Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C:6]([OH:8])=O.CCN(CC)CC.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[F:43][C:44]([F:74])([F:73])[C:45]1[CH:46]=[C:47]([C:55]([CH3:72])([CH3:71])[C:56]([N:58]([CH3:70])[C@H:59]2[C@H:63]([C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[CH2:62][NH:61][CH2:60]2)=[O:57])[CH:48]=[C:49]([C:51]([F:54])([F:53])[F:52])[CH:50]=1>C1COCC1>[F:53][C:51]([F:52])([F:54])[C:49]1[CH:48]=[C:47]([C:55]([CH3:71])([CH3:72])[C:56]([N:58]([CH3:70])[C@H:59]2[C@H:63]([C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[CH2:62][N:61]([C:6]([C@@H:2]3[CH2:3][CH2:4][CH2:5][O:1]3)=[O:8])[CH2:60]2)=[O:57])[CH:46]=[C:45]([C:44]([F:43])([F:73])[F:74])[CH:50]=1
Reactant: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CNC[C@H]1c1ccccc1
Reactant: O=C(O)[C@@H]1CCCO1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)[C@@H]1CN(C(=O)[C@@H]2CCCO2)C[C@H]1c1ccccc1
Reaction time: 48 h
Yield: 21.3 %

Procedure:
To a stirred solution of (S)-tetrahydro-furan-2-carboxylic acid (described in J. Med. Chem., 1995, 38(15, 2830) (5.0 mg, 0.043 mmol) in THF (2 ml) at RT were added Et3N (12 μl, 0.086 mmol), BOP (25 mg, 0.057 mmol) and rac-2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-((3S,4R)-4-phenyl-pyrrolidin-3-yl)-isobutyramide (Intermediate VII-1) (20 mg, 0.043 mmol). Stirring was continued at 40° C. for 48 hours. Concentration and purification by preparative HPLC afforded 5.1 mg (25%) of the title compound.
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[I:7]I.[NH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:20])[N:11]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C.O>[NH2:9][C:10]1[C:19]([I:7])=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[C:12]([CH3:20])[N:11]=1
Reactant: II
Reactant: COC(=O)c1ccc(N)nc1C
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(I)c(N)nc1C
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
Sodium periodate (4.05 g, 18.9 mmol) and iodine (9.62 g, 37.9 mmol) were added to a solution of methyl 6-amino-2-methylnicotinate (8.40 g, 50.5 mmol) in DMF (45 ml), and the mixture was then stirred at 50° C. for 1.5 hours. The reaction mixture was added to a cold solution of 250 ml of saturated sodium thiosulphate solution in 150 ml of water. The solid formed was filtered off with suction, washed with water and dried. This gave 13.4 mg (88.9% of theory) of methyl 6-amino-5-iodo-2-methylnicotinate. HPLC-MS: log P=1.55; mass (m/z): 293.0 (M+H)+; 1H-NMR (D6DMSO) 2.50 (s, 3H), 3.74 (s, 3H), 6.81 (br. s, 1H), 8.25 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=3)[N:12]=2)=[CH:4][N:3]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>CS(C)=O.[Cl-].[Na+].O>[Cl:20][C:15]1[CH:14]=[C:13]([C:11]2[N:12]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)=[N:3][CH:4]=3)[NH:9][CH:10]=2)[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: Clc1ccc(-c2nc(-c3ccc(Cl)c(Cl)c3)c[nH]2)cn1
Reactant: C1CNCCN1
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Clc1ccc(-c2c[nH]c(-c3ccc(N4CCNCC4)nc3)n2)cc1Cl
Temperature: 25 °C
Yield: 58.4 %

Procedure:
A solution of 2-Chloro-5-[4-(3,4-dichloro-phenyl)-1H-imidazol-2-yl]-pyridine (72.8 g) and piperazine (61.8 g) in DMSO (478 mL) was heated to 105 degrees 16 hours. The reaction mixture was cooled to room temperature and diluted with 2500 mL half-saturated brine. The resultant precipitate was collected by filtration and triturated with 2000 mL hot methanol. The solids were collected by filtration, the mother liquor was concentrated to about 100 mL, and the additional precipitate was collected and combined with the original solids to provide 1-{5-[4-(3,4-dichloro-phenyl)-1H-imidazol-2-yl]-pyridin-2-yl}-piperazine (49 g).
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([F:11])[CH:5]=[CH:4][C:3]=1[OH:12].NC1C=CC(O)=CC=1[F:21]>>[F:21][C:4]1[CH:5]=[C:6]([F:11])[C:7]([NH2:8])=[CH:2][C:3]=1[OH:12]
Reactant: O=[N+]([O-])c1c(F)ccc(O)c1F
Reactant: Nc1ccc(O)cc1F
Product: Nc1cc(O)c(F)cc1F
Yield: 97 %

Procedure:
This compound was prepared from 2,4-difluoro-3-nitrophenol (2.35 g, 13.4 mmol) in the manner described for 4-amino-3-fluorophenol, affording 1.89 g (97%) of 2,4-difluoro-5-aminophenol as a tan solid. 1H-NMR (DMSO-d6) δ 9.26 (s, 1H), 6.89 (t, J=10.7 Hz, 1H), 6.33 (t, J=9.2 Hz, 1H), 4.82 (s, 2H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]([F:38])([F:37])[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[C:17]([CH:34]=[CH:35][CH:36]=2)[CH2:18][O:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([CH3:33])([CH2:30][CH:31]=[CH2:32])[C:27](O)=[O:28])=[CH:22][CH:21]=2)=[CH:11][CH:10]=1.[CH2:39]([NH:41][CH2:42][CH3:43])[CH3:40].CCN(CC)CC>ClCCl>[F:37][C:8]([F:38])([F:7])[C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[C:17]([CH:34]=[CH:35][CH:36]=2)[CH2:18][O:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]([CH3:33])([CH2:30][CH:31]=[CH2:32])[C:27]([N:41]([CH2:42][CH3:43])[CH2:39][CH3:40])=[O:28])=[CH:24][CH:25]=2)=[CH:13][CH:14]=1
Reactant: CCNCC
Reactant: C=CCC(C)(C(=O)O)c1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCC(C)(C(=O)N(CC)CC)c1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1
Temperature: 50 °C
Yield: 71.9 %

Procedure:
Oxalyl chloride (57.7 mg, 0.45 mmol) was added dropwise to 49.5 (100 mg, 0.23 mmol) in anhydrous dichloromethane (4 mL). The resulting mixture was refluxed in a sealed tube at 50° C. overnight. The dichloromethane was removed under a stream of N2. Anhydrous ether (2 mL) was added dropwise, followed by diethyl amine (50 mg, 0.69 mmol) and Et3N (70 mg, 0.69 mmol). The mixture was refluxed overnight. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified via flash chromatography (25% ethyl acetate in hexanes). 82 mg of 49.6 was obtained. MS ESI m/e: 496 (M−H). 1H NMR (500 MHz) (CDCl3) δ 7.72 (4H, s); 7.69 (1H, s); 7.6-7.5 (3H, m); 7.14 (2H, d, J=8.5 Hz); 7.05 (2H, d, J=8.5 Hz); 5.7-5.6 (1H, m); 5.15 (2H, s); 5.03-5 (2H, m); 3.5-3.2 (2H, m); 3.0-2.9 (2H, m); 2.74-2.64 (2H, m); 1.62 (3H, s); 1.13 (3H, s); 0.72 (3H, s).
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([Br:7])[N:6]=1.[O:8]=[S:9]1(=[O:36])[CH2:14][CH2:13][CH:12]([C:15]2[C:23]3[C:18](=[C:19]([C:33]([NH2:35])=[O:34])[CH:20]=[C:21](B4OC(C)(C)C(C)(C)O4)[CH:22]=3)[NH:17][CH:16]=2)[CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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.O>[Br:7][C:5]1[N:6]=[C:2]([C:21]2[CH:22]=[C:23]3[C:18](=[C:19]([C:33]([NH2:35])=[O:34])[CH:20]=2)[NH:17][CH:16]=[C:15]3[CH:12]2[CH2:11][CH2:10][S:9](=[O:8])(=[O:36])[CH2:14][CH2:13]2)[S:3][CH:4]=1
Reactant: Brc1csc(Br)n1
Reactant: CC1(C)OB(c2cc(C(N)=O)c3[nH]cc(C4CCS(=O)(=O)CC4)c3c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: NC(=O)c1cc(-c2nc(Br)cs2)cc2c(C3CCS(=O)(=O)CC3)c[nH]c12
Reaction time: 0.67 h
Yield: 4.6 %

Procedure:
To a microwave vial was added 2,4-dibromo-1,3-thiazole (0.035 g, 0.143 mmol), 3-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide (0.060 g, 0.143 mmol) and potassium carbonate (0.059 g, 0.429 mmol) along with 1,4-dioxane (1.073 mL)/water (0.358 mL). The mixture was degassed with nitrogen and Pd(PPh3)4 (0.017 g, 0.014 mmol) was added. The reaction mixture was heated in the microwave under ‘high’ absorption setting for 40 minutes at 150° C. The reaction mixture was filtered through a Thiol SPE cartridge (500 mg) eluting with 1:1 MeOH/DCM (10 mL). The eluent was concentrated under nitrogen and purified by RP-HPLC on an X-Bridge C18 column with Acetonitrile/Water (0.1% NH4OH), giving 3 mg (4.6%) of the title compound.
Reaction SMILES: CO.[CH3:3][S:4][C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:12]=1)([CH3:10])[C:6]([O:8]C)=[O:7].[OH-].[Na+]>O>[CH3:3][S:4][C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:12]=1)([CH3:10])[C:6]([OH:8])=[O:7]
Reactant: COC(=O)C(C)(SC)c1cccc(Oc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CSC(C)(C(=O)O)c1cccc(Oc2ccccc2)c1
Yield: 99.3 %

Procedure:
Methanol (4 ml) and 2 ml of water were added to 663 mg of methyl α-methylthio-α-(m-phenoxyphenyl)propionate, and then 300 mg of sodium hydroxide was added. The mixture was heated under reflux for 2 hours, diluted with 30 ml of water, and extracted with 10 ml of diethyl ether. The aqueous layer was acidified with about 1 ml of conc. hydrochloric acid, and extracted three times with 20 ml of diethyl ether. The organic layer was washed with 10 ml of water, and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave 628 mg of α-methylthio-α-(m-phenoxyphenyl)propionic acid as an oil in a yield of 99%. This product crystallized on standing at room temperature. Recrystallization from hexane and carbon tetrachloride afforded colorless crystals having a melting point of 87° to 88° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4]Br.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:19]=1[OH:27]>O>[Br:1][CH2:2][CH2:3][CH2:4][O:27][C:19]1[CH:20]=[C:21]([N+:24]([O-:26])=[O:25])[CH:22]=[CH:23][C:18]=1[Cl:17]
Reactant: BrCCCBr
Reactant: O=[N+]([O-])c1ccc(Cl)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Cl)c(OCCCBr)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,3-dibromo propane (1.3 mL, 12.65 mmol) and cesium carbonate (4.1 g, 12.65 mmol) was added to the DMF (18 mL) solution of 2-chloro-5-nitro phenol (2.0 g, 11.5 mmol) and the reaction mixture stirred overnight at room temperature. Water (20 mL) was added to the mixture, extracted with DCM (3×25 mL) and combined extracts were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash column chromatography to get the title compound 26a in 64% (2.176 g) yield as colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH:11]=O)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[CH3:29][C:30]1[N:31]=[C:32]([CH2:35][CH2:36][NH2:37])[S:33][CH:34]=1>>[CH3:1][N:2]1[C:10]([CH2:11][NH:37][CH2:36][CH2:35][C:32]2[S:33][CH:34]=[C:30]([CH3:29])[N:31]=2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Reactant: Cc1csc(CCN)n1
Product: Cc1csc(CCNCc2nc3c(N4CCOCC4)nc(-n4c(C)nc5ccccc54)nc3n2C)n1

Procedure:
Following General Procedure L for reductive amination, 9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-morpholino-9H-purine-8-carbaldehyde and 2-(4-methylthiazol-2-yl)ethanamine were reacted to give 321. [M+H]+ 504.6.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[CH:6][CH:5]=1)(=O)[CH3:2].[ClH:10].[C:11]([O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:14])[NH:12][NH2:13]>C(O)C>[ClH:10].[N:7]1[CH:8]=[CH:9][C:4]([C:1](=[N:13][NH:12][C:11]([O:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:14])[CH3:2])=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccncc1
Reactant: NNC(=O)Oc1ccccc1
Agent: Cl
Solvent: CCO
Product: CC(=NNC(=O)Oc1ccccc1)c1ccncc1
Yield: 96.4 %

Procedure:
A mixture of 12.11 gm (0.1 mole) of 4-acetylpyridine, 18.85 gm (0.1 mole) of phenyl carbazate hydrochloride and 250 ml of absolute ethanol is refluxed 6 hr and cooled. The reaction mixture is evaporated to dryness in vacuo to give a rose-colored solid. The crude product is crystallized from absolute ethanol to yield 28.13 gm (97%) of the title compound having a melting point of 159.1° C.
Reaction SMILES: [CH:1]1([O:5][C:6]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=2[C:8]([OH:10])=O)[CH2:4][CH2:3][CH2:2]1.[N:19]1([C:25]2[S:26][C:27]([C:30]#[N:31])=[CH:28][N:29]=2)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>>[CH:1]1([O:5][C:6]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][C:7]=2[C:8]([N:22]2[CH2:23][CH2:24][N:19]([C:25]3[S:26][C:27]([C:30]#[N:31])=[CH:28][N:29]=3)[CH2:20][CH2:21]2)=[O:10])[CH2:2][CH2:3][CH2:4]1
Reactant: N#Cc1cnc(N2CCNCC2)s1
Reactant: CS(=O)(=O)c1ccc(OC2CCC2)c(C(=O)O)c1
Product: CS(=O)(=O)c1ccc(OC2CCC2)c(C(=O)N2CCN(c3ncc(C#N)s3)CC2)c1
Yield: 54 %

Procedure:
Prepared in analogy to example 1 (b) from 2-cyclobutoxy-5-methanesulfonyl-benzoic acid (Example A9) and 2-piperazin-1-yl-thiazole-5-carbonitrile (Example 6(a)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) followed by trituration in ether to yield the title compound as an off-white crystalline solid (yield 54%). MS (m/e): 447.2 (M+H+, 100%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH2:8]/[CH:9]=[CH:10]/[C:11]([OH:13])=O)=[O:7].[NH:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17]>O1CCCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([CH2:8]/[CH:9]=[CH:10]/[C:11]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=[O:17])=[O:13])=[O:7]
Reactant: O=C(O)/C=C/CC(=O)c1ccco1
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: C1CCOC1
Product: O=C(C/C=C/C(=O)N1CCC[C@H]1C(=O)O)c1ccco1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 0.02 moles of 4-(2-furoyl)crotonic acid in 100 ml. of tetrahydrofuran is added 0.022 moles of N,N'-carbonyldiimidazole. The mixture is stirred for 3 hours at room temperature and 0.021 moles of L-proline are added. The mixture is refluxed 2 hours and stirred at room temperature for 16 hours to give 1-[4-(2-furoyl)crotonyl]-L-proline.
Reaction SMILES: [C:1]1([CH2:7][C:8]#N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[Br:12][C:13]1[CH:18]=C[C:16]([N+:19]([O-])=[O:20])=[CH:15][CH:14]=1.O>CO>[Br:12][C:13]1[CH:14]=[CH:15][C:16]2[C:8]([CH:18]=1)=[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[O:20][N:19]=2
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: N#CCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Brc1ccc2noc(-c3ccccc3)c2c1
Temperature: 50 °C
Yield: 55.2 %

Procedure:
Phenylacetonitrile (8.1 g, 69 m mol) was added to a room temperature solution of potassium hydroxide (85%) (74 g, 1.1 mol) in methanol (150 ml). To this was added 4-bromo-1-nitrobenzene (12.7 g, 63 m mol) suspended in methanol (130 ml). An exotherm was noted and the reaction was maintained at 50° C. for 5 hrs. After cooling to room temperature, water (400 ml) was added. The precipitate was collected and washed with water. The crude product (13.15 g) was crystallized from hot methanol (200 ml) to yield yellow needles (9.52 g, mp 113°-116° C.).
Reaction SMILES: [CH2:1]([N:8]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:9][C:10]([C:12]1[CH:20]=[C:16]([C:17]([NH2:19])=[O:18])[C:15]([OH:21])=[CH:14][CH:13]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[C:31](=O)([O-])[O-].[K+].[K+]>CC(CC)=O>[CH2:22]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:9][C:10]([C:12]1[CH:20]=[C:16]([C:17]([NH2:19])=[O:18])[C:15]([O:21][CH3:31])=[CH:14][CH:13]=1)=[O:11])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C([O-])[O-]
Reactant: NC(=O)c1cc(C(=O)CN(Cc2ccccc2)Cc2ccccc2)ccc1O
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CI
Product: COc1ccc(C(=O)CN(Cc2ccccc2)Cc2ccccc2)cc1C(N)=O

Procedure:
5-(N,N-Dibenzylglycyl)salicylamide (37.4 g) was heated at reflux for 2 hours with methyl iodide (10 ml) and anhydrous potassium carbonate (20 g) in ethyl methyl ketone (350 ml). The inorganic salts were filtered off and the solvent was evaporated in vacuo. The residue was dissolved in ethyl acetate, washed with water and again evaporated. The residual oil was crystallised from isopropanol to give 5-(N,N-dibenzylglycyl)-o-anisamide as a white solid, (14 g) m.p. 113°-114° .
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=O.[C:11]([O:15][CH3:16])(=[O:14])[CH2:12][SH:13].C([O-])([O-])=O.[Na+].[Na+]>CO.[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:13][C:12]([C:11]([O:15][CH3:16])=[O:14])=[CH:7][C:6]=2[CH:9]=1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cc2cc(Br)ccc2s1

Procedure:
A solution of 5-bromo-2-fluorobenzaldehyde (6 g, 29.6 mmol), methyl thioglycolate (2.64 mL, 29.6 mmol), and Na2CO3 (3.14 g, 29.6 mmol) in methanol was heated to reflux for 1 hour, poured into brine, and extracted with ethyl acetate (3×). The combined extracts were washed with brine and filtered through silica gel to provide the desired product. MS (ESI(−)) m/e 270 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[N:44]1([CH2:50][CH:51]([N:54]2[CH:58]=[C:57]([C:59]3[C:60]4[CH:67]=[CH:66][N:65](COCC[Si](C)(C)C)[C:61]=4[N:62]=[CH:63][N:64]=3)[CH:56]=[N:55]2)[CH2:52][CH3:53])[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>C1COCC1>[N:62]1[C:61]2[NH:65][CH:66]=[CH:67][C:60]=2[C:59]([C:57]2[CH:56]=[N:55][N:54]([CH:51]([CH2:52][CH3:53])[CH2:50][N:44]3[CH2:49][CH2:48][N:47]([C:4]([C:3]4[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=4[OH:1])=[O:6])[CH2:46][CH2:45]3)[CH:58]=2)=[N:64][CH:63]=1
Reactant: CCC(CN1CCNCC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Reactant: O=C(O)c1ccccc1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(CN1CCN(C(=O)c2ccccc2O)CC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Reaction time: 8 h

Procedure:
To a solution of 2-hydroxybenzoic acid (0.0045 g, 0.033 mmol) in tetrahydrofuran (0.5 mL, 6 mmol) was added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.012 g, 0.033 mmol) and N,N-diisopropylethylamine (5.7 uL, 0.033 mmol) and mixed for 1 hour until dissolution. The reaction was stirred overnight, then 4-{1-[1-(piperazin-1-ylmethyl)propyl]-1H-pyrazol-4-yl}-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (0.010 g, 0.022 mmol from step 4 in example 115 and 0.5 mL THF were added. After 0.5 hour, the reaction was purified by LCMS (pH 10) to give 14 mg white solid which was stirred in 1 mL MeOH and 50 microL EDA for 2 hours. The reaction was purified by LCMS (pH 10) to give 2.2 mg white solid. 1H NMR (400 MHz, DMSO): δ 8.64 (1H, s); 8.6 (1H, s); 8.22 (1H, s); 7.55 (1H, d); 7.35 (1H, m); 6.99 (1H, m); 6.93 (1H, m); 688 (1H, m); 6.75 (1H, m); 4.39 (1H, m); 3.5-2.2 (10H, br); 1.78 (2H, m); 0.65 (3H, t). LCMS (M+1); 446.
Reaction SMILES: OO.[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[CH3:14])[NH:10]C(=O)[C:8]2=[O:16].S(=O)(=O)(O)[OH:18]>[OH-].[Na+]>[NH2:10][C:11]1[CH:12]=[C:13]([CH3:14])[C:5]([O:4][CH3:3])=[CH:6][C:7]=1[C:8]([OH:16])=[O:18]
Reactant: O=S(=O)(O)O
Reactant: COc1cc2c(cc1C)NC(=O)C2=O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(C(=O)O)c(N)cc1C
Yield: 61 %

Procedure:
10% Hydrogen peroxide (H2O2) (80 mL) was added dropwise to a stirring solution of 5-methoxy-6-methyl-1H-indole-2,3-dione (4.7 g, 24.6 mmol) in 3N NaOH (aq.) (100 mL). The H2O2 solution was added over a period of 1.5 h in order to keep the temperature below 35° C. The solution was then acidified to pH 4 with 2.5M sulfuric acid. A precipitate formed and was collected by filtration. The solid was washed with water and dried to give 2-amino-5-methoxy-4-methylbenzoic acid (2.7 g, 14.9 mmol, 61%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[CH:19]=2)=[N:7][N:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=12)=[O:4].[F-:25].[K+].O>CC(N(C)C)=O>[Br:24][C:20]1[CH:19]=[C:18]([C:6]2[C:5]([C:3](=[O:4])[CH2:2][F:25])=[C:9]3[CH:10]=[CH:11][C:12]([C:14]([F:16])([F:17])[F:15])=[CH:13][N:8]3[N:7]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: O=C(CBr)c1c(-c2cccc(Br)c2)nn2cc(C(F)(F)F)ccc12
Reactant: [F-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: O=C(CF)c1c(-c2cccc(Br)c2)nn2cc(C(F)(F)F)ccc12
Yield: 49.9 %

Procedure:
A solution of 2-bromo-1-[2-(3-bromophenyl)-6-(trifluoromethyl)pyrazolo[1,5-a]pyridin-3-yl]ethanone (300 mg, 0.65 mmol, obtained from composite batches), KF (190 mg, 3.27 mmol) in DMA (10 mL) was heated for 3 h at 80° C. Water (25 mL) was added and the aqueous layer was extracted with EtOAc (2×50 mL). The organic layers were combined and purified by LC (2-10% EtOAc in hexanes) to yield the desired product (130 mg, 42%) as a pale yellow glass. ESIMS (M+H)+=401.
Reaction SMILES: [CH2:1]([C:12]1[N:16]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][NH2:24])=[CH:19][CH:18]=2)[O:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH:29]=O>>[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29][NH:24][CH2:23][C:20]1[CH:19]=[CH:18][C:17]([C:15]2[O:14][N:13]=[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:16]=2)=[CH:22][CH:21]=1
Reactant: CCCCCCCCCCCc1noc(-c2ccc(CN)cc2)n1
Reactant: O=Cc1cccc(Cl)c1
Product: CCCCCCCCCCCc1noc(-c2ccc(CNCc3cccc(Cl)c3)cc2)n1
Yield: 86 %

Procedure:
The same procedure as employed in the preparation of Example 226 (step a) but using 1-[4-(3-undecyl-1,2,4-oxadiazol-5-yl)phenyl]methanamine and 3-chlorobenzaldehyde gave the title compound as a colorless oil (86%). 1H NMR (DMSO-d6, 300 MHz) δ 8.03 (d, J=8.3 Hz, 2H), 7.58 (d, J=8.3 Hz, 2H), 7.43 (s, 1H), 7.65-7.23 (m, 3H), 3.77 (s, 2H), 3.70 (s, 2H), 3.30 (s, 1H), 2.75 (t, J=7.2 Hz, 2H), 1.79-1.65 (m, 2H), 1.41-1.16 (m, 16H), 0.84 (t, J=7.0 Hz, 3H). HPLC (Condition A), Rt: 5.19 min (HPLC purity: 98.4%).
Reaction SMILES: Br[CH:2]([CH3:13])[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[CH3:12].[CH3:14][C:15]1[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17]>>[CH3:12][C:6]1[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:5]=1[NH:4][CH2:3][CH:2]([NH:17][C:16]1[CH:18]=[CH:19][CH:20]=[C:21]([CH3:22])[C:15]=1[CH3:14])[CH3:13]
Reactant: Cc1cccc(NCC(C)Br)c1C
Reactant: Cc1cccc(N)c1C
Product: Cc1cccc(NCC(C)Nc2cccc(C)c2C)c1C
Yield: 84.2 %

Procedure:
N-(β-Bromopropyl)-2,3-dimethyl-aniline, prepared as indicated in point (b) above, is reacted with 2,3-dimethylaniline as given in Example 3, Method (c), point (b) to obtain 1,2-bis(2',3'-dimethylphenyl-amino)-propane with a yield of 84.2%. The hydrobromide of the product melts at 204°-208° C.
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:5][CH2:4]1.[NH:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[C:7]1[CH2:15][OH:16].C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH:5]1([CH2:4][N:6]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]=[C:7]2[CH2:15][OH:16])[CH2:3][CH2:2]1
Reactant: OCc1nc2ccccc2[nH]1
Reactant: BrCC1CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: OCc1nc2ccccc2n1CC1CC1
Temperature: 60 °C
Reaction time: 72 h
Yield: 25.8 %

Procedure:
To a solution of (bromomethyl)cyclopropane (0.39 mL, 4.02 mmol) and (1H-benzoimidazol-2-yl)-methanol (596 mg, 4.02 mmol) in DMF (10 mL) was added N,N-diisopropylethylamine (0.84 mL, 4.82 mmol). The reaction mixture was stirred at 60° C. for 3 days. Then it was cooled to room temperature and quenched with saturated NaHCO3 (15 mL) and the phases were separated. The aqueous phase was washed with CH2Cl2 (3×20 mL). Then the combined organic layers were washed with brine (2×30 mL), dried (MgSO4), filtered, concentrated, and dried in vacuo to afford a dark brown oil. Purification by flash column chromatography on silica gel using 2% CH3OH/CH2Cl2 afforded the product as a yellow solid (210 mg, 26%). 1H NMR (CDCl3) δ 0.40-0.45 (m, 2H), 0.52-0.61 (m, 2H), 1.22-1.33 (m, 1H), 4.13 (d, 2H, J=6.6 Hz), 4.88 (s, 2H), 7.22-7.24 (m, 2H), 7.36-7.38 (m, 1H), 7.66-7.69 (m, 1H).