Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[I:14]Cl>CO>[I:14][C:10]1[C:11]([CH3:13])=[CH:12][C:3]([O:2][CH3:1])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(C)cc1OC
Reactant: ClI
Solvent: CO
Product: COC(=O)c1cc(I)c(C)cc1OC
Temperature: 50 °C

Procedure:
Methyl 2-methoxy-4-methylbenzoate (1.5 g, 8.32 mmol, 1 eq) was dissolved in methanol. To this solution was added dropwise iodine monochloride (6.75 g, 41.6 mmol, 5 eq) in methanol at room temperature. The reaction mixture was heated at 50° C. for 15 h. Finally, methanol was concentrated, diluted with water and extracted with ethyl acetate. The organic layer was washed with 0.1 N HCl (50 ml), water (100 ml) and brine solution (100 ml). The product was purified by column chromatography using 60-120 silica gel and using 5% ethyl acetate/hexane as eluent. Yield: 1.7 g (80%). 1H NMR (400 MHz, CDCl3): δ 2.44 (s, 3H), 3.86 (s, 3H), 3.88 (s, 3H), 6.86 (s, 1H), 8.20 (s, 1H). LCMS: (ES+) m/z=307.0 (M+H).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[CH2:9]=[O:10].[BH4-].[Na+].[C:13]([O-])([O-])=O.[K+].[K+]>CO>[CH3:9][O:10][C:3](=[O:5])[C@@H:2]1[CH2:6][CH2:7][CH2:8][N:1]1[CH3:13]
Reactant: C=O
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: O=C([O-])[O-]
Agent: [BH4-]
Agent: [K+]
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@@H]1CCCN1C
Temperature: 0 °C

Procedure:
The L-proline is dissolved in methanol, the solution is cooled to 0° C. and 36% aqueous formaldehyde is added with stirring. To this solution is then added powdered NaBH4 in portions while maintaining the temperature between -5° and +5° C. The reaction is filtered, the filter cake extracted with solvent and combined with the filtrate, and the solvents evaporated to dryness. The residual N-methyl-L-proline is then dissolved in and reacted with methanol in the presence of H2SO4 at reflux for 4-24 hr. The reaction mixture is cooled to 0° C., and with vigorous stirring a solution of K2CO3 is slowly added to the mixture, until the pH is between pH 7 and 8, then the title product is extracted from the basic mixture and isolated after drying and removal of the solvent.
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-])=O)=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][CH:3]=1.C(O)(=O)C.C(O)C.[OH-].[NH4+]>[Zn].O>[NH2:12][C:11]1[C:2]([Cl:1])=[CH:3][CH:4]=[C:5]2[C:10]=1[CH:9]=[N:8][CH:7]=[CH:6]2
Reactant: O=[N+]([O-])c1c(Cl)ccc2ccncc12
Agent: [NH4+]
Agent: [OH-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: Nc1c(Cl)ccc2ccncc12

Procedure:
A mixture of 9.5 g. of 7-chloro-8-nitroisoquinoline, and 14.4 g. of zinc and 48 ml. of acetic acid in 450 ml. of ethanol and 70 ml. of water is heated on a steam bath for five minutes. The reaction mixture is cooled, made alkaline with aqueous ammonium hydroxide and extracted with ethyl acetate. The ethyl acetate is removed from the extract in vacuo to give, as the residue, 8-amino-7-chloroisoquinoline.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:13][CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>>[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22]([N:10]2[CH2:11][CH2:12][CH2:13][CH:9]2[C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:1])([F:14])[F:15])=[CH:4][CH:5]=2)(=[O:24])=[O:23])=[CH:18][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: FC(F)(F)c1ccc(C2CCCN2)cc1
Product: Cc1ccc(S(=O)(=O)N2CCCC2c2ccc(C(F)(F)F)cc2)cc1

Procedure:
The title compound, white solid, m.p. 99° C. and MS: m/e=369 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(4-trifluoromethyl-phenyl)-pyrrolidine and toluene-4-sulfonyl chloride.
Reaction SMILES: [Br:1][C:2]1[C:3]([Br:15])=[C:4]([Br:14])[C:5]([Br:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]=12.[NH2:16][C:17]1[C:18]([F:30])=[CH:19][C:20]([Cl:29])=[C:21]([CH:28]=1)[C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23]>C1(C)C=CC=CC=1>[Br:13][C:5]1[C:4]([Br:14])=[C:3]([Br:15])[C:2]([Br:1])=[C:7]([C:8]([NH:16][C:17]2[CH:28]=[C:21]([C:22]([O:24][CH:25]([CH3:26])[CH3:27])=[O:23])[C:20]([Cl:29])=[CH:19][C:18]=2[F:30])=[O:9])[C:6]=1[C:11]([OH:10])=[O:12]
Reactant: O=C1OC(=O)c2c(Br)c(Br)c(Br)c(Br)c21
Reactant: CC(C)OC(=O)c1cc(N)c(F)cc1Cl
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)c1cc(NC(=O)c2c(Br)c(Br)c(Br)c(Br)c2C(=O)O)c(F)cc1Cl
Reaction time: 8 h

Procedure:
Tetrabromophthalic anhydride (6.67 g, 0.014 mole) and 1-methylethyl 5-amino-2-chloro-4-fluorobenzoate (3.33 g, 0.014 mole) were heated to reflux with stirring in about 150 ml of toluene, then left overnight at room temperature. Filtration of the reaction mixture gave the title compound, m.p. 160°-165° C. (decomp.).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:26]1[N:31]([CH3:32])[C:30](=[O:33])[CH:29]=[C:28]([C:34]2[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=2)[N:27]=1>O1CCCC1>[CH3:32][N:31]1[C:30](=[O:33])[CH:29]=[C:28]([C:34]2[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=2)[N:27]=[C:26]1[N:15]1[CH2:16][CH2:17][CH:12]([C:9]2[CH:8]=[CH:7][C:6]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:11][CH:10]=2)[CH2:13][CH2:14]1
Reactant: c1cc(N2CCCC2)ccc1C1CCNCC1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1c(N2CCC(c3ccc(N4CCCC4)cc3)CC2)nc(-c2ccncc2)cc1=O
Yield: 81 %

Procedure:
A solution of 4-(4-pyrrolidin-1-yl-phenyl)-piperidine (215 mg, 0.933 mmol) and triethylamine (391 mg, 3.86 mmol), 2-chloro-3-methyl-6-(pyridin-4-yl)-3H-pyrimidin-4-one (187 mg, 0.844 mmol) in tetrahydrofuran (10 mL) was refluxed for 5 hr. The resulting solution was diluted with tetrahydrofuran and filtrated. After removal of the solvents under reduced pressure and the purification of the resulting residue by CHEM ELUT CE1010 (manufactured by VARIAN) eluting dichloromethane/ethanol (15/1, v/v) and wash with ethyl acetate afforded 3-methyl-6-pyridin-4-yl-2-(4-(4-pyrrolidin-1-yl-phenyl)-piperidin-1-yl)-3H-pyrimidin-4-one (284 mg, 81%) as a solid.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=CC=C[CH:2]=1.[N:11]1[CH:12]=[N:13][N:14]2[CH:19]=[C:18]([CH2:20][NH:21][C:22]([C:24]3[S:25][C:26]([CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[CH:27][CH:28]=3)=[O:23])[CH:17]=[CH:16][C:15]=12.N1C=CN2C=CC(CNC(=O)C3C=CC(C4CCNCC4)=CC=3)=CC=12>>[CH3:2][CH:1]([S:7]([N:32]1[CH2:33][CH2:34][CH:29]([C:26]2[S:25][C:24]([C:22]([NH:21][CH2:20][C:18]3[CH:17]=[CH:16][C:15]4[N:14]([N:13]=[CH:12][N:11]=4)[CH:19]=3)=[O:23])=[CH:28][CH:27]=2)[CH2:30][CH2:31]1)(=[O:9])=[O:8])[CH3:6]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C(NCc1ccc2ncnn2c1)c1ccc(C2CCNCC2)s1
Agent: O=C(NCc1ccn2ccnc2c1)c1ccc(C2CCNCC2)cc1
Product: CC(C)S(=O)(=O)N1CCC(c2ccc(C(=O)NCc3ccc4ncnn4c3)s2)CC1

Procedure:
The title compound was prepared as described in Example 682, substituting propane-2-sulfonyl chloride for benzenesulfonyl chloride and N-([1,2,4]triazolo[1,5-a]pyridin-6-ylmethyl)-5-(piperidin-4-yl)thiophene-2-carboxamide for N-(imidazo[1,2-a]pyridin-7-ylmethyl)-4-(piperidin-4-yl)benzamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 9.03 (t, J=5.8 Hz, 1H), 8.86 (d, J=1.5 Hz, 1H), 8.48 (s, 1H), 7.83 (dd, J=9.1, 0.9 Hz, 1H), 7.64 (m, 2H), 6.97 (dd, J=3.7, 0.9 Hz, 1H), 4.53 (d, J=5.8 Hz, 2H), 3.71 (m, 2H), 3.25 (m, 1H), 3.02 (m, 3H), 2.00 (m, 2H), 1.56 (m, 2H), 1.22 (d, J=6.8 Hz, 6H); MS (ESI(+)) m/e 448 (M+H)+.
Reaction SMILES: [F:1][CH2:2][C:3]([N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20])([CH2:6][CH2:7][CH2:8][OH:9])[C:4]#[N:5].N1C=CC=CC=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[F:1][CH2:2][C:3]([N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20])([CH2:6][CH2:7][CH2:8][O:9][S:28]([CH3:27])(=[O:30])=[O:29])[C:4]#[N:5]
Reactant: N#CC(CF)(CCCO)N1C(=O)c2ccccc2C1=O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)OCCCC(C#N)(CF)N1C(=O)c2ccccc2C1=O
Reaction time: 8 h
Yield: 86.5 %

Procedure:
A mixture of 2-fluoromethyl-2-phthalimido-5-hydroxypentanenitrile (42.8 g), dry pyridine (170 ml), and dry dichloromethane (350 ml) is stirred and cooled with ice/salt mixture. Freshly distilled methanesulfonylchloride (15.7 g) in dichloromethane (200 ml) is slowly added, and stirring is continued at room temperature overnight. The mixture is then poured onto ice/2N HCl, and the organic phase is extracted subsequently with 1N HCl, water, 10% sodium bicarbonate, and water (3×). Drying (MgSO4), treatment with charcoal (room temperature), and evaporation gives 2-fluoromethyl-2-phthalimido-5-methanesulfonyloxypentanenitrile as a brown oil (42 g).
Reaction SMILES: S([CH2:5][CH2:6][C:7]#[CH:8])(C)(=O)=O.[CH2:9]([C:16]1([OH:22])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:9]([C:16]1([OH:22])[CH2:21][CH2:20][N:19]([CH2:8][CH2:7][C:6]#[CH:5])[CH2:18][CH2:17]1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: OC1(Cc2ccccc2)CCNCC1
Reactant: C#CCCS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C#CCCN1CCC(O)(Cc2ccccc2)CC1
Yield: 86.3 %

Procedure:
A mixture of 1-mesylbut-3-yne (1.63 g, 11.0 mmol), 4-benzyl-4-hydroxypiperidine (1.91 g, 10.0 mmol) and K2CO3 (4.14 g, 30.0 mmol) in 50 mL of CH3CN is refluxed for 12 hr. The mixture is filtered and washed with EtOAc (3×30 mL). The filtrate is evaporated in vacuo and is purified by flash chromatography to give the product as a colorless solid (2.1 g, 86%): mp 51-53° C.; 1H NMR (CDCl3) 1.50 (m, 2 H), 1.65 (m, 3 H), 1.97 (s, 1 H), 2.35 (m, 4 H), 2.62 (m, 4 H), 2.75 (s, 1 H), 7.21-7.31 (m, 5 H).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])=[CH:5][CH:4]=1.ClC1C=CC=C(C(OO)=[O:26])C=1.C([O-])(O)=O.[Na+].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.O>[Cl:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][S:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:26])=[O:11])=[CH:7][CH:8]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S(Cc1ccc(CCl)cc1)c1ccccc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: O=S(=O)(Cc1ccc(CCl)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
27.61 g (0.104 mol) (1a) was dissolved in 400 ml CH2Cl2. This solution was added dropwise to an ice-cooled solution of 36.03 g (0.208 mol) 3-chloroperbenzoic acid in 600 ml CH2Cl2 and 33.61 g (0.375 mol) NaHCO3 in 200 ml H2O. After the addition of (1a) the mixture was allowed to warm up to room temperature, and this was followed by another 2 hours' stirring. The reaction mixture was then poured into 500 ml 5% Na2CO3 solution. The organic layer was washed with 500 ml 5% Na2S2O3 solution. The CH2Cl2 was dried over MgSO4 and evaporated. The precipitate was purified by recrystallization from hexane/toluene. Yield: 26.65 g (91%); m.p.=170.3-170.9° C. (dec.)
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:8]1.Br[C:23]1[C:28]([Cl:29])=[CH:27][C:26]([C:30]([F:33])([F:32])[F:31])=[CH:25][N:24]=1>>[Cl:29][C:28]1[C:23]([N:17]2[CH2:16][CH2:15][C:14]3[C:19](=[CH:20][CH:21]=[C:12]([N:9]4[CH2:10][CH2:11][C@H:7]([N:3]5[CH2:4][CH2:5][CH2:6][C@@H:2]5[CH3:1])[CH2:8]4)[CH:13]=3)[CH2:18]2)=[N:24][CH:25]=[C:26]([C:30]([F:32])([F:31])[F:33])[CH:27]=1
Reactant: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CCNC3)C1
Reactant: FC(F)(F)c1cnc(Br)c(Cl)c1
Product: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CCN(c2ncc(C(F)(F)F)cc2Cl)C3)C1

Procedure:
The title compound was synthesized in substantially the same way as Example 1 by condensation of 6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-1,2,3,4-tetrahydro-isoquinoline with 2-bromo-3-chloro-5-trifluoromethyl-pyridine.
Reaction SMILES: [C:1]([Cl:4])(=O)C.O.O.O.[C:8]([NH:11][C@@H:12]1[C@@H:17]([NH2:18])[CH:16]=[C:15]([C:19]([OH:21])=[O:20])[O:14][C@H:13]1[C@H:22]([OH:27])[C@H:23]([OH:26])[CH2:24][OH:25])(=[O:10])[CH3:9]>CO>[ClH:4].[C:8]([NH:11][C@@H:12]1[C@@H:17]([NH2:18])[CH:16]=[C:15]([C:19]([O:21][CH3:1])=[O:20])[O:14][C@H:13]1[C@H:22]([OH:27])[C@H:23]([OH:26])[CH2:24][OH:25])(=[O:10])[CH3:9]
Reactant: CC(=O)N[C@H]1[C@H]([C@H](O)[C@H](O)CO)OC(C(=O)O)=C[C@@H]1N
Reactant: CC(=O)Cl
Solvent: CO
Solvent: O
Product: COC(=O)C1=C[C@H](N)[C@@H](NC(C)=O)[C@H]([C@H](O)[C@H](O)CO)O1
Product: Cl
Temperature: 20 °C
Reaction time: 0.25 h
Yield: 106.8 %

Procedure:
Acetyl chloride (75 ml; 1.05 mole) was added drop-wise with stirring to methanol (7500 ml) at 0–5° C. under nitrogen. The mixture was stirred at this temperature for a further 15 minutes then held at approximately 10° C. as (2R,3R,4S)-3-(acetylamino)4-amino-2-[(1R,2R)-1,2,3-trihydroxypropyl]-3,4-dihydro-2H-pyran-6-carboxylic acid trihydrate (see J. Med. Chem. 1998, 41, 787–797) (250 g; 726 mmoles) was added in portions. The mixture was stirred at approximately 60° C. for 5 hours then cooled to approximately 20° C. and stirred at this temperature overnight. The solvent was removed and the residue twice evaporated down again with methanol (2×500 ml) to give a mixture of a foam and gum. This was re-dissolved in methanol (˜1000 ml), evaporated and the residue then triturated with DCM and re-evaporated. The trituration DCM process was repeated. The residue was dried overnight in a vacuum-oven at approximately 30° C., crushed and then dried overnight again to give Intermediate 2 as a white powder (264.2 g).
Reaction SMILES: [C:1]1([NH:7][C:8]([C:10]2([CH3:27])[CH2:15][CH2:14][C:13]3[C:16]([CH3:26])=[C:17]([O:22]C(=O)C)[C:18]([CH3:21])=[C:19]([CH3:20])[C:12]=3[O:11]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].C(O)(=O)C>C(O)C.O>[C:1]1([NH:7][C:8]([C:10]2([CH3:27])[CH2:15][CH2:14][C:13]3[C:16]([CH3:26])=[C:17]([OH:22])[C:18]([CH3:21])=[C:19]([CH3:20])[C:12]=3[O:11]2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(C(=O)Nc1ccccc1)O2
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C(=O)Nc1ccccc1)O2
Reaction time: 2 h
Yield: 86 %

Procedure:
In a two-necked, round-bottomed flask, 2.75 g (7.48 mmol) of the compound obtained in Stage B of Example 1 are dissolved in 60 cm3 of 80% ethanol. Under a nitrogen stream, 18 cm3 of 2.5N sodium hydroxide are added. The mixture is left to stir at ordinary temperature for 2 h. The mixture is diluted with water, acidified with acetic acid and then the product is extracted with dichloromethane. The organic phase is washed with water and then dried. The mixture is purified by passing through a column of silica gel, eluting with isopropyl ether to obtain N-phenyl-6-hydroxy-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxamide (yield: 86%; melting point: 107°-109° C.) and then the reaction is carried out as in Stage C of Example 1, replacing N-phenyl-6-acetoxy-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxamide with N-phenyl-6-hydroxy-3,4-dihydro-2,5,7,8-tetramethyl-2H-1-benzopyran-2-carboxamide.
Reaction SMILES: C([O:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[NH:11][C:12]1[S:13][C:14]2[CH:20]=[C:19]([CH2:21][N:22]3[C:26]4=[N:27][CH:28]=[C:29]([CH2:31][NH2:32])[CH:30]=[C:25]4[N:24]=[CH:23]3)[CH:18]=[CH:17][C:15]=2[N:16]=1)(=O)C.N1C=CC=CC=1.[C:39](Cl)([CH3:41])=[O:40]>C(Cl)Cl>[OH:4][C@@H:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C@H:6]1[NH:11][C:12]1[S:13][C:14]2[CH:20]=[C:19]([CH2:21][N:22]3[C:26]4=[N:27][CH:28]=[C:29]([CH2:31][NH:32][C:39](=[O:40])[CH3:41])[CH:30]=[C:25]4[N:24]=[CH:23]3)[CH:18]=[CH:17][C:15]=2[N:16]=1
Reactant: CC(=O)Cl
Reactant: CC(=O)O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(CN)cnc43)cc2s1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NCc1cnc2c(c1)ncn2Cc1ccc2nc(N[C@@H]3CCCC[C@H]3O)sc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.2 %

Procedure:
To a stirred solution of (1R,2R)-2-((6-((6-(aminomethyl)-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (50 mg, 0.12 mmol) from Example 91 in DCM (2 mL) were added pyridine (40 μL, 0.48 mmol) and AcCl (27 μL, 0.36 mmol). The resulting mixture was stirred at rt for 3 h before it was concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford N-((3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridin-6-yl)methyl)acetamide (45 mg, 82%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ 8.58 (s, 1H), 8.40 (br s, 1H), 8.31 (s, 1H), 7.84-8.10 (m, 2H), 7.65 (s, 1H), 7.24-7.41 (m, 1H), 7.10-7.24 (m, 1H), 5.47 (s, 2H), 4.37 (d, J=5.5 Hz, 2H), 3.34 (d, J=8.7 Hz, 2H), 1.97-2.16 (m, 1H), 1.89 (br s, 1H), 1.86 (s, 3H), 1.61 (br s, 2H), 0.99-1.39 (m, 4H). LCMS (ESI) m/z 451 (M+H)+.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:29])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[F:30][C:31]1[C:36]([O:37][CH3:38])=[CH:35][CH:34]=[C:33]([F:39])[C:32]=1[C:40]1[N:45]=[C:44]([C:46](O)=[O:47])[CH:43]=[CH:42][C:41]=1[F:49].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CO>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:29][C:46]([C:44]3[CH:43]=[CH:42][C:41]([F:49])=[C:40]([C:32]4[C:33]([F:39])=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:31]=4[F:30])[N:45]=3)=[O:47])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: COc1ccc(F)c(-c2nc(C(=O)O)ccc2F)c1F
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc(F)c(-c2nc(C(=O)Nc3cnc4c(c3N3C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C3)CCC4OC(C)=O)ccc2F)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.3 %

Procedure:
A mixture of 3-amino-4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (14.1 mg, 0.035 mmol), 6-(2,6-difluoro-3-methoxyphenyl)-5-fluoropyridine-2-carboxylic acid (9.0 mg, 0.032 mmol), HATU (30.2 mg, 0.08 mmol) in DMF (0.07 mL) and DIPEA (0.017 mL, 0.095 mmol) was stirred at room temperature for 16 h. The mixture was diluted with MeOH and purified by preparative LC-MS (XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the sub-title compound as a white powder (8.0 mg, 38%). LCMS calc. for C34H39F3N5O6 (M+H)+: m/z=670.3. Found: 670.3.
Reaction SMILES: [Mg].[Cl:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:4]=1[CH2:5]Cl.[CH3:12][N:13]([CH:15]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C:17]1=[O:22])[CH3:14].[Cl-].[NH4+]>CCOCC>[ClH:2].[Cl:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:4]=1[CH2:5][C:17]1([OH:22])[CH2:18][CH2:19][CH2:20][CH2:21][CH:16]1[CH:15]([N:13]([CH3:12])[CH3:14])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CN(C)C(c1ccccc1)C1CCCCC1=O
Reactant: Fc1cccc(Cl)c1CCl
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CN(C)C(c1ccccc1)C1CCCCC1(O)Cc1c(F)cccc1Cl
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 102 %

Procedure:
0.38 g (15.6 mmole) of magnesium turnings was stirred in 10 ml of ether of analysis purity. 2.79 g (15.6 mmole) of 2-chloro-6-fluorobenzyl chloride dissolved in 10 ml of ether were added dropwise so that the reaction mixture boiled gently. After completion of the addition the reaction mixture was stirred for one hour at RT. 3.00 g (13.0 mmole) of the 2-(dimethylaminophenylmethyl)cyclohexanone prepared according to Example 1 were dissolved in 15 ml of ether, added dropwise to the Grignard reagent while cooling in an ice bath, and stirred for 15 hours at RT. The reaction mixture was worked up by adding 20 ml of saturated ammonium chloride solution while cooling in an ice bath, and was extracted three times at RT with 30 ml of ether each time. The combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator (500 to 10 mbar). 4.92 g of crude base (101% of theory) were obtained, from which 3.28 g of 1-(2-chloro-6-fluorobenzyl)-2-(dimethylaminophenylmethyl)cyclohexanol, hydrochloride (61.2% of theory) were obtained according to the procedure described in Example 1 (3rd Stage) with chlorotrimethylsilane/water in 2-butanone. The hydrochloride decomposes on heating above 225° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]([NH:14][CH2:15][C:16]([OH:18])=[O:17])=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].O[N:20]1[C:24](=[O:25])[CH2:23][CH2:22][C:21]1=[O:26].C1(N=C=NC2CCCCC2)CCCCC1>O1CCOCC1.C(Cl)Cl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][O:11][C:12](=[O:13])[NH:14][CH2:15][C:16]([O:18][N:20]2[C:24](=[O:25])[CH2:23][CH2:22][C:21]2=[O:26])=[O:17])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(O)CNC(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(CNC(=O)OCc1ccc([N+](=O)[O-])cc1)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.9 %

Procedure:
To a solution of 2.83 g of product from Example 255 in 43 ml of dioxane is added 1.28 g of N-hydroxysuccinimide and 2.30 g of 1,3-dicyclohexylcarbodiimide, hereinafter called DCC, in 13 ml of dioxane. The formed suspension is stirred at room temperature overnight. The urea by-product is collected and the filtrate is concentrated in vacuo to give an oil. The oil is dissolved in methylene chloride, washed with water, the layers are separated and the organic phase is cooled. The formed crystals are collected and dried to give 1.87 g of the desired product.
Reaction SMILES: Cl[CH2:2]Cl.[C:4]([O:7][OH:8])(=[O:6])[CH3:5].[CH3:9][OH:10]>>[O-:7][OH:8].[C:9]([O:7][C:4](=[O:6])[CH3:5])(=[O:10])[CH3:2]
Reactant: CO
Reactant: ClCCl
Reactant: CC(=O)OO
Product: CC(=O)OC(C)=O
Product: [O-]O
Yield: 31 %

Procedure:
A portion of the beads produced (20 g) were swelled in 60 ml of a solution of dichloromethane and methanol (equal volume ratios) and 80 g of peracetic acid solution obtained from 31% hydroperoxide and acetic anhydride, were added drop by drop with cooling and the reaction was continued for 4 hours at room temperature in order to oxidize triphenylphosphine units. The beads containing triphenylphosphine oxide units were dipped into 100 ml of monochlorobenzene containing 10 g of oxalic chloride and the solution was stirred for 5 hours at room temperature so as to convert triphenylphosphine oxide units into triphenylphosphine dichloride units. The beads were washed with dichloromethane (CH2Cl2) completely and dried. Yield of the beads was 24.9 g. The beads produced contained pendant diphenylphosphine dichloride groups and had the structural formula: ##STR9##
Reaction SMILES: [CH3:1][N:2]([CH:4]([CH:7]1[CH2:16][CH2:15][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:9][CH2:8]1)[C:5]#N)[CH3:3].[C:17]1([Mg]Cl)[CH:22]=[CH:21]C=[CH:19][CH:18]=1.[Cl-].[NH4+].O>C1COCC1.C(OCC)C>[O:14]1[C:10]2([CH2:15][CH2:16][CH:7]([CH:4]([N:2]([CH3:3])[CH3:1])[C:5]3[CH:21]=[CH:22][CH:17]=[CH:18][CH:19]=3)[CH2:8][CH2:9]2)[O:11][CH2:12][CH2:13]1
Reactant: Cl[Mg]c1ccccc1
Reactant: CN(C)C(C#N)C1CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(C)C(c1ccccc1)C1CCC2(CC1)OCCO2
Reaction time: 20 h

Procedure:
A solution of the aminonitrile 3 (23.56 g, 105 mmol) in abs. THF (100 ml) was added dropwise, under argon and while cooling with ice, to a 25% solution of phenylmagnesium chloride (144 ml, 262.5 mmol) in THF, and stirring was carried out for 20 h at RT. For working up the reaction mixture, saturated ammonium chloride solution (100 ml) and water (100 ml) were added, while cooling with ice, and extraction with diethyl ether (3×100 ml) was carried out. The organic phase was washed with water and saturated sodium chloride solution, dried (Na2SO4) and concentrated.