Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([OH:16])=O)[CH2:6][CH2:5]2.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[CH3:32][NH:33][O:34][CH3:35].C(N(CC)C(C)C)(C)C>C1COCC1.C(Cl)Cl>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH3:17])([C:14]([N:33]([O:34][CH3:35])[CH3:32])=[O:16])[CH2:6][CH2:5]2
Reactant: CNOC
Reactant: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)O)O2
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: CON(C)C(=O)C1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 69 %

Procedure:
To a solution of 5.47 g 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (21.9 mmol) in 170 mL THF was added 3.92 g CDI (24.2 mmol) and stirred for 1.25 h at room temperature. To this was added a solution of 2.14 g N,O-dimethylhydroxylamine hydrochloride (21.97 mmol) and 8.2 g N,N-diisopropylethylamine in 50 mL CH2Cl2 dropwise over 1 h. The reaction was stirred overnight, concentrated, 250 mL CH2Cl2 added and washed sequentially with 100 mL 0.625 M HCl, 100 mL 1.0 M NaHCO3 and 100 mL saturated NaCl. The organics were dried over Na2SO4, concentrated and purified by flash chromatography yielding 4.43 g of 6-hydroxy-N-methoxy-N,2,5,7,8-pentamethylchroman-2-carboxamide as an off-white crystalline solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]([F:15])([F:14])[F:13])[N:5]=[CH:4][CH:3]=1.[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C=O)C.O>[N:16]([C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]([F:15])([F:14])[F:13])[N:5]=[CH:4][CH:3]=1)=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)c1c(Cl)ccnc1C(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1c(N=[N+]=[N-])ccnc1C(F)(F)F
Temperature: 45 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
To a stirred solution of methyl 4-chloro-2-(trifluoromethyl)nicotinate (9.75 g, 40.7 mmol) in DMF (300 mL) is added sodium azide (21.2 g, 326 mmol). The solution is warmed to 45° C. for 3 hours and then to 50° C. for 1 hour. The reaction is diluted with water (300 mL) and extracted with ether-pentane (1:1, ca. 1 L). The organic layer is back extracted with water (3×). The organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford 9.50 g (95%) of the title compound as a brown oil: 1H NMR (400 MHz, CD3OD), 8.651 (d, 1H), 7.603 (d, 1H), 3.878 (s, 3H).
Reaction SMILES: C([Li])CCC.[CH2:6]([O:11][CH:12]1[NH:16][C:15](=[O:17])[CH2:14][CH2:13]1)[CH2:7][CH2:8][CH2:9][CH3:10].[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CCCCCC.O1CCCC1>[C:18]([N:16]1[CH:12]([O:11][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:13][CH2:14][C:15]1=[O:17])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCCCOC1CCC(=O)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCOC1CCC(=O)N1C(=O)c1ccccc1
Reaction time: 0.25 h
Yield: 62.3 %

Procedure:
15.56 cm3 of a 1.5M solution of n-butyllithium in hexane is added at -60° C. to a solution of 4 g of 5-(1-pentyloxy) pyrrolidin-2-one in 80 cm3 of tetrahydrofuran. Agitation is carried out for 15 minutes at -60° C. and then under these conditions a solution of 3.28 g of benzoyl chloride in 20 cm3 of tetrahydrofuran is added. After allowing the temperature to return to ambient, the solvent is evaporated under reduced pressure. The residue is chromatographed on silica (eluent: ethyl acetate-n-hexane 1-3) and 4 g of sought product is obtained.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Cl:10][CH:11]([CH3:15])[C:12](Cl)=[O:13]>N1C=CC=CC=1.O1CCCC1>[CH2:1]([O:9][C:12](=[O:13])[CH:11]([Cl:10])[CH3:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CC(Cl)C(=O)Cl
Reactant: CCCCCCCCO
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCCCCCCOC(=O)C(C)Cl
Reaction time: 24 h

Procedure:
Racemic 2-chloropropionate octyl ester was prepared by reacting 130 gm (1.0 mol) of n-octanol with 127 gm (1.0 mol) of 2-chloropropionyl chloride in 240 ml of pyridine and 50 ml of tetrahydrofuran. The reaction was carried out for 24 hours after which the solution was washed with lo0 ml of 1 N HCl and 100 ml of distilled water. 500 ml of ether was added, then washed with 3×500 ml of saturated solution of NaHCO3 and 500 ml of saturated solution of NaCl. The organic phase was finally dried over MgSO4. The total weight of 2-chloropropionate octyl ester obtained was 248 gm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.[CH3:51][NH:52][O:53][CH3:54]>ClCCl>[CH3:54][O:53][N:52]([CH3:51])[C:20]([C:17]1[CH:16]=[N:15][C:14]([N:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]2)=[N:19][CH:18]=1)=[O:22]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(C(=O)O)cn2)CC1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CON(C)C(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
To a suspension of 2-(4-(tert-butoxycarbonyl)piperazin-1-yl)pyrimidine-5-carboxylic acid (13.8 g, 44.8 mmol), EDCI (12.8 g, 67.2 mmol) and HOBT (7.2 g, 53.7 mmol) in dichloromethane (200 mL) was added triethylamine (25 mL, 179.2 mmol), and the mixture was stirred at RT for 1 h, followed by the addition of N,O-dimethylhydroxylamine (5 g, 53.7 mmol). The reaction was stirred for another 3 h. LCMS showed the reaction was completed. The reaction mixture was washed with water (100 mL), and the organic layer was dried, filtered and concentrated. The residue was purified by silica gel chromatography (petroleum ether:ethyl acetate=1:1) to give the title compound (11.2 g, 67%) as a white solid. MS (ES+) C16H25N5O4 requires: 351. found: 296 [M−56+H]+.
Reaction SMILES: [S:1]1[C:5]([NH:6][C:7]2[CH:12]=[C:11](Cl)[N:10]=[C:9]([S:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:28])[CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:17][CH:16]=3)[N:8]=2)=[N:4][CH:3]=[N:2]1.Cl.[CH:30]1([C:33]2([F:37])[CH2:36][NH:35][CH2:34]2)[CH2:32][CH2:31]1.CCN(C(C)C)C(C)C>O1CCOCC1>[S:1]1[C:5]([NH:6][C:7]2[CH:12]=[C:11]([N:35]3[CH2:36][C:33]([CH:30]4[CH2:32][CH2:31]4)([F:37])[CH2:34]3)[N:10]=[C:9]([S:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:28])[CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:17][CH:16]=3)[N:8]=2)=[N:4][CH:3]=[N:2]1
Reactant: O=C(CC(F)(F)F)Nc1ccc(Sc2nc(Cl)cc(Nc3ncns3)n2)cc1
Reactant: FC1(C2CC2)CNC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CC(F)(F)F)Nc1ccc(Sc2nc(Nc3ncns3)cc(N3CC(F)(C4CC4)C3)n2)cc1
Yield: 20.6 %

Procedure:
To a microwave tube was added N-(4-(4-(1,2,4-thiadiazol-5-ylamino)-6-chloropyrimidin-2-ylthio)phenyl)-3,3,3-trifluoropropanamide (100 mg, 0.25 mmol), 3-cyclopropyl-3-fluoroazetidine hydrochloride (100 mg, 0.7 mmol), DIPEA (0.1 ml) and dioxane. The mixture was microwaved at 130 C for 20 mins, partitioned between ethylacetate and bicarbonate and organic layer concentrated to an oil. The product was purified by HPLC to afford the product as a white solid (27 mg, 20%) 1H NMR d6 DMSO 0.42-0.48 (2H, m), 0.6-0.63 (2H, m), 1.38-1.43 (1H, m), 3.55-3.65 (2H, m), 3.8-4.0 (4H, m), 5.65 (1H,s), 7.65 (2H, d), 7.75 (2H, d), 8.2 (1H,s), 10.7 (1H,s), 12.1 (1H,s); MS ESI+ve 526 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[N:18]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([N:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)=[O:30])=[C:23]([CH3:37])[CH:22]=3)=[O:20])[CH2:17][C:16]3[CH:15]=[N:14][N:13]([CH3:38])[C:12]=3[NH:11][C:10]=2[CH:39]=1>ClCCl.C(N(CC)CC)C>[C:1]([N:34]1[CH2:33][CH2:32][N:31]([C:29](=[O:30])[CH2:28][CH2:27][C:24]2[CH:25]=[CH:26][C:21]([C:19]([N:18]3[CH2:17][C:16]4[CH:15]=[N:14][N:13]([CH3:38])[C:12]=4[NH:11][C:10]4[CH:39]=[C:6]([Cl:5])[CH:7]=[CH:8][C:9]3=4)=[O:20])=[CH:22][C:23]=2[CH3:37])[CH2:36][CH2:35]1)(=[O:3])[CH3:2]
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3cc(Cl)ccc32)ccc1CCC(=O)N1CCNCC1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(C(=O)CCc2ccc(C(=O)N3Cc4cnn(C)c4Nc4cc(Cl)ccc43)cc2C)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of acetyl chloride (0.39 mg, 0.005 mmol) in dichloromethane (0.05 ml) was added to a solution of 3-[4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-methyl-phenyl]-1-piperazin-1-yl-propan-1-one (2.47 mg, 0.005 mmol) in di-chloromethane (0.05 ml) and triethylamine (0.0035 ml). The mixture was stirred at room temperature for 20 h then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=535.5
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:20]=[C:19]([OH:21])[CH:18]=[C:17](Br)[CH:16]=2)=[CH:9][C:8]=1[CH3:23])[CH3:2].[C:25]1([CH2:31][C:32]#[CH:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(N(CC)CC)C.CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu](I)I>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][CH2:14][C:15]2[CH:16]=[C:17]([C:33]#[C:32][CH2:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:18]=[C:19]([OH:21])[CH:20]=2)=[CH:9][C:8]=1[CH3:23])[CH3:2]
Reactant: C#CCc1ccccc1
Reactant: CCOC(=O)COc1ccc(SCc2cc(O)cc(Br)c2)cc1C
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(SCc2cc(O)cc(C#CCc3ccccc3)c2)cc1C

Procedure:
[4-(3-Bromo-5-hydroxy-benzylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (2 g; 4.9 mmol), 3-phenyl-1-propyn (1.7 g; 14.6 mmol), bis(triphenylphosphine)palladium (II) chloride (0.27 g; 0.39 mmol) and copper iodide (0.056 g; 0.29 mmol) were dissolved in a mixture of triethylamine (5 mL) and DMF (10 mL) under an atmosphere of nitrogen. The reaction mixture was reacted in a microwave oven at 100° C. for 1 h. Further 3-phenyl-1-propyn (1.7 g; 14.6 mmol) was added and the reaction mixture was reacted in a microwave oven at 100° C. for further 1 h. The reaction mixture was purified by preparative HPLC (method A). Yield: 0.8 g. HPLC-MS: m/z: 434.6 (M+1); Rt: 2.43 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][Br:11])=[N:7][C:6]=2[CH:12]=1.[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CC#N.CCOCC>[Br-:11].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][P+:19]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[N:7][C:6]=2[CH:12]=1
Reactant: Clc1ccc2oc(CBr)nc2c1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOCC
Product: Clc1ccc2oc(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)nc2c1
Product: [Br-]
Reaction time: 0.5 h

Procedure:
A solution of the bromide (500 mg) (Step 3) and triphenylphosphine (740 mg) in CH3CN (5 mL) was stirred at room temperature overnight. The reaction mixture was diluted with Et2O (20 mL), stirred for 30 min, and filtered to give the title compound as a white solid.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[NH2:10][C@@H:11]1[CH2:16][CH2:15][C@H:14]([C:17]([OH:19])=[O:18])[CH2:13][CH2:12]1.[OH-].[Na+]>CC#N.O>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([NH:10][C@@H:11]2[CH2:16][CH2:15][C@H:14]([C:17]([OH:19])=[O:18])[CH2:13][CH2:12]2)[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: N[C@H]1CC[C@@H](C(=O)O)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: O=C(O)[C@H]1CC[C@@H](Nc2nc(Cl)nc(Cl)n2)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A mixture of cyanuric chloride (493.65 mg, 2.7 mmol, 1 equivalent) in CH3CN/H2O (1/1, 20 ml) was cooled to 0° C. cis-4-aminocyclohexylcarboxylic acid (283.26 mg, 2.7 mmol, 1 equivalent) was added, followed by 1N NaOH (10.7 ml, 2 equivalents). The reaction was stirred at 0° C. for 15 min. LCMS analysis showed the complete consumption of the 2,4,6-trichloro-1,3,5-triazine. The crude product was used in the next step.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:14]=[CH:13][C:12]2[O:11][CH:10]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH2:22][O:23][CH3:24])=[CH:17][CH:16]=3)[CH:9]3[CH2:25][C:26](=[O:28])[CH2:27][CH:8]3[C:7]=2[CH:6]=1.[CH2:29]([Mg]Cl)[CH3:30]>C1COCC1>[CH2:29]([C:26]1([OH:28])[CH2:25][CH:9]2[CH:10]([C:15]3[CH:16]=[CH:17][C:18]([O:21][CH2:22][O:23][CH3:24])=[CH:19][CH:20]=3)[O:11][C:12]3[CH:13]=[CH:14][C:5]([O:4][CH2:3][O:2][CH3:1])=[CH:6][C:7]=3[CH:8]2[CH2:27]1)[CH3:30]
Reactant: COCOc1ccc(C2Oc3ccc(OCOC)cc3C3CC(=O)CC32)cc1
Reactant: CC[Mg]Cl
Solvent: C1CCOC1
Product: CCC1(O)CC2c3cc(OCOC)ccc3OC(c3ccc(OCOC)cc3)C2C1
Temperature: 120 °C
Reaction time: 0.75 h
Yield: 79.6 %

Procedure:
Heat CeCl3-7H2O (97 mg, 0.26 mmol) under vacuum at 70° C. for two hours and then warm slowly to 120° C. and continue heating overnight. Cool to room temperature and add THF (3 mL) followed by cyclopentanone 23 (100 mg, 0.26 mmol) and stir the solution for 45 minutes. Cool the reaction to −10° C., add EtMgCl (3.0 M in THF, 87 ul, 0.26 mmol) and stir the reaction for 30 minutes. Quench the reaction with saturated aqueous NH4 Cl and extract with EtOAc (2×), Combine the organic extracts, wash with brine, dry (Na2SO4), filter and concentrate. Purify by flash chromatography (10 g silica gel, 40 mL/min, dry loading on 700 mg of silica gel, 0-30% EtOAc/hexanes for 20 minutes and 30% EtOAe/hexanes for 13 minutes) to afford Alcohol 31 (86 mg, 0.207 mmol, 81%). 1H NMR (δ, 400 MHz, CDCl3) 7.36 (d, 2H, J=8.8 Hz), 7.05 (d, 2H, J=8.8 Hz), 6.90-6.87 (m, 2H), 6.83 (dd, 1H, J==8.8, 2.6 Hz), 5.19 (s, 2H) 5.14 (d, 1H,J=6.8 Hz), 5.10 (d, 1H, J=6.8 Hz), 5.05 (d, 1H, J=2.2 Hz), 3.54 (dd, 1H, J=7.6, 7.6 Hz), 3.51 (s, 3H), 3.49 (s, 3H), 2.70 (ddd, 1H, J=2.2, 7,6, 9.6 Hz), 2.22 (dd, 1H, J=13.6, 7.9 Hz), 2.03 (d, 1H, J=13.6 Hz), 1.84 (dd, 1H, J=14.1, 10.1 Hz), 1.67 (dd, 1H, J=14.1, 9.2 Hz), 1.52 (m, 2H), 0.89 (t, 3H, J=7.3 Hz).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[C@H:9]([CH2:10][CH2:11][NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:8][CH2:7][N:6]1[C@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:22])=O.OC1C=CC=CN=1>C1COCC1.CCOCC>[CH2:13]([N:12]1[CH2:11][CH2:10][C@@H:9]2[CH2:8][CH2:7][N:6]([C@H:21]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH3:22])[C@@H:5]2[C:3]1=[O:2])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)[C@@H]1[C@H](CCNCCc2ccccc2)CCN1[C@@H](C)c1ccccc1
Agent: Oc1ccccn1
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@@H](c1ccccc1)N1CC[C@H]2CCN(CCc3ccccc3)C(=O)[C@H]21

Procedure:
A solution of (2S,3R)-3-(2-Phenethylamino-ethyl)-1-((S)-1-phenyl-ethyl)-pyrrolidine-2 carboxylic acid methyl ester (400 mg, 1.05 mmol) and 2-hydroxyl pyridine (100 mg, 1.05 mmol) in THF (10 mL) is stirred at 40° C. for 24 hrs. The reaction is diluted with 50 mL of ether and washed with 2×120 mL of water. After dried and concentrated to give a pale liquid (350 mg, LC/MS shown a clean product only.) without further purification for next step reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]2[NH:8][C:7]3[CH2:12][CH:13]([C:15]([OH:17])=[O:16])[CH2:14][C:6]=3[C:5]=2[CH:4]=1.Cl.[CH2:19](O)[CH3:20]>>[CH2:19]([O:16][C:15]([CH:13]1[CH2:12][C:7]2[NH:8][C:9]3[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[C:6]=2[CH2:14]1)=[O:17])[CH3:20]
Reactant: COc1ccc2[nH]c3c(c2c1)CC(C(=O)O)C3
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C1Cc2[nH]c3ccc(OC)cc3c2C1
Temperature: 25 °C

Procedure:
To a suspension of 1,2,3,4-tetrahydro-7-methoxycyclopent[b]indole-2-carboxylic acid (10 g, 0.043 mole) in 100 ml of absolute ethanol, was added 3 ml of ethereal HCl solution, and the mixture was stirred at ambient temperature for twenty hours. The mixture was concentrated to a brown oil (10 g), which was eluted on a silica gel column with 1% ethyl acetate/dichloromethane via HPLC. The desired fractions were combined and concentrated to afford a brown oil, which solidified on cooling to give 8.0 g of a lavender solid ,mp 82°-3° C.
Reaction SMILES: Cl.[C:2]1([N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[NH2:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]([N:18]([CH2:28][CH3:29])[C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[C:21]([OH:27])[CH:20]=1)[CH3:17].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[C:2]1([N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:9]=[CH:23][C:22]2[CH:25]=[CH:26][C:19]([N:18]([CH2:28][CH3:29])[CH2:16][CH3:17])=[CH:20][C:21]=2[OH:27])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NN(c1ccccc1)c1ccccc1
Reactant: CCN(CC)c1ccc(C=O)c(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCN(CC)c1ccc(C=NN(c2ccccc2)c2ccccc2)c(O)c1

Procedure:
A solution of N,N-diphenylhydrazine hydrochloride (79.5 g, 0.36 mol, from Aldrich, Milwaukee, Wis.) in ethanol (500 ml) was slowly added to a solution of 4-diethylamino-2-hydroxybenzaldehyde (58.0 g, 0.3 mol, from Aldrich, Milwaukee, Wis.) in ethanol (500 ml) in the presence of excess sodium carbonate. The reaction mixture was refluxed until all of the aldehyde reacted in about ½ hour. The residue obtained after evaporation of the solvent (800 ml) was treated with ether, and the ether extract was washed with water until the pH of the water reached 7. The organic layer was dried over anhydrous magnesium sulphate, treated with activated charcoal, and filtered. Then, the ether solvent was evaporated. The residue was recrystallized from ethanol. Crystalline 4-diethylamino-2-hydroxybenzaldehyde N,N-diphenylhydrazone was filtered off and washed with cold ethanol. The yield was 85 g (78.8%). The melting point was found to be 95.5–96.5° C. (recrystallized from a mixture of 2-propanol and ether in a 10:1 ratio by volume). The 1H NMR spectrum (100 MHz) of the product in CDCl3 was characterized by the following chemical shifts (δ, ppm): 11.55 (s, 1H, OH); 7.55–6.95 (m, 11H, CH═N, Ph); 6.7 (d, J=8.6 Hz; 1H, 6-H of 1,2,4-subst. Ph); 6.23 (s, 1H, 3-H of 1,2,4-subst. Ph); 6.1 (d, J=8.6 Hz, 1H, 5-H of 1,2,4-subst. Ph); 3.3 (q, J=8.0 Hz, 4H, CH2); 1.1 (t, J=8.0 Hz, 6H, CH3). An elemental analysis yielded the following results in weight percent C, 76.68; H, 7.75; and N, 11.45; which compared with calculated values for C23H25N3O in weight percent of C, 76.85; H, 7.01; and N, 11.69.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)([C:11]3[S:12][CH:13]=[CH:14][CH:15]=3)[OH:10])([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.[C:21]1([O:27][CH2:28][CH2:29][CH2:30][Br:31])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CO>[Br-:31].[OH:10][C:9]([C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)([C:11]1[S:12][CH:13]=[CH:14][CH:15]=1)[C:4]12[CH2:5][CH2:6][N+:1]([CH2:30][CH2:29][CH2:28][O:27][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([CH2:8][CH2:7]1)[CH2:2][CH2:3]2
Reactant: OC(c1cccs1)(c1cccs1)C12CCN(CC1)CC2
Reactant: BrCCCOc1ccccc1
Solvent: CO
Product: OC(c1cccs1)(c1cccs1)C12CC[N+](CCCOc3ccccc3)(CC1)CC2
Product: [Br-]
Yield: 45.5 %

Procedure:
Following the general procedure outlined in Example 4, 1-azabicyclo[2.2.2]oct-4-yl(di-2-thienyl)methanol (0.0578 g, 0.189 mmol) and 3-bromopropyl phenyl ether (0.033 mL, 0.209 mmol) in 1 MeOH/1 CHCl3 (4.0 mL) were reacted to give the desired product (0.0448 g, 45.4%). EI-MS m/z 440(M+) Rt (1.94 min).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([P:16]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:20][CH:19]=3)Cl)=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[CH2:47]Br>C1COCC1.CCOCC.CCCCCC>[C:1]1([CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([P:16]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[CH2:47][P:16]([C:18]3[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][CH2:26][C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)=[CH:22][CH:23]=3)[C:13]3[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][CH2:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:11][CH:12]=3)[C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)=[CH:20][CH:19]=3)=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCc1ccccc1-c1ccccc1CBr
Reactant: ClP(c1ccc(CCCc2ccccc2)cc1)c1ccc(CCCc2ccccc2)cc1
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: c1ccc(CCCc2ccc(P(Cc3ccccc3-c3ccccc3CP(c3ccc(CCCc4ccccc4)cc3)c3ccc(CCCc4ccccc4)cc3)c3ccc(CCCc4ccccc4)cc3)cc2)cc1
Reaction time: 10 h
Yield: 34.6 %

Procedure:
Di[p-(3-phenylpropyl)phenyl]chlorophosphine 1 (6.0 g, 13.1 mmol) was dissolved in 150 ml THF and Li (0.185 g, 26.2 mmol) was chopped directly into the reaction flask under Ar. A deep red solution was resulted in 10 min and all the lithium was consumed in 4 h. The solution was then filtered and 2,2'-dibromomethyl-1,1'-biphenyl (2.23 g, 6.5 mmol) in 20 ml THF was added dropwise with an ice-water bath. The color of the solution was slowly changed to pale yellow. The mixture was stirred for additional 10 h before the solvent was removed by vacuum. 50 ml diethyl ether was added and it was washed with 3×10 ml H2O. The ether phase was dried over MgSO4 and the solvent was then removed by vacuum. The resulting pale yellow viscous oil was purified over silica gel column. 2.3 g (69% yield) of 11 was eluted with Et2O/hexane (1/10), 11 was characterized by 1H, 13C, 31P NMR and Mass spectrometry.
Reaction SMILES: [CH3:1][S:2]([NH:5][CH:6]1[CH2:11][CH2:10][CH:9]([NH:12]C(=O)OC(C)(C)C)[CH2:8][CH2:7]1)(=[O:4])=[O:3].C(O)(C(F)(F)F)=O.C(OCC)C>C(Cl)Cl>[NH2:12][CH:9]1[CH2:10][CH2:11][CH:6]([NH:5][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:7][CH2:8]1
Reactant: CC(C)(C)OC(=O)NC1CCC(NS(C)(=O)=O)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CS(=O)(=O)NC1CCC(N)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 154.9 %

Procedure:
1,1-Dimethylethyl {4-[(methylsulfonyl)amino]cyclohexyl}carbamate (0.922 g, 3.15 mmol) was dissolved in DCM (50 mL). TFA was added (2.429 mL, 31.5 mmol) and the reaction allowed to stir at rt for 1 h. Evaporated off the volatiles and added DCM (50 mL) followed by evaporation of volatiles. The DCM addition/evaporation was repeated several times to give a maroon semi-solid. The residual semi-solid was treated with diethyl ether (10 mL) after which the suspension was sonicated and triturated, then filtered. Solids were triturated with more diethyl ether (10 mL). The product was suction dried to give title compound of Step B as a light pink solid (0.938 g). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.80 (br. s., 2H), 7.07 (d, J=7.2 Hz, 1H), 3.33 (s, 2H), 3.01-3.14 (m, 1H), 2.78-3.01 (m, 2H), 1.80-2.02 (m, 4H), 1.17-1.47 (m, 4H).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C:11]2[C:12]([Cl:18])=[N:13][CH:14]=[CH:15][C:16]=2[CH3:17])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[F-].[K+].[CH:21]1([NH2:24])[CH2:23][CH2:22]1.O>CC1C=CC=CC=1C>[Cl:18][C:12]1[C:11]([NH:10][C:8]([C:7]2[C:2]([NH:24][CH:21]3[CH2:23][CH2:22]3)=[N:3][CH:4]=[CH:5][CH:6]=2)=[O:9])=[C:16]([CH3:17])[CH:15]=[CH:14][N:13]=1
Reactant: Cc1ccnc(Cl)c1NC(=O)c1cccnc1Cl
Reactant: NC1CC1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1C
Product: Cc1ccnc(Cl)c1NC(=O)c1cccnc1NC1CC1
Temperature: 135 °C
Reaction time: 0.17 h

Procedure:
2-Chloro-N-(2-chloro-4-methyl-3-pyridinyl)-3-pyridine carboxamide (50 g), potassium fluoride (30.85.g), cyclopropylamine (40.43 g) were suspended in o-xylene (150 ml) and heated to 130-140° C. in autoclave for 5-8 h. Then the reaction mass was cooled to 25-30° C., diluted with o-xylene (250 ml) and further heated the reaction mass to 70-75° C. Thereafter, DM water (150 ml) added and stirred for 10 min at 70-75° C. The aqueous layer was separated at hot condition and organic layer was washed with DM water (150 ml) at 70-75° C. and organic layer was concentrated at 60-63° C. under reduced pressure up to residual weight attained is approximately 200 g. The concentrated mass was cooled to 25-30° C. and stirred for 15 min and further cooled to 5-10° C. and stirred for 30 min. Filtered the solid obtained and washed with chilled o-xylene (50 ml, 5-10° C.). Dried the obtained solid at 45-50° C. under reduced pressure.