Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=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]1.Br[CH2:23][C:24]1[CH:32]=[C:31]([CH3:33])[C:30]2[C:26](=[CH:27][N:28]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[N:29]=2)[CH:25]=1.[H-].[Na+]>CN(C)C=O>[CH3:33][C:31]1[C:30]2[C:26](=[CH:27][N:28]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:39])([CH3:41])[CH3:40])[N:29]=2)[CH:25]=[C:24]([CH2:23][O:1][CH2:2][C:3]2([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])[CH2:5][CH2:4]2)[CH:32]=1
Reactant: Cc1cc(CBr)cc2cn(COCC[Si](C)(C)C)nc12
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(COCC2(c3ccccc3)CCN(C(=O)OC(C)(C)C)CC2)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 4-(hydroxymethyl)-4-phenylpiperidine-1-carboxylate (102 mg, 0.350 mmol) and 5-(bromomethyl)-7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazole (113 mg, 0.318 mmol) in dimethylformamide (0.75 mL) at 0° C. was added sodium hydride (16.8 mg, 0.70 mmol). The resulting solution was stirred at at 0° C. for 30 min. The reaction was quenched by the cautious addition of saturated ammonium chloride and diluted with diethyl ether. The ethereal was washed with water (2×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (12%→25% EtOAc/Hex) gave 170 mg (94%) as a colorless oil. 1H-NMR (CDCl3, 500 MHz) δ 7.99 (s, 1H), 7.31-7.40 (m, 4H), 7.25 (m, 1H), 7.21 (s, 1H), 6.79 (s, 1H), 5.70 (s, 2H), 4.37 (s, 2H), 3.73 (bs, 2H), 3.63 (m, 2H), 3.40 (s, 2H), 3.04 (m, 2H), 2.57 (s, 3H), 2.16 (m, 2H), 1.91 (m, 2H), 1.43 (s, 9H), 0.94 (m, 2H), −0.03 (s, 9H); 13C NMR (126 MHz, CDCl3) δ ppm 155.1, 149.2, 143.3, 132.5, 128.5, 128.1, 127.4, 126.3, 125.7, 122.9, 121.9, 116.1, 81.8, 79.3, 78.9, 73.8, 67.4, 41.8, 40.1 (br), 32.0, 28.6, 18.0, 17.2, −1.3.
Reaction SMILES: C1(O[C:8](=[O:30])[NH:9][C:10]2[CH:15]=[C:14]([O:16][C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[N:22]([C:26](=[O:29])[NH:27][CH3:28])[CH:21]=[CH:20]4)[N:13]=[CH:12][N:11]=2)C=CC=CC=1.[CH2:31]([N:33]([CH2:38][CH3:39])[CH2:34][CH2:35][CH2:36][NH2:37])[CH3:32].C[N:41](C)C=O>>[CH3:28][NH:27][C:26]([N:22]1[C:23]2[C:19](=[CH:18][C:17]([O:16][C:14]3[CH:15]=[C:10]([NH:9][C:8]([NH:41][NH:37][CH2:36][CH2:35][CH2:34][N:33]([CH2:38][CH3:39])[CH2:31][CH3:32])=[O:30])[N:11]=[CH:12][N:13]=3)=[CH:25][CH:24]=2)[CH:20]=[CH:21]1)=[O:29]
Reactant: CNC(=O)n1ccc2cc(Oc3cc(NC(=O)Oc4ccccc4)ncn3)ccc21
Reactant: CCN(CC)CCCN
Reactant: CN(C)C=O
Product: CCN(CC)CCCNNC(=O)Nc1cc(Oc2ccc3c(ccn3C(=O)NC)c2)ncn1
Temperature: 25 °C
Yield: 70 %

Procedure:
Phenyl(6-(1-methylcarbamoyl-1H-indol-5-yloxy)pyrimidin-4-yl)carbamate (161 mg, 0.400 mmol) was dissolved in N,N-dimethylformamide (1.0 ml), and 3-(diethylamino)propylamine (130 mg, 1.00 mmol) was added while the reaction mixture was stirred at room temperature. After the reaction mixture was stirred overnight, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was distilled off, and the residue was purified by NH silica gel column chromatography (eluent; ethyl acetate:methanol=50:1). The crystals were precipitated from ethyl acetate-hexane, filtered off, and dried under aeration to yield the title compound (123 mg, 0.280 mmol, 70%) as white crystals.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]2[C:14]=1[C:13](=[O:15])[CH:12]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11]1.S(=O)(=O)(O)O.[C:22](NC(N)=O)([CH3:25])([CH3:24])[CH3:23]>O>[C:22]([C:3]1[C:2]([OH:1])=[C:14]2[C:6]([CH:7]3[CH:12]([C:13]2=[O:15])[CH2:11][CH2:10][CH2:9][CH2:8]3)=[C:5]([CH3:16])[CH:4]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: Cc1ccc(O)c2c1C1CCCCC1C2=O
Reactant: CC(C)(C)NC(N)=O
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1cc(C(C)(C)C)c(O)c2c1C1CCCCC1C2=O
Temperature: 90 °C
Yield: 78.1 %

Procedure:
To 20 g of 8-hydroxy-5-methyl-1,2,3,4,4a,9a-hexahydro-9-fluorenone were added 200 ml of water and 200 ml of concentrated sulfuric acid and the mixture was stirred with heating at 90° C. At the same temperature, thereto was gradually added 53.71 g of N-tert-butylurea, followed by stirring with heating for 14 hours. Then, 10 g of N-tert-butylurea was further added, followed by further stirring at 90° C. for 5 hours. The reaction mixture was poured into 2 liters of water and extracted with chloroform. The chloroform layer was washed with saturated aqueous sodium chloride solution and then dried with magnesium sulfate. The solvent was distilled off and the residue was purified by a silica gel column chromatography (eluent: ethyl acetate:n-hexane=1:10) and thereafter recrystallized from n-hexane to obtain 19.67 g of 7-tert-butyl-8-hydroxy-5-methyl-1,2,3,4,4a,9a-hexahydro-9-fluorenone.
Reaction SMILES: [OH:1][NH2:2].[C:3]1(=[O:9])[O:8][C:6](=[O:7])[CH2:5][CH2:4]1>C1C=CC=CC=1.N1C=CC=CC=1>[C:3]([OH:8])(=[O:9])[CH2:4][CH2:5][C:6]([OH:1])=[O:7].[NH2:2][OH:1]
Reactant: O=C1CCC(=O)O1
Agent: NO
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: O=C(O)CCC(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
This example that demonstrates how this method could be performed. Part 1: To a solution of 2 g hydroxy amine in 100 ml dry benzene and 100 ml pyridine, 9.4 g succinic anhydride is added and the reaction mixture stirred at room temperature for 2 h and refluxed for 2 h. The solvent is evaporated under vacuum and the residue is purified by flash chromatography using silica gel.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:9]([NH2:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1.C([O:16][C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][N:32]2[C:40]3[C:35](=[CH:36][C:37]([C:41](O)=[O:42])=[CH:38][CH:39]=3)[C:34]([CH3:44])=[C:33]2[CH3:45])=[CH:27][CH:26]=1)=[O:18])(C)(C)C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:9]([NH:11][C:41]([C:37]2[CH:36]=[C:35]3[C:40](=[CH:39][CH:38]=2)[N:32]([CH2:31][C:28]2[CH:27]=[CH:26][C:25]([C:20]4[C:19]([C:17]([OH:18])=[O:16])=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:30][CH:29]=2)[C:33]([CH3:45])=[C:34]3[CH3:44])=[O:42])[CH3:10])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc([C@@H](C)N)c1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Product: COc1cccc([C@@H](C)NC(=O)c2ccc3c(c2)c(C)c(C)n3Cc2ccc(-c3ccccc3C(=O)O)cc2)c1

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (R)-1-(3-methoxyphenyl)ethanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 533 [M+H]+.
Reaction SMILES: [NH2:1][C:2](=[O:38])[CH:3]([OH:37])[CH:4]([NH:12][C:13]([C:15]1[C:16]([N:21]2[CH:29]=[C:28]3[C:23]([CH2:24][N:25]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:27]3)=[N:22]2)=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>O.C(#N)C>[NH2:1][C:2](=[O:38])[C:3](=[O:37])[CH:4]([NH:12][C:13]([C:15]1[C:16]([N:21]2[CH:29]=[C:28]3[C:23]([CH2:24][N:25]([C:30]([O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[O:31])[CH2:26][CH2:27]3)=[N:22]2)=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:14])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCc2cn(-c3ncccc3C(=O)NC(Cc3ccccc3)C(O)C(N)=O)nc2C1
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCc2cn(-c3ncccc3C(=O)NC(Cc3ccccc3)C(=O)C(N)=O)nc2C1
Yield: 49.5 %

Procedure:
Oxidation of tert-butyl 2-(3-(4-amino-3-hydroxy-4-oxo-1-phenylbutan-2-ylcarbamoyl)pyridin-2-yl)-4,5-dihydro-2H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate (170 mg, 0.327 mmol) as described in example 1.4 and purification by chromatography over Chromabond RP-C18 (eluent: water/acetonitrile) gave 84 mg of an amorphous solid; ESI-MS [M+H]+: 519.2.
Reaction SMILES: [CH2:1]1COC23OCCOC2([C@]2(CC[C@H]4[C@@H](C[C@H](COC)C5[C@]4(C)CCCC5)[C@@H]2C3)C)[O:2]1.[C:31]([C@@H:33]1[CH:50]2[C@:45]([CH3:52])([CH2:46][CH2:47][C:48](=[O:51])[CH2:49]2)[C@@H:44]2[C@H:35]([C@H:36]3[C@@:40]([CH2:42][CH2:43]2)([CH3:41])[C:39](=[O:53])[CH2:38][CH2:37]3)[CH2:34]1)#N>>[CH3:1][O:2][CH2:31][C@@H:33]1[CH:50]2[C@:45]([CH3:52])([CH2:46][CH2:47][C:48](=[O:51])[CH2:49]2)[C@@H:44]2[C@H:35]([C@H:36]3[C@@:40]([CH2:42][CH2:43]2)([CH3:41])[C:39](=[O:53])[CH2:38][CH2:37]3)[CH2:34]1
Reactant: COC[C@H]1C[C@@H]2[C@H](CC[C@@]3(C)[C@H]2CC24OCCOC23OCCO4)[C@@]2(C)CCCCC12
Reactant: C[C@]12CCC(=O)CC1[C@@H](C#N)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Product: COC[C@H]1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Yield: 88 %

Procedure:
The title compound II-ap was prepared in 88% yield from 3,3:17,17-bis(ethylendioxy)-6α-methoxymethylandrostane by the procedure described above for the preparation of 6α-cyanoandrostane-3,17-dione (II-ac, Prepn. 3). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness. 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 3.25 (s, 3H), 3.24 (m, 2H), 2.53-0.75 (m, 21H), 1.11 (s, 3H), 0.87 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:17]([CH3:18])=[CH:16][C:5]2[CH2:6][C:7](=[O:15])[N:8]([CH2:11][CH2:12][CH2:13][Cl:14])[CH:9]=[CH:10][C:4]=2[CH:3]=1.[CH3:19][NH:20][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=1>>[ClH:14].[CH3:1][C:2]1[C:17]([CH3:18])=[CH:16][C:5]2[CH2:6][C:7](=[O:15])[N:8]([CH2:11][CH2:12][CH2:13][N:20]([CH3:19])[CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([O:31][CH3:32])[CH:24]=3)[CH:9]=[CH:10][C:4]=2[CH:3]=1
Reactant: CNCCc1ccc(OC)c(OC)c1
Reactant: Cc1cc2c(cc1C)CC(=O)N(CCCCl)C=C2
Product: COc1ccc(CCN(C)CCCN2C=Cc3cc(C)c(C)cc3CC2=O)cc1OC
Product: Cl

Procedure:
This compound was prepared analogous to Example 1(b) by reacting 1-(7,8-dimethyl-1,3-dihydro-2H-3-benzazepin-2-on-3-yl)-3-chloro-propane with N-methyl-N-[2-(3,4-dimethoxy-phenyl)-ethyl]-amine.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[OH:15][C:16]1([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35].CO>C(OCC)(=O)C>[C:33]([OH:38])(=[O:37])[C:34]([OH:36])=[O:35].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:19]3[CH2:20][CH2:21][C:16]([OH:15])([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([C:29]([F:30])([F:32])[F:31])[CH:23]=4)[CH2:17][CH2:18]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: OC1(c2ccc(Cl)c(C(F)(F)F)c2)CCNCC1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(O)(c2ccc(Cl)c(C(F)(F)F)c2)CC1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-hydroxy-4-(3-trifluoromethyl-4-chlorophenyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 85% overall yield. FDMS m/e=469 (M+ of free base). α[D]589 =-11.53 (c=0.54, methanol).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([C:8]2[CH:9]=[C:10]([C:21](O)=[O:22])[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)[CH:13]=2)=[O:7])[CH2:3]1.[F:24][C:25]([F:35])([F:34])[C:26]1[N:31]=[CH:30][C:29]([CH2:32][NH2:33])=[CH:28][CH:27]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[OH:1][CH:2]1[CH2:5][N:4]([C:6]([C:8]2[CH:9]=[C:10]([C:21]([NH:33][CH2:32][C:29]3[CH:30]=[N:31][C:26]([C:25]([F:35])([F:24])[F:34])=[CH:27][CH:28]=3)=[O:22])[CH:11]=[C:12]([C:14]3[CH:15]=[CH:16][C:17]([CH3:20])=[CH:18][CH:19]=3)[CH:13]=2)=[O:7])[CH2:3]1
Reactant: NCc1ccc(C(F)(F)F)nc1
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(C(=O)N3CC(O)C3)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(C(=O)NCc3ccc(C(F)(F)F)nc3)cc(C(=O)N3CC(O)C3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 5-(3-hydroxyazetidine-1-carbonyl)-4′-methylbiphenyl-3-carboxylic acid (80 mg, 0.26 mmol) in N,N-dimethylformamide (1.5 mL) were added C-(6-trifluoromethyl-pyridin-3-yl)-methylamine (70 mg, 0.40 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (200 mg, 0.53 mmol), and N,N-diisopropylethylamine (200 pt, 1.15 mmol). The reaction mixture was stirred for 16 hours at 25° C. The reaction mixture was purified by preparative HPLC to afford a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][C@@H:10]1[C:14]([OH:16])=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17]N(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].CI>O.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][C@@H:10]1[C:14]([O:16][CH3:17])=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCC[C@@H]1C(=O)O
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1CCC[C@H]1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of (1S,2R)-2-[(tert-butoxycarbonyl)amino]cyclopentanecarboxylic acid (0.88 g) and DMF (8.0 ml) were added cesium carbonate (2.5 g) and methyl iodide (0.82 g) under ice-cooling, followed by stirring at room temperature for 1.5 hours. To the reaction mixture ethyl acetate and water under ice-cooling were added. The organic layer was separated, the aqueous layer was extracted with ethyl acetate (15 ml), and the organic layer was combined and washed with a 10% aqueous citric acid solution, a saturated sodium bicarbonate solution, water, and saturated brine in this order. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain methyl (1S,2R)-2-[(tert-butoxycarbonyl)amino]cyclopentanecarboxylate (0.85 g).
Reaction SMILES: ClCC([C:5]1[CH:13]=[CH:12][C:11]2[N:10]([CH3:14])[C:9]3[C:15](=[O:18])[CH2:16][CH2:17][C:8]=3[C:7]=2[CH:6]=1)=O.P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].[Cl:27][C:28]1C=CC=C(C(OO)=O)C=1.[C:38]([O-:41])(O)=[O:39].[Na+]>C(Cl)(Cl)Cl>[Cl:27][CH2:28][C:38]([O:41][C:5]1[CH:13]=[CH:12][C:11]2[N:10]([CH3:14])[C:9]3[C:15](=[O:18])[CH2:16][CH2:17][C:8]=3[C:7]=2[CH:6]=1)=[O:39]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C([O-])O
Reactant: Cn1c2c(c3cc(C(=O)CCl)ccc31)CCC2=O
Agent: O=P([O-])([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cn1c2c(c3cc(OC(=O)CCl)ccc31)CCC2=O
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a stirred solution of 7-chloroacetyl-1,4-dihydro-4-methylcyclopent[b]indol-3(2H)-one (2.0 g) in chloroform (100 ml) was added sodium phosphate (1.02 g) followed by m-chloroperbenzoic acid (2.5 g, 50-60% purity). The mixture was stirred at room temperature under a nitrogen atmosphere for 14 hours. Saturated NaHCO3 aqueous solution (50 ml) was added, the layers separated and the organic layer washed with water (2×50 ml). The solution was dried (Na2SO4), filtered and concentrated to give a yellow oil which crystallized upon standing. Recrystallization from with EtOH provided 7-chloroacetyloxy-1,4-dihydro-4-methylcyclopent[b]indol-3(2H)-one (1.1 g).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][N:6]=1)=[O:4].Br[C:14]1C=CC(C(O)=O)=NC=1.Cl.N1CCC1>>[N:2]1([C:3]([C:5]2[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][N:6]=2)=[O:4])[CH2:12][CH2:14][CH2:1]1
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: CN(C)C(=O)c1ccc(Br)cn1
Agent: C1CNC1
Agent: Cl
Product: O=C(c1ccc(Br)cn1)N1CCC1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 161a, from 5-bromopyridine-2-caboxylic acid (1.50 g, 7.43 mmol) and azetidine hydrochloride (954 mg, 10.2 mmol) to give a yellow solid (1.38 g, 77% yield). 1H NMR (400 MHz, CDCl3) δ 8.58 (d, J=2.02 Hz, 1 H) 7.93-7.99 (m, 1 H) 7.90 (d, J=2.27 Hz, 1 H) 4.65 (t, J=7.71 Hz, 2 H) 4.20 (dd, J=8.34, 7.33 Hz, 2 H) 2.27-2.36 (m, 2 H); LCMS for C9H9BrN2O m/z 241.00 (M+H)+.
Reaction SMILES: ClC(OC(Cl)=O)C.[S:8]1[CH:12]=[CH:11][C:10]2[C:13]([O:17][CH:18]([CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:19][CH2:20][N:21](CC3C=CC=CC=3)[CH3:22])=[CH:14][CH:15]=[CH:16][C:9]1=2.ClCCCl.N>CO>[S:8]1[CH:12]=[CH:11][C:10]2[C:13]([O:17][CH:18]([CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:19][CH2:20][NH:21][CH3:22])=[CH:14][CH:15]=[CH:16][C:9]1=2
Reactant: CC(C)CC(CCN(C)Cc1ccccc1)Oc1cccc2sccc12
Agent: CC(Cl)OC(=O)Cl
Agent: N
Solvent: CO
Solvent: ClCCCl
Product: CNCCC(CC(C)C)Oc1cccc2sccc12
Yield: 86.7 %

Procedure:
Add 1-chloroethylchloroformate (0.58 mL, 5.38 mmol) to a stirred solution of [3-(benzo[b]thiophen-4-yloxy)-5-methyl-hexyl]-benzyl-methyl-amine (0.9619 g, 2.62 mmol) and 1,2-dichloroethane (25 mL). Heat the reaction to reflux under nitrogen for 1.5 hours. Add methanol (30 mL) and heat the reaction at reflux for 30 minutes. Cool the reaction to room temperature and make it basic using 2M ammonia in methanol. Concentrate on a rotary evaporator to give the crude product. Purify the crude product by flash chromatography on silica gel eluting with 0.5% concentrated ammonium hydroxide/5% ethanol/chloroform to yield 0.6303 g (87%) of [3-(benzo[b]thiophen-4-yloxy)-5-methyl-hexyl]-methyl-amine: mass spectrum (ion spray) m/z=278.2(M+1); HPLC (90/5/5 to 0/95/5 water/acetonitrile/5% formic acid in water) XTerra MS C18 2.1 mm×50 mm×3.5 micron: Retention time: 2.52 minutes, Purity: >99.9%.
Reaction SMILES: [CH3:1][Si:2]([CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1)([CH3:4])[CH3:3].C(=[C:18]([C:22]([O-:24])=[O:23])[C:19]([O-:21])=[O:20])(C)C.N1CC[CH2:28][CH2:27][CH2:26]1.C(O)(=O)C>C1(C)C=CC=CC=1.O>[CH3:26][C:27]1([CH3:28])[O:21][C:19](=[O:20])[C:18](=[CH:11][C:10]2[CH:13]=[CH:14][C:7]([O:6][CH2:5][Si:2]([CH3:4])([CH3:3])[CH3:1])=[CH:8][CH:9]=2)[C:22](=[O:23])[O:24]1
Reactant: CC(C)=C(C(=O)[O-])C(=O)[O-]
Reactant: C1CCNCC1
Reactant: C[Si](C)(C)COc1ccc(C=O)cc1
Solvent: CC(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)OC(=O)C(=Cc2ccc(OC[Si](C)(C)C)cc2)C(=O)O1
Yield: 45 %

Procedure:
4-(Trimethylsilanylmethoxy)benzaldehyde (obtained in step 1 of Example 1) (5 g, 0.024 mol) and isopropylidenemalonate (3.8 g, 0.0264 mol) in 10 ml of dry toluene in the presence of 0.24 ml of piperidine and 0.14 g of acetic acid are refluxed for 5 hours in a reactor equipped with Dean-Stark apparatus. The water formed is removed azeotropically. The mixture is cooled and the toluene is removed by distillation. The reaction mixture is taken up in 50 ml of diisopropyl ether. The organic phase is washed 3 times with water, dried over sodium sulfate and filtered, and the solvent is evaporated off under vacuum. The yellow oil obtained (7.48 g) is purified by chromatography on a column of silica (eluent: 95/5 heptane/EtOAc). 3.64 g of clean fractions (yield; 45% of the derivative of Example 6 are recovered in the form of a yellow solid:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]=2)O1.Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>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>[N:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[C:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Brc1ccccn1
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccccn2)CC1
Temperature: 85 °C
Yield: 74.6 %

Procedure:
A mixture of tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.500 g, 1.04 mmol), 2-bromopyridine (0.164 g, 1.04 mmol), sodium carbonate (0.439 g, 4.14 mmol), tetrakis(triphenylphosphine)palladium(0) (0.120 g, 0.103 mmol) in ethylene glycol dimethyl ether (20 mL) and water (10 mL) was heated at about 85° C. for about 12 hours. The reaction mixture was allowed to cool to ambient temperature and the solvent was removed under reduced pressure. The residue was partitioned between water (25 mL) and dichloromethane (50 mL). The organic layer was separated and the aqueous layer was further extracted with dichloromethane (2×50 mL). The combined organic extracts were dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by using preparative RP-HPLC (Rainin C18, 8 mm, 300 Å, 35 cm; 5-100% acetonitrile—0.1M ammonium acetate over 20 min, 100% acetonitrile hold 10 minutes, 21 mL/min) to give tert-butyl 4-(pyridin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.202 g, 0.776 mmol) as a white solid; RP-HPLC (Table 1, Method b) Rt 2.78 min; m/z: (M+H)+ 261.
Reaction SMILES: [C:1]([N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([CH2:13][CH:14]=O)[C:7]=2[CH:6]=[CH:5]1)(=[O:3])[CH3:2].[CH3:16][O:17][C:18](=[O:39])[CH:19]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[CH3:16][O:17][C:18](=[O:39])[CH:19]=[CH:14][CH2:13][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:7]=1[CH:6]=[CH:5][N:4]2[C:1](=[O:3])[CH3:2]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(=O)n1ccc2c(CC=O)cccc21
Solvent: C1CCOC1
Product: COC(=O)C=CCc1cccc2c1ccn2C(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
To a solution of 1-acetyl-indole-4-acetaldehyde (2.40 g, 11.93 mmol) prepared according to the method of H. Plieninger, et. al., Chem.Ber., 1956, 89:270 in THF (100 mL) was added methyl(triphenylphos-phoranylidene)acetate (4.78 g, 14.3 mmol). The solution was stirred at ambient temperature overnight. The solvent was removed in vacuo and the residue chromatographed (eluting with ethyl acetate/hexanes). Recrystallization from ethyl acetate/hexanes resulted in 2.12 g of the title compound as a white solid in two crops; MS(CI/NH3) m/e 258 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ2.60 (s, 3H), 3.70 (s, 3H), 3.75 (dd, 2H), 3.75 (m, 1H), 6.63 (dd, 1H), 7.05 (d, 1H), 7.12-7.22 (m, 2H), 7.29 (t, 1H), 7.43 (d, 1H), 8.35 (d, 1H).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:7]([C:12]#[N:13])([CH3:11])[CH2:8][O:9][CH3:10])C.[BH4-].[Na+].C(O)(=O)C>CO.O.[Co](Cl)Cl>[CH2:14]([N:6]1[C:7]([CH2:8][O:9][CH3:10])([CH3:11])[CH2:12][NH:13][C:4](=[O:3])[CH2:5]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)CN(Cc1ccccc1)C(C)(C#N)COC
Agent: Cl[Co]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: COCC1(C)CNC(=O)CN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 545 mg (1.78 mmol) [benzyl-(1-cyano-2-methoxy-1-methyl-ethyl)-amino]-acetic acid ethyl ester in 10 mL MeOH was added 460 mg (3.57 mmol) cobalt(II) chloride. The mixture was cooled with ice and 270 mg (7.13 mmol) sodium borohydride was added. The resulting mixture was stirred at RT for 1 h. The reaction mixture was diluted with a small amount of water, acidified with acetic acid and stirred for 30 min. The organic solvent was removed by distillation; the residue was alkalized with 4 N aqueous NaOH solution and filtered through Celite. The solvent was extracted with EtOAc. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo.