Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)=[N:4][CH:5]=[CH:6][N:7]=1.[C:18](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:12][CH:13]=2)=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: O=C(O)Cc1ccc(-c2nccnc2Cl)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)Cc1ccc(-c2nccnc2Cl)cc1
Reaction time: 1 h
Yield: 35.7 %

Procedure:
To a solution of 0.40 g (1.6 mmol) of [4-(3-chloropyrazin-2-yl)phenyl]acetic acid in 3.0 mL of DMF was added 0.67 g (4.8 mmol) of potassium carbonate and 0.14 mL (2.3 mmol) iodomethane. After 1 h at 40° C., the reaction mixture was cooled, diluted with CH2Cl2, washed three times with water followed by brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (silica gel, linear gradient 0-75% EtOAc in hexanes) afforded 0.15 g (36%) methyl [4-(3-chloropyrazin-2-yl)phenyl]acetate. ES-MS M+1=263.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH3:22])=[C:14](Br)[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])(C)(C)C.[CH2:29]([S:31]SCC)[CH3:30]>C(OCC)C>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH3:22])=[C:14]([S:31][CH2:29][CH3:30])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc2c(cc1Br)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Reactant: CCSSCC
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: CCSc1cc2c(nc1C)N1[C@H](C2)CN(C(=O)OC(C)(C)C)C[C@H]1C
Temperature: -78 °C
Reaction time: 1 h
Yield: 57.2 %

Procedure:
A solution of 0.50 g (1.31 mmol) (4R,9aR)-7-bromo-4,6-dimethyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (example 6, intermediate) in 30 mL diethyl ether was cooled to −100° C. and 1.05 mL tert-butyl-lithium (1.57 mmol; 1.5M solution in n-pentane) was added dropwise. After 15 min. diethyl disulfide was added and the reaction was stirred at −78° C. for 1 h. The reaction mixture was quenched with 10% aqueous citric acid solution and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by column chromatography over silica gel (0.030–0.063 mm) with ethyl acetate:n-hexane (1:4) as eluant to give the product as a light yellow solid (57.2%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[C:27](=[O:28])[N:26]2[CH:22]([CH2:23][CH:24]([OH:29])[CH2:25]2)[C:21](=[O:30])[NH:20][C:19]2([C:31]([OH:33])=[O:32])[CH:17]([CH2:18]2)[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].F[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=1>CS(C)=O>[C:1]([O:5][C:6]([NH:8][CH:9]1[C:27](=[O:28])[N:26]2[CH:22]([CH2:23][CH:24]([O:29][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=3)[CH2:25]2)[C:21](=[O:30])[NH:20][C:19]2([C:31]([OH:33])=[O:32])[CH:17]([CH2:18]2)[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1ccccn1
Reactant: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)O)NC(=O)C2CC(O)CN2C1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NC1CCCCCC=CC2CC2(C(=O)O)NC(=O)C2CC(Oc3ccccn3)CN2C1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 57.6 %

Procedure:
To a mixture of (14-tert-butoxycarbonylamino-18-hydroxy-2,15-dioxo-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid (150 mg, 0.32 mmol; prepared in Ex. 25, step 4) in 3 mL of DMSO was added potassium t-butoxide (91 mg, 0.81 mmol). The mixture was stirred at rt for 5 min, and then 2-fluoro-pyridine (39 mg, 0.40 mmoL) was added and the mixture was stirred at rt overnight. The reaction was quenched by adding 10 mL of water, and then the pH was adjusted to 4 using 0.1 N HCL. It was then extracted with ethyl acetate, dried, concentrated in vacuo to obtain a yellow oil. This crude product was purified by flash chromatography on silica gel eluting with 10% methanol in ethyl acetate to isolate 100 mg (56%) of 14-tert-butoxycarbonylamino-2,15-dioxo-18-(pyridin-2-yloxy)-3,16-diaza-tricyclo[14.3.0.04,6]nonadec-7-ene-4-carboxylic acid as a white solid. 1H NMR (500 MHz, MeOD) δ 1.24-1.53 (m, 6H), 1.36 (s, 9H), 1.55-1.68 (m, 3H), 1.73-1.90 (m, 1H), 2.02-2.11 (m, 1H), 2.16 (q, J=8.65 Hz, 1H), 2.35-2.45 (m, 1 H), 2.51 (dd, J=7.63, 2.75 Hz, 2H), 4.06-4.14 (m, 1H), 4.27 (d, J=11.29 Hz, 1 H), 4.33 (s, 1H), 4.58 (t, J=7.93 Hz, 1H), 5.46-5.57 (m, 2H), 5.70 (s, 1H), 6.79 (d, J=8.54 Hz, 1H), 6.93-7.02 (m, 1H), 7.68 (t, J=7.63 Hz, 1H), 8.16 (d, J=4.85 Hz, 1 H). LC-MS (YMC Xterra ODS S7 micrometer column: 3.0×50 mm length. Gradient: 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B. Gradient time: 4 min. Hold time: 1 min. Flow rate: 4 mL/min. Detector Wavelength: 220 nm. Solvent A: 10% MeOH/90% H2O/0.1% TFA. Solvent B: 10% H2O/90% MeOH/0.1% TFA.)(Retention time: 2.90 min), MS m/z 543 (M++1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1C=CC(S(N([N:26]=[O:27])C)(=O)=O)=CC=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([N:26]=[O:27])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(N=O)CC1

Procedure:
To a solution of piperazine-1-carboxylic acid tert-butyl ester (26 mmol) in DCM (130 mL) was added, in one portion, Diazald (4 eq.). After stirring at reflux for 12 h, the solution was cooled, concentrated and the residue was purified by flash chromatography (0-20% EtOAc/Heptane) to afford 4-nitrosopiperazine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]#[N:10])[CH2:4][CH2:3]1.[NH2:11][OH:12]>C(O)C>[OH:12][NH:11][C:9](=[NH:10])[CH2:8][N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: NO
Reactant: CN1CCN(CC#N)CC1
Solvent: CCO
Product: CN1CCN(CC(=N)NO)CC1

Procedure:
A mixture (4-methylpiperazin-1-yl)acetonitrile (400 mg), hydroxylamine (50% aqueous solution, 2.0 mL) and ethanol (10.0 mL), was stirred at room temperature for 18 hours. The reaction mixture was evaporated to dryness to give a crystalline solid that was washed with hexane and dried under vacuum to give N-hydroxy-2-(4-methylpiperazin-1-yl)ethanimidamide (405 mg). 1H-NMR (400 MHz; CDCl3): 5.19 (br s, 3H), 3.00 (s, 2H), 2.75-2.28 (br m, 8H), 2.70 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:14][C:13]=2[CH3:26])[C:10](=[O:27])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH:28][C:29]1[CH:36]=[CH:35][C:32]([CH:33]=O)=[CH:31][CH:30]=1>C(O)(=O)C>[OH:28][C:29]1[CH:36]=[CH:35][C:32](/[CH:33]=[CH:1]/[C:2]2[N:11]([C:12]3[CH:17]=[CH:16][C:15]([C:18]#[C:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:14][C:13]=3[CH3:26])[C:10](=[O:27])[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)=[CH:31][CH:30]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Cc1cc(C#Cc2ccccc2)ccc1-n1c(C)nc2ccccc2c1=O
Solvent: CC(=O)O
Product: Cc1cc(C#Cc2ccccc2)ccc1-n1c(/C=C/c2ccc(O)cc2)nc2ccccc2c1=O
Reaction time: 8 h

Procedure:
4-iodo-2-methylbenzenamine (24, 233 mg, 1 mmol) on reaction with ethynyl benzene (25a, 102 mg, 1 mmol) by employing Sonagashira coupling conditions using Pd(PPh3)4 (69.3 mg, 0.06 equiv) as catalyst, CuI (22.8 mg, 0.12 equiv) as cocatalyst, butyl amine (261 mg, 3 equiv) as base and ether as solvent and kept the reaction for 6 h. After completion of the reaction as indicated by TLC and the reaction mixture is extracted into ether (4×25 mL) from the aqueous layer and concentrated in vacuo. The compound was further purified by column chromatography using 60-120 silica gel (ethyl acetate/hexane, 1:9) to obtain 2-methyl-4-(phenylethynyl)benzenamine compound (26a) as pure product. Anthranilic acid (27, 137 mg, 1 mmol) on reaction with acetic anhydride at 150° C. and reflux for 30 min, after completion of reaction aqueous sodium bicarbonate solution is added and extracted in ethyl acetate (4×25 mL) from the aqueous layer and concentrated in vacuo afforded 2-methyl 4H-benzo[d][1,3]oxazin-4-one compound (28) as pure product. To a stirred solution of 2-methyl-4-(phenylethynyl)benzenamine (26a, 207 mg, 1 mmol) with 2-methyl-4H-benzo[α][1,3]oxazin-4-one (28, 161 mg, 1 mmol) in acetic acid and reflux for 8 h. After completion of the reaction as indicated by TLC. The reaction mixture was quenched with NaHCO3 and extracted in ethyl acetate (4×25 mL) from the ice cold aqueous layer and dried over anhydrous Na2SO4 afforded 2-methyl-3-(2-methyl-4-(phenylethynyl)phenyl)quinazolin-4(3H)-one (29a). Reaction of 2-methyl-3-(2-methyl-4-(phenyl ethynyl)phenyl)quinazolin-4(3H)-one (29a, 350 mg, 1 mmol) with 4-hydroxy benzaldehyde (30b, 122 mg, 1 mmol) was taken in acetic acid Then the resulting mixture was stirred under reflux conditions for 8 h and then the reaction mixture was quenched with NaHCO3 and extracted in ethyl acetate (4×25 mL) from the ice cold aqueous layer and dried over anhydrous Na2SO4. The resulting product (4b) was purified by column chromatography employing EtOAc/Hexane as an eluent.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]=[C:9]2[O:12][Si](C)(C)C)=[CH:4][CH:3]=1.Cl[C:18]([CH3:21])([CH3:20])[CH3:19]>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([C:18]([CH3:21])([CH3:20])[CH3:19])[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)OC1=CCCc2ccc(Br)cc21
Reactant: CC(C)(C)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)C1CCc2ccc(Br)cc2C1=O
Temperature: -40 °C
Yield: 100.8 %

Procedure:
step a—A solution of (7-bromo-3,4-dihydronaphthalen-1-yloxy)trimethylsilane (6.85 g, 11.5 mmol, CASRN 309929-09-7) and DCM (23.0 mL) was cooled to −40° C. 2-Chloro-2-methylpropane (1.12 g, 1.32 mL, 12.1 mmol) was added and the solution stirred under nitrogen. A solution of TiCl4 (2.19 g, 1.27 mL, 11.5 mmol) in DCM (6 mL) was added dropwise while maintaining the solution at −40° C. Soon after addition was complete TLC indicated ca. 50% conversion. The reaction was stirred at RT over the weekend then poured onto ice. The mixture was partitioned between EtOAc and H2O and aqueous layer was neutralized with satd. aq. NaHCO3. The mixture was filtered through a plug of celite to a remove chunky white precipitate. The organic layer was separated, washed with brine, dried (MgSO4), filtered and concentrated. The crude product was applied to a hexane equilibrated SiO2 column and eluted with an EtOAc/hexane gradient (0 to 5% EtOAc) to afford 3.26 g (quantitative) of 7-bromo-2-tert-butyl-3,4-dihydro-2H-naphthalen-1-one (109) a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.C(N(C(C)C)CC)(C)C.[NH2:19][CH2:20][CH2:21][S:22]([OH:25])(=[O:24])=[O:23]>O1CCCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:19][CH2:20][CH2:21][S:22]([OH:25])(=[O:24])=[O:23])[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: NCCS(=O)(=O)O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(O)CCNc1cc(Cl)nc(Cl)n1
Yield: 254.4 %

Procedure:
A stirred mixture of 2,4,6-trichloropyrimidine (6.9 g) in 75 ml of tetrahydrofuran is treated with diisopropylethylamine (15 ml) and solid taurine (4.7 g). The resulting suspension is heated at reflux for 48 hours. The reaction mixture is cooled to 20°-25° followed by solvent evaporation which gives 26 g of an oil which is chromatographed on 170 g of silica gel and eluting with chloroform/5.0M ammonia in methanol (7/3). An initial fraction of 250 mL is collected followed by 20 ml fractions. Fractions 23-57 contained the desired product. Solvent evaporation gives a semi-solid which is taken up in chloroform/methanol (10/1) and stirred at 20°-25° for 30 minutes. Filtration provided 3.71 g of a solid.
Reaction SMILES: [CH:1]1([C:7]([NH:9][C:10]2[N:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][N:11]=2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(O)C.[Pt]=O>[CH:1]1([C:7]([NH:9][C:10]2[N:15]=[CH:14][C:13]([NH2:16])=[CH:12][N:11]=2)=[O:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(Nc1ncc([N+](=O)[O-])cn1)C1CCCCC1
Agent: O=[Pt]
Solvent: CCO
Product: Nc1cnc(NC(=O)C2CCCCC2)nc1
Reaction time: 1 h
Yield: 10362.7 %

Procedure:
Platinum oxide (50 mg, 0.22 mmol) was added to a solution 2-(N-cyclohexanoyl)amino-5-nitropyrimidine (1.15 g, 4.6 mmol) in ethanol (100 ml) at ambient temperature and the reaction stirred for 1 hour under an atmosphere of hydrogen. The reaction was filtered through a pad of celite and the solvents were evaporated in vacuo to give 2-(N-cyclohexanoyl)amino-5-aminopyrimidine (105 g, 100% yield) as brown solid:
Reaction SMILES: C1([O:7][C:8](=[O:16])[C@@:9]2([C:12]([F:15])([F:14])[F:13])[O:11][CH2:10]2)C=CC=CC=1.O.[OH-].[Na+]>CO>[O:11]1[CH2:10][C@@:9]1([C:12]([F:15])([F:14])[F:13])[C:8]([OH:16])=[O:7]
Reactant: O=C(Oc1ccccc1)[C@]1(C(F)(F)F)CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)[C@]1(C(F)(F)F)CO1
Reaction time: 1 h
Yield: 86.1 %

Procedure:
Into a 100 ml three-necked round-bottomed flask equipped with a dropping funnel and a stirrer, the (S)-2,3-epoxy-2-trifluoromethylpropionic acid phenyl ester (7.2 g, 31.0 mmol) obtained in Example 7, methanol (20 ml) and water (20 ml) were charged and cooled to 0° C. on an ice bath, whereupon 3N sodium hydroxide aqueous solution (30 ml, 90 mmol) was dropwise added over a period of one hour by means of the dropping funnel, and stirring was further carried out at the same temperature for one hour. After completion of the reaction, methanol was distilled off, followed by extraction with diisopropyl ether (30 ml×twice). Then, hydrochloric acid was added to adjust the pH to 3, followed by extraction with ethyl acetate (30 ml×3 times). The obtained organic layer was dried over anhydrous magnesium sulfate, followed by filtration and concentration to obtain the desired (S)-2,3-epoxy-2-trifluoromethylpropionic acid (4.17 g, 26.7 mmol, yield: 87%, optical purity: 78% ee).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=2[C:17]2[CH:18]=[CH:19][C:20]([C:23]([NH:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:24])=[N:21][CH:22]=2)=[CH:4][C:3]=1[F:33].[Cl:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][C:40]=1[Cl:41].C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.CCOC(C)=O.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]>[Cl:34][C:35]1[CH:36]=[C:37]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=3[C:17]3[CH:18]=[CH:19][C:20]([C:23]([NH:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[O:24])=[N:21][CH:22]=3)=[CH:4][C:3]=2[F:33])[CH:38]=[CH:39][C:40]=1[Cl:41]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(F)ccc2CNc2ccc(Br)c(F)c2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(F)ccc2CNc2ccc(-c3ccc(Cl)c(Cl)c3)c(F)c2)cn1
Temperature: 25 °C

Procedure:
Ethyl 3-(5-(2-(((4-bromo-3-fluorophenyl)amino)methyl)-5-fluorophenyl)picolinamido)propanoate (100 mg, 0.19 mmol), (3,4-dichlorophenyl)boronic acid (44 mg, 0.23 mmol), Pd(dppf)Cl2 (21 mg, 0.03 mmol), and K2CO3 (53 mg, 0.39 mmol) were dissolved in 1,4-dioxane (4 mL) and water (1 mL) and the resulting mixture was heated to 80° C. After 16 h the resulting mixture was cooled to room temperature, diluted with EtOAc, washed with water and brine, dried (Na2SO4), concentrated and purified via column chromatography to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:35]([C:36]([F:39])([F:38])[F:37])=[CH:34][CH:33]=[CH:32][C:3]=1[CH2:4][N:5]([CH2:18][CH:19]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]([NH:16][CH3:17])[CH:13]=[CH:14][CH:15]=1.[CH3:40][O:41][C:42](=[O:45])[CH2:43]Br>CO>[CH3:40][O:41][C:42](=[O:45])[CH2:43][N:16]([C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH2:8][CH2:7][CH2:6][N:5]([CH2:4][C:3]2[CH:32]=[CH:33][CH:34]=[C:35]([C:36]([F:37])([F:38])[F:39])[C:2]=2[Cl:1])[CH2:18][CH:19]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:11]=1)[CH3:17]
Reactant: COC(=O)CBr
Reactant: CNc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Solvent: CO
Product: COC(=O)CN(C)c1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Temperature: 50 °C
Yield: 74.7 %

Procedure:
A solution of (3-{3-[(2-chloro-3-trifluoromethyl-benzyl)-diphenylethyl-amino]-propoxy}-phenyl)-N-methyl-amine (81 mg, 0.15 mmol) in methanol (15 ml) was treated with bromo-acetic acid methyl ester (46 mg, 0.30 mmol) diisopropylethylamine (46 mg, 0.36 mmol). The resulting solution was heated at 50° C. for 4 hours, cooled down and concentrated. The crude material was dissolved in EtOAc and washed with brine (1×), dried over sodium sulfate, and filtered. The filtrate was concentrated to afford title compound as an oil (70 mg, 76%). MS(ES) m/e 625.2 (M+).
Reaction SMILES: [OH:1][C:2]([C:5]1[CH:36]=[CH:35][C:8]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24]C(=O)OC(C)(C)C)[CH2:19]3)[N:15]3[N:32]=[CH:33][CH:34]=[C:14]3[N:13]=2)=[O:10])=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>C(Cl)Cl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[NH2:24][C@@H:20]1[CH2:21][CH2:22][CH2:23][N:18]([C:16]2[N:15]3[N:32]=[CH:33][CH:34]=[C:14]3[N:13]=[C:12]([NH:11][C:9](=[O:10])[C:8]3[CH:35]=[CH:36][C:5]([C:2]([OH:1])([CH3:3])[CH3:4])=[CH:6][CH:7]=3)[CH:17]=2)[CH2:19]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3ccnn23)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(O)c1ccc(C(=O)Nc2cc(N3CCC[C@@H](N)C3)n3nccc3n2)cc1
Reaction time: 6 h

Procedure:
(R)-tert-butyl 1-(5-(4-(2-hydroxypropan-2-yl)benzamido)pyrazolo[1,5-a]pyrimidin-7-yl)piperidin-3-ylcarbamate was dissolved in CH2Cl2. Trifluoroacetic acid was added and the mixture was let stirred for 6 hours. The reaction mixture was concentrated to dryness in vacuo, and part of the residue was purified by preparatory HPLC (20-50% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white powder. 1H NMR (400 MHz, DMSO-d6) δ=10.97 (s, 1H), 8.13 (d, J=2.3 Hz, 1H), 8.11-8.03 (m, 2H), 8.03-7.97 (m, 2H), 7.64-7.57 (m, 2H), 7.48 (s, 1H), 6.40 (d, J=2.3 Hz, 1H), 4.23 (br. s., 1H), 3.97 (br. s., 2H), 3.47 (d, J=7.1 Hz, 2H), 3.28 (br. s., 1H), 2.08 (br. s., 1H), 1.96 (br. s., 1H), 1.85-1.64 (m, 2H), 1.46 (s, 6H); ESI-MS: m/z 377.4 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[C:13](O)([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:12][CH2:11][C:10]3([CH3:25])[CH3:24])OCC[O:3]1.CC1C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH3:24][C:10]1([CH3:25])[C:9]2[C:14](=[CH:15][CH:16]=[C:7]([C:2](=[O:3])[CH3:1])[CH:8]=2)[C:13]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:12][CH2:11]1
Reactant: CCOC(=O)CC1(O)CCC(C)(C)c2cc(C3(C)OCCO3)ccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)CC1=CCC(C)(C)c2cc(C(C)=O)ccc21

Procedure:
A solution of (+/-) 6-(2-methyl-1,3-dioxolan-2-yl)-1,2,3,4-tetrahydro-4,4-dimethyl-1-hydroxy-1-(carboethoxymethyl)-naphthlene ((Compound D16, 321 mg, 0.90 mmol) and catalytic amount of TsOH in 20 ml of benzene was refluxed for 12 h. During the reaction the water generated from the reaction was periodically removed by a Dean-Stark trap. The solvent was removed and the residue was purified by column chromatography (silica, ethyl acetate/hexane (1/3)) to give the title compound as an oil (215 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[C:7]([CH:9]1[CH2:13][C:12]([O:14]CC)=[CH:11][C:10]1=O)=O)([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:20]([NH:27][NH2:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CC(O)=O>C(O)C>[C:1]([O:5][C:6]([C:7]1[C:9]2[CH2:13][C:12](=[O:14])[CH2:11][C:10]=2[N:27]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:28]=1)=[O:18])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC1=CC(=O)C(C(=O)C(=O)OC(C)(C)C)C1
Reactant: NNCc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)c1nn(Cc2ccccc2)c2c1CC(=O)C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.1 %

Procedure:
To a solution of the intermediate from step A (2.15 g, 8.45 mmol) in ethanol (100 mL) was added benzyl hydrazine hydrochloride (1.8 g, 9.22 mmol) and HOAc (10 mL). The reaction mixture was stirred at room temperature for 16 hours and then refluxed at 70° C. for 30 minutes. The reaction was cooled to room temperature and concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with water, saturated NaHCO3, and brine. The organic layer was dried over anhydrous Na2SO4 filtered and concentrated in vacuo. The residue was purified by flash chromatography (SiO2) using 30% ethyl acetate-hexanes to give the desired product (1.64 g) a brown oil.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Br:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([NH:18]C(=O)OC(C)(C)C)[CH:16]=2)[NH:11][C:10]=1[C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([O:37][C:38]2[CH:43]=[C:42]([C:44]#[N:45])[CH:41]=[C:40]([Cl:46])[CH:39]=2)[C:31]=1[F:47])=[O:27]>C(Cl)(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:18][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]([C:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([O:37][C:38]3[CH:43]=[C:42]([C:44]#[N:45])[CH:41]=[C:40]([Cl:46])[CH:39]=3)[C:31]=1[F:47])=[O:27])=[C:9]2[Br:8]
Reactant: CC(C)(C)OC(=O)Nc1ccc2[nH]c(C(=O)NCc3ccc(Cl)c(Oc4cc(Cl)cc(C#N)c4)c3F)c(Br)c2c1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]c4ccc(N)cc4c3Br)c2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 119.8 %

Procedure:
Trifluoroacetic acid (0.5 mL, 6.49 mmol) was added to a suspension of 1,1-dimethylethyl (3-bromo-2-{[({4-chloro-3-[(3-chloro-5-cyanophenyl)oxy]-2-fluorophenyl}methyl)amino]carbonyl}-1H-indol-5-yl)carbamate (0.082 g, 0.126 mmol) in chloroform (2 mL). The resulting solution was stirred at room temperature overnight. The solvent was evaporated to give the title compound (0.100 g, 107%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.34 (s, 1H), 9.86 (br. s., 2 H), 8.66 (t, 1H), 7.78-7.84 (m, 1H), 7.56 (t, 1H), 7.41-7.52 (m, 5H), 7.25 (dd, 1H), 4.49-4.72 (m, 2H).