Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N([O-])=O.[Na+].N[C:6]1[CH:7]=[CH:8][C:9]([O:12][C:13]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:14]=2[C:15]([O:17][CH3:18])=[O:16])=[N:10][CH:11]=1.[F:24][B-](F)(F)F.[H+]>O>[Cl:23][C:20]1[CH:21]=[CH:22][C:13]([O:12][C:9]2[CH:8]=[CH:7][C:6]([F:24])=[CH:11][N:10]=2)=[C:14]([CH:19]=1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1cc(Cl)ccc1Oc1ccc(N)cn1
Reactant: F[B-](F)(F)F
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1cc(Cl)ccc1Oc1ccc(F)cn1
Temperature: 140 °C
Reaction time: 5 h
Yield: 42 %

Procedure:
To a solution of sodium nitrite (224 mg, 3.25 mmol) in water (5 mL) was added methyl 2-[(5-aminopyridin-2-yl)oxy]-5-chlorobenzoate (907 mg, 3.25 mmol) and 48% tetrafluoroboric acid in water (5 mL) at 0° C. The reaction mixture was stirred for 5 h. The resulting precipitate was collected by filtration and dried under reduced pressure at room temperature. To the solids of tetrafluoroborate were added chlorobenzene (5 mL) and the mixture was heated at 140° C. for 40 min. The reaction mixture was diluted with ethyl acetate. The solution was washed with brine and concentrated. The residue was purified by flush column chromatography on silica gel eluting with hexane/ethyl acetate (8/1) to afford 382 mg (42%) of the title compound: 1H-NMR (CDCl3) δ 7.98 (1H, d, J=2.8 Hz), 7.90 (1H, d, J=3.1 Hz), 7.59–7.41 (2H, m), 7.14 (1H, d, J=8.6 Hz), 6.99 (1H, dd, J=8.9, 3.5 Hz), 3.72 (3H, s).
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(O)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:31]([C:30]3[CH:33]=[CH:34][C:27]([O:26][CH3:25])=[CH:28][CH:29]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3ccncc3)CC2)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-c2nc3c(N4CCN(Cc5ccncc5)CC4)c(Br)cnc3[nH]2)cc1
Temperature: 70 °C
Reaction time: 8.5 h

Procedure:
To a mixture of 5-bromo-3-nitro-4-(4-pyridin-4-ylmethyl-piperazin-1-yl)-pyridin-2-ylamine (0.047 g, 0.12 mmol) and ethanol (3.0 ml) was added 4-methoxybenzaldehyde (0.026 g, 0.18 mmol) with the aid of ethanol (1.0 ml), followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.50 ml, 0.50 mmol). The reaction mixture was stirred at 70° C. for 8.5 h, then allowed to cool to room temperature and concentrated in vacuo. The residue was absorbed on silica gel, and the free-running powder was placed on a 10 g isolute silica column which was eluted with a gradient of methanol (0 to 4%) in ethyl acetate/dichloromethane (v/v; 1:1). The title compound was obtained as a pale yellow solid after trituration with diethyl ether (0.018 g, 31%). 1H-NMR (500 MHz, DMSO-d6) 2.63 (br s, 4H, piperazine N(CH2)2), 3.68 (br s, 4H, piperazine N(CH2)2), 3.62 (s, 2H, NCH2-pyridyl), 3.84 (s, 3H, OCH3), 7.10 (d, J=8.9 Hz, 2H) and 8.14 (d, J=8.8 Hz, 2H) (3,5-C6H4OMe and 2,6-C6H4OMe), 7.40 (d, J=5.9 Hz, 2H, pyridine 3-H and 5-H), 8.20 (s, 1H, imidazo[4,5-b]pyridine 5-H), 8.54 (d, J=5.9 Hz, 2H, pyridine 2-H and 6-H), 13.38 (br s, 1H, imidazo[4,5-b]pyridine N—H);
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH2:14])[CH2:11][CH2:10][N:9]1[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=O)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C([BH3-])#N.[Na+].C(O)(=O)C>C1(C)C=CC=CC=1>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([NH:14][CH:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:11][CH2:10][N:9]1[C:15](=[O:24])[C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: N[C@H]1CCN(C(=O)c2cc(Cl)cc(Cl)c2)[C@H](Cc2ccccc2)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: O=C(c1cc(Cl)cc(Cl)c1)N1CC[C@H](NC(c2ccccc2)c2ccccc2)C[C@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 68 h

Procedure:
A solution of 200 mg (0.551 mmol) of (2R*,4S*)-2-benzyl-1-(3,5-dichlorobenzoyl)-4-piperidinamine and 110 mg (0.606 mmol) of benzophenone in 5 ml of toluene are kept at reflux for 18 hours. The reaction mixture is then concentrated in a rotary evaporator and dissolved in 3 ml of methanol, and 69 mg (1.10 mmol) of sodium cyanoborohydride are added at RT. The reaction mixture is adjusted to pH=5 with 80 μl of acetic acid and stirred at RT for 68 hours. The title compound ##STR98## is obtained as white foam (120 mg, 41%). TLC: toluene/ethyl acetate (7:3) Rf =0.79, FD-MS: M+ =528,530; IR: 1630 cm-1.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([CH3:8])[CH:2]=1.ClCCCl.[N+:13]([O-])([OH:15])=[O:14]>O>[N+:13]([C:5]1[C:6]([OH:7])=[CH:1][CH:2]=[C:3]([CH3:8])[CH:4]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(O)cc1
Solvent: O
Solvent: ClCCCl
Product: Cc1ccc(O)c([N+](=O)[O-])c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 99.1 %

Procedure:
A 100 mL reaction flask fitted with reverse dean-stark apparatus was charged with 10.804 g (0.1 mol) p-cresol, 65 mL 1,2 dichloro ethane, and 2.161 g of catalyst as prepared in example 5. The flask was flushed with nitrogen. The reaction mixture was refluxed at 110° C. for 1 h followed by dropwise addition of 8.6 mL (0.133 mol) 70% HNO3. The water formed during the reaction was removed using reverse dean-stark apparatus. The reaction was carried out for 8 h. The reaction was monitored by GC analysis. In this reaction, 98.7% conversion of p-cresol was obtained with 99.1% 2-nitro p-cresol and 0.9% of other products.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.[OH:16][CH:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1.[Na]>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH:20]3[CH2:21][CH2:22][CH:17]([OH:16])[CH2:18][CH2:19]3)[CH2:7][C@@H:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1
Reactant: O=C1CCC(O)CC1
Reactant: Clc1ncc2c(n1)N1CCOC[C@H]1CN2
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Na]
Solvent: ClCCl
Product: OC1CCC(N2C[C@@H]3COCCN3c3nc(Cl)ncc32)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 8.4 %

Procedure:
To (R)-2-chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x2, 250 mg, 1.103 mmol) and 4-hydroxycyclohexanone (126 mg, 1.103 mmol) in CH2Cl2 (8 mL) was added titanium(IV) chloride in CH2Cl2 (1M, 2.427 mL, 2.427 mmol) dropwise to give an orange suspension. The reaction mixture was stirred at ambient temperature for 4 hours and then cooled to 0° C. Sodium triacetoxyhydroborate (514 mg, 2.427 mmol) was added in two portions. The reaction mixture was stirred for 1 hour and then quenched with aqueous saturated NH4Cl (1 mL). The reaction mixture was diluted with ethyl acetate and washed with aqueous saturated NH4Cl (3×10 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was then loaded onto an ISCO® silica gel cartridge (12 g) and eluted using an ethyl acetatehexane gradient. The product was collected and concentrated in vacuo to afford the title compound as a colorless foam (30 mg, 8%). ESI-MS m/z [M+H]+ calc'd for C15H21ClN4O2, 325.14; found 325.2.
Reaction SMILES: [CH2:1]([N:5]1[CH2:18][CH2:17][C:8]2[NH:9][C:10]3[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][C:15]=3[C:7]=2[CH2:6]1)[CH2:2][CH2:3][CH3:4].[CH3:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]=[CH2:27])=[CH:22][N:21]=1.[OH-].[K+]>CN1C(=O)CCC1>[CH2:1]([N:5]1[CH2:18][CH2:17][C:8]2[N:9]([CH2:27][CH2:26][C:23]3[CH:22]=[N:21][C:20]([CH3:19])=[CH:25][CH:24]=3)[C:10]3[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][C:15]=3[C:7]=2[CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCc2[nH]c3ccc(C)cc3c2C1
Reactant: C=Cc1ccc(C)nc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Product: CCCCN1CCc2c(c3cc(C)ccc3n2CCc2ccc(C)nc2)C1

Procedure:
The title compound is prepared from a mixture of 2-butyl-2,3,4,5-tetrahydro-8-methyl-1H-pyrido[4,3-b]indole, 2-methyl-5-vinylpyridine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: Cl.[CH3:2][NH:3][C@@H:4]([CH2:9][CH2:10][CH:11]=[CH2:12])[C:5]([O:7][CH3:8])=[O:6].[F:13][C:14]([F:22])([F:21])[CH2:15][CH2:16][S:17](Cl)(=[O:19])=[O:18]>>[F:13][C:14]([F:22])([F:21])[CH2:15][CH2:16][S:17]([N:3]([C@@H:4]([CH2:9][CH2:10][CH:11]=[CH2:12])[C:5]([O:7][CH3:8])=[O:6])[CH3:2])(=[O:19])=[O:18]
Reactant: O=S(=O)(Cl)CCC(F)(F)F
Reactant: C=CCC[C@H](NC)C(=O)OC
Agent: Cl
Product: C=CCC[C@@H](C(=O)OC)N(C)S(=O)(=O)CCC(F)(F)F
Yield: 56 %

Procedure:
Step M (1): Same procedure as Step I (1). (S)-Methyl 2-(methylamino)hex-5-enoate hydrochloride from Step K (2) was sulfonylated with 3,3,3-trifluoropropane-1-sulfonyl chloride according to the procedure outlined in Step I (1). The procedure provided 242 mg (56% yield) of (S)-methyl 2-(3,3,3-trifluoro-N-methylpropylsulfonamido)hex-5-enoate. LC-MS (M+H)+=318.3; 1H NMR (500 MHz, CDCl3) δ ppm 1.73-1.85 (m, 1H) 2.02-2.21 (m, 3H) 2.59-2.73 (m, 2H) 2.87 (s, 3H) 3.16-3.32 (m, 2H) 3.76 (s, 3H) 4.55 (dd, J=10.68, 4.58 Hz, 1H) 4.99-5.14 (m, 2H) 5.74-5.87 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[CH:37][C:4]=1[CH2:5][N:6]([C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:22][C@H:21]([OH:23])[CH2:20][C@@H:19]2[C:24]2[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=2)=[CH:12][C:11]=1[F:30])(=[O:9])=[O:8].S(OC)(O[CH3:47])(=O)=O.[H-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[CH:37][C:4]=1[CH2:5][N:6]([C:31]1[CH:36]=[CH:35][N:34]=[CH:33][N:32]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:22][C@H:21]([O:23][CH3:47])[CH2:20][C@@H:19]2[C:24]2[N:28]([CH3:29])[N:27]=[CH:26][CH:25]=2)=[CH:12][C:11]=1[F:30])(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3C[C@H](O)C[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3C[C@H](OC)C[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Yield: 53.1 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1a by using the N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S*,2R*,4R*)-4-hydroxy-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (120 mg, 0.199 mmol) prepared in Example 121c, dimethyl sulfate (18.8 μL, 0.199 mmol), sodium hydride (63%; 11.1 mg, 0.291 mmol) and THF (2.0 mL), to yield the title compound (65.0 mg, 53%) as a colorless oil.
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][NH:6][CH2:7][C@H:8]([OH:38])[CH2:9][O:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14]([C:18]2[N:22]=[C:21]([C:23]3[CH:28]=[C:27]([O:29][CH3:30])[N:26]=[C:25]([CH:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)[CH:24]=3)[O:20][N:19]=2)=[CH:13][C:12]=1[CH2:36][CH3:37])C>C1COCC1.CO.[Li+].[OH-]>[CH:31]1([C:25]2[CH:24]=[C:23]([C:21]3[O:20][N:19]=[C:18]([C:14]4[CH:15]=[C:16]([CH3:17])[C:11]([O:10][CH2:9][C@@H:8]([OH:38])[CH2:7][NH:6][CH2:5][C:4]([OH:39])=[O:3])=[C:12]([CH2:36][CH3:37])[CH:13]=4)[N:22]=3)[CH:28]=[C:27]([O:29][CH3:30])[N:26]=2)[CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: CCOC(=O)CNC[C@H](O)COc1c(C)cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc1CC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1cc(-c2noc(-c3cc(OC)nc(C4CCCC4)c3)n2)cc(C)c1OC[C@@H](O)CNCC(=O)O
Yield: 53.3 %

Procedure:
A solution of (S)-2-((3-(4-(5-(2-cyclopentyl-6-methoxypyridin-4-yl)-1,2,4-oxadiazol-3-yl)-2-ethyl-6-methylphenoxy)-2-hydroxypropyl)amino)acetic acid ethyl ester (60 mg, 0.114 mmol) in THF (3 mL), methanol (3 mL) and 2 N aq. LiOH (1 mL) is stirred at rt for 2 h. The solvent is evaporated and the residue is dissolved in 2 N aq. HCl (10 mL) and extracted four times with DCM (4×20 mL). The org. extracts are combined, dried over MgSO4, filtered and concetrated. The crude product is purified by prep. HPLC to give the title compound (31 mg) as a white solid; LC-MS*: tR=0.86 min, [M+H]+=511.19; 1H NMR (CD3OD): δ 7.88 (s, 1H), 7.86 (s, 1H), 7.54 (s, 1H), 7.30 (s, 1H), 4.30-4.36 (m, 1H), 4.01 (s, 3H), 3.87-3.98 (m, 2H), 3.63 (s, 2H), 3.46 (dd, J1=12.5 Hz, J2=2.9 Hz, 1H), 3.24-3.32 (m, 2H), 2.81 (q, J=7.6 Hz, 2H), 2.42 (s, 3H), 2.07-2.17 (m, 2H), 1.86-1.98 (m, 4H), 1.74-1.82 (m, 2H), 1.32 (t, J=7.6 Hz, 3H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:23]C)[N:12]2[CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]2)=[C:8]([NH2:25])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[NH2:25][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:23])[N:12]2[CH2:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH2:20][N:19]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:18]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCC3CCCNC3)c2n1
Reactant: IC1CCCCC1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCC3CCCN(C4CCCCC4)C3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[2-(3-piperidinyl)ethyl]-9H-purin-6-amine and iodocyclohexane.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:32]=[CH:31][C:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)=[CH:14][N:13]=2)=[CH:8][C:7]=1[F:33])=[O:5])C.O.[OH-].[Li+].Cl>C(O)C.O>[C:4]([C:6]1[CH:32]=[CH:31][C:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][CH2:19]3)=[CH:14][N:13]=2)=[CH:8][C:7]=1[F:33])([OH:5])=[O:3]
Reactant: CCOC(=O)c1ccc(OCc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cn2)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(COc3ccc(C(=O)O)c(F)c3)nc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.1 %

Procedure:
To a solution of tert-butyl 4-[2-(4-ethoxycarbonyl-3-fluorophenoxymethyl)pyridin-5-yl]piperidine-1-carboxylate (Example 9) (60 mg, 0.131 mmol) in ethanol (0.9 mL)-water (0.2 mL) was added lithium hydroxide monohydrate (16 mg, 0.393 mmol). The mixture was stirred at room temperature overnight, diluted with water, neutralized by the addition of 1N hydrochloric acid and then extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound as a white crystal (57 mg, quantitative yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:11](=[O:12])[CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7]1)=[O:5])[CH3:2].CN(C=O)C.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:1]([O:3][C:4]([C:6]1([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:11](=[O:12])[CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14])[CH2:7]1)=[O:5])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(Cc2ccccc2)CN(C(=O)OC(C)(C)C)CCC1=O
Temperature: 60 °C
Reaction time: 20 h
Yield: 38.2 %

Procedure:
To a solution of 4-oxo-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (73.36 g, 0.27 mol) in DMF (734 mL) lithium carbonate (50 g, 0.676 mol) was added, followed by benzyl bromide (55.44 g, 0.324 mol). The mixture was heated to about 60° C. and stirred for about 20 hours. The reaction mixture was then cooled to room temperature and extracted with IPE, washed with water and dried over magnesium sulfate. After filtration and concentration in vacuo a solid was obtained. Recrystallization of the crude product in hexane afforded a white solid (33.6 g, yield 38.2% h).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]2[C:9]=1[C:10]([CH2:18][C:19]([O:21]C)=[O:20])=[CH:11][NH:12]2>O.CO>[Cl:7][C:8]1[C:16]([Cl:17])=[CH:15][CH:14]=[C:13]2[C:9]=1[C:10]([CH2:18][C:19]([OH:21])=[O:20])=[CH:11][NH:12]2
Reactant: COC(=O)Cc1c[nH]c2ccc(Cl)c(Cl)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C(O)Cc1c[nH]c2ccc(Cl)c(Cl)c12
Yield: 72.1 %

Procedure:
An aqueous solution prepared by dissolving 120 mg of potassium carbonate in 2.5 ml of water was added to a solution of 44 mg of methyl 4,5-dichloroindole-3-acetate in 5 ml of methanol. The mixture was refluxed for 1.5 hours, after which the methanol was removed by distillation under reduced pressure, and the aqueous solution thus obtained was extracted with ethyl acetate. The aqueous phase was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate phase was washed with distilled water and a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure to obtain a crude product. The crude product was purified by a silica gel thin-layer chromatography to obtain 30 mg of 4,5-dichloroindole-3-acetic acid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8](=[O:9])[C:7]2=[CH:10][C:11]([N+:14]([O-])=O)=[CH:12][CH:13]=[C:6]2[C:5]1=[O:17].[H][H]>[Ni].C(O)C>[NH2:14][C:11]1[CH:10]=[C:7]2[C:8](=[O:9])[N:4]([CH2:3][CH2:2][OH:1])[C:5](=[O:17])[C:6]2=[CH:13][CH:12]=1
Reactant: [H][H]
Reactant: O=C1c2ccc([N+](=O)[O-])cc2C(=O)N1CCO
Agent: [Ni]
Solvent: CCO
Product: Nc1ccc2c(c1)C(=O)N(CCO)C2=O

Procedure:
N-(2-Hydroxyethyl)-4-nitrophthalimide (30.0 g.), ethanol (300 ml.), and Raney nickel (3.0 g.) are mixed and hydrogenated at 100°C. and 1500 psi. until hydrogen uptake ceases. The hot solution is filtered to remove the Raney nickel and the solvent evaporated to yield 4-amino-N-(2-hydroxyethyl)-phthalimide, the amine which melts at 171°-173°C.
Reaction SMILES: [CH2:1]([C:3]1[O:7][N:6]=[C:5]([NH:8][CH:9]([P:18](=[O:25])([O:22]CC)[O:19]CC)[P:10](=[O:17])([O:14]CC)[O:11]CC)[CH:4]=1)[CH3:2]>Cl>[CH2:1]([C:3]1[O:7][N:6]=[C:5]([NH:8][CH:9]([P:18](=[O:19])([OH:25])[OH:22])[P:10](=[O:11])([OH:17])[OH:14])[CH:4]=1)[CH3:2]
Reactant: CCOP(=O)(OCC)C(Nc1cc(CC)on1)P(=O)(OCC)OCC
Agent: Cl
Product: CCc1cc(NC(P(=O)(O)O)P(=O)(O)O)no1
Yield: 79.6 %

Procedure:
A solution of 4.9 g of tetraethyl [(5-ethyl-3-isoxazolyl)amino]methylene-bis(phosphonate) in 46 ml of concentrated hydrochloric acid was heated under reflux for 3 hours. After the reaction mixture was concentrated, the solid obtained was washed with acetone to give 2.8 g of [(5-ethyl-3-isoxazolyl)amino]methylene-bis(phosphonic acid) as a solid.
Reaction SMILES: [C:1]1([N:7]2[CH:15]=[C:14]3[C:9]([CH:10]=[C:11]([C:16]4[CH:17]=[C:18]([CH:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)[N:19]5[C:24]=4[C:23]([NH2:25])=[N:22][CH:21]=[N:20]5)[CH:12]=[CH:13]3)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:32][N:33]([CH3:38])[CH2:34][C:35](O)=[O:36].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH3:32][N:33]([CH2:34][C:35]([N:29]1[CH2:30][CH2:31][CH:26]([C:18]2[N:19]3[C:24]([C:23]([NH2:25])=[N:22][CH:21]=[N:20]3)=[C:16]([C:11]3[CH:12]=[CH:13][C:14]4[C:9]([CH:10]=3)=[N:8][N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:15]=4)[CH:17]=2)[CH2:27][CH2:28]1)=[O:36])[CH3:38]
Reactant: Nc1ncnn2c(C3CCNCC3)cc(-c3ccc4cn(-c5ccccc5)nc4c3)c12
Reactant: CN(C)CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)CC(=O)N1CCC(c2cc(-c3ccc4cn(-c5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Yield: 22.2 %

Procedure:
A mixture 5-(2-phenyl-2H-indazol-6-yl)-7-piperidin-4-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (80 mg, 0.20 mmol), N,N-dimethylglycine (22 mg, 0.22 mmol), EDCl (41 mg, 022 mmol), HOBt (29 mg, 0.22 mmol), and N,N-diisopropylethylamine (102 μL, 0.59 mmol) in DMF (1 mL) was stirred at rt for 17 h. The residue was purified by preparative HPLC using a gradient elution from 15% to 45% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 22 mg (23%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 9.16 (s, 1 H), 8.11 (d, 2 H), 7.93 (s, 1 H), 7.85 (d, 1 H), 7.69 (s, 1 H), 7.56-7.62 (m, 2 H), 7.45 (t, 1 H), 7.23 (dd, 1 H), 6.66 (s, 1 H), 4.31 (dd, 1 H), 3.36-3.51 (m, 1 H), 3.08-3.24 (m, 2 H), 3.01-3.06 (m, 1 H), 2.63-2.80 (m, 1 H), 2.18 (s, 6 H), 1.99-2.12 (s, 2 H), 1.44-1.77 (m, 1 H); ES-MS m/z 495.18 [M+H]+, HPLC RT (min) 2.13.
Reaction SMILES: [C:1]([C:4]1[C:12]2[O:11][C:10]([C:13]3([CH3:28])[CH2:17][CH2:16][CH2:15][N:14]3C(OCC3C=CC=CC=3)=O)=[N:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])[NH2:2].[H][H]>CO.[Pd]>[CH3:28][C:13]1([C:10]2[O:11][C:12]3[C:4]([C:1]([NH2:2])=[O:3])=[CH:5][CH:6]=[CH:7][C:8]=3[N:9]=2)[CH2:17][CH2:16][CH2:15][NH:14]1
Reactant: [H][H]
Reactant: CC1(c2nc3cccc(C(N)=O)c3o2)CCCN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC1(c2nc3cccc(C(N)=O)c3o2)CCCN1
Yield: 44.1 %

Procedure:
A mixture of benzyl 2-(7-carbamoylbenzo[d]oxazol-2-yl)-2-methylpyrrolidine-1-carboxylate (144 mg, 0.37 mmol), 10% Pd/C (20 mg) in methanol (10 mL) was stirred at room temperature over 1 atm hydrogen for 3 h. Then the mixture was filtered and the filtrate was evaporated under reduced pressure. The residue was purified by flash chromatography. 40 mg of yellow oil of 2-(2-methylpyrrolidin-2-yl)benzo[d]oxazole-7-carboxamide was obtained, yield 43%. 1H-NMR (400 MHz, DMSO-d6): δ 1.58 (s, 3H), 1.76-1.87 (m, 3H), 2.47-2.49 (m, 1H), 2.86-2.91 (m, 1H), 2.97-3.02 (m, 1H), 7.41-7.44 (t, J=6.4 Hz, 1H), 7.69 (s, 1H), 7.74-7.76 (d, J=5.6 Hz, 1H), 7.82 (s, 1H), 8.85-8.87 (d, J=6.4 Hz, 1H). LC-MS (ESI) m/z: 246 (M+1)+.
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[CH:13]=[C:12]2[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:7][C:6]=1[C:26]([OH:28])=[O:27])(=O)C.C(O)C.Cl>O>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[CH:13]=[C:12]2[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:7][C:6]=1[C:26]([OH:28])=[O:27]
Reactant: CC(=O)Nc1ccc(-n2c(-c3ccccc3)cc3c2CCCC3)cc1C(=O)O
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc(-n2c(-c3ccccc3)cc3c2CCCC3)cc1C(=O)O

Procedure:
A mixture of 4.0 g. (0.011 mole) of 1-(4-acetamido-3-carboxyphenyl)-2-phenyl-4,5,6,7-tetrahydroindole, 50 ml. of ethanol, 10 ml. of water, and 2 ml. of conc. hydrochloric acid was heated under reflux under nitrogen for 4 hours, concentrated to 10 ml., diluted with 100 ml. of water, adjusted to pH 4 and filtered. Recrystallization of the collected solid from 75% ethanol gave 0.83 g. (23%) of crystals, m.p. 205.5°-206.5°.
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[C:8]([O:13][CH2:14][CH2:15][O:16][C:17](ON1C(=O)CCC1=O)=[O:18])(=[O:12])[CH2:9][CH2:10][CH3:11]>>[C:8]([O:13][CH2:14][CH2:15][O:16][C:17]([NH:1][C@H:2]([CH2:3][OH:4])[C:5]([OH:7])=[O:6])=[O:18])(=[O:12])[CH2:9][CH2:10][CH3:11]
Reactant: N[C@H](CO)C(=O)O
Reactant: CCCC(=O)OCCOC(=O)ON1C(=O)CCC1=O
Product: CCCC(=O)OCCOC(=O)N[C@H](CO)C(=O)O
Yield: 48.4 %

Procedure:
Following the general procedure for the synthesis of acyloxyalkyl carbamates, D-serine (252 mg, 2.4 mmol) and (2,5-dioxoazolidinyloxycarbonyloxy)ethyl butanoate (546 mg, 2.0 mmol) were reacted to provide 255 mg (40% yield) the title compound (30) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (CDCl3, 400 MHz): δ=6.80 (m, 1H), 6.09 (t, 1H), 5.81 (br s, 1H), 4.41 (m, 1H), 4.07 (m, 1H), 3.92 (m, 1H), 2.31 (m, 2H), 1.65 (m, 2H), 1.50 (d, 3H), 0.99 (m, 3H). MS (ESI) m/z 286.07 (M+Na)+; 262.06 (M−H)−.