Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].C([O:6][C:7]1[C:24]([O:25][CH2:26][CH3:27])=[CH:23][C:22]2[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C@@H:16]([O:28]C(=O)C)[CH2:15][CH2:14]4)[CH2:11][C:10](=[O:32])[C:9]=2[CH:8]=1)(=O)C.Cl>CO>[OH:6][C:7]1[C:24]([O:25][CH2:26][CH3:27])=[CH:23][C:22]2[C@@H:21]3[C@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C@@H:16]([OH:28])[CH2:15][CH2:14]4)[CH2:11][C:10](=[O:32])[C:9]=2[CH:8]=1
Reactant: CCOc1cc2c(cc1OC(C)=O)C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC(C)=O)CC[C@@H]12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCOc1cc2c(cc1O)C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 6 h
Yield: 97.5 %

Procedure:
Under nitrogen, a 20% solution of potassium hydroxide in methanol (15 ml) was added dropwise at room temperature to a suspension of compound 5 (3.0 g, 7.26 mmol) in anhydrous methanol (60 ml). The resulting mixture was stirred at room temperature for 6 hr. The mixture was neutralized with 3 N HCl and the solvent was removed under reduced pressure. The residue was diluted with water (100 ml) and extracted with ethyl acetate (3×100 ml). The combined organic layer was washed with brine (2×100 ml), and dried over sodium sulfate. Removal of the solvents provided a white solid 6 (2.34 g, 98%), which was then crystallized from ethyl acetate/hexane to afford title compound 6 as white crystals: mp 197-199° C. (lit. 12 mp 194-196° C.); 1H NMR (CDCl3) δ7.61 (s, 1 H, 4-aromatic CH), 7.20 (s, 1 H, 1-aromatic CH), 4.44 (q, J=6.9 Hz, 2 H, 2-CH2-), 3.83 (t, J=8.5 Hz, 1 H, 17α-H), 2.85-1.40 (m, 20H), 0.97 (s, 3 H, 18-CH3).
Reaction SMILES: F[C:2]1[CH:20]=[CH:19][C:5]([C:6]([N:8]([CH2:14][C:15]([F:18])([F:17])[F:16])[CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].CC[N:26]([CH2:29][CH3:30])CC>CCO>[N+:21]([C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:2]=1[NH:26][CH2:29][C@H:30]1[CH2:4][CH2:5][CH2:6][O:7]1)[C:6]([N:8]([CH2:9][C:10]([F:11])([F:13])[F:12])[CH2:14][C:15]([F:16])([F:17])[F:18])=[O:7])([O-:23])=[O:22]
Reactant: O=C(c1ccc(F)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F
Reactant: CCN(CC)CC
Solvent: CCO
Product: O=C(c1ccc(NC[C@H]2CCCO2)c([N+](=O)[O-])c1)N(CC(F)(F)F)CC(F)(F)F

Procedure:
Following the general procedure for Intermediate 2 using 4-fluoro-3-nitro-N,N-bis(2,2,2-trifluoroethyl)benzamide (78 mg, 0.224 mmol) and R-(−)-tetrahydrofurfurylamine (0.025 mL, 0.246 mmol) in 3 mL of EtOH containing Et3N (0.047 mL, 0.336 mmol). The product was purified by flash chromatography on silica gel using 2:1/hexanes:EtOAc as eluent. Yield: 96 mg (95%); 1H NMR (CDCl3) 1.72 (m, 1H), 1.99 (m, 2H), 2.13 (m, 1H), 3.99 (m, 1H), 3.53 (m, 1H), 3.85 (m, 1H), 3.97 (m, 1H), 4.25 (m, 5H), 6.99 (d, J=8.98 Hz, 1H), 7.53 (d, J=8.98 Hz, 1H), 8.30 (s, 1H), 8.51 (brs, 1H); MS (ESI) 430.31 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:18]([N:19]([CH3:23])[CH:20]([CH3:22])[CH3:21])=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:24]([O:26]C)=[O:25])[CH:15]=2)[N:10]=1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:18]([N:19]([CH3:23])[CH:20]([CH3:22])[CH3:21])=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:24]([OH:26])=[O:25])[CH:15]=2)[N:10]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3F)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a solution of methyl 2-(2,4-difluorophenyl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylate (150 mg, 0.40 mmol) in methanol (25 mL) and water (1 mL) was added sodium hydroxide (64.7 mg, 1.62 mmol), and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo, and then dissolved in water (30 mL), and adjusted to pH 4 with hydrochloric acid (3N) to give the precipitate, which was collected by filtration to afford 2-(2,4-difluorophenyl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylic acid as a light yellow solid (100 mg, 69%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][N:18]([CH:19]([CH3:21])[CH3:20])[C:12]2=[N:11][C:10]=1[C:22](O)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][C:27]=1[CH3:34]>C(OCC)(=O)C.CCCCCC>[F:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH:31][C:22]([C:10]2[N:11]=[C:12]3[N:18]([CH:19]([CH3:20])[CH3:21])[CH2:17][CH2:16][N:13]3[C:14](=[O:15])[C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:23])=[CH:28][C:27]=1[CH3:34]
Reactant: Cc1cc(CN)ccc1F
Reactant: CC(C)N1CCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1cc(CNC(=O)c2nc3n(c(=O)c2OCc2ccccc2)CCN3C(C)C)ccc1F
Yield: 93.7 %

Procedure:
Coupling of 6-(benzyloxy) 1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylic acid (0.300 g, 0.91 mmol) and 4-fluoro-3-methylbenzylamine (0.133 g, 0.95 mmol) as described for the synthesis of intermediate 3 gave 0.384 g (93% yield) of the title amide as white crystals (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.23 (6H, d, J=6.6 Hz, 2×CH3), 2.25 (3H, broad d, J=1.8 Hz, CH3), 3.67 (2H, t, J=9 Hz, CH2), 4.13 (2H, t, J=9 Hz, CH2), 4.41 (1H, m, CH), 4.46 (2H, d, J=5.8 Hz, NCH2), 5.08 (2H, s, OCH2), 6.94 (1H, m, aromatic), 7.04-7.08 (1H, m, aromatic), 7.11 (1H, m, aromatic), 7.3-7.36 (3H, m, aromatics), 7.42-7.46 (2H, m, aromatics), 7.69 (1H, broad t, NH). HRMS (ESI+) calculated for C25H28FN4O3 [M+H+]: 451.2145. found: 451.2141.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[CH3:13][O:14][C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C>O>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][CH:20]=1)[O:21][C:2]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: COc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1cccc(Oc2ccc([N+](=O)[O-])cc2C#N)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.9 %

Procedure:
In a 250 ml single-neck flask equipped with a magnetic stirrer and a reflux condenser fitted with a nitrogen bubbler were placed 9.13 g (0.050 moles) of 2-chloro-5-nitrobenzonitrile, 6.39 g (0.0515 moles) of 3-methoxyphenol, 7.10 g (0.0515 moles) of anhydrous potassium carbonate (K2CO3) and 75 ml of acetonitrile. The mixture was heated to reflux and held there for 3 hrs. The reaction mixture was cooled to room temperature and diluted with 150 ml of water. The product separated as a solid. The solid was filtered off, washed thoroughly with water, and air-dried. The air-dried solid was recrystallized from approximately 200 ml of absolute ethanol to give 7.15 g (53% yield) of purified 2-(3-methoxyphenoxy)-5-nitrobenzonitrile, mp 102°-103.5° C.
Reaction SMILES: I[CH2:2][CH2:3][OH:4].C(=O)(O)[O-].[Na+].[CH3:10][O:11][C:12]1[CH:28]=[CH:27][C:15]([CH2:16][S:17][C@@H:18]2[CH2:22][NH:21][C@H:20]([C:23](=[O:26])[NH:24][CH3:25])[CH2:19]2)=[CH:14][CH:13]=1.[Cl-].[Na+]>CN(C)C=O>[OH:4][CH2:3][CH2:2][N:21]1[CH2:22][C@@H:18]([S:17][CH2:16][C:15]2[CH:27]=[CH:28][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)[CH2:19][C@H:20]1[C:23](=[O:26])[NH:24][CH3:25]
Reactant: CNC(=O)[C@@H]1C[C@H](SCc2ccc(OC)cc2)CN1
Reactant: OCCI
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNC(=O)[C@@H]1C[C@H](SCc2ccc(OC)cc2)CN1CCO
Temperature: 40 °C
Reaction time: 24 h

Procedure:
934 μl of 2-iodoethanol and 1.01 g of sodium bicarbonate were added, whilst ice-cooling, to a solution of 2.80 g of (2S, 4S)-4-(4-methoxybenzylthio)-2-methylcarbamoylpyrrolidine dissolved in 18 ml of dry dimethylformamide, and the mixture was stirred at 40° C. for 24 hours. At the end of this time, the reaction mixture was poured into an aqueous solution of sodium chloride and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure, and the residue was purified by column chromatography through silica gel (eluted with a 15:1 by volume mixture of ethyl acetate and methanol), to afford 2.22 g of the title compound as colorless crystals, melting at 88°-89.5° C.
Reaction SMILES: N#N.C[O:4][C:5]([C:7]1[N:8]=[CH:9][O:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][O:19][CH3:20])[CH:13]=1)=[O:6].[OH-].[Na+].Cl>C1COCC1>[CH3:20][O:19][CH2:18][C:14]1[CH:13]=[C:12]([C:11]2[O:10][CH:9]=[N:8][C:7]=2[C:5]([OH:6])=[O:4])[CH:17]=[CH:16][CH:15]=1
Reactant: COCc1cccc(-c2ocnc2C(=O)OC)c1
Agent: Cl
Agent: N#N
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1cccc(-c2ocnc2C(=O)O)c1
Reaction time: 1.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-(3-methoxymethyl-phenyl)-oxazole-4-carboxylic acid methyl ester (280 mg, 1.13 mmol) in THF (11.0 mL) was treated with a 1N NaOH (5.5 mL). The resulting mixture was stirred for 1.5 h then acidified with 1N HCl, extracted twice with EA (2×20 mL) and the combined organic phases were washed with brine (20 mL). The organic layer was dried over MgSO4, filtered, and the solvent removed under reduced pressure to give the title compound as a white solid. LC-MS-conditions 02: tR=0.77 min, [M+AcCN+H]+=275.35.
Reaction SMILES: [F:1][C:2]([F:30])([O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([S:19](/[CH:22]=[CH:23]/[CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)(=[O:21])=[O:20])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1)[CH:3]([F:5])[F:4].[NH2:31][OH:32]>C1COCC1.O>[OH:32][NH:31][CH:23]([CH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)[CH2:22][S:19]([N:16]1[CH2:17][CH2:18][N:13]([C:10]2[CH:9]=[CH:8][C:7]([O:6][C:2]([F:1])([F:30])[CH:3]([F:4])[F:5])=[CH:12][CH:11]=2)[CH2:14][CH2:15]1)(=[O:20])=[O:21]
Reactant: NO
Reactant: O=S(=O)(/C=C/C1CCOCC1)N1CCN(c2ccc(OC(F)(F)C(F)F)cc2)CC1
Solvent: C1CCOC1
Solvent: O
Product: O=S(=O)(CC(NO)C1CCOCC1)N1CCN(c2ccc(OC(F)(F)C(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-4-{[(E)-2-(tetrahydro-2H-pyran-4-yl)vinyl]sulfonyl}piperazine (3.13 g, 0.007 mol) was dissolved in THF (50 ml) and 50% hydroxylamine in H2O (12 ml) was added. Stirred at ambient temperature overnight, quenched with saturated NH4Cl solution and extracted with ethyl acetate. The organic phase was dried over MgSO4, filtered and evaporated to dryness to yield racemic 1-{[2-(hydroxyamino)-2-(tetrahydro-2H-pyran-4-yl)ethyl]sulfonyl}-4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]piperazine This was separated into its enantiomers using an AD Chiralpak chiral prep HPLC column and eluting with 20% methanol/acetonitrile. The second compound off the column gave the required enantiomer, 1-{[(2S)-2-(hydroxyamino)-2-(tetrahydro-2H-pyran-4-yl)ethyl]sulfonyl}-4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]piperazine.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]=[CH:6][S:7][CH:8]=1.[C:9]([C:11]1[CH:12]=[CH:13][C:14]([C@@H:20]2[C:25]([C:26]#[N:27])=[C:24]([CH3:28])[N:23]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=3)[C:22](=[O:39])[N:21]2[CH3:40])=[C:15]([S:17]([O-:19])=[O:18])[CH:16]=1)#[N:10].[Na+].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C>[C:9]([C:11]1[CH:12]=[CH:13][C:14]([C@@H:20]2[C:25]([C:26]#[N:27])=[C:24]([CH3:28])[N:23]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=3)[C:22](=[O:39])[N:21]2[CH3:40])=[C:15]([S:17]([CH2:3][C:4]2[N:5]=[CH:6][S:7][CH:8]=2)(=[O:19])=[O:18])[CH:16]=1)#[N:10]
Reactant: ClCc1cscn1
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)[O-])N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(=O)(=O)Cc2cscn2)N(C)C(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 110 °C

Procedure:
The reaction was carried out under argon. 4-(Chloromethyl)thiazole hydrochloride (86 mg, 505 μmol; 5.0 eq.), sodium 5-cyano-2-{(4S)-5-cyano-3,6-dimethyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidin-4-yl}benzenesulfinate (150 mg, 101 μmol; purity 32%), potassium carbonate (77 mg, 556 μmol; 5.5 eq.), potassium iodide (84 mg, 505 μmol; 5.0 eq.) and 18-crown-6 (13.4 mg, 51 μmol; 0.5 eq.) were suspended in DMF (3 ml). The mixture was then heated in a closed tube at 110° C. for 15 h. Molecular sieve (4 Å), potassium iodide (84 mg, 505 μmol; 5.0 eq.) and further 4-(chloromethyl)thiazole hydrochloride (86 mg, 505 μmol; 5.0 eq.) were then added, and the reaction mixture was again heated in a closed tube at 100° C. for 2 h. The mixture was then filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Gromsil C-18 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). The title compound was obtained as a solid (37 mg, 66% of theory).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][C@@H:12]3[CH2:14][C@H:9]2[CH2:10][N:11]3[CH3:15])=[CH:6][C:5]([C:16]#[N:17])=[CH:4][C:3]=1[NH:18][C:19]1[N:24]=[C:23]([N:25](CC)[CH2:26][C:27]2C=CC(OC)=CC=2)[C:22]2=[N:37][CH:38]=[C:39]([C:40]#[N:41])[N:21]2[N:20]=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)CCl>[Cl:1][C:2]1[C:7]([N:8]2[CH2:13][C@@H:12]3[CH2:14][C@H:9]2[CH2:10][N:11]3[CH3:15])=[CH:6][C:5]([C:16]#[N:17])=[CH:4][C:3]=1[NH:18][C:19]1[N:24]=[C:23]([NH:25][CH2:26][CH3:27])[C:22]2=[N:37][CH:38]=[C:39]([C:40]#[N:41])[N:21]2[N:20]=1
Reactant: CCN(Cc1ccc(OC)cc1)c1nc(Nc2cc(C#N)cc(N3C[C@@H]4C[C@H]3CN4C)c2Cl)nn2c(C#N)cnc12
Solvent: COc1ccccc1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CCNc1nc(Nc2cc(C#N)cc(N3C[C@@H]4C[C@H]3CN4C)c2Cl)nn2c(C#N)cnc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.1 %

Procedure:
2-((2-chloro-5-cyano-3-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (163 mg, 0.186 mmol) (crude, <=0.190 mmol) was dissolved in ClCH2CH2Cl (10 mL). Anisole (1 ml, 9.15 mmol) and TFA (2 ml, 26.0 mmol) were added and the mixture stirred at room temperature for 3 hours. The reaction mixture was evaporated to a sticky oil, dissolved in DMSO and purified by prep HPLC to give 48.5 mg of 2-((2-chloro-5-cyano-3-((1S,4S)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl)phenyl)amino)-4-(ethylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([F:19])([F:18])[F:17])[CH2:12][CH2:11]2)=[CH:6][C:4]=1[NH2:5].[Cl:20][C:21]1[CH:34]=[CH:33][C:24]([CH2:25][NH:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:23][C:22]=1[N:35]=[C:36]=[S:37]>C1COCC1>[Cl:20][C:21]1[CH:34]=[CH:33][C:24]([CH2:25][NH:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:23][C:22]=1[NH:35][C:36]([NH:5][C:4]1[CH:6]=[C:7]([N:10]2[CH2:11][CH2:12][CH:13]([C:16]([F:19])([F:17])[F:18])[CH2:14][CH2:15]2)[CH:8]=[CH:9][C:3]=1[NH:2][CH3:1])=[S:37]
Reactant: CNc1ccc(N2CCC(C(F)(F)F)CC2)cc1N
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1
Solvent: C1CCOC1
Product: CNc1ccc(N2CCC(C(F)(F)F)CC2)cc1NC(=S)Nc1cc(CNC(=O)C(C)(C)C)ccc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 2-methylamino-5-(4-trifluoromethyl-piperidin-1-yl)aniline (90 mg, 0.3 mmol) and N-(4-chloro-3-isothiocyanatobenzyl)-2,2-dimethyl-propionamide (93 mg, 0.3 mmol) in THF (10 mL) was stirred at rt for 4 h. The reaction mixture was concentrated and directly used in the next step. Yield: 180 mg (98%). HPLC-method A: Rt=2.23 min. MS m/z: 556 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:11][CH:10]([CH2:12][OH:13])[CH2:9][C:4]21[O:8][CH2:7][CH2:6][O:5]2.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:21][S:22]([O:1][CH2:2][CH:3]1[CH2:11][CH:10]([CH2:12][O:13][S:22]([CH3:21])(=[O:24])=[O:23])[CH2:9][C:4]21[O:5][CH2:6][CH2:7][O:8]2)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1CC(CO)C2(C1)OCCO2
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1CC(COS(C)(=O)=O)C2(C1)OCCO2
Temperature: 0 °C
Reaction time: 18 h

Procedure:
6,8-Bis(hydroxymethyl)-1,4-dioxaspiro[4.4]nonane (8.18 g, 43.5 mmol) was dissolved in dichloromethane (200 ml) and chilled to 0° C. To the chilled solution was added 4-dimethylaminopyridine (0.53 g, 4.4 mmol) and distilled triethylamine (18.2 ml, 131 mmol). Then methanesulfonyl chloride (7.41 ml, 11.0 g, 95.7 mmol) was added drop-wise via syringe over 10 min and the reaction was allowed to come to ambient temperature and stir for 18 h under nitrogen. The reaction was quenched with saturated sodium bicarbonate (25 ml) and stirred for 30 min. After stirring, the layers were separated and the aqueous phase extracted with dichloromethane (2×50 ml). The organics were combined, dried over sodium sulfate, filtered and concentrated to yield a reddish brown oil (14.9, 99.4%).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[NH:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][C:6]1=[O:14].O>S(=O)(=O)(O)O>[N+:1]([C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][CH:11]=1)[NH:5][C:6](=[O:14])[CH2:7]2)([O-:4])=[O:2]
Reactant: O=C1Cc2ccccc2N1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C1Cc2cc([N+](=O)[O-])ccc2N1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 47.9 %

Procedure:
Fuming nitric acid (1.58 ml, 39.4 mmol) was added dropwise to a solution of oxindole (5 g, 37.5 mmol) in concentrated sulphuric acid (25 ml) cooled by an ice bath and maintained below 5° C. The mixture was stirred for 30 minutes at 0° C. and then poured into water. The precipitate was collected by filtration and thoroughly washed with water. The solid was suspended in 50% acetic acid (100 ml) and heated at 90° C. for 1 hour. The mixture was allowed to cool, the solid product was collected by filtration, washed with water and dried under vacuum over phosphorus pentoxide at 40° C. to give 5-nitrooxindole (3.2 g, 48%).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][N:15]=1)=[O:13].[C:22](Cl)(=[O:27])[CH2:23][CH:24]([CH3:26])[CH3:25]>C(OCC)(=O)C.CCCCCC>[Cl:11][C:7]1[CH:6]=[C:5]2[C:10]([C:2]([NH:1][C:22](=[O:27])[CH2:23][CH:24]([CH3:26])[CH3:25])=[C:3]([C:12]([C:14]3[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][N:15]=3)=[O:13])[NH:4]2)=[CH:9][CH:8]=1
Reactant: COc1ccnc(C(=O)c2[nH]c3cc(Cl)ccc3c2N)c1
Reactant: CC(C)CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccnc(C(=O)c2[nH]c3cc(Cl)ccc3c2NC(=O)CC(C)C)c1

Procedure:
The title compound was prepared according to the procedure described in Example 19 employing 3-amino-6-chloro-2-(4-methoxy-pyridine-2-carbonyl)indole (Example 72) and isovaleryl chloride. m.p.: 162-163° C. (ethyl acetate/hexane)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH2:13][CH2:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[NH:9][C:8]2=[O:18])[CH2:3][CH2:2]1.[NH2:19][C@H:20]([CH2:35][C:36]1[CH:41]=[CH:40][C:39]([CH2:42][CH3:43])=[C:38]([CH2:44][CH3:45])[CH:37]=1)[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([N:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:25][CH2:24]1)=[O:22]>>[N:29]1([CH:26]2[CH2:27][CH2:28][N:23]([C:21](=[O:22])[C@H:20]([NH:19]/[C:4](=[N:7]/[C:8]#[N:9])/[N:1]3[CH2:2][CH2:3][CH:4]([N:7]4[CH2:13][CH2:12][C:11]5[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=5[NH:9][C:8]4=[O:18])[CH2:5][CH2:6]3)[CH2:35][C:36]3[CH:41]=[CH:40][C:39]([CH2:42][CH3:43])=[C:38]([CH2:44][CH3:45])[CH:37]=3)[CH2:24][CH2:25]2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Reactant: CCc1ccc(C[C@@H](N)C(=O)N2CCC(N3CCCCC3)CC2)cc1CC
Product: CCc1ccc(C[C@@H](N/C(=N/C#N)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCCCC3)CC2)cc1CC

Procedure:
Prepared analogously to Example 73 from 3-piperidin-4-yl-1,3,4,5-tetrahydrobenzo[d][1,3]diazepin-2-one and (R)-2-amino-1-[1,4′]bipiperidinyl-1′-yl-3-(3,4-diethylphenyl)-propan-1-one
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](Cl)=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][O:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[CH2:27][CH:26]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[NH2:37])[CH2:25][CH2:24]2>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][NH:37][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[CH:26]2[CH2:25][CH2:24][C:23]3[C:28](=[CH:29][CH:30]=[C:21]([O:20][CH3:19])[CH:22]=3)[CH2:27]2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1)CCC(c1ccccc1N)C2
Reactant: O=C(Cl)Cc1ccc(OCc2ccccc2)cc1
Product: COc1ccc2c(c1)CCC(c1ccccc1NCCc1ccc(OCc3ccccc3)cc1)C2
Yield: 36.4 %

Procedure:
Synthesized from 4-benzyloxyphenylacetyl chloride (2.3 g) and 2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine (1.5 g) according to an analogous synthetic method to Example 152, the title compound (1.0 g) was obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:17](=[O:19])[CH3:18])[CH:5]=[C:6]([CH3:16])[C:7]=1[O:8][Si:9]([CH3:15])([CH3:14])[C:10]([CH3:13])([CH3:12])[CH3:11].C[Si](OS(C(F)(F)F)(=O)=O)(C)C.C(N(CC)CC)C.[C:39]1([CH2:45][S:46][CH:47]([C:51](O)=[O:52])[C:48](O)=[O:49])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(Cl)Cl>[CH3:16][C:6]1[CH:5]=[C:4]([C:17]2[O:19][C:48](=[O:49])[C:47]([S:46][CH2:45][C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[C:51]([OH:52])[CH:18]=2)[CH:3]=[C:2]([CH3:1])[C:7]=1[O:8][Si:9]([CH3:14])([CH3:15])[C:10]([CH3:13])([CH3:11])[CH3:12]
Reactant: O=C(O)C(SCc1ccccc1)C(=O)O
Reactant: CC(=O)c1cc(C)c(O[Si](C)(C)C(C)(C)C)c(C)c1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(-c2cc(O)c(SCc3ccccc3)c(=O)o2)cc(C)c1O[Si](C)(C)C(C)(C)C

Procedure:
The title compound was prepared by Method A using 3', 5'-dimethyl-4'-[[dimethyl(1,1-dimethylethyl)silyl]oxy] acetophenone (1.50 g, 5.39 mmol), trimethylsilyltriflate (1.24 mL, 6.47 mmol), triethylamine (1.50 mL, 10.78 mmol), methylene chloride (13 mL), and diethyl ester of [(phenylmethyl)thio]propanedioic acid (1.00 g, 3.54 mmol). m.p. 137°-139° C.; 1H NMR (400 MHz, DMSO-d6) δ 0.21 (s, 6 H), 0.99 (s, 9H), 2.22 (s, 6 H), 3.96 (s, 2 H), 6.54 (s, 1 H), 6.99 (d, 1 H), 7.21 (m, 5 H), 7.44 (m, 2 H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24]([NH:26][C:27]3[N:28]=[C:29]([Br:32])[S:30][CH:31]=3)=[O:25])[N:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:32][C:29]1[S:30][CH:31]=[C:27]([NH:26][C:24]([NH:23][C:19]2[CH:20]=[CH:21][CH:22]=[C:17]([O:16][CH2:15][CH2:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[N:18]=2)=[O:25])[N:28]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCOc2cccc(NC(=O)Nc3csc(Br)n3)n2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccc(OCCC2CCNCC2)n1)Nc1csc(Br)n1

Procedure:
To a stirred solution of 4-(2-{6-[3-(2-bromo-thiazol-4-yl)-ureido]-pyridin-2-yloxy}-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (285 mg, 0.54 mmol) in anhydrous CH2Cl2 (6 mL) at RT, under N2, TFA (1.5 mL) was added. After 1.5 h the solvent was evaporated in vacuo. The residue was carefully treated with a saturated solution of NaHCO3 (aq) (10 mL), the precipitate was filtered off, washed with Et2O (3×5 mL) and dried in a vacuum oven at 60° C. for 5 h to yield the title compound as a white amorphous solid. MS m/z: 426.2, 428.2 (M+H). Calc'd. for C16H20BrN5O2S-426.33.