Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[CH:8][C:9]=1[CH3:10].[Cl:12][C:13]1[CH:18]=[C:17](Cl)[N:16]=[CH:15][N:14]=1.O>CN(C=O)C.CCOC(C)=O>[Cl:12][C:13]1[CH:18]=[C:17]([O:11][C:6]2[CH:7]=[CH:8][C:9]([CH3:10])=[C:4]([CH3:3])[CH:5]=2)[N:16]=[CH:15][N:14]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Cc1ccc(O)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(Oc2cc(Cl)ncn2)cc1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
218 mg (5.00 mmol) sodium hydride (55%, suspension in mineral oil) were added to 617 mg (5.00 mmol) 3,4-dimethylphenol in 10 ml DMF and the mixture was stirred for 10 min at RT. Then 768 mg (5.00 mmol) 4,6-dichloropyrimidine were added and the mixture was stirred for 48 h at RT. Water and EtOAc were added to the reaction mixture, the organic phase was separated off, dried on sodium sulphate, filtered and evaporated down. The residue was dried i. vac.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@@H:22]4[NH:27][S:28]([CH2:31][C:32](O)=[O:33])(=[O:30])=[O:29])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2].ON1C2C=CC=CC=2N=N1.C(Cl)CCl.[CH3:49][NH:50][CH3:51]>CN(C=O)C.O>[C:1]([C:3]1[CH:4]=[C:5]([C:13]2[O:17][N:16]=[C:15]([C:18]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:19]=3[CH2:20][CH2:21][C@@H:22]4[NH:27][S:28]([CH2:31][C:32]([N:50]([CH3:51])[CH3:49])=[O:33])(=[O:29])=[O:30])[N:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:12])[CH3:11])#[N:2]
Reactant: CNC
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@@H]4NS(=O)(=O)CC(=O)O)no2)cc1C#N
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@@H]4NS(=O)(=O)CC(=O)N(C)C)no2)cc1C#N
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 70.6 %

Procedure:
Prepared using General Procedure 19: To a stirred solution of (S)-2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)acetic acid 71 (48 mg, 0.1 mmol) in DMF (0.4 mL) was added N-hydroxybenzotriazole (46 mg, 0.3 mmol) and EDC (57 mg, 0.3 mmol). After 5 min, dimethylamine (40 wt % solution in water, 34 μL, 0.3 mmol) was added and the reaction mixture was stirred 18 h at room temperature. The reaction was added dropwise to water (20 mL) and the solid was filtered. The crude material was purified by column chromatography (MeOH/DCM) to give 36 mg (70%) of (S)-2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)-N,N-dimethylacetamide 195. LCMS-ESI (m/z) calculated for C25H27N5O5S: 509.2; found 532.2 [M+Na]+, tR=8.99 min (Method 2). (R)-2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)-N,N-dimethylacetamide 194 was synthesized in an analogous fashion from (R)-2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)acetic acid.
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22](C(OC(C)(C)C)=O)[C@H:21]([C:31](=[O:33])[NH2:32])[C:20]([CH3:34])=[C:19]1[CH3:35])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3].C(ON([C@H]1CN[C@H](C(N)=O)C=C1C)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)C=C>>[CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][NH:22][C@H:21]([C:31]([NH2:32])=[O:33])[C:20]([CH3:34])=[C:19]1[CH3:35])[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(N)=O)C(C)=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: C=CCON([C@H]1CN[C@H](C(N)=O)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Product: C=CCON([C@H]1CN[C@H](C(N)=O)C(C)=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 75.1 %

Procedure:
The title compound was prepared from (2S,5R)-tert-butyl 5-(N-(allyloxy)-2-nitrophenylsulfonamido)-2-carbamoyl-3,4-dimethyl-5,6-dihydropyridine-1(2H)-carboxylate (Intermediate 195, 1.36 g, 2.66 mmol) following the procedure described for Intermediate 21. The workup yielded an organic layer that was dried over magnesium sulfate, filtered and concentrated to afford the desired product as a light pink solid (0.82 g, 75%).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:15][CH2:16][CH2:17][CH:18]([C:24](=[O:45])[C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)[C:26]=1OC1CCCC1)[C:19]([O:21]CC)=[O:20])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>ClCCl>[CH2:8]([O:15][CH2:16][CH2:17][C:18]1[C:19](=[O:20])[O:21][C:26]2[C:25]([C:24]=1[OH:45])=[CH:30][CH:29]=[C:28]([O:31][CH3:32])[C:27]=2[O:33][CH:34]1[CH2:35][CH2:36][CH2:37][CH2:38]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)C(CCOCc1ccccc1)C(=O)c1ccc(OC)c(OC2CCCC2)c1OC1CCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(O)c(CCOCc3ccccc3)c(=O)oc2c1OC1CCCC1

Procedure:
Trifluoroacetic acid (35 mL) was added dropwise to a solution of ethyl 4-(benzyloxy)-2-(2,3-bis(cyclopentyloxy)-4-methoxybenzoyl)butanoate (14 g, 25 mmol) and dichloromethane (280 mL) at rt. The reaction was maintained overnight, diluted with dichloromethane (200 mL), and washed with sat'd NaHCO3 (200 mL×2) and then brine (200 mL). The organic layer was dried, filtered, concentrated, and purified by silica gel chromatography (ethyl acetate:petroleum ether) to give 3-(2-(benzyloxy)ethyl)-8-(cyclopentyloxy)-4-hydroxy-7-methoxy-2H-chromen-2-one: MS (ESI): 411.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25]C)[CH:20]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15]C)[CH:10]=2)=[N:6][CH:7]=1.B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=2)=[N:6][CH:7]=1
Reactant: COc1cccc(CNc2nc(Nc3cccc(OC)c3)ncc2Cl)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1cccc(CNc2nc(Nc3cccc(O)c3)ncc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
Into a 1-neck round-bottom flask were added 5-chloro-N(4)-(3-methoxybenzyl)-N(2)-(3-methoxyphenyl)pyrimidine-2,4-diamine (90 mg, 0.2 mmol) and methylene chloride (5 mL). To the mixture was added a solution of boron tribromide in methylene chloride (3.0 mL, 3.0 mmol, 1.0 M) at 0° C. The mixture was allowed to warm up to rt and stirred overnight. The resultant mixture was cooled in a dry ice bath when NaHCO3 (saturated aqueous solution, 10 mL) was added. The mixture was allowed to warm up to rt and DCM was added. The aqueous layer was extracted with DCM twice. The organic layers were combined, dried, filtered, and concentrated under vacuum to give the desired product (40 mg, 50%). LCMS for C17H16ClN4O2 (M+H)+: m/z=343.0.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:8]([N+:11]([O-:13])=[O:12])=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.Cl>O>[O:17]1[CH2:18][CH2:19][N:14]([C:2]2[CH:3]=[C:4]([C:8]([N+:11]([O-:13])=[O:12])=[CH:9][N:10]=2)[C:5]([OH:7])=[O:6])[CH2:15][CH2:16]1
Reactant: C1COCCN1
Reactant: O=C(O)c1cc(Cl)ncc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Product: O=C(O)c1cc(N2CCOCC2)ncc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 4 h
Yield: 75.6 %

Procedure:
A mixture of 2-chloro-5-nitroisonicotinic acid (28.5 g, 141 mmol), morpholine (36.8 g, 423 mmol) and k2CO3 (58.4 g, 423 mmol) was stirred at 100° C. for 4 h. The mixture was cooled to room temperature and poured into water (1.5 L). It was acidified with 4N HCl to pH=1 and extracted with EA (1 L×3). The combined organic layers were washed with brine (1 L×5), then dried over anhydrous Na2SO4, filtered and concentrated in vacuo to afford the desired product as a yellow solid (27 g, 76%); LC/MS: MS (ES+) m/e 254 (MH+); 1H NMR (300 MHz, DMSO-d6) δ ppm 3.68 (t, J=4.8 Hz, 1H), 3.77 (t, J=4.8 Hz, 4H), 6.99 (s, 1H), 8.91 (s, 1H).
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[CH3:9][C:10]1([CH3:16])[CH2:14][CH2:13][CH2:12][C:11]1=[O:15]>>[CH3:6][N:4]([CH:3]=[C:12]1[CH2:13][CH2:14][C:10]([CH3:16])([CH3:9])[C:11]1=[O:15])[CH3:5]
Reactant: CC1(C)CCCC1=O
Reactant: COC(OC)N(C)C
Product: CN(C)C=C1CCC(C)(C)C1=O
Temperature: 25 °C
Yield: 83 %

Procedure:
A mixture of N,N-dimethylformamide dimethyl acetal (67 mL, 503 mmol) and 2,2-dimethylcyclopentanone (10 g, 90 mmol) was heated at reflux for 2 days. The reaction mixture was then cooled down to room temperature and concentrated. Water (˜380 mL) was added to the residue, and the resulting solution was extracted with methylene chloride. The organic layer was separated, dried over MgSO4 and concentrated to give the title compound (12.5 g) as a yellow-orange oil.
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[CH:13]1[CH:18]=[C:17]2[CH:19]=[C:20]([C:22](O)=[O:23])[S:21][C:16]2=[CH:15][CH:14]=1.N>>[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@@H:5]3[NH:12][C:22]([C:20]3[S:21][C:16]4[CH:15]=[CH:14][CH:13]=[CH:18][C:17]=4[CH:19]=3)=[O:23])[CH2:3]1)[CH2:9]2
Reactant: NC1C2CC3CC1CN(C3)C2
Reactant: O=C(O)c1cc2ccccc2s1
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1cc2ccccc2s1

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and thianaphthene-2-carboxylic acid (Aldrich) according to methods A and C; yield 57 mg, 0.16 mmol (50%): 1H NMR (300 MHz, methanol-d4) δ 1.98 (d, J=13 Hz, 2H), 2.20 (s, 1 H), 2.36 (d, J=14 Hz, 2H), 2.49 (s, 2H), 3.57 (s, 2H), 3.67 (d, J=2 Hz, 4H), 4.42 (s, 1 H), 7.39-7.50 (m, 2H), 7.88-7.96 (m, 2H), 8.12 (s, 1H); MS (DCI/NH3) m/z 313 (M+H)+; Anal. C18H20N2OS.HCl.0.12H2O: C, H, N.
Reaction SMILES: N1C=CC=CC=1.FC(F)(F)S([O:12][S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])(=O)=O.[F:22][C:23]1[CH:45]=[CH:44][C:26]([C:27]([C:29]2[C:38](O)=[CH:37][CH:36]=[C:35]3[C:30]=2[CH:31]=[CH:32][C:33]([S:40]([CH3:43])(=[O:42])=[O:41])=[CH:34]3)=[O:28])=[CH:25][CH:24]=1.S(=O)(=O)(O)[O-].[Na+]>C(Cl)Cl>[F:22][C:23]1[CH:24]=[CH:25][C:26]([C:27]([C:29]2[C:38]([O:12][S:13]([C:16]([F:17])([F:18])[F:19])(=[O:14])=[O:15])=[CH:37][CH:36]=[C:35]3[C:30]=2[CH:31]=[CH:32][C:33]([S:40]([CH3:43])(=[O:42])=[O:41])=[CH:34]3)=[O:28])=[CH:44][CH:45]=1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CS(=O)(=O)c1ccc2c(C(=O)c3ccc(F)cc3)c(O)ccc2c1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc2c(C(=O)c3ccc(F)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Reaction time: 0.5 h
Yield: 108.6 %

Procedure:
Pyridine (0.38 ml, 4.65 mmol) and trifluoromethanesulfonic anhydride (0.39 ml, 2.32 mmol) were added to a solution of 5-(4-fluorobenzoyl)-6-hydroxy-2-methylsulfonylnaphthalene (0.4 g, 1.16 mmol), [prepared as described in Example 2, step 3 above], in methylene chloride (10 ml) at 0° C. After 0.5 h, additional amounts of pyridine (0.38 ml, 4.65 mmol) and trifluoromethanesulfonic anhydride (0.39 ml, 2.32 mmol) were added and stirring was continued. After 0.5 h, 1N sodium bisulfate was added and the stirring was continued for an additional 30 minutes. The organic layer was separated, washed with brine, and dried over sodium sulfate. The solvent was removed in vacuo to give 0.6 g of 5-(4-fluorobenzoyl)-6-trifluoromethylsulfonyloxy-2-methylsulfonylnaphthalene as an oil (90% yield).
Reaction SMILES: S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[CH3:16][O:17][C:18]1[N:23]=[C:22]([C:24]([NH:26][CH3:27])=O)[CH:21]=[CH:20][C:19]=1[N+:28]([O-:30])=[O:29].[N-:31]=[N+:32]=[N-:33].[Na+].C([O-])(O)=O.[Na+]>CC#N>[CH3:16][O:17][C:18]1[C:19]([N+:28]([O-:30])=[O:29])=[CH:20][CH:21]=[C:22]([C:24]2[N:26]([CH3:27])[N:33]=[N:32][N:31]=2)[N:23]=1
Reactant: CNC(=O)c1ccc([N+](=O)[O-])c(OC)n1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: CC#N
Product: COc1nc(-c2nnnn2C)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 48.6 %

Procedure:
Triflic anhydride (0.29 mL, 1.724 mmol) was added dropwise to a solution of 6-methoxy-N-methyl-5-nitropicolinamide (Preparation 188, 0.182 g, 0.862 mmol) and sodium azide (0.224 g, 3.45 mmol) in MeCN (4.3 mL) at −10° C. The reaction mixture was warmed to room temperature over 3 hours. The reaction mixture was neutralised with saturated aqueous NaHCO3. The mixture was extracted with EtOAc and the organic layer washed with saturated aqueous NaHCO3 and then with brine, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by Biotage silica gel column chromatography eluting with cyclohexane/EtOAc 70/30 to 50/50 to afford the title compound as a white solid (99 mg, 49%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH2:6][CH:7]([C:12]([O:14][CH3:15])=[O:13])[C:8]([O:10][CH3:11])=[O:9].[C:21]1([CH3:30])[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>>[CH3:20][O:19][C:18]1[CH:17]=[CH:16][C:5]([CH2:6][CH:7]([C:8]([O:10][CH3:11])=[O:9])[C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:3]=1[CH2:2][O:1][C:28]([NH:27][C:24]1[CH:25]=[CH:26][C:21]([CH3:30])=[CH:22][CH:23]=1)=[O:29]
Reactant: Cc1ccc(N=C=O)cc1
Reactant: COC(=O)C(Cc1ccc(OC)c(CO)c1)C(=O)OC
Product: COC(=O)C(Cc1ccc(OC)c(COC(=O)Nc2ccc(C)cc2)c1)C(=O)OC

Procedure:
Using dimethyl 2-(3-(hydroxymethyl)-4-methoxybenzyl]malonate and p-tolylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5].[Si:12]([O:19][CH2:20][CH:21]([CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31])[CH2:22]OS(C)(=O)=O)([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1.[Na+].[Cl-]>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:22][CH:21]([CH2:28][O:29][Si:30]([C:33]([CH3:34])([CH3:36])[CH3:35])([CH3:31])[CH3:32])[CH2:20][O:19][Si:12]([C:15]([CH3:16])([CH3:17])[CH3:18])([CH3:13])[CH3:14])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5]
Reactant: CC(C)(C)[Si](C)(C)OCC(CO[Si](C)(C)C(C)(C)C)COS(C)(=O)=O
Reactant: O=Cc1c(Cl)cc(O)cc1Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCC(COc1cc(Cl)c(C=O)c(Cl)c1)CO[Si](C)(C)C(C)(C)C

Procedure:
3.43 g (18 mmol) A1, 7.40 g (18 mmol) methanesulfonic acid 3-(tert-butyldimethylsilanyloxy)-2-(tert-butyldimethylsilanyloxymethyl)propyl ester (Kim, H. S., et al., J. Med. Chem. 44 (2001) 3092-3108), 3.72 g (27 mmol) potassium carbonate and 41 mg (0.15 mmol) 18-crown-6 were stirred in 40 ml dimethylformamide at 40° C. overnight. 600 ml ethyl acetate and 250 ml aqueous NaCl were added. The organic layer was washed four times with saturated aqueous NaCl (80 ml each), dried over sodium sulfate and evaporated to dryness. Column chromatography of the residue on SiGel (heptane/ethyl acetate 10:1) yielded 508 mg (27%) A26.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]([N:8]([CH2:17][C:18]([OH:20])=O)[C:9]2[CH:16]=[CH:15][C:12]([O:13][CH3:14])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[NH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH2:17][C:18]([NH:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:20])[C:9]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[CH:15][CH:16]=2)=[O:7])=[CH:21][CH:22]=1
Reactant: COc1ccc(N(CC(=O)O)C(=O)c2ccc(Cl)cc2)cc1
Reactant: CCOC(=O)CN
Product: CCOC(=O)CNC(=O)CN(C(=O)c1ccc(Cl)cc1)c1ccc(OC)cc1

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-chlorobenzoyl)-2-(p-anisidino)acetic acid and ethyl glycinate and suitable processing produces ethyl N-[N-(p-chlorobenzoyl)-2-(p-anisidino)acetyl]glycinate (oil), saponification of which and processing of the reaction product yields N-[N-(p-chlorobenzoyl)-2-(p-anisidino)acetyl]glycine (M.P. 138° to 140°).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Si:8]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)([CH3:17])[CH2:9][N:10]2[C:14]([S:15][CH3:16])=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([Si:8]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)([CH3:17])[CH2:9][N:10]2[C:14]([S:15]([CH3:16])=[O:33])=[N:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1
Reactant: CSc1ncnn1C[Si](C)(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1ncnn1C[Si](C)(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 3 h
Yield: 111.3 %

Procedure:
To a solution of 1.8 g (0.005 mol) of bis(4-fluorophenyl)methyl(5-methylthio-1H-1,2,4-triazol-1-ylmethyl)silane in 15 mL of methylene chloride cooled to 0° C. was added 1.1 g (0.005 mol) of m-chloroperbenzoic acid (80%). The reaction temperature rose to 10°. The reaction mixture was stirred at 25° for 3 hours, then diluted with methylene chloride, washed with 7% aqueous NaHCO3 and brine, dried over Na2SO4 and evaporated to give 2.1 g of the title compound as an oil, pure except for traces of solvent and starting material: nD 1.5717; ir (neat) 3020, 1590, 1500, 1232, 1164, 1110, 1070, 825 cm-1 ; nmr (CDCl3) δ 0.7 (3H, s), 2.8 (3H, s), 4.6 (2H, ABq), 7.1 (4H, m), 7.5 (4H, m), 7.9 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][N:11]([CH3:30])[C:12]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:17][CH2:16][CH:15]([CH2:18]O[Si](C)(C)C)[CH2:14][CH2:13]1.O([Si](C)(C)C)S(C(F)(F)F)(=O)=O.C([SiH](CC)CC)C.[OH-].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][CH2:18][CH:15]2[CH2:14][CH2:13][C:12]([N:11]([CH3:10])[CH3:30])([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CN(C)C1(c2ccccc2)CCC(CO[Si](C)(C)C)CC1
Agent: CC[SiH](CC)CC
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)C1(c2ccccc2)CCC(COCc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under argon, 4-fluorobenzaldehyde (149 mg, 1.2 mmol) and dimethyl(1-phenyl-4-trimethylsilanyloxymethylcyclohexyl)amine (306 mg, 1 mmol) were dissolved in abs. DCM (20 ml) and cooled to 0° C. Trimethylsilyl triflate (387 μl, 2 mmol) was added dropwise at 0° C. and the mixture was stirred for 60 min at this temperature, after which triethylsilane (319 μl, 2 mmol) was added dropwise at 0° C. With slow heating to RT, the mixture was stirred overnight. For the work-up, DCM (10 ml) and 1 M NaOH (5 ml) were added and the mixture was stirred vigorously for 15 min. The organic phase was separated off, washed with 1 M NaOH (2×2 ml) and with water (1×2 ml), dried, filtered and concentrated. The residue was purified by chromatography on silica gel [40 g of silica gel 60; eluent: 600 ml of EE/MeOH (1:1) and 600 ml of MeOH/conc. NH3 (400:1)]. The two diastereoisomers of [4-(4-fluorobenzyloxymethyl)-1-phenylcyclohexyl]dimethylamine were isolated (17 mg of less polar diastereoisomer (yellow oil) and 106 mg of more polar diastereoisomer (yellow oil)). 75 mg of the more polar diastereoisomer were dissolved in 2-butanone (2 ml), with heating, chlorotrimethylsilane (83.4 μl) was added dropwise at RT and the mixture was stirred for 2 h. The solvent was completely distilled off and the residue was covered with a layer of dry ether and mechanically detached from the wall of the flask. The resulting solid was filtered off with suction, washed with ether (4×2 ml) and dried to give 79 mg of the hydrochloride of the more polar diastereoisomer of [4-(4-fluorobenzyloxymethyl)-1-phenylcyclohexyl]-dimethylamine (greyish-white solid, m.p. 176-181° C.).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.CC1(C)C(C)(C)OB([C:18]2[CH:19]=[C:20]3[C:24](=[CH:25][CH:26]=2)[CH:23]([NH:27][S:28]([CH:31]([CH3:33])[CH3:32])(=[O:30])=[O:29])[CH2:22][CH2:21]3)O1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.O.C(Cl)Cl.C1C(=O)[N-]C(=O)C1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Br[Pd+]>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[CH:23]([NH:27][S:28]([CH:31]([CH3:33])[CH3:32])(=[O:29])=[O:30])[CH2:22][CH2:21]2
Reactant: Fc1ccccc1CBr
Reactant: CC(C)S(=O)(=O)NC1CCc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Agent: Br[Pd+]
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)[N-]1
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CC(C)S(=O)(=O)NC1CCc2cc(Cc3ccccc3F)ccc21
Temperature: 80 °C
Reaction time: 16 h
Yield: 67.3 %

Procedure:
A mixture of 2-fluorobenzyl bromide (33 μL, 0.27 mmol), N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)propane-2-sulfonamide (100 mg, 0.27 mmol), trans-Bromo(N-succinimidyl)bis(triphenylphosphine)palladium(II) (11 mg, 0.014 mmol), and sodium carbonate (145 mg, 1.37 mmol) in degassed tetrahydrofuran (1.33 mL) and water (0.66 mL) was stirred at 80° C. for 16 h. The reaction was then diluted with 6 mL of DCM and 2 mL of water and the mixture was filtered over a phase separator. The organic phase was evaporated to dryness in vacuo to afford a brown oil in. Purification by silica flash column chromatography (EtOAc/heptane: from 0% to 60% of EtOAc) afforded the title compound as an oil (63.1 mg, 66%). MS (ESI): m/z [M−H]− 346.0
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[N:16]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=4)[CH:14]=[C:13]([C:27]([O:29]C)=O)[C:9]=3[NH:10][C:11]=2[CH:12]=1)([O-:3])=[O:2].[NH3:31]>CO>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[N:16]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:25])([F:24])[F:26])[CH:18]=4)[CH:14]=[C:13]([C:27]([NH2:31])=[O:29])[C:9]=3[NH:10][C:11]=2[CH:12]=1)([O-:3])=[O:2]
Reactant: COC(=O)c1cc(-c2cccc(C(F)(F)F)c2)nc2c1[nH]c1cc([N+](=O)[O-])ccc12
Reactant: N
Solvent: CO
Product: NC(=O)c1cc(-c2cccc(C(F)(F)F)c2)nc2c1[nH]c1cc([N+](=O)[O-])ccc12
Temperature: 80 °C
Yield: 79 %

Procedure:
A suspension of methyl 7-nitro-2-(3-(trifluoromethyl)phenyl)-5H-pyrido[3,2-b]indole-4-carboxylate (250 mg, 0.602 mmol) in 7 N NH3 in MeOH (5 mL) in a sealed microwave vial was heated in an oil bath at 80° C. for 16 h. After cooling to RT, the solid was collected by filtration and washed with MeOH to afford 7-nitro-2-(3-(trifluoromethyl)phenyl)-5H-pyrido[3,2-b]indole-4-carboxamide (200 mg, 0.475 mmol, 79% yield). MS (ESI) m/z 401.1 (M+H). 1H NMR (500 MHz, DMSO-d6) δ ppm 12.26 (1H, br. s.), 8.62-8.81 (5H, m), 8.54 (1H, d, J=8.85 Hz), 8.03-8.19 (2H, m), 7.75-7.88 (2H, m).
Reaction SMILES: [CH:1]1([C:6]([OH:31])([CH2:21][C:22]2[O:23]C(C)(C)[O:25][C:26](=O)[CH:27]=2)[C:7]#[C:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3([C:18]#[N:19])[CH2:17][CH2:16]3)=[C:11]([F:20])[CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.BrC1C=CC(C2(C#N)CC2)=C(F)C=1.C1(C2(CCC3C=CC(C(C)(C)C#N)=C(F)C=3)CC(=O)CC(=O)O2)CCCC1>>[CH:1]1([C:6]2([CH2:7][CH2:8][C:9]3[CH:14]=[CH:13][C:12]([C:15]4([C:18]#[N:19])[CH2:16][CH2:17]4)=[C:11]([F:20])[CH:10]=3)[CH2:21][C:22](=[O:23])[CH2:27][C:26](=[O:25])[O:31]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC1(C)OC(=O)C=C(CC(O)(C#Cc2ccc(C3(C#N)CC3)c(F)c2)C2CCCC2)O1
Agent: CC(C)(C#N)c1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1F
Agent: N#CC1(c2ccc(Br)cc2F)CC1
Product: N#CC1(c2ccc(CCC3(C4CCCC4)CC(=O)CC(=O)O3)cc2F)CC1

Procedure:
The desired product was prepared analogously to step 4 of Example A(97), substituting 1-{4-[3-Cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-2-fluoro-phenyl}-cyclopropanecarbonitrile [prepared analogously to step 3 of Example A(97) substituting 1-(4-bromo-2-fluoro-phenyl)-cyclopropanecarbonitrile in place of 2-(4-bromo-2-fluorophenyl)-2-methylpropanenitrile)] in place of 2-{4-[2-(2-cyclopentyl-4,6-dioxotetrahydro-2H-pyran-2-yl)ethyl]-2-fluorophenyl}-2-methylpropanenitrile. 1H NMR (CDCl3) δ: 1.27-1.30 (m, 2H), 1.51-1.73 (m, 10H), 1.84-1.89 (m, 2H), 2.19 (p, J=8.08 Hz, 1H), 2.58-2.71 (m, 4H), 3.36 (d, J=4.04 Hz, 2H), 6.81-6.86 (m, 2H), 7.16-7.18 (m, 1H). MS (ESI): 368 (M−H).