Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12](=[O:36])[NH:13][C@H:14]([CH:33]([CH3:35])[CH3:34])[C:15]([N:17]2[CH2:22][CH2:21][C@@:20]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)([OH:23])[C:19]([CH3:32])([CH3:31])[CH2:18]2)=[O:16])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C([Sn](CCCC)(CCCC)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=1)CCC>C1(C)C=CC=CC=1.CO.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>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([C@@:20]2([OH:23])[CH2:21][CH2:22][N:17]([C:15](=[O:16])[C@H:14]([NH:13][C:12]([C:10]3[CH:9]=[C:4]([CH:3]=[C:2]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=4)[CH:11]=3)[C:5]([O:7][CH3:8])=[O:6])=[O:36])[CH:33]([CH3:35])[CH3:34])[CH2:18][C:19]2([CH3:31])[CH3:32])=[CH:25][CH:26]=1
Reactant: COC(=O)c1cc(Br)cc(C(=O)N[C@@H](C(=O)N2CC[C@](O)(c3ccc(Cl)cc3)C(C)(C)C2)C(C)C)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1cc(C(=O)N[C@@H](C(=O)N2CC[C@](O)(c3ccc(Cl)cc3)C(C)(C)C2)C(C)C)cc(-c2ccccn2)c1
Yield: 75.4 %

Procedure:
Methyl 3-bromo-5-((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamoyl)benzoate (40 mg, 0.069 mmol) was dissolved in toluene (3 mL) at 25° C. then 2-(tributylstannyl)pyridine (76 mg, 0.207 mmol) was added. The reaction was degassed then placed under nitrogen. Tetrakis(triphenylphosphine)palladium(0) (4 mg, 3.45 μmol) was added and the reaction heated at reflux for 2 hours. The reaction was concentrated in vacuo to give a dark residue which was then dissolved in MeOH, filtered to remove insoluble material, then purified by LCMS HPLC. The obtained colorless oil was dissolved in EtOAc, dried over sodium sulfate and concentrated in vacuo to give methyl 3-((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamoyl)-5-(pyridin-2-yl)benzoate (30 mg, 0.052 mmol, 75% yield) as a white glass. MS found: (M+H)+=578.34.
Reaction SMILES: O=[O+][O-].[CH2:4]([O:6][C:7]([C:9]1(/[CH:29]=C/C)[CH2:14][CH2:13][CH:12]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:11][CH2:10]1)=[O:8])[CH3:5].[O:32]=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C(Cl)Cl>[CH2:4]([O:6][C:7]([C:9]1([CH:29]=[O:32])[CH2:10][CH2:11][CH:12]([NH:15][S:16]([C:19]2[CH:20]=[CH:21][C:22]([C:25]([F:26])([F:28])[F:27])=[CH:23][CH:24]=2)(=[O:17])=[O:18])[CH2:13][CH2:14]1)=[O:8])[CH3:5]
Reactant: O=O
Reactant: C/C=C/C1(C(=O)OCC)CCC(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Agent: O=[O+][O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)C1(C=O)CCC(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Reaction time: 8 h
Yield: 91 %

Procedure:
O3 was passed through a solution of 1-((E)-Propenyl)-4-(4-trifluoromethyl-benzenesulfonylamino)-cyclohexanecarboxylic acid ethyl ester (Intermediate 118, 965 mg, 2.83 mmol) in DCM (30 ml) at −78° C. for 12 min. The solution was kept at −78° C. and O2 gas was passed through it for 10 min. The reaction was monitored by LCMS. When no starting material was present, the reaction mixture was left to warm for 15 mins. The ozonide was then quenched/reduced by adding PS-PPh3 (loading=2.34 mmol/g) (6040 mg, 14.13 mmol) and the solution was left to shake overnight. The reaction was filtered through a fritt and beads and washed with DCM. The DCM filtrate and wash were concentrated in vacuo to yield the title compound as a tan solid (850 mg, 91%). LCMS [M−H]=406.2
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[O:14])=[CH:9][C:8]=1[N+:15]([O-])=O)C>C(O)(=O)C.[Fe]>[O:3]=[C:4]1[NH:15][C:8]2[CH:9]=[C:10]([CH:13]=[O:14])[CH:11]=[CH:12][C:7]=2[O:6][CH2:5]1
Reactant: CCOC(=O)COc1ccc(C=O)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: O=Cc1ccc2c(c1)NC(=O)CO2
Temperature: 60 °C
Reaction time: 0.75 h
Yield: 66.2 %

Procedure:
(4-Formyl-2-nitrophenoxy)acetic acid ethyl ester (1.9 g) in acetic acid (40 mL) was treated with iron powder (4.2 g) and the mixture was stirred at 60° C. for 0.75 hours, filtered and evaporated to dryness. It was partitioned between aqueous sodium bicarbonate and ethyl acetate. The organic fraction was chromatographed on silica gel (ethyl acetate) to give a white solid (0.88 g). MS (−ve ion electrospray) m/e 176 (M−H)−.
Reaction SMILES: [CH2:1]([NH:7][C:8]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[S:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:17]([C:22](O)=[O:23])#[C:18][C:19]([OH:21])=[O:20]>>[CH2:11]([N:10]1[C:22](=[O:23])[C:17](=[CH:18][C:19]([OH:21])=[O:20])[S:9][C:8]1=[N:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=C(O)C#CC(=O)O
Reactant: CCCCCCNC(=S)NCCCCCC
Product: CCCCCCN=C1SC(=CC(=O)O)C(=O)N1CCCCCC
Yield: 31.6 %

Procedure:
Prepared by the method described in Example 1 from N,N'-dihexylthiourea (114.2 g, 468 mmoles) and acetylenedicarboxylic acid (53.4 g, 468 mmoles). Recrystallization from acetonitrile gave the product (50.4 g) mp 66°-69° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:18])[CH2:10][C:11]([CH3:17])([CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[CH:5][CH:4]=1.COC1C=CC(C(=O)CCC(O)=O)=CC=1>>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9](=[O:18])[CH2:10][C:11]([CH3:16])([CH3:17])[C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:8]=1
Reactant: COC(=O)C(C)(C)CC(=O)c1ccc(OC)cc1
Agent: COc1ccc(C(=O)CCC(=O)O)cc1
Product: COC(=O)C(C)(C)CC(=O)c1ccc(O)cc1

Procedure:
Following the procedure of Step B of Example 1 but substituting the product from Step B of this example for 4-methoxy-gamma-oxobenzenebutanoic acid there was obtained 4-hydroxy-alpha,alpha-dimethyl-gamma-oxobenzenebutanoic acid, methyl ester.
Reaction SMILES: [CH2:1]([C:8]1[C:9]([NH:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][OH:21])=[N:10][C:11](Cl)=[N:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>[Pd].C(O)C>[CH2:1]([C:8]1[C:9]([NH:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][OH:21])=[N:10][CH:11]=[N:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: OCCOCCNc1nc(Cl)ncc1Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: OCCOCCNc1ncncc1Cc1ccccc1
Yield: 4.5 %

Procedure:
A mixture of 5-benzyl-2-chloro-4-[2-(2-hydroxyethoxy)ethylamino]pyrimidine (3.50 g, 12.08 mmoles), ethanol (190 mL) and 10% Pd on carbon (Aldrich) (0.84 g) was shaken in to presence of hydrogen at 2-3 atm for 17 hours. The reaction mixture was filtered through a pad of CELITE®, and the filtrates were spin evaporated in vacuo. The residual syrup was dissolved in dichloromethane (40 mL) and washed with water (20 mL) brine (20 mL) and then dried over sodium sulfate. The dry solution was spin evaporated in vacuo to give a residue that was triturated under hexanes to give 0.15 g (5% yield) of 5-benzyl-4-[2-(2-hydroxyethoxy)ethylamino]pyrimidine as a white solid, mp 86-87° C.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][O:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([Cl:23])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1.[CH3:24][C@H:25]1[CH2:30][CH2:29][CH2:28][C@@H:27]([CH3:31])[NH:26]1>>[CH3:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH:27]([CH3:31])[N:26]1[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][O:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([Cl:23])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1
Reactant: ClCCOc1ccc(COc2ccc(Cl)c3ccccc23)cc1
Reactant: C[C@@H]1CCC[C@H](C)N1
Product: CC1CCCC(C)N1CCOc1ccc(COc2ccc(Cl)c3ccccc23)cc1
Yield: 47.2 %

Procedure:
A stirred mixture of 0.4 grams (0.001 mole) of 2-chloro-1-(4-((4-chloronaphthyloxy)methyl)phenoxy)ethane and 5 mL (0.037 mole) of cis-2,6-dimethylpiperidine was heated to just below reflux for about 72 hours. After this time, the reaction mixture was analyzed by thin layer chromatography (TLC), which indicated the reaction was incomplete. The reaction mixture was concentrated under reduced pressure and subject to column chromatography on silica gel, yielding 0.2 gram of compound 106. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][CH:10]([N:14]([CH2:18][CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:15][CH2:16][CH3:17])[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[N:32]1([C:38](Cl)=[O:39])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>C(Cl)Cl>[N:32]1([C:38]([N:22]2[CH2:21][CH2:20][CH:19]([CH2:18][N:14]([CH:10]3[CH2:9][CH2:8][C:7]4[C:12](=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=4)[CH2:11]3)[CH2:15][CH2:16][CH3:17])[CH2:24][CH2:23]2)=[O:39])[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: CCCN(CC1CCNCC1)C1CCc2ccc([N+](=O)[O-])cc2C1
Reactant: O=C(Cl)N1CCOCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCN(CC1CCN(C(=O)N2CCOCC2)CC1)C1CCc2ccc([N+](=O)[O-])cc2C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To an ice-cold solution of (7-nitro-1,2,3,4-tetrahydro-naphthalen-2-yl)-piperidin-4-ylmethyl-propyl-amine, as prepared in Example 4, (400 mg, 1.2 mmol) and triethylamine (170 μl, 1.4 mmol, 1.2 eq.) in methylene chloride (40 mL) under an inert atmosphere morpholine-4-carbonyl chloride (170 μL, 1.4 mmol) was added dropwise. The ice bath was removed and the reaction was stirred at room temperature for 4 h. The methylene chloride was washed 2 times with water (30 mL), dried (MgSO4), filtered, and concentrated to afford morpholin-4-yl-(4-{[(7-nitro-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-methyl}-piperidin-1-yl)-methanone as a clear oil (540 mg).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[CH:15]=[C:14]([C:16]4[CH:17]=[N:18][C:19]5[N:20]([C:22]([C:25]6([C:28]7[CH:29]=[C:30]8[C:35](=[CH:36][CH:37]=7)[N:34]=[CH:33][CH:32]=[CH:31]8)[CH2:27][CH2:26]6)=[CH:23][N:24]=5)N=4)[CH:13]=[N:12]3)[CH2:7][CH2:6]2)[O:4]CC1.O1C2(CCC(O)CC2)OC[CH2:39]1>>[N:34]1[C:35]2[C:30](=[CH:29][C:28]([C:25]3([C:22]4[N:20]5[CH:39]=[C:16]([C:14]6[CH:13]=[N:12][N:11]([CH:8]7[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]7)[CH:15]=6)[CH:17]=[N:18][C:19]5=[N:24][CH:23]=4)[CH2:26][CH2:27]3)=[CH:37][CH:36]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: OC1CCC2(CC1)OCCO2
Reactant: c1cnc2ccc(C3(c4cnc5ncc(-c6cnn(C7CCC8(CC7)OCCO8)c6)nn45)CC3)cc2c1
Product: O=C1CCC(n2cc(-c3cnc4ncc(C5(c6ccc7ncccc7c6)CC5)n4c3)cn2)CC1
Temperature: 100 °C

Procedure:
The crude reaction mixture containing 6-(1-{2-[1-(1,4-dioxaspiro[4.5]dec-8-yl)-1H-pyrazol-4-yl]imidazo[1,2-b][1,2,4]triazin-7-yl}cyclopropyl)quinoline (˜30 mg, 0.07 mmol), prepared using a procedure analogous to that described for the synthesis of Example 88 starting from 1,4-dioxaspiro[4.5]decan-8-ol, was concentrated and treated directly with AcOH (1 mL), water (100 μL) and heated to 100° C. for 1 h to afford the desired product, which was purified by RP-HPLC. LCMS: (M+H)=449.2.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:5][CH:4]=1.[CH2:13]([NH:15][CH2:16][CH3:17])[CH3:14]>C1C=CC=CC=1>[CH2:13]([N:15]([CH2:2][C:3]1[O:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:5][CH:4]=1)[CH2:16][CH3:17])[CH3:14]
Reactant: CCOC(=O)c1ccc(CCl)o1
Reactant: CCNCC
Solvent: c1ccccc1
Product: CCOC(=O)c1ccc(CN(CC)CC)o1

Procedure:
Ethyl 5-(chloromethyl)-2-furoate (0.1 mole) is refluxed with diethylamine (0.25 mole) in 40 ml of benzene for one hour. The benzene solution is filtered off and washed with water. The organic layer is separated and dried over magnesium sulfate. The magnesium sulfate is removed by filtration and the organics are evaporated to dryness. The residue is distilled to give a pure fraction of ethyl 5-(N,N-diethylaminomethyl)-2-furoate boiling at 97°-106° C. at 0.1 mm of Hg.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([OH:12])=[CH:7][CH:8]=2)[CH:3]=1.Cl[C:14]([O:16][CH2:17][C:18]#[CH:19])=[O:15]>>[CH2:17]([O:16][C:14]([O:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:12][C:14]([O:16][CH2:17][C:18]#[CH:19])=[O:15])=[CH:7][CH:8]=2)[CH:3]=1)=[O:15])[C:18]#[CH:19]
Reactant: C#CCOC(=O)Cl
Reactant: Oc1ccc2ccc(O)cc2c1
Product: C#CCOC(=O)Oc1ccc2ccc(OC(=O)OCC#C)cc2c1
Yield: 83.6 %

Procedure:
Analogous to Example 19, 2,7-dihydroxynaphthalene was reacted with propargyl chloroformate to produce the title compound. Yield was 83.6% theory. m.p. 94°-96° C. IR (cm-1) 3330, 2100, 1755, 1610, 1510 1H-NMR (δ, ppm) 2.42 (CH≡C--), 4.86 (≡C--CH2 --), 7.20, 8.10 (Ph)
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C:11]1[C:19]2[C:14](=[CH:15][C:16]([C:20](OC)=[O:21])=[CH:17][CH:18]=2)[NH:13][CH:12]=1)(=O)[CH2:8][CH3:9]>O1CCCC1>[OH:21][CH2:20][C:16]1[CH:15]=[C:14]2[C:19]([C:11]([CH2:7][CH2:8][CH3:9])=[CH:12][NH:13]2)=[CH:18][CH:17]=1
Reactant: CCC(=O)c1c[nH]c2cc(C(=O)OC)ccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCc1c[nH]c2cc(CO)ccc12
Yield: 91.6 %

Procedure:
A suspension of lithium aluminum hydride (1.71 g) in dry tetrahydrofuran (90 ml) was added slowly via cannula to methyl 3-propionylindole-6-carboxylate (1.6 g) as a stirred suspension in dry tetrahydrofuran (60 ml) under an atmosphere of nitrogen. After addition was complete, the mixture was heated to reflux for 90 min, then cooled and poured carefully onto ice (200 ml). The mixture was extracted with ethyl acetate; the extracts were washed (water (twice), brine), dried (MgSO4) and evaporated to give a dark oil. The product was purified by flash chromatography, eluting with 7:3 hexane:ethyl acetate, to give 6-hydroxymethyl-3-propylindole (1.2 g, 92%) as a white solid; mp 68°-71°; partial NMR (250 MHz, DMSO-d6): 0.93(t, 3H, CH2CH3), 1.64(m, 2H, CH2CH3), 2.65(t, 2H, CH2CH2CH3), 4.55(d, 2H, CH2OH), 5.03(t, 1H, OH), 10.67(br s, 1H, NH).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]([CH2:27][C:28]([O:30][CH3:31])=[O:29])[C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:25])[C:22]([OH:24])=O)[C:17]1=[O:26])(=[O:14])=[O:13])[CH:6]=[CH:5]2.Cl.CN(C)CCCN=C=NCC.[CH:44]1[CH:45]=[CH:46]C2N(O)N=[N:50][C:48]=2[CH:49]=1.N1CCCCC1>C(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]([C@H:16]1[CH2:20][CH2:19][N:18]([C@@H:21]([CH3:25])[C:22](=[O:24])[N:50]3[CH2:46][CH2:45][CH2:44][CH2:49][CH2:48]3)[C:17]1=[O:26])[CH2:27][C:28]([O:30][CH3:31])=[O:29])(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: COC(=O)CN([C@H]1CCN([C@@H](C)C(=O)O)C1=O)S(=O)(=O)c1ccc2cc(Cl)ccc2c1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CN([C@H]1CCN([C@@H](C)C(=O)N2CCCCC2)C1=O)S(=O)(=O)c1ccc2cc(Cl)ccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.5 %

Procedure:
To a solution of (2S)-2-{(3S)-3-[[(6-chloro-2-naphthyl)sulfonyl](2-methoxy-2-oxoethyl)amino]-2-oxopyrrolidin-1-yl}propanoic acid (0.032 g) in DCM (5ml) were added 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.02 g), HOBT (0.014 g) and triethylamine (0.034 ml) and the mixture was stirred at room temperature for 1 h. Piperidine (0.01 ml) was added and the resultant mixture stirred at room temperature for 72 h. The mixture was concentrated under reduced pressure and the residue purified using mass directed preparative h.p.l.c. to give the title compound (0.017 g) as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[CH:20][C:6]1=2)=[O:4].[N:21]1([CH2:26][C@@H:27]2[CH2:31][CH2:30][CH2:29][NH:28]2)[CH2:25][CH2:24][CH2:23][CH2:22]1.C(OCC)(=O)C.CO>C(O)C>[N:21]1([CH2:26][C@@H:27]2[CH2:31][CH2:30][CH2:29][N:28]2[CH2:2][C:3]([N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[NH:8][C:7]3[CH:17]=[CH:18][CH:19]=[CH:20][C:6]2=3)=[O:4])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: C1CN[C@H](CN2CCCC2)C1
Reactant: O=C1Nc2ccccc2N(C(=O)CCl)c2ccccc21
Solvent: CO
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C1Nc2ccccc2N(C(=O)CN2CCC[C@H]2CN2CCCC2)c2ccccc21

Procedure:
The title compound is prepared analogously to Example 31 from 5-(chloroacetyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one and (S)-(+)-2-[(1-pyrrolidinyl)methyl]pyrrolidine to give colorless crystals, mp. 142°-144° C. (ethyl acetate/methanol 99:1 v/v); [α]D20 =-18.5° (ethanol).
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15]Cl)=[CH:9][CH:8]=1)C.[C:20]([C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([CH3:22])[CH3:21]>>[CH3:18][O:17][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]#[C:14][CH2:15][O:35][C:32]2[CH:31]=[CH:30][C:29]([C:20]([CH3:22])([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH3:21])=[CH:34][CH:33]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:19]
Reactant: CCOC(=O)[C@H](Cc1ccc(C#CCCl)cc1)OC
Reactant: CC(C)(c1ccccc1)c1ccc(O)cc1
Product: CO[C@@H](Cc1ccc(C#CCOc2ccc(C(C)(C)c3ccccc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-Chloro-prop-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 5, Step A and 4-cumylphenol in a manner analogous to that described for Example 5, Step B. MS(ES) for C28H28O4[M+NH4]+: 446.2.
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.CS([C:15]1[N:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:17][N:16]=1)(=O)=O>CS(C)=O>[F:24][C:21]([F:22])([F:23])[C:19]1[C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:17][N:16]=[C:15]([O:10][C:7]2[CH:8]=[CH:9][C:4]([NH2:3])=[CH:5][CH:6]=2)[N:20]=1
Reactant: Nc1ccc(O)cc1
Reactant: CS(=O)(=O)c1ncc(-c2ccccc2)c(C(F)(F)F)n1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Nc1ccc(Oc2ncc(-c3ccccc3)c(C(F)(F)F)n2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
With cooling, 2.2 g of powdered potassium hydroxide are added to a solution of 2.1 g of 4-aminophenol in 50 ml of dimethylsulfoxide and the mixture is stirred for 1 hour to form a clear solution. To the batch are then added, in portions, 6 g of 2-methylsulfonyl-4-trifluoromethyl-5-phenylpyrimidine and the mixture is stirred for 4 hours at room temperature. The mixture is then poured into ice-water and extracted with ether. The washed and dried ethereal extracts yield a product of m.p. 123°-126° C., which is the title compound of formula ##STR21##
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][C@H:23]2[CH2:25][O:24]2)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[CH2:26]([NH2:28])[CH3:27].O1CCCC1.Cl>ClCCl>[ClH:1].[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][C@H:23]([OH:24])[CH2:25][NH:28][CH2:26][CH3:27])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:15][CH:14]3[CH2:16][CH:10]([CH2:11][CH:12]([CH2:13]3)[CH2:17]1)[CH2:9]2)=[O:5]
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(C[C@H]2CO2)ccc1Cl
Reactant: CCN
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCNC[C@@H](O)Cc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1

Procedure:
2-Chloro-5-[(2S)-2-oxiranylmethyl]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (Example 13b) (110 mg), ethylamine (70% aqueous solution, 2 mL) and tetrahydrofuran (10 mL) were heated together at 50° C. under nitrogen for 20 hours, cooled and concentrated to give an oil. This was purified by Waters' MCX resin and then by column chromatography eluting with 9:1:0.1 dichloromethane/methanol/ammonia. The oil obtained was dissolved in dichloromethane (5 mL) and 1M ethereal hydrogen chloride (4 mL) was added. The resulting white solid was filtered off to give the titled compound (109 mg).
Reaction SMILES: [C-]#N.[K+].[C:4](#[N:6])C.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH:33]([CH3:35])[CH3:34])[C:15]([O:17][CH:18](Cl)[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:20]=2)=[O:16])=[CH:10][CH:9]=1>CCOCC>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH:33]([CH3:35])[CH3:34])[C:15]([O:17][CH:18]([C:4]#[N:6])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:20]=2)=[O:16])=[CH:10][CH:9]=1
Reactant: CC#N
Reactant: CC(C)C(C(=O)OC(Cl)c1cccc(Oc2ccccc2)c1)c1ccc(Cl)cc1
Agent: [C-]#N
Agent: [K+]
Solvent: CCOCC
Product: CC(C)C(C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1)c1ccc(Cl)cc1

Procedure:
1.5 g of potassium cyanide were added to a mixture of 80 ml of acetonitrile and the solution obtained in Example 9 and the mixture was stirred at 20° C. for 72 hours. Ether was added to the mixture which was then filtered to remove insolubles. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. Elution with a 95-5 cyclohexane-acetone mixture yielded 6.5 g of RS α-cyano-3-phenoxy-benzyl 2-(p-chlorophenyl)-2-isopropyl-acetate.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][C:11]([CH2:15][CH2:16][N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:12]2)=[CH:7][CH:6]=1)=O.[H-].C([Al+]CC(C)C)C(C)C.O>O1CCCC1.C1(C)C=CC=CC=1>[OH:2][CH2:3][C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][C:11]([CH2:15][CH2:16][N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:12]2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc2c(c1)C=C(CCN1CCCC1)CC2
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc2c(c1)C=C(CCN1CCCC1)CC2
Reaction time: 1 h
Yield: 88.7 %

Procedure:
1-[2-(3,4-Dihydro-7-methoxycarbonyl-2-naphthalenyl)ethyl]pyrrolidine (1.0 g) was dissolved in tetrahydrofuran (20 ml), and thereto was added dropwise a 1.5M solution of diisobutyl aluminum hydride in toluene (7.0 ml) under ice-cooling, and the mixture was stirred for one hour. To the reaction solution was added dropwise water to decompose the excess amount of the reducing agent, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (eluent; chloroform:methanol=30:1), and the fractions containing the desired compound were combined, and concentrated under reduced pressure to give the desired compound (0.8 g) as an oily product.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:20]([O:27][C:28]([NH:30][C@H:31]([C:35](O)=[O:36])[CH:32]([CH3:34])[CH3:33])=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(O)C>ClCCl>[CH2:20]([O:27][C:28]([NH:30][C@H:31]([C:35]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[O:7])=[CH:18][CH:19]=1)=[O:36])[CH:32]([CH3:34])[CH3:33])=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: COc1ccc(COC(=O)c2ccc(O)cc2)cc1
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(COC(=O)c2ccc(OC(=O)[C@@H](NC(=O)OCc3ccccc3)C(C)C)cc2)cc1

Procedure:
4-Methoxybenzyl 4hydroxybenzoate was acylated with N-benzyloxycarbonyl-L-valine by the method described in Example A-I-1, step b. The title compound (2.71 g) was obtained after silica gel column chromatography (0, 1% ethanol in dichloromethane). Rf (2%MeOH/CHCl3) 0.70.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:23]1[CH2:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.CC(O)C.CCN(C(C)C)C(C)C>O>[Br:1][C:2]1[C:3]([N:23]2[CH2:29][CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: C1CNCCNC1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Solvent: O
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CCCNCC2)c(Br)c1
Temperature: 25 °C

Procedure:
A mixture of 5-bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2, 198 mg, 0.50 mmol), 1,4-diazepane (60.2 mg, 0.60 mmol), iPrOH (2 mL) and DIPEA (0.171 mL, 0.129 g, 2.0 mmol) were subjected to MW irradiation 140° C. for 80 min. The vial was cooled to RT and the RM was poured into water (40 mL) to give a suspension. The supernatant was decanted off and the residue was dried under vacuum to afford the title compound. UPLC-MS (Condition 8) tR=1.15 min, m/z=459.1/461.1 [M+H]+, m/z=457.1/459.1 [M−H]−.