Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][N:7]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:8](=[O:20])[N:9]2[C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])=[C:4]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:36])[CH:3]=1.[Cl:37][CH2:38][CH2:39][CH2:40][S:41](Cl)(=[O:43])=[O:42]>>[Cl:37][CH2:38][CH2:39][CH2:40][S:41]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][N:7]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)[C:8](=[O:20])[N:9]2[C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:19])=[C:4]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[Cl:36])[CH:3]=1)(=[O:43])=[O:42]
Reactant: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(N)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Reactant: O=S(=O)(Cl)CCCCl
Product: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(NS(=O)(=O)CCCCl)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1

Procedure:
The 3-chloro-N-[5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)-2-oxo-1,2,3,4-tetrahydroquinazolin-7-yl]propane-1-sulfonamide was prepared from 7-amino-5-(2chlorophenyl)-1-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)-3,4-dihydroquinazolin-2(1H)-one (COMPOUND CCC4, STEP A) and 3-chloropropane-1-sulfonyl chloride by a procedure analogous to that described in COMPOUND CCC5, STEP A: Mass spectrum (ESI) 678.1 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([N:9]([C@H:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([C:23](=[O:32])[C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[C@@H:15]([CH3:33])[CH2:14]2)[C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1.[C:34](O)(=[O:37])[CH2:35][OH:36].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>>[C:35]([NH:1][CH2:2][C:3]1[CH:4]=[C:5]([N:9]([C@H:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]([C:23](=[O:32])[C:24]3[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=3)[C@@H:15]([CH3:33])[CH2:14]2)[C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1)(=[O:36])[CH2:34][OH:37]
Reactant: COc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3cccc(CN)c3)C[C@@H]2C)cc1
Reactant: O=C(O)CO
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Product: COc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3cccc(CNC(=O)CO)c3)C[C@@H]2C)cc1

Procedure:
N-[3-(aminomethyl)phenyl]-N-[(2S,4R)-1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]acetamide was then further coupled with glycolic acid using coupling reagent such as EDCI with HOBt to afford N-{3-[(glycoloylamino)methyl]phenyl}-N-[(2S,4R)-1-(4-methoxybenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]acetamide
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7](S(C)=O)=[N:6]2.[CH2:24]1[N:29]([C:30]2[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=2)[CH2:28][CH2:27][O:26][CH2:25]1.CN1CCCC1=O>>[Br:1][C:2]1[CH:3]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([NH:36][C:33]1[CH:32]=[CH:31][C:30]([N:29]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)=[CH:35][CH:34]=1)=[N:6]2
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: CS(=O)c1ncc2c(Br)cc(-c3ccc(S(C)(=O)=O)cc3)n2n1
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)c1ccc(-c2cc(Br)c3cnc(Nc4ccc(N5CCOCC5)cc4)nn23)cc1
Temperature: 150 °C
Yield: 66.8 %

Procedure:
Into a 30 mL vial, [A] 5-Bromo-2-methanesulfinyl-7-(4-methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (0.14 g, 0.00034 mol), 4-(4-morpholino)aniline (0.181 g, 0.00101 mol), and N-Methylpyrrolidinone (0.22 mL, 0.0023 mol) were added. The mixture was heated at 150° C. for 3 hours. The mixture was purified via ISCO column chromatography with DCM and MeOH as eluant (0 to 15% methanol). The collected fractions afforded [5-Bromo-7-(4-methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(4-morpholin-4-yl-phenyl)-amine as a yellow solid (120 mg, 67%). MP 242-244° C. LCMS (E/I+) 451.23 (M+H). NMR 1H (DSMO-d6)-9.43 (s, 1H), 8.86 (s, 1H), 8.16 (d, 2H, J=7.76 Hz), 7.62 (d, 2H, J=8.93 Hz), 7.54 (t, 1H, J=7.77 Hz), 7.41 (t, 1H, J=7.16 Hz), 7.34 (s, 1H), 6.93 (d, 2H, J=8.97 Hz), 3.74 (t, 4H, J=4.29 Hz), 3.06 (t, 4H, J=4.64 Hz).
Reaction SMILES: [CH2:1]([C@H:4]1[C@:21]2(O)[C@:16]([CH3:24])([CH2:17][CH2:18][C:19](=[O:23])[CH2:20]2)[C@@H:15]2[C@H:6]([C@H:7]3[C@@:11]([CH2:13][CH2:14]2)([CH3:12])[C:10](=[O:25])[CH2:9][CH2:8]3)[CH2:5]1)[C:2]#[CH:3].S(Cl)(Cl)=O>N1C=CC=CC=1>[CH2:1]([C@H:4]1[C:21]2[C@:16]([CH3:24])([CH2:17][CH2:18][C:19](=[O:23])[CH:20]=2)[C@@H:15]2[C@H:6]([C@H:7]3[C@@:11]([CH2:13][CH2:14]2)([CH3:12])[C:10](=[O:25])[CH2:9][CH2:8]3)[CH2:5]1)[C:2]#[CH:3]
Reactant: C#CC[C@@H]1C[C@H]2[C@@H]3CCC(=O)[C@@]3(C)CC[C@@H]2[C@@]2(C)CCC(=O)C[C@]12O
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: C#CC[C@@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)C=C12
Temperature: 0 °C
Reaction time: 0.07 h

Procedure:
6β-Propargyl-5α-hydroxyandrostane-3,17-dione (10) (0.3 mmol) was dissolved in dry pyridine (10 ml), cooled in an ice-bath and thionyl chloride was added. After stirring for 3-5 minutes, the reaction mixture was poured over ice-water, extracted with ethyl acetate, washed (water), dried, and evaporated in vacuo. The residue was subjected to column chromatography (hexane/ethyl acetate). Recrystallization from acetone/hexane gave the title compound (60% of the analytical product); m.p. 159°-160° C.; IR (KBr) 3245, 2120, 1734, and 1662 (C=O) cm-1 ; 1H-NMR (CDCl3) δ 0.93 (s, 3H, 18-CH3), 1.26 (s, 3H, 19-CH3), 2.6-2.8 (m, 1H), 5.84 (s, 1H, 4-H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([CH2:8][CH2:9][C:10]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](O)=[O:13])[CH:7]=1.S(Cl)([Cl:24])=O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([CH2:8][CH2:9][C:10]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([Cl:24])=[O:13])[CH:7]=1
Reactant: COc1ccc(Br)cc1CCc1c(F)cccc1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Product: COc1ccc(Br)cc1CCc1c(F)cccc1C(=O)Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-[2-(5-bromo-2-methoxyphenyl)-ethyl]-3-fluorobenzoic acid (0.81 g, 2.3 mol, 1 equiv) in THF (13 mL) was added thionyl chloride (0.84 mL, 11.5 mmol, 5 equiv). The solution was heated to reflux. After one hour, the solution was cooled to room temperature and concentrated to give 2-[2-(5-bromo-2-methoxy-phenyl)-ethyl]-3-fluoro-benzoyl chloride as an oil, which was used without further purification.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.[BrH:10]>>[Br:10][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: OCCc1ccccn1
Reactant: Br
Product: BrCCc1ccccn1
Yield: 100 %

Procedure:
To 2-(hydroxyethyl)pyridine (10 mL, 88.8 mmol) was added HBr (conc) (90 mL). The mixture was heated to reflux overnight. The next day, excess HBr was removed and the resulting solid recrystallized from iPrOH to provide 2-(bromoethyl)pyridine, yield=100%. 1H NMR (300 MHz, DMSO) δ3.0 (t, 2H), 3.9 (t, 2H), 7.79 (t, 1H), 7.8 (d, 1H), 8.4 (t, 1H), 8.7 (d, 1H).
Reaction SMILES: O1CCCCC1[N:7]1[CH:11]=[N:10][C:9]([C:12]2[N:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[N:27]([CH:28]5[CH2:33][CH2:32][O:31][CH2:30][CH2:29]5)[CH2:26][C:25](=[O:34])[NH:24][C:21]4=[N:22][CH:23]=3)=[CH:14][CH:13]=2)=[N:8]1.O1CCC(N2C3C(=NC=C([Sn](C)(C)C)N=3)NC(=O)C2)CC1.BrC1C=CC(C2N=CN(C3CCCCO3)N=2)=NC=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>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].CN(C)C=O>[NH:7]1[CH:11]=[N:10][C:9]([C:12]2[N:17]=[CH:16][C:15]([C:18]3[N:19]=[C:20]4[N:27]([CH:28]5[CH2:29][CH2:30][O:31][CH2:32][CH2:33]5)[CH2:26][C:25](=[O:34])[NH:24][C:21]4=[N:22][CH:23]=3)=[CH:14][CH:13]=2)=[N:8]1
Reactant: O=C1CN(C2CCOCC2)c2nc(-c3ccc(-c4ncn(C5CCCCO5)n4)nc3)cnc2N1
Agent: [Pd]
Agent: Brc1ccc(-c2ncn(C3CCCCO3)n2)nc1
Agent: C[Sn](C)(C)c1cnc2c(n1)N(C1CCOCC1)CC(=O)N2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CN(C2CCOCC2)c2nc(-c3ccc(-c4nc[nH]n4)nc3)cnc2N1
Temperature: 95 °C
Yield: 39 %

Procedure:
6-(6-(1-(Tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)pyridin-3-yl)-4-(tetrahydro-2H-pyran-4-yl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one. A mixture of 4-(tetrahydro-2H-pyran-4-yl)-6-(trimethylstannyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (1 equiv), 5-bromo-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)pyridine (1.2 equiv), tris(dibenzylideneacetone)dipalladium (0.1 equiv), tri-o-tolylphosphine (0.2 equiv), triethylamine (3 equiv) and N,N-dimethylformamide was heated at 95° C. for 3 h under nitrogen. Concentration and chromatography purification give the desired product in 39% yield. MS (ESI) m/z 463.1 [M+1]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9].[ClH:37].C(O)C.C(=O)([O-])[O-].[NH4+:45].[NH4+]>ClCCl.CO>[ClH:37].[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:8]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([CH3:27])[C:15]([CH2:17][NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25](=[NH:45])[NH2:26])=[CH:21][CH:20]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9]
Reactant: [NH4+]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C)c1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCO
Solvent: CO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Yield: 71 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide and ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 71% of theory, C27H29N7O3 (499.6); Rf value: 0.28 (silica gel; dichloromethane/methanol=5:1); EKA mass spectrum: (M+H)+=500; (M+H+Na)++=261.8; (M+2H)++=250.8.
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.Br[CH2:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[C:15]#[N:16].C([O-])([O-])=O.[Cs+].[Cs+].C1OCCOCCOCCOCCOCCOC1>CC(C)=O.CCCCCC.C(OCC)(=O)C>[O:10]=[C:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][N:2]1[CH2:12][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[C:15]#[N:16]
Reactant: N#Cc1ccccc1CBr
Reactant: O=C1NCc2ccccc21
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: N#Cc1ccccc1CN1Cc2ccccc2C1=O
Temperature: 70 °C
Reaction time: 16 h
Yield: 44.3 %

Procedure:
A mixture of 2,3-dihydro-isoindol-1-one (0.066 g, 0.5 mmol,), 2-bromomethyl-benzonitrile (0.117 g, 0.6 mmol), Cs2CO3 (0.408 g, 1.25 mmol), and 18-crown-6 (0.013 g, 0.05 mmol) in acetone (3 mL) was stirred at 70° C. for 16 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-(1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-benzonitrile (0.055 g, 44%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.22 (s, 2H), 5.08 (s, 2H), 7.28-7.70 (m, 7H), 7.92 (d, 1H).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:15]3[CH:14]=[C:13]([C:16]4[C:21]([Cl:22])=[CH:20][N:19]=[C:18](Cl)[N:17]=4)[S:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[CH2:24]([O:31][C:32]([N:34]1[CH2:38][CH2:37][CH:36]([CH2:39][CH2:40][NH2:41])[CH2:35]1)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C>O1CCOCC1>[CH2:24]([O:31][C:32]([N:34]1[CH2:38][CH2:37][CH:36]([CH2:39][CH2:40][NH:41][C:18]2[N:17]=[C:16]([C:13]3[S:12][C:11]4[CH:10]=[CH:9][CH:8]=[C:7]([C:5](=[O:6])[NH:4][CH:1]5[CH2:3][CH2:2]5)[C:15]=4[CH:14]=3)[C:21]([Cl:22])=[CH:20][N:19]=2)[CH2:35]1)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCCC1CCN(C(=O)OCc2ccccc2)C1
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(Cl)ncc3Cl)cc12
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C(NC1CC1)c1cccc2sc(-c3nc(NCCC4CCN(C(=O)OCc5ccccc5)C4)ncc3Cl)cc12
Temperature: 90 °C
Reaction time: 8 h
Yield: 57.9 %

Procedure:
A mixture of 2-(2,5-dichloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid cyclopropylamide (0.10 g, 0.27 mmol), racemic 3-(2-aminoethyl)-pyrrolidine-1-carboxylic acid benzyl ester (0.14 g, 0.55 mmol) and triethylamine (0.11 mL, 0.81 mmol) in 1,4-dioxane (1.5 mL) in a sealed reaction vessel is stirred at 90° C. overnight. The reaction is cooled to room temperature and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution, the organic layer is separated, dried over Na2SO4, filtered and concentrated. The crude solid is washed with ethyl acetate, dried under vacuum to provide 3-{2-[5-chloro-4-(4-cyclopropylcarbamoyl-benzo[b]thiophen-2-yl)-pyrimidin-2-ylamino]-ethyl}-pyrrolidine-1-carboxylic acid benzyl ester as a white solid (90 mg, 56% yield). A stirred solution of this intermediate (16 mg, 0.028 mmol) in TFA (0.5 mL) and water (0.1 mL) is heated in a sealed tube at 100° C. for 20 minutes. At room temperature the mixture is concentrated and the residue is dissolved in methanol, passed through a SCX column, washed with methanol and 2 M NH3/methanol to give the crude product. It is further passed through a short pad of silica gel to afford the title compound as a solid (11 mg, 90% yield). ES+(m/z) 442 (35Cl) and 444 (37Cl) [M+H].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:4]=1[CH:5]=O.[C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])[CH3:14].[OH-].[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:4]=1[CH:5]=[CH:14][C:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15]
Reactant: CC(=O)c1ccccc1
Reactant: COc1cccc(OC)c1C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cccc(OC)c1C=CC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(39) To a solution of 2,6-dimethoxybenzaldehyde (250 mg, 1.50 mmol) and acetophenone (180 mg, 1.50 mmol) in 2.2 ml of methanol was added 1.0 ml of 40% sodium hydroxide in water at 10° C. After stirring overnight at room temperature, a solid precipitated. The precipitate was recrystallized from methanol to afford 350 mg (87.1%) of a white, flaky solid: mp 54.9-55.8° C. (lit. mp 54-55° C., Noyce and Jorgenson, J. Am. Chem. Soc., 1963, 85, 2420-2426). 1H NMR (250 MHz) δ 8.33-8.26 (d, 1 H), 8.05-7.97 (m, 3 H), 7.57-7.49 (m, 3 H), 7.30 (m, 1 H), 6.61-6.57 (d, 2 H), 3.92 (s, 6 H); 13C NMR (62.7 MHz) 192.3, 160.6, 139.2, 136.0, 132.4, 131.7, 128.6, 125.1, 113.1, 105.8, 103.9, 56.0 ppm.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[OH-].[Na+].I[C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([C:22]([OH:24])=[O:23])[CH:14]([C:18]([F:21])([F:20])[F:19])[O:15]2)=[CH:10][CH:9]=1>C1COCC1.O.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>[CH:2]1([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([C:22]([OH:24])=[O:23])[CH:14]([C:18]([F:21])([F:20])[F:19])[O:15]3)=[CH:10][CH:9]=2)[CH2:3][CH2:1]1
Reactant: O=C(O)C1=Cc2ccc(I)cc2OC1C(F)(F)F
Reactant: C#CCBr
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1=Cc2ccc(C3CC3)cc2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
To a suspension of (9-BBN)2 (1.96 g, 8.7 mmol) in 10 mL THF was added propargyl bromide (0.53 g, 4.4 mmol). After heating for 2 h and cooling to room temperature, NaOH (0.52 g, 13 mmol) in 4.3 mL of H2O was added and the reaction was stirred for 1 h. In a separate flask under argon was added the title product of Example 146 Step 1 in 5 mL of THF and Pd(PPh3)4. The reaction from the original flask was transferred to the second flask via cannula. After refluxing for 18 h and cooling to room temperature, 25 mL of H2O was added. The organic solvent was removed from the reaction under vacuum. The aqueous layer was extracted three times with 70 mL EtOAc. The combined organic extractions were washed one time with 50 mL of 1 N HCl and one time with 50 mL of saturated brine. Following drying over MgSO4 and concentrating under vacuum, the product was purified by flash column chromatography and reverse phase chromatography on YMC ODS-AQ in MeOH/H2O to yield desired product (0.40 g, 40%).
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[N:14][O:15][CH:16]=2)=[N:6][CH:5]=1.[NH2:25][CH:26]([CH3:29])[CH2:27][OH:28]>>[F:23][C:20]1[CH:19]=[CH:18][C:17]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:25][C@H:26]([CH3:29])[CH2:27][OH:28])=[O:24])=[CH:5][N:6]=3)=[CH:16][O:15][N:14]=2)=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(OCc2conc2-c2ccc(F)cc2)nc1
Reactant: CC(N)CO
Product: C[C@H](CO)NC(=O)c1ccc(OCc2conc2-c2ccc(F)cc2)nc1
Yield: 41 %

Procedure:
As described for example 325, 6-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (60 mg, 0.18 mmol) was converted, using D-alaminol instead of rac-2-amino-1-propanol, to the title compound (28 mg, 41%) which was obtained as a white solid MS: m/e=372.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8]O)=[C:6]([C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])[CH:5]=[C:4]([Cl:17])[N:3]=1.O=S(Cl)Cl.C([O-])([O-])=O.[K+].[K+].[CH3:28][NH:29][C@@H:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:33][CH2:32][CH2:31]1>C(Cl)Cl.O.CCOC(C)=O.CC#N>[Cl:1][C:2]1[C:7]([CH2:8][N:29]([CH3:28])[CH:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:33][CH2:32][CH2:31]2)=[C:6]([C:10]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:11])[CH:5]=[C:4]([Cl:17])[N:3]=1
Reactant: O=C(c1cc(Cl)nc(Cl)c1CO)N1CCCC1
Reactant: CN[C@H]1CCCc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: CN(Cc1c(C(=O)N2CCCC2)cc(Cl)nc1Cl)C1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of (2,6-dichloro-3-hydroxymethyl-pyridin-4-yl)-pyrrolidin-1-yl-methanone (400 mg, 1.45 mmol) and SOCl2 (1 mL) in CH2Cl2 (10 mL) is stirred at room temperature for 1 hour, and then concentrated. The residue is treated with K2CO3 (1.0 g, 7.2 mmol), CH3CN (10 mL) and (S)-methyl-(1,2,3,4-tetrahydro-naphthalen-1-yl)-amine (250 mg, 1.55 mmol). The resulting mixture is stirred at room temperature overnight. EtOAc (50 mL) and water (40 mL) are added to the residue. The organic layer is separated, washed once with brine, dried (Na2SO4) and concentrated. The residue is chromatographed on silica gel (4:1 hexane:EtOAc) to give the title compound.
Reaction SMILES: [F:1][C:2]([F:49])([F:48])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:35]=[C:34](B4OC(C)(C)C(C)(C)O4)[CH:33]=[CH:32][C:31]=3[O:45][CH3:46])[C@H:14]2[CH3:47])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[C:51]1[CH:60]=[CH:59][C:54]([C:55]([O:57][CH3:58])=[O:56])=[CH:53][C:52]=1[CH3:61].[OH-].[K+]>ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O1CCOCC1>[F:1][C:2]([F:48])([F:49])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:28])([F:27])[F:29])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:35]=[C:34]([C:51]4[CH:60]=[CH:59][C:54]([C:55]([O:57][CH3:58])=[O:56])=[CH:53][C:52]=4[CH3:61])[CH:33]=[CH:32][C:31]=3[O:45][CH3:46])[C@H:14]2[CH3:47])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1-c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reactant: COC(=O)c1ccc(Br)c(C)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2ccc(OC)c(-c3ccc(C(F)(F)F)cc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1

Procedure:
A mixture of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[2′-methoxy-5′-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-4-(trifluoromethyl)biphenyl-2-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (60 mg, 0.085 mmol), methyl 4-bromo-3-methylbenzoate (29 mg, 0.128 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium dichloride dichloromethane adduct (28 mg, 30%), aqueous potassium hydroxide (57 μL, 3M, 0.171 mmol) and 1,4-dioxane (1 mL) was placed in a sealed tube and subjected to microwave irradiation at 140° C. for 15 minutes. The crude reaction was purified by preparative TLC on SiO2 (eluted with 30% EtOAc in hexanes) to afford methyl 2″-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4′-methoxy-2-methyl-4″-(trifluoromethyl)-1,1′:3′,1″-terphenyl-4-carboxylate as a solid foam. LCMS calc.=725.18; found=726.49 (M+1)+. 1H NMR signals are doubled because of atropoisomerism. 1H NMR (CDCl3, 500 MHz) 7.94 (d, J=8.5 Hz, 1H), 7.88-7.83 (m, 2H), 7.71 (s, 0.5H), 7.69 (s, 0.5H), 7.68-7.60 (m, 2H), 7.45-7.39 (m, 2H), 7.38, 7.37 (d, J=2 Hz, 1H), 7.28 (d, J=8 Hz, 0.5H), 7.24 (d, J=8 Hz, 0.5H), 7.14 (d, J=2 Hz, 1H), 7.07 (t, J=8 Hz, 1H), 5.58 (d, J=8.5 Hz, 0.5H), 5.28 (d, J=8 Hz, 0.5H), 4.96 (d, J=10 Hz, 0.5H), 4.93 (d, J=9.5 Hz, 0.5H), 4.16 (d, J=15.5 Hz, 0.5H), 3.96 (d, J=16 Hz, 0.5H), 3.92 (s, 3H), 3.86 (s, 3H), 3.82-3.93 (m, 1H), 2.37 (s, 1.5H), 2.31 (s, 1.5H), 0.54 (d, J=6.5 Hz, 1.5H), 0.42 (d, J=6.5 Hz, 1.5H).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C@@H:9]2[C@H:4]([CH2:5][C@@H:6]([C:16]([OH:18])=[O:17])[N:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)[CH2:3]1.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+]>O1CCCC1>[OH:1][C@H:2]1[CH2:11][CH2:10][C@@H:9]2[C@@H:4]([CH2:5][C@@H:6]([C:16]([OH:18])=[O:17])[N:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)[CH2:3]1
Reactant: COC(=O)N1C[C@@H]2CCC(=O)C[C@H]2C[C@H]1C(=O)O
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)N1C[C@@H]2CC[C@H](O)C[C@@H]2C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.5 %

Procedure:
To a slurry of 17.3 g of (3S, 4aR, 8aR) 6-oxo-2-methoxycarbonyl-1,2,3,4,4a, 5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid (46 mmol) in 240 mL of tetrahydrofuran is added 106 mL if 1.0 M L-Selectride in tetrahydrofuran. The mixture is stirred for 1 hour at room temperature, then quenched with 130 mL of 1.4 M hydrochloric acid. The layers are separated and the aqueous phase extracted with 50 mL of tert-butyl methyl ether. The organic phases are combined and extracted with 75 mL of saturated aqueous sodium carbonate. The aqueous phase is washed twice with 30 mL portions of tert-butyl methyl ether then acidified to pH 1 with 6 M hydrochloric acid. The product is extracted into 75 mL of tert-butyl methyl ether. The organic mixture is dried with sodium sulfate, and concentrated to 8.17 g of yellow solid. The product is crystallized from 20 mL of tert-butyl methyl ether to provide 6.92 g of the title compound (59% yield).
Reaction SMILES: NC1C(C(=O)C)=CC=CN=1.C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C.C([O:31][C:32]1([CH3:46])[O:37][C:36]([C:38]([CH3:41])([CH3:40])[CH3:39])=[N:35][C:34]2[N:42]=[CH:43][CH:44]=[CH:45][C:33]1=2)(=O)C(C)(C)C.Cl>CN(C)C1C=CN=CC=1.O.C1(C)C=CC=CC=1>[C:32]([C:33]1[C:34]([NH:35][C:36](=[O:37])[C:38]([CH3:41])([CH3:40])[CH3:39])=[N:42][CH:43]=[CH:44][CH:45]=1)(=[O:31])[CH3:46]
Reactant: CC(C)(C)C(=O)OC1(C)OC(C(C)(C)C)=Nc2ncccc21
Agent: CC(=O)c1cccnc1N
Agent: CC(C)(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)c1cccnc1NC(=O)C(C)(C)C
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To a mixture of 1-(2-aminopyridin-3-yl)ethanone (272 mg, 2 mmol), 4-dimethylaminopyridine (24 mg, 0.2 mmol), triethylamine (0.64 mL, 4.6 mmol) and toluene (2 mL) was added pivaloyl chloride (0.52 mL, 4.2 mmol) dropwise at room temperature, which was stirred at room temperature for one hour and at 60° C. for five hours. After formation of 2-tert-butyl-4-methyl-4H-pyrido[2,3-d][1,3]oxazin-4-yl pivalate was confirmed, to the reaction mixture were added water (2 mL) and 5N hydrochloric acid (0.8 mL), which was stirred at room temperature for 30 minutes. After the reaction mixture was separated, to the aqueous layer was added 5N aqueous sodium hydroxide (1 mL) and extracted with toluene. The solvent was evaporated under a reduced pressure and the precipitated solid was filtered to obtain the title compound (415 mg).