Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:3].[C:12]([C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][CH:24]=1)[C:18]([NH2:21])([CH3:20])[CH3:19])(=[O:14])[CH3:13].C(N(C(C)C)CC)(C)C>ClCCl>[C:12]([C:15]1[CH:16]=[C:17]([C:18]([NH:21][C:2](=[O:3])[O:4][C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=2)([CH3:20])[CH3:19])[CH:22]=[CH:23][CH:24]=1)(=[O:14])[CH3:13]
Reactant: O=C(Cl)Oc1ccc(Cl)cc1
Reactant: CC(=O)c1cccc(C(C)(C)N)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1cccc(C(C)(C)NC(=O)Oc2ccc(Cl)cc2)c1
Reaction time: 2 h
Yield: 81 %

Procedure:
4-Chlorophenyl chloroformate (317 μL, 2.24 mmol) in dichloromethane (2 mL) was added to a mixture of 3-acetyl-α, α-dimethylbenzylamine 24 and diisopropylethylamine (390 μL, 2.24 mmol). The reaction mixture was stirred for 2 h. It was then diluted with dichloromethane, washed with 1 N HCl, and then brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by column chromatography using hexane/ethyl acetate as eluent to give 25 (594 mg, 81%). 1H NMR (CDCl3, 400 MHz) δ 1.73 (s, 6H), 2.60 (s, 3H), 5.65 (s, 1H), 7.02 (d, J=8.4 Hz, 1H), 7.25 (d, J=6 Hz, 2H), 7.44 (t, J=8 Hz, 1H), 7.65 (d, J=7.6 Hz, 1H), 7.82 (d, J=7.6 Hz, 1H), 8.07 (1H, s); 13C NMR (DMSO-d, 100 MHz) δ 27.45, 29.79, 55.50, 124.23, 124.55, 127.31, 129.28, 129.55, 129.79, 130.39, 137.30, 148.70, 150.32, 152.97, 198.64; ESI-HRMS for C18H19NO3Cl (M+H)+ calcd. 332.1053. found 332.1059.
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([NH:10][C:11](=[O:14])[CH2:12][Cl:13])[CH2:3]2.[CH3:15][C:16]([C:19]1[CH:24]=[C:23]([SH:25])[CH:22]=[C:21]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:20]=1[OH:30])([CH3:18])[CH3:17].C(N(CC)CC)C>C(#N)C>[ClH:13].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([NH:10][C:11](=[O:14])[CH2:12][S:25][C:23]1[CH:22]=[C:21]([C:26]([CH3:27])([CH3:28])[CH3:29])[C:20]([OH:30])=[C:19]([C:16]([CH3:18])([CH3:17])[CH3:15])[CH:24]=1)[CH2:3]2
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: O=C(CCl)NC1CN2CCC1CC2
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(SCC(=O)NC2CN3CCC2CC3)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
The title compound was prepared by dissolving the product of Example 17 (2.0 g, 0.0084 mole) and 2,6-bis (1,1-dimethylethyl)-4-mercaptophenol (1.99 g, 0.0084 mole) in acetonitrile (25 ml). Triethylamine (5 ml) was added to the mixture and the mixture stirred at room temperature for 12 hours then refluxed for 72 hours. The hot mixture was filtered and the solvent removed on a rotary evaporator. The residue was triturated with hexane and dissolved in hot ethyl acetate and allowed to cool. After filtering, the solvent was removed by a rotary evaporator and the residue recrystallized from ethyl acetate-methanol-ethyl ether to give a tan solid. The structure was confirmed by mass spectroscopy M+ 404.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([C:17](=[O:21])[CH2:18][CH2:19]Cl)[C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[N:9]([CH3:12])[C:10](=[O:11])[C:4]=2[CH:3]=1.[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1.C.CCOCC>O1CCOCC1>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([C:17](=[O:21])[CH2:18][CH2:19][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[C:7]3[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=3[N:9]([CH3:12])[C:10](=[O:11])[C:4]=2[CH:3]=1
Reactant: CN1C(=O)c2cc(Cl)ccc2N(C(=O)CCCl)c2ccccc21
Reactant: C1CCNC1
Solvent: C1COCCO1
Solvent: CCOCC
Product: CN1C(=O)c2cc(Cl)ccc2N(C(=O)CCN2CCCC2)c2ccccc21

Procedure:
3.5 gm (0.01 mol) of 2-chloro-5-(3-chloro-propionyl)-5,10-dihydro-10-methyl-11H-dibenzo[b,e][1,4]diazepin-11-one and 3.5 gm (0.05 mol) of pyrrolidine were refluxed in 50 ml of dioxane for 4 hours. After addition of activated charcoal, the reaction mixture was filtered, and the filtrate was evaporated in vacuo. The residue was dissolved in chloroform, the solution was extracted with water, and the organic phase was evaporated in vacuo. The oily residue was obtained as crystals after addition of ether. After recrystallization from cyclohexane 2.6 gm of the crystalline title compound, m.p. 118°-120° C., were obtained.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][C@@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@@H:11]([CH3:20])[N:10]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:9]1=[O:25])(C)(C)C>C(OCC)(=O)C>[NH2:7][C@H:8]1[CH2:13][C@@H:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C@@H:11]([CH3:20])[N:10]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:9]1=[O:25]
Reactant: CC(C)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)C[C@@H](c2ccccc2)[C@H]1C
Solvent: CCOC(C)=O
Product: CC(C)CN1C(=O)[C@@H](N)C[C@@H](c2ccccc2)[C@H]1C
Temperature: 23 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl[(3S,5S,6R)-6-methyl-1-(2-methylpropyl)-2-oxo-5-phenylpiperidin-3-yl]carbamate (140 mg, 0.39 mmol) in ethyl acetate (10 mL), pre-cooled to 0° C. was sparged with HCl gas for ˜1 min. The ice-bath was removed and the acidic solution was allowed to warm to 23° C. as stirring was continued for 2 h. The mixture was then concentrated to dryness to afford the title compound as a hydrochloride salt. MS: m/z=261.3 (M+1).
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.[C:18]1([C:24](Cl)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>N1C=CC=CC=1>[C:24]([O:7][CH2:6][C@H:5]1[O:8][C@@H:1]([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:2][C@@H:3]1[OH:4])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Solvent: c1ccncc1
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O2)c(=O)[nH]c1=O

Procedure:
This compound was prepared from thymidine and triphenylmethyl chloride in dry pyridine by the procedure of Horwitz and Urbanski.
Reaction SMILES: N[C@H:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]([CH3:17])=[CH:10][C:11]([Cl:16])=[N:12][C:13]=3[CH:14]=2)[O:5][C:4]([CH3:19])([CH3:18])[C@@H:3]1[OH:20].[C:21]([BH3-])#[N:22].[Na+].C(=O)([O-])O.[Na+]>CO>[Cl:16][C:11]1[CH:10]=[C:9]([CH3:17])[C:8]2[CH:7]=[C:6]3[O:5][C:4]([CH3:19])([CH3:18])[C@H:3]([OH:20])[C@@H:2]([NH:22][CH2:21][CH2:15][CH2:2][CH2:3][CH3:4])[C:15]3=[CH:14][C:13]=2[N:12]=1
Reactant: [BH3-]C#N
Reactant: Cc1cc(Cl)nc2cc3c(cc12)OC(C)(C)[C@H](O)[C@H]3N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CCCCCN[C@H]1c2cc3nc(Cl)cc(C)c3cc2OC(C)(C)[C@@H]1O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 41 %

Procedure:
To a solution of (3R*,4S*)-4-amino-7-chloro-2,2,9-trimethyl-3,4-dihydro-2H-pyrano[2,3-g]quinolin-3-ol (60 mg, 0.205 mmol) in methanol (1.2 mL), butyl aldehyde (35 mg, 0.041 mmol) was added, and the resulting mixture was stirred at room temperature for 20 minutes. Sodium cyanoborohydride (52 mg, 0.82 mmol) was added thereto, and the resulting mixture was stirred at room temperature for 1 hour. Upon the completion of the reaction, saturated sodium hydrogencarbonate aqueous solution was added thereto, and the resulting solution was extracted with ethyl acetate, washed with saturated sodium chloride solution, and dried over magnesium sulfate and concentrated. The resulting mixture was purified by silica gel column (hexane/ethyl acetate=3/1) to obtain the aimed product (yield: 41%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[S:21]CCC(OCC)=O)=[CH:10][CH:9]=2)=[CH:4][N:3]=1.CC([O-])(C)C.[K+].CO>C1COCC1>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[C:13]([F:14])=[CH:12][C:11]([C:15]3[C:16]([SH:21])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:10][CH:9]=2)=[CH:6][N:7]=1
Reactant: CCOC(=O)CCSc1ccccc1-c1ccc(-c2cnc(N)nc2)c(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ncc(-c2ccc(-c3ccccc3S)cc2F)cn1
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a solution of ethyl 3-(4′-(2-aminopyrimidin-5-yl)-5′-fluorobiphenyl-2-ylthio)propanoate (6.5 g, 16 mmol) in THF (70 mL) was added t-BuOK (3.68 g, 32.8 mmol) under a N2 atmosphere. After stirring for 10 min, methanol (5 mL) was added and the resulting mixture purified by FCC to give the title compound (4.8 g, 16 mmol, 98%). MS (ESI): mass calcd. for C16H12FN3S, 297.07; m/z found, 298.1 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[CH3:27])[C:6]1[N:7]=[C:8]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[S:9][C:10]=1[C:11]#[N:12])=[O:4].[N-:28]=[N+:29]=[N-:30].[Na+]>CN(C)C=O.CCOC(C)=O>[N:28]([CH2:2][C:3]([N:5]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[CH3:27])[C:6]1[N:7]=[C:8]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[S:9][C:10]=1[C:11]#[N:12])=[O:4])=[N+:29]=[N-:30]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1c(Cl)cccc1CN(C(=O)CCl)c1nc(N2CCOCC2)sc1C#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(Cl)cccc1CN(C(=O)CN=[N+]=[N-])c1nc(N2CCOCC2)sc1C#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.5 %

Procedure:
To a solution of 2-chloro-N-[(3-chloro-2-methylphenyl)methyl]-N-[5-cyano-2-(4-morpholinyl)-1,3-thiazol-4-yl]acetamide (200 mg, 0.470 mmol) (prepared according to the procedures of example 59) in N,N-Dimethylformamide (DMF) (2 mL) was added sodium azide (92 mg, 1.410 mmol) at rt. The mixture was stirred at rt for 3 hr before diluted in 100 ml EtOAc and washed with 20 mL H2O twice. The organic layer was concentrated to give 200 mg crude product (99%), which was used in the next step without further purification. LC/MS (ES) m/z=432.2 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([OH:14])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[N:15](=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]([CH3:38])[S:25]([C:28]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=1)(=[O:27])=[O:26])[NH2:16].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.CN(C)C(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12]([NH:16]/[N:15]=[CH:17]/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:24]([CH3:38])[S:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:35])([F:36])[F:37])=[CH:30][CH:29]=2)(=[O:27])=[O:26])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CN(c1ccccc1C=NN)S(=O)(=O)c1ccc(C(F)(F)F)cc1
Reactant: COc1ccc(CC(=O)O)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CC(=O)N(C)C
Product: COc1ccc(CC(=O)N/N=C/c2ccccc2N(C)S(=O)(=O)c2ccc(C(F)(F)F)cc2)cc1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 58 %

Procedure:
A flask is charged with (3,4-dimethoxyphenyl)acetic acid (0.34 mmol), 4-dimethylaminopyridine (0.66 mmol), a solution of N-{2-[hydrazonomethyl]phenyl}-N-methyl-4-(trifluoromethyl)benzenesulfonamide (0.33 mmol) in N,N-dimethylacetamide (1 mL), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.33 mmol). The reaction is stirred at room temperature for 18 hours. The reaction is worked up by evaporating the reaction mixture. The product is purified on silica gel with ethyl acetate-methylene chloride mixtures or methanol-methylene chloride mixtures. A 58% yield of N-[2-((E)-{[(3,4dimethoxyphenyl)acetyl]hydrazono}methyl)phenyl]-N-methyl-4-(trifluoromethyl)benzenesulfonamide is obtained. 1H NMR (400 MHz, CDCl3) (mixture of geometric isomers) d 3.25 (s); 3.90 (2s); 4.10 (m); 6.58 (m); 6.87 (m); 6.96 (m); 7.45 (m); 7.82 (m); 8.20 (m); 8.29 (m); 8.90&8.96 (2bs). ESI− for C25H24F3N3O5S: m/z=534 (M−H)−.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:9]([N:11]3[CH2:13][CH:12]3[CH3:14])=[N:8][CH:7]=[N:6][C:5]=2[C:4]([CH3:15])=[N:3]1.[I-].[Na+]>CC(C)=O>[CH3:1][N:2]1[C:10]2[C:9]3[N:8]([CH2:14][CH:12]([CH3:13])[N:11]=3)[CH:7]=[N:6][C:5]=2[C:4]([CH3:15])=[N:3]1
Reactant: Cc1nn(C)c2c(N3CC3C)ncnc12
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1nn(C)c2c1N=CN1CC(C)N=C21
Yield: 89.5 %

Procedure:
The above aziridine (9 g, 0.044 mol) is dissolved in 100 ml of acetone, sodium iodide (8 g, 0.053 mol) is added and the mixture is refluxed 1.5 hr and evaporated in vacuo. The residue is partitioned in 150 ml of methylene dichloride and 60 ml of 20% sodium carbonate solution. The organic layer is separated, dried (MgSO4) and evaporated in vacuo to give 8 g (89%) of 7,8-dihydro-1,3,8-trimethyl-1H-imidazo[1,2-c]pyrazolo[3,4-e]pyrimidine, mp 115°-117° C. from heptane.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].N1C=CC=CC=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](=[O:26])[CH3:25])=[CH:19][C:18]=1[S:27](Cl)(=[O:29])=[O:28]>O1CCOCC1>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24](=[O:26])[CH3:25])=[CH:19][C:18]=1[S:27]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([C:5]#[N:6])[CH:3]=1)(=[O:28])=[O:29]
Reactant: N#Cc1cccc(N)c1
Reactant: CC(=O)Cc1ccc(Cl)c(S(=O)(=O)Cl)c1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CC(=O)Cc1ccc(Cl)c(S(=O)(=O)Nc2cccc(C#N)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Aminobenzonitrile (442 mg, 3.7 mmol, 1 eq) is dissolved in dry pyridine (606 ul, 7.5 mmol, 2 eq), under an inert atmosphere of argon. 2-Chloro-5-(2-oxo-propyl)-benzenesulfonyl chloride (Intermediate A)(1.0 g, 3.7 mmol) in 1,4-dioxane (2 ml) is added and the reaction mixture is stirred at room temperature overnight. The solvents are removed in vacuo and the residue is dissolved in DCM and 0.5M HCl. The phases are separated and the organic portion is washed with brine, dried over MgSO4, filtered and concentrated in vacuo to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Cl[C:11]1[C:12]2[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[N:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][N:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)[C:12]2[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[S:23][C:13]=2[N:14]=1
Reactant: NCc1ccc(F)cc1
Reactant: O=[N+]([O-])c1cc2c(Cl)nc(-c3cnccn3)nc2s1
Product: O=[N+]([O-])c1cc2c(NCc3ccc(F)cc3)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 4-fluorobenzylamine with 4-chloro-2-(pyrazin-2-yl)-6-nitro-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(4-fluorobenzylamino)-6-nitro-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@@H:4]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9](OS(C(F)(F)F)(=O)=O)=[CH:8][CH:7]=1.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O>[CH3:1][O:2][C:3](=[O:28])[C@@H:4]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[O:30][CH3:29])=[CH:8][CH:7]=1
Reactant: COC(=O)[C@H](Cc1ccc(OS(=O)(=O)C(F)(F)F)cc1)NC(=O)OC(C)(C)C
Reactant: COc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)[C@H](Cc1ccc(-c2ccccc2OC)cc1)NC(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 65 %

Procedure:
(S)-2-tert-Butoxycarbonylamino-3-(4-trifluoromethanesulfonyloxyphenyl) propionic acid methyl ester (1.88 g, 4.39 mmol, prepared as described in Preparation 23, was dissolved in glyme (58 ml) and water (4 ml). To this solution 2-methoxyphenylboronic acid (2.0 g, 13.16 mmol), tetrakistriphenylphosphine palladium (0) (2.79 g, 2.41 mmol) and potassium carbonate (2.12 g, 15.37 mmol) were added. The reaction mixture was degassed and then heated at 80° C. for 6 h. The mixture was diluted with EtOAc (100 ml), washed with saturated aqueous NaHCO3 (100 ml) and brine (100 ml) and dried over MgSO4. The mixture was filtered and concentrated in vacuo. The residue was purified by flash chromatography over silica gel (9:1 to 4:1 hexanes/EtOAc) to give (S)-2-tert-butoxycarbonylamino-3-(2′-methoxy-biphenyl-4-yl)-propionic acid methyl ester (1.1 g, 65%) as a white solid.
Reaction SMILES: [ClH:1].Cl.[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:30][CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[C:11]([C:26]([F:29])([F:28])[F:27])[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:15][CH:14]=1)[CH2:4][CH2:5][CH3:6].Cl.[CH2:38](OCC)C>C(Cl)Cl>[ClH:1].[ClH:1].[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:30][CH:31]2[CH2:36][CH2:35][N:34]([CH3:38])[CH2:33][CH2:32]2)=[C:11]([C:26]([F:28])([F:27])[F:29])[C:12]=1[C:13]1[CH:14]=[CH:15][C:16]([O:19][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[CH:17][CH:18]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCOCC
Reactant: CCCCc1nnc(OC2CCNCC2)c(C(F)(F)F)c1-c1ccc(OC2CCCCC2)cc1
Agent: Cl
Solvent: ClCCl
Product: CCCCc1nnc(OC2CCN(C)CC2)c(C(F)(F)F)c1-c1ccc(OC2CCCCC2)cc1

Procedure:
To a solution of 3-butyl-4-(4-cyclohexyloxy-phenyl)-6-(piperidin-4-yloxy)-5-trifluoromethyl-pyridazine dihydrochloride (0.14 mmol, 0.075 g) and aqueous formaldehyde (37%, 0.68 mmol, 0.070 mL) in dry DCM (1.2 mL) was added macroporous resin-bound triacetoxyborohydride (loading 2.36 mmol/gram, 0.82 mmol, 0.35 g). The mixture was shaken for 12 hours. The reaction was filtered and the resin was washed with DCM (10 mL). The solvent was removed under reduced pressure. The crude product was purified on a 4 g SiO2 cartridge with 4-6% (2N NH3 in MeOH) in DCM to give 3-butyl-4-(4-cyclohexyloxy-phenyl)-6-(1-methyl-piperidin-4-yloxy)-5-trifluoromethyl-pyridazine. The neutral amine was treated with 2N HCl in diethyl ether (0.5 mL) and DCM (0.5 mL). The volatiles were removed under reduced pressure and the salt was triturated with diethyl ether and filtered to provide the title compound (0.05 g). LCMS: m/z 493 [M+1]; 1H NMR (400 MHz, CD3OD) δ 7.10-7.19 (2 H, m), 7.00-7.09 (2 H, d), 5.54-5.82 (1 H, m), 4.38-4.43 (1 H, m), 3.66 (1 h, d), 3.54 (1 H, d), 3.10-3.35 (2 H, m), 2.89-2.98 (3 H, m), 2.64-2.73 (2 H, m), 2.58 (1 H, d), 2.46 (1 H, d), 2.27 (1 H, t), 1.96-2.13 (3 H, m), 1.78-1.83 (2 H, m), 1.14-1.66 (10 H, m), 0.77 (3 H, t).
Reaction SMILES: [F:1][C:2]1[C:10]2[C:9]([CH3:12])([CH3:11])[O:8][B:7]([OH:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[C:14](Cl)=[N:15][OH:16].[Cl:18][C:19]1[CH:24]=[C:23]([C:25]([C:27]([F:30])([F:29])[F:28])=[CH2:26])[CH:22]=[C:21]([Cl:31])[CH:20]=1>CN(C=O)C>[Cl:18][C:19]1[CH:24]=[C:23]([C:25]2([C:27]([F:30])([F:28])[F:29])[O:16][N:15]=[C:14]([C:3]3[CH:4]=[CH:5][C:6]4[B:7]([OH:13])[O:8][C:9]([CH3:12])([CH3:11])[C:10]=4[C:2]=3[F:1])[CH2:26]2)[CH:22]=[C:21]([Cl:31])[CH:20]=1
Reactant: CC1(C)OB(O)c2ccc(C(Cl)=NO)c(F)c21
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Solvent: CN(C)C=O
Product: CC1(C)OB(O)c2ccc(C3=NOC(c4cc(Cl)cc(Cl)c4)(C(F)(F)F)C3)c(F)c21
Temperature: 0 °C
Reaction time: 12 h

Procedure:
To a solution of the crude compound 4-fluoro-N,1-dihydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborole-5-carbimidoyl chloride (180 mg. 0.70 mmol) and 1,3-dichloro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (203 mg, 0.84 mmol) in DMF (5 mL) at rt was added TEA (117 μL, 0.84 mmol). The reaction mixture was stirred for 12 h, poured into ice-water and extracted three times with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by prep-TLC eluted with PE-EA (3:2) and then purified by combiflash to give the title compound 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-4-fluoro-3,3-dimethylbenzo[c][1,2]oxaborol-1(3H)-ol[80 mg; yield 24.8% over the last 3 steps] as a white solid. 1H NMR (500 MHz, DMSO-d6): δ 9.479 (s, 1H), 7.810 (t, J=1.5 Hz, 1H), 7.753 (t, J=7.5 Hz, 1H), 7.671 (d, J=1.5 Hz, 2H), 7.582 (d, J=7.5 Hz, 1H), 4.376 (d, J=18.0 Hz, 1H), 4.270 (d, J=18.0 Hz, 1H), 1.55 (s, 6H) ppm; HPLC purity: 100% at 220 nm and 100% at 254 nm; MS: m/z=462.0 (M+1, ESI+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH3:9].[N+:10]([O-])([O-:12])=[O:11].[K+]>OS(O)(=O)=O>[Cl:1][C:2]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]([F:8])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(F)ccc1Cl
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cc(F)c([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
To a stirred solution of 2-chloro-5-fluorotoluene (10.356 g, 71.628 mmol, Lancaster, used as received) in conc. H2SO4 (70 mL) at 0° C., KNO3 (7.252 g, 71.72 mmol) was added in four equal portions. The resulting pale yellow solution was allowed to warm to room temperature and was stirred overnight at room temperature. It was then poured into ice water (350 g) and extracted with ether (3×100 mL). Ether was dried over anhydrous Na2SO4, removed under vacuum, and the resulting oil was dried further under vacuum to afford 12.277 g (90%) of the title compound as an oil, which was used as such for the next reaction; 1H NMR (CDCl3); δ 2.459 (s, 2H), 7.193 (d, 1H, J1 =11.1 Hz), 8.083 (d, 1H, J1 =6.6 Hz).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][OH:9])[CH3:2].Cl[C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[N:12]=1>>[CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][C:11]1[C:20]2[C:15](=[CH:16][C:17]([O:21][CH3:22])=[CH:18][CH:19]=2)[CH:14]=[C:13]([NH:23][C:24]2[CH:28]=[C:27]([CH3:29])[NH:26][N:25]=2)[N:12]=1)[CH3:2]
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: CCOCCOCCO
Product: CCOCCOCCOc1nc(Nc2cc(C)[nH]n2)cc2cc(OC)ccc12

Procedure:
Similar procedure as described in example 10 was used, starting from 2-(2-ethoxy-ethoxy)-ethanol and (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give {1-[2-(2-ethoxy-ethoxy)-ethoxy]-6-methoxy-isoquinolin-3-yl}-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 387(MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][CH:11]=[C:10]3[NH:14][N:15]=[C:16]([NH2:17])[C:9]=23)=[CH:4][CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[N:26]=[C:27]=[O:28]>CN(C=O)C>[NH2:17][C:16]1[C:9]2[C:10](=[CH:11][N:12]=[CH:13][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:27]([NH:26][C:20]3[CH:21]=[C:22]([CH3:25])[CH:23]=[CH:24][C:19]=3[F:18])=[O:28])=[CH:7][CH:6]=2)[NH:14][N:15]=1
Reactant: Cc1ccc(F)c(N=C=O)c1
Reactant: Nc1ccc(-c2cncc3[nH]nc(N)c23)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(-c3cncc4[nH]nc(N)c34)cc2)c1
Reaction time: 16 h

Procedure:
The product from Example 1D (50 mg, 0.22 mmol) in DMF (1 mL) was treated with 1-fluoro-2-isocyanato-4-methyl-benzene (0.03 mL, 0.22 mmol) and stirred for 16 hours. The crude product was directly purified via preparative HPLC on an Agilent Zorbax Stablebond C-18 (7 micron particle size) preparative column using a solvent gradient of 30% to 100% acetonitrile in 0.1% aqueous TFA at a flow rate of 15 mL/minute. The product was further purified via silica gel chromatography eluting with 5% methanol/CH2Cl2 to provide 4 mg ofthe title compound. MS (ESI(+)) m/e 377 (M+H)+; 1H NMR (300 MHz, DMSO-D6) δ ppm 2.28 (s, 3H) 4.61 (s, 2H) 6.77-6.85 (m, 1H) 7.12 (dd, J=11.53, 8.14 Hz, 1H) 7.49 (d, J=8.81 Hz, 2H) 7.63 (d, J=8.48 Hz 2 H) 7.94 (s, 1H) 8.01 (dd, J=8.31, 1.86 Hz, 1H) 8.55 (d, J=2.71 Hz, 1H) 8.73 (s, 1H) 9.24 (s, 1H) 12.26 (s, 1H).