Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:19]3[C:14](=[C:15]([NH2:20])[CH:16]=[CH:17][CH:18]=3)[N:13]=[CH:12][N:11]=2)=[CH:5][CH:4]=1.[Cl:23][C:24]1[C:29]([C:30](O)=[O:31])=[C:28]([F:33])[C:27]([CH2:34][NH:35][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:26][CH:25]=1.C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[Cl:23][C:24]1[C:29]([C:30]([NH:20][C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:14]=2[N:13]=[CH:12][N:11]=[C:10]3[NH:9][C:6]2[CH:7]=[N:8][C:3]([C:2]([F:1])([F:21])[F:22])=[CH:4][CH:5]=2)=[O:31])=[C:28]([F:33])[C:27]([CH2:34][NH:35][C:36](=[O:41])[C:37]([CH3:39])([CH3:38])[CH3:40])=[CH:26][CH:25]=1
Reactant: Nc1cccc2c(Nc3ccc(C(F)(F)F)nc3)ncnc12
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)O)c1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(C(=O)Nc2cccc3c(Nc4ccc(C(F)(F)F)nc4)ncnc23)c1F
Yield: 8.9 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-(6-(trifluoromethyl)pyridin-3-yl)quinazoline-4,8-diamine (Intermediate-24, 150 mg, 0.49 mmol), 6-chloro-2-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-2, 170 mg, 0.59 mmol), oxalyl chloride (112 mg, 0.89 mmol), DMF (1 drop) and DIPEA (190 mg, 1.47 mmol) in CH2Cl2 (5 mL) to afford 25 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.68 (s, 1H), 10.36 (s, 1H), 9.23 (s, 1H), 8.83-8.80 (d, J=7.8 Hz, 1H), 8.75 (s, 1H), 8.69-8.65 (d, J=9.6 Hz, 1H), 8.37-8.34 (d, J=8.7 Hz, 1H), 8.16 (br t, 1H), 7.97-7.94 (d, J=8.7 Hz, 1H), 7.79 (t, 1H), 7.41-7.33 (m, 2H), 4.31-4.29 (d, J=5.4 Hz, 2H), 1.13 (s, 9H); MS (m/z): 575.18 (M+H)+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:15]2[C:10](=[CH:11][C:12]([C:16](=[O:18])[CH3:17])=[CH:13][CH:14]=2)[C:9]([CH3:20])([CH3:19])[CH2:8][CH:7]=1.[C:21]([C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1)([OH:23])=[O:22].[OH-].[Na+]>CO>[O:18]=[C:16]([C:12]1[CH:13]=[CH:14][C:15]2[C:6]([C:2]3[S:1][CH:5]=[CH:4][CH:3]=3)=[CH:7][CH2:8][C:9]([CH3:20])([CH3:19])[C:10]=2[CH:11]=1)[CH:17]=[CH:28][C:27]1[CH:30]=[CH:31][C:24]([C:21]([OH:23])=[O:22])=[CH:25][CH:26]=1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CC=C2c1cccs1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C)CC=C(c2cccs2)c2ccc(C(=O)C=Cc3ccc(C(=O)O)cc3)cc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 62.6 mg (0,222 mmol) 3,4-dihydro-1-(2-thienyl)-4,4-dimethyl-6-acetylnaphthalene (Compound D33) in 4.0 mL of MeOH were added 33.4 mg (0.222 mmol) of 4-carboxy benzaldehyde, and 240.0 mg (6.00 mmol; 2.0 mL of 3M aqueous NaOH). The resulting solution was stirred at room temperature for 12 h, concentrated under reduced pressure, and the residual oil dissolved in EtOAc. The solution was treated with 10% HCl, and the organic layer washed with H2O, and saturated aqueous NaCl, before being dried over Na2 SO4. Removal of the solvents under reduced pressure gave the title compound as a pale green solid after recrystallization from EtOH.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](=[O:15])[CH2:13][C:12]([CH3:16])=[N:11]2)=[CH:6][CH:5]=1)([OH:3])=[O:2].[OH:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][CH:19]=1>CN(C)C=O.CO>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:14](=[O:15])[C:13](=[CH:22][C:21]3[CH:24]=[CH:25][C:18]([OH:17])=[CH:19][CH:20]=3)[C:12]([CH3:16])=[N:11]2)=[CH:8][CH:9]=1)([OH:3])=[O:2]
Reactant: CC1=NN(c2ccc(C(=O)O)cc2)C(=O)C1
Reactant: O=Cc1ccc(O)cc1
Solvent: CO
Solvent: CN(C)C=O
Product: CC1=NN(c2ccc(C(=O)O)cc2)C(=O)C1=Cc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
218 g (1 mole) of 1-p-carboxyphenyl-3-methyl-2-pyrazolin-5-one were suspended in 600 ml of dimethylformamide. The mixture obtained was heated with stirring to 100° C., whereupon a solution of 122 g (1mole) of p-hydroxybenzaldehyde in 400 ml of methanol was added. The dissolution of both compounds was complete. The dye started crystallizing after some 30 min. The heating was stopped after 2 h and the reaction mixture was allowed to cool down to room temperature. The dye was filtered with suction and rinsed with methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[N:6][CH:7]=1.Cl[C:26]1[CH:31]=[CH:30][N:29]=[C:28]([C:32]([OH:34])=[O:33])[CH:27]=1.C(N(CC)CC)C>C(O)C>[C:32]([C:28]1[CH:27]=[C:26]([N:21]2[CH2:20][CH2:19][CH:18]([CH2:17][NH:16][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)=[O:24])[CH2:23][CH2:22]2)[CH:31]=[CH:30][N:29]=1)([OH:34])=[O:33]
Reactant: O=C(Nc1ccc(Cl)cn1)c1ccccc1NCC1CCNCC1
Reactant: O=C(O)c1cc(Cl)ccn1
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(O)c1cc(N2CCC(CNc3ccccc3C(=O)Nc3ccc(Cl)cn3)CC2)ccn1
Yield: 25 %

Procedure:
Using a similar procedure to that described in Example 52, N-(5-chloropyridin-2-yl)-2-(piperidin-4-ylmethylamino)benzamide (150 mg, 0.43 mmol), 4-chloropicolinic acid (95 mg, 0.60 mmol), triethylamine (87 mg, 0.86 mmol), and ethanol (2 mL) yielded 50 mg (25%) of the title compound.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]1([C:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CCCCCCC.C(OCC)(=O)C>ClCCl.C(S([O-])(=O)=O)(F)(F)F.[Ag+]>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][C:4]([C:15]2([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)=[CH:3][CH:2]=1
Reactant: COc1ccccc1
Reactant: C1=C(c2ccccc2)CCCC1
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCCC
Product: COc1ccc(C2(c3ccccc3)CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of AuCl3 (7.6 mg, 0.025 mmol) and AgOTf (19.3 mg, 0.075 mmol) was stirred in dichloromethane (2 mL) for 30 min. Anisole (54 mg, 0.5 mmol) and 1-Phenyl-1-cyclohexene (158 mg, 1 mmol) were then added sequentially. The resulting mixture was stirred at room temperature overnight. Evaporation of the solvent under reduced pressure gave 130 mg of crude material. Flash chromatography (heptane:ethyl acetate 95:5) afforded 90 mg of a as a colorless oil. Rf=0.33 (heptane:ethyl acetate 95:5). 1H-NMR (400 MHz, CDCl3): 7.27-7.25 (m, 4H), 7.19 (d, 2H, J=8.8 Hz), 7.12 (m, 1H), 6.81 (d, 2H, J=8.8 Hz), 3.77 (s, 3H), 2.30-2.20 (m, 4H), 1.62-1.44 (m, 6H).
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:11])[S:4]([NH:7][CH2:8][CH2:9][NH2:10])(=[O:6])=[O:5].[CH:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C1C=CC=CC=1>[ClH:1].[CH:12](=[N:10][CH2:9][CH2:8][NH:7][S:4]([N:3]([CH3:11])[CH3:2])(=[O:6])=[O:5])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=Cc1ccccc1
Reactant: CN(C)S(=O)(=O)NCCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CN(C)S(=O)(=O)NCCN=Cc1ccccc1
Yield: 41.1 %

Procedure:
A mixture of 4.0 g (0.02 mole) of 2-[N-[(dimethylamino)sulfonyl]amino]ethylamine hydrochloride and 2.0 g (0.02 mole) of benzaldehyde was stirred and treated immediately with 2.0 g (0.02 mole) of triethylamine, followed by the addition of 200 ml of dry benzene. The solution was heated to reflux employing a Dean-Stark apparatus. After 2 hr at reflux, the benzene solution was cooled and washed twice with 100 ml portions of water. The organic phase was separated, dried over magnesium sulfate, and concentrated under reduced pressure to an oil, which was dissolved in ether and treated with HCl gas to precipitate a yellowish solid. The product was collected by filtration, washed with ether and air dried to provide 2.4 g (50%) of product. The NMR spectrum was consistent with the assigned structure and the solid was used without additional purification.
Reaction SMILES: [CH2:1]1[N:12]2[C:13]3[C:9]([C@@H:10]4[CH2:17][NH:16][CH2:15][CH2:14][C@@H:11]42)=[CH:8][CH:7]=[CH:6][C:5]=3[CH2:4][S:3][CH2:2]1.Cl[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1>>[F:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][CH2:21][CH2:20][CH2:19][N:16]2[CH2:15][CH2:14][C@@H:11]3[N:12]4[CH2:1][CH2:2][S:3][CH2:4][C:5]5[CH:6]=[CH:7][CH:8]=[C:9]([C:13]4=5)[C@@H:10]3[CH2:17]2)=[CH:24][CH:25]=1
Reactant: c1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCSC2
Reactant: Fc1ccc(OCCCCl)cc1
Product: Fc1ccc(OCCCN2CC[C@H]3[C@@H](C2)c2cccc4c2N3CCSC4)cc1

Procedure:
The title compound of EXAMPLE 5 was prepared from (7bR,11aS)-1,2,7b,8,9,10,11,11a-octahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole and 1-(3-chloropropoxy)-4-fluorobenzene following the procedure described in EXAMPLE 4. 1H NMR(CDCl3, 300 MHz): δ 7.0-6.78 (m, 6H) 6.65 (t, 1H, J=7.3 Hz), 3.95 (t, 2H, J=6.2 Hz), 3.84 (dd, 2H, J=16.4 Hz), 3.59 (m, 2H), 3.25 (m, 2H), 3.15 (m, 2H), 2.85 (m, 2H), 2.65 (m, 2H), 2.45 (m, 4H), 2.30 (m, 2H) ppm. LRMS (ES)+: 399 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:3]1[CH:8]2[CH2:9][CH:5]([CH2:6][CH2:7]2)[CH:4]1[C:10](O)=[O:11].Cl.CN(C)CCCN=C=NCC.[OH:46][N:47]1C2C=CC=CC=2N=N1.NO>CN(C=O)C.C(OCC)(=O)C>[OH:46][NH:47][C:10]([C@@H:4]1[C@H:3]([N:2]([CH3:1])[S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:33]=[CH:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:25]=3)=[CH:18][CH:17]=2)(=[O:15])=[O:14])[C@@H:8]2[CH2:9][C@H:5]1[CH2:6][CH2:7]2)=[O:11]
Reactant: On1nnc2ccccc21
Reactant: CN(C1C2CCC(C2)C1C(=O)O)S(=O)(=O)c1ccc(OCc2ccc3ccccc3c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: NO
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN([C@@H]1[C@H]2CC[C@H](C2)[C@@H]1C(=O)NO)S(=O)(=O)c1ccc(OCc2ccc3ccccc3c2)cc1
Reaction time: 20 h
Yield: 50 %

Procedure:
To a solution of 3-{methyl-[4-(naphthalen-2-ylmethoxy)-benzenesulfonyl]-amino}-bicyclo[2.2.1]heptane-2-carboxylic acid (125 mg, 0.268 mmol) in DMF (1 mL) were added 1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochloride (103 mg, 0.536 mmol), 1-hydroxybenzotriazole (72.5 mg, 0.536 mmol) and hydroxylamine (50% in water, 82 μL, 1.34 mmol) at room temperature. The mixture was stirred for 20 h, diluted with ethyl acetate (5 mL), and washed with water (3×3 mL) and brine (3 mL). The organic layer was concentrated and the residue was purified by RP-HPLC to give (1R,2S,3R,4S)-N-hydroxy-3-(methyl{[4-(2-naphthylmethoxy)phenyl]sulfonyl}amino)bicyclo[2.2.1]heptane-2-carboxamide (50% yield). MS (ESI) [M+H] 481.2
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:56])[C@H:10]([CH2:52]CSC)[NH:11][C:12](=[O:51])[C@:13]([NH2:50])([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[N:14]([C:20](=[O:42])[CH2:21][NH:22][C:23](=[O:41])[C@H:24]([CH2:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[CH:36][CH:35]=1)[NH:25]C(OC(C)(C)C)=O)[C:15](=[O:19])[CH:16]([CH3:18])[CH3:17])[C:2]1[CH:7]=CC=C[CH:3]=1.[CH2:57]([O:64][C:65](=[O:112])[C@H:66](CCSC)[NH:67][C:68](=[O:107])[C@H:69]([CH2:100][C:101]1[CH:106]=[CH:105][CH:104]=[CH:103][CH:102]=1)[NH:70][C:71](=[O:99])[CH:72]([NH2:98])[N:73]([C:79](=[O:97])[C@H:80]([CH2:89][C:90]1[CH:95]=[CH:94][C:93]([OH:96])=[CH:92][CH:91]=1)[NH:81]C(OC(C)(C)C)=O)[C:74](=[O:78])[CH:75]([CH3:77])[CH3:76])[C:58]1C=CC=C[CH:59]=1>>[NH2:25][C@H:24]([C:23]([NH:22][CH2:21][C:20]([N:14]([C:15](=[O:19])[CH:16]([CH3:17])[CH3:18])[C@:13]([NH2:50])([C:12]([NH:11][C@H:10]([C:9]([OH:8])=[O:56])[CH2:52][CH:58]([CH3:59])[CH3:57])=[O:51])[CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)=[O:42])=[O:41])[CH2:33][C:34]1[CH:35]=[CH:36][C:37]([OH:40])=[CH:38][CH:39]=1.[NH2:81][C@H:80]([C:79]([N:73]([C:74](=[O:78])[CH:75]([CH3:76])[CH3:77])[CH:72]([NH2:98])[C:71]([NH:70][C@H:69]([C:68]([NH:67][C@H:66]([C:65]([OH:64])=[O:112])[CH2:1][CH:2]([CH3:7])[CH3:3])=[O:107])[CH2:100][C:101]1[CH:102]=[CH:103][CH:104]=[CH:105][CH:106]=1)=[O:99])=[O:97])[CH2:89][C:90]1[CH:95]=[CH:94][C:93]([OH:96])=[CH:92][CH:91]=1
Reactant: CSCC[C@H](NC(=O)[C@](N)(Cc1ccccc1)N(C(=O)CNC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)C(C)C)C(=O)OCc1ccccc1
Reactant: CSCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)C(N)N(C(=O)C(C)C)C(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)C(N)N(C(=O)C(C)C)C(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)O
Product: CC(C)C[C@H](NC(=O)[C@](N)(Cc1ccccc1)N(C(=O)CNC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)C(C)C)C(=O)O

Procedure:
Repetition of the procedure detailed in Example 13 using an equivalent quantity of N-t-butoxycarbonyl-L-tyrosyl-glycyl-α-aminoisobutyryl-L-phenylalanyl-L-methionine benzyl ester or N-t-butoxycarbonyl-L-tyrosyl-α-aminoisobutyrylglycyl-L-phenylalanyl-L-methionine benzyl ester affords L-tyrosylglycyl-α-aminoisobutyryl-L-phenylalanyl-L-leucine or L-tyrosyl-α-aminoisobutyrylglycyl-L-phenylalanyl-L-leucine, respectively.
Reaction SMILES: [C:1]1([CH2:7][N:8]([CH2:16][C@@H:17]2[CH2:22][CH2:21][NH:20][CH2:19][C@H:18]2[OH:23])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S1[CH:28]=[CH:27][CH:26]=[CH:25]1.[H][H]>CO.[Pd]>[C:1]1([CH2:7][N:8]([CH2:16][C@@H:17]2[CH2:22][CH2:21][N:20]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:19][C@H:18]2[OH:23])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccsc1
Reactant: O[C@@H]1CNCC[C@H]1CN(Cc1ccccc1)Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCCCN1CC[C@@H](CN(Cc2ccccc2)Cc2ccccc2)[C@H](O)C1

Procedure:
A mixture of intermediate (71) (0.083 mol) and butylaldehyde (7 g) in methanol (300 ml) was hydrogenated with palladium-on-carbon (10%) (2 g) as a catalyst in the presence of a thiophene solution (3 ml). After uptake of hydrogen (1 equivalent), the catalyst was filtered over celite and the filtrate was evaporated. The residue was dissolved in aqueous HCl 2N (500 ml). The mixture was washed with toluene and then separated into its layers. The aqueous layer was basified with 50% aqueous NaOH and then extracted three times with toluene. The combined organic layer was dried, filtered and the solvent was evaporated, yielding 29 g of (trans)-4-[[bis(phenylmethyl)amino]-methyl]-1-butyl-3-piperidinol (intermediate 72).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:10])[CH:9]=1)=[O:3].C[O-].[Na+].CO.[CH:16]1([CH:22]=O)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>C(OC)(OC)OC>[CH:16]1([CH:22]=[CH:1][C:2]([C:4]2[CH:5]=[CH:6][CH:7]=[C:8]([OH:10])[CH:9]=2)=[O:3])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CC(=O)c1cccc(O)c1
Reactant: O=CC1CCCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Product: O=C(C=CC1CCCCC1)c1cccc(O)c1
Reaction time: 0.67 h

Procedure:
A mixture of 3-hydroxyacetophenone on Wang resin (6.0 g, 5.52 mmol) was swelled in trimethyl orthoformate (60 mL) for 10 min. 25% NaOMe in MeOH (2.4 g, 11.0 mmol) was added and the mixture was stirred for 40 min. Cyclohexanecarboxaldehyde (1.9 g, 16.56 mmol) was added and stirring was continued for 40 min. The resin was filtered and washed with alternating MeOH and CH2Cl2 (×5) and dried under high vacuum overnight to give 6.62 g of 3-cyclohexyl-1-(3-hydroxyphenyl)-2-propen-1-one on Wang resin.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.C1(S([N:19]2[C:23]3=[N:24][CH:25]=[CH:26][CH:27]=[C:22]3[C:21]([C:28]3[CH:33]=[CH:32][N:31]=[C:30](Cl)[N:29]=3)=[CH:20]2)(=O)=O)C=CC=CC=1>>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:30]2[N:29]=[C:28]([C:21]3[C:22]4[C:23](=[N:24][CH:25]=[CH:26][CH:27]=4)[NH:19][CH:20]=3)[CH:33]=[CH:32][N:31]=2)=[C:4]([CH3:9])[CH:3]=1
Reactant: Cc1cc(Br)ccc1N
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Product: Cc1cc(Br)ccc1Nc1nccc(-c2c[nH]c3ncccc23)n1
Yield: 41.4 %

Procedure:
Using the procedure of example 1, 4-bromo-2-methylaniline (300 mg) was reacted with compound 1f (200 mg) to provide compound 41 (85 mg, 41%). 1H NMR (400 MHz, DMSO) δ 12.28 (br s, 1H), 8.75 (br s, 1H), 8.55 (d, J=7.8 Hz, 1H), 8.43 (s, 1H), 8.28 (d, J=7.2 Hz, 1H), 8.26 (m, 1H), 7.52 (m, 2H), 7.40 (d, J=10.8 Hz, 1H), 7.27 (d, J=7.2 Hz, 1H), 7.06 (dd, J=10.8 Hz, 6.0 Hz, 1H), 2.25 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:38])[C@@H:7]([NH2:37])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][C:18](=[O:20])[N:17]([CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[S:16]2(=[O:28])=[O:27])=[C:11]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:46](Cl)(=[O:48])[CH3:47].Cl>C(Cl)Cl.O>[C:1]([O:5][C:6](=[O:38])[C@@H:7]([NH:37][C:46](=[O:48])[CH3:47])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][C:18](=[O:20])[N:17]([CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[S:16]2(=[O:27])=[O:28])=[C:11]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(=O)N[C@@H](Cc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a Solution of (S)-2-Amino-3-{3-Benzyloxy-4-[1,1,4-Trioxo-5-(2-Trimethylsilanylethyl)-1,2,5-thiadiazolidin-2-yl]-phenyl}-propionic acid tert-butyl ester (150 mg, 0.27 mmol) and triethylamine (0.57 mL, 0.41 mmol) in methylene chloride (10 mL) at 0° C. is added acetyl chloride (0.21 mL, 0.3 mmol) dropwise then the mixture is stirred at RT for 2 h. Water and 1N HCl is added until pH 4 and the mixture is extracted with methylene chloride. The organic phase is washed with brine and dried over sodium sulfate. The solvent is removed under reduced pressure to give the title compound as an oil.
Reaction SMILES: [BH4-].[Li+].C(O[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])=[C:10]([Cl:21])[CH:9]=1)(=O)C.[O:22]1CCC[CH2:23]1>>[Cl:21][C:10]1[CH:9]=[C:8]([CH2:7][CH2:23][OH:22])[CH:13]=[CH:12][C:11]=1[O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20]
Reactant: COCCOCOc1ccc(COC(C)=O)cc1Cl
Reactant: C1CCOC1
Agent: [BH4-]
Agent: [Li+]
Product: COCCOCOc1ccc(CCO)cc1Cl
Temperature: 60 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
2.4 g (110 mmol) of lithium borohydride is added in portions to a solution of 10.6 g (36.7 mmol) of [3-chloro-4-(2-methoxy-ethoxymethoxy)-phenyl]-methyl acetate diluted in 110 ml of tetrahydrofuran. The reaction mixture is stirred at 60° C. for 2 hours. The reaction mixture is then poured into 500 ml of ice and then extracted with ethyl acetate. The organic phases are combined, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and evaporated. The solvents are evaporated to give 7.3 g (77%) of 2-[3-chloro-4-(2-methoxy-ethoxymethoxy)-phenyl]-ethanol in the form of a colorless oil.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].F[C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:10]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:9])[C@H:3]2[CH2:2][NH:1][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=2)=[O:11])=[C:13]([C:19]2[N:20]=[CH:21][CH:22]=[CH:23][N:24]=2)[CH:14]=1
Reactant: Fc1ccc(C(F)(F)F)cn1
Reactant: C[C@@H]1CCCN(C(=O)c2ccc(F)cc2-c2ncccn2)[C@@H]1CN
Product: C[C@@H]1CCCN(C(=O)c2ccc(F)cc2-c2ncccn2)[C@@H]1CNc1ccc(C(F)(F)F)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(4-fluoro-2-(pyrimidin-2-yl)phenyl)methanone and 2-fluoro-5-(trifluoromethyl)pyridine. ESI-MS (m/z): 474 [M+1]+. 1H NMR (300 MHz, DMSO-d6) δ 9.00-6.55 (m, 10H), 4.90-2.80 (m, 5H), 1.95-0.65 (m, 8H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[Li+].[CH3:14]C([N-]C(C)C)C.CI>C1COCC1>[CH3:14][CH:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:10]([OH:12])=[O:11]
Reactant: O=C(O)CCc1ccc(Cl)cc1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC(Cc1ccc(Cl)cc1)C(=O)O
Temperature: -30 °C
Reaction time: 1 h

Procedure:
A solution of 3-(4-chlorophenyl)propionic acid (1.85 g, 10 mmol) in 10 mL of THF was added to 16 mL of freshly prepared 1.5 M LDA (24 mmol) at dry ice-acetone bath temp. The reaction mixture was stirred 1 hr as it warmed to −30° C. and 1.6 mL (25 mmol) of methyl iodide was added. The resulting mixture was stirred at the same temp. for 0.5 h and the stirring was continued at RT overnight. The reaction was quenched with 1 N HCl, and diluted with ether. The solution was washed with water, 10% sodium thiosulfate and brine. The organic layer was dried over MgSO4. Solvent removal gave a mixture of the desired methylated product and the starting acid. Repetition of the above procedure on this residue gave the desired 2-methyl-3-(4-chlorophenyl) propionic acid contaminated with ˜5% of the starting acid as an oil. NMR: 1.5 (d, 3H), 4.78 (q, 1H). 6.84 & 7.26 (2d, 4H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:15]([CH:31]3[CH2:34][CH2:33][CH2:32]3)[C:16]3[C:21]([C:22]=2[C:23]#[N:24])=[CH:20][CH:19]=[C:18]([O:25][CH2:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:17]=3)=[CH:10][CH:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:15]([CH:31]3[CH2:34][CH2:33][CH2:32]3)[C:16]3[C:21]([C:22]=2[C:23]#[N:24])=[CH:20][CH:19]=[C:18]([O:25][CH2:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:17]=3)=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2c(C#N)c3ccc(OCS(C)(=O)=O)cc3n2C2CCC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)COc1ccc2c(C#N)c(-c3ccc(N)cc3)n(C3CCC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
To [4-(3-Cyano-1-cyclobutyl-6-methanesulfonylmethoxy-1H-indol-2-yl)-phenyl]-carbamic acid tert-butyl ester (1.21 g, 2.47 mmol) in CH2Cl2 (6 mL) was added TFA (2 mL) and stirred at room temperature for 1 h. The reaction mixture was diluted in CH2Cl2, washed with aq. NaHCO3, dried and concentrated. Trituration with acetone (5 mL) provided 2-(4-amino-phenyl)-1-cyclobutyl-6-methanesulfonylmethoxy-1H-indole-3-carbonitrile (891 mg, 91%) as a light pink solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[C:10]([O:11][CH2:12][CH3:13])=[CH:9][CH:8]=[N:7][CH:6]=1)[CH3:2].[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]2[CH:23]=[C:22]([CH2:24][O:25][S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:21]=2[CH:36]=1>C(O)C>[S:26]([C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=1)([O-:28])(=[O:27])=[O:25].[CH3:15][O:16][C:17]1[CH:18]=[CH:19][C:20]2[CH:23]=[C:22]([CH2:24][N+:7]3[CH:8]=[CH:9][C:10]([O:11][CH2:12][CH3:13])=[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:14])[CH:6]=3)[C:21]=2[CH:36]=1
Reactant: CCOC(=O)c1cnccc1OCC
Reactant: COc1ccc2c(c1)C(COS(=O)(=O)c1ccc(C)cc1)=C2
Solvent: CCO
Product: CCOC(=O)c1c[n+](CC2=Cc3ccc(OC)cc32)ccc1OCC
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
19.52 g of 4-ethoxynicotinic acid ethyl ester are added to a solution of 31.84 g (0.1 mol) of p-toluenesulphonic acid (5-methoxybenzocyclobuten-1-yl)methyl ester in 150 ml of 95% ethanol and the whole is stirred for 3 days at room temperature. After distilling off the solvent under reduced pressure, 1-[(5-methoxybenzocyclobuten-1-yl)methyl]-3-ethoxycarbonyl-4-ethoxypyridinium tosylate is obtained in the form of a light-yellow foam.