Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][OH:7].[C:8]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:11])[CH:9]=[CH2:10]>>[CH2:13]([O:12][C:8]([CH2:9][CH2:10][CH:5]([NH:4][CH2:3][CH2:2][NH2:1])[CH2:6][OH:7])=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: NCCNCCO
Reactant: C=CC(=O)OCc1ccccc1
Product: NCCNC(CO)CCC(=O)OCc1ccccc1

Procedure:
A solution of 2-(2-aminoethylamino) ethanol (4.6648 g; 44.8 mmole) dissolved in 35 mL of benzyl acrylate was heated at reflux for 24 hours. The excess reagent was removed under reduced pressure and the resulting oil was purified by flash chromatography using a mixture of dichloromethane and ethyl acetate (60:40) to elute the desired material. Fractions were collected and analyzed to determine which of these contain the product. Solvents were eliminated under vacuum to give 5.8 g (21.9%) of N,N,N′-tris[2-(benzyloxycarbonylethyl]-2-(2aminoethylamino) ethanol (8).
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]2.[C:23]12([C:33](Cl)=[O:34])[CH2:32][CH:27]3[CH2:28][CH:29]([CH2:31][CH:25]([CH2:26]3)[CH2:24]1)[CH2:30]2.N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:23]12([C:33]([O:1][CH2:2][C@@:3]34[C@@H:20]5[C@H:11]([C@H:12]6[C@@:16]([CH2:18][CH2:19]5)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]6)[CH2:10][CH2:9][C:8]3=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]4)=[O:34])[CH2:30][CH:29]3[CH2:28][CH:27]([CH2:26][CH:25]([CH2:31]3)[CH2:24]1)[CH2:32]2
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO)[C@@H]1CCC2=O
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43COC(=O)C34CC5CC(CC(C5)C3)C4)[C@@H]1CCC2=O

Procedure:
A solution of 22 g of 19-hydroxyandrost-4-ene-3,17 -dione, 18 g of 1-adamantanecarboxylic acid chloride, and 29 ml of pyridine in 2.2 liters of toluene is refluxed overnight. The reaction mixture is cooled, and the toluene layer is washed with water, dried over magnesium sulfate and filtered then the solvent is removed. The resulting residue is crystallized from methanol to give 19-(1 -adamantanylcarbonyloxy)androst-4-ene-3,17-dione, M.P. 161°-163° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]([OH:14])=O)[CH:8]=2)[O:3]1.[NH2:16][C:17]1[CH:26]=[C:25]2[C:20]([CH2:21][CH:22]([CH2:28][OH:29])[C:23](=[O:27])[NH:24]2)=[CH:19][CH:18]=1>>[OH:29][CH2:28][CH:22]1[CH2:21][C:20]2[C:25](=[CH:26][C:17]([NH:16][C:12]([C:7]3[CH:8]=[C:9]4[C:4](=[CH:5][CH:6]=3)[O:3][C:2]([CH3:1])([CH3:15])[CH2:11][CH2:10]4)=[O:14])=[CH:18][CH:19]=2)[NH:24][C:23]1=[O:27]
Reactant: Nc1ccc2c(c1)NC(=O)C(CO)C2
Reactant: CC1(C)CCc2cc(C(=O)O)ccc2O1
Product: CC1(C)CCc2cc(C(=O)Nc3ccc4c(c3)NC(=O)C(CO)C4)ccc2O1

Procedure:
This material was prepared analogous to the procedures described for Example 2, steps (a-b). 2,2-Dimethyl-chroman-6-carboxylic acid (90 mg, 0.4 mmol, Maybridge) and 7-amino-3-hydroxymethyl-3,4-dihydro-1H-quinolin-2-one (85 mg, 0.44 mmol, prepared according to the procedure described in WO03049702) provided the title compound as an off-white amorphous solid. MS (ESI, pos. ion) m/z: 381 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C([Cl:15])=O>CCOC(C)=O.CN(C=O)C>[Cl:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:15])=[O:5]
Reactant: Cc1cccc(C(=O)O)c1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cccc(C(=O)Cl)c1Cl
Reaction time: 1.5 h

Procedure:
To a suspension of 2-chloro-3-methylbenzoic acid (6.75 g, 39.39 mmol) [prepared as described above] in EtOAc were added a few drops of DMF and oxalyl chloride (5.1 ml, 1.5 eq.). After stirring the reaction mixture for 1.5 h, the solvent was removed in vacuo to give 2-chloro-3-methylbenzoyl chloride, which was used in the next step without further purification.
Reaction SMILES: [CH3:1][CH:2]([NH:4][S:5](Cl)(=[O:7])=[O:6])[CH3:3].[CH3:9][S:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=1.C(N(CC)CC)C>ClCCl>[CH3:9][S:10][C:11]1[CH:17]=[CH:16][C:14]([NH:15][S:5]([NH:4][CH:2]([CH3:3])[CH3:1])(=[O:7])=[O:6])=[CH:13][CH:12]=1
Reactant: CC(C)NS(=O)(=O)Cl
Reactant: CSc1ccc(N)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSc1ccc(NS(=O)(=O)NC(C)C)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
(1-Methylethyl)sulfamoyl chloride (6.63 g, 0.034 mol) was added dropwise to a solution of 4-(methylthio) aniline (4.48 g, 0.032 mol) and triethylamine (4.87 ml, 0.035 mol) in dry dichloromethane (100 ml) at 0° C. under a nitrogen atmosphere. After addition, the resultant mixture was allowed to warm to room temperature and was stirred for 6 hr. The reaction mixture was further extracted with dichloromethane and the organic extracts washed with water (2×50 ml), dried (MgSO4) and concentrated in vacuo to yield N-(4-methylthiophenyl)-N′-(1-methylethyl)sulfamide as a white solid. δ (1H NMR, DMSO, ppm): 0.8 (6H, d), 2.3 (3H, s), 3.2 (1H, m), 3.35 (1H, s), 6.9-7.1 (4H, m), 9.5 (1H, s). M.P. 65-68° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[C:11]2[C:6](=[CH:7][C:8](Br)=[C:9]([CH3:12])[CH:10]=2)[C:5](=[O:14])[CH2:4][CH2:3]1.[Cl-].[Li+].C([Sn](CCCC)(CCCC)[C:23]([C:29]1[CH:39]=[CH:38][C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:31][CH:30]=1)=[CH:24][Si:25]([CH3:28])([CH3:27])[CH3:26])CCC>[Cu](I)I.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>[CH3:12][C:9]1[C:8]([C:23]([C:29]2[CH:30]=[CH:31][C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:38][CH:39]=2)=[CH:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[CH:7][C:6]2[C:5](=[O:14])[CH2:4][CH2:3][C:2]([CH3:15])([CH3:1])[C:11]=2[CH:10]=1
Reactant: Cc1cc2c(cc1Br)C(=O)CCC2(C)C
Reactant: CCCC[Sn](CCCC)(CCCC)C(=C[Si](C)(C)C)c1ccc(C(=O)OCC)cc1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Product: CCOC(=O)c1ccc(C(=C[Si](C)(C)C)c2cc3c(cc2C)C(C)(C)CCC3=O)cc1
Temperature: 80 °C

Procedure:
A solution of 1,2,3,4-tetrahydro-4,4,6-trimethyl-1-oxo-7-bromonaphthalene (8.5 g, 31.8 mmol) was purged with argon (2×). Lithium chloride (4.0 g), copper iodide (0.860 g), tetrakis(triphenylphosphine)palladium(0) (1.8 g, 1.6 mmol) and ethyl 4-(1-(tributylstannyl)-2-(trimethylsilyl)-ethen-1-yl)-benzoate (24.0 g, 44.5 mmol) were then added and the resulting mixture was again purged with argon. The mixture was heated to 80° C. for ˜4 hours, and then cooled to room temperature. The mixture was poured into cold water (1 L) and was diluted with ethyl ether. The organic phase was separated, washed with cold water (2×1 L), saturated sodium bicarbonate (1 L), brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (8×15 cm, 0 to 5% ethyl acetate/toluene) to give the title material which was triturated in hexane (12.2 g, 88%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([NH:7][C:8]([C:10]2[S:14][C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[N:12][C:11]=2[CH3:22])=[O:9])[CH2:2]1.[CH3:23][O:24][C:25]([C:27]1[CH:28]=[C:29](OB(O)O)[CH:30]=[CH:31][CH:32]=1)=[O:26]>>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:13]2[S:14][C:10]([C:8]([NH:7][C@H:3]3[CH2:4][CH2:5][CH2:6][N:1]([C:31]4[CH:32]=[C:27]([CH:28]=[CH:29][CH:30]=4)[C:25]([O:24][CH3:23])=[O:26])[CH2:2]3)=[O:9])=[C:11]([CH3:22])[N:12]=2)=[CH:20][CH:19]=1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)N[C@H]1CCCNC1
Reactant: COC(=O)c1cccc(OB(O)O)c1
Product: COC(=O)c1cccc(N2CCC[C@H](NC(=O)c3sc(-c4ccc(Cl)cc4)nc3C)C2)c1
Yield: 49.6 %

Procedure:
Using (S)—N-(piperidin-3-yl)-2-(4-chlorophenyl)-4-methylthiazol-5-carboxamide (336 mg, 1.00 mmol) and 3-(methoxycarbonyl)phenylboric acid (360 mg, 2.00 mmol), the same procedure was followed as in Example 2 to give 233 mg (50%) of the desired compound as a colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:3]=1[C:4]([NH:6][CH:7]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:12]=1)[CH2:8][CH2:9][OH:10])=O.FC1C=CC=C(F)C=1C(NC(C1C=CC(Cl)=CC=1)CCO)=O>>[F:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:2]([F:1])[C:3]=1[C:4]1[O:10][CH2:9][CH2:8][CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([CH3:19])([CH3:18])[CH3:20])[CH:12]=2)[N:6]=1
Reactant: CC(C)(C)c1cccc(C(CCO)NC(=O)c2c(F)cccc2F)c1
Agent: O=C(NC(CCO)c1ccc(Cl)cc1)c1c(F)cccc1F
Product: CC(C)(C)c1cccc(C2CCOC(c3c(F)cccc3F)=N2)c1
Yield: 68.6 %

Procedure:
The procedure is as for Example 85, but 4.0 g (11.5 mmol) of N-(2,6-difluorobenzoyl)-3-amino-3-(3-tert-butylphenyl)-1-propanol are employed instead of N-(2,6-difluorobenzoyl)-3-amino-3-(4-chlorophenyl) 1-propanol. 2.6 g (68.6%) of 2-(2,6-difluorophenyl)-4-(3-tert-butylphenyl)-5,6-dihydro(4H)1,3- oxazine are obtained as a colorless oil.
Reaction SMILES: [S:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=[N:2]1.Cl.[CH3:10][NH:11][O:12][CH3:13].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[CH3:13][O:12][N:11]([CH3:10])[C:6]([C:5]1[S:1][N:2]=[CH:3][CH:4]=1)=[O:8]
Reactant: O=C(O)c1ccns1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccns1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-isothiazole carboxylic acid (5 g, 38.7 mmol) in dichloromethane (200 mL), 4-(dimethylamino)pyridine (473 mg, 3.87 mmol), N,O-dimethylhydroxylamine hydrochloride (4.53 g, 46.4 mmol) (N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride (8.17 g, 42.6 mmol) and triethylamine (13.63 μL, 97.0 mmol) were added and the reaction was stirred overnight at room temperature. The reaction mixture was then successively washed with 1N HCl, 1N NaOH and brine. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The crude residue obtained was used as such for the next step. 1H NMR (400 MHz, acetone-d6): 8.59 (s, 1H), 7.97 (s, 1H), 3.94 (s, 3H), 3.38 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[N:6][C:7]=1[Cl:8].[OH:10]O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[N+:6]([O-:10])[C:7]=1[Cl:8]
Reactant: Oc1cnc(Cl)c(Cl)c1
Reactant: OO
Solvent: CC(=O)O
Product: [O-][n+]1cc(O)cc(Cl)c1Cl

Procedure:
3.28 g (20 mmol) of 5,6-dichloro-3-pyridinol in 15 ml of glacial acetic acid were N-oxidized at 100° C. using 2.14 g (21 mmol) of 35% hydrogen peroxide. When the reaction was complete, the mixture was neutralized, extracted with ethyl acetate and washed until neutral, and the solvent was removed by evaporation.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[OH:10].Br[CH2:12][C@@H:13]([CH3:16])[CH2:14][Cl:15]>>[Cl:15][CH2:14][C@H:13]([CH3:16])[CH2:12][O:10][C:3]1[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=1[F:1]
Reactant: C[C@@H](CCl)CBr
Reactant: Oc1cc(F)c(F)cc1F
Product: C[C@@H](CCl)COc1cc(F)c(F)cc1F

Procedure:
Prepared by Procedure U and Scheme AK using 2,4,5-trifluorophenol and (2S)-1-bromo-3-chloro-2-methylpropane.
Reaction SMILES: [CH2:1]([N:3]([CH2:8][CH3:9])[CH2:4][CH2:5][NH:6][CH3:7])[CH3:2].[C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:21][CH2:22][NH:23][C:24](=[O:38])[C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][N:34]=[C:33](Cl)[N:32]=4)=[CH:27][CH:26]=3)[CH:19]=2)[NH:14][CH:13]=1)#[N:11]>>[C:10]([C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH2:21][CH2:22][NH:23][C:24](=[O:38])[C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH:36]=[CH:35][N:34]=[C:33]([N:6]([CH2:5][CH2:4][N:3]([CH2:8][CH3:9])[CH2:1][CH3:2])[CH3:7])[N:32]=4)=[CH:27][CH:26]=3)[CH:19]=2)[NH:14][CH:13]=1)#[N:11]
Reactant: CCN(CC)CCNC
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Product: CCN(CC)CCN(C)c1nccc(-c2ccc(C(=O)NCCc3ccc4[nH]cc(C#N)c4c3)cc2)n1

Procedure:
Using 2-(diethylamino)-ethyl-methyl-amine and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates.
Reaction SMILES: [CH2:1]([N:3](CC)[C:4]([C:6]1[CH:11]=[C:10]([C:12]2[CH:13]=[N:14][N:15]([CH2:17][CH2:18][CH2:19][OH:20])[CH:16]=2)[CH:9]=[CH:8][C:7]=1[NH:21][C:22]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][N:25]=[C:24]([NH:32][C:33]2[CH:45]=[CH:44][C:36]([CH2:37][P:38](=[O:43])([OH:42])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=2[O:46][CH3:47])[N:23]=1)=[O:5])C.OCCCN1C=C(C2C=CC(NC3C(C(F)(F)F)=CN=C(NC4C=CC(CP(=O)(OCC)OCC)=CC=4OC)N=3)=C(C(=O)NC)C=2)C=N1>>[OH:20][CH2:19][CH2:18][CH2:17][N:15]1[CH:16]=[C:12]([C:10]2[CH:9]=[CH:8][C:7]([NH:21][C:22]3[C:27]([C:28]([F:29])([F:30])[F:31])=[CH:26][N:25]=[C:24]([NH:32][C:33]4[CH:45]=[CH:44][C:36]([CH2:37][P:38](=[O:42])([OH:43])[O:39][CH2:40][CH3:41])=[CH:35][C:34]=4[O:46][CH3:47])[N:23]=3)=[C:6]([C:4](=[O:5])[NH:3][CH3:1])[CH:11]=2)[CH:13]=[N:14]1
Reactant: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)cc3C(=O)N(CC)CC)n2)c(OC)c1
Agent: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)cc3C(=O)NC)n2)c(OC)c1)OCC
Product: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)cc3C(=O)NC)n2)c(OC)c1
Yield: 70 %

Procedure:
Prepared analogously to Compound 3A with diethyl (4-{[4-({4-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-2-(methylcarbamoyl)phenyl}amino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (234 mg, 338 μmol) to yield 156 mg of the desired product (70%). 1H NMR (400 MHz, CD3OD) δ 8.30-8.36 (m, 1H), 8.26 (s, 1H), 8.14 (s, 1H), 7.92 (s, 1H), 7.86 (d, J=8.08 Hz, 1H), 7.83 (d, J=2.02 Hz, 1H), 7.63 (dd, J=2.02, 8.59 Hz, 1H), 7.04 (s, 1H), 6.80 (s, 1H), 4.30 (t, J=6.82 Hz, 2H), 3.88 (s, 3H), 3.84 (t, J=6.95 Hz, 2H), 3.58 (t, J=6.19 Hz, 2H), 2.92-3.02 (d, J=21.9 Hz, 2H), 2.91 (s, 3H), 2.10 (t, J=6.44 Hz, 2H), 1.15 (t, J=6.95 Hz, 3H). MS (ESI): m/z 664.21 [M+H]+. UPLC: tR=1.13 min (UPLC-TOF: polar—3 min).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([O:19][C:20]([N:22]1[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>N1C=CC=CC=1>[CH2:12]([O:19][C:20]([N:22]1[CH2:26][CH2:25][C@@H:24]([O:27][S:7]([C:4]2[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=2)(=[O:9])=[O:8])[CH2:23]1)=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(OCc1ccccc1)N1CC[C@@H](O)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O[C@@H]2CCN(C(=O)OCc3ccccc3)C2)cc1
Reaction time: 48 h

Procedure:
22.25 g (0.117 moles) of toluene-4-sulfonyl chloride, dissolved in 30 ml of pyridine, were added dropwise to a stirred solution of 11.79 g (0.053 moles) of (3R)-N-benzyloxycarbonyl-3-hydroxypyrrolidine [J. Chem. Soc., Chem. Commun. 1984, 1298]in 50 ml of pyridine, cooled below 0° C. After the addition, the reaction mixture was kept at 5° C. for 48 hours.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:18]1[O:22][C:21](=[O:23])[C@H:20]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)[CH2:19]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-:35].[Li+]>C(COC)OC.O>[C:1]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[C@@H:18]([OH:22])[CH2:19][C@@H:20]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:27][CH:26]=1)[C:21]([OH:23])=[O:35])([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)cc1)[C@@H]1C[C@@H](Cc2ccc(C(F)(F)F)cc2)C(=O)O1
Agent: [Li+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(F)cc1)[C@@H](O)C[C@@H](Cc1ccc(C(F)(F)F)cc1)C(=O)O

Procedure:
Analogously to Example 1 i), 1.05 g of 5(S)-[1(S)-(Boc-amino)-2-(p-fluorophenyl)ethyl]-3(R)-(p-trifluoromethylphenylmethyl)-dihydrofuran-2-(3H)-one in 35.5 ml of dimethoxyethane and 17.9 ml of water are hydrolysed with 8.7 ml of 1 M lithium hydroxide solution to form the title compound which is used further directly.
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10]=2)[NH:5][CH:4]=[C:3]1[C:16]#[N:17].P(Cl)(Cl)([Cl:20])=O>CN(C)C=O>[Cl:20][C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17]
Reactant: N#Cc1c[nH]c2cc3ccccc3cc2c1=O
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: N#Cc1cnc2cc3ccccc3cc2c1Cl
Temperature: 105 °C
Yield: 49.5 %

Procedure:
A reaction mixture of 3.5 g (16 mmol) of 4-oxo-1,4-dihydrobenzo[g]quinoline-3-carbonitrile in 35 mL of phosphorus oxychloride and 22 drops of N,N-dimethylformamide (DMF) is heated at 100-110° C. for 5 hours. After cooling, the mixture is concentrated to dryness in vacuo to give a dark residue. The residue is partitioned between methylene chloride and ice-cooled saturated aqueous sodium carbonate solution. The organic layer is washed with ice-cooled brine and dried over sodium sulfate. The organic solvent is passed through a short column of silica gel, and further eluted with additional methylene chloride. Removal of the solvent yields 1.89 g (49.5%) of the product as a bright yellow solid, mp 253-255° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10](OC)[C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].FC(F)(F)C(O)=O.C([SiH](CC)CC)C.C(=O)(O)[O-].[Na+]>C(#N)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[CH2:10][C:11]1[C:19]2[C:14](=[N:15][CH:16]=[C:17]([C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)[CH:18]=2)[NH:13][CH:12]=1)([O-:3])=[O:2]
Reactant: COC(c1cccc([N+](=O)[O-])c1)c1c[nH]c2ncc(-c3cccnc3)cc12
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: O=[N+]([O-])c1cccc(Cc2c[nH]c3ncc(-c4cccnc4)cc23)c1

Procedure:
To 3-[(3-nitro-phenyl)-methoxy-methyl]-5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridine (535, 431 mg, 1.20 mmol, per Example 26, Scheme 49 Step 1) in acetonitrile (130 mL), were added trifluoroacetic acid (18 mL, 230 mmol) and triethylsilane (36 mL, 230 mmol). The reaction was refluxed for three hours. The reaction mixture was poured into sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 80% ethyl acetate in hexane to give the compound (P-1402, 323 mg, 82%). MS(ESI)[M+H+]+=331.2.
Reaction SMILES: [C:1]([NH:5][C@H:6]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)[CH2:7][CH2:8][CH3:9])(=O)[CH2:2][CH3:3].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([NH:5][C@H:6]([C:10]1[CH:11]=[CH:12][C:13]([O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[CH:14][CH:15]=1)[CH2:7][CH2:8][CH3:9])[CH2:2][CH3:3]
Reactant: CCC[C@H](NC(=O)CC)c1ccc(Oc2ccccc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCN[C@@H](CCC)c1ccc(Oc2ccccc2)cc1
Temperature: 0 °C
Yield: 99 %

Procedure:
The butylamine prepared above (57 mg, 0.21 mmol) in THF (1 mL) at room temperature was treated with 1M LAH in THF (0.42 mL). The solution was warmed to reflux for 4 hours, cooled to 0° C. and quenched with sodium sulfate decahydrate. The slurry was filtered through celite and concentrated to provide 53 mg (99%) of the title compound as a colorless oil.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]4[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=4)=[C:14]([O:28][CH3:29])[CH:13]=3)[C:5]2=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:38]2[CH:39]=[N:40][N:41]([CH:43]3[CH2:48][CH2:47][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:45][CH2:44]3)[CH:42]=2)O1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:29][O:28][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][C:15]=1[O:18][CH2:19][C:20]1[CH:21]=[N:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=1)[CH2:11][N:8]1[C:5]2=[N:6][CH:7]=[C:2]([C:38]3[CH:39]=[N:40][N:41]([CH:43]4[CH2:44][CH2:45][N:46]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:47][CH2:48]4)[CH:42]=3)[CH:3]=[C:4]2[N:10]=[CH:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: COc1ccc(COc2ccc(Cn3cnc4cc(I)cnc43)cc2OC)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccc(Cn3cnc4cc(-c5cnn(C6CCN(C(=O)OC(C)(C)C)CC6)c5)cnc43)cc2OC)cn1
Temperature: 100 °C
Reaction time: 1 h
Yield: 59.9 %

Procedure:
To a stirred suspension of 6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine (0.20 g, 0.40 mmol) in N,N-dimethylformamide (8 mL) and water (2 mL) was added tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (0.15 g, 0.40 mmol), potassium carbonate (0.22 g, 1.59 mmol), and tetrakis(triphenylphosphino)palladium(O) (0.021 g, 0.018 mmol). The mixture was heated to 100° C. After 1 h, the reaction mixture was allowed to cool to room temperature and was filtered through Celite. The filtrate was concentrated, and the residue purified via silica gel chromatography (5% methanol/dichloromethane elute) to provide 0.15 g (60%) of tert-butyl 4-(4-(3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Mg].[C:11]([N:14]1[CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]1)(=[O:13])[CH3:12].Cl>O1CCCC1>[OH:20][C:17]1([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)[CH2:18][CH2:19][N:14]([C:11](=[O:13])[CH3:12])[CH2:15][CH2:16]1
Reactant: COc1ccc(Br)cc1
Reactant: CC(=O)N1CCC(=O)CC1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc(C2(O)CCN(C(C)=O)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.3 %

Procedure:
4-Bromoanisole (22.4 g, 0.12 mol) in tetrahydrofuran (180 ml) was slowly added to magnesium (2.9 g, 0.12 mol) in tetrahydrofuran (20 ml) and the mixture stirred for one hour at room temperature. The solution formed was slowly added to a solution of 1-acetyl-4-piperidone (16.9 g, 0.12 mol) in tetrahydrofuran (200 ml) at -78° C., and the suspension produced was stirred to room temperature for 2 hours. Hydrochloric acid (120 ml, 1M) was added and the organic phase was separated and concentrated in vacuo. The residue was taken up in dichloromethane (300 ml), washed with water (300 ml) and dried (MgSO4). Concentration in vacuo and trituration with diethyl ether gave 1-[4-hydroxy-4-(4-methoxyphenyl)-piperidin-1-yl]ethanone (14.75 g, 50% yield) as a white solid; δH (CDCl3) 1.7-2.1 (4H, m, 2× piperidinyl CH2), 2.1 (3H, s, COCH3), 3.1 (1H, m, piperidinyl H), 3.6-3.8 (3H, m, piperidinyl H), 3.8 (3H, s, ArOCH3), 4.6 (1H, m, OH), 6.9 (2H, d, J 10 Hz, ArH), and 7.4 (2H, d, J 10 Hz, ArH).