Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[C:4]2[C:9]([C:10](=[O:13])[C:11]=1Cl)=[CH:8][CH:7]=[CH:6][CH:5]=2.[S:15]([O-])([O-])(=O)=O.[Na+].[Na+].[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1.C(O)(=O)C>O>[O:14]=[C:3]1[C:2]2[N:1]=[C:27]([C:26]3[CH:29]=[CH:30][C:23]([F:22])=[CH:24][CH:25]=3)[S:15][C:11]=2[C:10](=[O:13])[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=2
Reactant: O=S(=O)([O-])[O-]
Reactant: O=Cc1ccc(F)cc1
Reactant: NC1=C(Cl)C(=O)c2ccccc2C1=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(=O)c2sc(-c3ccc(F)cc3)nc21
Yield: 91.8 %

Procedure:
To a suspension of 5.0 g (24 mmol) of 2-amino-3-chloro-1,4-dihydro-1,4-dioxonaphthalene in 130 mL of water, 8.4 g (35 mmol) of nonahydrated sodium sulfide are added. The reaction mixture is heated to reflux for 20 min, then 50 mL of an aqueous solution containing 1.0 g of sodium sulfate are added. The color of the medium changes completely to blue. 2.60 mL (24 mmol) of 4-fluorobenzaldehyde and 6.36 mL of glacial acetic acid are added successively. After 1 h of reflux, the greenish precipitate obtained is filtered, dried, and purified on a flash column (support: silica; conditioning: heptane; eluant: dichloromethane/heptane, 60/40). The yellow crystals formed after evaporation of the solvent are washed successively with the isopropanol and ether, then uncolored and recrystallized in dichloromethane to produce 2.0 g of 4,9-dihydro-4,9-dioxo-2-(4-fluorophenyl)naphtho[2,3-d]thiazole in the form of yellow crystals.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:11]([CH3:12])=[CH:10][C:7]([C:8]#[N:9])=[CH:6][C:5]=1[CH3:13].[CH2:14]([N:21]1[C:29]2[C:28](Cl)=[N:27][C:26]([NH2:31])=[N:25][C:24]=2[CH:23]=[CH:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN1C(=O)CCC1.O>[NH2:31][C:26]1[N:27]=[C:28]([O:3][C:4]2[C:5]([CH3:13])=[CH:6][C:7]([C:8]#[N:9])=[CH:10][C:11]=2[CH3:12])[C:29]2[N:21]([CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:22]=[CH:23][C:24]=2[N:25]=1
Reactant: Cc1cc(C#N)cc(C)c1O
Reactant: Nc1nc(Cl)c2c(ccn2Cc2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cc(C#N)cc(C)c1Oc1nc(N)nc2ccn(Cc3ccccc3)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.7 %

Procedure:
To a stirred suspension of NaH (155 mg, 6.47 mmol) in dry NMP (4 mL) was added 4-hydroxy-3,5-dimethylbenzonitrile (570 mg, 3.88 mmol), and the mixture was stirred at room temperature for 30 min under argon. The reaction mixture was added to a solution of 5-benzyl-4-chloro-5H-pyrrolo[3,2-d]pyrimidin-2-amine (400 mg, 1.55 mmol) in dry NMP (4 mL) and heated at 160° C. for 16 h. After completion of the reaction, the resulting mixture was diluted with water and washed with EtOAc. The combined organic layers were washed with water, 2% NaOH, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (2:1-1:4) to give the product as a light yellow solid (342 mg, 60%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][NH2:11])=[CH:4][CH:3]=1.C[O:13][C:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21]Br.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:21][C:16]3[C:15](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:14]2=[O:13])=[CH:6][CH:7]=1
Reactant: NCCCc1ccc(Br)cc1
Reactant: COC(=O)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2CN1CCCc1ccc(Br)cc1
Reaction time: 1.5 h
Yield: 75.6 %

Procedure:
A mixture of 3-(4-bromophenyl)-propylamine (6.21 g, 29 mmol), 2-bromomethyl-benzoic acid methyl ester (6.57 g, 29 mmol), and K2CO3 (6.91 g, 50 mmol) in toluene (100 mL) was heated at reflux with stirring for 1.5 h. Workup and silica gel column chromatography using a gradient of hexanes to 50% ethyl acetate in hexanes afforded 2-[3-(4-bromophenyl)-propyl]-2,3-dihydroisoindol-1-one (7.24 g, 88%). GC/MS gave: m/z (rel.int.) 331 (M+, 9), 329 (M+, 9), 147 (100), 146 (54) 119 (34), and 91 (33). 1H NMR (300 MHz, CDCl3): δ 1.97 (dt, 2H), 2.64 (t, 2H), 3.66 (t, 2H), 4.35 (s, 2H), 7.08 (dd, 2H), 7.38 (dd, 2H), 7.46 (m, 2H), 7.51 (dt, 1H), 7.85 (d, 1H). 13C NMR (300 MHz, CDCl3): δ 29.9, 32.5, 41.9, 49.9, 119.7, 122.7, 123.6, 128.0, 130.2 (2C), 131.2, 131.4 (2C) 132.9, 140.3, 141.1, 168.5.
Reaction SMILES: [C:1]([OH:6])(=[O:5])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.Cl[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:17](=[O:18])[O:16]1.C(OCC)(=O)C>CN(C)C=O>[C:1]([O:6][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:17](=[O:18])[O:16]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: O=C1OC(Cl)c2ccccc21
Reactant: CCCC(=O)O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCC(=O)OC1OC(=O)c2ccccc21
Reaction time: 192 h

Procedure:
To a solution of butyric acid (1.10 g., 12.5 mmol.) in dimethylformamide (13 ml.) is added triethylamine (1.78 g., 17.6 mmol.) and 3-chlorophthalide (2.10 g., 12.5 mmol.). The reaction mixture is stirred for 8 days, ethyl acetate (40 ml.) is added and the mixture is filtered. The filtrate is washed with 4×15 ml. water, dried over magnesium sulfate, filtered and concentrated in vacuo. Yield 2.28 g. (82.8%). 1H-NMR ppm (CDCl3): 7.93 (dd, J=0.7. 7.5 Hz, 1H), 7.76 (dt, J=1.1, 7.5 Hz, 1H), 7.65 (dt, J=1.0, 8.2 Hz, 1H), 7.58 (dd, J=0.7, 8.2 Hz, 1H), 7.46 (s, 1H), 2.42 (t, J=7.4 Hz, 2H), 1.72 (sextet, J=7.4 Hz, 2H), 0.99 (t, J=7.4 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:9].P(Cl)(Cl)Cl.[Cl:14][C:15]1[CH:23]=[C:19]([C:20](O)=[O:21])[C:18]([OH:24])=[CH:17][CH:16]=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:20](=[O:21])[C:19]2[CH:23]=[C:15]([Cl:14])[CH:16]=[CH:17][C:18]=2[OH:24])=[CH:4][C:3]=1[F:9]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: Nc1ccc(Br)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClP(Cl)Cl
Product: O=C(Nc1ccc(Br)c(F)c1)c1cc(Cl)ccc1O
Yield: 90 %

Procedure:
4-Bromo-3-fluoroaniline (0.570 g, 3.00 mmol) and phosphorus trichloride (0.176 ml, 2.0 mmol) were added to a solution of 5-chlorosalicylic acid (0.690 g, 4.00 mmol) in toluene (30 ml), and the mixture was refluxed for 2 hours. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, and the mixture was concentrated under reduced pressure and extracted with tetrahydrofuran. The organic layer was washed with saturated aqueous sodium hydrogencarbonate and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (0.930 g, 90%) as a white solid.
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([C:23](=[O:33])[N:24]([CH2:31][CH3:32])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:20]=[C:19]([Cl:34])[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[ClH:34].[Cl:34][C:19]1[CH:20]=[C:21]([CH:22]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=2)[CH:18]=1)[C:23]([N:24]([CH2:31][CH3:32])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:33]
Reactant: CCN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1)c1ccccc1
Product: Cl
Reaction time: 1.5 h
Yield: 195 %

Procedure:
A solution {2-[3-chloro-5-(ethyl-phenyl-carbamoyl)-phenoxy]-ethyl}-pyridin-4-yl-carbamic acid tert-butyl ester (0.080 g) in a mixture of dichloromethane (1 ml) and trifluoroacetic acid (1 ml) was stored at room temperature for 90 min and then concentrated under reduced pressure. The residue was triturated with ethereal hydrogen chloride to give the title compound (0.068 g) as a colourless solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[N:10][C:9]([Br:19])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].N([O-])=O.[Na+].[N-:24]=[N+:25]=[N-].[Na+].CCOCC>C(O)(C(F)(F)F)=O.O>[N:1]([C:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)=[N:10][C:9]([Br:19])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])=[N+:24]=[N-:25]
Reactant: COC(=O)c1cc(Br)nc(-c2ccc(Cl)cc2)c1N
Reactant: [N-]=[N+]=[N-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CCOCC
Product: COC(=O)c1cc(Br)nc(-c2ccc(Cl)cc2)c1N=[N+]=[N-]
Yield: 218.7 %

Procedure:
Methyl 3-amino-6-bromo-2-(4-chlorophenyl)isonicotinate (3.86g, 11 3 mmol) was dissolved in TFA (57 mL) and the solution was cooled in an ice bath. Solid sodium nitrite (1.72 g, 24 9 mmol) was added slowly with stirring to give a brown solution with gas evolution. After 30 min solid sodium azide (7.35 g, 113 mmol) was added in portions over 5 min with gas evolution. Et2O (57 mL) was slowly added and a precipitate formed. After stirring for 0.5 h, water was added and the mixture was extracted with EtOAc. The combined organic phases were washed with water (3×) and brine (1×) and then saturated aqueous Na2CO3 solution (so that the aqueous phase was basic) and brine (1×). After drying with sodium sulfate, the solvent was removed to leave methyl 3-azido-6-bromo-2-(4-chlorophenyl)isonicotinate (2.41 g, 6.56 mmol, 58.0% yield) as a fluffy yellow solid. 1 H NMR (400 MHz, chloroform-d) δ ppm 7.79 (1H, s), 7.68-7.73 (2H, m), 7.42-7.47 (2H, m), 4.00 (3H, s).
Reaction SMILES: [OH:1][C:2]1([CH:8]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:30]1(B(O)O)[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=1.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[OH:1][C:2]1([CH:8]([C:23]2[CH:24]=[CH:25][C:26]([O:29][C:38]3[C:39]4[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:35]=[CH:36][CH:37]=3)=[CH:27][CH:28]=2)[CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:14][CH2:15]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: OB(O)c1cccc2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCN(CC(c2ccc(O)cc2)C2(O)CCCCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(CC(c2ccc(Oc3cccc4ccccc34)cc2)C2(O)CCCCC2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of tert-butyl 4-[2-(1-hydroxycyclohexyl)-2-(4-hydroxyphenyl)ethyl]piperazine-1-carboxylate (120 mg, 0.30 mmol), naphthalene-1-boronic acid (54 mg, 0.31 mmol) in dry dichloromethane (2 mL) was added copper (II) acetate (19 mg, 0.10 mmol), triethylamine (71 □L, 0.51 mmol), and powdered 4A sieves (100 mg) was stirred at room temperature for 16 h, after which time the reaction was filtered through a pad of Celite®, which was washed with dichloromethane (20 mL), and concentrated in vacuo. The product was purified via Biotage Horizon (FLASH 25 S, silica, gradient from 1 0% EtOAc/hexane to 60% EtOAc/hexane) to yield tert-butyl 4-{2-(1-hydroxycyclohexyl)-2-[4-(1-naphthyloxy)phenyl]ethyl}piperazine-1-carboxylate as a colorless oil. MS (ESI) m/z 531; HRMS: calcd for C33H42N2O4+H+, 531.32173; found (ESI, [M+H]+), 531.3203.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[C:3]=1[C:15]#[N:16].C(O[CH:20](OCC)[N:21]([CH3:23])[CH3:22])C>C1(C)C=CC=CC=1>[CH3:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([C:4]2[C:3]([C:15]#[N:16])=[C:2]([N:1]=[CH:20][N:21]([CH3:23])[CH3:22])[NH:6][N:5]=2)=[CH:12][CH:11]=1
Reactant: CCOC(OCC)N(C)C
Reactant: COc1ccc(-c2n[nH]c(N)c2C#N)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(-c2n[nH]c(N=CN(C)C)c2C#N)cc1
Temperature: 0 °C

Procedure:
Under a N2 atmosphere, a suspension of 1.87 g (8.16 mmol) of 5-amino-3-(4-methoxy-phenyl)-1H-pyrazole-4-carbonitrile (for preparation see: J. Heterocyclic Chem. 27, 647 (1990)) in 33 ml of toluene is boiled under reflux for 3.5 hours with 1.64 ml of N,N-dimethylformamide diethyl acetal (95%; 9.1 mmol). Crystallization by cooling to 0° C., filtering with suction and washing with hexane yield N'-[3-(4-methoxy-phenyl)-4-cyano-1H-pyrazol-5-yl]-N,N-dimethylformamidine; m.p. 169-171° C.; TLC: Rf =0.18 (ethyl acetate:hexane=1:1); MS: (M)+ =269.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)Cl.C(C1NC=CN=1)(C1NC=CN=1)=O.Cl.[CH3:28][NH:29][O:30][CH3:31]>CN(C=O)C>[CH3:31][O:30][N:29]([CH3:28])[C:4](=[O:5])[C:3]1[CH:7]=[CH:8][C:9]([CH3:11])=[N:10][C:2]=1[CH3:1]
Reactant: Cc1ccc(C(=O)O)c(C)n1
Reactant: CNOC
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc(C)nc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a flask containing 2,6-dimethylnicotinic acid (2.80 g, 18.5 mmol) was added CH2Cl2 and DMF (6 mL). The suspension was stirred at room temperature as carbonyl diimidazole (3.50 g, 21.6 mmol) was added. The suspension remained throughout the day and was allowed to stir overnight at room temperature. After 18 hours, N,O-dimethylhydroxylamine hydrochloride (3.00 g, 30.8 mmol) was introduced and the mixture was stirred at room temperature again for 24 hours. The reaction mixture was quenched with water and 1 N NaOH, and extracted with CH2Cl2 (4×50 mL). The combined organics were washed with brine, dried over Na2SO4, filtered and concentrated to give a colorless oil. Flash chromatography on silica gel (50% EtOAc-hexane) afforded the title compound as a colorless oil.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=[C:5]1[CH3:13].[N+:14]([C:17]1[CH:18]=[N:19][NH:20][CH:21]=1)([O-:16])=[O:15].C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[CH3:13][C:5]1[N:4]([CH2:3][CH2:2][N:19]2[CH:18]=[C:17]([N+:14]([O-:16])=[O:15])[CH:21]=[N:20]2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]=1
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: Cc1nc2ccccc2n1CCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: Cc1nc2ccccc2n1CCn1cc([N+](=O)[O-])cn1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To 1-(2-chloroethyl)-2-methyl-1H-benzoimidazole) (4.42 g, 22.71 mmol), in MeCN (50 mL), 4-nitro-1H-pyrazole (2.57 g, 22.71 mmol) and Cs2CO3 (8.14 g, 24.98 mmol) was added. After stirring at 80° C. for 18 h the reaction mixture was allowed to reach rt and filtered. The filter cake was washed with DCM and the filtrate was concentrated in vacuo, then the residue was dissolved in DCM and washed with H2O. The combined aq. layers were reextracted with DCM, the combined org. layers were dried (MgSO4), filtered and the solvent removed under reduced pressure to yield 2-methyl-1-(2-(4-nitro-1H-pyrazol-1-yl)-ethyl)-1H-benzoimidazole, which is used in the next step without further purification. LC-MS conditions B: tR=0.42 min, [M+H]+=272.07.
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[N:6][N:7]2[CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1.[F:18][C:19]1[C:24]([F:25])=[CH:23][C:22]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=[C:21]([O:33][CH3:34])[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>C1COCC1.O>[F:18][C:19]1[C:24]([F:25])=[CH:23][C:22]([C:26]2[CH:27]=[CH:28][C:29]([O:32][CH2:2][C:3]3[CH:11]=[CH:10][CH:9]=[C:8]4[C:4]=3[CH:5]=[N:6][N:7]4[CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)=[CH:30][CH:31]=2)=[C:21]([O:33][CH3:34])[CH:20]=1
Reactant: BrCc1cccc2c1cnn2C1CCCCO1
Reactant: COc1cc(F)c(F)cc1-c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc3c2cnn3C2CCCCO2)cc1
Yield: 52.5 %

Procedure:
4-Bromomethyl-1-(tetrahydro-pyran-2-yl)-1H-indazole (0.5 g, 1.69 mmol), 3-(4′,5′-difluoro-2′-methoxy-biphenyl-4-ol (0.4 g, 1.69 mmol) and potassium carbonate (0.23 g, 1.69 mmol) in 15 mL THF/3 mL DMF was heated to 70° C. overnight. The reaction was cooled and distributed between EtOAc and H2O. The organic layer was separated and concentrated in vacuo. The crude product was purified by flash chromatography with a gradient from 0-25% ethyl acetate in hexanes to yield 4-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-1-(tetrahydro-pyran-2-yl)-1H-indazole as a white solid (400 mg, 52.5%). HR-MS (ES) calculated for C26H24F2N2O3, 473.1646; found m/z 473.1647 [M+Na]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.CN(C([O:23]N1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.Cl.[C:48]1([CH:54]2[CH2:58][CH2:57][NH:56][CH2:55]2)[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:56]2[CH2:57][CH2:58][C:54]([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)([OH:23])[CH2:55]2)=[O:15])=[CH:6][CH:7]=1
Reactant: c1ccc(C2CCNC2)cc1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2oncc2C(=O)N2CCC(O)(c3ccccc3)C2)cc1
Reaction time: 2 h
Yield: 40.2 %

Procedure:
A solution of 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10 mg, 0.05 mmol), TBTU (19 mg, 0.06 mmol, 1,2 equ.) and N-ethyl-N-isopropylpropan-2-amine (26 μL, 0.15 mmol, 3 equ) in DMF (0.3 mL) was added to 3-phenylpyrrolidine hydrochloride (10 mg, 0.05 mmol) and the reaction mixture was left at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents the product was dried in vacuum to yield the title compound (7 mg). MS (ESI, pos. ion) m/z calcd for C21H20N2O3: 348.1474, found 348.1470.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:47])[C@@H:12]([NH:21][C:22](=[O:46])[C@H:23]([NH:38][C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C:24]2[CH:29]=[CH:28][C:27]([NH:30]C(OC(C)(C)C)=O)=[CH:26][CH:25]=2)[C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH3:14])[S:8][CH:9]=1)=[O:4].C(OC(OC(OC(C)(C)C)=O)=O)(C)(C)C>FC(F)(F)C(O)=O.ClCCl.O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:47])[C@@H:12]([NH:21][C:22](=[O:46])[C@@H:23]([C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[NH:38][C:39]([O:41][C:42]([CH3:44])([CH3:45])[CH3:43])=[O:40])[C@H:13]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH3:14])[S:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1csc(NC(=O)[C@@H](NC(=O)[C@H](NC(=O)OC(C)(C)C)c2ccc(NC(=O)OC(C)(C)C)cc2)[C@@H](C)c2ccccc2)n1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)c1csc(NC(=O)[C@@H](NC(=O)[C@H](NC(=O)OC(C)(C)C)c2ccc(N)cc2)[C@@H](C)c2ccccc2)n1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 57.9 %

Procedure:
2-{(2S,3S)-2-[(R)-2-tert-butoxycarbonylamino-2-(4-tert-butoxycarbonylamino-phenyl)-acetylamino]-3-phenyl-butyrylamino}-thiazole-4-carboxylic acid methyl ester (510 mg, 0.76 mmol) was dissolved in 30% v/v trifluoroacetic acid in dichloromethane solution (10 mL) at 0° C. The mixture was stirred at 0° C. for 2.5 hours and then partitioned between ethyl acetate and saturated aqueous sodium carbonate. The aqueous layer was adjusted to pH=9 by the addition of solid sodium carbonate and the organic layer collected, dried over sodium sulfate, filtered and concentrated. The residue was without further purification dissolved in tetrahydrofuran (50 mL) and the resulting solution cooled to 0° C. A solution of di-tert-butyldicarbonate (167 mg, 0.76 mmol) in tetrahydrofuran (5 mL) was added dropwise and after stirring overnight the reaction mixture was evaporated and the residue was purified by chromatography over silica gel gradient eluted with 0 to 100% ethyl acetate in hexanes to afford 2-{(2S,3S)-2-[(R)-2-(4-amino-phenyl)-2-tert-butoxycarbonylamino-acetylamino]-3-phenyl-butyrylamino}-thiazole-4-carboxylic acid methyl ester as a white solid (250 mg, 58%).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[C:8]([C:11]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:9][NH:10][C:5]2=[N:4][CH:3]=1.[C:18]([O:24][CH2:25]Cl)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:18]([O:24][CH2:25][N:10]1[C:5]2[C:6](=[N:7][C:2]([Br:1])=[CH:3][N:4]=2)[C:8]([C:11](=[O:12])[NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:9]1)(=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: CC(C)(C)NC(=O)c1c[nH]c2ncc(Br)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)NC(=O)c1cn(COC(=O)C(C)(C)C)c2ncc(Br)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 34 %

Procedure:
To a stirred mixture of 2-bromo-N-tert-butyl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide in DMF (5 mL) was added chloromethyl pivalate (225 mg, 1.5 mmol) followed by K2CO3 (276 mg, 2 mmol). The mixture was stirred at room temperature for 16 hours. The mixture was poured into water and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine and dried over Na2SO4. After filtration and concentration, the residue was purified by column chromatography on silica gel eluting with petroleum ether/EtOAc (5:1, v/v) to give (2-bromo-7-(tert-butylcarbamoyl)-5H-pyrrolo[3,2-b]pyrazin-5-yl)methyl pivalate (140 mg, 34% over two steps) as white solid. MS: (M+H)+=411; 1H NMR (300 MHz, CDCl3): δ 8.41 (s, 1H), 8.33 (s, 1H), 7.80 (s, 1H), 6.20 (s, 2H), 1.52 (s, 9H), 1.15 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=2[C:19](O)=[O:20])[CH2:13][CH2:12]1)(=[O:10])=[O:9].CC[N:28]=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C([O-])=O.[NH4+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=2[C:19]([NH2:28])=[O:20])[CH2:13][CH2:12]1)(=[O:10])=[O:9]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1ccccc1N1CCN(S(=O)(=O)c2ccccc2Cl)CC1
Agent: O=C[O-]
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: CN(C)C=O
Product: NC(=O)c1ccccc1N1CCN(S(=O)(=O)c2ccccc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
2-(4-(2-Chlorophenylsulfonyl)piperazin-1-yl)benzoic acid (76 mg, 0.02 mmole), EDCI (39 mg, 0.02 mmole), HOBt (31 mg, 0.02 mmole) and ammonium formate (13 mg, 0.02 mmole) were combined in 1 ml of dry DMF. The mixture was treated with 1 equivalent of TEA and stirred at room temperature overnight. The title compound was obtained in yield of 37% after purification on preparative HPLC. 1H NMR (400 MHz, DMSO-D6) δ ppm 3.21 (s, 4 H), 3.31 (s, 4 H), 5.87 (br, s, 2 H), 6.68 (s, 1 H), 6.75 (s, 1 H), 6.90 (s, 1 H), 7.26 (s, 1 H), 7.59 (s, 1 H), 7.72 (s, 2 H), 8.02 (s, 1 H); ESI-MS: m/z 380.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([F:23])[CH:22]=1)[O:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([O:14][CH:15]([CH3:19])[CH2:16][O:17][CH3:18])[CH:13]=1)[C:9]#N.C(O)C.[OH2:27].[OH-:28].[Na+]>>[F:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([F:23])[CH:22]=1)[O:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([O:14][CH:15]([CH3:19])[CH2:16][O:17][CH3:18])[CH:13]=1)[C:9]([OH:28])=[O:27]
Reactant: COCC(C)Oc1cc(C#N)cc(Oc2cc(F)cc(F)c2)c1
Reactant: [OH-]
Reactant: O
Agent: [Na+]
Solvent: CCO
Product: COCC(C)Oc1cc(Oc2cc(F)cc(F)c2)cc(C(=O)O)c1
Temperature: 90 °C
Yield: 99.1 %

Procedure:
3-(3,5-difluorophenoxy)-5-(2-methoxy-1-methylethoxy)benzonitrile (1.00 equiv; 9.40 mmol; 3.00 g) was charged to a 100 ml round-bottomed flask (1 neck, condenser, magnetically stirred) with ethanol (515 mmol; 30.0 ml; 23.7 g). Water (138 mmol; 2.49 ml; 2.49 g), then sodium hydroxide (18.9M in water, 47.0 mmol; 2.49 ml; 3.75 g) was charged and the mixture heated to reflux (bath temperature 90° C.) for 4 hours. The mixture was cooled and solvent removed in vacuo affording a colourless solution (water not removed). The mixture was partitioned between water (50 ml) and MTBE (50 ml) and the layers separated (aqueous layer pH=14). The aqueous phase was acidified with HCl solution (2M, aq, 50 ml) and extracted with MTBE (50 ml). The organic layer was dried over MgSO4, filtered and the volatiles removed in vacuo affording 3-(3,5-difluorophenoxy)-5-(2-methoxy-1-methylethoxy)benzoic acid as a colourless oil (3.15 g, 99%).