Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[OH:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1.[Cl:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][C:27]=1[C:33]([F:36])([F:35])[F:34]>>[Cl:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:1]([NH:22][C:21]2[CH:23]=[CH:24][C:18]([OH:17])=[CH:19][CH:20]=2)=[O:2])=[CH:28][C:27]=1[C:33]([F:34])([F:35])[F:36]
Reactant: Nc1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1ccc(O)cc1
Reactant: O=C(Cl)Cl
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: O=C(Nc1ccc(O)cc1)Nc1ccc(Cl)c(C(F)(F)F)c1

Procedure:
As shown in Scheme 1, in the presence of N,N′-carbonyldiimidazole, phosgene or triphosgene, 4-aminophenol (Compound I) reacts with 3-trifluoromethyl-4-chloro-aniline (Compound II) to give 1-(4-chloro-3-(trifluromethyl)phenyl)-3-(4-hydroxyphenyl)urea (Compound III). 2-(N-(methyl-d3)) carbamoyl pyridine (Compound V) is obtained by reacting methyl picolinate (Compound IV) with (methyl-d3)amine or (methyl-d3)amine hydrochloride directly or in the presence of the base such as sodium carbonate, potassium carbonate, sodium hydroxide, triethylamine, pyridine and the like. In the presence of base (such as potassium tert-butoxide, sodium hydride, potassium hydride, potassium carbonate, cesium carbonate, potassium phosphate, potassium hydroxide, sodium hydroxide) and an optional catalyst (such as cuprous iodide and proline, or cuprous iodide and picolinic acid), Compound III reacts with Compound V to form compound CM-4307. The above reactions are conducted in an inert solvent, such as dichloromethane, dichloroethane, acetonitrile, n-hexane, toluene, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide and so on, and at a temperature of 0-200° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][CH2:14]Br)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(P(N(C)C)(N(C)C)=O)C.[Li]CCCC.[N+:32]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([O-:34])=[O:33]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][CH2:14][CH:35]([N+:32]([O-:34])=[O:33])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCC1CCBr
Agent: [Li]CCCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC1CCC(c1ccccc1)[N+](=O)[O-]
Temperature: -2 °C
Reaction time: 0.75 h

Procedure:
To a −78° C. solution of 200 mg (1.460 mmol) 2-(2-bromo-ethyl)-pyrrolidine-1-car boxylic acid tert-butyl ester (CAS: 958026-65-8) in 4.3 ml tetrahydrofuran over mol-sieves and 851.0 ul HMPA, was added drop-wise 1.92 ml (3.064 mmol) n-BuLi (1.6 M in hexane). After 45 minutes at −78° C., a solution of 406.2 mg (1.460 mmol) nitromethyl-benzene in 0.6 ml tetrahydrofuran over mol-sieves was added drop-wise. After 1 hour at −78° C., the reaction mixture was allowed to warm up slowly (during 5 hours) to −2° C. The mixture was then cooled again to −78° C. and quenched at this temperature with 0.4 ml of acetic acid, then with 8 ml saturated ammonium chloride. Back to room temperature, the aqueous phase was extracted 2 times with ethylacetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The crude yellow oil (993 mg) was purified with flash column chromatography on silica eluting from n-heptane and ethyl acetate (0 to 15%) to provide 242 mg (y: 49.6%) of the title compound as a colorless oil. MS (m/e): 335.2 (M+H+).
Reaction SMILES: [N:1]1([CH2:8][CH2:9][CH2:10][N:11](CC2C=CC=CC=2)[CH3:12])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[N:1]1([CH2:8][CH2:9][CH2:10][NH:11][CH3:12])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: CN(CCCN1CCCCCC1)Cc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CNCCCN1CCCCCC1

Procedure:
3-(Azepan-1-yl)-N-benzyl-N-methylpropan-1-amine (100 mg) was dissolved in MeOH (20 mL) and to the solution was added 10% Pd/C (50 mg). The reaction mixture was shook under 50 psi hydrogen atmosphere for 2 h. The catalyst was filtered over Cellite and washed with methanol. The filtrated was evaporated to give 3-(azepan-1-yl)-N-methylpropan-1-amine, used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:44][CH:45]([F:47])[F:46])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]3[N:27]=[N:28][N:29]([CH:31]4[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]4)[CH:30]=3)[N:9]=2)[CH:7]=1.Cl.C(#N)C.O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:44][CH:45]([F:47])[F:46])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][N:10]([CH2:25][C:26]3[N:27]=[N:28][N:29]([CH:31]4[CH2:32][CH2:33][NH:34][CH2:35][CH2:36]4)[CH:30]=3)[N:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(Cn3cc(NC(=O)c4cnn5cccnc45)c(-c4cc(Cl)ccc4OC(F)F)n3)nn2)CC1
Agent: Cl
Solvent: O
Solvent: CC#N
Solvent: CO
Product: O=C(Nc1cn(Cc2cn(C3CCNCC3)nn2)nc1-c1cc(Cl)ccc1OC(F)F)c1cnn2cccnc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 2.5 %

Procedure:
To a solution of tert-butyl 4-[4-([3-[5-chloro-2-(difluoromethoxy)phenyl]-4-[pyrazolo[1,5-a]pyrimidine-3-amido]-1H-pyrazol-1-yl]methyl)-1H-1,2,3-triazol-1-yl]piperidine-1-carboxylate (1.98 g, 2.96 mmol) in methanol (30 mL) was added concentrated HCl aqueous solution (15 mL). The resulting solution was stirred for 5 h at room temperature. The resulting mixture was concentrated under vacuum. This resulted in 1.85 g crude product, which was sufficient for next step without further purification. A small portion was purified for characterization and biological submission. The crude product (100 mg) was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, silica gel; mobile phase, ACN/H2O (10 mmol NH4HCO3)=18% increasing to ACN/H2O (10 mmol NH4HCO3)=49% within 9 min; Detector, UV 254 nm. 42.1 mg product was obtained. This resulted in 42.0 mg of N-[3-[5-chloro-2-(difluoromethoxy)phenyl]-1-[[1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl]methyl]-1H-pyrazol-4-yl]pyrazolo[1,5-a]pyrimidine-3-carboxamide as a light yellow solid. LCMS (Method 36) [M+H]+=569.2, RT=2.59 min. 1H NMR (400 MHz, DMSO-d6) δ: (ppm) 9.69 (s, 1H), 9.34 (d, 1H, J=6.4 Hz), 8.68-8.64 (m, 2H), 8.40 (s, 1H), 8.22 (s, 1H), 7.67-7.61 (m, 2H), 7.45 (d, 1H, J=8.4 Hz), 7.28 (dd, 1H, J=4.2, 7.0 Hz), 7.06 (t, 1H, J=73.4 Hz), 5.49 (s, 2H), 4.58-4.51 (m, 1H), 3.05-3.02 (m, 2H), 2.62-2.57 (m, 1H), 2.30-2.25 (br, 1H), 2.01-1.98 (m, 2H), 1.87-1.73 (m, 2H).
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][C@H:15]1[CH3:27].C(N(CC)CC)C>C(Cl)Cl>[CH3:27][C@H:15]1[N:14]([CH2:13][CH:12]=[O:11])[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:16]1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1CCO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1CC=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Dimethyl sulfoxide (0.732 mL, 10.3 mmol) was added to a solution of oxalyl chloride (0.582 mL, 6.88 mmol) in DCM (13 mL) at −78° C. After stirring for 10 minutes, tert-butyl (3R)-4-(2-hydroxyethyl)-3-methylpiperazine-1-carboxylate (1.4 g, 5.7 mmol) in DCM (6.6 mL) was added over 15 minutes. The reaction was stirred at −78° C. for 1 hour, then triethylamine (3.99 mL, 28.6 mmol) was added. The reaction was stirred, with warming to room temperature, for 1 hour. The reaction mixture was diluted with DCM, washed twice with water and once with brine, dried over sodium sulfate and concentrated to afford product, used without further purification (1.20 g, 86%). 1H NMR (300 MHz, CDCl3): δ 9.72 (t, 1H), 3.90-3.65 (m, 2H), 3.43 (d, 1H), 3.15 (ddd, 1H), 3.04 (dd, 1H), 2.89-2.67 (m, 2H), 2.52-2.34 (m, 2H), 1.46 (s, 9H), 1.02 (d, 3H); LCMS (M+H2O+H)+: 261.2.
Reaction SMILES: [CH:1]1([N:4]([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)(=[O:21])=[O:20])[CH:5]2[CH2:10][CH2:9][CH2:8][N:7]([CH2:11][C:12]([NH:14][CH2:15][CH:16](C)[CH3:17])=[O:13])[CH2:6]2)[CH2:3][CH2:2]1.Cl.C1(N(C2CCCNC2)S(C2C=CC=[C:42]([C:46](F)(F)[F:47])[CH:41]=2)(=O)=O)CC1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:1]1([N:4]([S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:29])[F:30])[CH:23]=2)(=[O:20])=[O:21])[CH:5]2[CH2:10][CH2:9][CH2:8][N:7]([CH2:11][C:12]([NH:14][C:15]3[CH:41]=[CH:42][C:46]([F:47])=[CH:17][CH:16]=3)=[O:13])[CH2:6]2)[CH2:2][CH2:3]1
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CC1)C1CCCNC1
Reactant: CC(C)CNC(=O)CN1CCCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(CN1CCCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)C1)Nc1ccc(F)cc1
Temperature: 40 °C
Reaction time: 16 h

Procedure:
General procedure for preparing compounds 42 and 43: A mixture of compound 6 (100 mg, 0.26 mmol), compound La or Lb (0.3 mmol) and K2CO3 (200 mg) in DMF (1 mL) was shaken at 40° C. for 16 hours. After cooling to room temperature, the reaction mixture was quenched with water, extracted with CHCl3, concentrated and purified by column (silica gel, EtOAc/hexanes 1/1) to give the desired product as a free base. The free base was converted to its HCl-salt by treating with HCl (1 N aqueous) and drying under vacuum.
Reaction SMILES: [CH3:1][C:2]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4].[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19](O)=[O:20])=[CH:14][CH:13]=1.B(F)(F)F.CCOCC>>[OH:4][C:3]1[C:2]([CH3:1])=[C:8]([OH:9])[CH:7]=[CH:6][C:5]=1[C:19](=[O:20])[CH2:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=1
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: Cc1c(O)cccc1O
Agent: FB(F)F
Solvent: CCOCC
Product: COc1ccc(CC(=O)c2ccc(O)c(C)c2O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-methyl resorcinol (1 eq) and p-methoxy phenyl acetic acid (1 eq) in boron trifluoride diethyl etherate (8 eq) was refluxed for 3½ h, whilst stirring, under nitrogen. The brown solution was allowed to cool to room temperature, quenched with NaOAc solution (10% w/v) and left to stand overnight. The resultant precipitate was filtered, washed with water and dried to give 1-(2,4-dihydroxy-3-methyl-phenyl)-2-(4-methoxy-phenyl)-ethanone as a solid.
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[CH3:25][CH:26]([NH2:29])[CH2:27][OH:28]>>[OH:28][CH2:27][CH:26]([NH:29][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[C:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1)[CH3:25]
Reactant: CC(N)CO
Reactant: COC(=O)c1ccc(/C=C/c2c(-c3ccccc3)noc2C)nc1
Product: Cc1onc(-c2ccccc2)c1/C=C/c1ccc(C(=O)NC(C)CO)cn1
Yield: 75 %

Procedure:
As described in example 4, 6-[(E)-2-(5-methyl-3-phenyl-isoxazol-4-yl)-vinyl]-nicotinic acid methyl ester (200 mg, 0.62 mmol), using DL-2-amino-1-propanol instead of ethanolamine, was converted to the title compound (170 mg, 75%) which was obtained as a white solid after purification by chromatography (silica, dichloromethane:methanol 100:0 to 93:7). MS: m/e=364.4 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH2:30])(=[O:29])=[O:28])=[CH:23][CH:22]=3)=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[C:40](Cl)(=[O:45])[CH2:41][CH2:42][CH2:43][CH3:44]>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:20]([C:21]3[CH:26]=[CH:25][C:24]([S:27]([NH:30][C:40](=[O:45])[CH2:41][CH2:42][CH2:43][CH3:44])(=[O:29])=[O:28])=[CH:23][CH:22]=3)=[C:11]3[CH:12]=[CH:13][C:14]([C:16]([F:17])([F:18])[F:19])=[CH:15][N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCCCC(=O)Cl
Reactant: NS(=O)(=O)c1ccc(-c2c(-c3cccc(F)c3)nn3cc(C(F)(F)F)ccc23)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CCCCC(=O)NS(=O)(=O)c1ccc(-c2c(-c3cccc(F)c3)nn3cc(C(F)(F)F)ccc23)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 57.7 %

Procedure:
To a solution of 4-[2-(3-fluoro-phenyl)-6-trifluoromethyl-pyrazolo[1,5-a]pyridin-3-yl]benzenesulfonamide (0.109 g 0.25 mmol) in chloroform (10 ml) was added diisopropylethylamine (Aldrich) (100 μl), 4-dimethylaminopyridine (0.02 g 0.16 mmol) and valeryl chloride (Aldrich) (0.072 g 0.6 mmol) and the reaction was stirred at room temperature for 20 hr. It was washed with M Na2CO3 (5 ml), water (5 ml) and dried (MgSO4). Removal of solvent gave a solid which was purified by SPE chromatography. Elution with cyclohexane:ethyl acetate (2:1) gave the title compound as a white solid (0.075 g 58%).
Reaction SMILES: [CH:1]([C:4]1([C:10]([OH:12])=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].S(Cl)([Cl:15])=O.[CH2:17]([NH2:19])[CH3:18]>CCOCC.O>[CH:1]([C:4]1([C:10]([Cl:15])=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].[CH2:17]([NH:19][C:10]([C:4]1([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1)=[O:11])[CH3:18]
Reactant: CCN
Reactant: CC(C)C1(C(=O)O)CCCCC1
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Solvent: O
Product: CC(C)C1(C(=O)Cl)CCCCC1
Product: CCNC(=O)C1(C(C)C)CCCCC1

Procedure:
1-isopropylcyclohexanoyl chloride was prepared from 1-isopropylcyclohexanoic acid and thionyl chloride. A solution of this acid chloride (2.6 g) in ether (25 ml) was added dropwise to a stirred solution of ethylamine (5 ml of a 70% solution in water) in ether (100 ml). After 2 hours the ethereal solution was washed with dilute hydrochloric acid and water, dried (MgSO4) and concentrated to give a white solid. This was recrystallised from petroleum ether (bp. 40°-60°) to give N-ethyl-1-isopropylcyclohexanamide, mp. 101°-2°.
Reaction SMILES: [C:1]([O:5][C:6](=[N:29][NH:30][C:31]([NH2:33])=[O:32])[CH2:7][C@H:8]([NH:11]C(OCC1C2CC3C(=CC=CC=3)C=2C=CC=1)=O)[CH:9]=[O:10])([CH3:4])([CH3:3])[CH3:2].C(NCC)C>CN(C=O)C>[C:1]([O:5][C:6](=[N:29][NH:30][C:31]([NH2:33])=[O:32])[CH2:7][C@H:8]([NH2:11])[CH:9]=[O:10])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(C[C@@H](C=O)NC(=O)OCc1cccc2c1Cc1ccccc1-2)=NNC(N)=O
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CC(C)(C)OC(C[C@H](N)C=O)=NNC(N)=O

Procedure:
(3S)-3-(1-Fluorenylmethyloxycarbonylamino)-4-oxobutyric acid tert-butyl ester semicarbazone (210 mg, 0.45 mol, Prepared in a similar manner to the benzyloxycarbonyl analog in Graybill et al., Int. J. Protein Res. , 44, pp. 173-82 (1994).) was dissolved in 10 ml of DMF and 2 ml of diethylamine and stirred for 2 h. The reaction was concentrated in vacuo to give (3S)-3-amino-4-oxobutyric acid tert-butyl ester semicarbazone. The 0° C. solution of the above residue and 603a (200 mg, 0.42 mmol) in 5 ml of DMF and 5 ml of CH2Cl2 was treated with 1-hydroxybenzotriazole (57 mg, 0.42 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (98 mg, 0.51 mmol). The reaction was stirred at RT for 18 h, poured onto EtOAc (75 ml) and washed with aq. 0.3 N KHSO4, sat. aq. NaHCO3 and sat. aq. NaCl, dried over Na2SO4 and concentrated in vacuo. Chromatography 2 (flash, SiO2, 0% to 4% MeOH/0.1% NH4OH/CH2Cl2) to give 240 mg (83%) of 604a.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1([C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)[CH3:2].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH2:42][C:43](O)=[O:44])[CH:28]=[CH:29][C:30]=1[NH:31][C:32]([NH:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH3:41])=[O:33].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][C:6]1([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:43](=[O:44])[CH2:42][C:27]3[CH:28]=[CH:29][C:30]([NH:31][C:32]([NH:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[CH3:41])=[O:33])=[C:25]([O:24][CH3:23])[CH:26]=3)=[CH:17][CH:16]=2)[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14]1)[CH3:2]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Reactant: CCOC(=O)CC1(c2ccc(N)cc2)Cc2ccccc2C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CC1(c2ccc(NC(=O)Cc3ccc(NC(=O)Nc4ccccc4C)c(OC)c3)cc2)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19 %

Procedure:
A solution of [2-(4-amino-phenyl)-indan-2-yl]-acetic acid ethyl ester (0.158 g, Reference Example 10) in dimethylformamide (2 mL) was treated with a solution of [3-methoxy-4-(3-o-tolyl-ureido)-phenyl]-acetic acid (0.169 g) in dimethylformamide (2 mL) which had been treated with diisopropylethylamine (1.3 mL) and a solution of O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.223 g) in dimethylformamide (2 mL). After stirring at room temperature for 2 hours the reaction mixture was evaporated and the residue was partitioned between ethyl acetate (30 mL) and hydrochloric acid (30 mL, 0.5N). The organic phase was washed with hydrochloric acid (30 mL, 0.5N), then with saturated sodium hydrogen carbonate solution (30 mL), then dried over magnesium sulfate and then evaporated. The residual beige coloured solid was subjected to chromatography on silica eluting with a mixture of ethyl acetate and cyclohexane (2:1, v/v) to give the title compound (0.06 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[CH2:9]O)=[CH:4][CH:3]=1.C(N(S(F)(F)[F:19])CC)C>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[CH2:9][F:19])=[CH:4][CH:3]=1
Reactant: CC(C)(CO)c1ccc(Br)cc1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CC(C)(CF)c1ccc(Br)cc1
Reaction time: 4 h

Procedure:
2-(4-Bromophenyl)-2-methylpropan-1-ol (500 mg, 2.182 mmol) was dissolved in Dichloromethane (7.2 mL) in a 20 mL vial. Diethylaminosulfur trifluoride (0.433 mL, 3.27 mmol) was then slowly added To a solution and the resultant mixture was stirred at ambient temperature overnight. At which time, an additional 0.5 eq of DAST was added and stirred for an additional 4 hours. The reaction mixture was purified directly by MPLC on silica gel (eluting with 5% ethyl acetate in hexanes) to afford the title compound. 1H NMR (500 MHz, CDCl3) δ 7.43-7.42 (d, 2H), 7.10-7.09 (d, 2H), 2.88 (s, 1H), 2.83 (s, 1H), 1.35 (s, 3H), 1.30 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH:3]1([C:6]2[N:10]([CH3:11])[C:9]3[CH:12]=[C:13]([N:16]4[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]4=[O:23])[CH:14]=[CH:15][C:8]=3[N:7]=2)[CH2:5][CH2:4]1.Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1>C1COCC1>[CH:3]1([C:6]2[N:10]([CH3:11])[C:9]3[CH:12]=[C:13]([N:16]4[CH:21]=[CH:20][C:19]([O:22][CH2:25][C:26]5[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=5)=[CH:18][C:17]4=[O:23])[CH:14]=[CH:15][C:8]=3[N:7]=2)[CH2:4][CH2:5]1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Reactant: Fc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4cccc(F)c4)cc3=O)cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.6 %

Procedure:
To a stirred suspension of NaH (40% oil dispersion, 50 mg) in THF (9 ml) was added a solution of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (150 mg) in THF (1 ml) at 0° C., and then the mixture was stirred at room temperature for 30 min. 1-Bromomethyl-3-fluorobenzene (150 mg) in THF (0.5 ml) was added, and the resulting mixture was stirred at room temperature for 12 h. The reaction mixture was quenched with ice-water and extracted with DCM. The extract was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by silica gel column chromatography (MeOH/DCM) followed by crystallization with DCM/hexane to give the title compound (49 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([CH2:20][CH2:21][NH2:22])[CH:15]=[CH:16][C:17]=1[O:18][CH3:19]>FC(F)(F)C(O)=O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[C:15]2[C:14](=[CH:13][C:12]([O:11][CH3:10])=[C:17]([O:18][CH3:19])[CH:16]=2)[CH2:20][CH2:21][NH:22]1
Reactant: COc1ccc(CCN)cc1OC
Reactant: O=Cc1ccccc1Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(cc1OC)C(c1ccccc1Cl)NCC2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of 2-chlorobenzaldehyde (0.5 M in dichloromethane) (800 μl) and 2-(3,4-dimethoxy-phenyl)-ethylamine (0.25 M in dichloromethane) (800 μl) was added trifluoroacetic acid (150 μl). The mixture was shaken at room temperature for 12-24 hours then evaporated to dryness. Toluene (1 ml) was added the mixture vortexed and re-evaporated to dryness. The residue was dissolved in methanol (1.5 ml) and dichloromethane (1 ml) and filtered through a SCX cartridge (Bakerbond JT7090-07, aromatic sulfonic acid). The cartridge was washed with methanol (3 ml) the product eluted with 0.5 M ammonia solution (5 ml). Product containing fractions were combined and evaporated to dryness. Toluene (1 ml) was added the mixture vortexed and re-evaporated to dryness to give 1-(2-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline which was used directly in the next step.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].ClC([O:13][C:14](Cl)(Cl)Cl)=O.[NH2:18][C:19]1[CH:24]=[CH:23][N:22]=[N:21][CH:20]=1.C(N(CC)CC)C>O1CCOCC1>[N:22]1[CH:23]=[CH:24][C:19]([NH:18][C:14]([NH:5][C:4]2[CH:3]=[C:2]([F:1])[CH:8]=[C:7]([F:9])[CH:6]=2)=[O:13])=[CH:20][N:21]=1
Reactant: Nc1ccnnc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Nc1cc(F)cc(F)c1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(Nc1ccnnc1)Nc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 126.1 %

Procedure:
To a stirred solution of 2.7 grams (0.021 mole) of 3,5-difluoroaniline in 100 ml of dioxane was added via syringe 1.5 ml (0.013 mole ) of trichloromethyl chloroformate. The reaction mixture was heated under reflux for 18 hours, cooled to ambient temperature, and 2.0 grams (0.021 mole) of 4-aminopyridazine and 7.01 ml (0.05 mole) of triethylamine were added. The reaction mixture was heated at 50° C. for one day, cooled to ambient temperature and filtered. The filter cake was washed with dioxane and dried. The solid was slurried in hot water for one hour. The mixture was filtered and the filter cake dried to give 4.1 grams of N-(4-pyridazinyl)-N'-(3,5-difluorophenyl)urea; m.p. 272°-273° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [N:1]([CH:4]([C:6]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])=[C:14]2[C:9]([CH:10]=[CH:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1)[CH3:5])=[N+]=[N-].CP(C)C.C(OCC)(=O)C>O1CCCC1.O>[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:15]1[C:6]([CH:4]([NH2:1])[CH3:5])=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][CH:11]=[CH:10]2
Reactant: CC(N=[N+]=[N-])c1ccc2cccnc2c1-c1ccccc1F
Agent: CP(C)C
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(N)c1ccc2cccnc2c1-c1ccccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 7-(1-azidoethyl)-8-(2-fluorophenyl)quinoline (0.033 g, 0.11 mmol) in tetrahydrofuran (0.3 mL) and water (0.0813 mL) was added 1.00 M trimethylphosphine in tetrahydrofuran (0.135 mL, 0.135 mmol) at room temperature and the mixture was stirred at room temperature for 1 hour. To the mixture was added ethyl acetate and the mixture was extracted with 1 N HCl twice. The combined extracts were neutralized with solid sodium bicarbonate, and extracted with dichloromethane. The combined organic layers were washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue had two peaks with the same desired mass and was used directly in next step (25 mg, 83%). LCMS calculated for C17H16FN2(M+H)±: m/z=267.1; found: 267.1.