Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[N:20]12[CH2:27][CH2:26][CH:23]([CH2:24][CH2:25]1)[C@@H:22](O)[CH2:21]2.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)[C:9]([O:11][C@@H:22]2[CH:23]3[CH2:26][CH2:27][N:20]([CH2:25][CH2:24]3)[CH2:21]2)=[O:10])=[CH:4][CH:3]=1
Reactant: O[C@H]1CN2CCC1CC2
Reactant: O=C(O)C(Nc1cccc(F)c1)c1ccc(F)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(Nc1cccc(F)c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.8 %

Procedure:
A mixture of 2-(4-fluorophenyl)-2-(3-fluorophenylamino)acetic acid (I3) (510 mg, 1.94 mmol), (R)-quinuclidin-3-ol (246 mg, 1.94 mmol), HOBT (356 mg, 2.32 mmol), and DCC (480 mg, 2.32 mmol) in THF (10 ml) was stirred at room temperature overnight (UPLC-MS monitoring: complete conversion). The solvent was evaporated, the crude was dissolved in EtOAc, and the insoluble was removed by filtration. The clear solution was washed with 1N K2CO3 and then with brine. The organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by silica gel chromatography (EtOAc/MeOH=8/2) to give (R)-quinuclidin-3-yl 2-(4-fluorophenyl)-2-(3-fluorophenylamino)acetate (360 mg, 50% yield, mixture of diastereomers).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][C:4]([NH:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:3]1.CN(C(O[N:32]1N=N[C:34]2C=CC=[CH:38][C:33]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.C(N)(C)C>CN(C=O)C>[CH:33]([NH:32][C:7]([C:6]1[N:2]([CH3:1])[N:3]=[C:4]([NH:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[CH:5]=1)=[O:9])([CH3:38])[CH3:34]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: Cc1onc(-c2ccccn2)c1CNc1cc(C(=O)O)n(C)n1
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CC(C)N
Product: Cc1onc(-c2ccccn2)c1CNc1cc(C(=O)NC(C)C)n(C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To a solution of 1-methyl-3-((5-methyl-3-(pyridin-2-yl)isoxazol-4-yl)methylamino)-1H-pyrazole-5-carboxylic acid (80 mg, 255 μmol) in DMF (3 mL) were added TBTU (91 mg, 281 μmol) and N,N-diisopropyl ethyl amine (217 μL, 1.28 mmol) followed by isopropylamine (24 μL, 281 μmol). The mixture was stirred at RT for 1 h, then evaporated. The residue was purified by flash-chromatography over NH2 silica gel using gradient EtOAc/heptane 10-70% to afford the title compound (75 mg, 83%) as a white solid. MS: m/e=355.2 [M+H]+.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[S:26][C:27]3[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=3[CH:29]=2)=[CH:21][CH:20]=1.[Cl-].[Al+3].[Cl-].[Cl-].[OH-].[Na+]>ClCCCl>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[S:26][C:27]3[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=3[C:29]=2[C:13](=[O:15])[C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[CH:17][CH:16]=2)=[CH:21][CH:20]=1
Reactant: O=C(O)c1ccc(OCCN2CCCC2)cc1
Reactant: Clc1ccc(-c2cc3ccccc3s2)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCCl
Product: O=C(c1ccc(OCCN2CCCC2)cc1)c1c(-c2ccc(Cl)cc2)sc2ccccc12
Reaction time: 8 h
Yield: 88.9 %

Procedure:
The hydrochloride salt of 4-(2-pyrrolidinoethoxy)benzoic acid (7.77 grams; 0.028 mole) was converted to its corresponding acid chloride. To the acid chloride then were added 7.0 grams (0.028 mole) of the above benzothiophene and 250 ml. of 1,2-dichloroethane. A white suspension resulted. The mixture was cooled to b 0° to 10° C. and was treated gradually with 7.6 grams (0.57 mole) of aluminum chloride, giving rise to a brownish-yellow solution. The mixture was stirred at 0°-25° C. overnight, and then was poured over a mixture of 200 ml. of ice and 75 ml. of 5N sodium hydroxide. The resulting mixture was evaporated to near dryness, and the residue was dissolved in chloroform. The chloroform solution was washed with water and evaporated, and the residue was heated with a mixture of 200 ml. of methanol and 15 ml. of 5N sodium hydroxide. The mixture then was evaporated to dryness, and the residue was dissolved in a mixture of chloroform and water. The chloroform layer was separated, dried over magnesium sulfate, and evaporated to an oil. A small amount of ethyl acetate was added, and the resulting mixture was scratched. Crystals formed and were collected. The mother liquor filtrate was concentrated and chromatographed to obtain 11.5 grams of crystals which were recrystallized from ethyl ether to give 6.63 grams (50 percent) of the title compound, melting point 97°-98° C.
Reaction SMILES: [F:1][C:2]1([F:17])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12](I)[CH:11]=2)=[O:9])[CH2:4][CH2:3]1.[I:18]C1C=C(C=CC=1)C(O)=O.FC1(F)CCNCC1>>[F:1][C:2]1([F:17])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([I:18])=[CH:12][CH:11]=2)=[O:9])[CH2:4][CH2:3]1
Reactant: O=C(O)c1cccc(I)c1
Reactant: O=C(c1cccc(I)c1)N1CCC(F)(F)CC1
Agent: FC1(F)CCNCC1
Product: O=C(c1ccc(I)cc1)N1CCC(F)(F)CC1

Procedure:
According to Step 77-1 in the synthetic method for compound 77-1, 4-iodobenzoic acid 1 and 4,4-difluoropiperidine 2 were used to obtain compound 83-1.
Reaction SMILES: [CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[NH:10][C:9]([CH3:14])=[N:8][C:7]=2[N:6]([CH3:15])[C:4]1=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:22][C:23]1[CH:38]=[CH:37][C:26]([C:27]([C:29]2[CH:36]=[CH:35][C:32]([CH2:33]Br)=[CH:31][CH:30]=2)=[O:28])=[CH:25][CH:24]=1>CN(C=O)C.O>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([C:27]([C:29]2[CH:36]=[CH:35][C:32]([CH2:33][N:10]3[C:11]4[C:12](=[O:13])[N:3]([CH2:1][CH3:2])[C:4](=[O:5])[N:6]([CH3:15])[C:7]=4[N:8]=[C:9]3[CH3:14])=[CH:31][CH:30]=2)=[O:28])=[CH:37][CH:38]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Reactant: CCn1c(=O)c2[nH]c(C)nc2n(C)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(=O)c2c(nc(C)n2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)n(C)c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 24.4 %

Procedure:
To a solution of l-ethyl-3,8-dimethylxanthine (170 mg), a synthetic process for which is described in Journal of American Chemical Society , 75, 114 (1953), in DMF (8 ml) were added potassium carbonate (169 mg) and 4-(4-chlorobenzoyl)benzyl bromide (278 mg) and the mixture was stirred at room temperature for 20 hours. This reaction mixture was diluted with water and extracted with ethyl acetate, and the extract was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. The solvent was then distilled off and the residue was recrystallized (ethyl acetate-hexane) to provide the title compound as colorless powder (87 mg, 24%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([CH2:9][CH2:10][NH:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([C:18](Br)=[CH:19][N:20]=2)[N:17]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:23]1(B(O)O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O.[O-]P([O-])([O-])=O.[K+].[K+].[K+].ClCCl>O.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].C(OCC)(=O)C.CCCCCCC>[C:1]([O:5][C:6](=[O:22])[N:7]([CH3:8])[CH2:9][CH2:10][NH:11][C:12]1[CH:13]=[CH:14][C:15]2[N:16]([C:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][N:20]=2)[N:17]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: CN(CCNc1ccc2ncc(Br)n2n1)C(=O)OC(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: O
Product: CN(CCNc1ccc2ncc(-c3ccccc3)n2n1)C(=O)OC(C)(C)C

Procedure:
Methyl-[2-(3-phenyl-imidazo[1,2-b]pyridazin-6-ylamino)-ethyl]-carbamic acid tert-butyl ester was prepared similarly to the procedure for example 5.6.60 from [2-(3-bromo-imidazo[1,2-b]pyridazin-6-ylamino)-ethyl]-methyl-carbamic acid tert-butyl ester (370.3 mg, 1.0 mmol), phenylboronic acid [98-80-6] (146.4 mg, 1.2 mmol), potassium phosphate tribasic monohydrate [27176-10-9] (460.2 mg, 2.0 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane [95464-05-4] (81.9 mg, 0.1 mmol) in 30% (v/v) water in 1,2-dimethoxyethane (12.5 mL) at 85° C. for 17 h. Off white powder from ethyl acetate/heptane, mp. 150-151° C. 1H NMR (400 MHz, DMSO-d6) δ ppm (rotamers present) 1.16 (br. s., 5H) 1.20-1.33 (m, 1H) 1.37 (br. s., 3H) 2.49-2.54 (m, 1H) 2.83 (br. s., 3H) 3.43 (br. s., 2H) 3.51 (br. s., 1H) 6.69 (d, J=8.84 Hz, 1H) 7.22 (br. s., 1H) 7.29-7.38 (m, 1H) 7.43-7.54 (m, 2H) 7.76 (d, J=8.84 Hz, 1H) 7.89 (br. s., 1H) 8.16 (d, J=6.82 Hz, 2H). 13C NMR (100 MHz, DMSO-d6) δ ppm 14.39, 22.55, 28.24, 28.49, 31.71, 34.17, 35.10, 46.33, 47.00, 78.60, 112.58, 126.28, 127.46, 128.93, 130.40, 134.52, 153.69, 155.40. LRMS (ESI) m/z 368.1 [(M+H)]+, calc'd for C20H25N5O2: 367.45.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][C:8]1[C:13]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:31]=[C:32]([CH:36]=[C:37]([C:39]2[C:43]([CH3:44])=[CH:42][S:41][CH:40]=2)[CH:38]=1)[C:33](O)=[O:34])=[O:5])C.[CH:45]1([NH2:48])[CH2:47][CH2:46]1>>[C:4]([CH2:6][CH2:7][C:8]1[C:9]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]2[CH:38]=[C:37]([C:39]3[C:43]([CH3:44])=[CH:42][S:41][CH:40]=3)[CH:36]=[C:32]([C:33](=[O:34])[NH:48][CH:45]3[CH2:47][CH2:46]3)[CH:31]=2)=[CH:10][CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])([OH:5])=[O:3]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)O)cc(-c3cscc3C)c2)c1CCC(=O)OCC
Reactant: NC1CC1
Product: Cc1cscc1-c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(C(=O)NC2CC2)c1

Procedure:
The title compound was prepared according to the general procedure described above starting from 3-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-5-(4-methyl-thiophen-3-yl)-benzoic acid and cyclopropylamine (10% yield after two steps).
Reaction SMILES: [CH3:1][N:2]([C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][C:17]([C:20]1[S:21][C:22]3([CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH2:23][N:24]=1)=[CH:16]2)[S:3]([C:6]1[S:7][CH:8]=[CH:9][CH:10]=1)(=[O:5])=[O:4].[CH:30](=O)[CH3:31].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>O1CCCC1>[CH2:30]([N:27]1[CH2:28][CH2:29][C:22]2([S:21][C:20]([C:17]3[NH:18][C:19]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[N:2]([CH3:1])[S:3]([C:6]3[S:7][CH:8]=[CH:9][CH:10]=3)(=[O:4])=[O:5])=[N:24][CH2:23]2)[CH2:25][CH2:26]1)[CH3:31]
Reactant: CN(c1cccc2cc(C3=NCC4(CCNCC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCN1CCC2(CC1)CN=C(c1cc3cccc(N(C)S(=O)(=O)c4cccs4)c3[nH]1)S2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a solution of N-methyl-N-[2-(1-thia-3,8-diazaspiro[4.5]dec-2-en-2-yl)-1H-indol-7-yl]thiophene-2-sulfonamide (100 mg) and acetaldehyde (90%, 100 μL) in tetrahydrofuran (3 mL) was added sodium triacetoxyborohydride (125 mg), and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography to give the title compound (83 mg, yield 80%) as white crystals from a fraction eluted with ethyl acetate. melting point 215° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH:12][CH:13]1[N:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[NH:15][C:14]1=[O:30])=[O:11].[H-].[Na+].[CH3:33][O:34][CH2:35][CH2:36]Cl.C(O)(=O)C>CN(C)C=O.O.C(OCC)(=O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH:12][CH:13]1[N:19]=[C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]2[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=2[N:15]([CH2:36][CH2:35][O:34][CH3:33])[C:14]1=[O:30])=[O:11]
Reactant: O=C(NC1N=C(c2ccccc2)c2ccccc2NC1=O)c1cc2ccccc2[nH]1
Reactant: COCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: COCCN1C(=O)C(NC(=O)c2cc3ccccc3[nH]2)N=C(c2ccccc2)c2ccccc21
Temperature: 0 °C
Yield: 24.3 %

Procedure:
To a solution of (3RS)-1,3-dihydro-3-(2-indolylcarbonylamino) -5-phenyl-2H-1,4-benzodiazepine-2one (394 mg) in N,N-dimethylformamide (4 ml) was added sodium hydride (62% suspension in mineral oil, 44 mg) under stirring at 0° C. in an ice-bath. The mixture was stirred for 1.0 hour at 0° to -5° C. 2-Methoxyethyl chloride (142 mg) was added thereto. The mixture was stirred for 6.0 hours at 60° to 70° C. and cooled. To the cooled reaction mixture were added acetic acid (0.5 ml), ethyl acetate (40 ml) and water (40 ml) under stirring. The organic layer was separated, washed with an aqueous solution of sodium bicarbonate and water, dried over magnesium sulfate and evaporated. The residue was chromatographed on silica gel with chloroform as an eluent to give the pure product of (3RS)-1,3-dihydro-3(2-indolylcarbonylamino) -5-phenyl-1-(2-methoxyethyl)-2H-1,4-benzodiazepine-2-one (110 mg).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:11][CH:10]2[O:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]3[O:35][CH2:34][CH2:33][N:32]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[C:31]=3[CH:41]=2)=[CH:5][CH:4]=1.[OH:42][C:43]1[CH:51]=[CH:50][CH:49]=[C:48]2[C:44]=1[CH:45]=[CH:46][NH:47]2>>[NH:47]1[C:48]2[C:44](=[C:43]([O:42][CH2:2][C:3]3[CH:8]=[CH:7][C:6]([CH:9]4[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)=[O:16])[CH2:11][CH:10]4[O:25][CH2:26][C:27]4[CH:28]=[CH:29][C:30]5[O:35][CH2:34][CH2:33][N:32]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[C:31]=5[CH:41]=4)=[CH:5][CH:4]=3)[CH:51]=[CH:50][CH:49]=2)[CH:45]=[CH:46]1
Reactant: Oc1cccc2[nH]ccc12
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(CCl)cc3)cc21
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(COc4cccc5[nH]ccc45)cc3)cc21

Procedure:
Analogously to Method I, 0.150 g of benzyl 4-(4-chloromethylphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate (Example 270b) and 0.0529 g of 4-hydroxyindole are reacted. The title compound is obtained as a violet oil. Rf=0.10 (1:2 EtOAc-heptane); Rt=5.58.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:20]=[CH:19][C:8]([O:9][C:10]2[S:11][C:12]3[C:13]([N:18]=2)=[N:14][CH:15]=[CH:16][CH:17]=3)=[CH:7][CH:6]=1.[NH:21]1[CH2:26][CH2:25][CH:24]([O:27][C:28]2[N:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[CH2:23][CH2:22]1.C(N(CC)C(C)C)(C)C>CC#N>[N:29]1[CH:30]=[CH:31][CH:32]=[N:33][C:28]=1[O:27][CH:24]1[CH2:25][CH2:26][N:21]([CH2:2][CH2:3][O:4][C:5]2[CH:20]=[CH:19][C:8]([O:9][C:10]3[S:11][C:12]4[C:13]([N:18]=3)=[N:14][CH:15]=[CH:16][CH:17]=4)=[CH:7][CH:6]=2)[CH2:22][CH2:23]1
Reactant: BrCCOc1ccc(Oc2nc3ncccc3s2)cc1
Reactant: c1cnc(OC2CCNCC2)nc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: c1cnc(OC2CCN(CCOc3ccc(Oc4nc5ncccc5s4)cc3)CC2)nc1
Temperature: 70 °C
Reaction time: 18 h
Yield: 38.5 %

Procedure:
To a solution of 2-[4-(2-bromoethoxy)phenoxy][1,3]thiazolo[4,5-b]pyridine (131 mg, 0.37 mmol) and 2-(piperidin-4-yloxy)-pyrimidine (80 mg, 0.45 mmol, 1.2 equiv.) in CH3CN (1.9 mL) was added N,N-diisopropylethylamine (97 μL, 0.56 mmol, 1.5 equiv.). The resulting solution was allowed to stir at 70° C. for 18 h. The solution was then cooled to rt, filtered and purified using preparative reverse phase HPLC to afford the desired product as a yellow-brown solid (64 mg, 38%). 1H NMR (600 MHz, CDCl3): 8.58-8.54 (m, 1H), 8.52-8.48 (m, 2H), 8.01-7.96 (m, 1H), 7.34-7.30 (m, 2H), 7.18 (dd, J=6.7, 4.8, 1H), 6.96 (d, J=8.1, 2H), 6.92-6.87 (m, 1H), 5.14-5.04 (m, 1H), 4.14 (t, J=5.6, 2H), 2.96-2.88 (m, 2H), 2.86 (t, J=5.5, 2H), 2.56-2.46 (m, 2H), 2.16-2.04 (m, 2H), 2.01-1.90 (m, 2H). MS (ESI): mass calcd. for C23H23N5O3S, 449.15; m/z found, 450.1 [M+H]+.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[NH:18][C:19]([C:32]3[CH:37]=[CH:36][N:35]=[C:34]([NH:38][CH2:39][C:40]4[CH:45]=[CH:44][C:43]([O:46][CH3:47])=[CH:42][CH:41]=4)[N:33]=3)=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[N:21]=2)[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.Br>C(Cl)Cl.C(O)(=O)C.C(OCC)C>[CH3:47][O:46][C:43]1[CH:42]=[CH:41][C:40]([CH2:39][NH:38][C:34]2[N:33]=[C:32]([C:19]3[NH:18][C:17]([CH:14]4[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]4)=[N:21][C:20]=3[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:29])[F:31])[CH:23]=3)[CH:37]=[CH:36][N:35]=2)=[CH:45][CH:44]=1
Reactant: COc1ccc(CNc2nccc(-c3[nH]c(C4CCN(C(=O)OCc5ccccc5)CC4)nc3-c3cccc(C(F)(F)F)c3)n2)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CCOCC
Product: COc1ccc(CNc2nccc(-c3[nH]c(C4CCNCC4)nc3-c3cccc(C(F)(F)F)c3)n2)cc1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 22.7 %

Procedure:
To a stirred solution of 4-[5-[2-(4-methoxybenzylamino)-pyrimidin-4-yl]-4-(3-trifluoromethylphenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid benzyl ester (1.0 g, 0.00156 mole) in methylene chloride (16 mL) under argon was slowly added 30% hydrogen bromide in acetic acid (16 mL). The mixture was stirred at 20° C. for 30 minutes and then diluted with diethyl ether (160 mL). The resulting mixture was stirred for I hour, filtered and solid washed with ether (10 mL). The resulting solid was dissolved in 10% aqueous sodium bicarbonate (40 mL) and methylene chloride (50 mL). The methylene chloride was separated and the aqueous layer washed with methylene chloride (25 mL). The organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated to a foam (0.80 g). The solid was chromatographed on silica using methylene chloride/methanol/aqueous ammonium hydroxide (90:10:2) to give upon concentration of product containing fractions 180 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:5]=[C:6]([C@H:9]([OH:22])[CH2:10]OS(C2C=CC(C)=CC=2)(=O)=O)[C:7]=1[F:8].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:5]=[C:6]([C@H:9]2[CH2:10][O:22]2)[C:7]=1[F:8]
Reactant: CCOC(=O)CCc1cc(F)c(F)c([C@H](O)COS(=O)(=O)c2ccc(C)cc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)CCc1cc(F)c(F)c([C@H]2CO2)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 82.3 %

Procedure:
To a solution of ethyl 3-[3,4-difluoro-5-((1S)-1-hydroxy-2-{[(4-methylphenyl)sulfonyl]oxy}ethyl)phenyl]propanoate (22.5 g, 52.5 mmol) in absolute ethanol (430 mL) was added potassium carbonate (7.27 g, 52.6 mmol) and the reaction was stirred at RT for 4 days. The reaction was concentrated and diluted with water and extracted with ethyl acetate (×2). The combined organic layers were washed with water and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. Purification by column chromatography (0-25% ethyl acetate:hexane) afforded the desired product (11.07 g, 82%).
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][CH2:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][C:13]=1[Cl:20])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[CH2:21](P(=O)(OCC)OCC)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>CN(C)C=O>[Si:3]([O:10][CH2:11][C:12]1[CH:19]=[CH:18][C:15](/[CH:16]=[CH:21]/[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:14][C:13]=1[Cl:20])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(C=O)cc1Cl
Reactant: CCOP(=O)(Cc1ccccc1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1ccc(/C=C/c2ccccc2)cc1Cl
Temperature: 40 °C
Reaction time: 2 h
Yield: 62.3 %

Procedure:
Sodium hydride (70% in mineral oil, 81 mg) was added to a mixture of 4-((tert-butyldimethylsilyloxy)methyl)-3-chlorobenzaldehyde (571 mg) and diethyl benzylphosphonate (502 mg) in N,N-dimethylformamide (2 ml) under a nitrogen atmosphere at room temperature and the mixture was stirred at 40° C. for 2 hr. Water was added to the reaction mixture and the resulting product was extracted three times with ether. The organic layers were combined, washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was subjected to silica gel column chromatography (hexane/ethyl acetate=50/1) to give the objective compound (448 mg) as a colorless oil.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9]/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13].[C:17]([C:20]1[CH:21]=[C:22]([C:25](=[O:30])C(Cl)(Cl)Cl)[NH:23][CH:24]=1)(=[O:19])[CH3:18].C(N(CC)C(C)C)(C)C>ClCCl>[C:17]([C:20]1[CH:21]=[C:22]([C:25]([NH:8][CH2:9]/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:30])[NH:23][CH:24]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)c1c[nH]c(C(=O)C(Cl)(Cl)Cl)c1
Reactant: CCOC(=O)/C=C/CN
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)/C=C/CNC(=O)c1cc(C(C)=O)c[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.2 %

Procedure:
Ethyl (2E)-4-aminobut-2-enoate trifluoroacetate (2.665 g, 10.963 mmol) was added to a solution of 1-(4-acetyl-1H-pyrrol-2-yl)-2,2,2-trichloroethanone (1.8 g, 7.07 mmol) and N,N-diisopropylethylamine (DIPEA) (5.4 mL, 32 mmol) in dichloromethane (20 mL) and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated under vacuum and the residue purified by flash chromatography (SiO2, hexane-EtOAc 1:1) to obtain the title compound as an off-white solid (1.2 g, 65% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].OS(O)(=O)=O.[N+:15]([O-])([OH:17])=[O:16].O>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:9])=[CH:4][C:5]([OH:8])=[C:6]([N+:15]([O-:17])=[O:16])[CH:7]=1
Reactant: Oc1ccc(Br)c(F)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1cc(Br)c(F)cc1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 45 %

Procedure:
To a solution of 4-bromo-3-fluorophenol (89 g, 465.9 mmol) in a mixture of CH2Cl2 (940 mL) and H2SO4 (52.1 mL, 978 mmol) at 0° C., HNO3 (65%) (32.9 ml, 468 mmol) was added dropwise (the mixture turned from colourless to black). The resulting mixture was stirred at 0 ° C. for 1 h and then poured into water. The organic layer was washed with brine, dried (Na2SO4) and the solvent was evaporated under reduced pressure to afford the crude compound which was purified by flash chromatography (SiO2, heptane/toluene 1:3) to give 4-bromo-5-fluoro-2-nitrophenol (49.5 g, 45%). 1H-NMR (400 MHz, CDCl3) 6.95 (d, J=9.0, 1H), 8.38 (d, J=6.2, 1H), 10.69 (s, 1H).