Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[CH:10]=[CH:11][C:12]3[N:18]=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[C:26][Si](C)(C)C)[CH:20]=4)[CH2:16][C:15](=[O:31])[NH:14][C:13]=3[CH:32]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>[OH-].[Na+].CO.C1COCC1>[C:25]([C:21]1[CH:20]=[C:19]([C:17]2[CH2:16][C:15](=[O:31])[NH:14][C:13]3[CH:32]=[C:9]([C:8]#[C:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH:10]=[CH:11][C:12]=3[N:18]=2)[CH:24]=[CH:23][CH:22]=1)#[CH:26]
Reactant: C[Si](C)(C)C#Cc1cccc(C2=Nc3ccc(C#Cc4ccccc4)cc3NC(=O)C2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C#Cc1cccc(C2=Nc3ccc(C#Cc4ccccc4)cc3NC(=O)C2)c1
Yield: 58.9 %

Procedure:
Prepared from 8-phenylethynyl-4-(3-trimethylsilanylethynyl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 132) (63 mg, 0.146 mmol) by treatment with 1N NaOH (3 drops) in MeOH (3 mL) and THF (0.5 mL) at 23° C. for 2 h. Obtained as a brown solid (31 mg).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([C:12]2[CH2:13][CH2:14][N:15]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:16][CH:17]=2)[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:30])[N:7]2[C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:29].[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[C:36](F)[CH:37]=1.C(O)(C(F)(F)F)=O>>[C:18]([N:15]1[CH2:14][CH2:13][CH:12]([C:10]2[CH:9]=[C:8]3[C:3]([CH:4]=[CH:5][C:6](=[O:30])[N:7]3[C:22]3[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:29])=[C:2]([C:35]3[CH:34]=[CH:33][C:32]([F:31])=[CH:37][CH:36]=3)[CH:11]=2)[CH2:17][CH2:16]1)([CH3:19])([CH3:21])[CH3:20]
Reactant: OB(O)c1cc(F)cc(F)c1
Reactant: CC(C)(C)N1CC=C(c2cc(Br)c3ccc(=O)n(-c4c(Cl)cccc4Cl)c3c2)CC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)N1CCC(c2cc(-c3ccc(F)cc3)c3ccc(=O)n(-c4c(Cl)cccc4Cl)c3c2)CC1

Procedure:
The title compound was prepared from 5-bromo-7-(1-tert-butyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(2,6-dichlorophenyl)quinolin-2(1H)-one (INTERMEDIATE ABA5) and using 3,5-difluorophenylboronic acid as described in EXAMPLE ABA11. 1H NMR (CD3OD, 500 MHz) TFA salt: δ 1.416 (s, 9H), 1.827 (m, 2H), 2.119 (d, J=14.7 Hz, 2H), 2.948 (m, 1H), 3.063 (t, J=11.0 Hz, 2H), 3.675 (d, J=12.6 Hz, 2H), 6.497 (s, 1H), 6.747 (d, J=9.9 Hz, 1H). 7.122 (m, 3H), 7.249 (s, 1H), 7.619 (t, J=7.6 Hz, 1H), 7.728 (m, 2H), 7.987 (d, J=10.1 Hz, 1H). Mass spectrum (ES): 541.5 (M+1).
Reaction SMILES: [CH:1]([O:4][S:5]([C:8]1[C:17]([N:18]=[N:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[C:16]([OH:28])[C:15]2[C:10](=[CH:11][C:12]([NH:29][C:30]3[N:35]=[C:34](Cl)[N:33]=[C:32]([Cl:37])[N:31]=3)=[CH:13][CH:14]=2)[CH:9]=1)(=[O:7])=[O:6])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].[NH:44]([CH2:48][CH2:49][OH:50])[CH2:45][CH2:46][OH:47]>CC(C)=O.Cl>[CH:1]([O:4][S:5]([C:8]1[C:17]([N:18]=[N:19][C:20]2[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=2)=[C:16]([OH:28])[C:15]2[C:10](=[CH:11][C:12]([NH:29][C:30]3[N:35]=[C:34]([N:44]([CH2:48][CH2:49][OH:50])[CH2:45][CH2:46][OH:47])[N:33]=[C:32]([Cl:37])[N:31]=3)=[CH:13][CH:14]=2)[CH:9]=1)(=[O:6])=[O:7])([CH3:3])[CH3:2]
Reactant: OCCNCCO
Reactant: COc1ccc(N=Nc2c(S(=O)(=O)OC(C)C)cc3cc(Nc4nc(Cl)nc(Cl)n4)ccc3c2O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COc1ccc(N=Nc2c(S(=O)(=O)OC(C)C)cc3cc(Nc4nc(Cl)nc(N(CCO)CCO)n4)ccc3c2O)cc1
Reaction time: 60 h
Yield: 77.8 %

Procedure:
7-(4,6-Dichloro-[1,3,5]-triazin-2-ylamino)-4-hydroxy-3-(4-methoxy-phenylazo)-napthalene-2-sulfonic acid isopropyl ester (Example 7, 200 mg, 0.36 mmol) in acetone (3 mL) was stirred under nitrogen with sodium carbonate (38 mg, 0.36 mmol). Diethanolamine (35 μL, 40 mg, 0.36 mmol) was added to the stirred suspension, and the reaction mixture was allowed to stir 60 h. The reaction mixture was diluted with hydrochloric acid (3 mL, 1 N) and filtered. The solid was triturated in methanol/ether (1:3) for 1 h and filtered to provide the title compound (179 mg, 0.28 mmol, 79%) as a red solid: NMR (DMSO-d6): δ 16.28 (s, 1H), 10.61 (s, 1H), 8.45 (s, 1H ), 8.30 (d, J=9 Hz, 1H), 7.88 (m, 2H), 7.76 (d, J=9 Hz, 2H), 7.15 (d, J=9 Hz, 2H), 4.78 (m, 1H), 3.90 (m, 13H), 1.23 (d, J=6 Hz, 6H); Analytical HPLC: 87%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:13]([F:16])([F:15])[F:14])=[N:4][N:5]([CH:8]([CH3:12])[C:9]([OH:11])=O)[C:6]=1[CH3:7].[F:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:32]3[CH2:31][CH2:30][CH2:29][NH:28][C:27]=3[CH:26]=[N:25]2)=[CH:20][CH:19]=1>>[Cl:1][C:2]1[C:3]([C:13]([F:16])([F:15])[F:14])=[N:4][N:5]([CH:8]([CH3:12])[C:9]([N:28]2[CH2:29][CH2:30][CH2:31][C:32]3[N:24]([C:21]4[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=4)[N:25]=[CH:26][C:27]2=3)=[O:11])[C:6]=1[CH3:7]
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1C(C)C(=O)O
Reactant: Fc1ccc(-n2ncc3c2CCCN3)cc1
Product: Cc1c(Cl)c(C(F)(F)F)nn1C(C)C(=O)N1CCCc2c1cnn2-c1ccc(F)cc1
Yield: 75 %

Procedure:
The title compound was prepared from 2-(4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl)propanoic acid and 1-(4-fluorophenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine using General Method B. The product mixture was washed with 2×1 M NaHSO4. The reaction slurry was purified by flash chromatography (SiO2, 24 g column, eluting with 5-50% EtOAc in hexanes) to provide 137 mg (75%) of the title compound as a white foam. 1H NMR (400 MHz, CDCl3) δ 8.41 (s, 1H), 7.43 (m, 2H), 7.15 (m, 2H), 5.52 (q, J=7.0 Hz, 1H), 3.75 (m, 1H), 3.41 (m, 1H), 2.81 (m, 2H), 2.28 (s, 3H), 1.85-1.99 (m, 2H), 1.81 (d, J=7 Hz, 1H); MS: (ES) m/z calculated for C20H19ClF4N5O [M+H]+ 456.1, found 456.1.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1)(=[O:4])=[O:3].[H-].[Na+].F[C:15]1[CH:20]=[CH:19][C:18]([S:21]([N:24]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[CH2:25][CH:26]([CH3:28])[CH3:27])(=[O:23])=[O:22])=[CH:17][CH:16]=1>O>[F:35][C:32]1[CH:31]=[CH:30][C:29]([N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[S:21]([C:18]2[CH:19]=[CH:20][C:15]([O:11][CH:8]3[CH2:7][CH2:6][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:10][CH2:9]3)=[CH:16][CH:17]=2)(=[O:23])=[O:22])=[CH:34][CH:33]=1
Reactant: CC(C)CN(c1ccc(F)cc1)S(=O)(=O)c1ccc(F)cc1
Reactant: CS(=O)(=O)N1CCC(O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(C)CN(c1ccc(F)cc1)S(=O)(=O)c1ccc(OC2CCN(S(C)(=O)=O)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.7 %

Procedure:
To a solution of 1-methanesulfonyl-piperidin-4-ol (61 mg) in anhydrous tetrohydrofuran (5 mL) at room temperature was added NaH (60% dispersion in mineral oil, 15 mg, 369 μmol) and the reaction was stirred at room temperature for 30 minutes. 4-Fluoro-N-(4-fluoro-phenyl)-N-isobutyl-benzenesulfonamide (100 mg, 308 μmol) was added and the reaction was heated at 90° C. for 3 hours. The reaction was allowed to cool to room temperature, water was added and then extracted with EtOAc, concentrated, purified by preparative reverse-phase HPLC and then freeze dried to give the title compound (51.8 mg). 1H NMR (400 MHz, DMSO): δ 7.44 (d, J=8.8 Hz, 2H), 7.13-7.14 (m, 7H), 4.69 (t, J=3.8 Hz, 1H), 3.35 (d, J=10.8 Hz, 4H), 3.28 (d, J=7.4 Hz, 3H), 3.12-3.14 (m, 2H), 2.91 (s, 3H), 2.03 (br s, 3H), 1.71-1.79 (m, 3H), 1.41 (t, J=6.8 Hz, 1H), 0.84 (d, J=6.6 Hz, 6H). LCMS (m/z, Method B) ES+ 484.9 [M+1]+.
Reaction SMILES: [CH3:1][NH:2][C:3]([C@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]([NH2:19])=[NH:18])=[CH:12][CH:11]=1)=[O:4].CN(C)/[CH:22]=[CH:23]/[C:24]([C:26]1[N:30]([CH:31]([CH3:33])[CH3:32])[C:29]([CH3:34])=[N:28][CH:27]=1)=O>COCCO>[CH3:1][NH:2][C:3]([C@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:19]=[C:24]([C:26]3[N:30]([CH:31]([CH3:33])[CH3:32])[C:29]([CH3:34])=[N:28][CH:27]=3)[CH:23]=[CH:22][N:18]=2)=[CH:12][CH:11]=1)=[O:4]
Reactant: Cc1ncc(C(=O)/C=C/N(C)C)n1C(C)C
Reactant: CNC(=O)[C@H]1CCCN1c1ccc(NC(=N)N)cc1
Solvent: COCCO
Product: CNC(=O)[C@H]1CCCN1c1ccc(Nc2nccc(-c3cnc(C)n3C(C)C)n2)cc1
Temperature: 200 °C
Yield: 35 %

Procedure:
(R)-1-(4-Guanidino-phenyl)-pyrrolidine-2-carboxylic acid methylamide (Method 59; 0.27 g, 1.0 mmol) and of (2E)-3-(dimethylamino)-1-(1-isopropyl-2-methyl-1H-imidazol-5-yl)prop-2-en-1-one, (Method 24 of WO 03/076436; 0.15 g, 0.0.68 mmol) were added to 2-methoxyethanol (4 ml) and heated at 200° C. for 2 hours in the microwave. The solvent was removed in vacuo and the gum was carefully chromatographed eluting with DCM, 1% MeOH/DCM, 2% MeOH/DCM and finally 3% MeOH/DCM to yield a yellow solid (101 mg, 35%). NMR (400.132 MHz, CDCl3) 8.28 (d, 1H), 7.39 (d, 2H), 7.34 (s, 1H), 6.89 (s, 1H), 6.83 (d, 1H), 6.61-6.57 (m, 3H), 5.62 (septet, 1H), 3.99 (t, 1H), 3.65 (t, 1H), 3.24-3.17 (m, 1H), 2.80 (d, 3H), 2.55 (s, 3H), 2.29-2.24 (m, 2H), 2.06-1.89 (m, 2H), 1.46 (d, 6H); m/z 420.
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3(O)[CH2:22][C@@H:21]([CH3:23])[O:20][C@@H:19]([CH3:24])[CH2:18]3)[CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(Cl)(=O)=O.C1CCN2C(=NCCC2)CC1>C(N(CC)CC)C>[CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3[CH2:22][C@H:21]([CH3:23])[O:20][C@H:19]([CH3:24])[CH:18]=3)[CH:14]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1CC(O)(c2ccc3c(c2)CN(Cc2ccccc2)C3)C[C@H](C)O1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCC2=NCCCN2CC1
Product: C[C@@H]1C=C(c2ccc3c(c2)CN(Cc2ccccc2)C3)C[C@H](C)O1

Procedure:
Prepared in analogy to Example A65(a) from (2S,6R)-4-(2-benzyl-2,3-dihydro-1H-isoindol-5-yl)-2,6-dimethyl-tetrahydro-pyran-4-ol (Example A70(a)) and methanesulfonyl chloride, triethylamine, and DBU. Brown oil. MS (m/e): 320.3 ([M+H]+, 100%).
Reaction SMILES: [CH:1]([C:4]1[N:5]([C:15]2[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][CH:16]=2)[C:6]2[C:11]([C:12]=1[C:13]#[N:14])=[CH:10][CH:9]=[CH:8][CH:7]=2)([CH3:3])[CH3:2].B(Br)(Br)Br.CO>C(Cl)Cl>[OH:21][C:18]1[CH:19]=[CH:20][C:15]([N:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]([C:13]#[N:14])=[C:4]2[CH:1]([CH3:3])[CH3:2])=[CH:16][CH:17]=1
Reactant: COc1ccc(-n2c(C(C)C)c(C#N)c3ccccc32)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CC(C)c1c(C#N)c2ccccc2n1-c1ccc(O)cc1
Temperature: 0 °C
Yield: 39.8 %

Procedure:
2-Isopropyl-1-(4-methoxy-phenyl)-1H-indole-3-carbonitrile (3 mg, 0.01 mmol) was dissolved in dry CH2Cl2 (0.5 ml) and stirred at 0° C. BBr3 (1M in CH2Cl2, 50 μl) was added and the mixture left in the fridge with stirring overnight. Some drops of MeOH were added and stirred. The solvent was removed in vacuo and the mixture partitioned in H2O/DCM. The organic phase was separated using a phase separator. The solvent was removed in vacuo and the mixture was chromatographed using a prepacked silica column (solvent: EtOAc:n-Heptane 3-7) to afford the desired 1-(4-hydroxy-phenyl)-2-isopropyl-1H-indole-3-carbonitrile (1.1 mg, 39%). 1H NMR (acetone-d6, 500 MHz): 7.64 (m, 1H), 7.32 (m, 2H), 7.28 (m, 1H), 7.22 (m, 1H), 7.11 (m, 2H), 6.98 (m, 1H), 3.07 (m, 1H) and 1.43 (d, 6H, J=7.0 Hz).
Reaction SMILES: [NH2-].[Na+].[CH3:3][C:4]([CH3:9])([CH3:8])[C:5](=[O:7])[CH3:6].[CH3:10][O:11][CH:12]([CH3:17])[C:13](OC)=[O:14].O>C(O)(=O)C>[CH3:10][O:11][CH:12]([C:13](=[O:14])[CH2:6][C:5](=[O:7])[C:4]([CH3:9])([CH3:8])[CH3:3])[CH3:17]
Reactant: COC(=O)C(C)OC
Reactant: CC(=O)C(C)(C)C
Agent: [NH2-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: COC(C)C(=O)CC(=O)C(C)(C)C
Reaction time: 0.25 h
Yield: 51.8 %

Procedure:
In a 200 mL-volume flask equipped with a stirrer, a thermometer and a dropping funnel was placed 8.20 g (210 mmol) of sodium amide, and the flask was purged with argon. Then, 80 mL of toluene was placed in the flask. Subsequently, 15.1 g (150.8 mmol) of 3,3-dimethyl-2-butanone was slowly dropped into the flask, and the resulting mixture was stirred for 15 minutes. Into the flask was further dropped 5.50 g (46.6 mmol) of methyl 2-methoxypropionate (prepared by the method of Reference Example 1), and the mixture was stirred for 30 minutes for carrying out a reaction. After the reaction was complete, 50 mL of water was placed in the flask under cooling with ice. The aqueous portion was taken out, neutralized with acetic acid, and subjected to extraction with ether. The ether extract was washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and distilled under reduced pressure (59° C., 492 Pa) to give 4.50 g (yield: 52%) of 2-methoxy-6,6-dimethyl-3,5-heptanedione as colorless liquid.
Reaction SMILES: COC1C=CC(C[N:10]2[CH2:27][C:14]3([CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]3)[O:13][CH:12]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:11]2=[O:34])=CC=1.O.[ClH:36]>C(#N)C>[ClH:36].[C:28]1([CH:12]2[O:13][C:14]3([CH2:15][CH2:16][NH:17][CH2:18][CH2:19]3)[CH2:27][NH:10][C:11]2=[O:34])[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COc1ccc(CN2CC3(CCN(C(=O)OC(C)(C)C)CC3)OC(c3ccccc3)C2=O)cc1
Agent: Cl
Solvent: CC#N
Solvent: O
Product: O=C1NCC2(CCNCC2)OC1c1ccccc1
Reaction time: 2 h
Yield: 100 %

Procedure:
To tert-butyl 10-[(4-methoxyphenyl)methyl]-9-oxo-8-phenyl-7-oxa-3,10-diazaspiro[5.5]undecane-3-carboxylate (215 mg, 0.46 mmol) in acetonitrile (2.5 mL) was added water (2.5 mL) followed by the addition of ceric ammonium nitrate (500 mg, 0.91 mmol). The reaction mixture was stirred for 2 hours. After this time, a further aliquot of ceric ammonium nitrate (250 mg, 0.46 mmol) was added and the reaction mixture was stirred for an additional 45 minutes, it was then diluted with 1M aq. HCl, extracted with ethyl acetate (2×25 mL), dried over MgSO4 and concentrated in vacuo. The residue was dissolved in methanol (1 mL) and HCl (1 mL of 4 M in dioxane, 4.00 mmol) was added. The reaction mixture was stirred for 1 hour, then concentrated in vacuo to give 10-phenyl-11-oxa-3,8-diazaspiro[5.5]undecan-9-one hydrochloride salt (130 mg, 100%). ESI-MS m/z calc. 246.1. Found 247.5 (M+1)+; Retention time: 0.46 minutes (3 min run).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[O:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)[CH:7]=[CH:6]2.[C:22](Cl)(=[O:27])[CH2:23][CH:24]([CH3:26])[CH3:25].[Sn](Cl)(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[O:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[C:17]=1[C:22](=[O:27])[CH2:23][CH:24]([CH3:26])[CH3:25])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc(-c3cc4ccccc4o3)ccc2c1
Reactant: CC(C)CC(=O)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COc1ccc2cc(-c3oc4ccccc4c3C(=O)CC(C)C)ccc2c1

Procedure:
Following the procedure described in Step 2 of Example 1, 2-(6-methoxy-2-naphthyl)-1-benzofuran (3.00 g, 10.9 mmol), was acylated with isovaleryl chloride (1.9 mL, 16 mmol), in presence of tin (IV) chloride (1.7 mL, 14 mmol) in chloroform (60 mL). Purification by flash chromatography using 15-100% chloroform in hexane as an eluant then by using the Biotage apparatus using 1.5% ethyl acetate in hexane as an eluant yielded the title compound as a yellow wax (1.34 g); 1HNMR (200 MHz, DMSO-d6): δ8.35 (s, 1H), 8.0 (d, 3H, J=8.2 Hz), 7.8 (d, 1H, J=10.2 Hz), 7.7 (d, 1H, J=7.7 Hz), 7.35-7.55 (m, 3H), 7.3 (d, 1H, J=8.7 Hz), 3.95 (s, 3H), 2.6 (d, 2H, J=7.7 Hz), 2.0-2.1 (m, 1H), and 0.75 ppm (d, 6H, J=7.7 Hz).
Reaction SMILES: C(OC(=O)C)(=O)C.[N+:8]([O-:11])(O)=[O:9].[Cl:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=1[CH3:21]>O>[Cl:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([N+:8]([O-:11])=[O:9])=[CH:15][C:14]=1[CH3:21]
Reactant: COc1ccc(C)c(Cl)c1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: COc1cc(Cl)c(C)cc1[N+](=O)[O-]
Temperature: -5 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
Acetic anhydride (10 mL) at −10° C. was treated with concentrated nitric acid (>69% pure, 1 mL) and then treated portionwise with 2-chloro-4-methoxy-1-methylbenzene (0.78 g, 5 mmol) at a rate that maintained the internal temperature lower than −5° C. The solution was stirred for additional one hour while warming to room temperature, poured into an ice and water mixture, and extracted with ethyl acetate several times. The organic layers were combined, washed with 10% Na2CO3 and brine, dried (MgSO4), and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel eluting with 9:1 hexanes/ethyl acetate to provide 0.75 g (71%) of the desired product. MS (DCI) m/e 219 (M+NH4)+; 1H NMR (CDCl3, 300 MHz) δ 7.78 (s, 1H), 7.09 (s, 1H), 3.94 (s, 3H), 2.35 (s, 3H).
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16]([NH:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:26][CH2:25][CH2:24][C:23]1=[O:27])=[O:17])=O)C1C=CC=CC=1>CO.[C].[Pd]>[O:27]=[C:23]1[CH2:24][CH2:25][CH2:26][N:22]1[CH2:21][CH2:20][CH2:19][NH:18][C:16]([C@@H:12]1[CH2:13][CH2:14][CH2:15][NH:11]1)=[O:17]
Reactant: O=C(NCCCN1CCCC1=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: O=C(NCCCN1CCCC1=O)[C@@H]1CCCN1
Yield: 71.9 %

Procedure:
In 150 ml of methanol was dissolved 4.32 g of compound (99) and the compound was hydrogenated using 432 mg of 10% palladium-carbon as a catalyst. Then, the catalyst was filtered off from the reaction mixture and the filtrate was concentrated to provide 1.99 g of (S)-N-[3-(2-oxo-1-pyrrolidinyl)propyl]-2-pyrrolidinecarboxamide (100).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].[C:23](Cl)([O:25][CH2:26][CH:27]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:24].Cl>O.O1CCOCC1.O1CCOCC1>[C:23]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1)([O:25][CH2:26][CH:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:34]2[C:39]1=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:24]
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: Nc1cccc(-c2ccc(C(=O)O)cc2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(Nc1cccc(-c2ccc(C(=O)O)cc2)c1)OCC1c2ccccc2-c2ccccc21
Temperature: 3 °C
Reaction time: 3 h

Procedure:
Dissolve 3′-aminobiphenyl-4-carboxylic acid (Preparation B, Step 3) (1.07 g, 5 mmol) and Na2CO3 (1.33 g, 12.5 mmol ) in H2O-dioxane (2:1, 45 mL), and cool the solution to ˜3° C. Add Fmoc-Cl (1.3 g) in dioxane (10 ml); stir at ice bath temperature for 3 hours, allow to warm to room temperature and stir for another 4 hours. Pour into ice water and acidify with aqueous HCl. Extract with EtOAc. Dry extracts over MgSO4, and strip solvent in vacuo. Recrystallize residue from CH3CN to give the title compound. HPLC Retention Time, 22.6 minutes (condition (b)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([NH:14][CH3:15])[CH2:12][N:11]([C:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:20][CH2:19]3)=[O:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:30]([C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][C:40]=1[F:41])[C:35]([OH:37])=O)#[N:31]>>[C:30]([C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][C:40]=1[F:41])[C:35]([N:14]([CH:13]1[CH:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[CH2:10][N:11]([C:16]([CH:18]2[CH2:19][CH2:20][N:21]([C:24]([C:26]3([CH3:29])[CH2:28][CH2:27]3)=[O:25])[CH2:22][CH2:23]2)=[O:17])[CH2:12]1)[CH3:15])=[O:37])#[N:31]
Reactant: CNC1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Reactant: N#Cc1cc(C(=O)O)ccc1F
Product: CN(C(=O)c1ccc(F)c(C#N)c1)C1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 97, the title compound 3-cyano-N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-fluoro-N-methyl-benzamide was prepared from {4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using 3-cyano-4-fluorobenzoic acid instead of 4-chloro-3-(trifluoromethyl)benzoic acid and was obtained as a light brown oil. MS m/e: 585.2 [M]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([I:9])[CH:5]=[C:6]([OH:8])[CH:7]=1.[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([O:1][C:2]1[CH:3]=[C:4]([I:9])[CH:5]=[C:6]([O:8][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: Oc1cc(O)cc(I)c1
Product: Ic1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Yield: 96 %

Procedure:
3,5-Dihydroxyiodobenzene (Tex. J. Sci., 1977, 28, 253) was reacted with two equivalents of benzyl bromide using the procedure described in Example 1 to give 3,5-dibenzyloxyiodobenzene as an oil in 96% yield. This was reacted with n-butyl-lithium using the procedure described in Note c. immediately above except that the reaction was carried out at -110° C. The organometallic reagent so formed was reacted with tetrahydropyran-4-one using the procedure described in that Note; the product was methylated and that product was hydrogenolysed using the procedure also described in Note c. immediately above. There was thus obtained 4-(3,5-dihydroxyphenyl)-4-methoxytetrahydropyran in 40% yield from 3,5-dibenzyloxyiodobenzene.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH:7]([CH3:14])[CH2:8][CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)(=O)C.[OH-].[Na+]>O>[CH:9]1([CH2:8][CH:7]([CH3:14])[CH2:6][CH2:5][OH:4])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CC(=O)OCCC(C)CC1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(CCO)CC1CCCC1
Temperature: 92.5 °C
Reaction time: 11 h
Yield: 91.5 %

Procedure:
4-cyclopentyl-3-methylbutyl acetate (1.98 kg, 10.0 mols, purity: 98%) sodium hydroxide (420 g, 10.5 mols) and water (8400 ml) were mixed together and heated at 90-95° C. under stirring for 10-12 h. The reaction mixture was cooled to 35° C. The aqueous phase was separated from the organic phase. The organic phase was washed once with 5% w/w aqueous NaCl and twice with water. The crude product was fractionated under reduced pressure to provide 4-cyclopentyl-3-methylbutan-1-ol (1.43 kg, yield: 92%; GC purity: 99%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:5])[CH3:4].[C:6]1([CH3:15])[C:7]([C:12](Cl)=[O:13])=[CH:8][CH:9]=[CH:10][CH:11]=1>C1(C)C=CC=CC=1.C(N(CC)CC)C>[C:6]1([CH3:15])[C:7]([C:12]([NH:1][CH2:2][CH:3]([OH:5])[CH3:4])=[O:13])=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CC(O)CN
Reactant: Cc1ccccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1ccccc1C(=O)NCC(C)O
Yield: 58 %

Procedure:
To 100 ml of a solution of 5.83 g of 1-amino-2-propanol in toluene, 18.0 ml of triethylamine was added, and 10 ml of a solution of 10.00 g of o-toluoyl chloride in toluene was added dropwise slowly with stirring under ice-cooling. After 30-minute-stirring, the ice-bath was removed, and the mixture was stirred for additional 1 hour at room temperature. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The extract was washed with 10% hydrochloric acid, ice-cold water and saturated aqueous sodium hydrogen carbonate solution sequentially, dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was crystallized by addition of diethyl ether to provide 7.25 g of the objective compound as colorless crystals. M.p. 78–81° C.