Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][N:8]=[C:7]1[NH:11][C:12](=[O:15])[O:13][CH3:14].[CH2:16]1[O:26][C:19]2([CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]2)[O:18][CH2:17]1.O>C1COCC1.CCOC(C)=O>[OH:25][C:22]1([C:10]2[S:6][C:7]([NH:11][C:12](=[O:15])[O:13][CH3:14])=[N:8][CH:9]=2)[CH2:23][CH2:24][C:19]2([O:18][CH2:17][CH2:16][O:26]2)[CH2:20][CH2:21]1
Reactant: COC(=O)Nc1nccs1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)Nc1ncc(C2(O)CCC3(CC2)OCCO3)s1
Temperature: 25 °C
Yield: 35.6 %

Procedure:
A solution of n-butyllithium (10.0 mL of 1.6 M solution in hexane, 15.93 mmol) was added to methyl 1,3-thiazol-2-ylcarbamate (1.05 g, 6.64 mmol) in THF (10 mL) at −78° C. with stirring under N2. After being stirred at −78° C. for 1 h, a solution of 1,4-cyclohexanedione mono-ethylene ketal (1.84 g, 11.75 mmol) in THF (10 mL) was added to the lithiated compound solution via syringe at −78° C. The reaction mixture was allowed to warm to room temperature slowly and stirred overnight. water and EtOAc were added. The aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with saturated NaCl, dried (MgSO4), concentrated and flash chromatographed (50% EtOAc/hexane t0 75% EtOAc/hexane) to give 0.744 g of the title compound in 51% yield. MS (EI) calcd: (M+H)+=315.1; found: 315.0.
Reaction SMILES: [N:1]1([C:7]2[C:12]([NH2:13])=[CH:11][CH:10]=[CH:9][C:8]=2[NH2:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][OH:21]>CN(C)C=O>[NH2:14][C:8]1[C:7]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)=[C:12]([NH:13][CH2:18][CH2:19][CH2:20][OH:21])[CH:11]=[CH:10][CH:9]=1
Reactant: OCCCBr
Reactant: Nc1cccc(N)c1N1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1cccc(NCCCO)c1N1CCCCC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 5.6 %

Procedure:
To a solution of 2-piperidin-1-yl-benzene-1,3-diamine (300 mg, 1.57 mmol) in N,N-dimethylformamide (4 mL) was added sodium hydride (60% suspension in mineral oil, 63 mg, 1.57 mmol) followed by 3-bromo-1-propanol (0.14 mL, 1.57 mmol) and the reaction mixture was stirred at 60° C. overnight. The resulting mixture was then extracted with ethyl acetate (150 mL) and the organic layer was washed twice with water (80 mL) and once with brine (80 mL), dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The crude residue was purified by flash chromatography (hexane/EtOAc, 60/40) to give 22 mg of 3-(3-amino-2-piperidin-1-yl-phenylamino)-propan-1-ol.
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:4](=[O:12])[O:3]1.Cl.[Na+].[Cl-]>C1COCC1>[CH3:11][O:10][C:8]([CH2:7][C@@H:5]([OH:6])[C:4]([OH:12])=[O:3])=[O:9]
Reactant: COC(=O)C[C@H]1OC(C)(C)OC1=O
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C[C@@H](O)C(=O)O

Procedure:
Methyl 2-((R)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)acetate (17.1 g, 90.9 mmol) was stirred in a 1:1 mixture of THF:1 M HCl (200 mL) for 1 h at room temperature. After addition of NaCl to nearly saturate the aqueous layer, the mixture was extracted with EtOAc, and the extracts were dried over Na2SO4 and concentrated to obtain (R)-3-(methoxycarbonyl)-2-hydroxypropanoic acid as an oil. 1H NMR (400 MHz, CDCl3) δ 4.58-4.55 (m, 1H), 3.75 (s, 3H), 2.98-2.84 (m, 2H).
Reaction SMILES: Cl.[CH2:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][N:3]1[CH2:12][C:13]([OH:15])=O.[NH2:16][C@@H:17]([CH2:35][O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)=[O:19]>>[CH2:37]([O:36][CH2:35][C@H:17]([NH:16][C:13](=[O:15])[CH2:12][N:3]1[CH2:4][CH2:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:2]1)[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)=[CH:23][CH:22]=1)=[O:19])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: O=C(O)CN1CCc2ccccc2C1
Agent: Cl
Product: O=C(CN1CCc2ccccc2C1)N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 35.2 %

Procedure:
Proceeding as in Example 1, but substituting 2-(3,4-dihydroisoquinolin-2(1H)-yl)acetic acid hydrochloride and (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 221, (S)-3-(benzyloxy)-2-(2-(3,4-dihydroisoquinolin-2(1H)-yl)acetamido)-N-(4-(4-fluorophenoxy)phenyl)propanamide (15.6 mg, 35.2%); Major isomer: 1H-NMR (400 MHz, DMSO-D6): σ 10.20 (s, 1H), 8.03 (d, 1H), 7.60 (d, 2H), 7.22-7.26 (m, 5H), 7.19-7.21 (m, 2H), 7.12-7.15 (m, 3H), 6.98-7.04 (m, 5H), 4.73 (m, 1H), 4.50 (s, 2H), 3.71-3.79 (m, 2H), 3.70 (s, 2H), 3.18 (s, 2H), 2.83-2.86 (m, 2H), 2.71-2.81 (m, 2H). MS (EI) for C33H32FN3O4: 554.6 (MH+).
Reaction SMILES: O1CCCC1.[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21](Cl)=[N:22][OH:23])=[CH:16][N:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:25]([C:27]1[CH:28]=[CH:29][C:30]([NH2:33])=[N:31][CH:32]=1)#[CH:26].C(N(CC)CC)C>O>[CH2:6]([O:13][C:14]1[N:15]=[CH:16][C:17]([CH2:20][C:21]2[CH:26]=[C:25]([C:27]3[CH:28]=[CH:29][C:30]([NH2:33])=[N:31][CH:32]=3)[O:23][N:22]=2)=[CH:18][CH:19]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: ON=C(Cl)Cc1ccc(OCc2ccccc2)nc1
Reactant: C#Cc1ccc(N)nc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ccc(-c2cc(Cc3ccc(OCc4ccccc4)nc3)no2)cn1
Temperature: 60 °C
Reaction time: 3 h
Yield: 12.9 %

Procedure:
To a tetrahydrofuran (7.00 mL) solution of (2-benzyloxy-pyridin-5-yl)acetohydroximoyl chloride (191 mg, 0.690 mmol) described in Manufacturing Example 12-1-5 and 5-ethynyl-pyridin-2-ylamine (40.0 mg, 0.339 mmol) described in Manufacturing Example 28-1-3 was added triethylamine (142 μL, 1.02 mmol) under nitrogen atmosphere at room temperature, which was stirred for 3 hours at 60° C. Water was added to the reaction mixture at room temperature, which was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (ethyl acetate:heptane=1:1→2:1) to obtain the title compound (15.7 mg, 12.9%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:10]=[C:6]2[CH:5]=[C:4]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])[N:3]=1.FC(F)(F)C(O)=O.[NH2:33][CH2:34][CH2:35][NH:36][C:37]1[CH:44]=[CH:43][C:40]([C:41]#[N:42])=[CH:39][N:38]=1.CCN(C(C)C)C(C)C>CS(C)=O>[Cl:25][C:19]1[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=1[C:4]1[N:3]=[C:2]([NH:33][CH2:34][CH2:35][NH:36][C:37]2[N:38]=[CH:39][C:40]([C:41]#[N:42])=[CH:43][CH:44]=2)[N:7]2[N:8]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:10]=[C:6]2[CH:5]=1
Reactant: Clc1ccc(-c2cc3nc(CN4CCOCC4)nn3c(Cl)n2)c(Cl)c1
Reactant: N#Cc1ccc(NCCN)nc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(NCCNc2nc(-c3ccc(Cl)cc3Cl)cc3nc(CN4CCOCC4)nn23)nc1

Procedure:
100 mg (0.25 mmol) of 5-chloro-7-(2,4-dichlorophenyl)-2-(morpholin-4-ylmethyl)[1,2,4]-triazolo[1,5-c]pyrimidine (Example 150A) and 60 mg (0.30 mmol) of 6-[(2-aminoethyl)amino]pyridine-3-carbonitrile (Example 13A) are introduced into DMSO (4 ml), 0.26 ml (1.5 mmol) of DIEA is added, and the reaction solution is irradiated in a microwave reactor at 140° C. for 45 min. The reaction mixture is purified by preparative HPLC. 62 mg (46% of theory) of the product are obtained as a solid.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([O:16]C)[CH:5]=1)([CH3:3])[CH3:2]>Br.C(O)(=O)C.O>[OH:16][C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:9]=[CH:8][C:7]=1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COc1cc(C(C)C)ccc1-c1ccccc1
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: CC(C)c1ccc(-c2ccccc2)c(O)c1

Procedure:
A mixture of 4-isopropyl-2-methoxybiphenyl (3.8g from Example 5) in aqueous hydrobromic acid (150ml; 48%) and acetic acid (glacial, 50ml) was stirred under reflux for 7 hours. The mixture was cooled, diluted with water and extracted with ether. The extract was washed with water, dried, evaporated and distilled to give 2-hydroxy-4-isopropylbiphenyl, b.p. 112°-113°/0.2 mm.
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][C@H:7]1[CH2:18][CH2:17][C:16]2[S:15][C:14]3[N:13]=[CH:12][N:11]=[C:10]([O:19][CH:20]4[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]4)[C:9]=3[C:8]1=2)(=[O:4])=[O:3].[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][C:28]1=[O:33].C(O)(=O)C.[Na]BCC(O)=O.C(OOC(=O)C)(=O)C>CO>[CH3:1][S:2]([O:5][CH2:6][C@H:7]1[CH2:18][CH2:17][C:16]2[S:15][C:14]3[N:13]=[CH:12][N:11]=[C:10]([O:19][CH:20]4[CH2:25][CH2:24][CH:23]([N:30]5[CH2:31][CH2:32][NH:27][C:28](=[O:33])[CH2:29]5)[CH2:22][CH2:21]4)[C:9]=3[C:8]1=2)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)OC[C@H]1CCc2sc3ncnc(OC4CCC(=O)CC4)c3c21
Reactant: O=C1CNCCN1
Agent: CC(=O)OOC(C)=O
Agent: O=C(O)CB[Na]
Solvent: CO
Solvent: CC(=O)O
Product: CS(=O)(=O)OC[C@H]1CCc2sc3ncnc(OC4CCC(N5CCNC(=O)C5)CC4)c3c21
Reaction time: 1 h
Yield: 74.3 %

Procedure:
To a solution of [(3S)-12-[(4-oxocyclohexyl)oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]methyl methanesulfonate (500 mg, 1.26 mmol, 1.00 equiv) in methanol (10 mL) was added piperazin-2-one (126 mg, 1.26 mmol, 1.00 equiv) and acetic acid (1 mL). The solution was stirred for 1 h and then acetyl ethaneperoxoate sodioboranyl acetate (534 mg, 2.52 mmol, 2.00 equiv) was added. Stirring was continued for 2 h at 0° C. The mixture was then quenched with saturated aqueous sodium bicarbonate, extracted with DCM (60 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The desired [(3S)-12-[[4-(3-oxopiperazin-1-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-3-yl]methyl methanesulfonate (450 mg, 74%) was obtained as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[Cl:9]N1C(=O)CCC1=O.O>C(#N)C.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(O)(=O)C>[Cl:9][CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: Cc1ccnc(Cl)c1
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CC(=O)O
Solvent: CC#N
Solvent: O
Product: ClCc1ccnc(Cl)c1
Temperature: 25 °C
Yield: 100 %

Procedure:
A mixture of 2-chloro-4-methyl-pyridine (7.28 g, 57.1 mmol), N-Chlorosuccinimide (11.4 g, 85.3 mmol), benzoyl peroxide (276 mg, 1.13 mmol), and acetic acid (200 μL, 3.5 mmol) in acetonitrile (30 mL) was heated at reflux for 2.5 h. The mixture was allowed to cool to room temperature, then poured into water (10 mL) and extracted with EtOAc. The organic phase was washed with brine, dried over MgSO4, and concentrated in vacuo at 35° C., yielding the crude product of 4-(chloromethyl)-2-chloropyridine (9.25 g) as an oil. The crude oil was carried on to the hydrolysis step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:13]3[CH2:17][CH2:16][C@@:15]4([C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=5[C:19](=[O:26])[O:18]4)[CH2:14]3)=[O:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.O1CCCC1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[CH3:45][N:46]1[CH:50]=[CH:49][C:48](B(O)O)=[N:47]1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:45][N:46]1[CH:50]=[CH:49][C:48]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3([C:11]([N:13]4[CH2:17][CH2:16][C@@:15]5([C:21]6[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=6[C:19](=[O:26])[O:18]5)[CH2:14]4)=[O:12])[CH2:10][CH2:9]3)=[CH:4][CH:3]=2)=[N:47]1
Reactant: Cn1ccc(B(O)O)n1
Reactant: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(Br)cc4)CC3)C2)c2ccccc21
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: Cn1ccc(-c2ccc(C3(C(=O)N4CC[C@@]5(C4)OC(=O)c4ccccc45)CC3)cc2)n1
Temperature: 120 °C

Procedure:
To a solution of (1R)-1′-{[1-(4-bromophenyl)cyclopropyl]carbonyl}-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one (20 mg, 0.00005 mol, example 238) in tetrahydrofuran (0.2 mL, 0.002 mol) were added tris(dibenzylideneacetone)dipalladium(0) (0.2 mg, 0.0000002 mol), tri-tert-butylphosphine (0.12 mg, 5.8×10−7 mol), (1-methyl-1H-pyrazol-3-yl)boronic acid (6.8 mg, 0.0000534 mol). The mixture was heated at 120° C. under microwave for 30 minutes. The reaction mixture then was filtered and the filtrate was diluted with methanol and purified with prep-HPLC to afford the desired product. LC/MS: 414.2 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[N:10]O)[CH3:9])[CH:5]=[CH:6][CH:7]=1.Cl.OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O>CO.[Pd]>[NH2:10][CH:8]([C:4]1[CH:3]=[C:2]([OH:1])[CH:7]=[CH:6][CH:5]=1)[CH3:9]
Reactant: CC(=NO)c1cccc(O)c1
Agent: [Pd]
Agent: Cl
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Solvent: CO
Product: CC(N)c1cccc(O)c1
Yield: 92.3 %

Procedure:
1-(3-Hydroxyphenyl)ethanone oxime (1.2 g; 7.9 mmol) was dissolved in methanol (20 mL), degassed with nitrogen. 10% Palladium on carbon (0.1 g) and conc. HCl (100 uL, 3 mmol) were added. The reaction was shaken under Parr shaker at 50 Psi for 5 h. The reaction was filtered and concentrated under reduced pressure to give crude 3-(1-aminoethyl)phenol (1.0 g, 100%) as a yellow oil. Analytical LCMS (M+H)+: m/z=138.0.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:65]=[CH:64][C:51]([CH2:52][NH:53][CH2:54][CH2:55][CH:56]([C:58]2[O:59][C:60]([CH3:63])=[CH:61][CH:62]=2)[CH3:57])=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:65]=[CH:64][C:51]([CH2:52][N:53]([CH2:54][CH2:55][CH:56]([C:58]2[O:59][C:60]([CH3:63])=[CH:61][CH:62]=2)[CH3:57])[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:46])([CH3:45])[CH3:47]
Reactant: Cc1ccc(C(C)CCNCc2ccc(C(C)(C)C)cc2)o1
Reactant: O=C(O)c1cccc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(C)CCN(Cc2ccc(C(C)(C)C)cc2)C(=O)c2cccc3cc[nH]c23)o1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 65.5 %

Procedure:
To a solution of 48 mg (0.3 mmol) of 1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 4 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 90 mg (0.3 mmol) of [rac]-(4-tert-butyl-benzyl)-[3-(5-methyl-furan-2-yl)-butyl]-amine in 1 ml DMF were added. After stirring for 2 h at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The orange residue was purified by column chromatography (8 g silica gel; heptane/EtOAc 6:1) to give 87 mg (63%) of a colorless viscous oil. MS (ISP) 443.5 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]=[O:9].[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[CH:8]=[O:9])=[CH:13][CH:12]=1
Reactant: O=Cc1cnccc1Cl
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: O=Cc1cnccc1-c1ccc(F)cc1
Temperature: 25 °C
Yield: 59 %

Procedure:
A mixture of 4-chloropyridine-3-carbaldehyde (33.44 g), (4-fluorophenyl)boronic acid (39.1 g), tetrakis(triphenylphosphine)palladium (6.73 g), 2 M aqueous potassium carbonate solution (314.4 mL) and 1,2-dimethoxyethane (500 mL) was heated under reflux for 6 hr. The reaction mixture was allowed to be cooled to room temperature, water was added thereof, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (28.04 g).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[N:9]=[C:10]([NH:13]C(=O)OC(C)(C)C)[S:11][CH:12]=2)[CH2:3][CH2:2]1.[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24]>C(Cl)Cl>[F:21][C:22]([F:27])([F:26])[C:23]([OH:25])=[O:24].[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[N:9]=[C:10]([NH2:13])[S:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)Nc1nc(CN2CCOCC2)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nc(CN2CCOCC2)cs1
Yield: 100 %

Procedure:
Tert-butyl 4-(morpholinomethyl)thiazol-2-ylcarbamate 90 (1.88 g, 6.28 mmol) was treated with 20 mL of 25% trifluoroacetic acid in CH2Cl2 for 18 h at room temperature. After all the solvent had been removed by concentrating and drying under high vacuum, the resulting residue was treated with a mixture of pentane/EtOAc to afford 91 (1.96 g, 100% yield) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:30]([OH:32])=O)[CH:28]=4)[CH:23]=[CH:22]3)[CH2:17][CH2:16]2)=[C:11]2[C:6]([C:7](=[O:35])[CH2:8][C:9]([CH3:34])([CH3:33])[O:10]2)=[CH:5][CH:4]=1.[C:36](N1C=CN=C1)([N:38]1C=CN=C1)=O.CN.C(OCC)(=O)C>C(O)C.O>[CH3:1][O:2][C:3]1[C:12]([CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][CH:18]([N:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:30]([NH:38][CH3:36])=[O:32])[CH:28]=4)[CH:23]=[CH:22]3)[CH2:17][CH2:16]2)=[C:11]2[C:6]([C:7](=[O:35])[CH2:8][C:9]([CH3:33])([CH3:34])[O:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1CCN1CCC(n3ccc4ccc(C(=O)O)cc43)CC1)OC(C)(C)CC2=O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc2ccn(C3CCN(CCc4c(OC)ccc5c4OC(C)(C)CC5=O)CC3)c2c1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
1.0 g of 1-{1-[2-(7-methoxy-2,2-dimethyl-4-oxochroman-8-yl)ethyl]piperidin-4-yl}-1H-indole-6-carboxylic acid was dissolved in 25 mL of ethanol, added with 851 mg of 1,1′-cabonyldiimidazole and the reaction mixture was stirred at 40° C. for 2 hours. The reaction mixture was cooled with an ice-water bath, added 1.81 mL of 40% methylamine aqueous solution thereto and stirred for 50 minutes. The reaction mixture was added with 40 mL of ethyl acetate and 20 mL of water and the organic layer was separated. The organic layer was washed with 20 mL of 10% sodium chloride solution and added with 8.5 mL of 1 N hydrochloric acid to adjust the pH to 7. The aqueous layer was discarded and the organic layer was washed with 10 mL of water. The organic layer was concentrated in vacuo, added with 3 mL of 1-propanol and concentrated again and the title compound was obtained.
Reaction SMILES: ClC1C=CC([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=CC=1C(F)(F)F.[CH3:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=1)=O.[BH4-].[Na+]>CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C.CO>[CH3:30][O:29][C:23]1[CH:22]=[C:21]([CH:19]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH3:18])[CH:26]=[CH:25][C:24]=1[O:27][CH3:28]
Reactant: COc1ccc(C(C)=O)cc1OC
Reactant: FC(F)(F)c1cc(N2CCNCC2)ccc1Cl
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C(C)N2CCNCC2)cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A quantity of 0.17 g (0.6 mmole, 1 eq) of 1-(4-chloro-3-trifluoromethyl-phenyl)-piperazine and 0.1 g (0.6 mmole, 1 eq) of 3,4-dimethoxyacetophenone and 2 mL of Ti(OiPr)4 are warmed to 70° C. for 2 hours. The reaction solution is cooled to room temperature and 20 mL of anhydrous methanol is added followed by 1.0 g of NaBH4 and the resulting solution is stirred at room temperature for 2 hours. The reaction is quenched by the addition of 1 N NaOH and extracted with CH2Cl2. The CH2Cl2 extracts are dried over anhydrous MgSO4 and concentrated in vacuo. The residue is chromatographed on SiO2 with ethyl to afford 1-[4-chloro-3-trifluoromethyl)phenyl]-4-[1-(3,4-dimethoxyphenyl)ethyl]piperazine (compound 2). Analysis 1H NMR (400 MHz, CDCl3): 7.31 (1H, d), 7.19 (1H, m), 6.90 (4H, m), 3.89 (6H, d), 3.38 (1H, m), 3.20 (4H, m), 2.61 (4H, m). MS (LC-MS): Calculated for C21H24ClF3N2O2 428.88, found 429.30 (M+). III. 3-{1-4-(4-Bromo-3-methoxy-phenyl)-piperazin-1-yl]-ethyl}-quinoline via Scheme C
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Br:9][CH2:10][CH2:11][CH2:12][CH2:13]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][CH2:12][CH2:11][CH2:10][Br:9])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: BrCCCCOc1ccc(Br)cc1

Procedure:
A solution of 4-bromophenol (3 g) and 1,4-dibromobutane (6.2 ml) in N,N-dimethylformamide (30 ml) was treated with potassium carbonate (2.89 g) at room temperature for 27 hours. The mixture was diluted with ethyl acetate and washed with brine. The organic layer was dried over magnesium sulfate, filtered, and evaporated. The residue was purified by silica gel chromatography (25:1 hexane-ethyl acetate elution) to give 1-bromo-4-(4-bromobutoxy)benzene (3.09 g).
Reaction SMILES: CN(C)CCCN=C=NCC.O.[C:13]([NH:20][C@H:21]([C:26]([OH:28])=O)[CH2:22][CH:23]([CH3:25])[CH3:24])([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].OC1C2N=NNC=2C=CC=1.[CH2:39]([O:46][C:47]([N:49]1[CH2:55][CH:54]([OH:56])[CH:53]([NH2:57])[CH2:52][CH2:51][CH:50]1[CH3:58])=[O:48])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>CN(C=O)C.CCOC(C)=O>[CH2:39]([O:46][C:47]([N:49]1[CH2:55][C@H:54]([OH:56])[C@@H:53]([NH:57][C:26](=[O:28])[C@@H:21]([NH:20][C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:22][CH:23]([CH3:24])[CH3:25])[CH2:52][CH2:51][C@H:50]1[CH3:58])=[O:48])[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC1CCC(N)C(O)CN1C(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H]1CC[C@@H](C)N(C(=O)OCc2ccccc2)C[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.8 %

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide (0.164 g, 0.22 mmol) was added to a solution of Boc-Leucine-hydrate (0.190 g, 0.76 mmol), diisopropyletbylamine (0.164 g, 0.22 ml, 1.27 mmol), hydroxybenztriazole (0.114 g, 0.83 mmol), and racemic (2R,5S,6S)-5-Amino-6-hydroxy-2-methyl-azepane-1-carboxylic acid benzyl ester (0.27 g, 0.57 mmol) in DMF (3.2 ml). The reaction was stirred overnight at RT, then was diluted with EtOAc (100 ml), washed with H2O (3×50 ml), brine (50 ml), dried with magnesium sulfate, filtered, concentrated in vacuo by rotary evaporation, and chromatographed (silica gel, 50% EtOAc/hexanes) to yield the title compound (0.218 g, 72%): 1H NMR: 7.40–7.29 (m, 5H), 6.75 (1H, bd), 5.12 (2H, AB), 5.0 (1H, bs), 4.15–3.72 (m, 2H), 3.06 (1H, d), 1.60–1.30 (m, 2H), 1.60–1.30 (m, 5H), 1.12 (3H, d), 0.97–0.87(6H, dd); Electrospray mass spec: M+H+=492.0.