Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2([N:27]([CH3:29])[CH3:28])[CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]2)=[CH:16][CH:15]=1.CI.[Cl-].[NH4+]>CCCCC.C(Cl)Cl.CO.C1C=CC=CC=1.O1CCCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2([N:27]([CH3:29])[CH3:28])[CH2:21][CH2:22][C:23](=[O:26])[CH:24]([CH3:1])[CH2:25]2)=[CH:18][CH:19]=1
Reactant: CN(C)C1(c2ccc(Cl)cc2)CCC(=O)CC1
Reactant: CC(C)NC(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: C1CCOC1
Solvent: CI
Product: CC1CC(c2ccc(Cl)cc2)(N(C)C)CCC1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution consisting of 0.51 gm. (0.005 mole) diisopropylamine in 10 ml. tetrahydrofuran is chilled in an ice: methanol bath and 3 ml. of 1.68 N butyllithium in pentane is added. To this mixture is then added a solution consisting of 1.25 gm. (0.005 mole) 4(p-chlorophenyl)-4-dimethylaminocyclohexanone (prepared in Preparation I, above) in 20 ml. tetrahydrofuran. After 5 min. stirring, 1.42 gm. methyl iodide is added. The reaction mixture is stirred for another 30 min. in the cold, and then it is allowed to warm up to 25° C. Stirring is continued for 21/2 hours when 20 ml. saturated aqueous ammonium chloride is added. Benzene is also added. The organic solvent phase is separated, washed initially with water and then with brine. The organic solvents are removed by evaporation under reduced pressure. The residue thus obtained is transferred to a chromatographic column containing 200 ml. silica gel. The chromatogram is developed with 2 liters of a mixture of 3% methanol in methylene chloride followed by 2 liters of a mixture of 5% methanol in methylene chloride. Fractions which are shown by TLC to contain product are collected and combined. The solvents are removed by evaporation under reduced pressure giving the desired 4-(p-chlorophenyl)-2-methyl-4-dimethylaminocyclohexanone. The compound is recrystallized from diethyl ether to give an analytical sample having a melting point at 110° to 111° C. This is recognized to be the cis isomer with respect to the 4-amino substituent, by NMR spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:17][C:18]([OH:20])=O)[C:5]2[C:6]([CH:16]=1)=[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:8][N:9]=2.[CH3:21][NH:22][CH3:23]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:17][C:18]([N:22]([CH3:23])[CH3:21])=[O:20])[C:5]2[C:6]([CH:16]=1)=[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:8][N:9]=2
Reactant: CNC
Reactant: O=C(O)Cc1cc(Cl)cc2c(-c3ccccc3)onc12
Product: CN(C)C(=O)Cc1cc(Cl)cc2c(-c3ccccc3)onc12

Procedure:
The title compound is prepared by reacting the acid chloride of 5-chloro-3-phenyl-2,1-benzisoxazole-7-acetic acid and dimethylamine in an aprotic solvent. The solution is washed with hydrochloric acid and evaporated. The title compound is obtained from the residue by conventional crystallization from alkanolic solution or by chromatography.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[N:18]1([C:24]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][C:25]=2[C:26](Cl)=[O:27])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>>[N:18]1([C:24]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][C:25]=2[C:26]([N:13]2[CH2:12][CH2:11][N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:16])[F:17])=[CH:5][CH:6]=3)[CH2:15][CH2:14]2)=[O:27])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1N1CCOCC1
Reactant: FC(F)(F)Oc1ccc(N2CCNCC2)cc1
Product: O=C(c1cc([N+](=O)[O-])ccc1N1CCOCC1)N1CCN(c2ccc(OC(F)(F)F)cc2)CC1

Procedure:
The title compound was prepared according to the procedure described for example 46 from 1-(4-Trifluoromethoxy-phenyl)-piperazine and 2-Morpholin-4-yl-5-nitro-benzoyl chloride (74%%, yellow solid, MS (m/e): 481.2(M+H, 100%)
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([S-:11])[CH3:10].[Na+]>>[C:2]1([CH2:1][S:11][CH2:9][CH3:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[S-]
Reactant: ClCc1ccccc1
Agent: [Na+]
Product: CCSCc1ccccc1

Procedure:
Commercially available benzyl chloride and sodium ethanethiolate are subjected to a nucleophilic substitution reaction to produce PhCH2SC2H5 after isolation and purification. In a Parr pressure vessel, 2.0 g (0.013 moles) of PhCH2SC2H5 is added to 200 ml of t-butanol. With stirring, 2.94 g (0.026 moles) of potassium t-butoxide is slowly added. The head space is flushed with an inert gas before exposure to 60 psi NO gas. The reaction is allowed to proceed at room temperature for 24 hours or until no further consumption of NO gas is observed. The resulting diazeniumdiolate salt is filtered, washed with t-butanol and diethyl ether, and vacuum dried before analysis.
Reaction SMILES: CN[C@@H]1CCCC[C@H]1NC.[F:11][CH:12]([F:39])[C:13]1[N:17]([C:18]2[N:26]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:24]=[C:23]3[C:19]=2[N:20]=[CH:21][NH:22]3)[C:16]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:15]=2[N:14]=1.Br[C:41]1[CH:42]=[N:43][CH:44]=[N:45][CH:46]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(Cl)Cl.[Cu]I>[F:39][CH:12]([F:11])[C:13]1[N:17]([C:18]2[N:26]=[C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[N:24]=[C:23]3[C:19]=2[N:20]=[CH:21][N:22]3[C:41]2[CH:42]=[N:43][CH:44]=[N:45][CH:46]=2)[C:16]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:15]=2[N:14]=1
Reactant: Brc1cncnc1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc2[nH]cnc12
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc2c1ncn2-c1cncnc1
Temperature: 102.5 °C
Yield: 52.6 %

Procedure:
trans-N,N′-Dimethylcyclohexane-1,2-diamine (0.071 mL, 0.450 mmol) in DMF (5 mL) was added to a mixture of 6-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-2-(4-morpholinyl)-9H-purine (180 mg, 0.448 mmol), 5-bromopyrimidine (356 mg, 2.24 mmol), CuI (85 mg, 0.448 mmol), and Cs2CO3 (321 mg, 0.986 mmol) under nitrogen, and the mixture was heated at 100-105° C. for 3 days. The mixture was cooled to room temperature, diluted with CH2Cl2, and filtered through celite. The celite plug was washed with CH2Cl2 and CH2Cl2/MeOH (9:1) before the solvents were removed under vacuum. Chromatography on silica, eluting with hexanes/EtOAc (70:30 to 20:80), followed by recrystallization from EtOAc/hexanes, gave 6-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-2-(4-morpholinyl)-9-(5-pyrimidinyl)-9H-purine (113 mg, 53%): mp (EtOAc/hexanes) 238-240° C.; 1H NMR (CDCl3) δ 9.47 (s, 2H), 9.30 (s, 1H), 8.89 (s, 1H), 7.53 (t, JHF=52.6 Hz, 1H), 7.37 (t, J=8.1 Hz, 1H), 7.29 (dd, J=8.4, 0.7 Hz, 1H), 6.97 (d, J=7.5 Hz, 1H), 4.02 (s, 3H), 3.80 (m, 4H), 3.72 (m, 4H); Anal. Calcd. for C22H19F2N9O2: C, 55.1; H, 4.0; N, 26.3. Found: C, 55.3; H, 4.1; N, 26.5.
Reaction SMILES: [OH-].C([N+](CCCC)(CCCC)CCCC)CCC.O[CH2:20][C@@H:21]([O:31][CH2:32][P:33]([OH:36])([OH:35])=[O:34])[CH2:22][N:23]1[CH:30]=[N:29][C:27]([NH2:28])=[N:26][C:24]1=[O:25].[CH2:37](Br)[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]>CO>[CH3:54][CH2:53][CH2:52][CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][O:36][P:33]1([O:34][CH2:20][C@H:21]([CH2:22][N:23]2[C:24](=[O:25])[N:26]=[C:27]([NH2:28])[N:29]=[CH:30]2)[O:31][CH2:32]1)=[O:35]
Reactant: Nc1ncn(C[C@@H](CO)OCP(=O)(O)O)c(=O)n1
Reactant: CCCCCCCCCCCCCCCCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCCCCCCCCCCCOP1(=O)CO[C@@H](Cn2cnc(N)nc2=O)CO1
Reaction time: 0.08 h

Procedure:
1 M Methanolic tetrabutylammonium hydroxide (0.61 ml; 0.61 mmol) was added to a solution of cyclic HPMP-5-azaC (161 mg, 0.61 mmol) in absolute methanol (50 ml), the mixture stirred for 5 min, then evaporated and the residue coevaporated with toluene (20 ml), followed by dry dioxane (20 ml). The residue was dissolved in dioxane (10 ml) and stirred with octadecyl bromide (500 mg, 1.5 mmol) at 95° C. for 3 h. The reaction mixture was evaporated, the residue chromatographed on a column of silica gel (30 ml) in system chloroform-methanol (85:15). Yield: 250 mg, 80%, white solid. ESI MS: 1051.0 (2M+Na)+ (41), 537.3 (M+Na)+ (64), 515.3 (23) (MH)+. HRMS (ESI): For C25H48N4O5P (MH+) calculated: 515.3362. Found: 515.3382. 1H NMR (DMSO-d6): 8.11 s, 1H (H-6); 7.46 brs, 1H and 7.45 brs, 1H (NH2); other signals not distinguished. 13C NMR (DMSO-d6): 166.50 (C-4); 159.62 (C-6); 153.95 (C-2); 73.19 d, J (P, C)=4.9 (C-2′); 72.04 d, J (P, C)=12.4 (C-3′); 65.19 d, J (P, C)=5.9 (OCH2); 62.70 d, J (P, C)=141.6 (P—C); 45.75 (C-1′); 31.44, 30.03, 29.18, 5 C, 29.09, 25.09, 23.24, 5 C, 22.24 and 19.37 (CH2); 13.65 (CH3).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9](=[O:26])[N:10]3[CH2:17][C@H:16]([O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])[CH2:15][C@H:11]3[C:12](=[O:14])[NH:13][C:7]=2[CH:6]=[CH:5][C:4]=1[O:27][CH3:28].[H-].[Na+].[CH3:31][Si:32]([CH2:35][CH2:36][O:37][CH2:38]Cl)([CH3:34])[CH3:33].O>CN(C=O)C>[CH3:1][O:2][C:3]1[C:8]2[C:9](=[O:26])[N:10]3[CH2:17][C@H:16]([O:18][Si:19]([C:22]([CH3:24])([CH3:25])[CH3:23])([CH3:20])[CH3:21])[CH2:15][C@H:11]3[C:12](=[O:14])[N:13]([CH2:38][O:37][CH2:36][CH2:35][Si:32]([CH3:34])([CH3:33])[CH3:31])[C:7]=2[CH:6]=[CH:5][C:4]=1[O:27][CH3:28]
Reactant: COc1ccc2c(c1OC)C(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(=O)N2
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(c1OC)C(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1C(=O)N2COCC[Si](C)(C)C
Reaction time: 0.5 h
Yield: 81.9 %

Procedure:
A solution of 171 (6.50 g, 15.99 mmol) in anhydrous DMF (27.5 mL) was added dropwise to a stirred suspension of NaH (0.422 g, 0.704 g of a 60% dispersion in mineral oil, 18.34 mmol) at 0° C. and the reaction mixture was allowed to stir for 30 minutes. A solution of SEM chloride (3.11 mL, 2.93 g, 17.59 mmol) in anhydrous DMF (5 mL) was added dropwise to the stirred reaction mixture at 0° C. and allowed to stir at room temperature for 16 h. The reaction mixture was poured into water (200 mL) to afford a white precipitate, which was extracted with diethyl ether (4×300 mL). The organic layer was washed with water (2×50 mL), brine (2×50 mL) and dried over anhydrous MgSO4. Filtration and evaporation of the solvent in vacuo afforded the crude product, which was purified by flash column chromatography using an 80:20 mixture of petroleum ether:EtOAc as eluent. Pure fractions were combined and evaporated in vacuo to afford the product (172) as a yellow oil (7.01 g, 13.1 mmol, 82%). 1H NMR (270 MHz, CDCl3) δ7.35 (s, 1H, ArH), 7.24 (s, 1H, ArH), 5.52 (d, 2H, J=9.89 Hz, SEM amino acetal CH2), 4.65 (d, 2H, J=9.90 Hz, SEM amino acetal CH2), 4.61-4.56 (m, 1H, 2), 4.23 (dd, 1H, J=4.40 Hz, 8.24 Hz, 11a), 3.94 (s, 3H, OMe), 3.92 (s, 3H, OMe), 3.68 (m, 4H, SEM 1′ CH2+3), 2.86 (m, 1H, 1), 2.02 (m, 1H, 1), 0.98 (t, 2H, J=8.25 Hz, SEM 2′ CH2), 0.88 (s, 9H, TBDMS t-Bu CH3), 0.10 (s, 6H, 2×TBDMS SiCH3), 0.03 (s, 9H, 3× SEM SiCH3); 13C NMR (67.8 MHz, CDCl3) δ170.0, 165.6, 151.8, 147.1, 133.9, 121.5, 111.2, 105.5, 78.1, 69.6, 67.0, 56.5, 56.2, 56.1, 53.6, 35.5, 25.7, 18.4, −1.3, −4.8.
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]2[CH2:21][C:20](=[O:22])[O:19][CH:18]([C:23]3[N:24]=[C:25]([C:28]([F:31])([F:30])[F:29])[S:26][CH:27]=3)[CH2:17]2)[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2].[OH-:32].[Na+].Cl>CO>[C:1]([CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][CH:14]([N:16]([CH2:21][C:20]([OH:19])=[O:22])[CH2:17][CH:18]([OH:32])[C:23]2[N:24]=[C:25]([C:28]([F:30])([F:29])[F:31])[S:26][CH:27]=2)[CH3:15])=[CH:11][CH:12]=1)([O:3][CH3:4])=[O:2]
Reactant: [OH-]
Reactant: COC(=O)COc1ccc(CC(C)N2CC(=O)OC(c3csc(C(F)(F)F)n3)C2)cc1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)COc1ccc(CC(C)N(CC(=O)O)CC(O)c2csc(C(F)(F)F)n2)cc1
Temperature: 0 °C

Procedure:
1.4 g (0.0031 mol) of N-[2-(4-Carbomethoxymethoxyphenyl)-1-methylethyl]-2-(2-trifluoromethyl-thiazol-4-yl)morpholin-6-one are dissolved in 10 ml of methanol. 3 ml (0.003 mol) of 1N sodium hydroxide solution are added to this stirred solution at room temperature. After 5 minutes 15 ml of ice-water are added, and the mixture is neutralised with 3 ml of 1N hydrochloric acid. The aqueous phase is extracted by shaking 3× with methylene chloride. The organic phase is dried over sodium sulphate, filtered and evaporated to dryness. The resulting residue is purified on a silica gel column using methylene chloride methanol=20:1 as eluant. This results, after concentration, in colourless crystals.
Reaction SMILES: [F:1][CH2:2][C:3]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH2:7][C:8](=[CH2:18])[CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:4]([OH:6])=[O:5].[N+](=[CH2:29])=[N-]>CCOCC>[F:1][CH2:2][C:3]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH2:7][C:8](=[CH2:18])[CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:4]([O:6][CH3:29])=[O:5]
Reactant: C=[N+]=[N-]
Reactant: C=C(CNC(=O)OC(C)(C)C)CC(CF)(NC(=O)OC(C)(C)C)C(=O)O
Solvent: CCOCC
Product: C=C(CNC(=O)OC(C)(C)C)CC(CF)(NC(=O)OC(C)(C)C)C(=O)OC

Procedure:
2-Fluoromethyl-2,5-di(tert-butoxycarbonylamino) 4-methylene-pentanoic acid (0.7 g) obtained in Step B above is dissolved in ether, and etheral diazomethane is added until a yellow colour persists Evaporation gives an oil (0.76 g) which is chromatographed on silica (AcOEt/petroleum ether 1:4). Yield of pure product 0.72 g.
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:19][CH2:20]Br>CN(C=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[I-]>[C:2]1([C:3]([O:5][CH2:6][CH3:7])=[O:4])([C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH2:20][CH2:19]1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: BrCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C(=O)OCC)CC1
Reaction time: 2 h
Yield: 88.6 %

Procedure:
To a solution of diethyl malonate (3.2 g, 20 mmol) and anhydrous potassium carbonate powder (6.9 g, 50 mmol) in DMF (50.0 mL) was added 1,2-dibromoethane (4.136 g, 22 mmol). After stirring for 2 hrs, catalytic amount of TBAI (0.738 g, 2.0 mmol) was added and the mixture was continued to stir at room temperature for 8 hrs. The reaction mixture was filtered and the solid was washed with diethyl ether 3 times. The filtrate was diluted with water (200 mL) and extracted with diethyl ether (75 mL×4). The combined organic phases were washed with 70 mL of brine, dried over Na2SO4 and concentrated in vacuo. The residue was chromatographed with a short alumina column (1:10 (v/v) EtOAc/n-hexane) to afford the desired compound as yellow oil (3.3 g, 88.7%).
Reaction SMILES: Cl.Cl.[NH:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]3[C:20]4[C:19]([NH2:21])=[N:18][CH:17]=[N:16][C:15]=4[N:14]([CH3:22])[CH:13]=3)=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Cl:56][C:57]1[CH:58]=[C:59]([CH2:64][C:65](O)=[O:66])[CH:60]=[C:61]([F:63])[CH:62]=1>CN(C=O)C.O.C(Cl)(Cl)Cl.CC(OC)(C)C>[Cl:56][C:57]1[CH:58]=[C:59]([CH2:64][C:65]([N:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]4[C:20]5[C:19]([NH2:21])=[N:18][CH:17]=[N:16][C:15]=5[N:14]([CH3:22])[CH:13]=4)=[CH:9][CH:10]=3)[CH2:5][CH2:4]2)=[O:66])[CH:60]=[C:61]([F:63])[CH:62]=1
Reactant: O=C(O)Cc1cc(F)cc(Cl)c1
Reactant: Cn1cc(-c2ccc3c(c2)CCN3)c2c(N)ncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: COC(C)(C)C
Solvent: ClC(Cl)Cl
Product: Cn1cc(-c2ccc3c(c2)CCN3C(=O)Cc2cc(F)cc(Cl)c2)c2c(N)ncnc21
Reaction time: 1.5 h

Procedure:
To a suspension of 5-(2,3-dihydro-1H-indol-5-yl)-7-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine 2HCl salt (200 mg, 0.59 mmol, 1 equiv) and HATU (247 mg, 0.65 mmol, 1.1 equiv) in 2 mL of DMF was added DIEA (0.36 mL, 2.07 mmol, 3.5 equiv) in one portion. The mixture turned into a clear but pitch dark solution, to which was added (3-Chloro-5-fluorophenyl)acetic acid (60 mg, 0.59 mmol,) as solids. After 1.5 h, added another 30 mg of the acid. After 30 min, the resulting suspension was diluted with 15 mL of water. The aq suspension was filtered, and the cake was washed with water, and dried under house vacuum. This solid was dissolved in 10% MeOH in DCM (not totally dissolved, some was loaded as suspension), and absorbed onto a dryload cartridge. Purification was done on an 24 g silica gel cartridge using gradient elution of 1% A in EtOAc to 100% A (A was a mixture of 9% MeOH in EtOAc, gradient: 0-5 min, 1% A, 5-15 min, 5-100% A, 15-60 min, 100% A). The desired fractions were combined and concentrated in vacuo to give a solid residue, which upon standing for 10 min developed a light tan color. The residue was taken up in CHCl3 (1 mL) and MTBE (6 mL) to give a suspension, which was filtered. The light tan colored cake was washed with MTBE (3 mL) and hexane (2×3 mL), and dried under vacuum at 65° C. for 20 h to give (93 mg) as light tan colored solids. LC-MS (ES) m/z=436 [M+H]+. 1H NMR (400 MHz, DMSO-d6+2 drops TFA) δ ppm 3.25 (t, J=8.2 Hz, 2H), 3.84 (s, 3H), 3.96 (s, 2H), 4.25 (t, J=8.5 Hz, 2H), 7.17 (d, J=9.6 Hz, 1H), 7.23-7.29 (m, 2H), 7.30-7.37 (m, 2H), 7.61 (s, 1H), 8.15 (d, J=8.3 Hz, 1H), 8.47 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][NH:9][C@H:10]1[CH2:15][NH:14][CH:13]([C:16]([NH2:18])=[O:17])[C:12]([CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Cl[C:38](Cl)([O:40]C(=O)OC(Cl)(Cl)Cl)Cl>C(#N)C.C(OCC)(=O)C>[CH2:1]([O:8][N:9]1[C:38](=[O:40])[N:14]2[CH2:15][C@H:10]1[CH:11]=[C:12]([CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:22])[CH3:23])[C@H:13]2[C:16]([NH2:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)[Si](C)(C)OCC1=C[C@@H](NOCc2ccccc2)CNC1C(N)=O
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](C)(C)OCC1=C[C@@H]2CN(C(=O)N2OCc2ccccc2)[C@@H]1C(N)=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 110 %

Procedure:
To a solution of (5R)-5-((benzyloxy)amino)-3-(((tert-butyldimethylsilyl)oxy)methyl)-1,2,5,6-tetrahydropyridine-2-carboxamide (Intermediate 163, 0.562 g, 1.44 mmol) and diisopropylethyl amine (1.000 mL, 5.74 mmol) in acetonitrile (200 mL) at 0° C. was added triphosgene (0.145 g, 0.49 mmol) as a solution in acetonitrile (6 mL). The triphosgene solution was added at a rate of 4 mL/hour. Once addition was complete the reaction was stirred at 0° C. overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate. The aqueous layer was extracted again with EtOAc and then DCM. The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%-100, ethyl acetate/hexanes) afforded the title compound (0.225 g, 37.5%) as a colorless film.
Reaction SMILES: [H-].[K+].[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)[CH:6]=[CH:5][CH:4]=1.[Cl-:22].[Cr+3:23].[Cl-].[Cl-]>C1COCC1>[Cl-:22].[Cl-:22].[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[C:14]2[Cr+2:23])[CH:6]=[CH:5][CH:4]=1
Reactant: [Cr+3]
Reactant: C1=CC(c2cccc3cccnc23)c2ccccc21
Agent: [Cl-]
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: [Cr+2]C1=Cc2ccccc2C1c1cccc2cccnc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 49 %

Procedure:
0.05 g of potassium hydride (1.23 mmol) was suspended in 20 ml of THF, and 0.3 g of 1-(8-quinolyl)indene (1.23 mmol) was slowly added. The resultant violet suspension was stirred at room temperature for three hours and then added dropwise to a mixture of 0.46 g of chromium(III)chloride 3THF (1.23 mmol) in 50 ml of THF and, when the addition was complete, the mixture was stirred for a further 16 hours. The solvent was removed under reduced presssure, and the resultant solid was extracted with hot toluene. After the solvent had been distilled off from the combined extracts, the product was obtained as a green powder, which was washed a number of times with hexane and dried under a high vacuum, giving 0.22 g of 1-(8-quinolyl)indenylchromium(III) dichloride (50%).
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)[CH2:2]1.[CH:16]1([NH2:19])[CH2:18][CH2:17]1>C(O)C>[CH:16]1([NH:19][CH2:2][C:3]2([OH:1])[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)[CH2:18][CH2:17]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CO2
Reactant: NC1CC1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(O)(CNC2CC2)CC1
Temperature: 25 °C
Yield: 93.6 %

Procedure:
A sealable reaction vessel was charged with 1,1-dimethylethyl 1-oxa-6-azaspiro[2.5]octane-6-carboxylate (14.07 mmol), ethanol (70 mL) and cyclopropylamine (42.2 mmol). The vessel was purged with nitrogen, sealed and placed in a 75° C. oil bath for 20 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The resulting oil was purified by silica gel chromatography (5% methanol in ethyl acetate). The appropriate fractions were concentrated under reduced pressure and dried to afford the title product (3.56 g, 94% yield) as a viscous colorless oil. MS(ES)+ m/e 271.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 4.20 (s, 1 H), 3.59 (d, J=12.6 Hz, 2 H), 3.05 (br. s., 2 H), 2.16-2.00 (m, 2 H), 1.49-1.31 (m, 14 H), 0.42-0.29 (m, 2 H), 0.24-0.13 (m, 2 H).
Reaction SMILES: N1CCCCC1.[N+:7]([C:10]1[CH:11]=[C:12]([CH:23]=[CH:24][CH:25]=1)[CH:13]=[CH:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16])([O-:9])=[O:8].[CH3:26][O:27][C:28]1[CH:29]=[C:30]([SH:34])[CH:31]=[CH:32][CH:33]=1.C(O)(=O)C>C1C=CC=CC=1.O>[N+:7]([C:10]1[CH:11]=[C:12]([CH:13]([S:34][C:30]2[CH:31]=[CH:32][CH:33]=[C:28]([O:27][CH3:26])[CH:29]=2)[CH2:14][C:15]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:16])[CH:23]=[CH:24][CH:25]=1)([O-:9])=[O:8]
Reactant: O=C(C=Cc1cccc([N+](=O)[O-])c1)c1ccccc1
Reactant: COc1cccc(S)c1
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCNCC1
Product: COc1cccc(SC(CC(=O)c2ccccc2)c2cccc([N+](=O)[O-])c2)c1

Procedure:
Piperidine, 1.2 ml, was added to a boiling solution of 3-nitrobenzalacetophenone (10 g, 0.04 mole) and 3-methoxybenzenethiol (6.64 g, 0.048 mole) in 100 ml benzene . After standing for 30 minutes without further heating, acetic acid, 10 ml, was added. The solution then was poured into water (about 100 ml), extracted with methylene chloride (5×100 ml), washed with water, dried (Na2SO4) and evaporated to dryness to yield the title compound as a solid, mp 105°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[OH:27])=[N:13][C:14]=1[CH2:15][CH3:16].[CH2:30]1C2C(=CC=CC=2)CCC1O>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:30][CH2:20][C@@H:19]2[OH:27])=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Reactant: OC1CCc2ccccc2C1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2CC[C@@H]1O

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting cis-(5-bromo-3,6-diethylpyrazin-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-2-ol, ethylene glycol dimethyl ether and tetrakis(triphenylphosphine) palladium and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ 1.18–1.31, 2.09, 2.54, 2.64, 2.95, 2.99, 4.33, 4.69, 5.43, 7.22–7.35, 7.51; HRMS (FAB) calcd for C24H25Cl2N3O+H 442.1453, found 442.1454.