Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[Cl:19]N1C(=O)CCC1=O>CN(C=O)C>[Cl:19][C:9]1[C:10]2[NH:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]=2[C:6]([O:5][CH2:4][C@@H:2]2[CH2:3][O:1]2)=[CH:7][CH:8]=1.[Cl:19][C:7]1[CH:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:6]=1[O:5][CH2:4][C@@H:2]1[CH2:3][O:1]1)=[CH:16][CH:15]=[CH:14][CH:13]=3
Reactant: O=C1CCC(=O)N1Cl
Reactant: c1ccc2c(c1)[nH]c1cccc(OC[C@@H]3CO3)c12
Solvent: CN(C)C=O
Product: Clc1ccc(OC[C@@H]2CO2)c2c1[nH]c1ccccc12
Product: Clc1ccc2[nH]c3ccccc3c2c1OC[C@@H]1CO1

Procedure:
A solution of 4-[(2S)-oxiranylmethoxy]-9H-carbazole (0.50 g, 2.09 mmol) and N-chlorosuccinimide (0.280 g, 2.09 mmol) in 5 mL dry DMF was stirred at ambient temperature for 48 hours. The reaction mixture was partitioned with EtOAc and H2O. The organic phase was washed with H2O and dried with Na2SO4. The solvent was removed (rotovap) and the residue purified by flash chromatography (methylene chloride-hexane-1:1) afforded 0.10 g of the title compound plus 0.50 g of 3-Chloro-4-[(2S)-oxiranylmethoxy]-9H-carbazole.
Reaction SMILES: CN(C(O[N:9]1[N:17]=[N:16][C:11]2[CH:12]=[CH:13]C=N[C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:48]=[CH:47][C:46]([C:49]2[C:54]([F:55])=[CH:53][CH:52]=[CH:51][N:50]=2)=[CH:45][C:27]=1[C:28]([NH:30][C:31]1[N:35]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:34]=[C:33]([C:42](O)=[O:43])[CH:32]=1)=[O:29].CCN(C(C)C)C(C)C.CC1C(N)=CNN=1>CN(C=O)C.CCOC(C)=O>[Cl:25][C:26]1[CH:48]=[CH:47][C:46]([C:49]2[C:54]([F:55])=[CH:53][CH:52]=[CH:51][N:50]=2)=[CH:45][C:27]=1[C:28]([NH:30][C:31]1[N:35]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[N:34]=[C:33]([C:42]([NH:16][C:11]2[C:12]([CH3:13])=[N:17][NH:9][CH:10]=2)=[O:43])[CH:32]=1)=[O:29]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1cc(NC(=O)c2cc(-c3ncccc3F)ccc2Cl)n(-c2ccccc2)n1
Agent: Cc1n[nH]cc1N
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1n[nH]cc1NC(=O)c1cc(NC(=O)c2cc(-c3ncccc3F)ccc2Cl)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 29.5 %

Procedure:
To a solution of HATU (0.3 mmol, 113 mg) and 5-(2-chloro-5-(3-fluoropyridin-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylic acid (Example 105, 0.23 mmol, 100 mg) in DMF (0.9 mL) was added DIPEA (1.10 mmol, 0.191 mL). The solution was stirred at room temperature for 15 minutes. 3-methyl-1H-pyrazol-4-amine (0.23 mmol, 100 mg) was added and the reaction stirred at room temperature for 18 hours. The reaction was diluted with EtOAc (20 mL), washed with NaHCO3 (20 mL), 10% aqueous citric acid solution (20 mL) and brine (20 mL). The organic layer was dried over sodium sulphate and concentrated in vacuo. The residue was purified using reverse phase column chromatography to afford the title compound as a yellow solid (35 mg, 29%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[NH2:11].[C:12](Cl)(Cl)=[O:13]>O1CCOCC1.C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]2[C:5]([O:7][C:12](=[O:13])[NH:11][C:3]=12)=[O:6]
Reactant: Cc1cccc(C(=O)O)c1N
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Cc1cccc2c(=O)oc(=O)[nH]c12
Reaction time: 8 h
Yield: 99.5 %

Procedure:
To a mixture of 10.0 g (66.0 mmol) of 3-methylanthranilic acid in 60 mL of 1,4-dioxane was slowly added 100 mL (193 mmol) of a 1.93 molar solution of phosgene in toluene, at room temperature. The mixture was stirred overnight. The mixture was concentrated in vacuo to yield a residue which was triturated with ethyl acetate-hexane (1:4), filtered, washed with hexane and dried to afford 11.66 g (99.5%) of the 3-methylisatoic anhydride as an off white solid. MS (Cl mode) m/z 160 (M-18, 100%), 178 (M+H, 90%).
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=O)[C:3]([CH3:6])([CH3:5])[CH3:4].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH2:48]([O:55][C:56](=[O:82])[NH:57][CH2:58][C:59]([N:61]1[CH2:65][CH:64]([C:66](=[O:78])[NH:67][C:68]2[C:77]3[C:72](=[CH:73][CH:74]=[CH:75][CH:76]=3)[CH:71]=[CH:70][CH:69]=2)[CH:63]2[NH:79][CH2:80][CH2:81][CH:62]12)=[O:60])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>CN1C(=O)CCC1.CCOC(C)=O>[C:13]([O:12][C:10](=[O:11])[NH:1][CH:2]([C:7]([N:79]1[CH2:80][CH2:81][CH:62]2[N:61]([C:59](=[O:60])[CH2:58][NH:57][C:56]([O:55][CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)=[O:82])[CH2:65][CH:64]([C:66](=[O:78])[NH:67][C:68]3[C:77]4[C:72](=[CH:73][CH:74]=[CH:75][CH:76]=4)[CH:71]=[CH:70][CH:69]=3)[CH:63]12)=[O:9])[C:3]([CH3:4])([CH3:5])[CH3:6])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: O=C(NCC(=O)N1CC(C(=O)Nc2cccc3ccccc23)C2NCCC21)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC(C(=O)N1CCC2C1C(C(=O)Nc1cccc3ccccc13)CN2C(=O)CNC(=O)OCc1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 109.4 %

Procedure:
A solution of Boc-Tle-OH (176 mg, 0.76 mmol) in NMP (3 mL) was cooled to 0° C. and treated with HATU (318 mg, 0.83 mmol) followed by NMM (0.15 mL). After 10 min, 56 (360 mg, 0.76 mmol) in NMP (2 mL) was added. The reaction mixture was allowed to warm to ambient temperature overnight. The solution was diluted with EtOAc, washed successively with 1M HCl, saturated NaHCO3, dried over anhydrous Na2SO4, filtered and concentrated to afford 57 (570 mg) which was used without further purification. Mass spectrum, m/z [686.4] (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:41]=[CH:42][CH:43]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:16]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([C:26]#[C:27][CH2:28][NH:29][C:30](=[N:38][C:39]#[N:40])OC5C=CC=CC=5)[CH:24]=4)[N:19]=[CH:18][N:17]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.CC(O)C.[NH:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1>C1COCC1>[C:39]([NH:38][C:30]([N:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1)=[N:29][CH2:28][C:27]#[C:26][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][N:17]=[C:16]2[NH:15][C:11]1[CH:10]=[C:9]2[C:14](=[CH:13][CH:12]=1)[N:6]([CH2:5][C:4]1[CH:41]=[CH:42][CH:43]=[C:2]([F:1])[CH:3]=1)[N:7]=[CH:8]2)#[N:40]
Reactant: N#CN=C(NCC#Cc1ccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c2c1)Oc1ccccc1
Reactant: C1COCCN1
Solvent: C1CCOC1
Solvent: CC(C)O
Product: N#CNC(=NCC#Cc1ccc2ncnc(Nc3ccc4c(cnn4Cc4cccc(F)c4)c3)c2c1)N1CCOCC1
Temperature: 80 °C
Yield: 20.1 %

Procedure:
Material from step F (9 mg, 0.016 mmol) is placed in a reaction vial and dissolved in 2 ml of a 1:1 THF:i-PrOH mixture. Morpholine (0.08 mmol) is added at r.t, and the sealed vial is heated in an oil bath at 80° C. Reaction progress at 80° C. is followed by LC/MS, and the reaction is stopped after reaching 90% conversion (3 hours). Chromatography of the crude on silica (MeOH/EtOAc) affords pure desired product (1.8 mg, 20%). MS ESI (+) m/z 560 (M+1) detected; 1H NMR (400 MHz, deuterated acetone containing 10% deuterated methanol) δ 8.58 (s, 1H), 8.55 (s, 1H), 8.39 (s, 1H), 8.11 (s, 1H), 7.84-7.76 (m, 4H), 7.65 (d, 1H), 7.37 (q, 1H), 7.12 (d, 1H), 7.04 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:34])=[C:6]([C@:8]([NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])(=[O:24])=[O:23])([CH3:20])[CH2:9][O:10][C@@:11]([CH3:19])([C:15]([F:18])([F:17])[F:16])[C:12]([NH2:14])=O)[CH:7]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:34])=[C:6]([C@:8]([NH:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N+:31]([O-:33])=[O:32])(=[O:23])=[O:24])([CH3:20])[CH2:9][O:10][C@@:11]([C:12]#[N:14])([CH3:19])[C:15]([F:17])([F:18])[F:16])[CH:7]=1
Reactant: C[C@@](CO[C@](C)(C(N)=O)C(F)(F)F)(NS(=O)(=O)c1ccccc1[N+](=O)[O-])c1cc(Br)ccc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: C[C@](C#N)(OC[C@](C)(NS(=O)(=O)c1ccccc1[N+](=O)[O-])c1cc(Br)ccc1F)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (R)-2-[(R)-2-(5-bromo-2-fluoro-phenyl)-2-(2-nitro-benzenesulfonylamino)-propoxy]-3,3,3-trifluoro-2-methyl-propionamide (20.83 g, 35.6 mmol) in CH2Cl2 (300 ml) was added under argon NEt3 (12.5 ml, 89 mmol) and at 0-5° C. trifluoroacetic anhydride (6.15 ml, 42.7 mmol). After stirring for 4 h at 25° C. the reaction mixture was added to a cold NaHCO3 solution and the product was extracted with CH2Cl2. Combined extracts were washed with cold 0.1 N aqueous HCl, water and saturated NaHCO3 solution, dried over MgSO4, filtered and concentrated to provide the title compound as a yellow oil, which was used as such for the next step: TLC (hexane-EtOAc 1:1): Rf=0.73; UPLC RtH5=1.364 min; ESIMS: 571, 573 [(M+NH4)+]; 1H NMR (360 MHz, CDCl3): δ 7.89 (d, 1H), 7.62 (ddd, 1H), 7.57 (ddd, 1H), 7.52 (m, 2H), 7.29 (m, 1H), 6.58 (dd, 1H), 6.19 (s, 1H), 4.17 (s, 2H), 1.81 (s, 3H), 1.72 (s, 3H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[CH:9]1([CH2:15][CH2:16]B(O)O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[CH:9]1([CH2:15][CH2:16][C:2]2[S:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: OB(O)CCC1CCCCC1
Reactant: O=Cc1ccc(Br)s1
Product: O=Cc1ccc(CCC2CCCCC2)s1
Yield: 57.7 %

Procedure:
The compound was synthesized as in Example 3.1 using 5-bromothiophene-2-carbaldehyde (250 mg, 1.31 mmol) in place of 5-bromo-2-formylfuran and 2-cyclohexylethylboronic acid (337 mg, 2.16 mmol) in place of hexylboronic acid to give 5-(2-cyclohexylethyl)thiophene-2-carbaldehyde (168 mg, 58%). Used without further characterization.
Reaction SMILES: CO[CH2:3][O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH2:16]OC)[CH:13]=2)[CH:8]=[CH:7][CH:6]=1.C([Li])CCC.[I:24]I.[Cl-].[NH4+]>C1COCC1.CCCCCC>[I:24][C:13]1[C:12]([O:15][CH3:16])=[CH:11][CH:10]=[C:9]2[C:14]=1[C:5]([O:4][CH3:3])=[CH:6][CH:7]=[CH:8]2
Reactant: II
Reactant: COCOc1ccc2cccc(OCOC)c2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc2cccc(OC)c2c1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
1.2 g of 1,7-bis-methoxymethoxy-naphthalene are dissolved in 9 ml of THF and cooled to -78°. 3.13 ml of a 1.6M n-butyl-lithium solution in hexane are added dropwise thereto and the mixture is stirred at room temperature overnight. Subsequently, it is again cooled to -78° and a solution of 1.25 g of iodine in 3.4 ml of THF is added dropwise. The mixture is warmed to room temperature and 10 ml of saturated ammonium chloride solution are added. The organic solvents are evaporated on a rotary evaporator and the residue is extracted three times with ether. After drying and evaporation the residue is chromatographed on silica gel with ethylene chloride. 0.72 g of 8-iodo-1,7-bis-methoxy-naphthalene is thus isolated. Yield: 40%. Mass spectrum: peaks inter alia at 374 (M+, 87%), 171 (40%), 45 (100%).
Reaction SMILES: [Br:1][CH2:2][C:3]1[C:4]([C:13]([F:16])([F:15])[F:14])=[N:5][N:6]([CH3:12])[C:7]=1[O:8][CH:9]([F:11])[F:10].[NH2:17][C:18]([NH2:20])=[S:19]>C(O)C>[BrH:1].[F:10][CH:9]([F:11])[O:8][C:7]1[N:6]([CH3:12])[N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[C:3]=1[CH2:2][S:19][C:18](=[NH:17])[NH2:20]
Reactant: Cn1nc(C(F)(F)F)c(CBr)c1OC(F)F
Reactant: NC(N)=S
Solvent: CCO
Product: Br
Product: Cn1nc(C(F)(F)F)c(CSC(=N)N)c1OC(F)F
Reaction time: 1 h
Yield: 77.4 %

Procedure:
To a solution of 19.1 g (purity: 75.0%, 46.3 mmol) of 4-bromomethyl-5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole in 30 ml of ethanol was added 3.5 g (46.3 mmol) of thiourea, followed by 1 hour of heating and refluxing under stirring. The solvent was removed by evaporation under reduced pressure and the residue was washed with a mixed solvent of ethyl acetate and n-hexane to obtain 13.8 g (yield: 77.5%) of 2-(5-difluoromethoxy-1-methyl-3-trifluoromethyl-1H-pyrazole-4-ylmethyl)-isothiourea hydrobromide as white crystals (melting point: 130 to 131° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]3[C:25]4[CH:26]=[CH:27][C:28]([NH2:30])=[CH:29][C:24]=4[CH2:23][CH2:22][O:21]3)[C@@H:14]([CH3:31])[CH2:13]1)=[CH:7][CH:6]=[CH:5]2.N1C=CC=CC=1.Cl[C:39]([O:41][CH2:42][CH2:43]Cl)=[O:40]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C@H:20]3[C:25]4[CH:26]=[CH:27][C:28]([N:30]5[CH2:43][CH2:42][O:41][C:39]5=[O:40])=[CH:29][C:24]=4[CH2:23][CH2:22][O:21]3)[C@H:14]([CH3:31])[CH2:13]1)=[CH:7][CH:6]=[CH:5]2
Reactant: C[C@H]1CN(c2cccc3cc(F)ccc23)CCN1CC[C@@H]1OCCc2cc(N)ccc21
Reactant: O=C(Cl)OCCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: C[C@@H]1CN(c2cccc3cc(F)ccc23)CCN1CC[C@@H]1OCCc2cc(N3CCOC3=O)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (1S)-1-{2-[(2S)-4-(6-fluoro-1-naphthyl)-2-methyl-piperazinyl]ethyl}-3,4-dihydro-1H-2-benzopyran-6-amine (0.217 g, mmol) in dry DMF (5 mL) was added pyridine (0.05 mL, mmol) and 2-chloroethyl chloroformate (0.055 mL, mmol), and the reaction stirred at room temperature under nitrogen for 2 h. The reaction was quenched by addition of 2M sodium hydroxide (3 mL), diluted with water and extracted into dichloromethane. The combined organic extracts were dried (MgSO4), filtered and evaporated in vacuo. The crude product was purified by prep LCMS to yield 3-((1S)-1-{2-[(2R)-4-(6-fluoro-1-naphthyl)-2-methylpiperazinyl]-ethyl}-3,4-dihydro-1H-2-benzopyran-6-yl)-1,3-oxazolidin-2-one. M+H=490.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:16](=S)=[S:17].N>C(O)C>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([N:13]=[C:16]=[S:17])=[CH:14][CH:15]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccc(OCCN2CCCC2)cc1
Reactant: S=C=S
Agent: N
Solvent: CCO
Product: S=C=Nc1ccc(OCCN2CCCC2)cc1

Procedure:
4-(2-Pyrrolidin-1-ylethoxy)aniline (17.3 g.) in ethanol (20 ml.) is added dropwise to a mixture of ethanol (55 ml.), carbon disulphide (10 ml.) and aqueous ammonia (density = 0.88, 20 ml.) at 0°C. After 2 hours the solid is collected and washed with acetone, m.p. 143° - 150°C. (dec.). This solid (23.6 g.), chloroform (114 ml.) and triethylamine (11.9 ml.) are stirred, and ethyl chloroformate (8.6 ml.) added with cooling so that the temperature remains below 0°C. After stirring for 30 minutes below 0°C. and 1 hour at 20°C., excess of 10% sodium hydroxide is added. The chloroform is separated, washed with water, dried and evaporated. The residue is dissolved in benzene and the solution filtered through alumina. The filtrate is evaporated and the residue distilled to give 4-(2-pyrrolidin-1-ylethoxy)phenyl isothiocyanate, b.p. 160° - 168°C./0.2 mm.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[C:11]([NH2:32])=[N:12][CH:13]=[C:14]([C:16]3[N:17]=[N:18][N:19]([CH2:21][CH2:22][CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26])[N:20]=3)[CH:15]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([N:40]=[C:41]=[O:42])=[CH:36][C:35]=1[C:43]([F:46])([F:45])[F:44]>O1CCCC1.C(OCC)(=O)C>[NH2:32][C:11]1[C:10]([C:9]#[C:8][C:4]2[CH:3]=[C:2]([NH:1][C:41]([NH:40][C:37]3[CH:38]=[CH:39][C:34]([Cl:33])=[C:35]([C:43]([F:45])([F:44])[F:46])[CH:36]=3)=[O:42])[CH:7]=[CH:6][CH:5]=2)=[CH:15][C:14]([C:16]2[N:17]=[N:18][N:19]([CH2:21][CH2:22][CH2:23][O:24][Si:25]([C:28]([CH3:29])([CH3:31])[CH3:30])([CH3:26])[CH3:27])[N:20]=2)=[CH:13][N:12]=1
Reactant: CC(C)(C)[Si](C)(C)OCCCn1nnc(-c2cnc(N)c(C#Cc3cccc(N)c3)c2)n1
Reactant: O=C=Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCCn1nnc(-c2cnc(N)c(C#Cc3cccc(NC(=O)Nc4ccc(Cl)c(C(F)(F)F)c4)c3)c2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3-((3-aminophenyl)ethynyl)-5-(2-(3-((tert-butyldimethylsilyl)oxy)propyl)-2H-tetrazol-5-yl)pyridin-2-amine (135 mg, 0.3 mmol, 1 eq) and 4-chloro-3-(trifluoromethyl)phenyl isocyanate (67 mg, 1 eq) in anhydrous tetrahydrofuran (3 mL) was stirred at room temperature and under nitrogen atmosphere for 3 hours. The mixture was then diluted with ethyl acetate, washed sequentially with aqueous ammonium chloride, saturated aqueous sodium bicarbonate, and brine, and dried with anhydrous sodium sulfate. The clear solution was decanted, concentrated under reduced pressure, and the resulting clear oil was dried in vacuo for 5 minutes. It was then treated with a small amount of EtoAc-Hex (1:9), followed by stirring at room temperature for 30 minutes. The white solid that appeared during the process was filtered giving 1-(3-((2-amino-5-(2-(3-((tert-butyldimethylsilyl)oxy)propyl)-2H-tetrazol-5-yl)pyridin-3-yl)ethynyl)phenyl)-3-(4-chloro-3-(trifluoromethyl)phenyl)urea in the amount of 201 mg.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:14][CH3:15])[CH2:9][CH2:10][NH:11][CH2:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.Cl[C:26]([O:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)=[O:27]>O1CCCC1>[CH3:36][O:35][C:32]1[CH:33]=[CH:34][C:29]([O:28][C:26](=[O:27])[N:11]([CH2:12][CH3:13])[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:14][CH3:15])=[CH:30][CH:31]=1
Reactant: COc1ccc(OC(=O)Cl)cc1
Reactant: CCNCCN(CC)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CCN(CC)C(=O)OC(C)(C)C)C(=O)Oc1ccc(OC)cc1
Reaction time: 8 h
Yield: 64.2 %

Procedure:
A solution of N-tert.-butoxycarbonyl-N,N'-diethylethylenediamine (3.22 g, 15 mmol) and N,N-diisopropylethylamine (2.6 mL, 15 mmol) in tetrahydrofuran (100 mL) was added over 1 hour to a stirred, cooled solution of 4-methoxyphenyl chloroformate (2.78 g, 15 mmol) in tetrahydrofuran (50 mL). After stirring at 20°-25° overnight, solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and water. The organic extract was washed with brine, dried (Na2SO4), filtered and concentrated. Flash chromatography of the residue over silica gel and elution with 10-20% ethyl acetate-90-80% n-butylchloride gave 3.53 g of the carbamate as an oil.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.Cl[C:19]1[C:20]([C:25]2(C(OC)=O)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)=[N:21][CH:22]=[CH:23][N:24]=1.[C:35](=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O.[Cl-].[Na+].O>[CH3:35][N:10]([C:11]1[CH:16]=[CH:15][C:14]([O:17][C:19]2[C:20]([CH:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[N:21][CH:22]=[CH:23][N:24]=2)=[CH:13][CH:12]=1)[C:2]1[S:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1
Reactant: COC(=O)C1(c2nccnc2Cl)CCOCC1
Reactant: Oc1ccc(Nc2nc3ccccc3s2)cc1
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CN(c1ccc(Oc2nccnc2C2CCOCC2)cc1)c1nc2ccccc2s1
Temperature: 163 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(benzo[d]thiazol-2-ylamino)phenol (0.094 g, 0.390 mmol) and methyl 4-(3-chloropyrazin-2-yl)tetrahydro-2H-pyran-4-carboxylate (0.1 g, 0.390 mmol) in DMSO (1 mL) was added cesium carbonate (0.254 g, 0.779 mmol). The resulting mixture was heated to 163° C. for ˜20 minutes. Reaction mixture was cooled back to 100 C and stirred overnight. Aqueous work up with multiple water and brine washes to remove DMSO and extraction with DCM. Purification by Shimadzu (phenomenex Gemini C18 5 um 100×30 mm; 254 UV; solvent A=0.1% TFA in water, solvent B=0.1% TFA in ACN; gradient run: 35% B to 80% B in 9 min; 1 min@ 80% B; flow rate=30 ml/min; 2 peaks contained mass 418: R1=3.91 to 4.26 min; R2=5.83 to 6.36 min) to afford the product. MS (ESI, pos. ion) m/z: 419.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: O.NN.C1(=O)[N:8]([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)C(=O)C2=CC=CC=C12.C(OCC)(=O)C>C(O)C>[NH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCOc1ccncc1
Agent: NN
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: NCCCOc1ccncc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 0.1 %

Procedure:
Hydrazine monohydrate [2.99 ml (61.6 mmol)] was added to a suspension of 5.0 g (20.5 mol) of 4-(3-phthalimidopropyloxy)pyridine in 50 ml of ethanol, and the mixture was stirred at room temperature for 3 hours. 100 ml of ethyl acetate was added and insoluble materials were filtered off. The volatile component in the filtrate was distilled off and then chloroform was added to the residue. The mixture was washed with brine and dried over potassium carbonate. The solvent was distilled off to obtain 2.99 g of the desired compound (yield: 99.5%, pale yellow oil).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH2:19][C:18]([CH2:25][C:26]([O:28]CCCC)=[O:27])([CH2:20][C:21]([O:23]C)=[O:22])[O:17][N:16]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[OH-].[Na+].Cl>CO>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:15]2[CH2:19][C:18]([CH2:25][C:26]([OH:28])=[O:27])([CH2:20][C:21]([OH:23])=[O:22])[O:17][N:16]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCOC(=O)CC1(CC(=O)OC)CC(c2cccc(OCc3ccccc3)c2)=NO1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)CC1(CC(=O)O)CC(c2cccc(OCc3ccccc3)c2)=NO1
Yield: 91.7 %

Procedure:
A mixture of butyl methyl 2,2′-(3-(3-(benzyloxy)phenyl)-4,5-dihydro-1,2-oxazole-5,5-diyl)diacetate (1.02 g), THF (15 mL), methanol (15 mL), and a 1 M aqueous sodium hydroxide solution (15 mL) was stirred overnight at room temperature. The reaction mixture was neutralized with 1 M hydrochloric acid at 0 C, followed by extraction with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure to obtain the title compound (0.786 g).
Reaction SMILES: [K+].[Br-:2].Br.C([N:11]([CH:30]([CH3:32])[CH3:31])[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([NH:21][S:22]([NH:25][C:26]([CH3:29])([CH3:28])[CH3:27])(=[O:24])=[O:23])=[CH:17][CH:16]=1)=[O:14])C1C=CC=CC=1>>[BrH:2].[C:26]([NH:25][S:22]([NH:21][C:18]1[CH:19]=[CH:20][C:15]([CH:13]([OH:14])[CH2:12][NH:11][CH:30]([CH3:31])[CH3:32])=[CH:16][CH:17]=1)(=[O:24])=[O:23])([CH3:29])([CH3:28])[CH3:27]
Reactant: [Br-]
Reactant: CC(C)N(CC(=O)c1ccc(NS(=O)(=O)NC(C)(C)C)cc1)Cc1ccccc1
Agent: Br
Agent: [K+]
Product: CC(C)NCC(O)c1ccc(NS(=O)(=O)NC(C)(C)C)cc1

Procedure:
Infrared (pelletized with KBr): 840, 1145, 1330, 1395, 1520, 1615, 2800, 2980, 3160, 3300 cm-1. Prepared from N-[4-(N-benzyl-N-isopropylglycyl)phenyl]-N'-tert.-butylsulfamide hydrobromide.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Cl[C:14]([F:19])([F:18])C(O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[F:18][CH:14]([F:19])[O:12][C:3]1[C:2]([F:1])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cccc(F)c1O
Reactant: O=C(O)C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc(F)c1OC(F)F
Yield: 41.3 %

Procedure:
A mixture of methyl 3-fluoro-2-hydroxy-benzoate (1.5 g, 8.8 mmol), 2-chloro-2,2-difluoro-acetic acid (1.62 g, 1.05 mL, 10.6 mmol) and potassium carbonate (1.46 g, 10.6 mmol) were heated in DMF (5 mL) at 120° C. for 5 hours. The reaction mixture was diluted with water (20 mL) and extracted with ether (2×10 mL). The organics were separated and washed sequentially with water (5 mL) and brine solution (5 mL). The organics were dried (MgSO4) and concentrated in vacuo to give residue which was purified by silica gel column chromatography using 0-30% EtOAc/hexanes as eluent to give methyl 2-(difluoromethoxy)-3-fluorobenzoate (0.8 g, 39%). To methyl 2-(difluoromethoxy)-3-fluorobenzoate (0.8 g, 3.64 mmol) was added 12% aq. NaOH (3 mL) and the reaction mixture was heated at 50° C. for 1 hour. The aqueous layer was extracted with 1:1 ether/hexane (2×5 mL). The aqueous layer was acidified to pH 1 with 6 N HCl solution to give a suspension. The solid was filtered and washed with water, then dried in vacuo to give 2-(difluoromethoxy)-3-fluoro-benzoic acid (555 mg, 31%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.83 (d, J=7.8 Hz, 1H), 7.43 (dd, J=13.1, 4.8 Hz, 1H), 7.35 (td, J=8.1, 4.9 Hz, 1H), 6.68 (t, J=74.4 Hz, 1H).