Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC([N:5]([CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([N:19]3[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]3)[CH:17]=2)[N:12]([C:25](=[O:27])[CH3:26])[CH:11]([CH3:28])[CH2:10]1)C(=O)[O-])(C)C.[ClH:29]>ClCCl>[ClH:29].[ClH:29].[C:25]([N:12]1[C:13]2[C:18](=[CH:17][C:16]([N:19]3[CH:23]=[C:22]([CH3:24])[N:21]=[CH:20]3)=[CH:15][CH:14]=2)[C@H:9]([NH2:5])[CH2:10][C@@H:11]1[CH3:28])(=[O:27])[CH3:26]
Reactant: CC(=O)N1c2ccc(-n3cnc(C)c3)cc2C(N(C(=O)[O-])C(C)(C)C)CC1C
Agent: Cl
Solvent: ClCCl
Product: CC(=O)N1c2ccc(-n3cnc(C)c3)cc2[C@H](N)C[C@@H]1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1,1-dimethylethyl[1-acetyl-2-methyl-6-(4-methyl-1H-imidazol-1-yl)-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see Intermediate 62) (5.7 g, 14.83 mmol) in dichloromethane (DCM) (40 mL) was treated at room temperature with HCl (4N in 1,4-dioxane, 20 ml, 80 mmol). An ice bath was used during the addition to keep the temperature below 30° C. Once the addition was completed, DCM (20 mL) was added and the resulting mixture was stirred at room temperature for 2 h then concentrated in vacuo to give (cis)-1-acetyl-2-methyl-6-(4-methyl-1H-imidazol-1-yl)-1,2,3,4-tetrahydro-4-quinolinamine di-hydrochloride as (5.12 g, 14.33 mmol, 97%) as a white solid.
Reaction SMILES: O[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[CH2:4][C:3]1([CH3:14])[CH3:13].C1C=CC(P([N:29]=[N+:30]=[N-:31])(C2C=CC=CC=2)=O)=CC=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[N:29]([CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[CH2:4][C:3]1([CH3:14])[CH3:13])=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC1(C)Cc2ccc(C#N)cc2C1O
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CC1(C)Cc2ccc(C#N)cc2C1N=[N+]=[N-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
To a solution of Step B. 3-hydroxy-2,2-dimethyl-2,3-dihydro-1H-indene-5-carbonitrile (4.98 g, 0.027 mol) in toluene (60 mL) at 0° C. was added DPPA (8.6 mL, 0.040 mol) via syringe dropwise followed by DBU (6.0 mL, 0.040 mol) via syringe dropwise. After stirring at 0° C. for 10 min and rt for 30 min, the mixture was heated at 80° C. for 60 h, then cooled to rt and partitioned between EtOAc (400 mL)/water (100 mL). Resulting layers were separated and the organic layer was washed with water (100 mL), aq HCl (1N, 60 mL×2), water (100 mL), sat. aq. NaHCO3 (80 mL), brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give yellow oil as the crude product. Purification by flash chromatography on silica gel (120 g) eluting with EtOAc/hexane mixtures provided the title compound as a colorless oil (4.12 g, 73% yield). HPLC Ret. time: 3.37 min. LCMS MH+ (m/z) 213.3. 1H NMR: (DMSO-d6, 400 MHz): δ 7.86 (s, 1H), 7.76 (d, 1H), 7.49 (d, 1H), 4.74 (s, 1H), 2.80 (m, 2H), 1.13 (s, 3H), 1.06 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]1[C:21]([OH:23])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)[CH2:27][CH2:28]CN=C=NCC.C(N(CC)CC)C.N1(C2C=CN=CC=2)CCCC1.C(O)C>C(Cl)Cl>[CH2:27]([O:22][C:21]([CH:9]1[CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:23])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)C(C(=O)O)C1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Agent: c1cc(N2CCCC2)ccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
To a stirred solution of N,N'-di-tert-butyloxycarbonylpiperazine-2-carboxylic acid (4.6 g, 0.013 mol), 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (3.2 g, 0.016 mol), triethylamine (2.2 mL, 0.016 mol) and 4-pyrrolidinopyridine (0.23 g, 1.5 mmol) in CH2Cl2 (120 mL) was added ethanol (0.93 mL, 0.016 mol). The mixture was left stirring overnight, then the mixture was washed with water (2×50 mL), 5% aqueous acetic acid (2×300 mL) and water (2×50 mL). The organic phase was separated, dried (Na2SO4) and evaporated. The residue was chromatographed on silica gel, eluting with petrol:EtOAc (1:1) to give the ester (3.3 g, 72%) as a colourless oil. 1H NMR (360 MHz, CDCl3) δ 1.28 (3H, t, J=7.1 Hz), 1.44 (9H, s), 2.70-3.32 (3H, m), 3.70-4.12 (2H, m), 4.14-4.26 (2H, m), 4.46-4.76 (2H, m). MS (ES+) 359 (M+1).
Reaction SMILES: [BH4-].[Na+].[OH:3][CH2:4][CH2:5][S:6]([C:9]1[CH:10]=[C:11]([C:27](=[O:44])[CH2:28][CH2:29][C:30]([C:32]2[CH:37]=[C:36]([O:38][CH3:39])[C:35]([O:40][CH3:41])=[C:34]([O:42][CH3:43])[CH:33]=2)=[O:31])[CH:12]=[C:13]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:14]=1[O:15][CH2:16][CH2:17][CH3:18])(=[O:8])=[O:7]>C(O)C.ClCCl>[OH:3][CH2:4][CH2:5][S:6]([C:9]1[CH:10]=[C:11]([CH:27]([OH:44])[CH2:28][CH2:29][CH:30]([C:32]2[CH:33]=[C:34]([O:42][CH3:43])[C:35]([O:40][CH3:41])=[C:36]([O:38][CH3:39])[CH:37]=2)[OH:31])[CH:12]=[C:13]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:14]=1[O:15][CH2:16][CH2:17][CH3:18])(=[O:8])=[O:7]
Reactant: CCCOc1c(OCc2ccccc2)cc(C(=O)CCC(=O)c2cc(OC)c(OC)c(OC)c2)cc1S(=O)(=O)CCO
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CCCOc1c(OCc2ccccc2)cc(C(O)CCC(O)c2cc(OC)c(OC)c(OC)c2)cc1S(=O)(=O)CCO
Temperature: 75 °C

Procedure:
Sodium borohydride (0.66 g) was added to a suspension of 1-[3-(2-hydroxyethylsulfonyl)-4-propoxy-5-benzyloxyphenyl]-4-(3,4,5-trimethoxyphenyl) butan-1,4-dione (from previous experiment) in ethanol (125 mL), and the mixture was heated at 75° C. for 2 h. The solution was cooled and diluted with dichloromethane. It was then washed with 2.5 N HCl (2 x) and water, dried, and evaporated to a syrup, Rf 0.11 (hexane-ethyl acetate., 1:1, v/v). This material was used directly in the next experiment without further purification.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[CH2:18][CH2:19][CH3:20].[BrH:21].N([O-])=O.[Na+]>O1CCOCC1.O.[Cu]Br>[Br:21][C:2]1[CH:7]=[CH:6][C:5]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])=[CH:4][C:3]=1[CH2:18][CH2:19][CH3:20]
Reactant: Br
Reactant: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1N
Agent: [Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50.3 %

Procedure:
2-(4-Amino-3-propylphenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (33.2 mmol, 10 g) was dissolved in dioxane (15 mL) and water (30 mL) was added. The suspension was heated to reflux then hydrobromic acid (48% weight in water, 149 mmol, 17 mL) was added drop wise via an addition funnel over a 20 minute period. The mixture was heated for a further 20 minutes before cooling to 0° C. A solution of sodium nitrite (33.2 mmol, 2.290 g) in water (30 mL) was added to the mixture over a 30 minute period and the mixture stirred at 0° C. for 30 minutes. A solution of copper (I) bromide (38.2 mmol, 5.48 g) in water (30 mL) and hydrobromic acid (48% weight in water, 149 mmol, 17 mL) was added drop wise to the mixture over a 20 minute period at 0° C. and the mixture was allowed to stir at 0° C. for 20 minutes. The mixture was warmed to 60° C. for 20 minutes then allowed to stir at room temperature overnight. The reaction mixture was extracted with diethyl ether (3×100 mL), the organic phase was dried over magnesium sulfate, filtered and the filtrate was concentrated under vacuum. The resulting residue was purified by silica gel column chromatography (eluting with 10% ethyl acetate/90% heptane) to afford the title compound (6.1 g). MS (ESI) m/z 365.5 [M−H]
Reaction SMILES: CN(C)C=O.Br[CH2:7][C:8]1[C:13]([CH:14]([F:16])[F:15])=[CH:12][CH:11]=[CH:10][C:9]=1[Cl:17].C(=O)([O-])[O-].[K+].[K+].[CH2:24]([N:30]1[CH2:35][CH2:34][CH:33]([NH:36][C:37]([C@:39]2([CH2:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[C@H:43]([CH3:44])[CH2:42][NH:41][CH2:40]2)=[O:38])[CH2:32][CH2:31]1)[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>O.C(OCC)(=O)C>[Cl:17][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([CH:14]([F:16])[F:15])[C:8]=1[CH2:7][N:41]1[CH2:42][C@@H:43]([CH3:44])[C@@:39]([CH2:45][C:46]([O:48][C:49]([CH3:51])([CH3:50])[CH3:52])=[O:47])([C:37](=[O:38])[NH:36][CH:33]2[CH2:32][CH2:31][N:30]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:35][CH2:34]2)[CH2:40]1
Reactant: FC(F)c1cccc(Cl)c1CBr
Reactant: CCCCCCN1CCC(NC(=O)[C@@]2(CC(=O)OC(C)(C)C)CNC[C@H]2C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCCCN1CCC(NC(=O)[C@@]2(CC(=O)OC(C)(C)C)CN(Cc3c(Cl)cccc3C(F)F)C[C@H]2C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.5 %

Procedure:
N,N-Dimethylformamide (400 μl), 2-(bromomethyl)-1-chloro-3-(difluoromethyl)benzene obtained in Example 10f (24.9 mg, 0.0976 mmol) and potassium carbonate (20.2 mg, 0.146 mmol) were added to tert-butyl 2-[(3R*,4S*)-3-[(1-hexylpiperidin-4-yl)carbamoyl]-4-methylpyrrolidin-3-yl]acetate obtained in Example 10i (20 mg, 0.0488 mmol), followed by stirring at room temperature overnight. Ethyl acetate and water were added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. This was concentrated, and the resulting crude product was purified by column chromatography (NH silica gel, elution solvent: heptane/ethyl acetate=98/2->80/20) to give the title compound (14.4 mg, yield 50.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][C:12](=[O:15])[CH2:13]Cl)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH:16]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)C(C)C)(C)C.[I-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:11][C:12](=[O:15])[CH2:13][N:32]2[CH2:33][CH2:34][N:29]([CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:30][CH2:31]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(CCl)Nc1ccc(Cl)cc1C(=O)O
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CN1CCN(C(c2ccccc2)c2ccccc2)CC1)Nc1ccc(Cl)cc1C(=O)O
Yield: 11 %

Procedure:
1.0 g (4.0 mmol) of 5-chloro-2-[(chloroacetyl)amino]benzoic acid obtained in Example 72-(i), 1.0 g (4.0 mmol) of 1-benzhydrylpiperazine, 1.1 g (8.8 mmol) of N,N-diisopropylethylamine, and 60 mg (0.4 mmol) of sodium iodide were stirred in 5 mL of DMF solution at 80° C. for 3 hours. Thereafter, the solvent was distilled off under reduced pressure, H2O was added to the residue, and solids were collected by filtration and dried. The obtained crude product was separated and purified by silica gel column chromatography, and the resultant was then recrystallized using ethyl acetate/n-hexane, thereby giving 198 mg of the target 5-chloro-2-({[4-(diphenylmethyl)piperazine-1-yl]acetyl}amino)benzoic acid (yield: 11%).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[S:7][C:6]2[C:17]3[C:22]([CH:23]=[CH:24][C:5]=2[N:4]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[C:3]1=[O:30])=[CH:21][CH:20]=[CH:19][CH:18]=3.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][C:41]=1[O:42][CH3:43])[C:36](Cl)=[O:37]>N1C=CC=CC=1.C(Cl)Cl>[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][C:41]=1[O:42][CH3:43])[C:36]([O:1][C@@H:2]1[C@H:8]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)[S:7][C:6]2[C:17]3[C:22]([CH:23]=[CH:24][C:5]=2[N:4]([CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[C:3]1=[O:30])=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:37]
Reactant: COc1ccc([C@@H]2Sc3c(ccc4ccccc34)N(CCN(C)C)C(=O)[C@@H]2O)cc1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc([C@@H]2Sc3c(ccc4ccccc34)N(CCN(C)C)C(=O)[C@@H]2OC(=O)c2ccc(OC)c(OC)c2)cc1
Reaction time: 17 h
Yield: 90.7 %

Procedure:
To a solution of 2.0 g (0.0047 mol) of (-)-cis-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-5-[2-(dimethylamino)ethyl]naphtho[ 1,2-b][1,4]thiazepin-4(5H)-one in 25 ml of dry pyridine was added dropwise 1.6 g (0.0082 mol) of 3,4-dimethoxybenzoyl chloride at ice-bath temperature. After the addition, the reaction mixture was kept at ice-bath temperatures for 17 hours and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate and cold 10% potassium carbonate. The combined ethyl acetate solutions were washed with brine, dried (MgSO4) and the solvent was removed to give 3.3 g of crude product, which was dissolved in methylene chloride and chromatographed using 45 g of silica gel. The comumn was eluted with 50 ml portions of methylene chloride-acetone (80:20). Fractions 21-50 were collected and the solvent was removed to give 2.5 g (92%) of (-)-cis-2,3-dihydro-3-[(3,4-dimethoxybenzoyl)oxy]-2-(4-methoxyphenyl)-5-[2-(dimethylamino)ethyl]naphtho[1,2-b][1,4]thiazepin-4(5H)-one as an amorphous solid, [α]D25 + 47.39° (C 0.928, MeOH).
Reaction SMILES: [Si](O[C@H](C1C=CC(O)=C2C=1C=CC(=O)N2)CNCCCCCCCCNC(C1C=C(S(C2C=C3C(=C(C)C=2)N=CC(C(N)=O)=C3NC2C=CC=C(OC)C=2)(=O)=O)C=CC=1)=O)(C(C)(C)C)(C)C.[NH2:67][CH2:68][C@@H:69]([C:78]1[C:83]2[O:84][CH2:85][C:86](=[O:88])[NH:87][C:82]=2[C:81]([OH:89])=[CH:80][CH:79]=1)[O:70][Si:71]([C:74]([CH3:77])([CH3:76])[CH3:75])([CH3:73])[CH3:72].[CH3:90][O:91][C:92]1[CH:93]=[C:94]([NH:98][C:99]2[C:108]3[C:103](=[C:104]([CH3:138])[CH:105]=[C:106]([S:109]([C:112]4[CH:117]=[CH:116][CH:115]=[C:114]([C:118](=[O:137])[NH:119][C:120]5[CH:125]=[CH:124][C:123]([C:126]6[CH:131]=[CH:130][C:129]([CH2:132][CH2:133][CH2:134][CH:135]=O)=[CH:128][CH:127]=6)=[CH:122][CH:121]=5)[CH:113]=4)(=[O:111])=[O:110])[CH:107]=3)[N:102]=[CH:101][C:100]=2[C:139]([NH2:141])=[O:140])[CH:95]=[CH:96][CH:97]=1>>[Si:71]([O:70][C@H:69]([C:78]1[C:83]2[O:84][CH2:85][C:86](=[O:88])[NH:87][C:82]=2[C:81]([OH:89])=[CH:80][CH:79]=1)[CH2:68][NH:67][CH2:135][CH2:134][CH2:133][CH2:132][C:129]1[CH:130]=[CH:131][C:126]([C:123]2[CH:122]=[CH:121][C:120]([NH:119][C:118]([C:114]3[CH:113]=[C:112]([S:109]([C:106]4[CH:107]=[C:108]5[C:103](=[C:104]([CH3:138])[CH:105]=4)[N:102]=[CH:101][C:100]([C:139]([NH2:141])=[O:140])=[C:99]5[NH:98][C:94]4[CH:95]=[CH:96][CH:97]=[C:92]([O:91][CH3:90])[CH:93]=4)(=[O:110])=[O:111])[CH:117]=[CH:116][CH:115]=3)=[O:137])=[CH:125][CH:124]=2)=[CH:127][CH:128]=1)([C:74]([CH3:77])([CH3:75])[CH3:76])([CH3:73])[CH3:72]
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(-c6ccc(CCCC=O)cc6)cc5)c4)cc23)c1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CN)c1ccc(O)c2c1OCC(=O)N2
Agent: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)NCCCCCCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c5ccc(O)c6[nH]c(=O)ccc56)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(-c6ccc(CCCCNC[C@H](O[Si](C)(C)C(C)(C)C)c7ccc(O)c8c7OCC(=O)N8)cc6)cc5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 148, using (R)-8-(2-amino-1-((tert-butyldimethylsilyl)oxy)ethyl)-5-hydroxy-2H-benzo[b][1,4]oxazin-3(4H)-one in place of Intermediate 2 and Intermediate 124 in place of Intermediate 112. ES/MS calcd. for C57H63N6O9SSi+ 1035.4. Found m/z=1035.6 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[OH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][CH2:28][NH2:29]>>[OH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][CH2:28][NH:29][C:17]([C:15]1[CH:16]=[C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])[CH:12]=[N:13][CH:14]=1)=[O:19]
Reactant: NCCc1ccccc1O
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Product: CCc1cc(-c2cncc(C(=O)NCCc3ccccc3O)c2)c(C)[nH]c1=O

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and 2-(2-hydroxy-phenyl)-ethyl-amine to afford the title compound. MS: m/e=378 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([N:16]2[CH2:20][C@@H:19]([N:21]([CH2:32][CH3:33])[C:22]([O:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C@H:18]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)[CH2:17]2)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[C:42]1C=CC(OC(=O)N([C@H]2[C@H](C3C=CC(Cl)=CC=3)CN(CC3C=CC=CC=3)C2)C2CC2)=CC=1.C(OC(N1CCC(C(O)=O)CC1)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]([N:16]2[CH2:20][C@@H:19]([N:21]([CH:32]3[CH2:42][CH2:33]3)[C:22]([O:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)=[O:23])[C@H:18]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)[CH2:17]2)=[O:15])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)C[C@H]1c1ccc(Cl)cc1
Reactant: O=C(Oc1ccc(F)cc1)N(C1CC1)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)cc1
Agent: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N2C[C@@H](N(C(=O)Oc3ccc(F)cc3)C3CC3)[C@H](c3ccc(Cl)cc3)C2)CC1

Procedure:
In analogy to the procedure described for the synthesis of rac-4-{(3R,4S)-3-(4-Chloro-phenyl)-4-[ethyl-(4-fluoro-phenoxycarbonyl)-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid tert-butyl ester the title compounds were prepared from rac-[(3S,4R)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-cyclopropyl-carbamic acid 4-fluoro-phenyl ester by cleavage of the benzyl group and subsequent coupling with 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid. The resulting rac-4-{(3R,4S)-3-(4-Chloro-phenyl)-4-[cyclopropyl-(4-fluoro-phenoxycarbonyl)-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid tert-butyl ester was subjected to separation by chiral HPLC on CHIRALPAK AD eluting with i-propanol/heptane. After evaporation of the product containing fractions 4-{(3S,4R)-3-(4-Chloro-phenyl)-4-[cyclopropyl-(4-fluoro-phenoxycarbonyl)-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid tert-butyl ester was obtained as light brown foam. MS m/e: 586.3 [M+H]+. 4-{(3R,4S)-3-(4-Chloro-phenyl)-4-[cyclopropyl-(4-fluoro-phenoxycarbonyl)-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid tert-butyl ester was obtained as yellow viscous oil. MS m/e: 586.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:4][N:3]=1.[CH3:24][NH:25][CH3:26]>C(O)C>[CH3:24][N:25]([CH3:26])[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:4][N:3]=1
Reactant: CS(=O)(=O)c1ccc(C(=C2CCCC2)c2ccc(Cl)nc2)cc1
Reactant: CNC
Solvent: CCO
Product: CN(C)c1ccc(C(=C2CCCC2)c2ccc(S(C)(=O)=O)cc2)cn1
Temperature: 180 °C

Procedure:
4.5 g of 2-chloro-5-[(cyclopentylidene)(4-methylsulfonylphenyl)-methyl]pyridine, prepared in Example 6, and 50 ml of a 33% solution of dimethyl-amine in ethanol are placed in a 125 ml autoclave. The mixture is heated at 180° C. under pressure for 7 hours. After cooling, the solvent is evaporated off under vacuum and the residue is taken up with water and then extracted with dichloromethane. The organic phase is dried over magnesium sulfate and evaporated under vacuum. The resulting oil crystallizes from an ethyl ether/isopropyl ether mixture to give 2.8 g of 2-(dimethylamino)-5-[(cyclopentylidene)(4-methylsulfonylphenyl)methyl]pyridine in the form of crystals melting at 122°-123° C.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:9](=[O:10])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[CH2:19][C:20]1[N:25]=[C:24]([NH:26][C:27]2[S:28][C:29]([C:32]#[N:33])=[CH:30][N:31]=2)[CH:23]=[CH:22][CH:21]=1>CS(C)=O>[CH3:2][N:3]1[C:9](=[O:10])[CH2:8][CH2:7][N:6]([CH2:19][C:20]2[N:25]=[C:24]([NH:26][C:27]3[S:28][C:29]([C:32]#[N:33])=[CH:30][N:31]=3)[CH:23]=[CH:22][CH:21]=2)[CH2:5][CH2:4]1
Reactant: CN1CCNCCC1=O
Reactant: N#Cc1cnc(Nc2cccc(CCl)n2)s1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CN1CCN(Cc2cccc(Nc3ncc(C#N)s3)n2)CCC1=O
Reaction time: 2 h

Procedure:
4-Methyl-[1,4]diazepan-5-one hydrochloride (0.092 g, 0.028 mmol) was dissolved in 1 mL DMSO. Triethylamine (0.12 mL, 0.84 mmol) was added followed by the addition 2-(6-Chloromethyl-pyridin-2-ylamino)-thiazole-5-carbonitrile (0.070 g, 0.28 mmol). The solution as stirred for 2 h. The reaction mixture was purified directly by loading the solution onto a reverse phase preparative column. The fractions containing pure product were concentrated and the white solid that resulted was characterized as the TFA salt. 1H NMR (CD3OD) δ 8.07 (s, 1H), 7.91 (dd, 1H, J=7.5, 8.2 Hz), 7.30 (d, 1H, J=7.3 Hz), 7.19 (d, 1H, J=8.4 Hz), 4.56 (s, 2H), 3.83 (bs, 2H), 3.64 (bs, 4H), 3.01 (s, 3H), 2.93 (bs, 2H). MS [M+H]+=343.2.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][CH2:22]I)[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>CN(C)C=O>[CH:1]1([NH:6][C:7]2[CH:8]=[C:9]([CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:10]=[C:11]3[C:15]=2[NH:14][C:13]([C:16]2[S:17][CH2:18][C@@H:19]([CH2:21][CH2:22][N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[N:20]=2)=[CH:12]3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: CS(=O)(=O)Cc1cc(NC2CCCC2)c2[nH]c(C3=N[C@H](CCI)CS3)cc2c1
Solvent: CN(C)C=O
Product: CS(=O)(=O)Cc1cc(NC2CCCC2)c2[nH]c(C3=N[C@H](CCN4CCOCC4)CS3)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
Cyclopentyl-{2-[(R)-4-(2-iodo-ethyl)-4,5-dihydro-thiazol-2-yl]-5-methanesulfonylmethyl-1H-indol-7-yl}-amine (116 mg, 0.22 mmol) prepared in Step A was dissolved in N,N-dimethylformamide (4 mL). Morpholine (57 mg, 0.66 mmol) was added thereto, and the mixture was stirred for 8 h at room temperature. The reaction was quenched by water, and the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography to give the title compound (68 mg, Yield 64%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:26])[CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]([C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:12][N:13]=1.C(NC(C)C)(C)C.[C:34](Cl)(=[O:36])[CH3:35]>O1CCCC1.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:26][C:34](=[O:36])[CH3:35])[CH:6]=[CH:7][C:8]=1[C:9]1[O:10][C:11]([C:14]2[C:15]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[N:16][O:17][C:18]=2[CH3:19])=[N:12][N:13]=1
Reactant: CC(=O)Cl
Reactant: COc1cc(N)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Agent: CN(C)c1ccncc1
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1cc(NC(C)=O)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Temperature: 25 °C
Reaction time: 6 h
Yield: 72.8 %

Procedure:
To a solution of 3-methoxy-4-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-phenylamine (200 mg, 0.57 mmol) in tetrahydrofuran (4 mL) were added N,N-diisopropylamine (111 mg, 0.86 mmol), 4-dimethylaminopyridine (7.0 mg, 0.06 mmol) and acetyl chloride (59 mg, 0.75 mmol) and the reaction mixture was stirred at ambient temperature for 6 h. The resulting suspension was extracted with ethyl acetate (20 mL) and the combined organic layers were washed with aqueous sodium carbonate (saturated). Drying over sodium sulfate and concentration afforded the title compound (162 mg, 72%) as a yellow solid. MS: m/e=391.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:9][C:10](N(OC)C)=[O:11])=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][N:25]=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])[CH2:9][C:10]([C:29]2[C:24]([F:23])=[N:25][CH:26]=[C:27]([CH3:30])[CH:28]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: Cc1ccc(F)nc1
Reactant: CON(C)C(=O)CC(c1ccc(Br)cc1)c1ccccc1C
Product: Cc1cnc(F)c(C(=O)CC(c2ccc(Br)cc2)c2ccccc2C)c1

Procedure:
In analogy to example 74, step 5, from 3-(4-bromo-phenyl)-N-methoxy-N-methyl-3-o-tolyl-propionamide (example 74, step 4) and 2-fluoro-5-methylpyridine (CAS RN: [2369-19-9]) was prepared the title compound as a colorless oil, MS (ESI+): m/z=411 ([M]+, 1Br).