Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:19]([NH2:21])=[O:20])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:14][C:15]([CH3:17])=[CH2:16])[C:6]=2[N:18]=1.[H][H]>C(O)C.[Pd]>[NH2:1][C:2]1[C:3]([C:19]([NH2:21])=[O:20])=[CH:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:7]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:6]=2[N:18]=1
Reactant: C=C(C)Cn1c2ccccc2c2cc(C(N)=O)c(N)nc21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)Cn1c2ccccc2c2cc(C(N)=O)c(N)nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 30.5 %

Procedure:
2-Amino-9-(2-methylprop-2-en-1-yl)-9H-pyrido[2,3-b]indole-3-carboxamide (xii-a, 143 mg) was dissolved in ethanol (40 mL) and placed under an argon atmosphere. 10% Palladium on carbon (26 mg) was added and the reaction placed under an atmosphere of hydrogen by repeated evacuation followed by back-filling using a balloon filled with hydrogen gas. The reaction stirred for 16 h at room temperature then the catalyst was removed by filtration through Celite® and the filtrate concentrated in vacuo. The residue was purified by silica gel chromatography (5% methanol in methylene chloride) to afford the title compound (44, 44 mg, 65%). NH4OAc standard conditions. DAD Retention time=7.45 min. M+H=283. 1H NMR (300 MHz, CDCl3): 8.22 (s, 1H), 7.83 (d, J=7.3 Hz, 1H), 7.30-7.36 (m, 3H), 7.21 (br s, 1H), 6.66 (br s, 1H), 5.67 (br s, 1H), 4.07 (d, J=7.3 Hz, 1H), 2.28-2.42 (m, 1H), 0.94 (d, J=6.7 Hz, 6H).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=O)[C:3]=1[C:11]([NH:13][C@@H:14]([CH3:18])[CH2:15][S:16][CH3:17])=[O:12].Cl.CN(C)CCCN1C=CN(C(N2C=CN(CC)C2)=O)C1.[F:40][C:41]([F:62])([F:61])[C:42]1[CH:43]=[C:44]([CH:54]=[C:55]([C:57]([F:60])([F:59])[F:58])[CH:56]=1)[CH2:45][C:46]1[CH:52]=[CH:51][C:49]([NH2:50])=[C:48]([CH3:53])[CH:47]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[F:40][C:41]([F:61])([F:62])[C:42]1[CH:43]=[C:44]([CH:54]=[C:55]([C:57]([F:60])([F:59])[F:58])[CH:56]=1)[CH2:45][C:46]1[CH:52]=[CH:51][C:49]([NH:50][C:5](=[O:7])[C:4]2[C:3](=[C:2]([I:1])[CH:10]=[CH:9][CH:8]=2)[C:11]([NH:13][C@@H:14]([CH3:18])[CH2:15][S:16][CH3:17])=[O:12])=[C:48]([CH3:53])[CH:47]=1
Reactant: CSC[C@H](C)NC(=O)c1c(I)cccc1C(=O)O
Reactant: Cc1cc(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc1N
Agent: CCN1C=CN(C(=O)N2C=CN(CCCN(C)C)C2)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CSC[C@H](C)NC(=O)c1c(I)cccc1C(=O)Nc1ccc(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 24 %

Procedure:
3-Iodo-N-((S)-1-methyl-2-methylthioethyl)-phthalamic acid (0.38 g) and N-(3-dimethylaminopropyl)-N′-ethylcarbonyldimidazole hydrochloride (0.2 g) were stirred in methylene chloride (10 ml) at room temperature for 30 minutes. 4-(3,5-Bis-trifluoromethyl-benzyl)-2-methylaniline (0.3 g) and p-toluenesulfonic acid hydrate (0.02 g) were added thereto and stirred at room temperature for 3 hours. After the reaction, the solvent was distilled off under reduced pressure and the resultant residue was purified by silica gel column chromatography to obtain N1-[4-(3,5-bis-trifluoromethyl-benzyl)-2-methylphenyl]-3-iodo-N2-((S)-1-methyl-2-methylthioethyl) phthalamide (0.15 g).
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:12][CH2:13][CH2:14][CH2:15][C@H:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:23]=[CH:24][C:25]3[S:30][CH2:29][C:28](=[O:31])[NH:27][C:26]=3[CH:32]=2)[CH2:17]1>>[NH2:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:12][CH2:13][CH2:14][CH2:15][C@H:16]1[O:20][C:19](=[O:21])[N:18]([C:22]2[CH:23]=[CH:24][C:25]3[S:30][CH2:29][C:28](=[O:31])[NH:27][C:26]=3[CH:32]=2)[CH2:17]1)=[O:6]
Reactant: NCCC[C@@H]1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1
Reactant: Nc1c(F)cccc1C(=O)O
Product: Nc1c(F)cccc1C(=O)NCCC[C@@H]1CN(c2ccc3c(c2)NC(=O)CS3)C(=O)O1
Yield: 56 %

Procedure:
Starting from 2-amino-3-fluorobenzoic acid and 6-[(R)-5-(3-amino-propyl)-2-oxo-oxazolidin-3-yl]-4H-benzo[1,4]thiazin-3-one (described in WO 2010/041219) and using Procedure D, the title compound was obtained as a beige solid (80 mg; 56% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]1[C:15](=[O:19])[C:16]([CH3:18])=[CH2:17])=[O:5])[CH3:2].[C:20]([OH:23])(=[S:22])[CH3:21]>>[CH2:1]([O:3][C:4]([CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]1[C:15](=[O:19])[CH:16]([CH3:18])[CH2:17][S:22][C:20](=[O:23])[CH3:21])=[O:5])[CH3:2]
Reactant: CC(O)=S
Reactant: C=C(C)C(=O)N1c2ccccc2CC1C(=O)OCC
Product: CCOC(=O)C1Cc2ccccc2N1C(=O)C(C)CSC(C)=O
Temperature: 25 °C
Reaction time: 96 h

Procedure:
The mixture of 3.0 g of 1-methacryloylindoline-2-carboxylic acid ethyl ester and 0.97 g of thioacetic acid is stirred under nitrogen at room temperature for 4 days. Traces of thioacetic acid are removed by distillation, to give the 1-(3-acetylthio-2-methylpropanoyl)-indoline-2-carboxylic acid ethyl ester, showing peaks in the NMR-spectrum at 9.45, 2.33 and 1.25 ppm. Said compound can also be prepared analogous to the method illustrated by Example 1.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[O:13]=[C:14]1[N:20]([CH:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][C@@H:30]([C:41](O)=[O:42])[CH2:31][C:32]3[CH:37]=[C:36]([CH3:38])[C:35]([OH:39])=[C:34]([CH3:40])[CH:33]=3)=[O:28])[CH2:23][CH2:22]2)[CH2:19][CH2:18][C:17]2[CH:44]=[CH:45][CH:46]=[CH:47][C:16]=2[NH:15]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>C1COCC1.CN(C=O)C.CCOC(C)=O>[O:13]=[C:14]1[N:20]([CH:21]2[CH2:22][CH2:23][N:24]([C:27]([O:29][C@H:30]([CH2:31][C:32]3[CH:33]=[C:34]([CH3:40])[C:35]([OH:39])=[C:36]([CH3:38])[CH:37]=3)[C:41](=[O:42])[N:10]3[CH2:9][CH2:8][CH:7]([C:4]4[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=4)[CH2:12][CH2:11]3)=[O:28])[CH2:25][CH2:26]2)[CH2:19][CH2:18][C:17]2[CH:44]=[CH:45][CH:46]=[CH:47][C:16]=2[NH:15]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1O
Reactant: c1cc(C2CCNCC2)ccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(c3ccncc3)CC2)cc(C)c1O
Reaction time: 2 h

Procedure:
67 mg (0.42 mmol) 1,2,3,4,5,6-hexahydro-[4,4′]bipyridinyl were added at RT to a solution of 182 mg (0.38 mmol) (R)-2-(4-hydroxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 133 mg (0.42 mmol) TBTU and 66 μL (0.47 mmol) triethylamine in 10 mL THF and 2 mL DMF and the reaction mixture was stirred for 2 h. 20 mL EtOAc were added, the organic phase was washed with 20 mL semisaturated NaHCO3 solution and dried on Na2SO4. After the elimination of the desiccant and solvent the residue was purified by HPLC. The fractions containing the product were combined, evaporated down, the residue was made alkaline with semisaturated NaHCO3 solution, extracted with 50 mL EtOAc and the organic phase was dried on Na2SO4. After the elimination of the desiccant and solvent the residue was stirred with DIPE, suction filtered and dried.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[CH:22]1([CH2:26]Br)[CH2:25][CH2:24][CH2:23]1>>[CH:22]1([CH2:26][O:1][C:2]2[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]3[C:19](=[O:20])[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:12]3=[O:21])[CH:5]=[CH:6][CH:7]=2)[CH2:25][CH2:24][CH2:23]1
Reactant: O=C1c2ccccc2C(=O)N1CCCc1cccc(O)c1
Reactant: BrCC1CCC1
Product: O=C1c2ccccc2C(=O)N1CCCc1cccc(OCC2CCC2)c1

Procedure:
Alkylation reaction of phenol 58 with cyclobutylmethyl bromide gave 2-(3-(3-(cyclobutylmethoxy)phenyl)propyl)isoindoline-1,3-dione as yellow oil. Yield (0.430 g, 34%): 1H NMR (400 MHz, CDCl3) δ 7.82-7.84 (m, 2H), 7.69-7.71 (m, 2H), 7.11-7.16 (m, 1H), 6.73-6.78 (m, 2H), 6.66 (dd, J=7.6, 2.4 Hz, 1H), 3.88 (d, J=6.4 Hz, 2H), 3.75 (t, J=7.2 Hz, 2H), 2.70-2.79 (m, 1H), 2.66 (t, J=8.0 Hz, 2H), 2.10-2.17 (m, 2H), 2.00-2.07 (m, 2H), 1.82-1.98 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14](=[NH:16])[NH2:15])=[N:6]1.[C:21]([CH:23](/[N:29]=[N:30]/[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:24](OCC)=[O:25])#[N:22]>>[NH2:22][C:21]1[N:15]=[C:14]([C:7]2[C:8]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[N:5]([CH2:4][C:3]3[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=3[F:1])[N:6]=2)[N:16]=[C:24]([OH:25])[C:23]=1/[N:29]=[N:30]/[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCOC(=O)C(C#N)/N=N/c1ccccc1
Reactant: N=C(N)c1nn(Cc2ccccc2F)c2ncccc12
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc(O)c1/N=N/c1ccccc1
Temperature: 25 °C

Procedure:
2.43 g (9.02 mmol) of 1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide from example I and ethyl cyano[(E)-phenyldiazenyl]acetate (1.96 g, 9.02 mmol) were heated under reflux for 12 h. After cooling to room temperature, the precipitate which had separated out was filtered off and washed several times with toluene. Flash chromatography (CH2Cl2/ethyl acetate 50:1→EA) afforded the desired product.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[C:12]1([C:18]2[C:19]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[C:20]3[CH:26]=[CH:25][NH:24][C:21]3=[N:22][CH:23]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:33]([O:37][C:38]([N:40]1[CH2:44][CH2:43][CH2:42][C@H:41]1[C@H:45]([C:49]1[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][CH:50]=1)[C:46](O)=[O:47])=[O:39])([CH3:36])([CH3:35])[CH3:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[Cl:55][C:52]1[CH:51]=[CH:50][C:49]([C@@H:45]([C@@H:41]2[CH2:42][CH2:43][CH2:44][N:40]2[C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:39])[C:46](=[O:47])[N:30]2[CH2:29][CH2:28][N:27]([C:19]3[C:18]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[CH:23][N:22]=[C:21]4[NH:24][CH:25]=[CH:26][C:20]=34)[CH2:32][CH2:31]2)=[CH:54][CH:53]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1[C@@H](C(=O)O)c1ccc(Cl)cc1
Reactant: c1ccc(-c2cnc3[nH]ccc3c2N2CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H]1[C@@H](C(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
DIEA (0.103 mL, 0.592 mmol) was added to 5-phenyl-4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine dihydrochloride (0.052 g, 0.15 mmol, see Example 19), (S)-2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-2-(4-chlorophenyl)acetic acid (0.0503 g, 0.148 mmol, see Example F) and TBTU (0.0570 g, 0.178 mmol) in DCM (1 mL) and stirred at room temperature for 1 hour. The mixture was directly loaded onto a column and purified by chromatography (1:1 hexane:ethyl acetate) to give (S)-tert-butyl 2-((S)-1-(4-chlorophenyl)-2-oxo-2-(4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)ethyl)pyrrolidine-1-carboxylate as a solid. The solid was then dissolved in DCM (1 mL), and TFA (0.2 mL) was added. The mixture was stirred at room temperature for 1 hour. The solvent was removed. The residue was dissolved in DCM (0.5 mL), and 2M HCl in ether (1 mL) was added. The resulting solid was collected by filtration to give (S)-2-(4-chlorophenyl)-1-(4-(5-phenyl-1H-pyrrolo[2,3-b]pyri din-4-yl)piperazin-1-yl)-2-((S)-pyrrolidin-2-yl)ethanone dihydrochloride (0.062 g, 63%). MS ESI (+) m/z 500 detected.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:9])=[C:4](Cl)[CH:5]=[CH:6][CH:7]=1.[SH-:10].[Na+]>N.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[Cl:1][C:2]1[C:3]([Cl:9])=[C:4]([SH:10])[CH:5]=[CH:6][CH:7]=1
Reactant: [SH-]
Reactant: Clc1cccc(Cl)c1Cl
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: N
Product: Sc1cccc(Cl)c1Cl

Procedure:
The method in which trichlorobenzene and sodium hydrosulfide are reacted at 125° C. under increased pressure in liquid ammonia solvent in the presence of copper acetate catalyst for 10 hours to yield dichlorothiophenol, which is then reacted with sodium monochloroacetate to yield dichlorophenylthioglycolic acid with a yield of 14 to 29% [Kogyo Kagaku Zasshi, 70, 1384 (1967)].
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:10])[NH2:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:11][C:12]([C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][N:15]=1)=O>C(O)(=O)C>[C:8]([C:7]1[C:2]2[N:1]=[C:12]([C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][N:15]=3)[NH:11][C:3]=2[CH:4]=[CH:5][CH:6]=1)(=[O:10])[NH2:9]
Reactant: COC(=O)c1ccc(C(=O)Nc2cccc(C(N)=O)c2N)nc1
Solvent: CC(=O)O
Product: COC(=O)c1ccc(-c2nc3c(C(N)=O)cccc3[nH]2)nc1
Reaction time: 0.5 h

Procedure:
The crude product from EXAMPLE 51A in acetic acid (40 ml) was heated to 90° C. for 1.5 hours. After cooling, the suspension was filtered. The filter cake was washed with acetic acid, and stirred in saturated NaHCO3 for 30 minutes. The solid was filtered, washed with water and ether, and dried under vacuum to provide the title compound as an off-white solid. MS (DCI/NH3) m/z: 297.1 (M+H)+.
Reaction SMILES: [CH:1]1([C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[N:15]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[N:15]1([NH:21][C:12]([C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[N:11]=2)=[O:14])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NN1CCCCC1
Reactant: O=C(O)c1cccc(C2CCCC2)n1
Product: O=C(NN1CCCCC1)c1cccc(C2CCCC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopentyl-pyridine-2-carboxylic acid and 1-piperidinamine (CAN 2213-43-6) as starting materials, MS (EI): m/e=274.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][C:10]2[C:13](Br)=[CH:14][S:15][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Zn](C)[CH3:18]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH2:11][C:10]2[C:13]([CH3:18])=[CH:14][S:15][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCc2scc(Br)c2CC1
Reactant: C[Zn]C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Product: CCOC(=O)N1CCc2scc(C)c2CC1
Temperature: 100 °C

Procedure:
The product of step (f) (375 mg, 1.23 mmol) was dissolved in 4 mL dioxane and treated with Me2Zn (1.25 mL of 2M in toluene) and Pd(dppf)2Cl2. After heating to 100° C. for 3 h, the reaction was cooled, quenched with water, filtered through silica gel (washing with EtOAc), and concentrated to give 337 mg of the sub-title compound as an oil.
Reaction SMILES: [OH:1][C@H:2]([C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)[CH2:3][NH:4][CH2:5][C@H:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:16]3[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=3[C:18]([O:20]C)=[O:19])[CH:12]=2)[O:7]1.[Li+].[OH-]>C1COCC1.CO.O>[OH:1][C@H:2]([C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)[CH2:3][NH:4][CH2:5][C@H:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:16]3[CH:25]=[CH:24][CH:23]=[CH:22][C:17]=3[C:18]([OH:20])=[O:19])[CH:12]=2)[O:7]1
Reactant: COC(=O)c1ccccc1-c1ccc2c(c1)CC[C@H](CNC[C@H](O)c1cccnc1)O2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccccc1-c1ccc2c(c1)CC[C@H](CNC[C@H](O)c1cccnc1)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.9 %

Procedure:
To a solution of methyl 2-[(2R)-2-({[(2R)-2-hydroxy-2-(3-pyridinyl)ethyl]amino}-methyl)-3,4-dihydro-2H-chromen-6-yl]benzoate (Example 83, 60 mg, 0.143 mmol) in THF (0.50 mL) and MeOH (0.50 mL) was added LiOH (1.0 mL of a 2.0 M aq solution), and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with 1.0 mL H2O and purified via preparative HPLC (gradient of 100:0 0.1% TFA/H2O:acetonitrile to 30:70 0.1% TFA/H2O:acetonitrile). The peak of interest was collected and concentrated in vacuo to provide 41 mg of desired final product as a bis-trifluoroacetic acid (TFA) salt; 1H NMR (DMSO-d6, δ): 1.68-1.80 (m, 1 H), 2.04-2.18 (m, 1 H), 2.72-2.90 (m, 2 H), 3.22-3.50 (m, 4 H), 4.58 (dd, 1 H), 5.41 (d, 1 H), 6.82 (d, 1 H), 7.02 (d, 1 H), 7.04 (s, 1 H), 7.30-7.40 (m, 2 H), 7.50 (t, 1 H), 7.62 (d, 1 H), 8.01 (t, 1 H), 8.58 (d, 1 H), 8.82 (d, 1 H), 8.90 (s, 1 H), 9.44 (bs, 1 H), 9.64 (bs, 1 H) MS: m/z=415.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[NH:18]1[CH:22]=[CH:21][CH:20]=[CH:19]1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.C(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:18]1[CH:22]=[CH:21][CH:20]=[CH:19]1)=[O:6]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Cl
Reactant: c1cc[nH]c1
Agent: CN(C)c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(c1cccc([N+](=O)[O-])c1Cl)n1cccc1
Reaction time: 6 h
Yield: 97 %

Procedure:
2-Chloro-3-nitrobenzoic acid (2 g, 10.0 mmol) and thionyl chloride (30 ml) were mixed at room temperature, and 4-dimethylaminopyridine (122 mg, 1.00 mmol) was added. The reaction mixture was refluxed for 12 hours and then concentrated to give a crude acid chloride. The acid chloride mentioned above was added to a solution of pyrrole (3.5 ml, 50.0 mmol) and triethylamine (7.0 ml, 50.0 mmol) in methylene chloride (80 ml) at room temperature. The reaction mixture was stirred at the same temperature for 6 hours and diluted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, filtered, and concentrated to give a crude compound. The crude compound was purified by silica gel column chromatography (hexane:ethyl acetate, 1: 0–7:3) to give the title compound (2.43 g) as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]#[N:10])=[CH:4][N:3]=1.[ClH:11]>C(O)C.CO.[Pd]>[ClH:11].[ClH:11].[NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH2:9][NH2:10])=[CH:4][N:3]=1
Reactant: Cc1cc(N)ncc1C#N
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CO
Product: Cc1cc(N)ncc1CN

Procedure:
A solution of 2-amino-5-cyano-4-methylpyridine (200 mg, 1.50 mmol) in a mixture of ethanol (17 mL) and methanol (7 mL) was hydrogenated for 48 h at atmospheric pressure in the presence of 1N hydrochloric acid (3 mL) and 10% palladium-on-charcoal (50 mg). The catalyst was removed by filtration through Celite, the filter washed with methanol, and the combined filtrate and washings evaporated. Crystallization from chloroform-methanol afforded pure title compound; yield 98 mg (31%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22](I)[CH:23]=3)[N:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C([SiH](CCCCCC)CCCCCC)CCCCC.[C]=O.CN([CH:57]=[O:58])C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([CH:57]=[O:58])[CH:23]=3)[N:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccnc3ccc(I)cc23)CC1
Reactant: CN(C)C=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCCC[SiH](CCCCCC)CCCCCC
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccnc3ccc(C=O)cc23)CC1

Procedure:
The similar procedure as described in Example 10b was used, starting from 4-(6-iodo-quinolin-4-yloxy)-piperidine-1-carboxylic acid tert-butyl ester (example 48a), diphenylpropyl phsophine, palladium acetate, triethyl amine, and trihexylsilane in anhydrous DMF (25 ml) was charged with carbon monoxide at 75 psi to give 4-(6-formyl-quinolin-4-yloxy)-piperidine-1-carboxylic acid tert-butyl ester. LC-MS m/e 357 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[C:12]([C:16]1[CH:21]=[CH:20][C:19](Br)=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13].CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1>[C:12]([C:16]1[CH:21]=[CH:20][C:19]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:11]=2[NH:10][CH2:9][CH2:8][CH2:7]3)=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: Nc1cccc2cccnc12
Reactant: CC(C)(C)c1ccc(Br)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1ccc(Nc2cccc3c2NCCC3)cc1
Temperature: 25 °C
Yield: 82 %

Procedure:
To a flask equipped with a magnetic stirrer, reflux condenser, and nitrogen inlet was added 8-aminoquinoline (14.4 grams, 0.10 moles), 4-tert-butyl bromobenzene (21.3 grams, 0.10 moles), tris(dibenzylideneacetone)dipalladium (0) (1.8 grams, 0.002 moles), rac-2,2′-bis(diphenylphosphino)-1,1′-binapthyl (2.5 grams, 0.004 moles), sodium tert-butoxide (19.4 grams, 0.20 moles) and anhydrous toluene (150 mL). The contents of the flask were refluxed for four days; cooled to room temperature; and filtered through a pad of silica gel. The silica gel pad was then eluted with dichloromethane (240 mL). The combined organic layers were concentrated in vacuo to yield a dark blue solid. The solid was chromatographed on silica gel, eluting with hexane/ethyl acetate (20:1) to afford 23 grams of the desired product as a yellow solid. 1H NMR (CDCl3) δ 8.8 (m, 1H), 8.2 (bs, 1H), 8.1 (d, 1H), 7.1-7.5 (m, 9H), 1.35 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C@H:8]([NH:10][C:11](=[O:22])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH3:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[N:29]1[CH:34]=[CH:33][CH:32]=[C:31](B(O)O)[CH:30]=1>COCCOC.O.[Pd]>[N:6]1[C:5]([C@H:8]([NH:10][C:11](=[O:22])[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][CH:14]=2)[CH3:9])=[CH:4][CH:3]=[C:2]([C:31]2[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=2)[CH:7]=1
Reactant: OB(O)c1cccnc1
Reactant: CC(C)c1ccc(CC(=O)N[C@H](C)c2ccc(Br)cn2)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)c1ccc(CC(=O)N[C@H](C)c2ccc(-c3cccnc3)cn2)cc1
Temperature: 100 °C

Procedure:
To a mixture of N-[(1R)-1-(5-bromopyridin-2-yl)ethyl]-2-(4-isopropylphenyl)-acetamide (40 mg, 0.11 mmol), tetrakis(triphenyl)phosphine)palladium (0) (1.3 mg, 0.01 mmol), sodium carbonate (22 mg, 0.20 mmol) in DME/water (4:1, 3.0 ml) was added 3-pyridyl boronic acid (19 mg, 0.16 mmol). The reaction was heated for ten minutes in the Smith Personal microwave system at 100° C. and then washed with brine. Organics were extracted with EtOAc and dried over Na2SO4, filtered and concentrated in vacuo to give a red oily solid. Reverse phase prep HPLC chromatography afforded the mono-trifluoroacetate salt of N-[(1R)-1-(3,3′-bipyridin-6-yl)ethyl]-2-(4-isopropylphenyl)acetamide as an oil. 1H NMR (CD3OD, 400 MHz) δ 9.18 (s, 1H); 8.95 (s, 1H); 8.84 (d, J=4.80 Hz, 1H); 8.78 (dd, J=1.20 Hz and 6.40 Hz, 1H); 8.29 (dd, J=2.40 and 8.40 Hz, 1H); 8.06 (dd, J=5.20 and 8.20 Hz, 1H); 7.61 (d, J=8.40 Hz, 1H); 7.19 (m, 4H); 5.10 (q, J=6.80 Hz, 1H); 3.55 (s, 2H); 2.86 (m, 1H); 1.55 (d, J=7.20 Hz, 3H); 1.21 (d, J=6.80 Hz, 6H); HRMS (ES) exact mass calcd for C23, H25, N3O: 360.2071, Found: 360.2070
Reaction SMILES: Br[C:2]1[N:3]([CH2:10][CH:11]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([I:22])=[CH:18][CH:17]=2)[CH2:12][OH:13])[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[H-].[Na+]>>[I:22][C:19]1[CH:20]=[CH:21][C:16]([O:15][CH2:14][CH:11]2[CH2:12][O:13][C:2]3=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]3[CH2:10]2)=[CH:17][CH:18]=1
Reactant: O=[N+]([O-])c1cn(CC(CO)COc2ccc(I)cc2)c(Br)n1
Agent: [H-]
Agent: [Na+]
Product: O=[N+]([O-])c1cn2c(n1)OCC(COc1ccc(I)cc1)C2
Yield: 78 %

Procedure:
Ring closure of alcohol 175 with NaH as in Example 2GGG for 5 h, followed by chromatography of the product on silica gel, eluting with 0-1% EtOAc/CH2Cl2 (foreruns) and then with 1.5-2% EtOAc/CH2Cl2, gave 6-[(4-iodophenoxy)methyl]-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (176) (78%) as a pale yellow solid: mp (CH2Cl2/pentane triturate) 239-240° C.; 1H NMR [(CD3)2SO] δ 8.09 (s, 1H), 7.60 (dt, J=9.0, 2.7 Hz, 2H), 6.82 (dt, J=9.0, 2.7 Hz, 2H), 4.59 (dd, J=10.9, 2.9 Hz, 1H), 4.44 (dd, J=11.0, 7.2 Hz, 1H), 4.28 (dd, J=12.5, 5.4 Hz, 1H), 4.09 (dd. J=10.0, 6.7 Hz, 1H), 4.06 (dd, J=10.0, 6.7 Hz, 1H), 4.03 (dd, J=12.5, 7.0 Hz, 1H), 2.82 (m, 1H). Anal. (C13H12IN3O4) C, H, N.