Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[OH-].[Li+].[CH3:4][O:5][C:6]1[CH:31]=[CH:30][C:9]2[S:10][C:11]([C:17]([NH:19][C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=3)=[O:18])=[C:12]([S:13][CH:14]([CH3:16])[CH3:15])[C:8]=2[CH:7]=1>CO.O.C(OCC)(=O)C>[CH3:4][O:5][C:6]1[CH:31]=[CH:30][C:9]2[S:10][C:11]([C:17]([NH:19][C:20]3[CH:29]=[CH:28][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[O:18])=[C:12]([S:13][CH:14]([CH3:16])[CH3:15])[C:8]=2[CH:7]=1
Reactant: COC(=O)c1ccc(NC(=O)c2sc3ccc(OC)cc3c2SC(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: COc1ccc2sc(C(=O)Nc3ccc(C(=O)O)cc3)c(SC(C)C)c2c1
Temperature: 25 °C
Yield: 78 %

Procedure:
A suspension of lithium hydroxide-monohydrate (20 mg, 0.48 mmol) and methyl 4-[[[5-methoxy-3-[(1-methylethyl)thio]benzo[b]thien-2yl]carbonyl]amino]benzoate (67 mg, 0.16 mmol) in 4 mL of methanol and 2 mL of water is heated at reflux for 1.5 hours. The reaction mixture is cooled to room temperature and then diluted with ethyl acetate and washed sequentially with 1N HCl, water, and brine. The organic layer is dried over MgSO4. Filtration followed by concentration in vacuo and recrystallization from ethyl acetate: hexane gives 4-[[[5-methoxy-3-[(1-methylethyl)thio]benzo[b]thien-2yl]carbonyl]amino]benzoic acid in 78% yield; mp=241°-245° C. dec.
Reaction SMILES: [NH2:1][C:2]([C:4]1[C:5]([F:19])=[C:6]([CH:15]=[CH:16][C:17]=1[F:18])[O:7][CH2:8][CH:9]=[CH:10][C:11]([O:13]C)=[O:12])=[O:3].[OH-].[Na+].Cl>C(O)(C)C.O>[NH2:1][C:2]([C:4]1[C:5]([F:19])=[C:6]([CH:15]=[CH:16][C:17]=1[F:18])[O:7][CH2:8][CH:9]=[CH:10][C:11]([OH:13])=[O:12])=[O:3]
Reactant: COC(=O)C=CCOc1ccc(F)c(C(N)=O)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: NC(=O)c1c(F)ccc(OCC=CC(=O)O)c1F
Temperature: 25 °C
Yield: 48 %

Procedure:
A solution of methyl 4-[3-(aminocarbonyl)-2,4-difluorophenoxy]-2-butenoate (1.25 g, 4.61 mmol, 1 equiv.) and NaOH (0.75 g, 18.44 mmol, 4 equiv.) in isopropanol (10 ml) and H2O (20 ml) was heated under reflux for 1 h. After cooling to r.t., the mixture was acidified with conc. HCl to pH 1. The white precipitant solid was filtered and washed with Et2O (50 ml), to give 568 mg, 48% yield, mp 187-188° C., HPLC-MS (method 1): m/z 258 [M+H]+, Rt=0.98 min. By 1H-NMR analysis it was determined to be a mixture of isomers in a ratio (3:2) E:Z.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10]2[NH:14][N:13]=[C:12]([CH:15]3[CH2:17][CH2:16]3)[CH:11]=2)[N:3]=1.[N:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[NH:24][C:25]([C@@H:27]1[CH2:32][C@H:31]2[C@H:29]([CH2:30]2)[NH:28]1)=[O:26].ClC1N=C(NC2NN=C(C3CC3)C=2)N=C(N2CCC[C@@]2(C)C(NC2C=NC(F)=CC=2)=O)N=1>>[Cl:8][C:6]1[N:5]=[C:4]([NH:9][C:10]2[NH:14][N:13]=[C:12]([CH:15]3[CH2:17][CH2:16]3)[CH:11]=2)[N:3]=[C:2]([N:28]2[C@H:27]([C:25]([NH:24][C:19]3[CH:20]=[N:21][CH:22]=[CH:23][N:18]=3)=[O:26])[CH2:32][C@H:31]3[C@@H:29]2[CH2:30]3)[N:7]=1
Reactant: Clc1nc(Cl)nc(Nc2cc(C3CC3)n[nH]2)n1
Reactant: O=C(Nc1cnccn1)[C@@H]1C[C@@H]2C[C@@H]2N1
Agent: C[C@@]1(C(=O)Nc2ccc(F)nc2)CCCN1c1nc(Cl)nc(Nc2cc(C3CC3)n[nH]2)n1
Product: O=C(Nc1cnccn1)[C@@H]1C[C@@H]2C[C@@H]2N1c1nc(Cl)nc(Nc2cc(C3CC3)n[nH]2)n1

Procedure:
Compound 121D was prepared from compounds 1A and 121C using the procedure as described for 1C. LC/MS [M+H]+: 439; Ret time (Method A): 1.70 min.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[CH:14]([NH:18]C1C(=O)NC=CC=1)[C:15]([NH2:17])=[O:16].N>>[NH2:18][CH:14]([C:8]1[C:9]([Cl:13])=[CH:10][CH:11]=[CH:12][C:7]=1[Cl:6])[C:15]([NH2:17])=[O:16]
Reactant: NC(=O)C(Nc1ccc[nH]c1=O)c1c(Cl)cccc1Cl
Agent: N
Agent: O=S(=O)(O)O
Product: NC(=O)C(N)c1c(Cl)cccc1Cl
Temperature: 0 °C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
To a stirred and cooled amount of 450 g of concentrated sulfuric acid there were added 23 g of intermediate (2). Stirring was continued overnight at room temperature. The reaction mixture was poured into 2000 g of ice-water and the whole was basified with ammonia. The product was extracted with trichloromethane and the extract was dried, filtered and evaporated. The residue was crystallized from 240 g of 2-propanol at -20° C. The product was filtered off, washed with 2-propanol and petroleumether and dried, yielding 13.5 g of (±)-α-amino-2,6-dichlorobenzeneacetamide; mp. 166.3° C. (interm. 3).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH:16]=[CH:17][N:18]([CH3:19])[C:12]2=[N:11][C:10]=1[C:20](O)=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:24][CH2:25][C:26](=[O:36])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=1>>[Cl:35][C:30]1[CH:29]=[C:28]([CH2:27][C:26](=[O:36])[CH2:25][NH:24][C:20]([C:10]2[N:11]=[C:12]3[N:18]([CH3:19])[CH:17]=[CH:16][N:13]3[C:14](=[O:15])[C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:21])[CH:33]=[CH:32][C:31]=1[Cl:34]
Reactant: NCC(=O)Cc1ccc(Cl)c(Cl)c1
Reactant: Cn1ccn2c(=O)c(OCc3ccccc3)c(C(=O)O)nc12
Agent: Cl
Product: Cn1ccn2c(=O)c(OCc3ccccc3)c(C(=O)NCC(=O)Cc3ccc(Cl)c(Cl)c3)nc12

Procedure:
Adapted from the procedure of example 5 using the product of example 9 and 1-amino-3-(3,4-dichloro-phenyl)-propan-2-one hydrochloride.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([OH:20])=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.[OH:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[C:4]([O:3][C:1](=[O:2])[NH:8][C@@H:9]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=1)[C:18]([N:26]1[CH2:27][CH2:28][CH:23]([OH:22])[CH2:24][CH2:25]1)=[O:20])([CH3:5])([CH3:6])[CH3:7]
Reactant: OC1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)cc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)cc1)C(=O)N1CCC(O)CC1
Reaction time: 0.08 h

Procedure:
To a stirred solution of Boc-3-(4-fluorophenyl)-(S)-alanine (10.0 g, 35.3 mmol), 4-hydroxypiperidine hydrochloride (5.1 g, 37.1 mmol) and HOBt (7.2 g, 52.9 mmol) in DMF (100 mL), was added DIPEA (12.3 mL, 70.6 mmol) and after 5 min, EDCI (7.4 g, 38.8 mmol) and the reaction stirred at rt for 16 h. The solvent was removed in vacuo and the residue partitioned between water (150 mL) and ethyl acetate (2×150 mL). The combined organic fractions were washed with sodium hydroxide solution (2M, 50 mL), hydrochloric acid (2N, 50 mL), dried (MgSO4) and concentrated in vacuo. The product was chromatographed on silica gel eluting with ethyl acetate to give the title compound as a white solid. m/z (ES+)=367 [M+H]+; RT=3.28 min.
Reaction SMILES: ClC1C=CC(N2C=CC(C(F)(F)F)=C2CO)=CC=1.ClC1C=CC([N:26]2[CH:30]=[CH:29][C:28]([C:31]([F:37])([F:36])[C:32]([F:35])([F:34])[F:33])=[C:27]2CO)=CC=1.FC1C=C(CCC(OCC)=O)C=C(F)C=1O.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.P(CCCC)(CCCC)CCCC>C1(C)C=CC=CC=1>[F:37][C:31]([F:36])([C:28]1[CH:29]=[CH:30][NH:26][CH:27]=1)[C:32]([F:35])([F:34])[F:33]
Reactant: OCc1c(C(F)(F)C(F)(F)F)ccn1-c1ccc(Cl)cc1
Agent: CCCCP(CCCC)CCCC
Agent: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Product: FC(F)(F)C(F)(F)c1cc[nH]c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed [1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrrol-2-yl]methanol and (1-(4-chlorophenyl)-3-(perfluoroethyl)-1H-pyrrol-2-yl)methanol (200 mg, 0.73 mmol, 1.00 equiv), ethyl 3-(3,5-difluoro-4-hydroxyphenyl)propanoate (211 mg, 0.92 mmol, 1.20 equiv), ADDP (482 mg, 1.91 mmol, 2.50 equiv), PBu3 (232 mg, 1.15 mmol, 1.50 equiv) and toluene (10 mL). The resulting solution was stirred overnight at 60° C. in an oil bath. The reaction progress was monitored by LCMS. The resulting mixture was then concentrated under vacuum. The resulting solution was diluted with diethyl ether (10 mL). The solids were filtered out and the resulting mixture was concentrated under vacuum. The resulting residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10) to yield ethyl 3-(4-[[1-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrrol-2-yl]methoxy]-3,5-difluorophenyl propanoate and 1-(4-chlorophenyl)-2-(2,6-difluoro-4-propylphenoxy)methyl)-3-(perfluoroethyl)-1H-pyrrole as yellow oil.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH2:17][CH2:18][CH3:19])=[CH:6]2)#[N:2].[Cl:24][C:25]1[S:26][C:27]([Cl:33])=[CH:28][C:29]=1[C:30](Cl)=O.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:24][C:25]1[S:26][C:27]([Cl:33])=[CH:28][C:29]=1[C:30]1[O:15][N:14]=[C:13]([CH2:12][N:8]2[C:9]3[C:5](=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH:6]=[C:7]2[CH2:17][CH2:18][CH3:19])[N:16]=1
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=N)NO
Reactant: O=C(Cl)c1cc(Cl)sc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(Cl)sc2Cl)n1
Temperature: 150 °C
Yield: 36.8 %

Procedure:
To a solution of 2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.100 g, 0.308 mmol) in anhydrous acetonitrile (3.0 mL) under N2, was added 2,5-dichloro-3-thiophenecarbonyl chloride (0.265 g, 1.23 mmol) and N,N-diisopropylethylamine (0.50 mL, 5.21 mmol). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.055 g (37% yield) of pure product: MS (ES) m/z 485 (M+1).
Reaction SMILES: C(N1CC[C@H](N)C1)(OCC1C=CC=CC=1)=O.C([N:24]1[CH2:29][CH2:28][CH:27]([N:30]([CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)[C:31](=[O:37])[N:32]([CH3:36])[CH:33]([CH3:35])[CH3:34])[CH2:26][CH2:25]1)(OC(C)(C)C)=O>>[CH:38]1([N:30]([C:31](=[O:37])[N:32]([CH3:36])[CH:33]([CH3:34])[CH3:35])[CH:27]2[CH2:28][CH2:29][NH:24][CH2:25][CH2:26]2)[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: CC(C)N(C)C(=O)N(C1CCCCC1)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: N[C@H]1CCN(C(=O)OCc2ccccc2)C1
Product: CC(C)N(C)C(=O)N(C1CCCCC1)C1CCNCC1

Procedure:
The title compound was prepared following the procedure described in Step B of Intermediate 1 using 1-BOC-4-{cyclohexyl[methyl(isopropyl)carbamoyl]amino}piperidine.
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5]CC)=O.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH:19][CH:20]([CH3:25])[C:21]([CH3:24])([CH3:23])[CH3:22])=[S:18])=[CH:12][CH:11]=1>ClCCl>[Cl:9][C:10]1[CH:11]=[CH:12][C:13]([N:16]2[C:2](=[O:8])[C:3](=[O:5])[N:19]([CH:20]([CH3:25])[C:21]([CH3:23])([CH3:22])[CH3:24])[C:17]2=[S:18])=[CH:14][CH:15]=1
Reactant: CCOC(=O)C(=O)Cl
Reactant: CC(NC(=S)Nc1ccc(Cl)cc1)C(C)(C)C
Solvent: ClCCl
Product: CC(N1C(=O)C(=O)N(c2ccc(Cl)cc2)C1=S)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.6 %

Procedure:
Ethyl chlorooxoacetate (0.62 mL, 5.60 mmol) was added to a stirring solution of the above thiourea (1.00 g, 3.72 mmol) in dichloromethane (15 mL) and the resulting mixture was stirred overnight at room temperature. Concentration, trituration of the residue with diethyl ether, and recrystallization from boiling methanol afforded 0.72 g (60%) of 1-(4-chloro-phenyl)-2-thioxo-3-(1,2,2-trimethyl-propyl)-imidazolidine-4,5-dione as a yellow solid: mp 198.8–199.5° C.; 1H NMR (DMSO-d6): δ 7.61 (d, 2H), 7.40 (d, 2H), 4.82 (q, 1H), 1.45 (d, 3H), 0.98 (s, 9H); IR (KBr): 3500, 2920, 1775 cm1; MS (m/z) 324 (M+).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([CH3:13])[CH:10]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[N:8]=2)[CH:6]=1.[NH2:24][C:25]1[N:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][N:26]=1>>[CH3:13][C:11]1[CH:10]=[C:9]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[N:8]=[C:7]([N:5]2[CH:6]=[C:2]([C:28]3[CH:27]=[N:26][C:25]([NH2:24])=[N:30][CH:29]=3)[N:3]=[CH:4]2)[N:12]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cnc(Br)c2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-n2cnc(-c3cnc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(4-bromo-imidazol-1-yl)-4-methyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example E.13) (0.31 g, 0.8 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (0.18 g, 0.8 mmol) according to the general procedure VI. Obtained as a white solid (0.093 g, 29%). MS (ISP) 398.0 [(M+H)+]; mp 267-269° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]([CH2:7][S:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=2)=[CH:5][CH:4]=1.[Br:18]Br>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][S:8][C:9]2[C:14]([Br:18])=[CH:13][N:12]=[C:11]([NH2:15])[CH:10]=2)=[CH:16][CH:17]=1
Reactant: BrBr
Reactant: COc1ccc(CSc2ccnc(N)c2)cc1
Solvent: CC(=O)O
Product: COc1ccc(CSc2cc(N)ncc2Br)cc1
Yield: 54.2 %

Procedure:
4-(4-methoxybenzylthio)pyridine-2-amine (2.4 g, 9.7 mmol) was dissolved in acetic acid (30 mL). Bromine (1M in AcOH, 9.8 ml, 9.8 mmol) was added dropwise at ambient temperature and the reaction stirred for 30-minutes. The solution was concentrated and the residue was neutralized with saturated NaHCO3 solution. The solution was extracted with EtOAc and the organic layer was dried and concentrated. The residue was purified by flash chromatography (70% EtOAc/hexanes) to obtain the desired product (1.71 g, 54% yield) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][OH:11])=[C:4]([C:12]#[C:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH:3]=1.CC([O-])(C)C.[K+]>CN(C=O)C>[C:14]([C:13]1[N:8]([CH2:9][CH2:10][OH:11])[C:5]2=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]2[CH:12]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)C#Cc1cc(Cl)ncc1NCCO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc2cc(Cl)ncc2n1CCO
Temperature: 80 °C
Yield: 44.3 %

Procedure:
To a solution of 2-(6-chloro-4-(3,3-dimethylbut-1-ynyl)pyridin-3-ylamino)ethanol (3.6 g, 14.3 mmol) in DMF (100 mL) was added t-BuOK (3.1 g, 28 mol) under N2 atmosphere. The mixture was heated at 80° C. for 12 h and then was quenched with H2O (200 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (150 mL×3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and purified by chromatography on silica gel (3% ethyl acetate in petroleum ether as eluant) to afford 2-(2-tert-butyl-5-chloro-1H-pyrrolo[2,3-c]pyridin-1-yl)ethanol (1.6 g, 44%). 1H-NMR (CDCl3, 300 MHz) δ 8.50 (s, 1H), 7.39 (s, 1H), 6.28 (s, 1H), 4.55 (t, J=6.6, 2H), 4.05 (t, J=6.6, 2 H), 1.49 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([F:12])[CH:6]=2.[C:13]([O-])([O-])=O.[K+].[K+].CB1OB(C)OB(C)O1>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.O1CCOCC1>[F:12][C:7]1[CH:6]=[C:5]2[C:10]([CH:11]=[C:2]([CH3:13])[CH:3]=[N:4]2)=[CH:9][CH:8]=1
Reactant: O=C([O-])[O-]
Reactant: Fc1ccc2cc(Br)cnc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CB1OB(C)OB(C)O1
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1cnc2cc(F)ccc2c1
Temperature: 90 °C
Yield: 74 %

Procedure:
3-bromo-7-fluoro-quinoline (Intermediate 30) (100 mg, 0.442 mmol) was combined with K2CO3 (153 mg, 1.10 mmol), anhydrous 1,4-dioxane (3 mL), and trimethylboroxine (0.092 mL, 0.663 mmol). Nitrogen was bubbled in to degas the reaction and Pd(PPh3)4 (50.9 mg, 0.044 mmol) was added. This was degassed again and then heated to 90° C. for 5 h. The reaction was cooled and partitioned between ethyl acetate and sat. aq. NaHCO3. The separated aqueous layer was extracted with ethyl acetate and the combined organics dried over MgSO4. Purification by silica gel flash chromatography (ethyl acetate/heptane) gave 7-fluoro-3-methyl-quinoline (52.7 mg) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.78 (d, J=1.8 Hz, 1H) 7.93 (s, 1H) 7.65-7.79 (m, 2H) 7.32 (td, J=8.6, 2.5 Hz, 1H) 2.52 (s, 3H); MS (M+1): 162.1.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:7]2[N:15]=[N:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23][OH:24])[N:18]=3)[C:8]=2[N:9]=[C:10]([NH2:12])[N:11]=1.[H-].[Na+].[CH2:27](Br)[CH:28]=[CH2:29]>CN(C=O)C>[CH2:27]([O:24][CH2:23][C:19]1[N:18]=[C:17]([CH2:16][N:13]2[C:8]3[N:9]=[C:10]([N:12]([CH2:22][CH:17]=[CH2:16])[CH2:6][CH:2]=[CH2:3])[N:11]=[C:6]([C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)[C:7]=3[N:15]=[N:14]2)[CH:22]=[CH:21][CH:20]=1)[CH:28]=[CH2:29]
Reactant: C=CCBr
Reactant: Nc1nc(-c2ccco2)c2nnn(Cc3cccc(CO)n3)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOCc1cccc(Cn2nnc3c(-c4ccco4)nc(N(CC=C)CC=C)nc32)n1
Reaction time: 0.25 h
Yield: 59.8 %

Procedure:
A solution of 7-(2-furyl)-3-(6-hydroxymethyl-2-pyridylmethyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine-5-amine (120 mg, 0.377 mmol) in DMF (5 mL) at 0° C. was treated with sodium hydride (30 mg, 0.743 mmol), stirred for 15 min, treated with allyl bromide (96 μl, 1.11 mmol), stirred at room temperature for 16 h, concentrated in vacuo to ˜2 mL and purified by chromatography [SiO2; isohexane:EtOAc (3:1)] to give the title compound (50 mg, 30%) as a yellow solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)CCC>>[N:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:8]#[N:9])[C:2]=1[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1
Reactant: N#Cc1cccnc1Cl
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Product: N#Cc1cccnc1-c1ccncc1
Yield: 39 %

Procedure:
Prepared in 39% yield from 2-chloro-3-cyanopyridine and 4-(tributylstannyl)pyridine according to the procedure described for Example 164A. MS (ESI+) m/z 181.9 (M+H)+; 1H NMR (CDCl3) δ 7.50 (dd, J=8.1, 4.7 Hz, 1H), 7.88 (d, J=6.4 Hz, 2H), 8.14 (dd, J=8.0, 1.9 Hz, 1H), 8.83 (d, J=4.4 Hz, 2H), 8.94 (dd, J=4.9, 1.9 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[CH:48]=[C:47]([CH3:49])[N:46]=[C:45]([CH3:50])[N:44]=2)=[CH:38][C:37]=1[CH3:51].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:36]5[C:37]([CH3:51])=[CH:38][C:39]([C:43]6[CH:48]=[C:47]([CH3:49])[N:46]=[C:45]([CH3:50])[N:44]=6)=[CH:40][C:41]=5[CH3:42])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cc(-c2cc(C)c(Br)c(C)c2)nc(C)n1
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6cc(C)nc(C)n6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 4-(4-bromo-3,5-dimethyl-phenyl)-2,6-dimethyl-pyrimidine following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 9): tR=1.24 min; Mass spectrum (ESI+): m/z=553 [M+H]+.
Reaction SMILES: B(Br)(Br)[Br:2].CO[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[CH:19][CH3:20])[C:15]([O:17][CH3:18])=[O:16].CO.O>C(Cl)Cl>[Br:2][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[CH:19][CH3:20])[C:15]([O:17][CH3:18])=[O:16]
Reactant: BrB(Br)Br
Reactant: CC=C(C(=O)OC)c1ccccc1COC
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CC=C(C(=O)OC)c1ccccc1CBr

Procedure:
At 0° C., 105.3 ml (140 mmol) of a 1.33 M boron tribromide solution in methylene chloride was dripped into 31 g (140 mmol) of methyl α-(2-methoxymethylphenyl)-β-methylacrylate in 500 ml of CH2Cl2, and the mixture was refluxed for 2 hours. 25 ml of methanol was then added, the mixture was stirred for a further 90 minutes at room temperature, hydrolyzed with water while cooling with ice, and washed neutral with 3% strength caustic solution, and the aqueous phase was extracted with methylene chloride. The combined organic phases were washed with water, dried and evaporated down. The crystals which precipitated were separated off, washed with a small amount of n-hexane and dried. The filtrates were evaporated down end purified chromatographically in a silica gel column (cyclohexane/MTBE:8/1). A total of 31 g of product was obtained in the form of pale yellow crystals.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH3:19][C:20]1[O:24][C:23]([CH:25]([C:27]2([CH3:31])[CH2:30][O:29][CH2:28]2)[NH2:26])=[N:22][N:21]=1>>[CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([NH:26][CH:25]([C:23]3[O:24][C:20]([CH3:19])=[N:21][N:22]=3)[C:27]3([CH3:31])[CH2:30][O:29][CH2:28]3)=[O:12])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Reactant: Cc1nnc(C(N)C2(C)COC2)o1
Product: Cc1nnc(C(NC(=O)c2cc(OCC(F)(F)F)c(C3CC3)cn2)C2(C)COC2)o1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (example 48c) and (5-methyl-1,3,4-oxadiazol-2-yl)-(3-methyloxetan-3-yl)methanamine (example 245b) as starting materials and isolated (25 mg, 35%); MS (ESI, m/z): 427.7 (M+H+).
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[N:10]1([C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[NH2:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.Cl.CN(C)CCCN=C=NCC.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[N:10]1([C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[NH:18][C:7]([C:5]2[O:6][C:2]([Br:1])=[CH:3][CH:4]=2)=[O:9])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=C(O)c1ccc(Br)o1
Reactant: Nc1ccccc1N1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: O=C(Nc1ccccc1N1CCCCC1)c1ccc(Br)o1
Reaction time: 8 h
Yield: 85 %

Procedure:
A solution of 5-bromofuroic acid (Aldrich) (1.0 mmol), 2-piperdinoaniline (1.0 mmol), 1-hydroxybenzotriazole hydrate (“HOBT”) (1.2 mmol), and triethylamine (“Et3N”) (2 mmol) in DCM (10 mL) was stirred for 10 min at room temperature. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (“EDCI”) (1.2 mmol) was then added and the resulting orange solution was stirred overnight. The reaction mixture was treated with saturated sodium bicarbonate (“NaHCO3”) solution (10 mL) and extracted with DCM. The combined organic layers were dried over MgSO4, and concentrated under reduced pressure to afford the crude product as an orange solid. Purification by silica gel chromatography afforded the pure yellow product in 85% yield. MS: 349 (M+1). 1H NMR (CDCl3, 300 MHz): δ 9.75 (br s, 1H), 8.45 (d, 1H), 7.22-7.05 (m, 4H), 6.50 (d, 1H), 3.00-2.80 (m, 4H), 1.95-1.80 (m, 4H), 1.75-1.60 (m, 2H).