Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:8]=[C:7]2[CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].[C:25]([Si:27]([CH3:30])([CH3:29])[CH3:28])#[CH:26]>>[CH2:15]([O:14][C:12](=[O:13])[CH2:11][N:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[C:26]#[C:25][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:7]([CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:8]1)[CH3:16]
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)CCCc1cn(CC(=O)OCC)c2c(Br)cccc12
Product: CCOC(=O)CCCc1cn(CC(=O)OCC)c2c(C#C[Si](C)(C)C)cccc12

Procedure:
To an ethanol (2 mL) solution of ethyl 4-{1-[2-(ethyloxy)-2-oxoethyl]-7-[(trimethylsilyl)ethynyl]-1H-indol-3-yl}butanoate (98 mg), potassium carbonate (50 mg) was added and the mixture was stirred at room temperature for 3 hours. To the reaction mixture, water was added, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous sodium sulfate and then concentrated to obtain the titled compound having the following physical properties (74 mg). Herein, ethyl 4-{1-[2-(ethyloxy)-2-oxoethyl]-7-[(trimethylsilyl)ethynyl]-1H-indol-3-yl}butanoate was prepared by the same operation as in Example 3, except for using ethyl 4-{7-bromo-1-[2-(ethyloxy)-2-oxoethyl]-1H-indol-3-yl}butanoate and ethynyl(trimethyl)silane.
Reaction SMILES: C[O:2][C:3]1[CH:19]=[CH:18][C:6]2[NH:7][C:8]3[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][C:9]=3[CH:10]=[CH:11][C:5]=2[CH:4]=1.B(Br)(Br)Br>CN(C)C=O>[OH:2][C:3]1[CH:19]=[CH:18][C:6]2[N:7]=[C:8]3[CH:15]=[CH:14][C:13](=[O:16])[CH:12]=[C:9]3[CH:10]=[CH:11][C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)C=Cc1cc(OC)ccc1N2
Agent: BrB(Br)Br
Solvent: CN(C)C=O
Product: O=c1ccc2nc3ccc(O)cc3ccc-2c1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 86.2 %

Procedure:
A solution of 2,8-dimethoxy-5H-dibenz[b,f] azepine (8) (1.0 g; 3.95 mmol) in warm CH2Cl2 (23.5 mL, dried over molecular sieve 4A), maintained under a CaSO4 drying tube, was cooled in an ice bath (8 separates as a fine suspension) and treated with BBr3 (1.85 mL; 19.6 mmol; 5 eq). The mixture immediately turned blue and became homogeneous. The ice bath was removed after 5 minutes and the reaction was stirred at ambient temperature for 3.5 hours. The mixture was carefully blended into H2O (350 mL) (HBr evolution!) and extracted four times with EtOAc (100 mL each). The combined EtOAc layers were washed with brine (100 mL) then transferred to a 3-neck round bottom flask and rapidly mechanically stirred with a solution of NaIO4 (3.0 g) in H2O (100 mL) for 15 minutes. During this time the reaction turned dark red-brown and a solid separated. The mixture was filtered and the collected solids were washed liberally with H2O and EtOAc then dried to give the title compound (1) (0.76 g; 86%). A portion was recrystallized from boiling DMF then vacuum dried at 130° C. to afford the analytical sample as fine black whiskers with mp=239-41° C. (dec.): IR (KBr) cm-1 3475, 1600, 1555, 1538, 1453, 1340, 1270, 1230, 1115, 885, 895, 795; 1H NMR (DMSO-d6) δ6.85 (br. s, 2H), 6.95-7.08 (m, 4H), 6.66 (br. d, J=7.5 Hz, 2H); mass spectrum, m/e 223, 195 (base), 178, 166; λmax =456 nm (7,270) (pH=4.98; 0.1 M acetate) λmax =574 nm (70,250) (pH=7.8; 0.1 M borate), pKa =6.34.
Reaction SMILES: [H-].[Na+].CCOP(OCC)([CH2:8][C:9]#[N:10])=O.[O:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](=O)[CH2:15]1>C1COCC1.CCOC(C)=O.O>[O:14]1[C:22]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:16]([CH2:8][C:9]#[N:10])=[CH:15]1
Reactant: O=C1COc2ccccc21
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#CCc1coc2ccccc12
Reaction time: 0.75 h
Yield: 89.3 %

Procedure:
Sodium hydride (268 mg, 6.7 mmol) was slurried in dry THF (10 ml) at 0° C. under nitrogen and diethyl cyanomethyl phosphonate (1.1 ml, 6.7 mmol) added dropwise and the whole stirred for 45 min. 3-Coumaranone (Lancaster) (900 mg, 6.7 mmol) was then added dropwise and the whole stirred at room temperature for 45 min. The reaction was diluted with EtOAc (15 ml) and water (15 ml), and the organic layer was then separated, dried (MgSO4) and evaporated and the residue flash chromatographed using 0-5% EtOAc in pentane to give the title product (940 mg, 91%); 1HNMR (400 MHz, CDCl3) δ: 3.77 (s, 2H), 7.25-7.40 (m, 2H), 7.52 (dd, 1H), 7.58 (dd, 1H), 7.67 (s, 1H); LRMS: M+NH4+, 175. (TS+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28](=[O:44])[CH2:29][CH2:30][C:31]([NH:33][C:34]2[CH:43]=[CH:42][C:37]([C:38]([O:40]C)=[O:39])=[CH:36][CH:35]=2)=[O:32])[CH2:24][CH:23]1[C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[CH:46]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].C(OCC)(=O)C.O>C1COCC1.CO>[C:1]([O:5][C:6]([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28](=[O:44])[CH2:29][CH2:30][C:31]([NH:33][C:34]2[CH:35]=[CH:36][C:37]([C:38]([OH:40])=[O:39])=[CH:42][CH:43]=2)=[O:32])[CH2:24][CH:23]1[C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([F:51])[CH:46]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc(NC(=O)CCC(=O)N2CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C(c3cccc(F)c3)C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](c1cccc2ccccc12)N(CC1CCN(C(=O)CCC(=O)Nc2ccc(C(=O)O)cc2)CC1c1cccc(F)c1)C(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 2 h
Yield: 52.5 %

Procedure:
To a solution of 208 mg of methyl 4-({4-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-(3-fluorophenyl)piperidin-1-yl]-4-oxobutanoyl}amino)benzoate in 2.0 mL of THF and 1.0 mL of methanol was added 1.00 mL of a 1 M aqueous sodium hydroxide solution at room temperature, followed by stirring at 60° C. for 2 hours. The reaction mixture was cooled to room temperature, ethyl acetate and water were added thereto, and a liquid separation operation was conducted. The obtained aqueous layer was neutralized by addition of 1.00 mL of 1 M hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-methanol) to obtain 107 mg of 4-({4-[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-(3-fluorophenyl)piperidin-1-yl]-4-oxobutanoyl}amino)benzoic acid as a yellow oily compound. ESI−: 680
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[O:10][C:11]2[C:12](=[C:14]([C:18](O)=[O:19])[CH:15]=[CH:16][CH:17]=2)[N:13]=1.Cl.Cl.[NH2:23][CH:24]1[CH2:31][CH:30]2[N:32]([CH3:33])[CH:26]([CH2:27][CH2:28][CH2:29]2)[CH2:25]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.ClCCl>[CH3:33][N:32]1[CH:26]2[CH2:27][CH2:28][CH2:29][CH:30]1[CH2:31][CH:24]([NH:23][C:18]([C:14]1[CH:15]=[CH:16][CH:17]=[C:11]3[O:10][C:9]([C:3]4[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])=[N:13][C:12]=13)=[O:19])[CH2:25]2
Reactant: CN1C2CCCC1CC(N)C2
Reactant: O=C(O)c1cccc2oc(-c3c(Cl)cccc3Cl)nc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CN1C2CCCC1CC(NC(=O)c1cccc3oc(-c4c(Cl)cccc4Cl)nc13)C2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 38.2 %

Procedure:
A mixture of 2-(2,6-dichlorophenyl)benzoxazole-4-carboxylic acid (71 mg, 0.23 mmol), 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride (64 mg, 0.28 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (88 mg, 0.46 mmol) and 1-hydroxybenzotriazole (62 mg, 0.46 mmol) in DMF (2 mL) was stirred at room temperature for 10 min, then triethylamine (0.16 mL, 1.16 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane (30 mL), and then washed with a saturated solution of sodium bicarbonate (10 mL). The aqueous layer was further extracted with dichloromethane (2×30 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:9:1 ethyl acetate/methanol/concentrated ammonium hydroxide) and recrystallization from acetonitrile to afford N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(2,6-dichlorophenyl)benzoxazole-4-carboxamide (39 mg, 38%) as off-white crystals: 1H NMR (500 MHz, CDCl3) δ 8.85 (s, 1H), 8.29 (d, J=7.5 Hz, 1H), 7.76 (d, J=7.5 Hz, 1H), 7.57-7.46 (m, 4H), 4.62-4.54 (m, 1H), 3.14-3.06 (m, 2H), 2.53 (s, 3H), 2.05-1.92 (m, 3H), 1.65-1.40 (m, 5H), 1.16-1.05 (m, 2H); MS (ESI+) m/z 444 (M+H); HPLC>99% (AUC), tR=12.70 min.
Reaction SMILES: [F:1][S:2]([F:13])([F:12])([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6](N)=[CH:5][CH:4]=1.[OH:14]S(O)(=O)=O.N([O-])=O.[Na+]>O>[F:1][S:2]([F:13])([F:12])([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([OH:14])=[CH:5][CH:4]=1
Reactant: O=S(=O)(O)O
Reactant: Nc1ccc(S(F)(F)(F)(F)F)cc1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Oc1ccc(S(F)(F)(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.58 h

Procedure:
40.00 g of 4-pentafluorosulfanylaniline were suspended in 500 ml of a 35% aqueous H2SO4 solution and a solution of 13.85 g of NaNO2 in 30 ml of water was added dropwise at 0° C. over a period of 10 minutes. Subsequently, the mixture was stirred at 0° C. for 35 minutes, then a solution, at 0° C., of 171.10 g of Cu(NO3)2 in 200 ml of water was poured in and, directly thereafter, 26.11 g of Cu2O were added in portions. The mixture is stirred at RT for a further 2 hours, then extraction is effected 3 times with 200 ml each time of CH2Cl2. Drying was effected over MgSO4 and the solvent was removed under reduced pressure. 38.00 g of a pale yellow oil were obtained which was used further without purification.
Reaction SMILES: C[O:2][C:3]1[C:12]([O:13]C)=[C:11]2[C:6]([CH:7]=[CH:8][N:9]=[CH:10]2)=[CH:5][CH:4]=1.[BrH:15]>C(O)(=O)C>[BrH:15].[OH:2][C:3]1[C:12]([OH:13])=[C:11]2[C:6]([CH:7]=[CH:8][N:9]=[CH:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2ccncc2c1OC
Agent: Br
Solvent: CC(=O)O
Product: Oc1ccc2ccncc2c1O
Yield: 61 %

Procedure:
7,8-Dimethoxyisoquinoline (3.2 g, 16.9 mmol) in a mixture of 47% HBr (30 ml) and acetic acid (30 ml) was heated under reflux overnight. After cooling the product crystallized out from the reaction mixture as yellow needles. The crystals were collected by filtration to yield 2.5 g (Yield 61%) of the HBr salt. MP 243°-14 245° C.;
Reaction SMILES: ClC(N(C)C)=C(C)C.[N:9]1([C:13]([C:15]2[CH:42]=[CH:41][C:18]([O:19][C:20]3[CH:21]=[C:22]([CH:26]=[C:27]([O:29][C@@H:30]([CH3:40])[CH2:31][O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[CH:28]=3)[C:23](O)=[O:24])=[C:17]([Cl:43])[CH:16]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1.[NH2:44][C:45]1[CH:50]=[N:49][C:48](C)=[CH:47][N:46]=1.N1C=CC=CC=1>C(Cl)Cl>[N:9]1([C:13]([C:15]2[CH:42]=[CH:41][C:18]([O:19][C:20]3[CH:21]=[C:22]([CH:26]=[C:27]([O:29][C@@H:30]([CH3:40])[CH2:31][O:32][Si:33]([C:36]([CH3:37])([CH3:38])[CH3:39])([CH3:35])[CH3:34])[CH:28]=3)[C:23]([NH:44][C:45]3[CH:50]=[N:49][CH:48]=[CH:47][N:46]=3)=[O:24])=[C:17]([Cl:43])[CH:16]=2)=[O:14])[CH2:10][CH2:11][CH2:12]1
Reactant: Cc1cnc(N)cn1
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2Cl)cc(C(=O)O)c1
Agent: CC(C)=C(Cl)N(C)C
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)Oc1cc(Oc2ccc(C(=O)N3CCC3)cc2Cl)cc(C(=O)Nc2cnccn2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 12.4 %

Procedure:
1-Chloro-N,N,2-trimethyl-1-propenylamine (0.073 mL, 0.55 mmol) was added to a solution of 3-[4-(azetidin-1-ylcarbonyl)-2-chlorophenoxy]-5-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethoxy)benzoic acid (260 mg, 0.5 mmol) in DCM (10 mL) and stirred at RT for 1 hour. 2-Amino-5-methylpyrazine (95 mg, 1 mmol) and pyridine (0.081 mL, 1.0 mmol) were added and the reaction stirred for a further 30 mins. The solvent was removed in vacuo. Water (10 mL) was added and the mixture extracted with ethyl acetate (2×10 mL). The extracts were combined and washed with 1N citric acid, water (10 mL) and brine (10 mL), dried (MgSO4), filtered, and evaporated in vacuo to give the crude product which was chromatographed on silica, eluting with a gradient of 50-100% ethyl acetate in isohexane, to give the desired compound (37 mg).
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[CH:34][C:35]=1C(F)(F)F)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=1)=[O:7].[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:5]3[CH:4]=[C:3]([C:2]([F:1])([F:40])[F:41])[CH:35]=[C:34]([C:2]([F:41])([F:40])[F:1])[CH:33]=3)[C@H:9]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=3)[CH2:10]2)=[CH:16][CH:17]=1
Reactant: O=C(c1ccc(C(F)(F)F)c(C(F)(F)F)c1)N1CCN(Cc2ccc([N+](=O)[O-])cc2)C[C@H]1Cc1ccc(Cl)c(Cl)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(CN2CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@H](Cc3ccc(Cl)c(Cl)c3)C2)cc1
Yield: 171.9 %

Procedure:
A mixture of (2R)-1-[3,4-bis(trifluoromethyl)benzoyl]-2-(3,4-dichlorobenzyl)-4-(4-nitrobenzyl)piperazine (157 mg), ammonium chloride (15.7 mg) and iron powder (157 mg) in a mixture of ethanol (5 ml) and water (1.25 ml) was refluxed for 1.5 hours. After cooling, the precipitates were filtered off and the filtrate was evaporated in vacuo. The residue was purified by column chromatography on silica gel with a mixture of toluene and ethyl acetate as an eluent to give (2R)-4-(4-aminobenzyl)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dichlorobenzyl)piperazine (128.4 mg).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(=O)([O-])[O-].[K+].[K+].[C:19]([O:23][C:24](=[O:27])[CH2:25]Br)([CH3:22])([CH3:21])[CH3:20]>CN1CCCC1=O>[C:3]1(=[O:12])[N:2]([O:1][CH2:25][C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:27])[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]12
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)CON1C(=O)c2ccccc2C1=O
Temperature: 50 °C
Reaction time: 4 h
Yield: 92.8 %

Procedure:
N-hydroxyphthalimide (3.87 g, 23 mmol) and potassium carbonate (2.14 g, 15.5 mmol) were suspended in 1-methyl-2-pyrrolidinone (23 mL) and heated to 40° C. t-Butyl-bromoacetate (4.58 g, 23 mmol) was added, and the reaction temperature was increased to 50° C., and held at this temperature for 4 hours, and then poured into 50 mL of ice water to precipitate the product. The solid was collected on a glass filter funnel and washed with water until the filtrate was colorless. The precipitate was dried on the filter funnel with the house vacuum, and by azeotroping with chloroform. This afforded 5.92 g (91% yield) of product with a melting point of 143-144° C. The compound was characterized as NMR and MS as follows: 1) C-NMR (CDCl3): 28.39, 73.82, 83.38, 124.04, 129.22, 134.99, 163.40, 166.29 ppm; 2) H-NMR (CDCl3): 1.46 (s, 9H); 4.68 (s, 2H); 7.74 (m, 2H); 7.83 (m, 2H) ppm; and 3) MS (ESI): 300.2 [M+Na]+, 577.3 [2M+Na]+.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.C1(N(C2N=C(C)ON=2)C)CC1.[CH:32]1([CH2:35][C@H:36]([NH2:43])[C:37]2[N:41]=[C:40]([CH3:42])[O:39][N:38]=2)[CH2:34]C1>>[CH:35]1([CH:36]([NH:43][C:12]([C:10]2[CH:9]=[CH:8][C:7]([N:15]3[CH2:18][C:17]([F:20])([F:19])[CH2:16]3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=2)=[O:14])[C:37]2[N:41]=[C:40]([CH3:42])[O:39][N:38]=2)[CH2:32][CH2:34]1
Reactant: Cc1nc([C@@H](N)CC2CC2)no1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Agent: Cc1nc(N(C)C2CC2)no1
Product: Cc1nc(C(NC(=O)c2ccc(N3CC(F)(F)C3)c(OCC3CC3)n2)C2CC2)no1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and cyclopropyl-(5-methyl-[1,2,4]oxadiazol-3-yl)-methylamine (which can e.g. be prepared in a similar manner than (S)-2-cyclopropyl-1-(5-methyl-[1,2,4]oxadiazol-3-yl)-ethylamine (Example 38 e)) as starting materials, MS (EI): m/e=420.0 [M+H]+.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][N:6]2[CH:11]=[CH:10][C:9]([C:12]3[S:16][C:15]([C:17]([OH:19])=O)=[CH:14][CH:13]=3)=[N:8][C:7]=12)=[O:2].C1[CH:21]=[CH:22][C:23]2N(O)N=[N:26][C:24]=2C=1.C(N(CC)CC)C.C1(CN)CC1.C(Cl)CCl>O.CN(C=O)C>[CH:23]1([CH2:24][NH:26][C:17]([C:15]2[S:16][C:12]([C:9]3[CH:10]=[CH:11][N:6]4[N:5]=[CH:4][C:3]([CH:1]=[O:2])=[C:7]4[N:8]=3)=[CH:13][CH:14]=2)=[O:19])[CH2:21][CH2:22]1
Reactant: O=Cc1cnn2ccc(-c3ccc(C(=O)O)s3)nc12
Reactant: On1nnc2ccccc21
Agent: NCC1CC1
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cnn2ccc(-c3ccc(C(=O)NCC4CC4)s3)nc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 19 %

Procedure:
To the reaction flask, 5-(3-formylpyrazolo[1,5-a]pyrimidin-5-yl)thiophene-2-carboxylic acid (43 mg, 0.16 mmol) was added to DMF (1 mL) along with HOBt (25 mg, 0.16 mmol), triethylamine (22 uL, 0.16 mmol) and cyclopropylmethylamine (11 mg, 0.16 mmol). The reaction mixture was stirred at room temperature for 5 minutes then EDC (31 mg, 0.16 mmol) was added. The reaction was allowed to stir for an additional 2 hours then diluted with water and filtered. The recovered solid was washed with more water followed by ethanol. The product, N-(cyclopropylmethyl)-5-(3-formylpyrazolo[1,5-a]pyrimidin-5-yl)thiophene-2-carboxamide, was collected as a solid in 19% yield. LCMS (M+1=327)
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH2:14][C:15]([NH:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH:13]=2)[N:3]=1.[NH2:21][CH2:22][C:23]1[C:30]([F:31])=[CH:29][C:26]([C:27]#[N:28])=[CH:25][C:24]=1[F:32].CC1C=CC(S(O)(=O)=O)=CC=1>O1CCOCC1>[C:27]([C:26]1[CH:25]=[C:24]([F:32])[C:23]([CH2:22][NH:21][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]3[CH:10]=[N:11][N:12]([CH2:14][C:15]([NH:17][CH:18]([CH3:20])[CH3:19])=[O:16])[CH:13]=3)[N:3]=2)=[C:30]([F:31])[CH:29]=1)#[N:28]
Reactant: N#Cc1cc(F)c(CN)c(F)c1
Reactant: CC(C)NC(=O)Cn1cc(Nc2nccc(Cl)n2)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1COCCO1
Product: CC(C)NC(=O)Cn1cc(Nc2nccc(NCc3c(F)cc(C#N)cc3F)n2)cn1

Procedure:
A solution of 2-(4-(4-chloropyrimidin-2-ylamino)-1H-pyrazol-1-yl)-N-isopropylacetamide (120 mg, 0.41 mmol) (II-1, prepared by Procedure D), 4-(aminomethyl)-3,5-difluorobenzonitrile (68 mg, 0.41 mmol) (III-1, prepared by Procedure E) and TsOH (56 mg, 0.33 mmol) in dioxane (2 mL) was heated to 160° C. for 2 h then concentrated in vacuo. The residue was dissolved in ethyl acetate, washed with Na2CO3(aq), dried (Na2SO4), concentrated in vacuo and purified by prep. TLC (5-10% v/v MeOH/DCM) to afford 2-(4-((4-((4-cyano-2,6-difluorobenzyl)amino)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)-N-isopropylacetamide I-1 (50 mg, 29%) as a white solid. LC-MS (Method A), RT=8.02 min. (ES+) 427.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:37]=[CH:36][C:18]([CH2:19][N:20]([CH2:32][C:33]([OH:35])=[O:34])[CH2:21][CH2:22][CH2:23][CH2:24][N:25]([CH2:29][CH2:30][CH3:31])[CH2:26][CH2:27][CH3:28])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.[CH2:38](O)[CH3:39]>>[CH2:38]([O:34][C:33](=[O:35])[CH2:32][N:20]([CH2:19][C:18]1[CH:36]=[CH:37][C:15]([CH2:14][N:7]([CH2:8][C:9]2[NH:13][CH:12]=[CH:11][N:10]=2)[CH2:6][C:2]2[NH:1][CH:5]=[CH:4][N:3]=2)=[CH:16][CH:17]=1)[CH2:21][CH2:22][CH2:23][CH2:24][N:25]([CH2:29][CH2:30][CH3:31])[CH2:26][CH2:27][CH3:28])[CH3:39]
Reactant: CCO
Reactant: CCCN(CCC)CCCCN(CC(=O)O)Cc1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Product: CCCN(CCC)CCCCN(CC(=O)OCC)Cc1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1

Procedure:
The compound (275.6 mg) obtained in Example 69-1 was dissolved in ethanol (11 ml) and the whole was refluxed under heating for 21 hours.
Reaction SMILES: [Na].C(O[C:5](=O)[CH:6]([CH3:12])[C:7]([O:9]CC)=[O:8])C.[Br:14][C:15]1[CH:16]=[C:17]([C:20]([Br:23])=[CH:21][CH:22]=1)CBr.[OH-].[K+]>C(O)C.O>[Br:14][C:15]1[CH:16]=[CH:17][C:20]([Br:23])=[CH:21][C:22]=1[CH2:5][CH:6]([CH3:12])[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: BrCc1cc(Br)ccc1Br
Agent: [K+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(Cc1cc(Br)ccc1Br)C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In a 1000 ml three-necked round-bottom flask equipped with a reflux condenser, a pressure-equalizing dropping funnel, and magnetic stirring bar, 6.10 g (0.27 mol) of sodium metal was dissolved in 150 ml of dry ethanol. To the resulting solution, 45.5 g (0.26 mol) of diethylmethylmalonate in 50 ml of dry ethanol was added dropwise within 10 min. This mixture was stirred for 15 min; then 84.3 g (0.26 mol) of 3,6-dibromobenzylbromide was added with vigorous stirring at such a rate, so that the reaction mixture was maintained at a gentle reflux. Additionally, this mixture was refluxed for 4 hours and, then, cooled to room temperature. A solution of 52.1 g of KOH in 140 ml of water was added. This mixture was refluxed for 3 hours to saponificate the ester formed. Ethanol and water were distilled off. To the residue, 200 ml of water and, then, 12 M HCl (to pH 1) were added. The substituted methylmalonic acid precipitated, and was separated, washed with 3×100 ml of cold water, and dried overnight on a watch glass. Crude 3-(2,5-dibromophenyl)-2-methylpropionic acid was obtained after decarboxylation of this substituted methylmalonic acid by heating it in a round bottom flask for 2 hours at 160° C. Crude 3-(2,5-dibromophenyl)-2-methylpropionic acid was used without further purification. A mixture of this acid, 70 ml of SOCl2, and 100 ml of CH2Cl2 was stirred for 3 hours at reflux. Thionyl chloride and CH2Cl2 were distilled off. The residue was dried in vacuum and, then, dissolved in 95 ml of CH2Cl2. To a suspension of 47.0 g (0.35 mol) of AlCl3 in 470 ml of CH2Cl2 the above-obtained solution of 3-(2,5-dibromophenyl)-2-methylpropionyl chloride was added dropwise with vigorous stirring for 1 hour at −20° C. This mixture was refluxed for 3 hours, cooled to ambient temperature, and, then, poured on 500 cm3 of ice. The organic layer was separated. The aqueous layer was extracted with 3×200 ml of methyl-tert-butyl ether. The combined extract was dried over K2CO3 and evaporated to dryness. The crude 4,7-dibromo-2-methyl-1-indanone was purified by flash chromatography on Silica Gel 60 (40-63 μm, d 50 mm, h 250 mm; eluant:hexanes/methyl-tert-butyl ether (1:1, vol.)). Yield, 54.1 g (70%).
Reaction SMILES: C([O:3][C:4](=O)[C:5]([F:14])([F:13])[C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][N:7]=1)C.[BH4-].[Na+]>CCO>[F:14][C:5]([F:13])([C:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][N:7]=1)[CH2:4][OH:3]
Reactant: CCOC(=O)C(F)(F)c1ccc(C)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(C(F)(F)CO)nc1
Temperature: 0 °C
Yield: 100 %

Procedure:
To a solution of difluoro-(5-methyl-pyridin-2-yl)-acetic acid ethyl ester (10.5 g, 0.05 mol), as prepared in the previous step, in EtOH (98 mL) cooled to 0° C. was added NaBH4 (3.7 g, 0.098 mol, 2×). After 3 h the reaction was carefully quenched with saturated NH4Cl (100 mL) and partitioned with EtOAc (200 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo to afford the product as a white solid (8.5 g, 0.05 mol, 100% crude yield). 1H NMR (300 Hz, CDCl3) δ 8.43 (s, 1H), 7.66 (m, 2H), 4.22 (t, J=12.3 Hz), 2.41 (s, 1H); LC/MS (m/z) [M+1]+ 174.1 (calculated for C8H10F2NO, 174.2).