Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [P:1]([O:5][CH2:6][C@:7]([NH:31]C(=O)OC(C)(C)C)([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH:20]3[CH2:25][CH2:24][C:23]4([CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[CH2:22][CH2:21]3)[CH:15]=2)[CH:10]=1)[CH3:8])([OH:4])([OH:3])=[O:2].C(O)(=O)C.Cl>O>[P:1]([OH:3])([OH:4])([O:5][CH2:6][C@:7]([NH2:31])([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:19][CH:20]3[CH2:21][CH2:22][C:23]4([CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]4)[CH2:24][CH2:25]3)[CH:15]=2)[CH:10]=1)[CH3:8])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@](C)(COP(=O)(O)O)c1ccc2cc(OC3CCC4(CCCCC4)CC3)ccc2c1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: C[C@](N)(COP(=O)(O)O)c1ccc2cc(OC3CCC4(CCCCC4)CC3)ccc2c1
Yield: 36 %

Procedure:
tert-Butyl (2R)-1-(phosphonooxy)-2-(6-(spiro[5.5]undecan-3-yloxy)naphthalen-2-yl)propan-2-ylcarbamate (13.6 mg, 0.0000248 mol) was dissolved in acetic acid (0.78 mL, 0.014 mol) and 10 M of hydrogen chloride in water (0.2 mL) was added and the mixture was stirred for Id. Lypholyzing gave (2R)-2-amino-2-(6-(spiro[5.5]undecan-3-yloxy)naphthalen-2-yl)propyl dihydrogen phosphate as a white solid (4.0 mg, 36%). LCMS give a single peak Rf=1.64 min (431.41, [M−16]+, 100%, 895.73, [M+M+1], 20%). 1H NMR (400 MHz, MeOD) δ=7.82-7.89 (m, 3H), 7.56 (d, J=5.5 Hz, 1H), 7.27 (s, 1H), 7.21 (d, J=8.6 Hz, 1H), 4.54-4.47 (m, 1H), 4.14-4.17 (m, 2H), 1.99-1.90 (m, 2H), 1.86 (s, 3H), 1.78-1.66 (m, 4H), 1.50 (m, 8H), 1.42-1.30 (m, 4H).
Reaction SMILES: [CH2:1]([N:5]1[C:10]2=[CH:11][N:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)=[CH:17][CH:16]=3)[CH:13]=[C:9]2[C:8](=[O:27])[N:7]([CH3:28])[C:6]1=[O:29])[CH:2]([CH3:4])[CH3:3].Cl[N:31]1[C:35](=[O:36])[CH2:34][CH2:33][C:32]1=[O:37]>C(Cl)(Cl)(Cl)Cl.CN(C=O)C>[O:37]=[C:32]1[CH2:33][CH2:34][C:35](=[O:36])[N:31]1[C:11]1[N:12]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)=[CH:17][CH:16]=2)[CH:13]=[C:9]2[C:8](=[O:27])[N:7]([CH3:28])[C:6](=[O:29])[N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:10]=12
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2cn(Cc3ccc(-c4ccccn4)cc3)cc21
Solvent: CN(C)C=O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)Cn1c(=O)n(C)c(=O)c2cn(Cc3ccc(-c4ccccn4)cc3)c(N3C(=O)CCC3=O)c21
Temperature: 100 °C
Yield: 17.2 %

Procedure:
1-isobutyl-3-methyl-6-(4-(pyridin-2-yl)benzyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (186 mg, 0.48 mmol) is dissolved in a mixture of CCl4 and DMF (3/1, v/v), and then N-chlorosuccinimide (67 mg, 0.51 mmol) is added. The reaction mixture is heated in a Biotage microwave at 100° C. for 30 min. Solvents are removed under vacuum, and the residue is purified by a semi-preparative HPLC to give pure product as white solids (40 mg, yield 20%). MS (ESI) m/z 486.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2].[C:24](Cl)(=[O:33])[C:25]1[C:26]([O:31][CH3:32])=[CH:27][CH:28]=[CH:29][CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[O:31][CH3:32])[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: COc1ccccc1C(=O)Cl
Reactant: CCOC(=O)c1cncc2c(COc3cccc(N)c3)csc12
Product: CCOC(=O)c1cncc2c(COc3cccc(NC(=O)c4ccccc4OC)c3)csc12

Procedure:
3-[3-(2-Methoxy-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester was prepared from 3-(3-amino-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (from Example 3 supra) and o-anisoyl chloride (Aldrich) following the procedure described in Example 10 as an off-white solid.
Reaction SMILES: [F:1][C:2]1[C:3]([I:12])=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[CH2:13]([O:15][C:16]([C:18]1[C:22]([CH3:23])=[C:21]([CH:24]=O)[NH:20][CH:19]=1)=[O:17])[CH3:14]>N1CCCCC1.CC(O)C>[CH2:13]([O:15][C:16]([C:18]1[C:22]([CH3:23])=[C:21](/[CH:24]=[C:5]2\[C:6](=[O:11])[NH:7][C:8]3[C:4]\2=[C:3]([I:12])[C:2]([F:1])=[CH:10][CH:9]=3)[NH:20][CH:19]=1)=[O:17])[CH3:14]
Reactant: O=C1Cc2c(ccc(F)c2I)N1
Reactant: CCOC(=O)c1c[nH]c(C=O)c1C
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: CCOC(=O)c1c[nH]c(/C=C2\C(=O)Nc3ccc(F)c(I)c32)c1C
Temperature: 80 °C

Procedure:
A suspension of 1,3-dihydro-5-fluoro-4-iodo-2H-indol-2-one (0.5 g, 1.8 mmol) (Example 2A) and 5-formyl-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (0.39 g, 2.17 mmol) (Example 116A above) in 1% piperidine in 2-propanol (6 mL) was heated at 80° C. for 3 h. The precipitate was collected and washed with water to give (Z)-5-(5-Fluoro-4-iodo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-4-methyl-1H-pyrrole-3-carboxylic acid ethyl ester. (Yield 0.67 g, 85%).
Reaction SMILES: [CH2:1]([C:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)C1C=CC=CC=1.[CH:17]1C(Cl)=CC=C(Cl)C=1>CCCCCC>[CH2:10]1[CH:11]2[CH:12]3[CH:13]=[CH:14][CH:15]([CH:16]2[CH:1]=[CH:8]1)[CH2:17]3
Reactant: O=C(Cc1ccccc1)Cc1ccccc1
Reactant: Clc1ccc(Cl)cc1
Solvent: CCCCCC
Product: C1=CC2C3C=CC(C3)C2C1

Procedure:
A one mole equivalent sample of product II and two mole equivalent of dibenzylketone is heated for 4 hours in a mechanically stirred dichlorobenzene solution. The mixture is diluted with addition of hexane and the solid product is filtered, washed with hexane and dried. Purification of this product may be carried out by recrystallization from acetone or methyl ethyl ketone. ##STR42##
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10](=[CH:11][CH:12]=1)[C:8](=[O:9])[O:7][C:6]([C:13](O)=[O:14])=[C:5]2[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH3:22]C1(C)OC(=O)CC(=O)O1.C(N(CC)CC)C.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.ClCCl>[C:13]([C:6]1[O:7][C:8](=[O:9])[C:10]2[C:4]([C:5]=1[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[CH:3][C:2]([Br:1])=[CH:12][CH:11]=2)(=[O:14])[CH3:22]
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(O)c1oc(=O)c2ccc(Br)cc2c1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1oc(=O)c2ccc(Br)cc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.9 %

Procedure:
[Step 1] To a solution of 6-bromo-4-phenyl-3-isocoumarincarboxylic acid (10.3 g), 2,2-dimethyl-[1,3]dioxane-4,6-dione (4.76 g), dimethylpyridin-4-yl-amine (5.50 g) and triethylamine (6.3 ml) in dichloromethane (100 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (8.6 g) at room temperature and the mixture was stirred at room temperature for 15 hrs. The mixture was diluted with dichloromethane, washed with 1N hydrochloric acid and saturated brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue dissolved in water (200 ml) and acetic acid (100 ml) and the mixture was heated under reflux for 10 hrs. The solvent was evaporated under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium hydrogen carbonate solution and saturated brine and dried by adding sodium sulfate. The obtained residue was crystallized from diisopropyl ether to give 3-acetyl-6-bromo-4-phenyl-isochromen-1-one (8.29 g, 81%).
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][S:5][C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[NH2:8].[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)CCl>[Br:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[CH2:4][S:5][C:6]1[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=1[NH:8][CH:27]1[CH2:28][CH2:29][N:24]([C:22]([O:21][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:23])[CH2:25][CH2:26]1
Reactant: Nc1ccccc1SCc1ccccc1Br
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2SCc2ccccc2Br)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(2-bromobenzyl)thioaniline (7.55 g) and 1-tert-butyloxycarbonylpiperidin-4-one (6.68 g) in 2-dichloroethane (100 ml) were added acetic acid (30 ml) and sodium triacetoxyborohydride (7.1 g), and the mixture was stirred at a room temperature for 2 hours. Additional amount of sodium triacetoxyborohydride (500 mg) was added, and the mixture was further stirred at a room temperature for 2 hours. The reaction was concentrated under reduced pressure, diluted with ethyl acetate, washed successively with water, a saturated aqueous sodium hydrogen carbonate solution, and water, dried over magnesium sulfate, and the solvent was removed. The residue thus obtained was purified by chromatography on a silica gel column (250 g) to give the title compound as a resinous product (11.2 g, 91%) from the fraction eluted with n-hexane:ethyl acetate=5:1.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10]=O)=[CH:6][C:3]=1[C:4]#[N:5].[NH2:12]/[C:13](/[CH3:17])=[CH:14]\[C:15]#[N:16]>C(O)(=O)C>[C:4]([C:3]1[CH:6]=[C:7]([CH:10]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[NH:12][C:2]([CH3:9])=[C:3]2[C:4]#[N:5])[CH:8]=[CH:9][C:2]=1[F:1])#[N:5]
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: C/C(N)=C/C#N
Solvent: CC(=O)O
Product: CC1=C(C#N)C(c2ccc(F)c(C#N)c2)C(C#N)=C(C)N1
Temperature: 90 °C
Reaction time: 4 h
Yield: 160.7 %

Procedure:
30 g (201.2 mmol) 2-fluoro-5-formylbenzonitrile and 35 g (431.6 mmol) 3-aminocrotononitrile were dissolved in acetic acid (500 ml) and heated to 90° C. After 4 h, the reaction mixture was cooled to rt, concentrated, neutralized with a saturated aqueous solution of sodium bicarbonate, and extracted with ethyl acetate. The organic extracts were combined, dried over sodium sulfate and concentrated under reduced pressure. The remaining solid was dissolved in ethyl acetate, and hexane was added. The precipitate was filtered off to afford the title compound (45 g, 80% of th.) as a pale yellow solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.[C:15](#[N:20])[CH2:16][CH2:17][CH2:18][CH3:19].[OH-].[Na+]>>[O:12]1[CH2:13][CH2:14][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[NH:2][C:15](=[NH:20])[CH2:16][CH2:17][CH2:18][CH3:19])[CH2:10][CH2:11]1
Reactant: CCCCC#N
Reactant: Nc1ccccc1N1CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCCC(=N)Nc1ccccc1N1CCOCC1

Procedure:
A mixture of 4-(2-aminophenyl)morpholine hydrochloride (6.5 g) and valeronitrile (35 ml) were heated at 160°-165° C. under nitrogen for 25 hours and then cooled. The mixture was treated with aqueous sodium hydroxide and the basified mixture was extracted with dichloromethane. The solvent was removed by evaporation and the residue distilled under a pressure of 50 mm Hg to remove half the unreacted valeronitrile. A solid separated on cooling which was separated by filtration, washed with hexane (50 ml) and recrystallised from hexane to give N-(2-morpholinophenyl)valeramidine. (m.p. 135°-136° C.).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH2:7]([O:14][C:15]([NH:17][CH:18]1[CH2:23][CH2:22][CH:21]([C:24]([OH:26])=O)[CH2:20][CH2:19]1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.[CH3:28][NH:29][O:30][CH3:31]>ClCCl.N1C=CC=CC=1>[CH2:7]([O:14][C:15](=[O:16])[NH:17][CH:18]1[CH2:19][CH2:20][CH:21]([C:24](=[O:26])[N:29]([O:30][CH3:31])[CH3:28])[CH2:22][CH2:23]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(NC1CCC(C(=O)O)CC1)OCc1ccccc1
Reactant: CNOC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CON(C)C(=O)C1CCC(NC(=O)OCc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.6 %

Procedure:
Oxalyl chloride (0.796 mL, 9.1 mmol) was added slowly to a solution of 4-benzyloxycarbonylamino-cyclohexanecarboxylic acid (2.3 g, 8.3 mmil) in dichloromethane (20 mL). The mixture was stirred at room temperature under nitrogen for 1 hour. Solvent was removed under reduced pressure. N,O-Dimethylhydroxylamine hydrochloride (0.971 g, 9.96 mmol) in anhydrous pyridine (10 mL) was added to the reaction residue. The mixture was stirred at room temperature for 3 hours. Solvent was removed under reduced pressure, and the residue was partitioned between ethyl acetate and water. Ethyl acetate solution was washed with brine, dried over sodium sulfate, filtered, and concentrated to give 1.0 g (38%) of (4-(methoxy-methyl-carbamoyl)-cyclohexyl)-carbamic acid benzyl ester as yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.36 (m, 5H), 4.59 (s, 2H), 3.88 (m, 1H), 3.70 (s, 3H), 3.17 (s, 3H), 2.76 (m, 1H), 1.86 (m, 2H), 1.66 (m, 6H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[OH:18][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:28]=1[N:27]=[CH:26][CH:25]=[CH:24]2.[H-].[Na+]>CN(C=O)C.[Cu]I>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([O:18][C:19]3[CH:20]=[CH:21][CH:22]=[C:23]4[C:28]=3[N:27]=[CH:26][CH:25]=[CH:24]4)[CH:7]=2)=[CH:9][CH:10]=1
Reactant: FC(F)(F)c1ccc(-c2ccnc(Cl)c2)cc1
Reactant: Oc1cccc2cccnc12
Agent: [Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(-c2ccnc(Oc3cccc4cccnc34)c2)cc1

Procedure:
This material was prepared according to the method described in Example 413 using 2-chloro-4-(4-trifluoromethyl-phenyl)-pyridine (Example 410 (c), 0.16 g, 0.6 mmol), 8-hydroxyquinoline (0.1 g, 0.7 mmol), sodium hydride (38 mg, 1.0 mmol) and copper (I) iodide (12 mg, 0.06 mmol) in DMF (3 ML). Purification on a Biotage 40S column (3:1 hexanes: EtOAc), provided the title compound as a white solid. MS (ESI, pos. ion) nm/z: 367 (M+1). Anal. Calcd for C21H13F3N2O: C, 68.85; H, 3.58; N, 7.65. Found: C, 68.88; H, 3.59; N, 7.51.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([OH:18])[CH:14]=3)[CH:9]2[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][NH:30]3)=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:38][C:39]([NH2:41])=[O:40]>C1COCC1.CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH2:38][C:39]([NH2:41])=[O:40])[CH:14]=3)[CH:9]2[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][NH:30]3)=[CH:22][CH:21]=2)=[CH:4][CH:3]=1
Reactant: NC(=O)CBr
Reactant: Oc1ccc2c(c1)CCN(c1ccc(F)cc1)C2Cc1ccc(OCCC2CCCCN2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: NC(=O)COc1ccc2c(c1)CCN(c1ccc(F)cc1)C2Cc1ccc(OCCC2CCCCN2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 4.8 %

Procedure:
To a solution of 2-(4-fluorophenyl)-1-{4-[(2-piperidyl)ethoxy]benzyl}-1,2,3,4-tetrahydroisoquinolin-6-ol (0.100 g, 0.2 mmol) in THF (1 ml) and DMF (5 drops) on ice was added sodium hydride (0.024 g, 0.6 mmol). To the flask was added bromoacetamide (0.083 g, 0.6 mmol). While warming to room temperature the reaction was allowed to stir for 6 hours. The reaction was quenched with an aqueous solution of sodium bicarbonate and extracted with dichloromethane. The organic layer was dried over MgSO4, filtered and concentrated. The product was purified by HPLC as described above to yield the title compound (0.005 g, 4.8% yield): ES-MS (m/z) 518 [M+H]+.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[C:8]1([C:14]2[C:18]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:17][NH:16][N:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CS(O[CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][C:41]2[N:42]=[C:43]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[O:44][C:45]=2[CH3:46])=[CH:35][CH:34]=1)(=O)=O>O>[CH3:46][C:45]1[O:44][C:43]([C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)=[N:42][C:41]=1[CH2:40][O:39][C:36]1[CH:35]=[CH:34][C:33]([CH2:32][CH2:31][N:16]2[CH:17]=[C:18]([CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:14]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)=[N:15]2)=[CH:38][CH:37]=1
Reactant: CCOC(=O)CCc1c[nH]nc1-c1ccccc1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCOS(C)(=O)=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(CCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
Sodium hydride (60%, oily, 170 mg) was added to an N,N-dimethylformamide solution (50 ml) of ethyl 3-(3-phenyl-1H-pyrazole-4-yl)propionate (890 mg) at 0° C., and this mixture was stirred at 0° C. for 30 minutes. 2-[4-(5-Methyl-2-phenyl-4-oxazolylmethoxy)phenyl]ethyl methane sulfonate (2.79 g) was added to the reaction mixture, which was stirred at 90° C. for 1 hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[1-[2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]ethyl]-3-phenyl-1H-pyrazol-4-yl]propionate (1.19 g, yield: 62%) was obtained as colorless crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 81–82° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1C=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:23][O:24][CH:25](OC)[O:26][CH3:27]>CO>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:3]=1[CH:25]([O:26][CH3:27])[O:24][CH3:23]
Reactant: COC(OC)OC
Reactant: Cc1ccc(Br)c(C=O)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COC(OC)c1cc(C)ccc1Br
Yield: 99 %

Procedure:
Step AI (3): 2-Bromo-5-methylbenzaldehyde (500 mg, 2.51 mmol) was dissolved in methanol (5.0 mL). p-Toluenesulfonic acid monohydrate (90 mg, 0.52 mmol) and trimethoxymethane (5 mL) were added. The reaction mixture was heated at reflux for 5 h. The reaction mixture was extracted with DCM and washed with saturated aqueous sodium bicarbonate. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuum to yield 1-bromo-2-(dimethoxymethyl)-4-methylbenzene (615 mg, 99%) as a colorless oil. LC-MS (M−OCH3)+=213.25. 1H NMR (CD3OD, 500 MHz) δ 7.41-7.39 (m, 2H) 6.98 (d, J=10 Hz, 1H) 5.51 (s, 1H) 3.37 (s, 6H) 2.30 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:29]=1)[N:7]=[C:8]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:9][C:10]([C:12](=[O:20])[N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])=[CH:11]2.[Si:30]([O:37][C@@H:38]1[CH2:42][CH2:41][N:40]([C:43]([C:45]2[CH:50]=[CH:49][C:48](C3OC(C)(C)C(C)(C)O3)=[CH:47][CH:46]=2)=[O:44])[CH2:39]1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]>>[Si:30]([O:37][C@@H:38]1[CH2:42][CH2:41][N:40]([C:43]([C:45]2[CH:50]=[CH:49][C:48]([C:2]3[CH:3]=[CH:4][C:5]4=[C:6]([CH:29]=3)[N:7]=[C:8]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:27])[CH3:26])[CH2:9][C:10]([C:12](=[O:20])[N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])=[CH:11]4)=[CH:47][CH:46]=2)=[O:44])[CH2:39]1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: CC1(C)OC(c2ccc(C(=O)N3CC[C@@H](O[Si](C)(C)C(C)(C)C)C3)cc2)OC1(C)C
Reactant: CCCN(CCC)C(=O)C1=Cc2ccc(Br)cc2N=C(NC(=O)OC(C)(C)C)C1
Product: CCCN(CCC)C(=O)C1=Cc2ccc(-c3ccc(C(=O)N4CC[C@@H](O[Si](C)(C)C(C)(C)C)C4)cc3)cc2N=C(NC(=O)OC(C)(C)C)C1

Procedure:
The title compound was prepared by the procedure as described in Example 124 (Step F) using tert-butyl (1E,4E)-8-bromo-4-(dipropylcarbamoyl)-3H-benzo[b]azepin-2-ylcarbamate and (R)-(3-(tert-butyldimethylsilyloxy)pyrrolidin-1-yl)(4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl)methanone. MS APCI (+) m/z 689 (M+1) detected.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH:30]=O)=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:32])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:33][O:34][CH2:35][C@@H:36]([NH2:38])[CH3:37].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH2:30][NH:38][C@@H:36]([CH3:37])[CH2:35][O:34][CH3:33])=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:32])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: COC[C@H](C)N
Reactant: O=Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC[C@H](C)NCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.7 %

Procedure:
To a stirred suspension of carbaldehyde 321 (336 mg, 0.749 mmol), (S)-1-methoxy-2-aminopropane (200 mg, 2.248 mmol) and acetic acid (68 mg, 1.124 mmol) in DCM (20 ml) at rt under nitrogen was added NaBH(OAc)3 (418 mg, 1.873 mmol). The reaction mixture was stirred at rt overnight and quenched with a solution of 10% HCl. The layers were separated; the aqueous layer was collected, washed twice with DCM and basified with 4N NaOH (pH 12) to form a suspension that was stirred for 30 min. The solid was collected by filtration, rinsed with water and air-dried and purified by flash column chromatography on silica gel (eluent 2% of ammonium hydroxyde in MeOH/DCM: 10/90) to afford the title compound 334 (182 mg, 0.35 mmol, 46% yield) as a yellow fluffy solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.71 (s, 1H), 8.58 (d, J=1.6 Hz, 1H), 8.51 (d, J=5.5 Hz, 1H), 8.31 (s, 1H), 8.23 (d, J=8.2 Hz, 1H), 7.91 (dd, J=8.2, 2.2 Hz, 1H), 7.73 (dd, J=13.6, 2.4 Hz, 1H), 7.38 (t, J=9.0 Hz, 1H), 7.23-7.17 (m, 1H), 6.64 (d, J=5.5 Hz, 1H), 6.57 (bd, J=2.7 Hz, 1H), 3.84 (d, J=14.5 Hz, 1H), 3.78 (d, J=14.5 Hz, 1H), 3.27 (dd, J=9.4, 6.3 Hz, 1H), 3.24 (s, 3H), 3.19 (dd, J=9.2, 5.5 Hz, 1H), 2.81-2.71 (m, 1H), 2.59-2.51 (m, 1H), 2.36-2.10 (m, 1H), 0.98 (d, J=6.3 Hz, 3H), 0.69-0.62 (m, 2H), 0.46-0.40 (m, 2H). MS (m/z): 522.4 (M+H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2([F:25])[CH2:23][CH:22]2[NH2:24])=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C@@:21]2([F:25])[CH2:23][C@H:22]2[NH:24][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=2[C:2]([F:13])([F:12])[F:1])=[CH:19][CH:20]=1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: NC1CC1(F)c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@@H]1C[C@]1(F)c1ccc(Cl)cc1)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2-trifluoromethylbenzoyl chloride (0.10 g; 0.54 mmol) in dichloromethane (2 ml) added dropwise to a stirred solution of the amine from example P5 (compound Z1.004; 2-(4-chlorophenyl)-2-fluoro-cyclopropylamine; 0.100 g; 0.54 mmol) and triethylamine (0.15 ml; 1.08 m) in dichloromethane (3 ml). Stirred for 1 hr at room temperature then allowed to stand for 18 hr. The white precipitate was filtered off, washed with 2M HCl, saturated NaHCO3 and water and air dried giving the pure cis isomer. 0.065 g (34%).
Reaction SMILES: C([O:3][C:4](=[O:23])[CH:5]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([S:21][CH3:22])[N:16]=1)[C:6]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)=O)C.COC(=O)C(C1C=CC(F)=CC=1)C(=O)C1C=C[N:32]=CC=1.C(O)C>N1C=CC=CC=1>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[NH:32][O:3][C:4](=[O:23])[C:5]=2[C:15]2[CH:20]=[CH:19][N:18]=[C:17]([S:21][CH3:22])[N:16]=2)=[CH:9][CH:10]=1
Reactant: CCOC(=O)C(C(=O)c1ccc(F)cc1)c1ccnc(SC)n1
Reactant: COC(=O)C(C(=O)c1ccncc1)c1ccc(F)cc1
Solvent: c1ccncc1
Solvent: CCO
Product: CSc1nccc(-c2c(-c3ccc(F)cc3)[nH]oc2=O)n1

Procedure:
Using the procedure from Example 1k set forth above, substitute 3-(4-fluorophenyl)-3-oxo-2-(2-methylsulfanyl-pyrimidin-4-yl)-propionic acid ethyl ester for 2-(4-fluorophenyl)-3-oxo-3-pyridin-4-yl-propionic acid methyl ester and ethanol for pyridine to produce the title compound.