Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)[N:6]=[C:5]2[OH:18].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C:38]([O:42][CH3:43])(=[O:41])[CH:39]=[CH2:40].CCN(C(C)C)C(C)C>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[OH:18][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH:40]=[CH:39][C:38]([O:42][CH3:43])=[O:41])[CH:3]=2)[N:8]=[C:7]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:6]=1
Reactant: Oc1nc(-c2cccnc2)nc2ccc(I)cc12
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C=Cc1ccc2nc(-c3cccnc3)nc(O)c2c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 49 %

Procedure:
To a solution of 6-iodo-2-(pyridin-3-yl) quinazolin-4-ol (synthesized as described in Scheme 1 and 4, substituting 5-iodo-2-nitrobenzoic acid for 2-nitro-5-propoxy-benzoic acid) (3.00 g, 8.6 mmol, 1.0 eq.), Pd(OAc)2 (48 mg, 0.21 mmol, 0.025 eq.) and PPh3 (113 mg, 0.43 mmol, 0.05 eq.) in DMF (8 mL) was added methyl acrylate (3.22 g, 25.8 mmol, 3.0 eq.) and DIPEA (1.22 g, 9.46 mmol, 1.1 eq.) under Ar atmosphere. The mixture was stirred at 110° C. overnight. After cooling, the mixture was filtered and the solid was washed with ethyl acetate three times to afford 1.30 g of xxxvi-a as green solid (yield 49%). LCMS m/z=308.0 (M+1) (Method B) (retention time=1.41 min).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.C([Li])CCC.CN(OC)[C:20]([CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:24][CH2:23]1)=[O:21].[Cl-].[NH4+]>C1COCC1>[CH2:28]([N:25]1[CH2:26][CH2:27][CH:22]([C:20](=[O:21])[C:2]2[CH:7]=[CH:6][C:5]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=2)[CH2:23][CH2:24]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Reactant: CON(C)C(=O)C1CCN(Cc2ccccc2)CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(c1ccc(OC(F)(F)F)cc1)C1CCN(Cc2ccccc2)CC1
Temperature: -60 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
1-Bromo-4-trifluoromethoxybenzene (5.3 g, 22.0 mmol) was dissolved in dry THF (70 ml) under a nitrogen atmosphere, and this solution was cooled to −60° C. n-Butyllithium (1.6 M) hexane solution (15 ml, 24.0 mmol) was added dropwise to the solution, and the mixture was allowed to reach a temperature of −30° C. and stirred for 1 hour. This mixture was cooled to −60° C. again, to which a solution of 1-benzylpiperidine-4-carboxylic acid N-methyl-N-methoxyamide (4.1 g, 15.6 mmol) prepared in Reference Example 147 in THF (10 ml) was added dropwise, and the mixture was stirred for 1 hour and then at 0° C. for 3 hours. The reaction mixture was poured into saturated ammonium chloride aqueous solution, and extracted with diethyl ether. The extract was washed with water and brine, dried over magnesium sulfate, and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=4/1) to afford 1-benzyl-4-(4-trifluoromethoxybenzoyl)piperidine (4.8 g, yield 85%) as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.[NH2:13][C:14]1[S:15][CH:16]=[CH:17][C:18]=1[C:19]#[N:20]>>[C:19]([C:18]1[CH:17]=[CH:16][S:15][C:14]=1[NH:13][C:10](=[O:12])[CH2:9][C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)#[N:20]
Reactant: COc1ccc(CC(=O)O)cc1
Reactant: N#Cc1ccsc1N
Product: COc1ccc(CC(=O)Nc2sccc2C#N)cc1

Procedure:
N-(3-cyanothiophen-2-yl)-2-(4-methoxyphenyl)acetamide was prepared from 2-(4-methoxyphenyl)acetic acid (1.37 g, 8.29 mmol) and 2-aminothiophene-3-carbonitrile (1.03 g, 8.29 mmol) according to protocol B. Retention time (min)=2.150, method [1], MS (ESI) 273.0 (M+H).
Reaction SMILES: C[Al](C)C.[CH:5]([NH2:8])([CH3:7])[CH3:6].C[O:10][C:11]([C:13]1[N:14]=[N:15][C:16]([O:19][CH2:20][C:21]2[C:22]([CH2:27][CH2:28][CH2:29][CH3:30])=[N:23][O:24][C:25]=2[CH3:26])=[CH:17][CH:18]=1)=O>C1(C)C=CC=CC=1.O1CCOCC1>[CH:5]([NH:8][C:11]([C:13]1[N:14]=[N:15][C:16]([O:19][CH2:20][C:21]2[C:22]([CH2:27][CH2:28][CH2:29][CH3:30])=[N:23][O:24][C:25]=2[CH3:26])=[CH:17][CH:18]=1)=[O:10])([CH3:7])[CH3:6]
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)OC)nn1
Reactant: CC(C)N
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CCCCc1noc(C)c1COc1ccc(C(=O)NC(C)C)nn1
Temperature: 90 °C
Reaction time: 1 h
Yield: 37.6 %

Procedure:
Trimethylaluminium (0.72 mL of a 2 M solution in toluene, 1.44 mmol) was added dropwise to a stirred solution of isopropylamine (85 mg, 1.44 mmol) in dioxane (3 mL) at room temperature under argon. After 1 h, a solution of 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-pyridazine-3-carboxylic acid methyl ester (110 mg, 0.36 mmol) in dioxane (3 mL) was added and the reaction mixture heated at 90° C. After 2 h the reaction mixture was cooled in an ice/water bath and quenched with Seignette salt solution (1 mL). The resultant mixture was filtered, the filter cake washed with dichloromethane, then the combined filtrates were concentrated then purified by chromatography (silica, 0 to 80% ethyl acetate in heptane) to give the title compound (45 mg, 38%) as a colourless oil. MS: m/e=333.4 [M+H]+.
Reaction SMILES: C([N:5]1[C:14]2[C:9](=[CH:10][C:11]([Cl:20])=[C:12]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[N:13]=2)[C:8](=[O:21])[C:7]([C:22]([O:24]CC)=[O:23])=[CH:6]1)(C)(C)C.Cl.O1CCOCC1>O>[Cl:20][C:11]1[CH:10]=[C:9]2[C:14](=[N:13][C:12]=1[N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)[NH:5][CH:6]=[C:7]([C:22]([OH:24])=[O:23])[C:8]2=[O:21]
Reactant: CCOC(=O)c1cn(C(C)(C)C)c2nc(N3CCCC3)c(Cl)cc2c1=O
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1c[nH]c2nc(N3CCCC3)c(Cl)cc2c1=O

Procedure:
A solution of EXAMPLE 80A (160 mg) in 1:1 9M HCl/1,4-dioxane (15 mL) was heated in a sealed tube at 115° C. for 15 minutes and at 95° C. for 24 hours then cooled, diluted with water (20 mL), and filtered. NMR (300 MHz, DMSO-d6) δ 15.25 (s, 1H), 13.11 (br s, 1H), 8.47 (s, 1H), 8.18 (s, 1H), 3.84-3.80 (m, 4H), 1.96-1.91 (m, 4H).
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[Cl:19][C:20]1[C:21]([N:30]2[CH2:35][CH2:34][CH:33]([NH2:36])[CH2:32][CH2:31]2)=[N:22][CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1>CC#N>[Cl:19][C:20]1[C:21]([N:30]2[CH2:31][CH2:32][CH:33]([NH:36][C:2]3[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=3[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH2:34][CH2:35]2)=[N:22][CH:23]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:25]=1
Reactant: CC(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: NC1CCN(c2ncc(C(F)(F)F)cc2Cl)CC1
Solvent: CC#N
Product: CC(C)N1C(=O)C(NC2CCN(c3ncc(C(F)(F)F)cc3Cl)CC2)=C(c2ccccc2)S1(=O)=O
Yield: 92.9 %

Procedure:
A solution of 4-chloro-2-isopropyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.200 g, 0.700 mmol), TEA (0.106 g, 1.050 mmol) and 1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]piperidin-4-amine (0.294 g, 1.050 mmol) in MeCN (mL) was heated in a microwave reactor at 120° C. for 30 mins. The residue was purified by silica gel column chromatography (Horizons Biotage) using a 1:1 mixture of heptane and EtOAc as eluant, to give the title compound (0.344 g, 93%); 1H NMR (500 MHz, CDCl3): δ 8.34-8.33 (m, 1H), 7.74-7.72 (m, 1H), 7.57-7.54 (m, 2H), 7.49-7.46 (m, 3H), 5.27 (d, 1H), 4.47-4.39 (m, 1H), 3.85-3.78 (m, 2H), 3.24-3.14 (m 1H), 2.55-2.48 (m 2H), 1.82-1.76 (m 2H), 1.60 (d 6H), 1.56-1.48 (m 2H); 13C NMR (125 MHz, CDCl3): δ 160.0, 158.7, 143.1, 136.2, 134.5, 131.8, 130.2, 129.0, 125.3, 121.3, 120.6, 120.3, 107.1, 66.1, 50.3, 47.9, 47.4, 32.4, 20.4; Mass Spectrum: M−H+ 529.
Reaction SMILES: C(ON=O)CC(C)C.[Br:9][C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1N.[CH:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Br:9][C:10]1[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccccc1Br
Reactant: c1ccccc1
Agent: CC(C)CCON=O
Product: Brc1ccccc1-c1ccccc1

Procedure:
A solution of 8.8 mL of isoamylnitrite in 120 mL of benzene at 45° C. was treated dropwise over 30 minutes with a solution of 7.5 g of 2-bromoaniline in 30 mL of benzene. After the addition was complete, the mixture was heated at reflux for 90 minutes then cooled and concentrated under vacuum. The product was purified by preparative high presssure liquid chromatography on silica, eluting with hexanes. 1H NMR (200 MHz,CDCl3): 7.23 (m,2H), 7.35 (m,1H), 7.44 (s,5H), 7.70 (d,8 Hz,1H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]2([C:18]3[C:10](=[CH:11][C:12]4[CH2:13][CH2:14][NH:15][C:16]=4[CH:17]=3)[O:9][CH2:8]2)[CH2:4][CH2:3]1.C[Al](C)C.[CH3:23][C:24]1[CH:29]=[C:28]([C:30]2[CH:35]=[N:34][CH:33]=[CH:32][N:31]=2)[CH:27]=[CH:26][C:25]=1[C:36]1[CH:41]=[CH:40][C:39]([C:42](OC)=[O:43])=[CH:38][CH:37]=1>C1(C)C=CC=CC=1.ClCCl>[CH3:1][N:2]1[CH2:3][CH2:4][C:5]2([C:18]3[C:10](=[CH:11][C:12]4[CH2:13][CH2:14][N:15]([C:42]([C:39]5[CH:38]=[CH:37][C:36]([C:25]6[CH:26]=[CH:27][C:28]([C:30]7[CH:35]=[N:34][CH:33]=[CH:32][N:31]=7)=[CH:29][C:24]=6[CH3:23])=[CH:41][CH:40]=5)=[O:43])[C:16]=4[CH:17]=3)[O:9][CH2:8]2)[CH2:6][CH2:7]1
Reactant: CN1CCC2(CC1)COc1cc3c(cc12)NCC3
Reactant: COC(=O)c1ccc(-c2ccc(-c3cnccn3)cc2C)cc1
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: Cc1cc(-c2cnccn2)ccc1-c1ccc(C(=O)N2CCc3cc4c(cc32)C2(CCN(C)CC2)CO4)cc1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 43.7 %

Procedure:
1'-Methyl-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (0.098 g, 0.403 mmol) (D8) was dissolved in toluene (5 ml) and was treated with trimethylaluminium (2.0 M in hexane) (0.810 ml, 1.612 mmol) with stirring under argon. After 0.25 h, a solution of methyl 2'-methyl-4'-pyrazinylbiphenyl-4-carboxylate (D86, 0.136 g, 0.447 mmol) in toluene (5 ml) was added. The reaction mixture was then heated to 80° C. After 2 h, the reaction mixture was allowed to cool and was stirred at room temperature. The reaction mixture was then poured onto a slurry of silica gel (9385~20 ml) in dichloromethane (30 ml). After effervescence had ceased, the slurry was filtered and the filter pad was washed with 20% MeOH/CH2Cl2 (~200 ml). The filtrate was then evaporated under reduced pressure to give a brown oil, which was purified by silica-gel chromatography (9385, 10% MeOH/CH2Cl2 as eluant) to give the title compound as a cream solid (0.091 g, 44%).
Reaction SMILES: [C:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][N:5]=1)(=O)[CH3:2].[NH2:14][OH:15].C([O-])(=O)C.[Na+].CO>O>[C:1](=[N:14][OH:15])([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: CC(=O)c1nccc2ccccc12
Reactant: NO
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(=NO)c1nccc2ccccc12
Reaction time: 16 h
Yield: 50.3 %

Procedure:
A solution of 1-acetyl-isoquinoline (3.42 g), hydroxylamine (1.53 g) and sodium acetate (2.46 g) in a 3:1 mixture of methanol:water (80 ml) was heated to reflux for 8 hours then allowed to stand for 16 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The combined extracts were dried, concentrated and chromatographed using ethyl acetate:hexane 3:7 as the eluant to give 1-acetyl-isoquinoline oxime (1.87 g, 58% yield) as a white crystalline solid m.p. 154.4°-155.3° C.; 1H NMR: 2.50(3H,s); 7.58-7.73(3H,m); 7.85(1H,m); 8.55(1H,m); 8.57(1H,m); 8.66(1H,s) ppm.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:9]=[CH:10][C:11](F)=[N:12][CH:13]=1.[NH2:15][C:16]1[C:21]([C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=2)=[CH:20][C:19]([Cl:29])=[CH:18][N:17]=1.O>CS(C)=O>[Cl:29][C:19]1[CH:20]=[C:21]([C:22]2[CH:23]=[CH:24][C:25]([O:28][C:11]3[CH:10]=[CH:9][C:8]([Cl:7])=[CH:13][N:12]=3)=[CH:26][CH:27]=2)[C:16]([NH2:15])=[N:17][CH:18]=1
Reactant: Fc1ccc(Cl)cn1
Reactant: Nc1ncc(Cl)cc1-c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1ncc(Cl)cc1-c1ccc(Oc2ccc(Cl)cn2)cc1
Temperature: 120 °C
Reaction time: 5 h
Yield: 99.6 %

Procedure:
A mixture of potassium carbonate (376 mg), 5-chloro-2-fluoropyridine (215 mg) and 4-(2-amino-5-chloropyridin-3-yl)phenol (300 mg) in DMSO (10 mL) was stirred at 120° C. for 5 hr. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with 1N NaOH aq. and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with EtOAc in hexane) to give the title compound (450 mg) as a pale yellow solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1/[CH:10]=[CH:11]/[S:12]([NH2:15])(=[O:14])=[O:13].[Br:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[C:19]([Cl:26])[CH:18]=1.O>O1CCOCC1>[Br:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:15][S:12](/[CH:11]=[CH:10]/[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[Cl:3])(=[O:13])=[O:14])=[O:22])=[C:19]([Cl:26])[CH:18]=1
Reactant: O=C(Cl)c1ccc(Br)cc1Cl
Reactant: NS(=O)(=O)/C=C/c1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(NS(=O)(=O)/C=C/c1ccccc1Cl)c1ccc(Br)cc1Cl
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% dispersion in mineral oil) (36 mg, 0.9 mmol) was added to a solution of (E)-2-(2-chloro-phenyl)-ethenesulfonic acid amide (65 mg, 0.3 mmol) in 1,4-dioxane (1.5 mL) and the reaction mixture was shaken for 30 minutes. Crude 4-bromo-2-chloro-benzoyl chloride (114 mg, 0.45 mmol) in dioxane (0.5 mL) was added and the reaction mixture was shaken at room temperature for 18 hours. Water (0.1 mL) was added to the reaction mixture and the whole was concentrated in vacuo. The resultant residue was purified by preparative HPLC under neutral conditions to give (E)-2-(2-chloro-phenyl)-ethenesulfonic acid 4-bromo-2-chloro-benzoylamide; sodium salt (38 mg, 29% yield).
Reaction SMILES: Br[C:2]1[CH:39]=[CH:38][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:15][C:10]=3[N:9]=[C:8]2[C@@H:28]2[C@H:30]([C:31]([O:33]CC)=[O:32])[C:29]2([CH3:37])[CH3:36])=[CH:4][CH:3]=1.[S:40]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[N:42]=[CH:41]1>>[CH3:36][C:29]1([CH3:37])[C@H:28]([C:8]2[N:7]([CH2:6][C:5]3[CH:38]=[CH:39][C:2]([C:43]4[N:42]=[CH:41][S:40][CH:44]=4)=[CH:3][CH:4]=3)[C:11]3[CH:12]=[CH:13][C:14]([O:16][CH2:17][C:18]4[CH:27]=[CH:26][C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[N:19]=4)=[CH:15][C:10]=3[N:9]=2)[C@@H:30]1[C:31]([OH:33])=[O:32]
Reactant: CCOC(=O)[C@H]1[C@@H](c2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(Br)cc2)C1(C)C
Reactant: CC1(C)OB(c2cscn2)OC1(C)C
Product: CC1(C)[C@H](c2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2ccc(-c3cscn3)cc2)[C@@H]1C(=O)O

Procedure:
The title compound was prepared using similar methods to those in Example 97 using racemic cis-ethyl 3-(1-(4-bromobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)-2,2-dimethylcyclopropanecarboxylate and thiazole-4-boronic acid pinacol ester in Step A. MS (ESI): mass calcd. for C33H28N4O3S, 560.19; m/z found, 561.2 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.89-8.85 (m, 1H), 8.20 (d, J=8.5, 1H), 8.11 (d, J=8.5, 1H), 7.92 (d, J=8.3, 2H), 7.85-7.81 (m, 1H), 7.77-7.71 (m, 1H), 7.68 (d, J=8.5, 1H), 7.57-7.53 (m, 2H), 7.34-7.31 (m, 1H), 7.25-7.23 (m, 1H), 7.16-7.08 (m, 3H), 5.47-5.33 (m, 4H), 2.30 (d, J=8.2, 1H), 2.08 (d, J=8.2, 1H), 1.21 (s, 3H), 1.01 (s, 3H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH:11]([NH2:14])([CH3:13])[CH3:12]>>[CH:11]([NH:14][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)([CH3:13])[CH3:12]
Reactant: CC(C)N
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: CC(C)Nc1ccc([N+](=O)[O-])cc1

Procedure:
Prepared from 1-fluoro-4-nitrobenzene and isopropylamine
Reaction SMILES: C(OC([NH:8][CH:9]([C:43]([CH3:46])([CH3:45])[CH3:44])[C:10]([N:12]1[CH2:16][CH:15]([O:17][C:18]2[C:27]3[C:22](=[C:23]([Cl:28])[CH:24]=[CH:25][CH:26]=3)[N:21]=[C:20]([O:29][CH2:30][CH3:31])[CH:19]=2)[CH2:14][CH:13]1[C:32]([NH:34][C:35]1([C:40]([OH:42])=[O:41])[CH2:37][CH:36]1[CH2:38][CH3:39])=[O:33])=[O:11])=O)(C)(C)C.Cl.[F:48][C:49]([F:68])([F:67])[C:50]1([O:54][C:55](=[O:66])OC2C=CC([N+]([O-])=O)=CC=2)[CH2:53][CH2:52][CH2:51]1.OS([O-])(=O)=O.[K+]>ClCCl.C(N(CC)CC)C>[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[C:27]2[C:22]=1[N:21]=[C:20]([O:29][CH2:30][CH3:31])[CH:19]=[C:18]2[O:17][CH:15]1[CH2:16][N:12]([C:10](=[O:11])[CH:9]([NH:8][C:55]([O:54][C:50]2([C:49]([F:48])([F:67])[F:68])[CH2:51][CH2:52][CH2:53]2)=[O:66])[C:43]([CH3:44])([CH3:46])[CH3:45])[CH:13]([C:32]([NH:34][C:35]2([C:40]([OH:42])=[O:41])[CH2:37][CH:36]2[CH2:38][CH3:39])=[O:33])[CH2:14]1
Reactant: CCOc1cc(OC2CC(C(=O)NC3(C(=O)O)CC3CC)N(C(=O)C(NC(=O)OC(C)(C)C)C(C)(C)C)C2)c2cccc(Cl)c2n1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1(C(F)(F)F)CCC1
Agent: Cl
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1cc(OC2CC(C(=O)NC3(C(=O)O)CC3CC)N(C(=O)C(NC(=O)OC3(C(F)(F)F)CCC3)C(C)(C)C)C2)c2cccc(Cl)c2n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 50.4 %

Procedure:
To 1-{[1-(2-tert-butoxycarbonylamino-3,3-dimethyl-butyryl)-4-(8-chloro-2-ethoxy-quinolin-4-yloxy)-pyrrolidine-2-carbonyl]-amino}-2-ethyl-cyclopropanecarboxylic acid (200 mg, 0.3 mmol) in dichloromethane (4 mL) was added HCl (4N in dioxane) at room temperature. After 2 h, analysis of the reaction mixture by LC-MS showed complete conversion of starting material. At this point, the reaction was cooled to 0° C. and triethylamine (2 mL) was added dropwise, followed by carbonic acid 4-nitro-phenyl ester 1-trifluoromethyl-cyclobutyl ester (300 mg, 1 mmol). The reaction was allowed to warm to room temperature and stirred 14 h. The reaction mixture was then poured into a 1N solution of KHSO4(aq) and extracted with ethyl acetate. The combined organic extracts were washed with 1N KHSO4(aq), water, and brine, and subsequently dried over magnesium sulfate. Concentration, followed by purification by reverse phase HPLC and lyophilization gave 110 mg (50% yield) of 1-({4-(8-chloro-2-ethoxy-quinolin-4-yloxy)-1-[3,3-dimethyl-2-(1-trifluoromethyl-cyclobutoxycarbonylamino)-butyryl]-pyrrolidine-2-carbonyl}-amino)-2-ethyl-cyclopropanecarboxylic acid as a white powder. LCMS found 727.03 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH2:21][OH:22]>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:20][CH2:21][OH:22])=[C:4]([C:9]([F:10])([F:11])[F:12])[CH:3]=1
Reactant: Oc1ccc(Br)cc1C(F)(F)F
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCCOc1ccc(Br)cc1C(F)(F)F

Procedure:
4-Bromo-2-(trifluoromethyl)phenol (83 mmol, 20 g), potassium carbonate (166 mmol, 22.94 g) and 2-bromoethanol (124 mmol, 8.79 mL, 15.56 g) were combined and heated to reflux for overnight in Acetonitrile (200 mL). The reaction mixture was washed with water, 0.5M NaOH, dried over sodium sulfate and concentrated in vacuo. The resulting residue was taken up in hot heptane (300 mL) and allowed to crystallise. The solid was filtered off to afford 2-(4-bromo-2-(trifluoromethyl)-phenoxy)ethanol. (20.74 g)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.[CH2:9](Br)[CH2:10][CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:9]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCCCBr
Reactant: Cc1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCOc1ccc(C)nc1
Yield: 48.4 %

Procedure:
A mixture of 11.0 g (0.10 mol) of 5-hydroxy-2-methylpyridine (commercially available), 13.8 g (0.10 mol) of n-butyl bromide and 6.00 g (0.04 mol) of anhydrous potassium carbonate with 100 ml of acetone was refluxed for 24 hours, the solvent was removed, 100 ml of water was added, and the mixture was extracted with chloroform. The chloroform layer was washed with water, dried over anhydrous sodium sulfate, and then concentrated under a reduced pressure. The residue was separated by silica gel column chromatography (ethyl acetate:hexane=1:4) to give 8.00 g of an oily product (yield 47.9%).
Reaction SMILES: [CH2:1]([N:5]1[C:9]([CH2:10][NH:11][CH2:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[C:8]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[N:7]=[C:6]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:2][CH2:3][CH3:4].[O:33]([C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][C:44]=1[C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:40]Br)[C:34]([CH3:36])=[O:35].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:48]([O:47][C:45](=[O:46])[C:44]1[CH:43]=[CH:42][C:39]([CH2:40][N:11]([CH2:10][C:9]2[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:7][C:8]=2[C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[CH2:12][CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)=[CH:38][C:37]=1[O:33][C:34](=[O:35])[CH3:36])([CH3:51])([CH3:50])[CH3:49]
Reactant: CCCCn1c(-c2ccccc2)nc(-c2ccc(OC)cc2)c1CNCC1CCCCC1
Reactant: CC(=O)Oc1cc(CBr)ccc1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCn1c(-c2ccccc2)nc(-c2ccc(OC)cc2)c1CN(Cc1ccc(C(=O)OC(C)(C)C)c(OC(C)=O)c1)CC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
To a solution of 4-({[3-Butyl-5-(4-methoxy-phenyl)-2-phenyl-3H-imidazol-4-ylmethyl]-cyclohexylmethyl-amine (4.0 g, 9.31 mmol) and 3-acetoxyl-4-tert-butoxycarbonyl-benzyl bromide (3.37 g, 10.24 mmol, 1.1 eq.) in 50 ml anhydrous acetonitrile is added anhydrous potassium carbonate (2.82 g, 20.5 mmol, 2.2 eq.), the resulting mixture is stirred at room temperature for 1 h, then raised to 50° C., stirred overnight. The solid precipitate is filtered off, washed with ethyl acetate, the combined organics is concentrated to dryness, purified through silica gel flash chromatography to give 3.99 g of 4-({[3-Butyl-5-(4-methoxy-phenyl)-2-phenyl-3H-imidazol-4-ylmethyl]cyclohexylmethyl-amino}-methyl)-2-acetoxy-benzoic acid tert-butyl ester MS (+VE) m/z 680 (M+1).
Reaction SMILES: O=[C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[OH-].[Na+].O=P(Cl)(Cl)[Cl:21]>>[Cl:21][C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cc2cccnc2[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)c1cc2cccnc2nc1Cl
Temperature: 0 °C
Yield: 55 %

Procedure:
Ethyl 2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate (405.0 mg, 1.86 mmol) was suspended in POCl3 (4.5 ml) under N2. The mixture was heated to reflux for 1.5 h, and then it was allowed to cool down and carefully poured over an ice-water mixture. The mixture was neutralized with solid NaOH and the product extracted with EtOAc. The combined organic extracts were dried (MgSO4), filtered and concentrated. Purification was done by flash chromatography (CH2Cl2/MeOH 97:3→95:5) to give 242.6 mg (55%) of the title compound.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:9][CH2:8][S:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[C:4]1=[O:14].C(N(CC)CC)C.[CH:22]1([N:28]=[C:29]=[O:30])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>O1CCCC1>[O:14]=[C:4]1[CH:3]([CH2:2][O:1][C:29](=[O:30])[NH:28][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH2:9][CH2:8][S:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]1=2
Reactant: O=C1c2ccccc2SCCC1CO
Reactant: O=C=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)OCC1CCSc2ccccc2C1=O
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a solution of 4-hydroxymethyl-3,4-dihydro-2H-benzo[b]thiepin-5-one (283 mg, 1.36 mmol) in 17 ml of tetrahydrofuran were added, at room temperature, triethylamine (0.21 ml, 1.5 mmol) and cyclohexyl isocyanate (682 μl, 5.56 mmol). The mixture was stirred at 80° C. for 24 hours, concentrated and purified by column chromatography on silica gel (eluent: 1:2 tert-butyl methyl ether/cyclohexane). The product was obtained in a yield of 190 mg (42%).