Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12]1[C:17](C#N)=[CH:16][C:15]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:14][N:13]=1.[ClH:25].[C:26](=[O:29])([O-])[O-:27].[Na+].[Na+]>O>[ClH:25].[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12]1[C:17]([C:26]([OH:27])=[O:29])=[CH:16][C:15]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:14][N:13]=1.[CH3:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[CH2:7][S:8][CH2:9][CH2:10][NH:11][C:12]1[C:17]([C:26]([OH:27])=[O:29])=[CH:16][C:15]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:14][N:13]=1
Reactant: O=C([O-])[O-]
Reactant: CCCCCc1cnc(NCCSCc2nc[nH]c2C)c(C#N)c1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCCCCc1cnc(NCCSCc2nc[nH]c2C)c(C(=O)O)c1

Procedure:
The 2-[2-(5-methyl-4-imidazolylmethylthio)ethyl]amino-3-cyano-5-n-pentylpyridine obtained above (2.53 g; 0.0074 moles) was treated with conc. hydrochloric acid (20 ml) and heated to reflux for 36 hours. After stripping the mixture to dryness, the residue was dissolved in a little water and basified to about pH6 with sodium carbonate solution giving a precipitate. The mixture was azeotroped to dryness and chromatographed on silica-gel using chloroform/ethanol (20:1) to collect the desired band. The 2-[2-(5-methyl-4-imidazolylmethylthio)ethyl]amino-5-n-pentylpyridine-3-carboxylic acid hemihydrochloride obtained (1.25 g) could not be crystallised and it was a straw-coloured glass. NMR data (DMSO-d6): --CH3CH2 at 0.88; (CH2)3 at 1.1-1.7; Im-CH3 at 2.24; pyr-CH2 at 2.47; CH2CH2S at 2.70; NCH2CH2 at 3.64; ImCH2S at 3.82; pyr-4H at 7,93; pyr-6H at 8.12 and Im-2H at 8.40.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([F:13])[C:10]([CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([N:31]1[CH2:30][CH2:29][CH:28]([NH:27][C:25]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:8]4[CH:9]=[C:10]([CH3:14])[C:11]([F:13])=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)[C:16]=3[NH:23][C:22]=2[CH3:24])=[O:26])[CH2:33][CH2:32]1)(=[O:36])[CH3:35]
Reactant: Cc1cc(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c(OCC2CC2)cc1F
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4cc(C)c(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-4-fluoro-5-methylphenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f40) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][O:9][C:10](=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:3]=1.CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:28]>[N+](CC)(CC)(CC)CC.[Cl-].C(#N)C>[Cl:28][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][O:9][C:10](=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCCC(=O)OCc1nccc(O)n1
Agent: CC[N+](CC)(CC)CC
Agent: [Cl-]
Solvent: CC#N
Solvent: CN(C)c1ccccc1
Product: CCCCCC(=O)OCc1nccc(Cl)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 300 mg (1.33 mMol) hexanoic acid 4-hydroxy-pyrimidin-2-ylmethyl ester, 487 mg (2.94 mMol) Et4NCl and 373 μl (2.94 mMol) N,N-dimethylaniline in 15 ml of acetonitrile, 1.22 ml (13.3 mMol) POCl3 are added. After stirring for 24 h at rt, the solution is concentrated in vacuo. The residue is re-dissolved in EtOAc and sat. NaHCO3, the aq. layer separated off and extracted twice with EtOAc. The organic phases are dried (Na2SO4) and concentrated. Chromatography (Combi Flash; hexane/ether 199:1→9:1→3:2) gives the title compound as an oil: MS: [M+1]+=243/245; TLC(CH2Cl2): Rf=0.26.
Reaction SMILES: [C:1]1([C:7]([OH:9])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[CH2:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.S([O-])([O-])(=O)=O.[NH4+].[NH4+]>O>[CH2:6]1[CH:1]2[CH:2]([C:10]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[C:7]2=[O:9])[CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C1=CCCCC1
Reactant: C1CCCCC1
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Solvent: O
Product: O=C1C2=C(CCCC2)C2CCCCC12
Temperature: 70 °C
Reaction time: 4.5 h
Yield: 43 %

Procedure:
In a 250 ml three neck round bottom flask, equipped with a mechanical stirrer, a thermometer and a reflux condenser 16.276 g of polyphosphoric acid was charged and heated to a temperature of 70° C. 16.276 g of 1-cyclohexenecarboxylic acid and 10.592 g of cyclohexane were added dropwise maintaining a temperature of the reaction mass below 100° C. The mixture was stirred at 78° C. for additional 4.5 hours. The dark brown reaction mass was was poured onto 237 g of ice and neutralised with 89 g aqueous ammonium sulphate solution in 474 g of water. The resulting mixture was then extracted 4 times with 300 ml of petroleum ether and 300 ml of diethyl ether. All organic layers were combined, washed successively with 5% aqueous ammonium hydroxide, brine dried over magnesium sulphate and concentrated in vacuum. Fractional distillation (b.p. 130° C. at 3.0 mmHg) of this crude product yielded 10.294 g of 1,2,3,4,4a,5,6,7,8,9a-decahydro-9H-fluoren-9-one. 1H-NMR (CDCl3): δ 2.73 (q, J=7 Hz, 1 H), 2.2–0.5 (m, 17 H).
Reaction SMILES: OC([CH2:13][C:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)NC=1)(C(O)=O)CC(=NO)C(O)=O.Cl.C(=O)([O-])[O-].[Na+].[Na+].O[C@](CC1C2C(=CC=CC=2)NC=1)(C(O)=O)CC(=[N:37]O)C(O)=O>O.C(OCC)(=O)C>[C:22]1([C@H:14]([NH2:37])[CH3:13])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)C(CC(O)(Cc1c[nH]c2ccccc12)C(=O)O)=NO
Reactant: O=C(O)C(C[C@@](O)(Cc1c[nH]c2ccccc12)C(=O)O)=NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@@H](N)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
After 44.7 g (0.131 mol) of the ammonium salt of 4-hydroxy-4-(3-indolylmethyl)-2-hydroxyiminoglutaric acid was dissolved in 500 ml of water at 25° C., the resulting aqueous solution was adjusted to pH 2 using 25.5 g of 36% hydrochloric acid. The acidic solution was extracted in 1300 ml of ethyl acetate, and the resulting ethyl acetate solution was rinsed with 200 ml of aqueous saturated sodium chloride solution. 500 ml of an aqueous sodium carbonate solution (13.9 g (0.131 mole) of sodium carbonate) was added to the resulting ethyl acetate solution for agitation, to separate the aqueous alkali solution from ethyl acetate. 23.1 g of 36% hydrochloric acid was added to the resulting aqueous alkali solution, to adjust the solution to pH 2. 6.99 g (57.6 mmol) of(R)-(+)-1-phenylethylamine was added dropwise to the resulting aqueous acidic solution and the solution stirred at 25° C. for one hour. The resulting crystal was filtered and dried under reduced pressure, to obtain 21.8 g (47.8 mmol) of the (R)-(+)-1-phenylethylamine salt of (4S)-4-hydroxy-4-(3-indolylmethyl)-2-hydroxyiminoglutaric acid. (Yield, 72.7%; optical purity, 87.4%.)
Reaction SMILES: O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.[C:16]([NH:19][NH:20][C:21]([C@@H:23]1[CH2:29][CH2:28][C@@H:27]2[CH2:30][N:24]1[C:25](=[O:39])[N:26]2[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:22])(=O)[CH3:17].N1C=CC=CC=1>C(Cl)Cl>[CH2:32]([O:31][N:26]1[C:25](=[O:39])[N:24]2[CH2:30][C@H:27]1[CH2:28][CH2:29][C@H:23]2[C:21]1[O:22][C:16]([CH3:17])=[N:19][N:20]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1nnc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.4 %

Procedure:
(CF3SO2)2O (0.50 mL) was slowly added to a solution of (2S,5R)—N′-acetyl-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide (0.5 g) and pyridine (0.5 mL) in dry DCM (10 mL) at −10° C. The reaction mixture was stirred at 0° C. for 1 h and then quenched carefully with sat. NaHCO3. The organic layer was separated and the aqueous layer was exacted with EtOAc (3×). The combined organic layer was dried over Na2SO4, concentrated and purified by silica gel column chromatography (gradient elution 10:1 to 1:1 petroleum ether/EtOAc) to afford (2S,5R)-6-(benzyloxy)-2-(5-methyl-1,3,4-oxadiazol-2-yl)-1,6-diaza-bicyclo[3.2.1]octan-7-one (0.3 g, 63%) as a slight yellow solid. ESI-MS (EI+, m/z): 315.0 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.CN([CH2:17][C:18]1[C:26]2[C:21](=[N:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)C>C1(C)C=CC=CC=1>[I:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH2:17][C:18]3[C:26]4[C:21](=[N:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: CN(C)Cc1c[nH]c2ncccc12
Reactant: Ic1ccc(N2CCNCC2)nc1
Solvent: Cc1ccccc1
Product: Ic1ccc(N2CCN(Cc3c[nH]c4ncccc34)CC2)nc1
Temperature: 25 °C
Yield: 88 %

Procedure:
To a solution of 1-(5-iodopyridin-2-yl)-piperazine (100 mg, 0.34 mmol) in toluene (2 mL) (prepared in Example 2(b)) was added 3-(N,N-dimethylaminomethyl)-1H-pyrrolo[2,3-b]pyridine (58 mg, 0.32 mmol) (prepared in Example 1(a)). The mixture was heated at reflux over night and then allowed to cool to room temperature. The resulting solid was filtered and dried in vacuo to give 3-[4-(5-iodopyridin-2-yl)-piperazin-1-yl]methyl-1H-pyrrolo[2,3-b]pyridine as a colourless solid (118 mg, 79%). δH(300 MHz DMSO-d6) 2.47 (4H, m, piperazinyl), 3.45 (4H, m, piperazinyl), 3.68 (2H, s), 6.71 (1H, d, J=9), 7.05 (1H, dd, J=4.8 and 7.9), 7.39 (1H, s), 7.75 (1H, d, J=8.8), 8.06 (1H, d, J=7.8), 8.21 (1H, d, J=4.5), 8.23 (1H, s), 11.51 (1H, br s, NH)
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[CH2:4][S:5][C:6]1[N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:20])[F:19])[C:8]([OH:11])=[N:9][N:10]=1.[Cl:27][C:28]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:29]=1[CH2:30]Br.C[O-].[Na+].Cl>CN(C=O)C>[Cl:27][C:28]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:29]=1[CH2:30][O:11][C:8]1[N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])[C:6]([S:5][CH2:4][C:3]2[C:22]([F:26])=[CH:23][CH:24]=[CH:25][C:2]=2[Cl:1])=[N:10][N:9]=1
Reactant: Oc1nnc(SCc2c(F)cccc2Cl)n1-c1ccccc1C(F)(F)F
Reactant: Fc1cccc(Cl)c1CBr
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cccc(Cl)c1COc1nnc(SCc2c(F)cccc2Cl)n1-c1ccccc1C(F)(F)F
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 5-((2-chloro-6-fluorobenzyl)thio)-4-(2-(trifluoromethyl)phenyl)-4H-1,2,4-triazol-3-ol (50 mg, 0.124 mmol), 2-chloro-6-fluorobenzyl bromide (39 mg, 0.175 mg), and sodium methoxide (18 mg, 0.33 mmol) in anhydrous DMF was stirred at 80° C. for 8 h. The reaction mixture was cooled to room temperature and neutralized to pH 5 with 5N HCl. The solvent was removed in vacuo and the residue was purified by reverse phase HPLC to afford 3-((2-Chloro-6-fluorobenzyl)oxy)-5-((2-chloro-6-fluorobenzyl)thio)-4-(2-(trifluoromethyl)phenyl)-4H-1,2,4-triazole (598). 1H NMR (400 MHz, CDCl3) δ: 7.81-7.79 (m, 1H), 7.63-7.60 (m, 2H), 7.33-7.24 (m, 2H), 7.19-7.14 (m, 2H), 7.10-7.04 (m, 2H), 6.90-6.85 (m, 2H), 5.20 (s, 2H), 4.23 (dd, J=13.0, 1.6, 1H), 4.15 (dd, J=13.0, 1.6, 1H). LC-MS ESI m/z; found 546.0 [M+H]+.
Reaction SMILES: C[O-].[Na+].Cl.[NH2:5][CH2:6][C:7]([NH2:9])=[O:8].C(O)(=O)C.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1[C:24](=O)[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>CO>[NH2:9][C:7](=[O:8])[CH2:6][NH:5]/[C:24](/[C:17]1[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:16]=1[O:15][CH3:14])=[CH:25]\[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: NCC(N)=O
Reactant: CCOC(=O)CC(=O)c1cc(OC)ccc1OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)/C=C(\NCC(N)=O)c1cc(OC)ccc1OC
Temperature: 65 °C
Yield: 106.9 %

Procedure:
A 5-L reaction vessel was charged with methanol (3.3 L), sodium methoxide (102.4 g, 1.8 moles), and glycinamide hydrochloride (202 g, 1.8 moles). The mixture was heated at 65° C. for 1 hour before cooling to 50° C. and adding acetic acid (514.25 mmoles, 30.88 g, 29.47 mL) and ethyl 3-(2,5-dimethoxyphenyl)-3-oxopropanoate (300 g, 1.03 mole). After heating at reflux for 16 hours, the reaction mixture was stirred as it was cooled to 10° C. After 30 min the resulting solid was collected by vacuum filtration, pulling dry to form a cake that was dried in a vacuum oven (20 mm Hg, 65° C.) for 14 hours to afford the title compound (339.4 g).
Reaction SMILES: [C:1]([N:5]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)[C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])(=[O:4])[CH2:2][CH3:3].[CH2:20]([NH:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:1]([N:5]([CH2:14][CH2:15][CH2:16][C:17]([N:27]([CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[O:19])[C:6]1[C:7]([CH3:13])=[CH:8][CH:9]=[CH:10][C:11]=1[CH3:12])(=[O:4])[CH2:2][CH3:3]
Reactant: CCOC(=O)CCCNCc1ccccc1
Reactant: CCC(=O)N(CCCC(=O)O)c1c(C)cccc1C
Product: CCOC(=O)CCCN(Cc1ccccc1)C(=O)CCCN(C(=O)CC)c1c(C)cccc1C

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-propionyl-4-(2,6-dimethylanilino)butyric acid and ethyl 4-(benzylamino)butyrate and suitable processing produces ethyl N-[N-propionyl-4-(2,6-dimethylanilino)butyryl]-4-(benzylamino)butyrate (oil), saponification of which and processing of the reaction product yields N-[N-propionyl-4-(2,6-dimethylanilino)butyryl]-4-(benzylamino)butyric acid (oil).
Reaction SMILES: C([O:5][C:6](=[O:35])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([CH2:27][C:28]2[CH:33]=[CH:32][C:31](Br)=[CH:30][CH:29]=2)[C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[C:36]([C:38]1[CH:43]=[CH:42][C:41](OB(O)O)=[CH:40][CH:39]=1)#[N:37].[ClH:48].C(OCC)(=O)C>C(OCC)C>[ClH:48].[C:36]([C:38]1[CH:43]=[CH:42][C:41]([C:31]2[CH:30]=[CH:29][C:28]([CH2:27][N:18]([C:19]3[N:20]=[CH:21][C:22]([CH2:25][CH3:26])=[CH:23][N:24]=3)[CH2:17][CH2:16][C:14]3[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:35])[S:12][CH:13]=3)=[CH:33][CH:32]=2)=[CH:40][CH:39]=1)#[N:37]
Reactant: N#Cc1ccc(OB(O)O)cc1
Reactant: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)Cc2ccc(Br)cc2)nc1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)O)n2)Cc2ccc(-c3ccc(C#N)cc3)cc2)nc1

Procedure:
A compound obtained using 2-[(4-{2-[(4-bromobenzyl)(5-ethylpyrimidin-2-yl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester synthesized in Example 402-1 and 4-cyanophenylboric acid as starting materials and by an operation similar to that of Example 407 was dissolved in diethyl ether, and reacted with 4 mol/L hydrochloric acid-ethyl acetate to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-:17].[Na+]>C1COCC1.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]([NH:8][C@@H:9]([CH3:13])[C:10]([OH:12])=[O:17])=[O:12])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C
Reactant: [OH-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 191.4 %

Procedure:
To a solution of (S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoic acid (18) (6.5 g, 19.7 mmol) in THF (30 mL) was added NaOH (1.7 g, 43.8 mmol) in H2O (60 mL) and the reaction mixture stirred at ambient temperature for 16 h. THF was subsequently removed in vacuo and the aqueous phase washed with EtOAc (50 mL). The aqueous phase was then adjusted to pH ˜2 by addition of 1M HCl and extracted with EtOAc (3×50 mL). The organics were combined dried over MgSO4 and evaporated to give the desired compound (20) as a white solid (5.7 g, 95%); AnalpH2_MeOH; Rt 2.61 min; m/z 303 (MH+); white solid
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH2:26][CH3:27])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]1)=[O:31]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH2:26][CH3:27])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:29][C:30]([N:32]2[CH2:37][CH2:36][N:35]([CH3:38])[CH2:34][CH2:33]2)=[O:31])=[CH:4][CH:3]=1
Reactant: CCOc1ccccc1N1CCN(C(=O)c2c[nH]c3cc(Cl)ccc23)CC1
Reactant: CN1CCN(C(=O)CCl)CC1
Product: CCOc1ccccc1N1CCN(C(=O)c2cn(CC(=O)N3CCN(C)CC3)c3cc(Cl)ccc23)CC1

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-ethoxy-phenyl)-piperazin-1-yl]-methanone (preparation described herein), with (commercially available) 2-chloro-1-(4-methyl-piperazin-1-yl)-ethanone gave the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[IH:13].[OH-].[Na+]>>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([I:13])=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: I
Reactant: Clc1ccc2c(Cl)ccnc2c1
Agent: [Na+]
Agent: [OH-]
Product: Clc1ccc2c(I)ccnc2c1
Temperature: 130 °C

Procedure:
4,7-Dichloroquinoline (50 g) was added, in small portions, to HI (425 mL) at r.t. and then heated at 130° C. for 5 h. The mixture was cooled, poured into ice/H2O (600 mL), made basic (pH 10) with 10N NaOH, and extracted with CHCl3. The combined organics were washed with NH4OAc buffer, 10% Na2S2O3 and brine. Drying (Na2SO4) and concentration provided the title compound that was used as such.
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][C:15]([N:18]1[CH2:23][CH2:22][CH:21]([N:24]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]([CH2:33][CH3:34])[C:25]2=[O:35])[CH2:20][CH2:19]1)([CH3:17])[CH3:16])=O)C1C=CC=CC=1.C(Cl)(Cl)Cl>CO.[Pd]>[NH2:11][CH2:12][CH2:13][CH2:14][C:15]([N:18]1[CH2:23][CH2:22][CH:21]([N:24]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[N:26]([CH2:33][CH3:34])[C:25]2=[O:35])[CH2:20][CH2:19]1)([CH3:17])[CH3:16]
Reactant: CCn1c(=O)n(C2CCN(C(C)(C)CCCNC(=O)OCc3ccccc3)CC2)c2ccccc21
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCn1c(=O)n(C2CCN(C(C)(C)CCCN)CC2)c2ccccc21
Reaction time: 48 h

Procedure:
A solution of 1-(5-benzyloxycarbonylamino-2-methyl-2-pentyl)-4-(3-ethyl-2-oxo-1-benzimidazolinyl)piperidine (93 mg, 0.19 mmol) in methanol (8 mL) containing chloroform (0.04 mL, 0.05 mmol) and 10% palladium/carbon (45 mg) was hydrogenated at atmospheric pressure for two days. The catalyst was removed by filtration, the solvent evaporated and the residue redissolved in chloroform. This solution was washed with aq. Na2CO3, dried (Na2SO4) and evaporated to give 1-(5-amino-2-methyl-2-pentyl)-4-(3-ethyl-2-oxo-1-benzimidazolinyl)piperidine as an oil.
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]([CH2:8][NH:9]CC2C=CC=CC=2)[CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:3]1>CO.[Pd]>[NH2:9][CH2:8][C@@H:7]1[CH2:6][CH2:5][N:4]([C:17]([O:19][C:20]([CH3:22])([CH3:21])[CH3:23])=[O:18])[CH2:3][C@H:2]1[OH:1]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CNCc2ccccc2)[C@H](O)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@@H](CN)[C@H](O)C1
Yield: 75.5 %

Procedure:
A mixture of intermediate (1-d) (max. 0.023 mol crude residue) in methanol (100 ml) was hydrogenated with palladium-on-carbon (10%, 1 g) as a catalyst. After uptake of H2 (1 equivalent), the catalyst was filtered off and the filtrate was evaporated. The residue was solidified in DIPE+ACN, filtered off and dried (vacuum, 40° C.), yielding 4 g (76%) of 1,1-dimethylethyl (trans)-4-(aminomethyl)-3-hydroxy-1-piperidine-carboxylate (intermediate 1-e, mp. 178° C.).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([CH2:12][OH:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[O:14]1[CH:19]=[CH:18][CH2:17][CH2:16][CH2:15]1>C(Cl)Cl.O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[Br:1][C:2]1[CH:11]=[CH:10][C:9]([CH2:12][O:13][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][O:14]2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: OCc1ccc(Br)c2cccnc12
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: O
Product: Brc1ccc(COC2CCCCO2)c2ncccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 128.4 %

Procedure:
To a solution of (5-bromoquinolin-8-yl)methanol (8.0 g, 33.6 mmol) in methylene chloride (120 mL) were added pyridinium p-toluenesulfonate (844 mg, 3.3 mmol) and 3,4-dihydro-2H-pyran (6.1 mL, 67.2 mmol) and stirred at RT for 16 h. The reaction mixture was diluted with water, extracted with methylene chloride, dried with magnesium sulfate and concentrated. Purification by MPLC (20% ethyl acetate in hexanes) afforded 13.9 g of the title compound as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11]C[N:9]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:8]2=[O:19])=[C:4]([Cl:22])[CH:3]=1.[OH:23][CH:24]1[CH2:28][CH2:27][NH:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O.[Cu]I>[Cl:22][C:4]1[CH:3]=[C:2]([N:26]2[CH2:27][CH2:28][CH:24]([OH:23])[CH2:25]2)[CH:21]=[CH:20][C:5]=1[CH2:6][CH:7]1[CH2:12][CH2:11][N:9]([CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)[C:8]1=[O:19]
Reactant: O=C1C(Cc2ccc(Br)cc2Cl)CCCN1C1CCCCC1
Reactant: OC1CCNC1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=C1C(Cc2ccc(N3CCC(O)C3)cc2Cl)CCN1C1CCCCC1
Yield: 19.2 %

Procedure:
Dissolve 3-(4-bromo-2-chloro-benzyl)-1-cyclohexyl-piperidin-2-one (Example 55) (0.2 g, 0.54 mmol), rac-3-hydroxy-pyrrolidine (0.053 mL, 0.64 mmol), copper (I) iodide (10.5 mg, 0.05 mmol), in dimethylacetamide (1 mL) with potassium carbonate (0.13 g, 0.95 mmol), and heat at 90° C. 48 h. Evaporate and purify the residue by chromatography on silica gel (eluting 10% to 100% ethyl acetate in hexane) to give the desired product (39 mg, 19%). MS (ES+) m/z=377 (M+H)+.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:34])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]4[N:17]=[C:18]([O:25][C:26]5[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=5)[CH:19]=[C:20](S(C)(=O)=O)[C:15]4=[N:14][CH:13]=3)=[CH:8][C:7]=2[CH3:33])[CH2:3][CH2:2]1.[NH2:35][CH2:36][CH:37]([OH:42])[C:38]([F:41])([F:40])[F:39].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH:1]1([NH:4][C:5](=[O:34])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]4[N:17]=[C:18]([O:25][C:26]5[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=5)[CH:19]=[C:20]([NH:35][CH2:36][CH:37]([OH:42])[C:38]([F:41])([F:40])[F:39])[C:15]4=[N:14][CH:13]=3)=[CH:8][C:7]=2[CH3:33])[CH2:3][CH2:2]1
Reactant: Cc1cc(-c2cnc3c(S(C)(=O)=O)cc(Oc4cccc(F)c4)nn23)ccc1C(=O)NC1CC1
Reactant: NCC(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: Cc1cc(-c2cnc3c(NCC(O)C(F)(F)F)cc(Oc4cccc(F)c4)nn23)ccc1C(=O)NC1CC1
Temperature: 160 °C

Procedure:
To a stirred solution of 96 mg (200 μmol) N-cyclopropyl-4-[6-(3-fluorophenoxy)-8-(methylsulfonyl)imidazo[1,2-b]pyridazin-3-yl]-2-methylbenzamide which was prepared according to intermediate example 486a in 2 mL NMP is added 77.5 mg (0.6 mmol) 3-amino-1,1,1-trifluoropropan-2-ol and 77.5 mg (0.6 mmol) DIPEA and the mixture is heated at 160° C. for 30 min in a microwave oven. After working up and purification 10.5 mg (9%) of the title compound are obtained.