Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([C:31](O)=[O:32])[CH:20]=[C:19]1[CH:34]1[CH2:36][CH2:35]1)[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(O[N:41]([C@H]1CN(C(OC(C)(C)C)=O)[C@H](C(=O)N)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][N:22]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[C@H:21]([C:31](=[O:32])[NH2:41])[CH:20]=[C:19]1[CH:34]1[CH2:35][CH2:36]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:7])=[O:8])[CH:2]=[CH2:3]
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(=O)O)C=C1C1CC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(N)=O)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Product: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(N)=O)C=C1C1CC1)S(=O)(=O)c1ccccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (2S,5R)-5-(N-(allyloxy)-2-nitrophenylsulfonamido)-1-(tert-butoxycarbonyl)-4-cyclopropyl-1,2,5,6-tetrahydropyridine-2-carboxylic acid (Intermediate 267, 2.33 g, 4.45 mmol) following the procedure described for Intermediate 20. The desired product was obtained as a tan foam (1.47 g, 63%).
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]2[O:6][C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[O:9][C:4]=2[CH:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([O:26][CH3:27])[CH:25]=1)[CH:21]=[O:22].C([Li])CCC.O1C2C=CC(C(C3C=C(OC)C=C(OC)C=3)O)=CC=2OCC1>>[CH3:27][O:26][C:24]1[CH:23]=[C:20]([CH:21]([C:3]2[C:4]3[O:9][C:8]([F:11])([F:10])[C:7]([F:13])([F:12])[O:6][C:5]=3[CH:14]=[CH:15][CH:2]=2)[OH:22])[CH:19]=[C:18]([O:17][CH3:16])[CH:25]=1
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: FC1(F)Oc2ccc(Br)cc2OC1(F)F
Agent: COc1cc(OC)cc(C(O)c2ccc3c(c2)OCCO3)c1
Agent: [Li]CCCC
Product: COc1cc(OC)cc(C(O)c2cccc3c2OC(F)(F)C(F)(F)O3)c1
Yield: 26.4 %

Procedure:
6-Bromo-2,2,3,3-tetrafluoro-2,3-dihydrobenzo[1,4]dioxine (1.50 g, 5.23 mmol), 3,5-dimethoxybenzaldehyde (0.79 g, 4.75 mmol), and n-butyl lithium (2.09 ml, 5.23 mmol) were treated in the same manner as described above for the synthesis of (2,3-dihydrobenzo[1,4]dioxin-6-yl)-(3,5-dimethoxyphenyl)methanol. The crude material was purified via flash column chromatography (5% EtOAc in hexane gradient to 30% EtOAc in hexane in about 40 min.) to give (3,5-Dimethoxy-phenyl)-(2,2,3,3-tetrafluoro-2,3-dihydro-benzo[1,4]dioxin-5-yl)-methanol as an oil (0.47 g, 26%): 1HNMR (CDCl3) 7.37 (dd, J=1, 7 Hz, 1H, Ar), 7.17 (t, J=8 Hz, 1H, Ar), 7.06 (dd, J=1, 8 Hz, 1H, Ar), 6.57 (d, J=2 Hz, 2H, Ar), 6.38 (t, J=2 Hz, 1H, Ar), 6.12 (d, J=3 Hz, 1H, CHOH), 3.77 (s, 6H, 2OCH3), 2.36 (d, J =3 Hz, 1H, OH). The product was carried over to the next step.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:16][CH2:15][C:14]3[CH:13]=[C:12]([NH2:17])[CH:11]=[CH:10][C:9]=3[CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:18]([C:25]1[CH:35]=[CH:34][CH:33]=[C:27]2[C:28]([O:30]C(=O)[C:26]=12)=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(C(C)C)C[CH2:41][O:42]C1C=CC(N)=CC=1OC)(C)C>>[O:18]([C:25]1[CH:26]=[C:27]2[C:33](=[CH:34][CH:35]=1)[C:41](=[O:42])[N:17]([C:12]1[CH:11]=[CH:10][C:9]3[CH2:8][CH:7]([CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:16][CH2:15][C:14]=3[CH:13]=1)[C:28]2=[O:30])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Nc1ccc2c(c1)CCC(CN1CCCC1)C2
Reactant: O=C1OC(=O)c2c(Oc3ccccc3)cccc21
Reactant: COc1cc(N)ccc1OCCN(C(C)C)C(C)C
Product: O=C1c2ccc(Oc3ccccc3)cc2C(=O)N1c1ccc2c(c1)CCC(CN1CCCC1)C2

Procedure:
6-Pyrrolidin-1-ylmethyl-5,6,7,8-tetrahydro-naphthalen-2-ylamine [WO 0121577 A2] was treated with 3-phenoxyphthalic anhydride in the same manner as for 4-(2-diisopropylamino-ethoxy)-3-methoxy-phenylamine in Example A4 to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[N:14]([O-])=O.[Na+].[ClH:18]>[Cl-].[Zn+2].[Cl-]>[Cl-:18].[C:3]1([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]([N+:1]#[N:14])=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cl
Reactant: O=N[O-]
Reactant: Nc1ccccc1-c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [Zn+2]
Product: N#[N+]c1ccccc1-c1ccccc1
Reaction time: 0.17 h

Procedure:
First, 500 mg of o-aminobiphenyl was dissolved in 2.4 ml of 13.6% hydrochloric acid (4 molar equivalents), and the resulting solution was subjected to ultrasonic treatment for 10 minutes and then kept at the freezing point. To the solution at the freezing point was added dropwise 0.8 ml of a 25 % aqueous solution of sodium nitrite (1 molar equivalent) slowly while stirring. After the addition, the mixture was stirred at the freezing point for 2 hours, followed by addition of 0. 6 ml of saturated zinc chloride while stirring at the freezing point. This caused precipitation of zinc chloride double salt of diazonium chloride.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][CH:12]=[C:13]2[NH2:16])=[N:8]1.F[C:18]1[C:23]([C:24]2[N:32]=[CH:31][N:30]=[C:29]3[C:25]=2[N:26]=[CH:27][N:28]3[CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][O:34]2)=[CH:22][CH:21]=[CH:20][N:19]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][CH:12]=[C:13]2[NH:16][C:18]2[C:23]([C:24]3[N:32]=[CH:31][N:30]=[C:29]4[C:25]=3[N:26]=[CH:27][N:28]4[CH:33]3[CH2:38][CH2:37][CH2:36][CH2:35][O:34]3)=[CH:22][CH:21]=[CH:20][N:19]=2)=[N:8]1
Reactant: Nc1cccc2nn(C3CCCCO3)cc12
Reactant: Fc1ncccc1-c1ncnc2c1ncn2C1CCCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: c1cnc(Nc2cccc3nn(C4CCCCO4)cc23)c(-c2ncnc3c2ncn3C2CCCCO2)c1
Reaction time: 1 h
Yield: 42.9 %

Procedure:
A solution of 2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-amine (37.4 mg, 172 μmol) and 6-(2-fluoropyridin-3-yl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (51.5 mg, 172 μmol) in THF (1.0 mL) was cooled in an ice bath and treated dropwise with LHMDS (0.55 mL of a 1.0 M solution in THF, 3 equiv.). A deep red solution was obtained. The mixture was stirred for 60 min and then quenched with water (0.050 mL). The mixture was extracted with EtOAc from saturated aqueous NaHCO3, dried (MgSO4) and concentrated to give a dark residue. 2-(Tetrahydro-2H-pyran-2-yl)-N-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-yl)-2H-indazol-4-amine (36.6 mg, 42.8% yield) was obtained by flash chromatography on silica (50% EtOAc/hexane) (yellow band on column) as a yellow oil which crystallized upon standing. 1H NMR (400 MHz, CDCl3) δ 12.75 (br. s., 1H); 9.77 (d, J=7.82 Hz, 1H); 9.12 (s, 1H); 8.44 (d, J=3.52 Hz, 1H); 8.38 (s, 2H); 8.06 (d, J=7.04 Hz, 1H); 7.41 (d, 1H); 7.35 (d, J=7.63 Hz, 1H); 6.92-7.03 (m, 1H); 5.88 (d, 1H); 5.73 (d, 1H); 4.13-4.30 (m, 2H); 3.84 (br. s., 2H); 2.17-2.35 (m, 3H); 2.00-2.16 (m, 3H); 1.79 (br. s., 6H). m/z (API-ES) 497.1 (M+H)+.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:18]([OH:20])=[O:19])[CH2:3][C:4]1[CH:9]=CC(OCC2C=CC=CC=2)=C[CH:5]=1.[CH:28]1[CH:29]=[CH:30][C:31]2N(O)N=N[C:32]=2[CH:33]=1.[CH2:38]1CCC(N=C=NC2CCCCC2)CC1>C(OCC)(=O)C.CN(C=O)C>[NH2:1][C@H:2]([C:18]([O:20][CH2:38][C:32]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:33]=1)=[O:19])[CH2:3][CH:4]([CH3:5])[CH3:9]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)C[C@H](N)C(=O)OCc1ccccc1

Procedure:
p-tosylate (22.2 kg; Bachem AG, Switzerland) was suspended in ethyl acetate (108 L), then TEA (about 7.1 L) was added at room temperature. Boc-Tyr(Bzl)-OH (20 kg; Senn Chemicals, Switzerland) and HOBt (7.3 kg) were added as solids. A solution of DCC (12.2 kg) in DMF (40 L) was added to the mixture at −6° C. The completion of the reaction was monitored by TLC and HPLC.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:35][C:36]([NH:38][C@@H:39]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[C@H:42]([O:49][C:50]3[CH:51]=[CH:52][C:53]4[N:54]([C:56]([N:59]5[CH2:64][CH2:63][CH2:62][CH2:61][C@@H:60]5[CH3:65])=[N:57][N:58]=4)[CH:55]=3)[CH2:41][CH2:40]2)=[O:37])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][Si](C(C)C)(C(C)C)C(C)C)=[C:12]([CH2:27][N:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:84](=O)([OH:86])[O-:85].[Na+]>C1COCC1.C(Cl)Cl>[CH:84]([OH:86])=[O:85].[C:1]([C:5]1[CH:6]=[C:7]([NH:35][C:36]([NH:38][C@@H:39]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[C@H:42]([O:49][C:50]3[CH:51]=[CH:52][C:53]4[N:54]([C:56]([N:59]5[CH2:64][CH2:63][CH2:62][CH2:61][C@@H:60]5[CH3:65])=[N:57][N:58]=4)[CH:55]=3)[CH2:41][CH2:40]2)=[O:37])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([CH2:27][N:28]3[CH2:29][CH2:30][N:31]([CH3:34])[CH2:32][CH2:33]3)[CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)[Si](Oc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCC[C@@H]5C)n4c3)c3ccccc32)cc1CN1CCN(C)CC1)(C(C)C)C(C)C
Reactant: O=C([O-])O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(O)c(CN5CCN(C)CC5)c4)c4ccccc43)cn12
Product: O=CO
Temperature: 50 °C
Yield: 33 %

Procedure:
A solution of Intermediate 61g (18 mg, 0.02 mmol) in THF (0.10 mL) was treated with tetrabutylammonium fluoride (1M in THF, 0.10 mL, 0.10 mmol) and the mixture was heated to 50° C. for 2 h. The mixture was diluted with DCM and a saturated aqueous sodium bicarbonate solution. The layers were separated and the aqueous layer was then extracted with DCM (2×). The combined organic layers were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by HPLC (Method 6; 5-95% MeCN in H2O, 0.1% HCO2H over 25 mins) to give the title compound (5 mg, 33%). LCMS (Method 5): Rt 3.52 min, m/z 747.6 [MH+]. 1H NMR (400 MHz, d6-DMSO): 0.91 (3H, d, J=6.4 Hz), 1.26 (9H, s), 1.44-1.56 (2H, m), 1.61-1.73 (2H, m), 1.74-1.98 (4H, m), 1.99-2.12 (2H, m), 2.13 (3H, s), 2.25-2.37 (3H, m), 2.37-2.49 (5H, m, obscured by DMSO), 2.86-2.95 (1H, m), 3.12-3.19 (1H, m, obscured by water), 3.20-3.44 (1H obscured by water), 3.64 (2H, s), 4.77-4.86 (1H, m), 5.51 (1H, t, J=4.4 Hz), 6.28 (1H, s), 6.81-6.85 (1H, m), 7.05 (1H, d, J=8.6 Hz), 7.15-7.21 (3H, m), 7.24-7.30 (2H, m), 7.30-7.39 (2H, m), 7.63 (1H, d, J=10.2 Hz), 7.69 (1H, d, J=1.7 Hz), 7.95 (1H, s), 8.36 (0.1H, s).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[C:12]([N:14]([CH2:20][C:21]1[N:25]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[OH:33])[C:24]2[CH:34]=[CH:35][CH:36]=[CH:37][C:23]=2[N:22]=1)[CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[O:13].C([O-])([O-])=O.[K+].[K+].[Cl:44][CH2:45][CH2:46][CH2:47]I>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[C:12]([N:14]([CH2:20][C:21]1[N:25]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH2:47][CH2:46][CH2:45][Cl:44])[C:24]2[CH:34]=[CH:35][CH:36]=[CH:37][C:23]=2[N:22]=1)[CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[O:13]
Reactant: COc1ccc(C(=O)N(CCC(C)C)Cc2nc3ccccc3n2Cc2ccccc2O)c(Cl)c1OC
Reactant: ClCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)N(CCC(C)C)Cc2nc3ccccc3n2Cc2ccccc2OCCCCl)c(Cl)c1OC
Yield: 99.7 %

Procedure:
A solution of 350 mg (0.67 mmole) of (2-chloro-3,4-dimethoxyphenyl)-N-({l-[(2-hydroxyphenyl)methyl] benzimidazol-2-yl}methyl)-N-(3-methylbutyl) carboxamide and 278 mg (2.01 mmole) of K2CO3 in 2 mL of anhydrous N,N-dimethylformamide is treated with 79.1 μL (0.737 mmole) 1-chloro-3-iodo propane at room temperature for 19 hr. The resulting solution is diluted with 60 mL of ethyl acetate, washed with 3×20 mL water and 1×20 mL of brine, dried over anhydrous Na2SO4 and the solvent is removed in vacuo to afford 400 mg (99%) of (2-chloro-3,4-dimethoxyphenyl)-N-[(1-{[2-(3-chloropropoxy)phenyl]methyl}benzimidazol-2-yl)methyl]-N-(3-methylbutyl) carboxamide.
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12].C(N(CC)CC)C.[C:20](Cl)([Cl:22])=[O:21]>C1COCC1.C1(C)C=CC=CC=1>[Cl:22][C:20]([O:8][C:7]1[C:2]([F:1])=[C:3]([F:12])[C:4]([F:11])=[C:5]([F:10])[C:6]=1[F:9])=[O:21]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: O=C(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=C(Cl)Oc1c(F)c(F)c(F)c(F)c1F
Reaction time: 2 h
Yield: 74.7 %

Procedure:
Pentafluorophenol (30 g; 163 mmol) and triethylamine (20 g, 200 mmol) were combined in 200 ml dry THF, and then added dropwise to a stirring solution of phosgene (20 g; 200 mmol) in 100 ml of toluene at 0° C. After 2 hours, the solution was filtered and evaporated to give the crude product as an oil, which was recrystallized from hexane to obtain 30 g (75%) pure pentafluorophenyl chloroformate.
Reaction SMILES: [S:1]1[C:5]([CH2:6][NH:7][C:8]2[CH:13]=[C:12](Cl)[N:11]=[C:10]([CH3:15])[N:9]=2)=[CH:4][C:3]2[CH:16]=[CH:17][CH:18]=[CH:19][C:2]1=2.[C:20]([C:23]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)([CH3:25])[CH3:24])([OH:22])=[O:21].C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:1]1[C:5]([CH2:6][NH:7][C:8]2[N:9]=[C:10]([CH3:15])[N:11]=[C:12]([C:28]3[CH:27]=[C:26]([C:23]([CH3:25])([CH3:24])[C:20]([OH:22])=[O:21])[CH:31]=[CH:30][CH:29]=3)[CH:13]=2)=[CH:4][C:3]2[CH:16]=[CH:17][CH:18]=[CH:19][C:2]1=2
Reactant: CC(C)(C(=O)O)c1cccc(B(O)O)c1
Reactant: Cc1nc(Cl)cc(NCc2cc3ccccc3s2)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: Cc1nc(NCc2cc3ccccc3s2)cc(-c2cccc(C(C)(C)C(=O)O)c2)n1
Temperature: 90 °C
Reaction time: 6 h
Yield: 15.3 %

Procedure:
Argon is bubbled through a mixture of benzo[b]thiophen-2-ylmethyl-(6-chloro-2-methyl-pyrimidin-4-yl)-amine [247 mg, 0.81 mmol], 3-(1-carboxy-1-methyl-ethyl)-phenyl boronic acid [304 mg, 1.46 mmol, see Example 49(b) step 2], Cs2CO3 (792 mg, 2.43 mmol), and tetrakis(triphenylphosphine)palladium (0) (92 mg, 0.08 mmol) in ethylene glycol dimethyl ether (2.5 mL) and water (0.5 mL), for a period of 10 minutes. The reaction vessel is sealed and heated to 90° C. After stirring for 6 hours the heating is turned off and the mixture is allowed to cool to ambient temperature upon standing for 24 hours. The mixture is diluted with water (20 mL) and extracted twice with EtOAc (30 mL). The organic extracts are combined and dried over magnesium sulfate, filtered and concentrated to afford 2-(3-{6-[(benzo[b]thiophen-2-ylmethyl)-amino]-2-methyl-pyrimidin-4-yl}-phenyl)-2-methyl-propionic acid [51.6 mg, 14.7%, Example 72] as a solid. LCMS RT=2.27 minutes, MS: 434 (M+H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].Cl[CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=[C:19]([CH3:27])[CH:18]=1.Cl>CN(C=O)C>[CH3:27][C:19]1[CH:18]=[C:17]([CH2:16][N:1]2[C:9]3[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[C:26]2[CH2:25][CH:24]=[CH:23][CH2:22][C:21]=2[N:20]=1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Reactant: Cc1cc(CCl)c2ccccc2n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(Cn2ccc3cc(C(=O)O)ccc32)c2c(n1)CC=CC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
Indole 5-carboxylic acid (0.5 g, 3.1 mmol) was added to a suspension of sodium hydride (0.27 g, 6.8 mmol, 60% oil dispersion) (washed with hexanes) in DMF (20 mL) cooled to 0° C. The reaction was allowed to stir for 1 h and the 4-chloromethyl-2-methyl-quinoline (0.72 g, 3.8 mmol) was added. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was neutralized with 1 N HCl and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over magnesium sulfate and concentrated to give the 1-[(2-methyl-5,8-dihydro-4-quinolinyl)methyl]-1H-indole-5-carboxylic acid (0.68 g, 69%) as a brown residue, MS (M+H)+=317.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][CH:15](O)[CH2:14]2)[CH2:10][C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.C(N(S(F)(F)[F:40])CC)C.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.ClCCl>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16][CH:15]([F:40])[CH2:14]2)[CH2:10][C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)NC1(C2CC(=O)N(Cc3ccccc3)C2)CC(O)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(C2CC(=O)N(Cc3ccccc3)C2)CC(F)C1
Reaction time: 12 h
Yield: 53.6 %

Procedure:
A 1.79 g (4.96 mmol) portion of 1-benzyl-4-[3-(tert-butoxycarbonylamino)-1-hydroxycyclobutan-3-yl]-2-pyrrolidone (Isomer B2) was dissolved in a mixed solvent consisting of 50 ml of toluene and 20 ml of dichloromethane to which, while cooling in an ice bath with stirring, was then added 1.31 ml (9.92 mmol) of diethylaminosulfur trifluoride, subsequently carrying out 12 hours of stirring at 50° C. While cooling in an ice bath with stirring, the reaction solution was alkalified by slowly adding saturated sodium bicarbonate aqueous solution and then mixed with chloroform to carry out separation of layers, and the resulting organic layer was washed with saturated brine. The aqueous layer was again extracted with chloroform, and the organic layers were combined and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under a reduced pressure and the resulting residue was purified by a silica gel column chromatography to give 964 mg (53.6%) of the title compound. 1H-NMR data of the thus obtained compound coincided with the aforementioned data of its enantiomer Isomer B1.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[C:11]1([S:17]([N:20]2[CH:24]=[CH:23][CH:22]=[CH:21]2)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Cl-].[Al+3].[Cl-].[Cl-]>ClC(Cl)C.C(OCC)(=O)C>[C:11]1([S:17]([N:20]2[CH:21]=[CH:22][CH:23]=[C:24]2[C:4]([C:3]2[C:2]([Cl:1])=[N:10][CH:9]=[CH:8][CH:7]=2)=[O:5])(=[O:19])=[O:18])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=S(=O)(c1ccccc1)n1cccc1
Reactant: O=C(Cl)c1cccnc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: O=C(c1cccnc1Cl)c1cccn1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
To a solution of 2-chloro-nicotinoyl chloride (1.17 g) (Aldrich, Milwaukee, Wis.) and 1-benzensulfonyl-1H-pyrrole (1 g) (Aldrich) in dichloroethane (15 mL) was added aluminum chloride (1.1 g). After stirring at room temperature for one hour, the reaction was diluted with ethyl acetate, washed with water, base and brine, dried and purified to give 820 mg of (1-benzenesulfonyl-1H-pyrrol-2-yl)-(2-chloro-pyridin-3-yl)-methanone.
Reaction SMILES: [BH3-]C#N.[Na+].[NH2:5][CH2:6][CH:7]1[CH2:16][CH2:15][CH2:14][C:13]2[C:12]([O:17][C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[CH:20][N:19]=3)=[CH:11][CH:10]=[CH:9][C:8]1=2.[C:27]1(=O)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>CC(O)=O.CO>[CH:27]1([NH:5][CH2:6][CH:7]2[CH2:16][CH2:15][CH2:14][C:13]3[C:12]([O:17][C:18]4[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[CH:20][N:19]=4)=[CH:11][CH:10]=[CH:9][C:8]2=3)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: O=C1CCCCC1
Reactant: NCC1CCCc2c(Oc3ccc(C(N)=O)cn3)cccc21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: NC(=O)c1ccc(Oc2cccc3c2CCCC3CNC2CCCCC2)nc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.4 %

Procedure:
Add NaBH3CN (63 mg, 1.00 mmol) to a solution of 6-(5-aminomethyl-5,6,7,8-tetrahydro naphthalen-1-yloxy)-nicotinamide (intermediate 20, 148 mg, 0.500 mmol) and cyclohexanone (98 mg, 1.00 mmol) dissolved in 5% AcOH/MeOH (5 ml) and stir at ambient temperature for 16 hours. Concentrate the reaction mixture and redissolved in EtOAc. Wash the EtOAc solution with 5% aq. KOH and brine before drying (MgSO4) and concentrating. Purify on silica gel (5% (1N NH3/MeOH)/DCM) to obtain 145 mg of the title compound as a white foam. Mass spectrum (ion spray): m/z=380 (M+1); 1HNMR (CDCl3): 8.56 (s, 1H), 8.15 (d, 1H), 7.22-7.14 (m, 2H), 6.90 (m, 2H), 5.79 (br. s, 2H), 2.99 (m, 1H), 2.96-2.79 (m, 2H), 2.63-2.41 (m, 3H), 1.91 (m, 2H), 1.85-1.67 (m, 6H), 1.31-1.04 (m, 6H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH:12]([Sn](CCCC)(CCCC)CCCC)=[CH2:13]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:12]([C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)=[CH2:13]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: Clc1ccc2ccccc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1ccc2ccccc2n1
Yield: 99.2 %

Procedure:
A solution of 2-chloroquinoline (1 g, 6.11 mmol) and vinyl tributyl tin (2.69 mL, 9.17 mmol) in toluene (30 mL) was treated with Pd(PPh3)4 (0.706 g, 0.611 mmol) and heated to reflux for 1.5 h. The reaction mixture was concentrated and the resulting material was purified directly by gradient elution on silica gel (0 to 25% EtOAc in hexanes) to afford the title compound as a colorless oil (941 mg, 99%). LRMS m/z (M+H) 156.1 found, 156.2 required.
Reaction SMILES: P([N:17]=[N+:18]=[N-:19])(=O)(OC1C=CC=CC=1)OC1C=CC=CC=1.C1CCN2C(=NCCC2)CC1.[N:31]1[C:40]2[C:35](=[CH:36][C:37]([CH:41](O)[CH3:42])=[CH:38][CH:39]=2)[CH:34]=[CH:33][CH:32]=1>C1(C)C=CC=CC=1>[N:17]([CH:41]([C:37]1[CH:36]=[C:35]2[C:40](=[CH:39][CH:38]=1)[N:31]=[CH:32][CH:33]=[CH:34]2)[CH3:42])=[N+:18]=[N-:19]
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: CC(O)c1ccc2ncccc2c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CC(N=[N+]=[N-])c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
In a 50 mL round bottom flask under N2 was dissolved diphenyl phosphorazidate (2.44 ml, 11.3 mmol), DBU (1.69 ml, 11.3 mmol) and 1-(quinolin-6-yl)ethanol (1.65 g, 9.53 mmol) (Prepared according to B. P. Lugovkin,/Zhurnal Obshchei Khimii 25 (1955) 392-397) in 20 mL of PhMe stirred at rt for 10 h. The crude mixture was directly purified by MPLC (ISCO) with Hexanes:AcOEt 100:0 to 0:100. MS m/z=199.2 [M+1]+. Calc'd for C11H10N4: 198.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][NH2:17])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([OH:20])C>C(OCC)=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][NH:17][CH:18]=[O:20])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCc1cccc(OCc2ccccc2)c1
Reactant: CCO
Solvent: CCOC=O
Product: O=CNCCc1cccc(OCc2ccccc2)c1

Procedure:
To a solution of 8.60 g of 2-[3-(benzyloxy)phenyl]ethylamine in 50 ml of ethanol, 4.6 ml of ethyl formate was added and the mixture was heated at reflux for 18 hours. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain 4.81 g of the desired compound as a pale orange oily substance.