Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)C(O)=O)([O-:3])=[O:2].S(=O)(=O)(O)O.[N-:21]=[N+]=[N-].[Na+]>C(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[NH2:21])([O-:3])=[O:2]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 80 °C

Procedure:
To a solution of 3,5-dinitrobenzoic acid (4.0 g, 18.9 mmol) in a mixture of concentrated sulfuric acid (6 mL), 30% fuming sulfuric acid (18 mL) and CHCl3 (25 mL) was added sodium azide (1.4 g, 21.7 mmol), in small portions. The resulting mixture was heated to reflux (80° C.) for 3 hours and then cooled to 25° C. after which it was poured on ice. An orange solid was isolated after vacuum filtration (3.25 g, 17.7 mmol, 94%). 1H NMR (300 MHz, CDCl3) δ 8.14 (t, J=1.8 Hz, 1H), 7.64 (d, J=1.8 Hz, 2H), 4.39 (s (br), 2H); 13C NMR (75 MHz, CDCl3) δ 151.9, 150.1, 113.1, 105.2; HRMS (ESI) Calculated for C6H4N3O4 [M−H]−: 182.0195. Found: 182.0207. m.p.: 113.1° C.
Reaction SMILES: [BrH:1].C([N:9]([CH2:22][C:23]([C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])=[C:27]([O:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])[CH:26]=1)=[O:24])[CH2:10][CH2:11][NH:12][C:13](=[O:21])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)C1C=CC=CC=1.C(O)C>O.[C].[Pd]>[C:39]([O:38][C:27]1[CH:26]=[C:25]([CH:23]([OH:24])[CH2:22][NH:9][CH2:10][CH2:11][NH:12][C:13](=[O:21])[CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:30]=[CH:29][C:28]=1[O:31][C:32](=[O:37])[C:33]([CH3:35])([CH3:36])[CH3:34])(=[O:44])[C:40]([CH3:41])([CH3:42])[CH3:43].[BrH:1]
Reactant: CC(C)(C)C(=O)Oc1ccc(C(=O)CN(CCNC(=O)Cc2ccccc2)Cc2ccccc2)cc1OC(=O)C(C)(C)C
Agent: [Pd]
Agent: Br
Solvent: CCO
Solvent: O
Product: CC(C)(C)C(=O)Oc1ccc(C(O)CNCCNC(=O)Cc2ccccc2)cc1OC(=O)C(C)(C)C
Reaction time: 18 h

Procedure:
A solution of 2-{N-benzyl-N-[2-(2-phenylacetamido)ethyl]amino}-3',4'-bis(pivaloyloxy)acetophenone hydrobromide (2.5 g.) in a mixture (50 ml.) containing 70% v/v of ethanol in water was hydrogenated for 18 hours at a pressure of 3.5 kg./cm2 at room temperature using 10% palladium-carbon (0.8 g.). The catalyst was separated by filtration and the filtrate evaporated. Trituration of the residue with ether (30 ml.) containing several drops of ethanol gave 1-[3,4-bis(pivaloyloxy)phenyl]-2-[2-(2-phenylacetamido)ethylamino]ethanol as its hydrobromide (1.7 g.) m.p. 111°-113° C. (hemi-hydrate).
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[S:3]([O:6][C:7]1[C:8]2[CH:9]=[C:10](C#CC3C=CC(C(OCC)=O)=CC=3)[CH:11]=[CH:12][C:13]=2[C:14]([CH3:18])([CH3:17])[CH2:15][CH:16]=1)(=[O:5])=[O:4].CC1(C)C2C=C([C:45]#[C:46][C:47]3[CH:57]=[CH:56][C:50]([C:51]([O:53][CH2:54][CH3:55])=[O:52])=[CH:49][CH:48]=3)C=CC=2C(=O)CC1>C1COCC1>[F:33][C:2]([F:32])([F:1])[S:3]([O:6][C:7]1[C:8]2[CH:9]=[CH:10][C:11]([C:45]#[C:46][C:47]3[CH:57]=[CH:56][C:50]([C:51]([O:53][CH2:54][CH3:55])=[O:52])=[CH:49][CH:48]=3)=[CH:12][C:13]=2[C:14]([CH3:17])([CH3:18])[CH2:15][CH:16]=1)(=[O:5])=[O:4]
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3=O)cc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CCC3(C)C)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC=C3OS(=O)(=O)C(F)(F)F)cc1

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-3-yl)ethynyl]benzoate (Compound 66), 800 mg (2.31 mmol) of ethyl 4-[(5,6,7,8-tetrahydro-8,8-dimethyl-5-oxonaphth-2-yl)ethynyl]benzoate (Compound 1) in 2 ml of THF was converted into the title compound (white solid) using 466 mg (2.5 ml, 2.54 mmol) of sodium bis(trimethylsilyl)amide (1.0M solution in THF) and a solution of 961 mg (2.54 mmol) of 2-[N,N-bis (trifluoromethylsulfonyloxy) amino]-5-chloropyridine in 2 ml of THF.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:23])[C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[N:18][CH:17]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C1CCCCC=1>CCO.[OH-].[OH-].[Pd+2]>[CH3:22][C:20]1[CH:19]=[N:18][CH:17]=[C:16]([CH:21]=1)[C:15]([NH:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:23]
Reactant: Cc1cncc(C(=O)NC2CCN(Cc3ccccc3)CC2)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1=CCCCC1
Solvent: CCO
Product: Cc1cncc(C(=O)NC2CCNCC2)c1
Yield: 102.6 %

Procedure:
N-(1-Benzyl-piperidin-4-yl)-5-methyl-nicotinamide (1.3 g, 4 mmol), Pd(OH)2/C (0.1 g) and cyclohexene (2 ml) were heated at reflux in EtOH (15 mL) for 2 h, after which time the reaction was filtered hot through a pad of Hyflo. The filtrate was concentrated to afford the title compound as a white powder (0.9 g, 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:23])[C:7]=1[NH:8][C:9]1[C:18]2[C:13](=[C:14]([OH:21])[C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[NH:12][C:11](=[O:22])[CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(C)=O.Br[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][Cl:41]>C(OCC)(=O)C>[Cl:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][O:21][C:14]1[C:15]([O:19][CH3:20])=[CH:16][CH:17]=[C:18]2[C:13]=1[NH:12][C:11](=[O:22])[CH:10]=[C:9]2[NH:8][C:7]1[C:6]([Cl:23])=[CH:5][N:4]=[CH:3][C:2]=1[Cl:1]
Reactant: ClCCCCCCBr
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCCCCCCCl
Temperature: 30 °C
Yield: 71.4 %

Procedure:
A mixture of 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxyquinolin-2(1H)-one (Intermediate 3) (19.9 g, 56.5 mmol), cesium carbonate (36.9 g, 113 mmol), and DMSO (190 mL) was heated at 30° C. for 15, minutes, and then 1-bromo-6-chlorohexane (12.4 g, 62.2 mmol) was added. The reaction was heated at 30° C. for 4.5 h, diluted with ethyl acetate (2 L), washed with 1M pH 7 phosphate buffer (2 L), and then washed with water (2L×2). The organic layer was dried, filtered, concentrated, and then purified by silica gel chromatography (100% ethyl acetate) to give 19 g of 8-(6-chlorohexyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 10.01 (s, 1H), 8.87 (s, 1H), 8.79 (s, 2H), 7.90 (d, 1H), 7.06 (d, 1H), 4.80 (s, 1H), 3.98 (t, 2H), 3.92 (s, 3H), 3.65 (t, 2H), 1.77 (m, 4H), 1.43 (m, 4H); MS (ESI): 470.3.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])([CH3:13])=[O:12])=[O:9])=[CH:4][C:3]=1[C:22]#[C:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=1.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][C:41]=1[O:42][CH3:43])[C:36](O)=[O:37]>>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]=[S:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])([CH3:13])=[O:12])=[O:9])=[CH:4][C:3]=1[C:22]#[C:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:36](=[O:37])[C:35]2[CH:39]=[CH:40][C:41]([O:42][CH3:43])=[C:33]([O:32][CH3:31])[CH:34]=2)[CH:25]=1
Reactant: COc1ccc(C(=O)O)cc1OC
Reactant: COC(=O)CCCCS(C)(=O)=NC(=O)c1cnc(N)c(C#Cc2cccc(N)c2)c1
Product: COC(=O)CCCCS(C)(=O)=NC(=O)c1cnc(N)c(C#Cc2cccc(NC(=O)c3ccc(OC)c(OC)c3)c2)c1

Procedure:
In a manner similar to that described in Example 25, methyl 5-[N-({6-amino-5-[(3-aminophenyl)ethynyl]pyridin-3-yl}carbonyl)-S-methylsulfonimidoyl]pentanoate and 3,4-dimethoxybenzoic acid were coupled to give the title compound as a white foam (102 mg).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]=3[CH3:23])=[CH:7][C:6]=2[C:5]2[CH:24]=[CH:25][CH:26]=[CH:27][C:4]=2[N:3]=1.[CH3:28][N:29]([CH3:34])[CH2:30][CH2:31][NH:32][CH3:33]>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:22]=[CH:21][C:17]([C:18]([N:32]([CH2:31][CH2:30][N:29]([CH3:34])[CH3:28])[CH3:33])=[O:19])=[CH:16][C:15]=3[CH3:23])=[CH:7][C:6]=2[C:5]2[CH:24]=[CH:25][CH:26]=[CH:27][C:4]=2[N:3]=1
Reactant: CNCCN(C)C
Reactant: Cc1cc(C(=O)Cl)ccc1CCc1cnc2c(N)nc3ccccc3c2c1
Product: Cc1cc(C(=O)N(C)CCN(C)C)ccc1CCc1cnc2c(N)nc3ccccc3c2c1

Procedure:
4-(2-(5-Aminobenzo[f][1,7]naphthyridin-2-yl)ethyl)-N-(2-(dimethylamino)ethyl)-N,3-dimethylbenzamide was prepared from 4-(2-(5-aminobenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylbenzoyl chloride (Example 116/Step 2) and N1,N1,N2-trimethylethane-1,2-diamine following the procedures described for Example 117. 1H NMR (methanol-d4): δ 8.84 (s, 1H), 8.63 (s, 1H), 8.39 (d, 1H), 7.76-7.83 (m, 2H), 7.60-7.64 (m, 1H), 7.37 (s, 1H), 7.19-7.29 (m, 2H), 3.96 (t, 2H), 3.48 (t, 2H), 3.32 (t, 2H), 3.20 (t, 2H), 3.09 (s, 3H), 3.06 (s, 6H), 2.42 (s, 3H). LRMS [M+H]=442.3
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13].FC(F)(F)S(O[CH2:22][C:23]([F:26])([F:25])[F:24])(=O)=O.C(=O)(O)[O-].[K+]>CC(C)=O>[F:24][C:23]([F:26])([F:25])[CH2:22][O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1ccc2ccccc2c1O
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc2ccccc2c1OCC(F)(F)F

Procedure:
A mixture containing 20.2 g. (0.1 mole) of methyl 1-hydroxy-2-naphthoate, 29 g. (0.125 mole) of 2,2,2-trifluoroethyl trifluoromethanesulfonate, 20 g. (0.2 mole) of anhydrous potassium bicarbonate and 200 ml. of dry acetone is refluxed for three days. Acetone is removed by distillation (steam bath). The residue is cooled and diluted with water. The resulting white solid is collected by filtration and washed successively with cold dilute sodium hydroxide solution and water. The solid is further purified by several rcrystallizations from aqueous alcohol followed by sublimation, (oil bath, 60°-75°/0.2 mm. Hg.) to give white solid, m.p. 69.5°-70.5°.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C@@H:6]([C:14]([O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[O:15])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[C:23]([O:30][CH3:31])(=[O:29])/[CH:24]=[CH:25]/[C:26]([O-])=[O:27].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[CH3:31][O:30][C:23](=[O:29])/[CH:24]=[CH:25]/[C:26]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][C@@H:6]([C:14]([O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[O:15])[C:7]([O:9][C:10]([CH3:12])([CH3:13])[CH3:11])=[O:8])=[O:27]
Reactant: COC(=O)/C=C/C(=O)[O-]
Reactant: CC(C)(C)OC(=O)[C@@H](CCCCN)C(=O)OCC[Si](C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)/C=C/C(=O)NCCCC[C@@H](C(=O)OCC[Si](C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
To a stirring mixture of (S)-tert-butyl 6-amino-2-((2-(trimethylsilyl)ethoxy)carbonyl)hexanoate (800 mg, 2.31 mmol), monomethyl fumarate (361 mg, 2.77 mmol), DIEA (1.1 mL, 6.93 mmol) in 10 mL acetonitrile was added HATU (1.14 g, 3.00 mmol) in one portion at 0° C. under an inert atmosphere of argon. The resulting reaction mixture was stirred at room temperature tor 2 h and then concentrated under reduced pressure. The resulting residue was diluted with EtOAc (50 mL) and washed with brine, dried over Na2SO4 and concentrated under reduced pressure. Purification by silica gel chromatography (EtOAc/pentane) afforded (S,E)-tert-butyl 6-(4-methoxy-4-oxobut-2-enamido)-2-((2-(trimethylsilyl)ethoxy)carbonyl)hexanoate (900 mg, 85%).
Reaction SMILES: [H-].[Na+].O1CCCC1.F[C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C:16](=[N:37][OH:38])[CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]2[C:30](=[O:31])[N:29]3[CH2:32][CH2:33][CH2:34][CH2:35][C:28]3=[N:27][C:26]=2[CH3:36])[CH2:19][CH2:18]1>O>[F:15][C:13]1[CH:12]=[CH:11][C:10]2[C:16]([CH:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]4[C:30](=[O:31])[N:29]5[CH2:32][CH2:33][CH2:34][CH2:35][C:28]5=[N:27][C:26]=4[CH3:36])[CH2:19][CH2:18]3)=[N:37][O:38][C:9]=2[CH:14]=1
Reactant: Cc1nc2n(c(=O)c1CCN1CCC(C(=NO)c3ccc(F)cc3F)CC1)CCCC2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCCC2
Yield: 77 %

Procedure:
To a suspension of 40 mg (0.9166 millimole) of 55% sodium hydride and 2 ml of tetrahydrofurane 0.1089 g (0.2532 millimole) of 3-[2-[4-[(2,4-difluorophenyl)-(hydroxyimino)-methyl]-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one is added. The reaction mixture is heated to boiling for an hour, whereupon 5 ml of water are added and the mixture is extracted twice with 10 ml of dichloromethane each. The combined organic phases are dried over magnesium sulfate and evaporated in vacuo. Thus 80 mg of the title compound are obtained, yield 77%. According to HPLC analysis the purity of the product is 97.5%.
Reaction SMILES: Br[C:2]1[C:3]([CH3:13])=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[Cl-].[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][Zn+])=[CH:18][N:17]=1.C1COCC1>C1COCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:15][C:16]1[N:17]=[CH:18][C:19]([CH2:22][C:2]2[C:3]([CH3:13])=[CH:4][C:5]([OH:12])=[C:6]([CH:11]=2)[C:7]([O:9][CH3:10])=[O:8])=[CH:20][CH:21]=1
Reactant: COC(=O)c1cc(Br)c(C)cc1O
Reactant: Clc1ccc(C[Zn+])cn1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Solvent: C1CCOC1
Product: COC(=O)c1cc(Cc2ccc(Cl)nc2)c(C)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5-bromo-2-hydroxy-4-methylbenzoate (0.61 g) in THF (20.0 mL) were added 0.5M (2-chloro-5-pyridyl)methylzinc chloride/THF solution (12.5 mL) and bis(tri-tert-butylphosphine)palladium(0) (0.13 g), and the mixture was stirred overnight at room temperature under argon atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.52 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=2)[S:9][CH:10]=1)=[O:5])C.[OH:20][CH2:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>>[OH:20][CH2:21][C:22]1[CH:27]=[C:26]([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:8]3[S:9][CH:10]=[C:6]([C:4]([OH:3])=[O:5])[N:7]=3)=[CH:18][CH:17]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: CCOC(=O)c1csc(COc2ccc(I)cc2)n1
Reactant: OCc1cccc(B(O)O)c1
Product: O=C(O)c1csc(COc2ccc(-c3cccc(CO)c3)cc2)n1

Procedure:
2-(3′-Hydroxymethyl-biphenyl-4-yloxymethyl)-thiazole-4-carboxylic acid was prepared using the procedure described above for the preparation of Example 22 from 2-(4-iodo-phenoxymethyl)-thiazole-4-carboxylic acid ethyl ester (of Intermediate 2) and 3-(hydroxymethyl)phenylboronic acid (available from Aldrich Chemical Company, Inc., Milwaukee, Wis.). Mass spectrum MH+=342.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:32]([C:43]1[CH:44]=[N:45][C:46]([C:49]2[CH:54]=[CH:53][C:52]([OH:55])=[CH:51][CH:50]=2)=[N:47][CH:48]=1)[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].[CH2:56]([CH:58]1[CH2:62][CH2:61][CH:60]([CH2:63]O)[CH2:59]1)[CH3:57]>C1COCC1>[CH2:56]([CH:58]1[CH2:62][CH2:61][CH:60]([CH2:63][O:55][C:52]2[CH:51]=[CH:50][C:49]([C:46]3[N:47]=[CH:48][C:43]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:44][N:45]=3)=[CH:54][CH:53]=2)[CH2:59]1)[CH3:57]
Reactant: CCCCCCCCCCCc1cnc(-c2ccc(O)cc2)nc1
Reactant: CCC1CCC(CO)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCc1cnc(-c2ccc(OCC3CCC(CC)C3)cc2)nc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A fully reacted mixture of equimolar amounts of diethyl azodicarboxylate and triphenylphosphine in THF is admixed with equimolar amounts of 4-(5-undecyl-pyrimidin-2-yl)phenol and 3-ethyl-cyclopentan-1-yl-methanol (prepared by LiAlH4 reduction of methyl 3-ethyl-cyclopentanecarboxylic acid). The mixture is stirred for 24 h at room temperature and then evaporated to dryness under reduced pressure. Purification by chromatography (silica gel, dichloromethane) and recrystallization affords the target compound.
Reaction SMILES: [C:1]([N:9]1[CH:22]([C:23](O)=[O:24])[CH2:21][C:20]2[CH:19]=[C:18]3[C:13]([O:14][C@@H:15]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]5[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([Cl:42])[CH:36]=5)=[CH:29][CH:28]=4)[C:16](=[O:26])[NH:17]3)=[CH:12][C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[CH3:45][O:46][C:47](=[O:63])[C@@H:48]([NH2:62])[CH2:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]2[CH:61]=[CH:60][N:59]=[CH:58][CH:57]=2)=[CH:52][CH:51]=1>>[CH3:45][O:46][C:47](=[O:63])[C@@H:48]([NH:62][C:23]([CH:22]1[CH2:21][C:20]2[CH:19]=[C:18]3[C:13]([O:14][C@@H:15]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]5[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([Cl:42])[CH:36]=5)=[CH:29][CH:28]=4)[C:16](=[O:26])[NH:17]3)=[CH:12][C:11]=2[CH2:10][N:9]1[C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:24])[CH2:49][C:50]1[CH:51]=[CH:52][C:53]([C:56]2[CH:57]=[CH:58][N:59]=[CH:60][CH:61]=2)=[CH:54][CH:55]=1
Reactant: O=C(O)C1Cc2cc3c(cc2CN1C(=O)c1ccccc1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)C(=O)N3
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccncc2)cc1
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(-c2ccncc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1C(=O)c1ccccc1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)C(=O)N3

Procedure:
(S)-2-({(S)-6-Benzoyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4-pyridin-4-yl-phenyl)-propionic acid methyl ester (61 mg, LC/MS: m/z 842) was prepared from Intermediate D (100 mg) and (S)-2-amino-3-(4-pyridin-4-yl-phenyl)-propionic acid methyl ester bis hydrochloride according to general procedure A.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:4][N:3]=1.[OH:12][C:13]([CH3:46])([CH3:45])[CH2:14][C@@:15]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:20][C:19](=[O:21])[N:18]([C@H:22]([C:24]2[CH:29]=[CH:28][C:27](B3OC(C)(C)C(C)(C)O3)=[CH:26][CH:25]=2)[CH3:23])[CH2:17][CH2:16]1.C([O-])(O)=O.[Na+]>COCCOC.CCO.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>[OH:12][C:13]([CH3:45])([CH3:46])[CH2:14][C@@:15]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[O:20][C:19](=[O:21])[N:18]([C@H:22]([C:24]2[CH:25]=[CH:26][C:27]([C:2]3[N:7]=[CH:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:4][N:3]=3)=[CH:28][CH:29]=2)[CH3:23])[CH2:17][CH2:16]1
Reactant: CC(C)(O)c1cnc(Cl)nc1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
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: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: C[C@@H](c1ccc(-c2ncc(C(C)(C)O)cn2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.3 %

Procedure:
To a solution of 2-(2-chloropyrimidin-5-yl)propan-2-ol (30 mg, 0.17 mmol) in DME (6 mL) was added Pd(PPh3)4 (10 mg, 0.01 mmol) under nitrogen. The mixture was stirred at room temperature for 1 hour. (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (60 mg, 0.125 mmol) in EtOH (2 mL) was added, followed by addition of satd aq NaHCO3 (2 mL). The mixture was stirred at 100° C. for 2 h. The reaction was quenched with water, and extracted with EtOAc. The combined organic layer was dried over anhydrous Na2SO4 and concentrated to give (S)-6-(2-hydroxy-2-methylpropyl)-3-((S)-1-(4-(5-(2-hydroxypropan-2-yl)pyrimidin-2-yl)phenyl)ethyl)-6-phenyl-1,3-oxazinan-2-one (21 mg, yield 25%). LC-MS Method 2 tR=0.98 min, m/z=512, 490, 472, 432; 1H NMR (CD3OD): δ 1.02 (s, 3H), 1.13 (s, 3H), 1.50 (d, 3H), 1.61 (s, 6H), 2.02 (s, 1H), 2.18 (m, 5H), 2.30 (m, 1H), 2.75 (m, 1H), 5.66 (m, 1H), 7.00 (m, 2H), 7.20-7.33 (m, 5H), 8.10 (m, 2H), 8.92 (s, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH:6]2[CH2:7][C:8]([CH2:10][CH:3]1[CH2:4][CH2:5]2)=[O:9].ClC(O[CH2:15][CH2:16]Cl)=O.O>C(Cl)(Cl)Cl>[CH2:1]([N:2]1[CH:6]2[CH2:5][CH2:4][CH:3]1[CH2:10][C:8](=[O:9])[CH2:7]2)[C:16]1[CH:15]=[CH:5][CH:4]=[CH:3][CH:10]=1
Reactant: O=C(Cl)OCCCl
Reactant: CN1C2CCC1CC(=O)C2
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C1CC2CCC(C1)N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
25 g of tropinone was dissolved in 100 mL of chloroform, and 50 mL of chloroethyl chloroformate was added thereto and stirred at room temperature for 6 hours. The reaction liquid was concentrated, 100 mL of methanol was added thereto, and heated overnight under reflux. The reaction liquid was cooled to room temperature and concentrated, and the resulting crude product was dissolved in 80 mL of N-methylpyrrolidone. 43 mL of benzyl bromide and 99 g of potassium carbonate were added thereto and stirred overnight at room temperature. The reaction liquid was poured into water, and extracted three times with ethyl acetate. The organic layer was washed with water and saturated saline water, dried with anhydrous magnesium sulfate, and the solvent was evaporated off under reduced pressure to obtain 29.5 g of the entitled compound as a pale yellow liquid.
Reaction SMILES: Cl.Cl.[CH:3]([N:6]1[CH2:11][CH2:10][CH:9]([O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][C:17]([C:22]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[O:23])=[CH:16]3)[CH2:8][CH2:7]1)([CH3:5])[CH3:4].[CH3:30][N:31]([CH3:35])[C:32](Cl)=[O:33]>>[CH3:30][N:31]([CH3:35])[C:32]([N:27]1[CH2:28][CH2:29][N:24]([C:22]([C:17]2[NH:18][C:19]3[C:15]([CH:16]=2)=[CH:14][C:13]([O:12][CH:9]2[CH2:8][CH2:7][N:6]([CH:3]([CH3:5])[CH3:4])[CH2:11][CH2:10]2)=[CH:21][CH:20]=3)=[O:23])[CH2:25][CH2:26]1)=[O:33]
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCNCC4)cc3c2)CC1
Reactant: CN(C)C(=O)Cl
Agent: Cl
Product: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCN(C(=O)N(C)C)CC4)cc3c2)CC1

Procedure:
The title compound was prepared in analogy to example 51, from [5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-piperazin-1-yl-methanone dihydrochloride and N,N-dimethylcarbamoyl chloride. Off-white solid. MS (m/z): 442.3 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C@H:6]([CH2:7][O:8][C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH2:5][CH2:4][C:3]1=O.[CH3:16][Li]>CCOCC>[CH3:1][N:2]1[CH:3]([CH3:16])[CH2:4][CH2:5][C@H:6]1[CH2:7][O:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: [Li]C
Reactant: CN1C(=O)CC[C@H]1COc1cccnc1
Solvent: CCOCC
Product: CC1CC[C@@H](COc2cccnc2)N1C
Temperature: -78 °C
Reaction time: 2 h

Procedure:
A 1.24 g (6.0 mmol) sample of 3-(1-methyl-2-oxo-5-(S)-pyrrolidinylmethoxy)-pyridine, prepared as in Example 22b above, was dissolved in 50 mL of ether and cooled to -78° C. To this solution was added 4.71 mL (6.6 mmol) of methyl lithium, and the solution was warmed to room temperature and stirred for 2 hours. The solution was cooled to 0° C., 66 mL of a 1M solution of LAlH4 was added, and the reaction mixture was stirred for 2 hours at room temperature. The reaction was quenched by addition of 1 mL of methanol, the solvents removed, and the residue purified by chromatography on silica gel, eluting with 200:1 to 100:1 chloroform:methanol. MS (DCI/NH3) m/e: 207 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 83.4-8.30 (m, 1H), 8.24-8.17 (m, 1H), 7.25-7.27 (m, 2H), 4.08-4.03 (m, 1H), 3.93-3.87 (m, 1H), 2.83-2.73 (m, 1H), 2.43 (s, 3H), 2.43-2.35 (m, 1H), 2.03-1.82 (m, 2H), 1.70-1.40 (m, 2H), 1.13 (d, J=6.7 Hz, 3H).