Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[CH:7]1([NH:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>C1C=CC=CC=1>[CH:14]1([N:13]([CH:7]2[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]2)[CH2:2][C:3]([O:5][CH3:6])=[O:4])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: COC(=O)CBr
Reactant: C1CCC(NC2CCCCC2)CC1
Solvent: c1ccccc1
Product: COC(=O)CN(C1CCCCC1)C1CCCCC1
Yield: 100 %

Procedure:
3.06 g (20 mmole) of methyl bromoacetate were added, whilst ice-cooling, to a solution of 7.25 g (40 mmole) of N,N-dicyclohexylamine in 50 ml of dry benzene, and the mixture was heated under reflux for 9 hours. At the end of this time, the reaction mixture was cooled, the precipitated materials were removed by filtration, and the filtrate was concentrated by evaporation under reduced pressure, to afford 5.07 g of the title compound as an oily substance.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:23])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Cl:22])=[N:10]2)=[C:4]([C:24]([F:27])([F:26])[F:25])[CH:3]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(P([CH:49]2[CH2:54][CH2:53]CCC2)C2CCCCC2)CCCCC1.C1(B(O)O)CC1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:15]([NH:14][C:11]1[CH:12]=[CH:13][N:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([CH:53]3[CH2:54][CH2:49]3)=[CH:3][C:4]=2[C:24]([F:27])([F:26])[F:25])[N:10]=1)=[O:23]
Reactant: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Reactant: O=C(Nc1ccn(Cc2ccc(I)cc2C(F)(F)F)n1)c1ccccc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(Nc1ccn(Cc2ccc(C3CC3)cc2C(F)(F)F)n1)c1ccccc1Cl
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a mixture of N-(1-{[4-iodo-2-(trifluoromethyl)phenyl]methyl}-1H-pyrazol-3-yl)-2-chlorobenzamide (for a preparation see Example 95)(30 mg, 0.059 mmol) was added potassium phosphate tribasic (38 mg, 0.179 mmol, Aldrich), tricyclohexyl phosphine (5 mg, 0.018 mmol, Aldrich), cyclopropyl boronic acid (16 mg, 0.186 mmol, Fluorochem) in toluene (2 ml). Water (0.1 ml) was added followed by palladium (II) acetate (4 mg, 0.018 mmol, ABCR). The resulting yellow suspension was heated to 100° C. and stirred under nitrogen overnight. The reaction mixture was partitioned between DCM (10 ml) and water (10 ml). The phases were separated using a hydrophobic frit and the aqueous layer was washed with DCM (10 ml). The organic layers were combined and the solvent removed in vacuo. The residue was dissolved in 1:1 MeOH:DMSO (1 ml) and purified by MDAP on Sunfire C18 column (Method B) using Acetonitrile-Water with a Formic acid modifier. The solvent was evaporated in vacuo to give the title compound as a yellow gum (6 mg); LCMS: (System 4) MH+=420, tRET=3.22 min.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:19]2[CH2:22][CH2:21][CH2:20]2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.IC.[C:25](=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:19]2[CH2:22][CH2:21][CH2:20]2)[CH2:9][C:10]([C:12]2[CH:13]=[CH:14][C:15](=[O:18])[N:16]([CH3:25])[CH:17]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(CC(c1ccc(Br)cc1)C1CCC1)c1ccc(=O)[nH]c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: Cn1cc(C(=O)CC(c2ccc(Br)cc2)C2CCC2)ccc1=O

Procedure:
In analogy to example 161, step 1, 5-[3-(4-bromo-phenyl)-3-cyclobutyl-propionyl]-1H-pyridin-2-one was reacted with iodomethane in the presence of potassium carbonate to give the title compound as a light yellow oil, MS (ESI+): m/z=374.1 [M+H]+.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:5]=[N:6][CH:7]=[N:8][CH:9]=1.[C:11]([C:13]1[CH:14]=[C:15]([F:21])[C:16]([F:20])=[C:17]([F:19])[CH:18]=1)#[CH:12].N>>[N:6]1[CH:5]=[C:4]([C:3]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]([F:21])[C:16]([F:20])=[C:17]([F:19])[CH:18]=3)[O:1][N:2]=2)[CH:9]=[N:8][CH:7]=1
Reactant: ON=C(Cl)c1cncnc1
Reactant: C#Cc1cc(F)c(F)c(F)c1
Agent: N
Product: Fc1cc(-c2cc(-c3cncnc3)no2)cc(F)c1F

Procedure:
The titled compound was prepared as the hydrochloride salt according to Method CB using the product of Example 44B (79 mg, 0.5 mmol) and 5-ethynyl-1,2,3-trifluorobenzene (Apollo, 78 mg, 0.5 mmol). 1H NMR (300 MHz, DMSO-d6) δ 7.88 (s, 1H), 7.95 (dd, J=8.6, 6.6 Hz, 2H), 9.29 (s, 2H), 9.36 (s, 1H) ppm; MS (DCI/NH3) m/z 278 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH:18]([C:19]([NH2:21])=[O:20])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:22])[NH:10]1.[N+]([NH:26][C:27]([NH2:29])=[O:28])([O-])=O>C(O)C>[CH2:11]([O:22][NH:21][C:19]([CH:18]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:22])[N:10]([CH:3]2[CH2:2][CH2:7][CH2:6][CH2:5][CH:4]2[NH:26][C:27](=[O:28])[NH2:29])[CH:9]1[C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NC(=O)C1c2ccccc2C(=O)NC1c1ccc(Cl)cc1Cl
Reactant: NC(=O)N[N+](=O)[O-]
Solvent: CCO
Product: NC(=O)NC1CCCCC1N1C(=O)c2ccccc2C(C(=O)NOCc2ccccc2)C1c1ccc(Cl)cc1Cl

Procedure:
To a mixed liquid of 269 mg of (3RS,4RS)-2-[(1SR,2SR)-2-aminocyclohexyl]-Nenzyloxy)-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide and 20 ml of ethanol was added 53 mg of nitrourea, followed by heating under reflux for 1 hour. The reaction solution was cooled and then concentrated, and the residue was purified by silica gel column chromatography (eluent:chloroform-methanol), then crystallized with acetonitrile, and collected by filtration to obtain 155 mg of (3RS,4RS)—N-(benzyloxy)-2-[(1SR,2SR)-2-(carbamoylamino)cyclohexyl]-3-(2,4-dichlorophenyl)-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a white crystal.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:19]=[CH:20][CH:21]=2)[CH2:11][CH2:12][O:13][CH2:14][CH2:15][C:16]([OH:18])=O)[CH:5]=[N:4]1)[CH3:2].[CH3:22][O:23][CH:24]([O:32][CH3:33])[CH2:25][NH:26][CH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH:27]1([N:26]([CH2:25][CH:24]([O:32][CH3:33])[O:23][CH3:22])[C:16](=[O:18])[CH2:15][CH2:14][O:13][CH2:12][CH2:11][C:10]2[CH:19]=[CH:20][CH:21]=[C:8]([C:6]3[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[CH:7]=3)[CH:9]=2)[CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: COC(CNC1CCCC1)OC
Reactant: CCn1cc(-c2cccc(CCOCCC(=O)O)c2)cn1
Product: CCn1cc(-c2cccc(CCOCCC(=O)N(CC(OC)OC)C3CCCC3)c2)cn1

Procedure:
The subtitled compound (138 mg) was prepared from 3-(3-(1-ethyl-1H-pyrazol-4-yl)phenethoxy)propanoic acid [Example 23 Step ii)] and N-(2,2-dimethoxyethyl)cyclopentanamine [Preparation 9] using a similar method to that described in Example 18, Step iii), extending the reaction time to 1 h. MS [M+H-MeOH]+=412 (MultiMode+) 1H NMR (400 MHz, CD3OD) δ 7.97 (s, 1H), 7.79 (s, 1H), 7.40 (s, 1H), 7.35 (d, J=7.5 Hz, 1H), 7.23 (t, J=7.5 Hz, 1H), 7.05 (d, J=7.7 Hz, 1H), 4.56 and 4.37 (2×t, J=5.1 Hz, 1H), 4.26-4.16 (m, 1H), 4.19 (q, J=7.4 Hz, 2H), 3.75-3.64 (m, 4H), 3.35 and 3.22 (2×d, J=4.9 Hz, 2H), 3.34 (s, 3H), 3.32 (s, 3H), 2.84 (t, J=6.8 Hz, 2H), 2.65 (t, J=6.3 Hz, 2H), 1.82-1.44 (m, 8H), 1.47 (t, J=7.3 Hz, 3H); a ˜1:1 mixture of rotamers is observed.
Reaction SMILES: [C:1]1([C:7]2[C:16]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[CH2:19][CH2:18]3)=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:29]([O:31]C)=[O:30])[CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>CO>[C:1]1([C:7]2[C:16]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[CH2:19][CH2:18]3)=[N:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:29]([OH:31])=[O:30])[CH:13]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)c(N3CCN(c4ccccn4)CC3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc2nc(-c3ccccc3)c(N3CCN(c4ccccn4)CC3)nc2c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 81 %

Procedure:
A solution of methyl 2-phenyl-3-(4-(pyridin-2-yl)piperazin-1-yl)quinoxaline-6-carboxylate (100 mg, 0.24 mmol, 1.00 equiv) and sodium hydroxide (47 mg, 1.18 mmol, 5.00 equiv) in methanol (10 mL) was placed in a 100-mL round bottom flask and stirred for 2 h at 50° C. in an oil bath. The pH of the solution was adjusted to 4-5 with hydrochloric acid (1 M), followed by extractions with 3×10 mL of dichloromethane. The organic layers were combined and concentrated under vacuum yielding 80 mg (83%) of 2-phenyl-3-(4-(pyridin-2-yl)piperazin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid.
Reaction SMILES: [CH3:1][S:2][CH2:3][C@@H:4]([C:6]([OH:8])=[O:7])[NH2:5].C(N(CC)CC)C.F[C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=1[N+:24]([O-:26])=[O:25]>O.CC(C)=O>[F:23][C:21]1[CH:20]=[CH:19][C:18]([N+:24]([O-:26])=[O:25])=[C:17]([NH:5][C@H:4]([C:6]([OH:8])=[O:7])[CH2:3][S:2][CH3:1])[CH:22]=1
Reactant: CSC[C@H](N)C(=O)O
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC(C)=O
Product: CSC[C@H](Nc1cc(F)ccc1[N+](=O)[O-])C(=O)O

Procedure:
16.2 g of (-)-S-Methyl-L-cysteine (0.1 mol) are suspended in a mixture of 120 ml of water and 120 ml of acetone in a four-necked flask under N2. 30.4 ml (22.2 g) of triethylamine (0.22 mol) are added rapidly while stirring. 15.9 g of 2,4-difluoronitrobenzene (0.1 mol) are added, with further stirring, to the resulting yellow solution. The mixture is heated to reflux for 7.5 hours while stirring (orange-colored solution) and the acetone is then stripped off under reduced pressure on a rotary evaporator; the aqueous residue is transferred to a separating funnel and extracted 2× with approximately 50 ml of methyl tert-butyl ether (MTB ether). This extract is composed, in the main, of 2,4-difluoronitrobenzene and is discarded. The aqueous phase is transferred to a four-necked flask and 150 ml of MTB ether are added to it, after which the mixture is adjusted, while being cooled (<25° C.), to pH 1 with approximately 25 ml of 38% sulfuric acid. The mixture is then stirred thoroughly until clear phases are formed. The ether phase is separated off and the aqueous phase is extracted once again with 50 ml of MTB ether. The extracts are dried over sodium sulfate and evaporated on a rotary evaporator. The yield comprises 27 g of a yellow oil which soon solidifies. M.p. 147° (from water/methanol).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([NH:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)=[O:4].Br[CH2:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl>CC(C)=O>[CH3:20][C:19]([CH3:22])([CH3:21])[C:18](=[O:23])[CH2:17][O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][NH:5][C:3](=[O:4])[C:2]([F:14])([F:15])[F:1])=[CH:8][CH:9]=1
Reactant: O=C(NCc1ccc(O)cc1)C(F)(F)F
Reactant: CC(C)(C)C(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Product: CC(C)(C)C(=O)COc1ccc(CNC(=O)C(F)(F)F)cc1

Procedure:
Mix 2,2,2-trifluoro-N-(4-hydroxy-benzyl)-acetamide (438 mg, 2.0 mmol), 1-bromopinacolone (430 mg, 2.4 mmol), anhydrous potassium carbonate (829 mg, 6.0 mmol) and potassium iodide (33 mg, 0.1 mmol) with acetone. Heat under reflux for 12 h. Acidify with 1N aqueous HCl and extract with EtOAc three times. Combine the organic extracts, wash with brine, dry over Na2SO4, filter and concentrate. Purify by chromatography on silica gel eluting with EtOAc/hexane (1:3) to give the desired intermediate as a colorless oil. MS (ES+) m/z: 335 (M+NH4)+. MS (ES−) m/z: 316 (M−H)−.
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:28][C:13]3=[N:14][CH:15]=[C:16]([O:18][CH:19]4[CH2:24][CH2:23][N:22]([CH:25]([CH3:27])[CH3:26])[CH2:21][CH2:20]4)[CH:17]=[C:12]3[CH:11]=2)=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].[CH3:32][S:33](Cl)(=[O:35])=[O:34]>CN(C=O)C>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:28]([S:33]([CH3:32])(=[O:35])=[O:34])[C:13]3=[N:14][CH:15]=[C:16]([O:18][CH:19]4[CH2:20][CH2:21][N:22]([CH:25]([CH3:27])[CH3:26])[CH2:23][CH2:24]4)[CH:17]=[C:12]3[CH:11]=2)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCC(Oc2cnc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1CCC(Oc2cnc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3S(C)(=O)=O)CC1
Temperature: 70 °C
Yield: 44 %

Procedure:
The suspension of 0.25 g (0.6 mmol) (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-pyrrolo[2,3-b]pyridin-2-yl]-methanone (example 13) and 30 mg (0.68 mmol; 55% dispersion in mineral oil) sodium hydride in 3 ml DMF was heated to 70° C. To the resulting solution 53 μl (77 mg, 0.67 mmol) methanesulfonyl chloride were added. After 1.5 h the heating bath was removed and the solution was poured on water and was extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The crude product was purified by flash-chromatography on silica gel with dichloromethane:methanol:ammonia (9:1:0.1 v/v) to give 13 mg (44%) of the product as a light brown foam.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[OH:12][CH:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1>C(Cl)Cl.C(OCC)C>[O:12]=[C:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(=O)C1
Reaction time: 18 h

Procedure:
To a solution of pyridinium chlorochromate (3.21 g, 0.0149 mol) in methylene chloride (18 mL) was added another solution of tert-butyl 3-hydroxypiperidine-1-carboxylate (1.00 g, 0.00497 mol) in 7 mL methylene chloride at rt. After stirring for 18 h, the reaction mixture was diluted with diethyl ether, filtered through a bed of celite, concentrated in-vacuo, and then purified by Combiflash to afford the desired product verified by NMR.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][CH:28]=[C:4]2[N:3]1[CH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.C([Sn](=O)CCCC)CCC.[N:45]([Si](C)(C)C)=[N+:46]=[N-:47].C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH2:23]([C:6]1[N:5]2[N:26]=[CH:27][CH:28]=[C:4]2[N:3]([CH:29]2[CH2:30][CH2:31][O:32][CH2:33][CH2:34]2)[C:2](=[O:1])[C:7]=1[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]2[NH:47][N:46]=[N:45][N:22]=2)=[CH:11][CH:10]=1)[CH2:24][CH3:25]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCOCC2)c2ccnn12
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=O)n(C2CCOCC2)c2ccnn12
Temperature: 110 °C
Reaction time: 48 h
Yield: 41.5 %

Procedure:
A mixture of 4′-{[5-oxo-7-propyl-4-(tetrahydro-2H-pyran-4-yl)-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.33 g), dibutyltin oxide (0.083 g), azidotrimethylsilane (2.3 g) and toluene (20 mL) was stirred at 110° C. for 48 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.15 g, 46%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[C:12]#[N:13])[CH2:4][CH2:3]1>N.CO.[Ni]>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=2)[CH2:12][NH2:13])[CH2:4][CH2:3]1
Reactant: CN1CCC(Oc2cccc(C#N)c2)CC1
Agent: [Ni]
Agent: N
Solvent: CO
Product: CN1CCC(Oc2cccc(CN)c2)CC1

Procedure:
3-(1-Methyl-piperidin-4-yloxy)-benzonitrile (1.20 g, 5.55 mmol) was dissolved (0.05 M) in NH3 in MeOH (111 ml). Hydrogenation was performed using a Raney-Ni 30×4 mm CatCart (H-Cube, 50 bar, 50° C., 1 ml/min). Evaporation in vacuo yielded a light orange oil. Yield: 1.16 g (95%). 1H NMR (400 MHz, CDCl3) δ 7.25-7.17 (m, 1H), 8-6.83 (m, 2H), 6.78-6.73 (dd, J=7.67 Hz, J=2.05 Hz), 4.32 (m, 1H), 3.80 (s, 2H), δ 2.69 (m, 2H), 2.36-2.25 (m, 5H), 2.05-1.95 (m, 2H), 1.88-1.72 (m, 4H). MS (ESI+) 221.1 (M+1H+).
Reaction SMILES: [NH:1]1[C:7](=O)[CH2:6][CH2:5][CH2:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2
Reactant: O=C1CCCc2ccccc2N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc2c(c1)CCCCN2
Temperature: 0 °C
Yield: 84.9 %

Procedure:
To a solution of 1,3,4,5-tetrahydrobenzo[b]azepin-2-one (12.9 g, 80.0 mmol) in 720 mL of tetrahydrofuran was added 80 mL of lithium aluminum hydride (1 M solution in tetrahydrofuran). The reaction mixture was stirred at reflux for 3 hours and cooled to 0° C. The reaction was quenched by the sequential addition of 3 mL of water, 3 mL of 15% sodium hydroxide, and 9 mL of water. The mixture was filtered through Celite and the filter cake rinsed with ethyl acetate. The filtrate was concentrated under reduced pressure to provide 10.0 g (85%) of the desired compound as an orange solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[CH:25]=[C:24]3[C:19]([C:20]([O:26][C:27]4[C:28]([F:37])=[C:29]5[C:33](=[CH:34][CH:35]=4)[NH:32][C:31]([CH3:36])=[CH:30]5)=[CH:21][N:22]=[N:23]3)=[CH:18][C:17]=2[O:38][CH3:39])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:37][C:28]1[C:27]([O:26][C:20]2[C:19]3[C:24](=[CH:25][C:16]([O:15][CH2:14][CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)=[C:17]([O:38][CH3:39])[CH:18]=3)[N:23]=[N:22][CH:21]=2)=[CH:35][CH:34]=[C:33]2[C:29]=1[CH:30]=[C:31]([CH3:36])[NH:32]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)cnnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)cnnc2cc1OCC1CCNCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.6 %

Procedure:
A solution of 7-(1-(tert-butoxycarbonyl)piperidin-4-ylmethoxy)-4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxycinnoline (100 mg, 0.186 mmol) in methylene chloride (3 ml) containing TFA (1 ml) was stirred at ambient temperature for 2 hours. The volatiles were removed under vacuum. The residue was partitioned between water and methylene chloride and the pH of the aqueous layer was adjusted to 13 with 6N aqueous sodium hydroxide. The organic layer was separated, washed with water, brine, dried (MgSO4) and evaporated. The residue was triturated with ether/pentane (1/1). The solid was filtered, washed with pentane and dried under vacuum to give 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(piperidin-4-ylmethoxy)cinnoline (50 mg, 62%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][CH:8]2[CH2:13][CH:12]([C:14]([OH:16])=[O:15])[CH2:11][CH2:10][NH:9]2)=[CH:5][CH:4]=1.Cl.[C:20]([O-])(O)=O.[Na+]>>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8]2[CH2:13][CH:12]([C:14]([O:16][CH3:20])=[O:15])[CH2:11][CH2:10][NH:9]2)=[CH:17][CH:18]=1
Reactant: O=C([O-])O
Reactant: O=C(O)C1CCNC(Cc2ccc(Cl)cc2)C1
Agent: Cl
Agent: [Na+]
Product: COC(=O)C1CCNC(Cc2ccc(Cl)cc2)C1
Yield: 87 %

Procedure:
To crude 2-(4-chlorobenzyl)piperidine-4-carboxylic acid hydrochloride (5.34 g, 20.9 mmol) was added HCl (1.25 M in MeOH, 60 mL). The resulting suspension was refluxed for 2 h and then concentrated to give a slightly yellow solid. The residue was taken up in satd NaHCO3 (100 mL). The aqueous phase was extracted with DCM (×3), the combined organic layers dried with a phase separator and evaporated to yield methyl 2-(4-chlorobenzyl)piperidine-4-carboxylate (3.85 g, 87%) as a brown oil. MS m/z 268, 270 (M+H)+
Reaction SMILES: C[O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1.[OH-].[Li+]>O1CCCC1.O>[CH3:12][O:11][C:9]([C:8]1[CH:13]=[CH:14][C:5]([CH2:4][C:3]([OH:15])=[O:2])=[CH:6][CH:7]=1)=[O:10]
Reactant: COC(=O)Cc1ccc(C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(CC(=O)O)cc1
Temperature: 25 °C
Yield: 102.5 %

Procedure:
Methyl 4-(2-methoxy-2-oxoethyl)benzoate (13.6 g) was dissolved in tetrahydrofuran (180 mL) and water (60 mL), and lithium hydroxide (2.75 g) was added. The reaction mixture was heated at room temperature for 24 hr, stirred and concentrated under reduced pressure. The residue was diluted with water, and washed with ethyl acetate. The aqueous layer was adjusted with 2.5N hydrochloric acid to pH 5-6, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate and the solvent was evaporated under reduced pressure to give the title compound (13.0 g) as a colorless solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.[F:16][C:17]([F:27])([F:26])[CH2:18][N:19]1[CH2:24][CH2:23][CH:22](O)[CH2:21][CH2:20]1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>>[F:27][C:17]([F:16])([F:26])[CH2:18][N:19]1[CH2:24][CH2:23][CH:22]([O:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]3)[CH2:21][CH2:20]1
Reactant: OC1CCN(CC(F)(F)F)CC1
Reactant: CCOC(=O)c1cc2cc(O)ccc2[nH]1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Product: CCOC(=O)c1cc2cc(OC3CCN(CC(F)(F)F)CC3)ccc2[nH]1

Procedure:
The title compound was prepared in analogy to example 40d), from ethyl 5-hydroxyindole-2-carboxylate and 1-(2,2,2-trifluoro-ethyl)piperidin-4-ol, using diisopropyl azodicarboxylate instead of diethyl azodicarboxylate. Off-white solid. MS (m/z): 371.2 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:33]=[CH:32][C:8]([O:9][CH2:10][C:11]([NH:13][C:14]2[NH:15][C:16](=[O:31])[C:17]3[N:18]=[CH:19][N:20]([C:29]=3[N:30]=2)[C@@H:21]2[O:28][C@H:25]([CH2:26][OH:27])[C@@H:23]([OH:24])[CH2:22]2)=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[N+:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[CH:44]([CH3:55])[CH2:45][O:46][C:47](N1C=C[N+](C)=C1)=[O:48])([O-:37])=[O:36]>ClCCl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]([NH:13][C:14]2[NH:15][C:16](=[O:31])[C:17]3[N:18]=[CH:19][N:20]([C:29]=3[N:30]=2)[C@@H:21]2[O:28][C@H:25]([CH2:26][OH:27])[C@@H:23]([O:24][C:47]([O:46][CH2:45][CH:44]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=3[N+:35]([O-:37])=[O:36])[CH3:55])=[O:48])[CH2:22]2)=[O:12])=[CH:32][CH:33]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(OCC(=O)Nc2nc3c(ncn3[C@H]3C[C@H](O)[C@@H](CO)O3)c(=O)[nH]2)cc1
Reactant: CC(COC(=O)n1cc[n+](C)c1)c1ccccc1[N+](=O)[O-]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(COC(=O)O[C@H]1C[C@H](n2cnc3c(=O)[nH]c(NC(=O)COc4ccc(C(C)(C)C)cc4)nc32)O[C@@H]1CO)c1ccccc1[N+](=O)[O-]
Yield: 80.7 %

Procedure:
As described for 11 with N2-((4-tertbutylphenoxy)acetyl)-2′-deoxyguanosine (6) (5 g, 6.58 mmol) in 50 ml dichloromethane and 2 (2.57 g, 7.9 mmol) in 50 ml dichloromethane. Purification via flash chromatography (0-10% methanol in toluene/ethyl acetate (1:1) yielded 3.53 g (81%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Li+].O1CCCC1.Cl>O.CO>[CH3:1][C:2]1[CH:11]=[C:10]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(COc2ccccc2)cc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(COc2ccccc2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of methyl 2-methyl-4-(phenoxymethyl)benzoate (66 mg, 0.26 mmol), lithium hydroxide (54 mg, 1.29 mmol), tetrahydrofuran (6 mL), methanol (2 mL), and water (2 mL) were stirred at room temperature for 12 hours. The mixture was neutralized to pH to 1 with concentrated hydrochloric acid and then extracted with ethyl acetate (20 mL×3). The combined organic phase was separated, dried over sodium sulfate, and then filtered. The filtrate was concentrated in vacuo to give 2-methyl-4-(phenoxymethyl)benzoic acid used in next step without further purification (42 mg, 67%). LRMS (M+H)− m/z: calcd 242.09. found 242.