Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[S:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27]Cl>>[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][N:8]1[C:9]([S:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19]
Reactant: ClCc1ccccn1
Reactant: Cc1cc(C)cc(Sc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Product: Cc1cc(C)cc(Sc2c(C(C)C)c(=O)[nH]c(=O)n2Cc2ccccn2)c1
Yield: 29.4 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenyl)thio-2,4-pyrimidinedione and 2-picolyl chloride were reacted by the same way with the example 1 to obtain the titled compound (112 mg, yield: 29.4%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[C:13](Br)[CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[C:19]1(B2OC(C)(C)C(C)(C)O2)[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]=1>CCOC(C)=O.C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([C:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH:20]=3)[CH:12]=2)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(c2ccc(N)c(Br)c2)CCOCC1
Reactant: CC1(C)OB(C2=CCCCC2)OC1(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)C1(c2ccc(N)c(C3=CCCCC3)c2)CCOCC1
Yield: 70 %

Procedure:
The title compound was prepared by the Suzuki coupling procedure of Example 16, step (d) using 4-(4-amino-3-bromo-phenyl)-tetrahydro-pyran-4-carboxylic acid methyl ester (as prepared in the Example 16, step (c), 380 mg, 1.21 mmol), and 2-cyclohex-1-enyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (277 mg, 1.33 mmol). Silica gel chromatography (0-2% EtOAc/DCM) afforded the title compound (268 mg, 70%) as a white solid. Mass spectrum (ESI, m/z): Calcd. for C19H25NO3, 316.2 (M+H). found 316.2.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.[Mg].C(O)(=O)C>CO>[CH3:1][N:2]([CH3:14])[C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc2ccc(=O)[nH]c2c1
Agent: [Mg]
Solvent: CC(=O)O
Solvent: CO
Product: CN(C)c1ccc2c(c1)NC(=O)CC2
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.9 %

Procedure:
To a solution of 1.0 g (5.7 mmol) of 7-dimethylamino-2-quinolone [A. Rice, Ann. Chim. 48: 958-996(1958)] in 40 mL of MeOH was added 1.3 g (5.7 mmol) of magnesium. The reaction was warmed gently on a steam bath, and then was allowed to stir for two hours at room temperature. Acetic acid (8 mL) was then added and the solution filtered. The filtrate was concentrated and the residue chromatographed on 200 g of silica gel, eluting with 97.5:2.5 (v/v) CH2Cl2 :MeOH. Fractions 50-60 (12 mL/fraction) were combined and concentrated to yield 0.4 g of the dihydroquinolone as a white solid, m.p. 154°-156° C.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[C:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH:22]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:27]C1CCC(B(O)O)=CC1>>[C:1]([O:5][C@@H:6]([C:10]1[C:19]([CH3:20])=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[C:21]1[CH2:26][CH2:25][CH:24]([CH3:27])[CH2:23][CH:22]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1CC=C(B(O)O)CC1
Reactant: Cc1cc2ccccc2c(C2=CCCCC2)c1[C@H](OC(C)(C)C)C(=O)O
Product: Cc1cc2ccccc2c(C2=CCC(C)CC2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(2S)-2-tert-Butoxy-2-(3-methyl-1-(4-methylcyclohex-1-enyl)naphthalen-2-yl)acetic acid was prepared following the procedure to make (S)-2-tert-butoxy-2-(1-cyclohexenyl-3-methylnaphthalen-2-yl)acetic acid of Example 6, except that 4-methylcyclohex-1-enylboronic acid was used instead of cyclohexenylboronic acid. 1H-NMR: 400 MHz, (CD3OD) δ: 7.92-7.78 (m, 1H), 7.70 (m,1H), 7.52 (s, 1H), 7.39 (m, 2H), 6.10-5.58 (m, 2H), 2.56 (s,3H), 2.65-1.84 (m, 6H), 1.50 (m, 1H), 1.22 (s, 9H), 1.14 (t, 3H). LCMS-ESF (m/z): [M−H]− calcd for C24H29O3: 365.49. found: 365.1.
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8][CH2:9][C:10]([O:12][CH:13]2[CH:17]([OH:18])[CH2:16][O:15][CH2:14]2)=[O:11])=[CH:6][C:5]([N:19]=[C:20]2[N:28]3[N:23]([CH2:24][CH2:25][CH2:26][CH2:27]3)[C:22](=[O:29])[S:21]2)=[C:4]([F:30])[CH:3]=1.N1C=CC=CC=1.[Cl:37][CH2:38][C:39](Cl)=[O:40]>ClCCl>[Cl:1][C:2]1[C:7]([S:8][CH2:9][C:10]([O:12][CH:13]2[CH:17]([O:18][C:39](=[O:40])[CH2:38][Cl:37])[CH2:16][O:15][CH2:14]2)=[O:11])=[CH:6][C:5]([N:19]=[C:20]2[N:28]3[N:23]([CH2:24][CH2:25][CH2:26][CH2:27]3)[C:22](=[O:29])[S:21]2)=[C:4]([F:30])[CH:3]=1
Reactant: O=C(Cl)CCl
Reactant: O=C(CSc1cc(N=c2sc(=O)n3n2CCCC3)c(F)cc1Cl)OC1COCC1O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(CCl)OC1COCC1OC(=O)CSc1cc(N=c2sc(=O)n3n2CCCC3)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.8 %

Procedure:
In 25 ml of dichloromethane were dissolved 1.19 g of 9-(4-chloro-2-fluoro-5-(4-hydroxytetrahydrofuran-3-yloxycarbonylmethylthio)phenylimino)- 8-thia-1,6diazabicyclo[4.3.0]nonan-7-one and 0.24 g of pyridine, followed by dropwise addition of a solution of 0.34 g of chloroacetyl chloride in dichloromethane. After stirring at room temperature overnight, the reaction mixture was washed with water, and subsequently with aqueous saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by chromatography on a silica gel column (eluted with ethyl acetate/hexane =2/3), to obtain 1.02 g of a compound described in Table 1 (No. 32) (74%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([CH3:13])([CH3:12])[CH2:10][NH2:11])=[CH:4][CH:3]=1.[CH2:14]([O:21][C:22](=[O:32])[NH:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[CH:30]=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[BH4-].[Na+].[OH-].[Na+]>CO>[CH2:14]([O:21][C:22](=[O:32])[NH:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[CH2:30][NH:11][CH2:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=CC1CCCCC1NC(=O)OCc1ccccc1
Reactant: CC(C)(CN)Cc1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(CNCC1CCCCC1NC(=O)OCc1ccccc1)Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.9 %

Procedure:
3-(4-Fluorophenyl)-2,2-dimethylpropylamine (253 mg, 1.39 mmol) and (2-formylcyclohexyl)carbamic acid benzyl ester (363 mg, 1.39 mmol) were dissolved in methanol (6 mL) and stirred at room temperature for 4 h. Sodium borohydride (84 mg, 2.22 mmol) was added, and the mixture was stirred for 30 min. 1.0 M aqueous sodium hydroxide was added, and the mixture was extracted with ether. The organic phase was washed with saturated aqueous sodium chloride and dried over sodium sulfate, and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with 5% methanol in dichloromethane containing 0.5% aqueous ammonium hydroxide, to provide a colorless gum (450 mg, 76%).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=1)=[O:4].[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:1][CH2:2][C:3](=[O:4])[NH:5][CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)=[O:26])=[CH:23][CH:22]=1
Reactant: Cc1ccc(C(NC(=O)CN)c2ccccc2)cc1
Reactant: O=C(O)c1ccc(Cl)cc1
Product: Cc1ccc(C(NC(=O)CNC(=O)c2ccc(Cl)cc2)c2ccccc2)cc1

Procedure:
Prepared in analogy to example 1.12 from rac-2-amino-N-(phenyl-p-tolyl-methyl)-acetamide (Example 3.3) and 4-chlorobenzoic acid.
Reaction SMILES: Cl[P:2]1([O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:7]=[P:6](Cl)([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:5]=[P:4](Cl)([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:3]=1.[N+:31]([C:34]1[CH:40]=[CH:39][C:37]([O-:38])=[CH:36][CH:35]=1)([O-:33])=[O:32].[Na+]>O1CCCC1>[N+:31]([C:28]1[CH:29]=[CH:30][C:25]([O:24][P:2]2([O:38][C:37]3[CH:39]=[CH:40][CH:34]=[CH:35][CH:36]=3)[N:7]=[P:6]([O:38][C:37]3[CH:39]=[CH:40][C:34]([N+:31]([O-:33])=[O:32])=[CH:35][CH:36]=3)([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[N:5]=[P:4]([O:38][C:37]3[CH:39]=[CH:40][C:34]([N+:31]([O-:33])=[O:32])=[CH:35][CH:36]=3)([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:3]=2)=[CH:26][CH:27]=1)([O-:33])=[O:32]
Reactant: ClP1(Oc2ccccc2)=NP(Cl)(Oc2ccccc2)=NP(Cl)(Oc2ccccc2)=N1
Reactant: O=[N+]([O-])c1ccc([O-])cc1
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(OP2(Oc3ccccc3)=NP(Oc3ccccc3)(Oc3ccc([N+](=O)[O-])cc3)=NP(Oc3ccccc3)(Oc3ccc([N+](=O)[O-])cc3)=N2)cc1

Procedure:
This material is obtained as a white solid by the treatment of sodium and phenol with hexachlorocyclotriphosphazene at -78° C. to produce the trichlorotriphenoxycyclotriphosphazene, according to D. Dell et al., J. Chem. Soc., 4072 (1965), which is incorporated herein by reference. This material is further reacted with sodium 4-nitrophenoxide in refluxing tetrahydrofuran to give the title compound in good yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:24]#[N:25])[S:11][C:12]=2[C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([CH3:23])=[CH:15][CH:14]=2)=[C:4]([CH3:26])[CH:3]=1.[N-:27]=[N+:28]=[N-:29].[Na+]>[Br-].[Zn+2].[Br-]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:24]3[NH:29][N:28]=[N:27][N:25]=3)[S:11][C:12]=2[C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([CH3:23])=[CH:15][CH:14]=2)=[C:4]([CH3:26])[CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(Cl)ccc1-c1cc(C#N)sc1-c1ccc(C)c2ccccc12
Agent: [Br-]
Agent: [Na+]
Agent: [Zn+2]
Product: Cc1cc(Cl)ccc1-c1cc(-c2nnn[nH]2)sc1-c1ccc(C)c2ccccc12
Temperature: 110 °C
Yield: 83.9 %

Procedure:
A round-bottomed flask was charged with 4-(4-chloro-2-methylphenyl)-5-(4-methylnaphthalen-1-yl)thiophene-2-carbonitrile (209 mg, 0.56 mmol), zinc bromide (338 mg, 1.50 mmol) and sodium azide (97.5 mg, 1.50 mmol). After degassed, DMF (3 mL) was added. The reaction mixture was heated to 110° C. and stirred at this temperature until complete. The reaction was cooled to rt, and 30 mL of 0.1 N aqueous HCl was added. The reaction mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulphate and then concentrated. The residue was purified by flash chromatography (hexane:EtOAc:AcOH=30:10:1). 196 mg (84%) of product was obtained as a white solid, 1H NMR (DMSO, 500 MHz) δ 8.03 (d, J=8.40 Hz, 1H), 7.88 (s, 1H), 7.80 (d, J=8.05 Hz, 1H), 7.55 (t, J=7.68 Hz, 1H), 7.48 (t, J=7.65 Hz, 1H), 7.45 (d, J=7.19 Hz, 1H), 7.37 (d, J=7.30 Hz, 1H), 7.23 (d, J=1.95 Hz, 1H), 7.09 (d, J=8.25 Hz, 1H), 7.04 (dd, J=8.25 Hz, J2=2.06 Hz, 1H), 2.65 (s, 3H), 2.17 (s, 3H); 13C NMR (DMSO, 125 MHz) δ 172.05, 141.01, 139.65, 138.35, 135.93, 133.73, 132.18, 132.10, 131.64, 131.31, 131.26, 129.80, 129.23, 127.62, 126.45, 126.26, 126.02, 125.53, 125.51, 124.67, 21.08, 19.82.
Reaction SMILES: [NH2:1][C:2]1[O:15][C:5]2[CH2:6][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:8][CH2:9][C:4]=2[C:3]=1[C:16]#[N:17].CO[CH:20](OC)[N:21]([CH3:23])[CH3:22]>>[C:16]([C:3]1[C:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:6][C:5]=2[O:15][C:2]=1/[N:1]=[CH:20]/[N:21]([CH3:23])[CH3:22])#[N:17]
Reactant: CCOC(=O)N1CCc2c(oc(N)c2C#N)C1
Reactant: COC(OC)N(C)C
Product: CCOC(=O)N1CCc2c(oc(/N=C/N(C)C)c2C#N)C1
Yield: 98.2 %

Procedure:
Ethyl 2-amino-3-cyano-4,7-dihydrofuro[2,3-c]pyridine-6(5H)-carboxylate from Example 36A (7.00 g, 29.8 mmol) was heated in dimethylformamide dimethylacetal (14.7 mL, 110 mmol) for 30 min to 110° C. The mixture was then concentrated in vacuo, and the residue was triturated with petroleum ether, the solvent was decanted, and the trituration was repeated. The remaining solid was then triturated with diethyl ether/petroleum ether (1:1), and the precipitate was collected by suction filtration to yield 8.5 g (98%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=O)[S:5][CH:6]=1.C([O:11][C:12](=[O:17])[CH2:13][N:14]=[N+]=[N-])C.[NH4+].[Cl-]>C(O)C>[Br:1][C:2]1[C:3]2[NH:14][C:13]([C:12]([OH:17])=[O:11])=[CH:7][C:4]=2[S:5][CH:6]=1
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: O=Cc1cc(Br)cs1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: O=C(O)c1cc2scc(Br)c2[nH]1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-Bromo-thiophene-2-carbaldehyde was annulated according to Procedure H (aldehyde and azido-acetic acid ethyl ester added as ethanol solution (1.2 M of ester) such that reaction temperature maintained at 0° C.; reaction mixture allowed to warm to 10° C., stirred for 1 h, poured into cold saturated aqueous NH4Cl; after ether extractions, combined acrylate organic phases washed with water until aqueous phase was neutral; acrylate not purified).
Reaction SMILES: [N:1]([CH2:4][CH:5]([OH:13])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[N+]=[N-].[H][H]>CO.[OH-].[OH-].[Pd+2]>[NH2:1][CH2:4][CH:5]([OH:13])[CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: [H][H]
Reactant: [N-]=[N+]=NCC(O)Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: NCC(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirring solution of 1-azido-3-phenyl-propan-2-ol (590 mg, 3.4 mmol) in 20 mL methanol under a nitrogen atmosphere was added 10 mg of Pd(OH)2/C (10%). Hydrogen gas was delivered via balloon. The solution was stirred overnight at room temperature. The catalyst was removed by filtering the solution through a bed of celite, and the filtrate was concentrated to give a clear oil under reduced pressure. M+1=152.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[C:6]([CH:9]=1)[CH2:7][NH2:8].[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([CH2:30][C:31](O)=[O:32])[CH:22]=[CH:23][C:24]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH3:17]>>[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([CH2:30][C:31]([NH:8][CH2:7][C:6]2[CH:9]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[N:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)=[O:32])[CH:22]=[CH:23][C:24]=1[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH3:17]
Reactant: CCOC(=O)c1ccc(CC(=O)O)cc1OCC
Reactant: NCc1cc(Cl)ccc1N1CCCCC1
Product: CCOC(=O)c1ccc(CC(=O)NCc2cc(Cl)ccc2N2CCCCC2)cc1OCC

Procedure:
Prepared from 5-chloro-2-piperidino-benzylamine and 3-ethoxy-4-ethoxycarbonyl-phenylacetic acid.
Reaction SMILES: C([N:8]1[CH2:31][C:12]2([CH2:17][CH2:16][N:15]([C:18]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH:27]([CH3:29])[CH3:28])=[C:22]([CH3:30])[CH:21]=3)=[O:19])[CH2:14][CH2:13]2)[O:11][CH:10]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CO>[CH:27]([O:26][C:23]1[CH:24]=[CH:25][C:20]([C:18]([N:15]2[CH2:14][CH2:13][C:12]3([CH2:31][NH:8][CH2:9][CH:10]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[O:11]3)[CH2:17][CH2:16]2)=[O:19])=[CH:21][C:22]=1[CH3:30])([CH3:29])[CH3:28]
Reactant: Cc1cc(C(=O)N2CCC3(CC2)CN(Cc2ccccc2)CC(c2ccccc2)O3)ccc1OC(C)C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1cc(C(=O)N2CCC3(CC2)CNCC(c2ccccc2)O3)ccc1OC(C)C
Temperature: 75 °C
Reaction time: 0.67 h
Yield: 78.5 %

Procedure:
To (10-benzyl-8-phenyl-7-oxa-3,10-diazaspiro[5.5]undecan-3-yl)-(4-isopropoxy-3-methyl-phenyl)methanone (264 mg, 0.53 mmol), ammonium formate (167 mg, 2.65 mmol), palladium (30 mg, 0.03 mmol) (10% on carbon) was added methanol (5 mL) and the reaction mixture was stirred at 75° C. for 40 minutes. The reaction mixture was cooled, filtered over celite and concentrated in vacuo. The residue was partitioned between ethyl acetate and 1:1 sat. aq. NaHCO3/25% aq. NaOH, dried over MgSO4, filtered and concentrated in vacuo to give (4-isopropoxy-3-methyl-phenyl)-(8-phenyl-7-oxa-3,10-diazaspiro[5.5]undecan-3-yl)methanone (170 mg, 79%), which was used directly without further purification in the next step. ESI-MS m/z calc. 408.5. found 409.7 (M+1)+; Retention time: 1.24 minutes (3 min run).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:49]([CH3:51])[CH3:50])[N:11](/[CH:20]=[CH:21]/[C@@H:22]([OH:48])[CH2:23][C:24]([O:26][C@@H:27](C3C=CC=CC=3)C(O)(C3C=CC=CC=3)C3C=CC=CC=3)=[O:25])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[Na]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:49]([CH3:51])[CH3:50])[N:11](/[CH:20]=[CH:21]/[C@@H:22]([OH:48])[CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1
Reactant: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1/C=C/[C@@H](O)CC(=O)O[C@@H](c1ccccc1)C(O)(c1ccccc1)c1ccccc1
Agent: [Na]
Solvent: CO
Product: COC(=O)C[C@H](O)/C=C/n1c(C(C)C)nc(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 82 %

Procedure:
A stirred suspension of (S)-1-hydroxy-1,1,2-triphenyleth-2-yl(3S,E)-5-[4,5-bis(4-fluorophenyl)-2-(1-methylethyl)-1H-imidazol-1-yl]-3-hydroxy-4-pentenoate (3.11 g) in methanol (30 ml) was treated with a solution of sodium (110 mg) in methanol (20 ml) plus methanol washings (2×5 ml). The resulting orange solution was stirred at room temperature for 2.5 h then the reaction mixture was concentrated. This was dissolved in dichloromethane (150 ml) and the solution was washed with water (50 ml) and brine (2×50 ml). The combined washings were extracted with dichloromethane (50 ml) and the combined organic phases were dried and evaporated to a pale buff solid (3.13 g). This was purified by CC eluting with System A 1:1 to give the title compound (1.588 g) as a white crystalline solid, νmax (nujol) 1738 cm-1 (C=O).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:24]#[N:25])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:9]=2)=[O:4].[CH3:26][O:27][C:28](=[O:34])[C:29]([CH3:33])([CH3:32])[CH2:30][NH2:31]>CCO>[CH3:26][O:27][C:28](=[O:34])[C:29]([CH3:33])([CH3:32])[CH2:30][NH:31][C:3]([C:5]1[N:6]=[C:7]([C:24]#[N:25])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH:9]=2)=[O:4]
Reactant: COC(=O)C(C)(C)CN
Reactant: COC(=O)c1nc(C#N)c2cc(CCc3ccccc3)ccc2c1O
Solvent: CCO
Product: COC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(CCc3ccccc3)ccc2c1O
Temperature: 150 °C
Yield: 85 %

Procedure:
A mixture of 1-cyano-4-hydroxy-7-phenethyl-isoquinoline-3-carboxylic acid methyl ester (50 mg, 0.15 mmol) and 3-amino-2,2-dimethyl-propionic acid methyl ester (99 mg, 0.75 mmol) in EtOH (2 mL) was heated at 150° C. in a microwave reactor for 3 h. The solvent was evaporated, and the residue was purified by column chromatography (0-25% EtOAc/hexanes) to give 55 mg of the title compound. 1H NMR (CDCl3, 200 MHz): δ=14.0 (s, 1H), 8.20-8.40 (m, 2H), 7.98 (d, 1H, J=0.8
Reaction SMILES: [N:1]1[C:6]2[CH:7]=[CH:8][NH:9][C:5]=2[C:4]([NH:10][C:11]2[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=2)[C:14]([OH:16])=O)=[N:3][CH:2]=1.[CH2:20]([CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH2:20]([CH:27]1[CH2:32][CH2:31][N:30]([C:14]([C:13]2[CH:12]=[C:11]([NH:10][C:4]3[C:5]4[NH:9][CH:8]=[CH:7][C:6]=4[N:1]=[CH:2][N:3]=3)[CH:19]=[CH:18][CH:17]=2)=[O:16])[CH2:29][CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: O=C(O)c1cccc(Nc2ncnc3cc[nH]c23)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(c1cccc(Nc2ncnc3cc[nH]c23)c1)N1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.2 %

Procedure:
A mixture of 3-(5H-pyrrolo[3,2-d]pyrimidin-4-ylamino)benzoic acid (153 mg), 4-benzylpiperidine (158 mg), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (173 mg), 1-hydroxybenzotriazole (138 mg) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 3 hrs. The reaction mixture was concentrated under reduced pressure, water was added and extracted with ethyl acetate containing tetrahydrofuran. The extract washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent, methanol:ethyl acetate=0:100→20:80). The obtained product was dissolved in ethyl acetate containing methanol and tetrahydrofuran, washed with aqueous sodium hydrogen carbonate solution and saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and diisopropyl ether was added to the obtained residue. The precipitate was collected by filtration to give the title compound (201 mg) as a pale-brown powder.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[CH:4][C:3]=1[O:12][C:13]([F:16])([F:15])[F:14].CC(C[AlH]CC(C)C)C.O>C1COCC1>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:12][C:13]([F:14])([F:16])[F:15]
Reactant: COC(=O)c1ccc(Br)c(OC(F)(F)F)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc(Br)c(OC(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a cooled and stirred solution of methyl 4-bromo-3-(trifluoromethoxy)benzoate (28.2, 2.60 g, 8.70 mmol) in THF (20 mL) under nitrogen, was added DIBAL-H (19.2 mL, 1.0 M in toluene) at −78° C. The reaction mixture was stirred at 0° C. for 10 minutes and 5.0 mL of water was added. The resulting mixture was stirred at room temperature for 2 hours. The solid was then filtered off. EtOAc (100 mL) was added, and the mixture was washed with brine (20 mL) and dried with Na2SO4. The solvent was removed to give 28.3. 1H NMR (CDCl3) δ 1.91 (s, 1H), 4.71 (s, 2H), 7.18 (d, J=6.3 Hz, 1H), 7.36 (s, 1H), 7.63 (d, J=6.3 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][CH2:4][C@H:5]1[CH2:10][C@@H:9]([C:11](=[O:18])[CH2:12][C:13](OCC)=[O:14])[CH2:8][CH2:7][N:6]1[C:19]([O:21][CH3:22])=[O:20].[OH-].[Na+].Cl.[NH2:28]O.Cl>CO.CO.O.O>[CH3:1][C:2]([CH3:24])([CH3:23])[CH2:3][CH2:4][C@H:5]1[CH2:10][C@H:9]([C:11]2[O:18][NH:28][C:13](=[O:14])[CH:12]=2)[CH2:8][CH2:7][N:6]1[C:19]([O:21][CH3:22])=[O:20]
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](CCC(C)(C)C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1CCC(C)(C)C
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 38.8 %

Procedure:
A solution of cis-methyl 2-(3,3-dimethylbutyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (549 mg, 1.61 mmol) (from example 95, step 1) in MeOH (1.2 mL) was added to a solution of NaOH (70 mg, 1.75 mmol) in MeOH/H2O (1.3 mL/0.08 mL) at −30° C. After 10 min was added hydroxylaminehydrochloride (223 mg, 3.22 mmol) and NaOH (129 mg, 3.22 mmol) in MeOH (1.6 mL) and H2O (1.6 mL). Stirring was continued at −30° C. for 30 min. The reaction solution was poured into 6 M HCl (2.4 mL) at 80° C. and heated at 80° C. for 1 h. Concentration of the organic solvent and extraction with DCM (×2), drying using a phase separator and evaporation gave an orange oil. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 30-60% Acetonitrile in H2O/MeCN/FA 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Trans-methyl 2-(3,3-dimethylbutyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (194 mg, 39%) was isolated as a white solid. 1H NMR (400 MHz, cdcl3) δ 0.89 (s, 9H), 1.02-1.78 (m, 6H), 1.89-2.03 (m, 2H), 2.83-3.09 (m, 2H), 3.71 (s, 3H), 3.99-4.51 (m, 2H), 5.65 (s, 1H). MS m/z 311 (M+H)+