Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.[C:21](N1C=CN=C1)([N:23]1C=CN=C1)=[S:22].N>O1CCCC1>[F:20][C:2]([F:1])([F:19])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][N:10]2[C:21](=[S:22])[NH2:23])=[CH:7][CH:8]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: FC(F)(F)c1ccc(C2NCCc3ccccc32)cc1
Agent: N
Solvent: C1CCOC1
Product: NC(=S)N1CCc2ccccc2C1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (0.5 g, 2 mmol) (Example 9, step 3) in dry tetrahydrofuran (10 mL) was treated with 1,1′-thiocarbonyldiimidazole (0.5 g, 3 mmol) and stirred at RT for 4 h. The solvent was removed and the resulting residue was dissolved in ammonia (2.0 M solution in methanol, 15 mL, 30 mmol) and stirred the resulting solution in a pressure tube at RT for 1 h followed by heating at 55° C. for 5 h. The solvent was removed under vacuum and the residue was purified by preparative HPLC [gradient 10-90% MeCN (0.1% TFA)/H2O (0.1% TFA)] to give 1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carbothioamide as a white solid. MS (ESI, pos. ion) m/z: 337 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[C@H:12]2[C:13]([O:15][C:16](=[O:17])[C@H:11]2[N:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]1=[O:25])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC=CC=1.[CH:32]([OH:35])([CH3:34])[CH3:33]>>[CH2:1]([N:8]1[C@H:12]([C:13]([O:35][CH:32]([CH3:34])[CH3:33])=[O:14])[C@H:11]([C:16]([OH:15])=[O:17])[N:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]1=[O:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1OC(=O)[C@H]2[C@@H]1N(Cc1ccccc1)C(=O)N2Cc1ccccc1
Reactant: CC(C)O
Solvent: c1ccccc1
Product: CC(C)OC(=O)[C@@H]1[C@H](C(=O)O)N(Cc2ccccc2)C(=O)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 48.5 %

Procedure:
A mixture of cis-1,3-dibenzyl-2-oxoimidazolidine-4,5-dicarboxylic acid anhydride (16.8 g), benzene (230 ml) and isopropanol (5.50 g) was refluxed for 10 hours. A part (about 150 ml) of the reaction mixture was concentrated under reduced pressure. The residue was stirred with n-hexane (30 ml) at room temperature for 5 hours. Crystals produced were filtered and dried to yield racemic cis-1,3-dibenzyl-5-isopropoxycarbonyl-2-oxoimidazolidine-4-carboxylic acid (9.61 g). M.P., 108°-109° C.
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[C:15]1([C:21]2[CH:25]=[CH:24][S:23][C:22]=2[CH3:26])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:27](O)(=[O:31])[C:28](C)=[CH2:29]>ClCCl>[CH3:26][C:22]1[S:23][C:24]2[CH2:29][CH2:28][C:27](=[O:31])[C:25]=2[C:21]=1[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1sccc1-c1ccccc1
Reactant: C=C(C)C(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: Cc1sc2c(c1-c1ccccc1)C(=O)CC2
Temperature: 100 °C

Procedure:
In a 2 l 5 neck round bottled flask equipped with nitrogen inlet, 250 ml pressure equalized addition funnel, reflux condenser, thermometer, and mechanical stir was added 1 Kg polyphosphoric acid (Aldrich, 84%). The temperature was raised to 100° C., then 180 g-phosphorus pentoxide was added and the temperature was raised to 130° C. Stirring was continued until all the phosphorus pentoxide had dissolved then the flask and contents were cooled to 80° C. A solution containing 79.2 g (455 mmol) 3-phenyl-2-methylthiophene and 40.1 g (465 mmol) methacrylic acid (Aldrich) dissolved in 100 ml dichloromethane was added slowly. Stirring continued with refluxing dichloromethane for 7 h, during which time an additional 130.8 g (1.52M) methacrylic acid in 250 ml dichloromethane was added (in portions, every 1.5 h). The contents of the flask were poured on to ice, the organic layer was collected with 20% dichloromethane in hexane, washed with water, neutralized with a saturated solution of sodium bicarbonate, then again washed with water. The organic fraction was dried over magnesium sulfate, filtered, then the solvents were removed in vacuo. Yield: 71.4 g (65%) (89.32 g dark orange oil, 80% by GC: used in subsequent steps without further purification). The title compound was analysed by 1H-NMR spectroscopy.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[O:8])=[CH:5][C:4]=1[CH3:22].Br[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=1>>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:32])([F:33])[F:34])[CH:26]=3)[CH:10]=2)=[O:8])=[CH:5][C:4]=1[CH3:22]
Reactant: FC(F)(F)c1cccc(CBr)c1
Reactant: COc1ccc(C(=O)c2c[nH]c3ncccc3c2=O)cc1C
Product: COc1ccc(C(=O)c2cn(Cc3cccc(C(F)(F)F)c3)c3ncccc3c2=O)cc1C
Yield: 15.6 %

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1, from 50 mg (0.17 mmol) of 3-(4-Methoxy-3-methyl-benzoyl)-1H-[1,8]naphthyridin-4-one, and 1-Bromomethyl-3-trifluoromethyl-benzene 53 mg (0.22 mmol), to give 12 mg of desired compound. LCMS (M+H)+: 453.1.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([Li])CCC.[CH3:14][C:15]([CH3:17])=[O:16]>O1CCCC1>[OH:16][C:15]([CH3:17])([CH3:14])[CH2:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: Cc1ccc(O)cn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(O)Cc1ccc(O)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of 6-methylpyridin-3-ol (2.54 g, 23.3 mmol) in tetrahydrofuran (100 mL) was added n-butyllithium solution (1.6 M in n-hexane, 32 mL, 51.2 mmol) dropwise at −20° C. After addition, the mixture was allowed to warm to room temperature and stirred at the same temperature for 1 h. Then the mixture was cooled to −78° C., and acetone (2.03 g, 35.0 mmol) was added dropwise. The resulting mixture was allowed to warm to room temperature over 20 h. The mixture was quenched with acetic acid (5.8 mL) and concentrated under reduced pressure. The resulting residue was chromatographed on a column of silica gel eluting with acetone/n-hexane (1:1) to give 3.90 g (quant.) of the title compound as a yellow oil.
Reaction SMILES: [Na].[CH3:2][CH:3]([S-:5])[CH3:4].Br[C:7]1[N:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=1.O>CN(C=O)C>[CH:3]([S:5][C:7]1[N:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=1)([CH3:4])[CH3:2]
Reactant: Nc1cnc(Br)cn1
Reactant: CC(C)[S-]
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Sc1cnc(N)cn1
Temperature: 100 °C

Procedure:
Sodium-2-propanethiolate (2.256 g, 20.69 mmol) was added to a stirred solution of 5-bromopyrazin-2-amine (3 g, 17.24 mmol) in DMF (15 mL) and heated at 100° C. under microwave conditions for 4 hours. A further portion of sodium-2-propanethiolate (2.256 g, 20.69 mmol) was added the reaction heated for a further 1 hour at 100° C. under microwave conditions. Water was added and the mixture extracted with EtOAc (×2). The combined organic layers were washed with water (×3), brine (×1), dried, (MgSO4), filtered and concentrated in vacuo to give the sub-title compound as a beige oil which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]([O:19]C(C)(C)C)=[O:18])=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)=[O:4]>Cl>[CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(c2ccc(OCCC(=O)OC(C)(C)C)cc2)CC1
Agent: Cl
Product: COC(=O)C1(c2ccc(OCCC(=O)O)cc2)CC1
Temperature: 25 °C
Yield: 94.6 %

Procedure:
A solution of 1-[4-(2-tert-butoxycarbonyl-ethoxy)-phenyl]-cyclopropanecarboxylic methyl ester (6.3 g, 20 mmol) in HCl (20%, 200 mL) was heated at 110° C. for 1 h. After cooling to room temperature, the resulting mixture was filtered. The solid was washed with water and dried under vacuum to give 1-[4-(2-carboxy-ethoxy)-phenyl]-cyclopropanecarboxylic methyl ester (5.0 g, 96%). 1H NMR (300 MHz, DMSO) δ 7.23-7.19 (m, 2 H), 6.85-6.81 (m, 2 H), 4.13 (t, J=6.0 Hz, 2 H), 3.51 (s, 3 H), 2.66 (t, J=6.0 Hz, 2 H), 1.43-1.39 (m, 2 H), 1.14-1.10 (m, 2 H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:11]([OH:18])=[C:10]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH:9]=2)=[CH:4][CH:3]=1.[C:23]1(=[O:30])[O:29][C:27](=[O:28])[CH2:26][CH2:25][CH2:24]1.O>C(COC)OC>[C:19]([C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:23](=[O:30])[CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:3][CH:4]=2)[CH:13]=[C:12]([C:14]([CH3:15])([CH3:16])[CH3:17])[C:11]=1[OH:18])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)c1cc(-c2ccc(N)cc2)cc(C(C)(C)C)c1O
Reactant: O=C1CCCC(=O)O1
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)c1cc(-c2ccc(NC(=O)CCCC(=O)O)cc2)cc(C(C)(C)C)c1O
Reaction time: 1 h

Procedure:
To a hot (70° C.) solution of 10.0 g (0.0336 mole) of the known compound 4'-amino-3,5-di-tertiary-butyl-4-hydroxybiphenyl in 100 ml of glyme was added 5.0 g (0.044 mole) of glutaric anhydride. After stirring for one hour, the mixture was cooled and poured into water. The precipitate was separated by filtration and recrystallized from a chloroform-hexane mixture to provide tan needles of N-(3',5'-di-tertiary-butyl-4'-hydroxy-4-biphenylyl)glutaramic acid, m.p. 217.5°-219° C. Analysis: Calculated for C25H33NO4 : % C, 73.0; % H, 8.1; % N, 3.4; Found: % C, 72.6; % H, 8.1; % N, 3.1.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[S:19][CH:20]=[CH:21][C:22]=2[NH:23][S:24]([CH:27]([CH3:29])[CH3:28])(=[O:26])=[O:25])=[CH:14][CH:13]=1)#[N:2].Cl[Sn]Cl.O>C(O)C>[NH2:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[S:19][CH:20]=[CH:21][C:22]=3[NH:23][S:24]([CH:27]([CH3:29])[CH3:28])(=[O:26])=[O:25])=[CH:14][CH:13]=2)[CH:5]=1
Reactant: CC(C)S(=O)(=O)Nc1ccsc1-c1ccc(-c2cc([N+](=O)[O-])ccc2C#N)cc1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: CC(C)S(=O)(=O)Nc1ccsc1-c1ccc(-c2cc(N)ccc2C#N)cc1
Temperature: 90 °C
Yield: 82 %

Procedure:
Prepare propane-2-sulfonic acid [2-(2′-cyano-5′-nitro-biphenyl-4-yl)-thiophen-3-yl]-amide in a manner analogous to the procedure set forth in Preparation 4. Add SnCl2.2 H2O (642 mg, 3.40 mmol) into a solution of propane-2-sulfonic acid [2-(2′-cyano-5′-nitro-biphenyl-4-yl)-thiophen-3-yl]-amide (279 mg, 0.654 mmol) in ethanol (6.54 mL). Heat the mixture at 90° C. for 3 h. Cool to room temperature. Concentrate to remove the solvent in vacuo. Dilute with dichloromethane, and add aqueous sodium bicarbonate solution to adjust pH to 8. Extract with with dichloromethane (3×100 mL) and dry the combined organic layers and concentrate to give a slightly colored solid. Purification by flash chromatography (Silica gel-Hexane/EtOAc 2:1) furnishes 212 mg, 0.534 mmol (82%) of title compound as a pale yellow solid. MS (m/e): 396.1 (M−1).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.C(N(CC)CC)C.Cl[C:24]([O:26][CH2:27][CH2:28][O:29][CH3:30])=[O:25]>C(Cl)Cl>[C:12]([O:11][C:9]([N:5]1[CH2:6][CH2:7][CH2:8][C@@H:3]([CH2:2][NH:1][C:24](=[O:25])[O:26][CH2:27][CH2:28][O:29][CH3:30])[CH2:4]1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: COCCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](CN)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCOC(=O)NC[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 67.3 %

Procedure:
To a solution of (S)-tert-butyl 3-(aminomethyl)piperidine-1-carboxylate (500 mg, 2.33 mmol) in CH2Cl2 at −10° C. was added triethylamine (650 μL, 4.66 mmol) followed by the dropwise addition of 2-methoxyethyl chloroformate (325 μL, 2.79 mmol). The reaction was warmed to room temperature and quenched with water. The aqueous layer was extracted with CH2Cl2, and the combined extracts were dried over MgSO4, filtered, and evaporated. Purification via silica gel chromatography using 0 to 10% EtOAc in CH2Cl2 afforded 2-methoxyethyl ((S)-1-(tert-butoxycarbonyl)piperidin-3-yl)methylcarbamate (496 mg, 67%). LC/MS: m/z 317.3 (M+H)+ at 2.56 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH2:23]([N:30]1[CH2:35][CH2:34][CH2:33][CH:32]([CH:36]([C:38]2[C:43]([Cl:44])=[CH:42][N:41]=[C:40]3[N:45]([Si:48]([CH:55]([CH3:57])[CH3:56])([CH:52]([CH3:54])[CH3:53])[CH:49]([CH3:51])[CH3:50])[CH:46]=[CH:47][C:39]=23)[OH:37])[CH2:31]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[CH2:23]([N:30]1[CH2:35][CH2:34][CH2:33][CH:32]([C:36]([C:38]2[C:43]([Cl:44])=[CH:42][N:41]=[C:40]3[N:45]([Si:48]([CH:52]([CH3:54])[CH3:53])([CH:55]([CH3:57])[CH3:56])[CH:49]([CH3:50])[CH3:51])[CH:46]=[CH:47][C:39]=23)=[O:37])[CH2:31]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(C(O)C3CCCN(Cc4ccccc4)C3)c(Cl)cnc21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(C(=O)C3CCCN(Cc4ccccc4)C3)c(Cl)cnc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.7 %

Procedure:
Dess-Martin periodinane (14.63 g, 34.5 mmol) was added to a solution of (1-benzylpiperidin-3-yl)(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methanol (5.89 g, 11.5 mmol) in DCM (120 mL) at about 0° C. and the resulting mixture was stirred for about 16 h while warming to ambient temperature. The solvent was removed under reduced pressure and the residue partitioned between saturated aqueous NaHCO3 (150 mL) and EtOAc (200 mL). The organic phase was washed with brine (120 mL) and concentrated under reduced pressure. Purification by silica gel chromatography eluting first with heptane (IL) and then with 1:7 EtOAc:heptane (1 L) yielded (1-benzylpiperidin-3-yl)(5-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-4-yl)methanone (1.45 g, 25%) as a yellow oil: LC/MS (Table 2, Method a) Rt=3.24 min; MS m/z: 511 (M+H)+
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([CH3:14])[N:3]=1.[CH2:15]([OH:18])[C:16]#[CH:17].[H-].[Na+].O>CN(C)C=O>[CH3:14][C:4]1[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[C:2]([O:18][CH2:15][C:16]#[CH:17])[N:3]=1
Reactant: Cc1nc(Cl)cc(-c2ccccc2)n1
Reactant: C#CCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOc1cc(-c2ccccc2)nc(C)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 76.8 %

Procedure:
In 10 ml of N,N-dimethylformamide were dissolved 304 mg of 4-chloro-2-methyl-6-phenylpyrimidine and 92 mg of 2-propyn-1-ol, to which 66 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 12 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 256 mg of 2-methyl-4-phenyl-6-(2-propynyloxy)pyrimidine (the present compound (77)).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][C:5]2[CH:8]=[CH:9][C:10]([O:12][CH2:13][CH2:14][CH2:15][CH:16]=O)=[N:11][C:4]=2[NH:3]1.[Cl:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CCOCC>ClC(Cl)C>[Cl:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[CH:21][C:20]=1[N:26]1[CH2:31][CH2:30][N:29]([CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:10]2[CH:9]=[CH:8][C:5]3[O:6][CH2:7][C:2](=[O:1])[NH:3][C:4]=3[N:11]=2)[CH2:28][CH2:27]1
Reactant: O=CCCCOc1ccc2c(n1)NC(=O)CO2
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCOCC
Product: O=C1COc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)nc2N1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 62.3 %

Procedure:
To a solution of 4-(3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yloxy)-butyraldehyde (0.325 g, 1.37 mmol) in dichloroethane (6 mL) was added a solution of 1-(2,3-dichloro-phenyl)-piperazine (0.318 g, 1.37 mmol) in dichloroethane (3 mL) via cannula. The mixture was stirred for 20 minutes at room temperature and NaBH(OAc)3 (0.377 g, 1.78 mmol) was added. The reaction was stirred for 2.5 h and quenched with saturated NaHCO3 and water. The mixture was extracted with EtOAc and the organic layer was washed with saturated NaHCO3, water and brine, dried over Na2SO4 and concentrated. Purification by chromatography on silica gel (0–5% MeOH/CH2Cl2) gave a foam. Et2O was added and product crashed out. The precipitate was filtered and dried to give the title compound as a white solid (0.386 g, 0.854 mmol, 63%). MS: APCI: M+1: 451.1 (Exact Mass: 450.12).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:21][C:22]([N:24]([CH3:26])[CH3:25])=[O:23]>CN(C=O)C>[CH3:25][N:24]([CH3:26])[C:22](=[O:23])[CH2:21][O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: COC(=O)c1ccc(O)c(OC)c1
Reactant: CN(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCC(=O)N(C)C)c(OC)c1
Yield: 46.4 %

Procedure:
Methyl 4-hydroxy-3-(methyloxy)benzoate (methyl vanillate, Aldrich) (3.85 g, 21.1 mmol) and potassium carbonate (2.92 g, 21.1 mmol) in DMF (10 mL) was treated at RT with 2-chloro-N,N-dimethylacetamide (Merck) (2.18 mL, 21.1 mmol) and the mixture was stirred over the weekend. The mixture was partitioned between ethyl acetate and 2M HCl. The organic phase was washed with, 2M HCl, saturated sodium bicarbonate solution (turns lightly coloured), acid (loses colour), brine, dried (MgSO4), and evaporated under reduced pressure, to give the product contaminated with starting material (5.0 g). The mixture was therefore re-dissolved in DMF (5 mL) and treated with potassium carbonate (1.38 g, 10 mmol) and 2-chloro-N,N-dimethylacetamide (1 mL, 10 mmol) for another day. The mixture was then partitioned between ethyl acetate and 2M HCl and treated as above. The filtrate was evaporated to give a solid (2.614 g) which was loaded in chloroform to a silica cartridge (70 g) and purified by chromatography on Flashmaster using a 0-100% ethyl acetate-cyclohexane gradient over 30 min. The appropriate fractions were combined and evaporated in vacuo to give the title compound (1.4 g, 25%) as a white solid. LCMS (System A) RT=0.69 min, ES+ve m/z 268 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][NH2:6])[CH3:3].[CH3:7][O:8][C:9]1[CH:24]=[CH:23][C:12]([C:13](=O)[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][C:16]2=O)=[CH:11][CH:10]=1.O>C(O)(=O)C>[CH3:1][N:2]([CH3:3])[CH2:4][CH2:5][N:6]1[C:16]2[CH2:17][CH2:18][CH2:19][CH2:20][C:15]=2[CH:14]=[C:13]1[C:12]1[CH:11]=[CH:10][C:9]([O:8][CH3:7])=[CH:24][CH:23]=1
Reactant: COc1ccc(C(=O)CC2CCCCC2=O)cc1
Reactant: CN(C)CCN
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc(-c2cc3c(n2CCN(C)C)CCCC3)cc1

Procedure:
4.41 g (0.05 mole) of dimethylaminoethylamine are added dropwise to a stirred suspension of 12.32 g (0.05 mole) of 2-(p-methoxyphenacyl)cyclohexanone in glacial acetic acid. After refluxing overnight, ice and water are added, and the cloudy mixture is washed with ether. The aqueous solution is basified with 10% sodium carbonate and extracted with ether. Removal of the ether after drying over sodium sulfate gives a light brown oil which solidifies on cooling. The resulting solid is recrystallized from methanol to give 1-(2-dimethylaminoethyl)-2(p-methoxyphenyl)-4,5,6,7-tetrahydroindole as white needles, m.p. 81°-82° C.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[CH:9]=[CH:10][C:11]3[O:20][CH2:19][CH2:18][C:17]4[S:16][C:15]([C:21]5[N:22]([CH:26]([CH3:28])[CH3:27])[N:23]=[CH:24][N:25]=5)=[N:14][C:13]=4[C:12]=3[CH:29]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.Cl.C[O:32]CCOC>>[CH:26]([N:22]1[C:21]([C:15]2[S:16][C:17]3[CH2:18][CH2:19][O:20][C:11]4[CH:10]=[CH:9][C:8]([C:7]5[C:2](=[O:32])[NH:3][CH:4]=[CH:5][CH:6]=5)=[CH:29][C:12]=4[C:13]=3[N:14]=2)=[N:25][CH:24]=[N:23]1)([CH3:28])[CH3:27]
Reactant: COCCOC
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(-c3cccnc3F)cc1-2
Agent: Cl
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(-c3ccc[nH]c3=O)cc1-2
Temperature: 80 °C
Yield: 89 %

Procedure:
To a solution of 306 (0.275 g, 0.675 mmol) in DME (5 mL) was added 10% aq HCl (5 mL). The reaction mixture was allowed to stir and heat at 80° C. for 18 hours before cooling, concentrating under reduced pressure, and diluting with EtOAc. The solution was washed sequentially with water, and brine, before drying over MgSO4 and concentrating under reduced pressure to 50 mL of EtOAc and the solids were collected by filtration to give 330 (244 mg, 89%). 1H NMR (400 MHz, DMSO) δ 11.79 (s, 1H), 9.00 (t, J=15.9, 1H), 8.10 (s, 1H), 7.67 (ddd, J=16.8, 8.8, 5.2, 2H), 7.37 (d, J=5.1, 1H), 7.08 (d, J=8.4, 1H), 6.31 (t, J=6.7, 1H), 5.88 (dt, J=13.2, 6.6, 1H), 4.58-4.20 (m, 2H), 3.46 (t, J=5.0, 2H), 1.55 (d, J=6.6, 6H). MS (ESI(+)): m/z 406.1 (M+H)
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[C:4]1=[O:17].CO[C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH:26]=[C:25]([S:30](Cl)(=[O:32])=[O:31])[CH:24]=[CH:23]2>>[C:12]([C:11]1[CH:10]=[C:9]([CH:16]=[CH:15][CH:14]=1)[CH2:8][N:5]1[CH2:6][CH2:7][C@H:3]([NH:2][S:30]([C:25]2[CH:24]=[CH:23][C:22]3[C:27](=[CH:28][CH:29]=[CH:20][CH:21]=3)[CH:26]=2)(=[O:32])=[O:31])[C:4]1=[O:17])#[N:13]
Reactant: COc1ccc2cc(S(=O)(=O)Cl)ccc2c1
Reactant: N#Cc1cccc(CN2CC[C@H](N)C2=O)c1
Agent: Cl
Product: N#Cc1cccc(CN2CC[C@H](NS(=O)(=O)c3ccc4ccccc4c3)C2=O)c1

Procedure:
The title compound is prepared from 3-(3-(S)-amino-2-oxopyrrolidin-1-ylmethyl)benzonitrile hydrochloride as in EXAMPLE 24, Part B, substituting naphthalene-2-sulfonyl chloride for 6-methoxynaphthalene-2-sulfonyl chloride. The title compound is obtained as a white solid.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH:5]1([CH2:8][N:9]2[C:15](=[O:16])[C@@H:14]([NH:17][C:18]([N:20]3[CH2:25][CH2:24][CH:23]([N:26]4[CH:30]=[C:29]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)[NH:28][C:27]4=[O:37])[CH2:22][CH2:21]3)=[O:19])[CH2:13][NH:12][C@H:11]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:10]2)[CH2:7][CH2:6]1.C(N(CC)CC)C>ClCCl>[C:1]([N:12]1[CH2:13][C@@H:14]([NH:17][C:18]([N:20]2[CH2:21][CH2:22][CH:23]([N:26]3[CH:30]=[C:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[NH:28][C:27]3=[O:37])[CH2:24][CH2:25]2)=[O:19])[C:15](=[O:16])[N:9]([CH2:8][CH:5]2[CH2:6][CH2:7]2)[CH2:10][C@@H:11]1[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: O=C(N[C@H]1CN[C@H](c2ccccc2)CN(CC2CC2)C1=O)N1CCC(n2cc(-c3ccccc3)[nH]c2=O)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1C[C@@H](NC(=O)N2CCC(n3cc(-c4ccccc4)[nH]c3=O)CC2)C(=O)N(CC2CC2)C[C@@H]1c1ccccc1
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
Acetyl chloride (2.1 □L, 0.03 mmol) was added to a solution of N-[(3R,6S)-1-(cyclopropylmethyl)-7-oxo-3-phenyl-1,4-diazepan-6-yl]-4-(2-oxo-4-phenyl-2,3-dihydro-1H-imidazol-1-yl)piperidine-1-carboxamide (16.9 mg, 0.03 mmol) and triethylamine (9 □L, 0.06 mmol) in dichloromethane (0.5 mL). After 30 min, the mixture was concentrated. Purification by silica gel chromatography (1% methanol/dichloromethane→5% methanol/dichloromethane) gave the title compound (17 mg). MS 571.3 (M+1).