c(-c2ccc(O)cc2)n(Cc2ccc(OCCN3CCCCCC3)cc2)c2ccc(O)cc12
Solvent: CC(C)O
Product: CC(=O)O
Temperature: 27 °C

Procedure:
Crystalline bazedoxifene free base (10 g) is charged in a mixture of methanol (120 mL) and isopropyl alcohol (50 mL) and heated to reflux temperature to make a clear solution. The solution is filtered and cooled to about 27° C. over a period of 15 minutes followed by addition of acetic acid (1.65 g) and then seed crystals of Form D (0.5 g). Then the mixture is further allowed to cool to 0° C. over a period of about 2 hours. The reaction mixture is maintained at the same temperature for 1 hour and the solid is collected by filtration, washed with precooled methanol (20 mL), and dried under vacuum at about 70° C. for about 6 hours to afford the title compound having HPLC Purity of 99.84%.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:12][N:13]2[C:17](=[O:18])[N:16]([CH2:19][CH:20]([OH:25])[C:21]([F:24])([F:23])[F:22])[C:15]([C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)=[N:14]2)[CH:3]=1.[Cl:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1B(O)O>>[Cl:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH2:12][N:13]2[C:17](=[O:18])[N:16]([CH2:19][CH:20]([OH:25])[C:21]([F:23])([F:22])[F:24])[C:15]([C:26]3[CH:27]=[CH:28][C:29]([Cl:32])=[CH:30][CH:31]=3)=[N:14]2)[CH:3]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: COC(=O)c1ccc(Br)cc1Cn1nc(-c2ccc(Cl)cc2)n(CC(O)C(F)(F)F)c1=O
Product: COC(=O)c1ccc(-c2ccccc2Cl)cc1Cn1nc(-c2ccc(Cl)cc2)n(CC(O)C(F)(F)F)c1=O

Procedure:
Analogously to the preparation of Example 122, 265 mg (0.50 mmol) of the compound from Example 104A were reacted with 194 mg (0.74 mmol) of 2-chlorophenylboronic acid. This gave 54 mg (19% of theory) of the target compound of a purity of 98% and 167 mg (49% of theory) of a purity of 83%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2.[Cl:12]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(#N)C>[Cl:12][CH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[N:5]2
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1ccc2nccnc2c1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CC#N
Product: ClCc1ccc2nccnc2c1
Reaction time: 6 h

Procedure:
In a 500 ml flask, 6-methyl-quinoxaline (10 g, 69.4 mmol) was dissolved together with N-chlorosuccinimide (14 g, 105.3 mmol) and benzoyl peroxide (BP, 0.4 g, 1.65 mmol) in 240 g of acetonitrile. The flask was connected to a reflux-condenser and the solution was refluxed for 6 hours followed by another addition of 0.1 g of benzoyl peroxide. Reflux was then continued for another 6 hours.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][OH:15])=[CH:9][CH:8]=1.[N:21]#[C:22][NH2:23].[OH:24][S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26].C(O)(C(F)(F)F)=O>C1COCC1>[OH:27][S:25]([C:28]([F:31])([F:30])[F:29])(=[O:26])=[O:24].[C:22](=[NH:21])([O:15][CH2:14][CH2:13][C:10]1[CH:9]=[CH:8][C:7]([O:6][C:5]2[CH:16]=[CH:17][CH:18]=[C:3]([C:2]([F:19])([F:20])[F:1])[CH:4]=2)=[CH:12][CH:11]=1)[NH2:23]
Reactant: OCCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Reactant: N#CN
Agent: O=S(=O)(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)OCCc1ccc(Oc2cccc(C(F)(F)F)c2)cc1
Temperature: 55 °C
Yield: 59.7 %

Procedure:
To a solution of 2-(4-(3-(trifluoromethyl)phenoxy)phenyl)ethanol (1.395 g, 4.94 mmol) and cyanamide (0.249 g, 5.93 mmol) in THF (15 mL) was added triflic acid (0.527 mL, 5.93 mmol) under argon. The mixture was heated at 55° C. for 3 h. The mixture was purified by a reverse phase biotage with TFA affording the title compound (1.4 g, 59.8% yield). LCMS: rt=1.23 min, [M+H+]=325
Reaction SMILES: Cl[C:2]1[S:3][C:4]([CH2:7][N:8]2[C:12]([CH3:13])=[N:11][C:10]([C:14]3[O:18][N:17]=[C:16]([C:19]4[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=4)[N:15]=3)=[N:9]2)=[CH:5][N:6]=1.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>CS(C)=O>[CH3:13][C:12]1[N:8]([CH2:7][C:4]2[S:3][C:2]([N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)=[N:6][CH:5]=2)[N:9]=[C:10]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=3)[N:15]=2)[N:11]=1
Reactant: C1COCCN1
Reactant: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cnc(Cl)s1
Solvent: CS(C)=O
Product: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)no2)nn1Cc1cnc(N2CCOCC2)s1
Temperature: 140 °C
Yield: 42.6 %

Procedure:
5-(1-((2-Chlorothiazol-5-yl)methyl)-5-methyl-1H-1,2,4-triazol-3-yl)-3-(4-(trifluoro methoxy)phenyl)-1,2,4-oxadiazole (45 mg, 0.1 mmol) was mixed with morpholine (87 mg, 1.0 mmol) in DMSO (0.5 mL). The mixture was heated to 140° C. overnight. The resulting crude product was purified by a silica gel column with (EtOAc/Hexane 50% to 100% EtOAc) to give 4-(5-((5-methyl-3-(3-(4-(trifluoromethoxy)phenyl)-1,2,4-oxadiazol-5-yl)-1H-1,2,4-triazol-1-yl)methyl)thiazol-2-yl)morpholine as a white solid (21 mg, 43%). MS (ES+) C20H18F3N7O3S requires: 493. found: 494[M+H]+; 1H NMR (600 MHz, CDCl3) δ 8.28 (d, J=8.8 Hz, 2H), 7.34 (d, J=8.4 Hz, 2H), 7.24 (s, 1H), 5.47 (s, 2H), 3.78 (t, J=4.9 Hz, 4H), 3.44 (t, J=4.9 Hz, 4H), 2.62 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:5][C:3]=1[NH2:4].[Cu](C#N)[C:15]#[N:16].N>CN1CCCC1=O>[NH2:4][C:3]1[CH:5]=[CH:6][C:7]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:8][C:2]=1[C:15]#[N:16]
Reactant: N#C[Cu]C#N
Reactant: Nc1ccc(OC(F)(F)F)cc1Br
Agent: N
Solvent: CN1CCCC1=O
Product: N#Cc1cc(OC(F)(F)F)ccc1N
Temperature: 163 °C
Reaction time: 6.5 h
Yield: 75 %

Procedure:
To a solution of 2-bromo-4-(trifluoromethoxy)aniline (15.1 g, 60.0 mmol) in N-methylpyrrolidone (100 mL) was added copper cyanide (10.6 g, 118 mmol) and the reaction mixture was stirred for 6.5 h at 163° C. After cooling to ambient temperature it was poured onto ice-water (300 mL) and aqueous ammonia (350 mL). The resulting brown precipitate was collected by filtration, washed with water (150 mL) and dissolved in dichloromethane (350 mL). The insoluble material was removed by filtration and the filtrate was washed with brine (100 mL) and dried over sodium sulfate. Purification by chromatography (SiO2, heptane:ethyl acetate=95:5 to 25:75:) afforded the title compound (9.09 g, 76%) as a brown solid. MS: m/e=405.1 [2M+H]+.