Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][C:4]1[CH:5]=[C:6]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][CH2:17][C:18]([C:20]3[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=3)=[O:19])[N:15]=2)[CH:7]=[CH:8][C:9]=1[OH:10].Br[CH2:29][CH2:30][CH:31]=[CH2:32]>>[CH2:32]([O:10][C:9]1[CH:8]=[CH:7][C:6]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][CH2:17][C:18]([C:20]3[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=3)=[O:19])[N:15]=2)=[CH:5][C:4]=1[O:3][CH:2]([F:1])[F:27])[CH2:31][CH:30]=[CH2:29]
Reactant: Cc1cccnc1C(=O)CCc1coc(-c2ccc(O)c(OC(F)F)c2)n1
Reactant: C=CCCBr
Product: C=CCCOc1ccc(-c2nc(CCC(=O)c3ncccc3C)co2)cc1OC(F)F

Procedure:
Using the compound obtained in Example 356 and 4-bromo-1-butene, white powdery 3-[2-(4-but-3-enyloxy-3-difluoromethoxy phenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one was obtained following the procedure of Example 3.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[C:21]1([CH2:27][CH2:28][CH2:29][C:30](O)=[O:31])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[CH:7]=[CH:6][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:30](=[O:31])[CH2:29][CH2:28][CH2:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[CH:10][CH:9]=1
Reactant: O=C(O)CCCc1ccccc1
Reactant: COc1ccc(CC(N)C(O)c2ccc(F)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: COc1ccc(CC(NC(=O)CCCc2ccccc2)C(O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.2 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(methyloxy)phenyl)-1-propanol (450 mg, 1.64 mmol) in acetonitrile (30 ml) were added 4-phenyl-n-butyric acid (268 mg, 1.64 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (470 mg, 2.45 mmol) and 1-hydroxy-1H-benzotriazole (250 mg, 1.64 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:acetone=1:1). Recrystallization from ethyl acetate-hexane gave the title compound (575 mg, 83%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20]1)[N:13]=2)[CH:5]=O.[CH2:28]1[C@@H:31]([C:32]([OH:34])=[O:33])[NH:30][CH2:29]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:20][CH2:21]1)[N:13]=2)[CH2:5][N:30]1[CH2:29][CH2:28][C@H:31]1[C:32]([OH:34])=[O:33]
Reactant: O=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reactant: O=C(O)[C@@H]1CCN1
Product: O=C(O)[C@@H]1CCN1Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1

Procedure:
Reaction of 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzaldehyde (93.3 mg, 0.249 mmol) and L-azetidine-2-carboxylic acid (76 mg, 0.748 mμmol) according to Reference R and the general procedure for reductive amination gave (S)-1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzyl)-azetidine-2-carboxylic acid as a light yellow solid. MS (ESI) m/z: Calculated: 459.1; Observed: 460.0 (M++1).
Reaction SMILES: [C:1](O)(=O)C.C(N)=N.C([O-])(=O)C.COCCO.[NH2:17][C:18]1[CH:46]=[CH:45][CH:44]=[CH:43][C:19]=1[NH:20][C:21]1[CH:33]=[CH:32][C:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[C:23]([NH:34][C:35](=[O:42])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:22]=1>O.C(OCC)(=O)C>[C:35]([NH:34][C:23]1[CH:22]=[C:21]([N:20]2[C:19]3[CH:43]=[CH:44][CH:45]=[CH:46][C:18]=3[N:17]=[CH:1]2)[CH:33]=[CH:32][C:24]=1[C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])(=[O:42])[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CC(C)(C)OC(=O)c1ccc(Nc2ccccc2N)cc1NC(=O)c1ccccc1
Reactant: CC(=O)O
Agent: CC(=O)[O-]
Agent: N=CN
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCO
Product: CC(C)(C)OC(=O)c1ccc(-n2cnc3ccccc32)cc1NC(=O)c1ccccc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 79.8 %

Procedure:
28 mg of formamidine acetate was acetate to 1.0 mL of ethylene glycol monomethyl ether solution containing 44 mg of tert-butyl 4-(2-aminoanilino)-2-(benzamido)benzoate at room temperature and stirred at 80° C. for 3 hours. After the reaction mixture was cooled to room temperature, ethyl acetate and water were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [PSQ100B (spherical) manufactured by Fuji Silysia Chemical Ltd., eluent; hexane:ethyl acetate=1:1] to obtain 36 mg of tert-butyl 2-(benzamido)-4-(1H-benzimidazol-1-yl)benzoate as pale yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12](F)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2].[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1>CS(C)=O>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: C1COCCN1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Nc1cc(N2CCOCC2)c(C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (5-fluoro-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example A1) (1.62 g, 5.0 mmol) and morpholine (2.18 mL, 25.0 mmol) in DMSO (10 mL) at 23° C. according to the general procedure B. Obtained as a yellow solid (1.83 g).
Reaction SMILES: CO[C:3](=O)[C@H:4]([CH2:13][CH2:14][CH2:15][CH3:16])[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].Cl.[CH3:19][O:20][C:21](=[O:32])[C@H:22]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=1)[NH2:23].C(O)(=O)C.C([BH3-])#N.[Na+]>C1(C)C=CC=CC=1.CO.O1CCCC1.O>[CH3:19][O:20][C:21](=[O:32])[C@H:22]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([OH:31])=[CH:29][CH:30]=1)[NH:23][CH2:3][C@@H:4]([NH:5][C:6]([O:8][C:9]([CH3:10])([CH3:11])[CH3:12])=[O:7])[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCCC[C@@H](CN[C@@H](Cc1ccc(O)cc1)C(=O)OC)NC(=O)OC(C)(C)C
Temperature: -78 °C
Yield: 32.7 %

Procedure:
Under an argon gas stream, N-(tert-butoxycarbonyl)-L-norleucine methyl ester (10.7 g, 38 mmol) was dissolved in toluene (68 ml), and cooled to -78° C. To the solution, while keeping the temperature at -60 to -70° C., was added gradually aluminum diisobutyl hydride (toluene 1.0 M solution, 51 ml). After stirring at -78° C. for an hour, the cooling bath was removed, methanol (2 ml) was added to the mixture. Tyrosine methyl ester hydrochloride (13.6 g, 59 mmol) and acetic acid (3.5 g, 59 mmol) were dissolved in methanol (69 ml)-tetrahydrofuran (98 ml), and added to the mixture. After addition of a suspension of sodium cyanoborohydride (2.7 g, 43 mmol) in tetrahydrofuran (30 ml), the mixture was stirred at room temperature for 2.5 hours, and water was added thereto. The solid was removed by decantation, and the solution was concentrated under reduced pressure. The organic matters were extracted with ethyl acetate, and washed with a saturated aqueous sodium bicarbonate solution, water and a saturated aqueous sodium chloride solution, successively. The organic layer was concentrated under reduced pressure and purified by column chromatography to give N-[(S)-2-(tert-butoxycarbonylamino)hexyl]-L-tyrosine methyl ester (4.9 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.CCN(C(C)C)C(C)C.[NH2:21][C:22]1[CH:23]=[C:24]([CH:31]=[CH:32][CH:33]=1)[O:25][CH2:26][C:27]([NH:29][CH3:30])=[O:28]>CS(C)=O.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([NH:21][C:22]2[CH:23]=[C:24]([CH:31]=[CH:32][CH:33]=2)[O:25][CH2:26][C:27]([NH:29][CH3:30])=[O:28])[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1
Reactant: CNC(=O)COc1cccc(N)c1
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)COc1cccc(Nc2nc(Cl)nc3[nH]ccc23)c1
Temperature: 100 °C
Yield: 56.6 %

Procedure:
To a solution of 2,4-Dichloro-7H-pyrrolo[2,3-d]pyrimidine (0.062 g, 0.33 mmol) in DMSO (1 mL) was added DIPEA (0.117 mL, 0.66 mmol) and 2-(3-aminophenoxy)-N-methylacetamide (0.095 g, 0.49 mmol). After heating at 100° C. for 15 h, it was diluted with EtOAc, washed with saturated NaHCO3, brine, dried and concentrated to give 2-(3-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)phenoxy-N-methylacetamide (0.062 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:13][NH2:14])=[CH:6][C:7]=1[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.[F:15][C:16]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:17]=1[CH:18]=O>Cl>[Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:13][N:14]=[CH:18][C:17]2[CH:20]=[CH:21][C:22]([F:24])=[CH:23][C:16]=2[F:15])=[CH:6][C:7]=1[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: NNc1cc(N2CCCC2)c(Cl)nn1
Reactant: O=Cc1ccc(F)cc1F
Agent: Cl
Product: Fc1ccc(C=NNc2cc(N3CCCC3)c(Cl)nn2)c(F)c1

Procedure:
3-Chloro-6-hydrazino-4-(pyrrolidin-1-yl)pyridazine (1.06 g, 4.9 mmol) and 2,4-difluorobenzaldehyde (437 ml, 4.9 mmol) were stirred in 0.2M hydrochloric acid (30 ml) for 2 hours. The precipitated imine was then collected by filtration and dried (1.37 g, 92%). MS (ES+) 338 [MH]+, 340 [MH]+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[S:5][C:6]([CH2:9][NH:10][C:11]([N:16]([CH3:18])[CH3:17])=[N:12][N+:13]([O-:15])=[O:14])=[CH:7][N:8]=1.[N:19]#[C:20]Br.O>CN(C=O)C.CC#N>[Cl:3][C:4]1[S:5][C:6]([CH2:9][N:10]([C:20]#[N:19])[C:11]([N:16]([CH3:18])[CH3:17])=[N:12][N+:13]([O-:15])=[O:14])=[CH:7][N:8]=1
Reactant: CN(C)C(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Reactant: N#CBr
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=N[N+](=O)[O-])N(C#N)Cc1cnc(Cl)s1

Procedure:
To a suspension of sodium hydride (60% dispersion in mineral oil) in DMF (3 ml) was added a solution of 1-(2-chloro-5-thiazolylmethyl)-3,3-dimethyl-2-nitroguanidine (0.49 g) in DMF (3 ml) dropwise over 5 minutes at room temperature under stirring. After stirring for five minutes, 2.08M solution of cyanogen bromide in CH3CN (1 ml) was added to the mixture over 5 minutes. After stirring for 1 hour, the reaction mixture was poured into 50 ml of water and the reaction vessel was washed with 10 ml of water. The washing was combined with the aqueous layer and precipitated pellets were obtained by filtration and recrystallized from EtOH to afford 0.334 g of 1-(2-chloro-5-thiazolylmethyl)-1-cyano-3,3-dimethyl-2-nitroguanidine (Compound No. 1) as a crystal, m.p. 152°-155° C.
Reaction SMILES: C([Mg]Cl)(C)C.[CH2:6]([O:13][C:14]1[CH:19]=[C:18](I)[CH:17]=[CH:16][C:15]=1[Cl:21])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[B:22](OC(C)C)([O:27]C(C)C)[O:23]C(C)C.Cl>C1COCC1>[CH2:6]([O:13][C:14]1[CH:19]=[C:18]([B:22]([OH:27])[OH:23])[CH:17]=[CH:16][C:15]=1[Cl:21])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Clc1ccc(I)cc1OCc1ccccc1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: OB(O)c1ccc(Cl)c(OCc2ccccc2)c1
Temperature: -50 °C

Procedure:
Add dropwise 374 mL (748 mmol) of a solution of iPrMgCl 2N in THF to a solution of 198 g (575 mmol) of 2-(benzyloxy)-1-chloro-4-iodobenzene in 1.2 L of anhydrous THF under argon and stirred at −50° C., maintaining the temperature between −40 and −50° C. Allow the reaction mixture to return to −10° C. and continue stirring for 1 h. Then add 172 mL (748 mmol) of triisopropyl borate and leave the reaction mixture to return slowly to RT. After stirring for 2 h, treat the mixture with 1 L of aqueous solution of HCl 5N, then extract with ether (2×600 mL). Wash the organic phase with 2×1 L of water, dry over Na2SO4 then concentrate under reduced pressure. Solidify the residue obtained in pentane, filter on a frit and wash with pentane. We thus obtain 113 g of [3-(benzyloxy)-4-chlorophenyl]boronic acid in the form of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9](=[O:38])[CH2:10][C@H:11]([C:19]1[CH:24]=[CH:23][C:22]([CH:25]2[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH2:26]2)=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18].Cl>O1CCOCC1>[CH3:1][O:2][C:3]1[N:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9](=[O:38])[CH2:10][C@H:11]([C:19]1[CH:20]=[CH:21][C:22]([CH:25]2[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]2)=[CH:23][CH:24]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18]
Reactant: COc1nnccc1C(=O)C[C@H](c1ccc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1)c1ccccc1C
Agent: Cl
Solvent: C1COCCO1
Product: COc1nnccc1C(=O)C[C@H](c1ccc(C2CCNCC2)cc1)c1ccccc1C
Yield: 79 %

Procedure:
To a solution of (R)-tert-butyl 4-(4-(3-(3-methoxypyridazin-4-yl)-3-oxo-1-o-tolylpropyl)-phenyl)piperidine-1-carboxylate (118 mg, 195 μmol) in 1,4-dioxane (4 mL) was added 37% aq. hydrochloric acid solution (0.32 mL, 3.9 mmol), then after 30 min the reaction mixture was partitioned between ethyl acetate and sat, aq. sodium hydrogencarbonte-solution. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. Chromatography (SiO2; gradient dichloromethane to dichloromethane/methanol/25% aq. ammonia solution 90:10:0.25) afforded the title compound (64 mg, 79%). Orange gum, MS: 416.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:20]=[C:19]([C:21]#[C:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:18]=[C:17]([OH:30])[CH:16]=2)=[CH:9][C:8]=1[CH3:31])[CH3:2].[F:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40]OC)=[CH:36][CH:35]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:20]=[C:19]([C:21]#[C:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:18]=[C:17]([O:30][CH2:40][C:37]3[CH:38]=[CH:39][C:34]([F:33])=[CH:35][CH:36]=3)[CH:16]=2)=[CH:9][C:8]=1[CH3:31])[CH3:2]
Reactant: CCOC(=O)COc1ccc(SCc2cc(O)cc(C#CCN3CCOCC3)c2)cc1C
Reactant: COCc1ccc(F)cc1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(SCc2cc(C#CCN3CCOCC3)cc(OCc3ccc(F)cc3)c2)cc1C
Reaction time: 16 h

Procedure:
{4-[3-Hydroxy-5-(3-morpholin-4-yl-prop-1-ynyl)-benzylsulfanyl]-2-methylphenoxy}-acetic acid ethyl ester (250 mg; 0.55 mmol), 1-fluoro-4-methoxymethyl-benzene (103.8 mg; 0.82 mmol), tributylphosphine (0.33 mg; 1.65 mmol) and 1,1′-(azodicarbonyl)dipiperidine (0.414 g; 1.65 mmol) were dissolved in THF (15 mL) in a dried reaction flask under an atmosphere of nitrogen. The reaction mixture was stirred for 16 h and purified by prep. HPLC (method A). Yield: 160 mg. HPLC-MS: m/z: 564.1 (M+H); Rt: 1.99 min.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]([CH3:15])[CH3:14])=[CH:9][CH:8]=1)=[O:6].[Br:16]([O-])(=O)=O.[Na+].[Br-].[Na+]>C(Cl)Cl.O.S(S([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+]>[Br:16][C:13]([C:10]1[CH:9]=[CH:8][C:7]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][Cl:1])=[CH:12][CH:11]=1)([CH3:15])[CH3:14]
Reactant: [O-][Br+2]([O-])[O-]
Reactant: CC(C)c1ccc(C(=O)CCCCl)cc1
Agent: O=S(=O)([O-])S(=O)(=O)[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(Br)c1ccc(C(=O)CCCCl)cc1
Temperature: 10 °C
Yield: 281.5 %

Procedure:
Dissolve 4-chloro-1-(4-isopropyl-phenyl)-butan-1-one (74.7 g, 333 mmol) in methylene chloride (250 mL) and add sodium bromate (17.6 g, 117 mmol) in water (75 mL) in a three-necked Morton flask equipped with an overhead stirrer. Cool the solution to 10° C. and irradiate with two 150W incandescent flood lamps. Add, by dropwise addition, a solution of sodium bromide (24 g, 233 mmol) and stir for 2 hours. Illuminate for another 30 minutes, add sodium dithionate (2.0 g), separate the organic phase, dry (MgSO4) and evaporate the solvent in vacuo to give the title compound (100 g, 99%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)[N:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13](S(C)(=O)=O)[N:12]=2)[CH:10]=1)=[O:5])[CH3:2].[CH3:31][C@H:32]([NH2:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=2)[N:9]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:39][C@H:32]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH3:31])[N:12]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: C[C@H](N)c1ccccc1
Reactant: CCOC(=O)c1cn(-c2ccnc(S(C)(=O)=O)n2)c(-c2cccc(C(F)(F)F)c2)n1
Product: CCOC(=O)c1cn(-c2ccnc(N[C@@H](C)c3ccccc3)n2)c(-c2cccc(C(F)(F)F)c2)n1

Procedure:
A solution of 1-(2-methylsulfonylpyrimidin4-yl)-2-(3-trifluoromethylphenyl)-1H-imidazole4-carboxylic acid ethyl ester (4.5 g, 0.0102 mol) in (S)-α-methylbenzylamine (20 mL) was stirred at room temperature for 30 min. The reaction was partitioned between 300 mL ethyl acetate and 300 mL pH 4.5 citric acid solution (buffered with NaOH) and the ethyl acetate dried over anhydrous magnesium sulfate. Concentration of the ethyl acetate afforded 4.8 g of the title compound. A portion of this material was purified by reverse phase HPLC on C18 silica eluting with a gradient of 100% water to 30% water: 70% acetonitrile (both containing 0.1% trifluoroacetic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:22])OC2C=CC=CC=2)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[F:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:33]2[CH2:32][CH2:31][N:30]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[F:23])[CH2:35][CH2:34]2)=[O:22])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: COc1nc2ccccc2nc1NC(=O)Oc1ccccc1
Reactant: Fc1ccccc1N1CCNCC1
Product: COc1nc2ccccc2nc1NC(=O)N1CCN(c2ccccc2F)CC1
Yield: 67.5 %

Procedure:
Phenyl N-(2-methoxyquinoxalin-3-yl)carbamate and 1-(2-fluorophenyl)-piperazine were reacted by the same way with the example 36 to obtain the titled compound.
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.[F:23][C:24]([F:34])([F:33])[O:25][C:26]1[CH:27]=[C:28]([NH2:32])[CH:29]=[CH:30][CH:31]=1>>[CH3:13][C:12]1[C:7]([NH:32][C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([O:25][C:24]([F:33])([F:34])[F:23])[CH:27]=2)=[N:8][C:9]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:10][C:11]=1[CH3:14]
Reactant: Nc1cccc(OC(F)(F)F)c1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Product: Cc1nc(NCc2ccccn2)nc(Nc2cccc(OC(F)(F)F)c2)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using [3-(trifluoromethoxy)phenyl]amine instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 2.09 (s, 3H), 2.35 (s, 3H), 4.73 (d, J=5.6 Hz, 2H), 6.08 (bs, 1H), 6.48 (bs, 1H), 6.88 (d, J=7.3 Hz, 1H), 7.16 (t, J=7.3 Hz, 1H), 7.22-7.34 (m, 3H), 7.62 (t, J=9.4 Hz, 1H), 7.75 (s, 1H), 8.57 (d, J=3.2 Hz, 1H); MS (ESI) m/z 390.7 (M+1)+.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].C(O)C1[O:13][CH:12]=[CH:11][CH:10]=1>C(N(CC)CC)C>[C:5]([O:4][CH2:1][C:2]1[O:13][CH:12]=[CH:11][CH:10]=1)(=[O:7])[CH3:6]
Reactant: OCc1ccco1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)OCc1ccco1
Yield: 99.5 %

Procedure:
Procedure was as in example 2, but acetic anhydride was added to the mixture of furfuryl alcohol and triethyl amine. The crude yield was 1149 g and the concentration was 58.7%, i.e., the yield was 99.5%. The crude product was washed 4 times with 200 ml water, whereby 641.3 g furfuryl acetate was obtained, its concentration was 96.2%, i.e., the yield was 91.0%.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([CH:19]=O)[CH:13]=[CH:12]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC(O)=O.[NH:25]1[CH2:28][CH:27]([C:29]([O:31][CH3:32])=[O:30])[CH2:26]1.[BH3-]C#N.[Na+]>ClCCCl>[Si:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([CH2:19][N:25]1[CH2:28][CH:27]([C:29]([O:31][CH3:32])=[O:30])[CH2:26]1)[CH:13]=[CH:12]2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2cc(C=O)ccc2c1
Reactant: COC(=O)C1CNC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COC(=O)C1CN(Cc2ccc3cc(O[Si](C)(C)C(C)(C)C)ccc3c2)C1
Temperature: 85 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
6-(tert-butyldimethylsilyloxy)-2-naphthaldehyde (4.0 g, 14 mmol), AcOH (1.8 g, 28 mmol) and methyl azetidine-3-carboxylate (3.2 g, 28 mmol, 2.0 equiv) in DCE (30 mL) were stirred at 85° C. for 1 h. Then NaBH3CN (1.8 g, 28 mmol, 2.0 equiv) was added to the mixture at 50° C. and stirred for 2 h at 85° C. The reaction mixture was quenched with water, extracted with DCM and washed with brine, dried over Na2SO4 and concentrated to obtain crude product. The crude product was purified by silica gel chromatography (DCM:MeOH=40:1) to give the title compound (2.7 g, 50%) as a yellow oil. ESI-MS (M+1)+: 386.2. 1H NMR (400 MHz, CDCl3) δ: 7.72-7.68 (m, 3H), 7.37-7.34 (m, 1H), 7.15-7.10 (m, 2H), 3.94 (s, 2H), 3.81-3.76 (m, 4H), 3.74 (s, 3H), 3.50-3.44 (m, 1H), 1.02 (s, 9H), 0.25 (s, 6H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)(=[O:13])=[O:12])[CH:9]=[CH:10][C:3]=12.[F:20][C:21]1[CH:22]=[CH:23][C:24]([O:30][CH3:31])=[C:25](B(O)O)[CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[F:20][C:21]1[CH:26]=[CH:25][C:24]([O:30][CH3:31])=[C:23]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[N:8]([S:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)(=[O:13])=[O:12])[CH:9]=[CH:10][C:3]=23)[CH:22]=1
Reactant: COc1ccc(F)cc1B(O)O
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(Br)ccnc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: COc1ccc(F)cc1-c1ccnc2c1ccn2S(=O)(=O)c1ccccc1
Temperature: 100 °C

Procedure:
A suspension of 4-bromo-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (10.00 g, 29.7 mmol), 5-fluoro-2-methoxyphenylboronic acid (5.54 g, 32.6 mmol), 2M aqueous potassium carbonate (66.7 mL, 133 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (1.453 g, 1.779 mmol) in 1,2-dimethoxyethane (250 mL) was degassed with nitrogen and heated at 100° C. for 1.5 hours. The mixture was diluted with ethyl acetate and washed with aqueous sodium bicarbonate (twice) and brine. The organic layer was dried over magnesium sulfate, filtered, concentrated, and purified on silica gel using an ISCO Companion flash system eluting with heptane/ethyl acetate (75:25 to 60:40) to afford the title compound. MS (ESI+) m/z 383.1 (M+H)+.