Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=C2N.IC.COC(C)(C)C.C([O-])([O-])=O.[Na+].[Na+].[CH3:26][N:27]([CH:29]=O)[CH3:28]>O>[Br:1][C:2]1[CH:10]=[C:9]2[C:8](=[CH:4][CH:3]=1)[NH:7][N:6]=[C:29]2[N:27]([CH3:28])[CH3:26]
Reactant: Nc1n[nH]c2ccc(Br)cc12
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: O
Solvent: CI
Product: CN(C)c1n[nH]c2ccc(Br)cc12
Temperature: 80 °C
Yield: 2 %

Procedure:
To a 25 mL round-bottom flask, was added 5-bromo-1H-indazol-3-amine (2.0 g, 9432 μmol), 2.0 M iodomethane in tert-butyl methyl ether (587 μL, 9432 mmol), 1.5 g of Na2CO3, and 5 mL of DMF. The reaction mixture was heated to 80° C. for 6 hours. The reaction mixture was then diluted with 30 mL of water and extracted twice with 50 mL of EtOAc. The organic layers were combined, concentrated, and purified by a silica gel column chromatography separation on an ISOC instrument, eluting with 0-60% EtOAc in hexane to give 5-bromo-N,N-dimethyl-1H-indazol-3-amine (45 mg, 2.0% yield), MS m/z: 241 (M+1); and 5-bromo-N-methyl-1H-indazol-3-amine (550 mg, 26% yield), MS m/z: 227 (M+1).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N:20]1[C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([CH:30]=O)[C:24]=2[N:23]=[CH:22][CH:21]=1>>[F:19][C:16]([F:17])([F:18])[C:13]1[N:11]2[N:12]=[C:7]([N:1]3[CH2:2][CH2:3][N:4]([CH2:30][C:25]4[CH:26]=[CH:27][CH:28]=[C:29]5[C:24]=4[N:23]=[CH:22][CH:21]=[N:20]5)[CH2:5][CH2:6]3)[CH:8]=[CH:9][C:10]2=[N:15][N:14]=1
Reactant: O=Cc1cccc2nccnc12
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4cccc5nccnc45)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with quinoxaline-5-carbaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 21 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.05% aqueous ammonia) and acetonitrile as eluents to give 5-[[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]methyl]quinoxaline.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3](=[S:16])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:6]=1[C:12]([O:14][CH3:15])=[O:13].[H-].[Na+].I[CH3:21].O>CN(C)C=O>[CH3:17][N:2]([CH3:1])[C:3](=[S:16])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:21])[C:6]=1[C:12]([O:14][CH3:15])=[O:13]
Reactant: CI
Reactant: COC(=O)c1c(O)cccc1OC(=S)N(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1c(OC)cccc1OC(=S)N(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of O-2-carbomethoxy-3-hydroxyphenyl dimethylthiocarbamate (1.0 g, 3.9 mmol) in N,N-dimethylformamide (10 ml) was added dropwise with stirring to a suspension of sodium hydride (0.19 g, 3.9 mmol) in N,N-dimethylformamide (15 ml) cooled to 0° C. in an ice bath. The reaction mixture was stirred for 1 hour at room temperature. Iodomethane (0.26 ml, 4.3 mmol) was added, and stirring was continued for an additional 3 hours, at which time the mixture was poured into water. Extraction with diethyl ether followed by washing of the extracts with water (3×), saturated aqueous sodium chloride solution, drying (sodium sulfate), and evaporation gave a syrup that was triturated with methanol to afford O-2-carbomethoxy-3-methoxyphenyl dimethylthiocarbamate as a white crystalline solid; yield 0.80 g (76%). NMR (CDCl3, 60 MHz: δ3.30 (d, NME2) p.p.m.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH2:9][C:10]2=[O:15])[CH:2]=[CH2:3].C[Si]([C:20]#[N:21])(C)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[NH2:21][CH2:20][C:10]1([OH:15])[C:11]2[C:6](=[C:5]([O:4][CH2:1][CH:2]=[CH2:3])[CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:8][CH2:9]1
Reactant: C[Si](C)(C)C#N
Reactant: C=CCOc1cccc2c1CCCC2=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: C=CCOc1cccc2c1CCCC2(O)CN

Procedure:
5 g. of 5-allyloxy-1,2,3,4-tetrahydro-1-naphthalenone is reacted with trimethylsilylcyanide and then with lithium aluminum hydride as described in Example 1 to give 1-aminomethyl-1-hydroxy-5-allyloxy-1,2,3,4-tetrahydronaphthalene. The latter compound is treated with HCl in ethanol as described in Example 3 to give 1-aminomethyl-5-allyloxy-3,4-dihydronaphthalene HCl; m.p. 166°-167° C.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].O.CC1(C)C(C)(C)OB([C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[O:22][CH2:21][CH2:20][CH2:19]3)O1.Br[C:28]1[N:29]([CH3:45])[C:30]2[C:35]([C:36]=1[CH:37]([CH2:42][CH2:43][CH3:44])[C:38]([O:40][CH3:41])=[O:39])=[CH:34][CH:33]=[CH:32][CH:31]=2>CN(C)C=O.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.[Pd]>[O:22]1[C:23]2[CH:24]=[CH:25][C:16]([C:28]3[N:29]([CH3:45])[C:30]4[C:35]([C:36]=3[CH:37]([CH2:42][CH2:43][CH3:44])[C:38]([O:40][CH3:41])=[O:39])=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:17][C:18]=2[CH2:19][CH2:20][CH2:21]1
Reactant: CCCC(C(=O)OC)c1c(Br)n(C)c2ccccc12
Reactant: CC1(C)OB(c2ccc3c(c2)CCCO3)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)c1c(-c2ccc3c(c2)CCCO3)n(C)c2ccccc12
Temperature: 110 °C
Yield: 85.6 %

Procedure:
Under a nitrogen atmosphere, sodium carbonate (370 mg, 3.5 mmol), water (20 mL), palladium tetrakis(triphenylphosphine) (620 mg, 0.54 mmol) and 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman (904 mg, 3.48 mmol) were added to a solution of methyl 2-(2-bromo-1-methyl-1H-indol-3-yl)pentanoate (1.13 g, 3.4 mmol) in N,N-dimethylformamide (80 mL). The mixture was heated at 110° C. for 2 hours, concentrated in vacuo and water (40 mL) was added. The aqueous layer was extracted with ethyl acetate (2×20 mL). The organic layer was washed with brine (20 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 95/5) to afford the desired product (12d) as a white solid (1.1 g, 2.91 mmol, 86%).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:7]([OH:24])=[C:8]([C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH2:16][CH2:17][C:18]4=[O:23])[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][C:33]1([CH2:37][O:38][CH3:39])[CH2:36][O:35][CH2:34]1>C(#N)C>[CH:1]1([CH2:4][O:5][C:6]2[C:7]([O:24][CH2:32][C:33]3([CH2:37][O:38][CH3:39])[CH2:36][O:35][CH2:34]3)=[C:8]([C:14]3[CH:22]=[CH:21][CH:20]=[C:19]4[C:15]=3[CH2:16][CH2:17][C:18]4=[O:23])[CH:9]=[CH:10][C:11]=2[O:12][CH3:13])[CH2:3][CH2:2]1
Reactant: COCC1(CBr)COC1
Reactant: COc1ccc(-c2cccc3c2CCC3=O)c(O)c1OCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COCC1(COc2c(-c3cccc4c3CCC4=O)ccc(OC)c2OCC2CC2)COC1
Temperature: 70 °C
Yield: 23.2 %

Procedure:
To a stirring solution of 4(3-(cyclopropylmethoxy)-2-hydroxy-4-methoxyphenyl)-2,3-dihydro-1H-inden-1-one (80 mg, 0.246 mmol) in acetonitrile (150 mL) was added potassium carbonate (102 mg, 0.740 mmol) and 3-bromomethyl-3-methoxymethyl-oxetane (120 mg, 0.615 mmol) and the resultant reaction mixture was heated to 70° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-50% ethyl acetate in pet ether) to afford the title compound as a solid (25 mg, 23%).
Reaction SMILES: C(O[C@@H](C1C(C)=C(C=O)C2=NC3=CN2C=1N1CCC(C)(OCCCC[C@H](C)OC2C=CC(F)=CC=2C2C=C3C=CC=2)CC1)C(OC)=O)(C)(C)C.[C:51]([O:55][C@@H:56]([C:61]1[C:90]([CH3:91])=[C:89]([CH:92]([OH:94])[CH3:93])[C:88]2=[N:95][C:85]3=[CH:86][N:87]2[C:62]=1[N:63]1[CH2:101][CH2:100][C:66]([CH3:102])([O:67][CH2:68][CH2:69][CH2:70][CH2:71][C@H:72]([CH3:99])[O:73][C:74]2[CH:75]=[CH:76][C:77]([F:98])=[C:78](F)[C:79]=2[C:80]2[CH:96]=[C:84]3[CH:83]=[CH:82][CH:81]=2)[CH2:65][CH2:64]1)[C:57]([O:59][CH3:60])=[O:58])([CH3:54])([CH3:53])[CH3:52]>>[C:51]([O:55][C@@H:56]([C:61]1[C:90]([CH3:91])=[C:89]([CH:92]([OH:94])[CH3:93])[C:88]2=[N:95][C:85]3=[CH:86][N:87]2[C:62]=1[N:63]1[CH2:64][CH2:65][C:66]([CH3:102])([O:67][CH2:68][CH2:69][CH2:70][CH2:71][C@H:72]([CH3:99])[O:73][C:74]2[CH:75]=[CH:76][C:77]([F:98])=[CH:78][C:79]=2[C:80]2[CH:96]=[C:84]3[CH:83]=[CH:82][CH:81]=2)[CH2:100][CH2:101]1)[C:57]([O:59][CH3:60])=[O:58])([CH3:52])([CH3:53])[CH3:54]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(C(C)O)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)c(F)c1-c1cccc-3c1
Agent: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(C=O)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(C(C)O)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Yield: 46.9 %

Procedure:
Prepared in 46.9% yield from methyl(2S)-2-(tert-butoxy)-2-[(22S)-17-fluoro-5-formyl-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate following the procedure for methyl(2S)-2-(tert-butoxy)-2-[(22S)-16,17-difluoro-5-(1-hydroxyethyl)-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate. LCMS (ESI, M+1): 702.4.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][CH2:14][N:15]1[C:36]2[C:37]3[C:17]([CH2:18][C@@H:19]4[C:31]([C:32]=3[CH:33]=[CH:34][CH:35]=2)=[CH:30][C@@H:22]([C:23](=[O:29])[N:24]([CH2:27][CH3:28])[CH2:25][CH3:26])[CH2:21][N:20]4[CH3:38])=[CH:16]1.NN>CO>[NH2:3][CH2:12][CH2:13][CH2:14][N:15]1[C:36]2[C:37]3[C:17]([CH2:18][C@@H:19]4[C:31]([C:32]=3[CH:33]=[CH:34][CH:35]=2)=[CH:30][C@@H:22]([C:23](=[O:29])[N:24]([CH2:25][CH3:26])[CH2:27][CH3:28])[CH2:21][N:20]4[CH3:38])=[CH:16]1
Reactant: CCN(CC)C(=O)[C@@H]1C=C2c3cccc4c3c(cn4CCCN3C(=O)c4ccccc4C3=O)C[C@H]2N(C)C1
Agent: NN
Solvent: CO
Product: CCN(CC)C(=O)[C@@H]1C=C2c3cccc4c3c(cn4CCCN)C[C@H]2N(C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.5 %

Procedure:
A solution of 2.1 g (4.1 mmol) of 9 in 35 mL of methanol was treated with 0.92 mL (29.3 mmol) of anhydrous hydrazine and stirred at room temperature overnight. The reaction was concentrated at reduced pressure. The residue was diluted with 25 mL of methylene chloride, undissolved solids were filtered off, and the filtrate was chromatographed on 300 g of silica gel using 15% methanol in methylene chloride as eluent to remove front running impurities, then 2% triethylamine and 15% methanol in methylene chloride as eluent to elute the product to yield 1.24 g (79.5%) of 10 as a yellow amorphous solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[NH:6][CH:7]=1.[CH:9](I)([CH3:11])[CH3:10]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5](=[O:8])[N:6]([CH:9]([CH3:11])[CH3:10])[CH:7]=1
Reactant: O=c1ccc(Br)c[nH]1
Reactant: CC(C)I
Product: CC(C)n1cc(Br)ccc1=O

Procedure:
5-bromo-1-isopropylpyridin-2(1H)-one was prepared from 5-bromopyridin-2(1H)-one and isopropyl iodide following a procedure analogous to that described in Example 59 Step 1.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([CH3:13])[CH:10]([CH2:14][NH2:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:16](=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C([BH3-])#N.[Na+].[OH-].[Na+]>CO>[CH2:1]([N:8]1[CH2:12][C@H:11]([CH3:13])[C@H:10]([CH2:14][NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CN(Cc2ccccc2)CC1CN
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@H]1CN(Cc2ccccc2)C[C@H]1CNCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
c is-1-Benzyl-4-methyl-3-aminomethylpyrrolidine (1000 mg) was dissolved in methanol (10 mL). While this solution was cooled on an ice bath, benzaldehyde (0.50 mL) was added dropwise and the mixture was stirred at room temperature for 1 hour. Subsequently, sodium cyanoborohydride (184 mg) was added and the mixture was stirred at room temperature for 1.5 hours. This was followed by a second addition of sodium cyanoborohydride (123 mg) and stirring for additional 5.5 hours. Subsequently, a 2mol/L aqueous solution of sodium hydroxide (5 mL) was added to the reaction mixture and the mixture was refluxed for 2 hours while heated. Following concentration under reduced pressure, the resulting residue was extracted with toluene (2×30 mL) and the toluene extracts were combined. The combined toluene layer was then washed with water, followed by drying over anhydrous sodium sulfate and concentration under reduced pressure. The resulting residue was purified on a silica gel column (hexane:ethyl acetate=4:1) to give 690 mg of cis-1-benzyl-3-benzylaminomethyl-4-methylpyrrolidine as a pale yellow oil.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[CH2:22]([C:26]1[N:31]=[C:30](Cl)[C:29]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:28][N:27]=1)[CH2:23][CH2:24][CH3:25]>>[CH2:22]([C:26]1[N:27]=[C:28]([NH:1][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:5][CH:4]=2)[C:29]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:30][N:31]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CN)cc1
Reactant: CCCCc1ncc(C(=O)OCC)c(Cl)n1
Product: CCCCc1ncc(C(=O)OCC)c(NCc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)n1

Procedure:
t-Butyl 4'-aminomethyl-biphenyl-2-carboxylate from Example 11A is reacted, by the method described in Example 1C, with ethyl 2-n-butyl-4-chloropyrimidine-5-carboxylate (0.40 g, 1.65 mmol) to give 2-n-butyl-4-{N-[(2'-t-butoxycarbonyl-biphenyl-4-yl)methyl]amino]-5-carboethoxypyrimidine. The t-butyl protecting group is removed by treatment with trifluoroacetic acid in methylene chloride at ambient temperature to afford the title compound.
Reaction SMILES: [CH2:1]([C:8]1[N:13]=[C:12]([Cl:14])[N:11]=[C:10](Cl)[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>N.C(OCC)(=O)C.[Zn]>[CH2:1]([C:8]1[CH:9]=[CH:10][N:11]=[C:12]([Cl:14])[N:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1cc(Cc2ccccc2)nc(Cl)n1
Agent: N
Agent: [Zn]
Solvent: CCOC(C)=O
Product: Clc1nccc(Cc2ccccc2)n1
Temperature: 20 °C
Reaction time: 16 h
Yield: 102.6 %

Procedure:
To an emulsion of 6-benzyl-2,4-dichloro-pyrimidine (239 mg, 1 mmol) in 25% aqueous ammonia solution (1 mL) was added after stirring for 10 min at 0° C. zinc powder (82 mg, 1.25 mmol). The reaction was stirred at 20° C. for 16 h. The yellow suspension was diluted with ethyl acetate an insoluble material was filtered off. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and evaporated under reduced pressure to yield the crude title compound (210 mg, 92%) as a yellow oil.
Reaction SMILES: C(O)(C)C.[CH3:5][O:6][C:7]([C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)=[O:8].Cl(O)(=O)(=O)=O>O>[CH3:5][O:6][C:7]([C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][CH2:15][NH:16]2)=[CH:11][CH:10]=1)=[O:8]
Reactant: COC(=O)c1ccc2cccnc2c1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC(C)O
Solvent: O
Product: COC(=O)c1ccc2c(c1)NCCC2
Temperature: 85 °C
Reaction time: 17 h

Procedure:
To a solution of bis (pentamethyl-cyclopentadiene iridium dichloride) (32 mg, 0.02 equiv.) in a degassed mixture of isopropanol (9.5 ml) and water (0.5 ml) was added quinoline-7-carboxylic acid methyl ester (374 mg, 2.00 mmol) and perchloric acid (70% in water, 0.02 ml, 0.1 equiv.). The mixture was stirred at 85° C. for 17 hours, then the solvents were evaporated. The residue was purified by flash chromatography (heptane/ethyl acetate gradient), yielding 1,2,3,4-tetrahydro-quinoline-7-carboxylic acid methyl ester as a white solid, 305 mg (80%). MS (ISP): m/e=192.4 (M+H+); δH (300 MHz; CDCl3) 7.23 (1H, d), 7.13 (1H, s), 6.98 (1H, d), 3.86 (3H, s), 2.52 (2H, m), 3.32 (2H, t), 2.79 (2H, t), 1.94 (2H, m).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:20]=[C:21]4[CH:26]=[C:25](C(O)=O)[CH:24]=[CH:23][N:22]4[C:30]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.C([N:40](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>[Pd].CO.CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:20]=[C:21]4[CH:26]=[C:25]([NH2:40])[CH:24]=[CH:23][N:22]4[C:30]=3[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:15][CH:14]=2)[CH2:10][CH2:11][CH2:12]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4cc(C(=O)O)ccn4c3-c3ccccc3)cc2)CCC1
Agent: [Pd]
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4cc(N)ccn4c3-c3ccccc3)cc2)CCC1
Temperature: 100 °C
Reaction time: 12 h
Yield: 129.9 %

Procedure:
A solution of 2-[4-(1-tert-butoxycarbonylamino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridine-7-carboxylic acid (1.20 g, 0.86 mmol) and 10% palladium on carbon (0.2 g) in MeOH (20 mL) in DMF (40 mL) and water (3.4 mL) was added triethylamine (0.38 mL, 2.73 mmol, 1.1 equiv) followed by diphenylphosphoryl azide (751 mg, 2.73 mmol, 1.1 equiv). The resulting mixture was stirred at room temperature 10 minutes, at 100° C. for 6 h, at room temperature for 12 h. To the resulting mixture was added triethylamine (0.38 mL, 2.73 mmol, 1.1 equiv) followed by diphenylphosphoryl azide (751 mg, 2.73 mmol, 1.1 equiv). The resulting mixture was heated at 100° C. for 12 h. The resulting mixture was separated between EtOAc (100 mL) and water (50 mL). The organic phase was dried (Na2SO4 anh) and concentrated under reduced pressure. The remaining material (1.4 g) was purified using MPLC (Biotage Isolera Flash NH2 Snap 10 reverse phase column; 100% CH2Cl2 for 3.5 min., gradient to 90% CH2Cl2: 10% MeOH over 1 min.; 90% CH2Cl2: 10% MeOH for 5.5 min., gradient to 80% CH2Cl2: 20% MeOH over 6 min., 80% CH2Cl2: 20% MeOH for 10.2 min.) to give {1-[4-(7-amino-3-phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (508 mg, 45%):
Reaction SMILES: [NH2:1][C:2](=[O:22])[CH2:3][CH:4]([C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)[C:5]([O:7]CC1C=CC=CC=1)=[O:6]>C(O)C.[Pd]>[NH2:1][C:2](=[O:22])[CH2:3][CH:4]([C:15]1[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=1)[C:5]([OH:7])=[O:6]
Reactant: NC(=O)CC(C(=O)OCc1ccccc1)c1ccc(O)cc1
Agent: [Pd]
Solvent: CCO
Product: NC(=O)CC(C(=O)O)c1ccc(O)cc1
Reaction time: 2 h
Yield: 100.4 %

Procedure:
A suspension of benzyl 4-amino-2-(4-hydroxyphenyl)-4-oxobutanoate (327 mg, 1.09 mmol) and palladium on charcol (10%, 50 mg) in ethanol (30 mL) was stirred under a hydrogen atmosphere for 2 h. After replacement of hydrogen with nitrogen the crude reaction mixture was filtered through a thin pad of celite and the filtrate evaporated to dryness to give the title compound as a white solid (229 mg, 100%). LC/MS: 0.81 min; z/e 210, calcd (M+1) 210. 1H NMR (400 MHz: DMSO-d6): 11.9 (1H), 9.10 (1H), 7.10 (1H), 6.85 (2H), 6.55 (1H), 6.50 (2H), 3.60 (1H), 2.60 (1H), 2.15 (1H).
Reaction SMILES: FC(F)(F)C([N:5]([CH2:20][C:21]1[CH:26]=[C:25]([C:27](OCC)=[O:28])[CH:24]=[CH:23][N:22]=1)[CH2:6][C:7](=[O:19])[N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=O.[BH4-].[Na+]>>[OH:28][CH2:27][C:25]1[CH:24]=[CH:23][N:22]=[C:21]([CH2:20][NH:5][CH2:6][C:7]([N:8]2[CH2:12][CH2:11][CH2:10][C@@H:9]2[CH2:13][N:14]2[CH2:15][CH2:16][CH2:17][CH2:18]2)=[O:19])[CH:26]=1
Reactant: CCOC(=O)c1ccnc(CN(CC(=O)N2CCC[C@@H]2CN2CCCC2)C(=O)C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Product: O=C(CNCc1cc(CO)ccn1)N1CCC[C@@H]1CN1CCCC1

Procedure:
Prepared by General Procedure U from ethyl 2-[(2,2,2-trifluoro-N-{2-oxo-2-[(2R)-2-(pyrrolidin-1-ylmethyl)pyrrolidin-1-yl]ethyl}acetamido)methyl]pyridine-4-carboxylate, using 5 equiv. of NaBH4. The residue was purified by column chromatography on silica gel using NH4OH (2%)+MeOH (20%) in CH2Cl2 to give the title as yellow oil. 1H NMR (300 MHz, CD3OD), δ ppm: 8.44 (d, 1H), 7.49 (s, 1H), 7.31 (d, 1H), 4.90 (s, 2H), 4.69 (s, 2H), 4.24 (m, 1H), 3.93 (s, 2H), 3.50-3.36 (m, 3H), 2.67-2.42 (m, 6H), 2.06-1.89 (m, 4H), 1.84-1.72 (s, 4H). ESI-MS (m/z): 333 [M+1].
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH:17]([CH3:19])[CH3:18])[CH2:13][CH2:12]2)=[O:10])=[N:7][CH:8]=1>C(Cl)Cl.O=[Mn]=O>[CH:17]([N:14]1[CH2:13][CH2:12][N:11]([C:9]([C:6]2[N:7]=[CH:8][C:3]([CH:2]=[O:1])=[CH:4][CH:5]=2)=[O:10])[CH2:16][CH2:15]1)([CH3:19])[CH3:18]
Reactant: CC(C)N1CCN(C(=O)c2ccc(CO)cn2)CC1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CC(C)N1CCN(C(=O)c2ccc(C=O)cn2)CC1
Reaction time: 6 h
Yield: 87 %

Procedure:
To a solution of (5-hydroxymethyl-pyridin-2-yl)-(4-isopropyl-piperazin-1-yl)-methanone (0.275 g, 1.10 mmol) in DCM (30 mL) was added MnO2 (0.400 g., 5.20 mmol). The reaction was stirred for 6 h, filtered through a pad of diatomaceous earth, and concentrated to give the desired aldehyde (0.250 g, 95%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[OH:7][C@@H:8]([C:12]1[O:13][C:14]([O:17][CH2:18][CH:19]([CH2:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22])=[CH:15][CH:16]=1)[CH2:9][C:10]#[N:11].N.CO.C(Cl)Cl>>[NH2:11][CH2:10][CH2:9][C@H:8]([C:12]1[O:13][C:14]([O:17][CH2:18][CH:19]([CH2:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22])=[CH:15][CH:16]=1)[OH:7]
Reactant: CCCC(CCC)COc1ccc([C@H](O)CC#N)o1
Agent: N
Agent: [Al+3]
Agent: [H-]
Solvent: CO
Solvent: ClCCl
Product: CCCC(CCC)COc1ccc([C@H](O)CCN)o1

Procedure:
LiAlH4 reduction of (R)-3-hydroxy-3-(5-((2-propylpentyl)oxy)furan-2-yl)propanenitrile following the method used in Example 1 gave after flash chromatography purification (2%-20% 7N NH3/MeOH—CH2Cl2 gradient) Example 32 as a colorless oil. Yield (0.080 g, 61%); 1H NMR (400 MHz, CD3OD) δ .6.11 (d, J=2.9 Hz, 1H), 5.11 (d, J=2.9 Hz, 1H), 4.56 (t, J=6.9 Hz, 1H), 3.88 (d, J=5.9 Hz, 2H), 2.65-2.78 (m, 2H), 1.88-1.96 (m, 2H), 1.70-1.80 (m, 1H), 1.30-1.44 (m, 8H), 0.085-0.97 (m, 6H); ESI-MS 270.2 m/z [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:16]3[CH2:15][CH2:14][NH:13][CH2:12][C:11]=3[C:10](=[O:17])[O:9][C:7]=2[CH:8]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>CN(C)C=O.C(OCC)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:16]3[CH2:15][CH2:14][N:13]([CH2:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:12][C:11]=3[C:10](=[O:17])[O:9][C:7]=2[CH:8]=1
Reactant: BrCCc1ccccc1
Reactant: COc1ccc2c3c(c(=O)oc2c1)CNCC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: COc1ccc2c3c(c(=O)oc2c1)CN(CCc1ccccc1)CC3
Yield: 27.5 %

Procedure:
A mixture of 8-methoxy-1,2,3,4-tetrahydro-chromeno[3,4-c]pyridin-5-one (1.5 g, 6.5 mmol), potassium carbonate (0.50 g, 4.7 mmol), and (2-bromethyl)benzene (1.0 mL, 1.4 g, 7.3 mmol) in 10 mL of N,N-dimethylformamide is heated at 900 for 18 hours. The cooled reaction mixture is added to 300 mL of water and 150 mL of ethyl ether. The insoluble material is filtered and washed with fresh ethyl ether. Recrystallization of the solid from aqueous 2-propanol gives 0.60 g (27%) of product; mp 135°-136° C.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[O:3].[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH:10]=[CH:9]1.[O-]S(C(F)(F)F)(=O)=O.C([Yb+2])C.[O-]S(C(F)(F)F)(=O)=O>ClCCl.C1(C)C=CC=CC=1>[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10]([CH:2]([OH:3])[C:1]([O:5][CH2:6][CH3:7])=[O:4])=[CH:9]1
Reactant: c1ccc2occc2c1
Reactant: CCOC(=O)C=O
Agent: CC[Yb+2]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)C(O)c1coc2ccccc12
Yield: 31 %

Procedure:
Ethyl glyoxylate 50% in toluene (3.72 mL, 18.6 mmol) was added to a solution of benzofuran (2.0 g, 16.9 mmol) and ethyl ytterbium (III) triflate (0.53 g, 0.8 mmol) in dichloromethane (15 mL). The reaction mixture was stirred at room temperature for 48 hours with two additions of an equivalent of ethyl glyoxylate 50% in toluene each day. The reaction mixture was concentrated in vacuo. The residue was purified by flash chromatography (cyclohexane/ethyl acetate 95/05 to 80/20) to provide the desired hydroxyl-ester (20a) (1.15 g, 5.2 mmol, 31%).