Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[NH2:5][C:6]1[C:11]2[O:12][CH2:13][CH2:14][O:15][C:10]=2[C:9]([C:16]([O:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:17])=[CH:8][C:7]=1[Cl:26]>C(N(CC)CC)C.CN(C=O)C>[NH2:5][C:6]1[C:11]2[O:12][CH2:13][CH2:14][O:15][C:10]=2[C:9]([C:16]([O:18][CH2:19][CH:20]2[CH2:21][CH2:22][N:23]([CH2:2][C:3]#[N:4])[CH2:24][CH2:25]2)=[O:17])=[CH:8][C:7]=1[Cl:26]
Reactant: Nc1c(Cl)cc(C(=O)OCC2CCNCC2)c2c1OCCO2
Reactant: N#CCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#CCN1CCC(COC(=O)c2cc(Cl)c(N)c3c2OCCO3)CC1
Temperature: 60 °C
Yield: 53 %

Procedure:
A mixture of chloroacetonitrile (2.15 ml) and (4piperidinyl)-methyl 8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-carboxylate (11 g) in N,N-diethylethanamine (7 ml) and DMF (150 ml) was stirred at 60° C. until the reaction was complete. Then, the mixture was cooled. The solvent was evaporated. The residue was partitioned between DCM and water. The separated organic layer was dried, filtered and the solvent was evaporated. The residue was crystallized from ACN and the precipitate was filtered off and dried (vacuum, 50° C.), yielding 6.6 g (53%) [1-(cyanomethyl)-4-piperidinyl]-methyl 8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-carboxylate (intermediate 14).
Reaction SMILES: C([Li])CCC.[C:6]([C:8]1[CH:13]=[CH:12][C:11]([C:14]23[O:21][CH2:20][C:17]([CH2:22][CH2:23][CH3:24])([CH2:18][O:19]2)[CH2:16][O:15]3)=[CH:10][CH:9]=1)#[CH:7].[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>O1CCCC1>[Si:25]([C:7]#[C:6][C:8]1[CH:9]=[CH:10][C:11]([C:14]23[O:15][CH2:16][C:17]([CH2:22][CH2:23][CH3:24])([CH2:18][O:19]2)[CH2:20][O:21]3)=[CH:12][CH:13]=1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C#Cc1ccc(C23OCC(CCC)(CO2)CO3)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC12COC(c3ccc(C#C[Si](C)(C)C(C)(C)C)cc3)(OC1)OC2
Reaction time: 0.17 h

Procedure:
n-Butyllithium (0.79 ml of 1.6M solution, in hexane) was added to a stirred solution of 1-(4-ethynylphenyl)-4-n-propyl-2,6,7-trioxabicyclo[2,2,2]octane (0.25 g.) in dry tetrahydrofuran (15 ml) at 0°, under nitrogen. The reaction mixture was stirred at 0° for 10 minutes. t-Butyldimethylsilyl chloride (0.23 g.) was added and the mixture was stirred at room temperature for 6 hours. The reaction mixture was evaporated in vacuo. Water was added and the aqueous mixture was extracted with diethyl ether. The ethereal extracts were washed with water, dried over anhydrous magnesium sulphate and evaporated in vacuo. The residue was purified by chromatography on alumina (Alumina Woelm TSC), eluting with 2:3 dichloromethane:hexane saturated with ammonia. 1-[4-(2-t-Butyldimethylsilylethynyl)phenyl]-4-n-propyl-2,6,7-trioxabicyclo[2,2,2]octane was obtained as pale yellow crystals (0.32 g.).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:20])[C@H:4]([CH2:16][CH:17]([CH3:19])[CH3:18])[NH:5]C(OCC1C=CC=CC=1)=O.[H][H]>[Pd].CO>[CH3:1][NH:2][C:3](=[O:20])[C@H:4]([CH2:16][CH:17]([CH3:19])[CH3:18])[NH2:5]
Reactant: CNC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CNC(=O)[C@@H](N)CC(C)C

Procedure:
A mixture of intermediate 20A (1.20 g, 4.31 mmol) and 10% palladium on carbon (300 mg) in MeOH (30 mL) was hydrogenated with a Parr shaker under 55 psi of hydrogen gas for 3 h. After filtration through celite, the filtrate was evaporated and azeotroped with EtOAc to give the desired intermediate 20B as white solid (quant. yield).LCMS (+ESI) m/z 145.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15](S(C)(=O)=O)[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[C:28]([C:30]1[CH:31]=[N:32][CH:33]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:35]=1)#[N:29]>>[O:25]1[CH2:26][CH2:27][N:22]([C:4]2[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=[C:2]([C:34]3[CH:35]=[C:30]([C:28]#[N:29])[CH:31]=[N:32][CH:33]=3)[N:3]=2)[CH2:23][CH2:24]1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: CC1(C)OB(c2cncc(C#N)c2)OC1(C)C
Product: N#Cc1cncc(-c2nc(N3CCOCC3)c3sc(CN4CCNCC4)cc3n2)c1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine, prepared via General Procedure B-3, was reacted with 3-cyanopyridine-5-boronic acid pinacol ester via General Procedure A. Purification on silica yielded 170. (400 MHz CDCl3): 2.68-2.71 (4H, m, CH2), 2.81 (3H, s, CH3), 3.30-3.32 (4H, m, CH2), 3.90-3.92 (6H, m, CH2), 4.06-4.08 (4H, m, CH2), 7.35 (1H, s, ar), 8.92 (1H, d(J=2.09), ar), 8.96-8.97 (1H, m, ar), 9.81 (1H, d(J=2.03), ar). MH+ 500.20
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]3[C:12](=O)[CH2:11][CH2:10][CH2:9][C:7]=3[O:8][C:4]=2[CH:3]=1.C([O-])(=O)C.[Na+].Cl.[NH2:22][OH:23]>O.C(O)C>[Br:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]3[C:12](=[N:22][OH:23])[CH2:11][CH2:10][CH2:9][C:7]=3[O:8][C:4]=2[CH:3]=1
Reactant: NO
Reactant: O=C1CCCc2oc3cc(Br)ccc3c21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: ON=C1CCCc2oc3cc(Br)ccc3c21
Temperature: 85 °C
Yield: 14.6 %

Procedure:
A mixture of the product of step A (6.80 g, 25.7 mmol), sodium acetate (3.16 g, 38.5 mmol) and hydroxylamine hydrochloride (2.67 g, 38.5 mmol) in water (28 mL) and ethanol (14 mL) was heated to 85° C. for 7 h. After cooling to 5° C., the reaction mixture was filtered. The solid obtained was washed with cold water and dried in vacuo to give 7-bromo-3,4-dihydrodibenzo[b,d]furan-1(2H)-one oxime (1.05 g, 15%) as an off-white solid: 1H NMR (DMSO-d6, 300 MHz) δ 10.95 (s, 1H), 7.88 (d, J=1.8 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.47 (dd, J=8.4, 1.8 Hz, 1H), 2.87 (t, J=6.3 Hz, 2H), 2.69 (t, J=6.3 Hz, 2H), 2.03-1.89 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[OH:37])[C:5]([CH2:7][NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[C@@H:17]1[CH2:26][CH2:25][C:24]2[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=2[CH2:18]1)=O.Cl[CH2:39][C:40]([N:42]([CH2:45][CH3:46])[CH2:43][CH3:44])=O>>[CH2:43]([N:42]([CH2:45][CH3:46])[CH2:40][CH2:39][O:37][C:36]1[CH:35]=[CH:34][C:4]([CH2:5][CH2:7][NH:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[C@@H:17]2[CH2:26][CH2:25][C:24]3[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:19]=3[CH2:18]2)=[CH:3][C:2]=1[F:1])[CH3:44]
Reactant: CCN(CC)C(=O)CCl
Reactant: COc1ccc([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCC(=O)c2ccc(O)c(F)c2)c1
Product: CCN(CC)CCOc1ccc(CCNc2cc(OC)ccc2[C@@H]2CCc3cc(O)ccc3C2)cc1F
Yield: 47.4 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(3-fluoro-4-hydroxybenzoyl)methylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-chloro-N,N-diethylacetamide (12 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (9.5 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[Na+].[Cl:13][CH2:14][CH2:15][CH:16](OS(C)(=O)=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@H:16]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:15][CH2:14][Cl:13]
Reactant: Clc1cccc2[nH]ccc12
Reactant: CS(=O)(=O)OC(CCCl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: ClCC[C@@H](c1ccccc1)n1ccc2c(Cl)cccc21
Reaction time: 0.5 h

Procedure:
To a solution of 4-chloroindole (0.222 g) in dry DMF (7.5 ml) was added sodium hydride (0.064 g) at room temperature. The mixture was stirred at the same temperature for 30 minutes and then the crude methanesulfonic acid 3-chloro-1-phenyl-propyl ester from the previous step was dissolved in DMF (5 ml) and added at 0° C. to the reaction mixture and stirred for 2 hours. The reaction mixture was partitioned between ethyl acetate and water, the organic layer was washed twice with water and once with brine, then dried over magnesium sulfate, filtered and evaporated to dryness to afford an oil. Purification of the crude product was done by column chromatography on silica gel, eluting the desired product with ethyl acetate-hexane (1:9). The (S) 4-chloro-1-(3-chloro-1-phenyl-propyl)-1H-indole thus produced weighed 0.251 g, sufficiently pure for use in the following step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:14]=[CH:13][C:12]([C:15]([OH:17])=O)=[CH:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1.[NH2:18][N:19]1[CH2:24][C:23]([CH3:25])=[N:22][NH:21][C:20]1=[O:26].C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-].CN(C=O)C>O>[CH3:25][C:23]1[CH2:24][N:19]([NH:18][C:15]([C:12]2[CH:13]=[N:14][C:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)=[N:10][CH:11]=2)=[O:17])[C:20](=[O:26])[NH:21][N:22]=1
Reactant: CC1=NNC(=O)N(N)C1
Reactant: COc1cccc(-c2ncc(C(=O)O)cn2)c1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(-c2ncc(C(=O)NN3CC(C)=NNC3=O)cn2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 64.3 %

Procedure:
A mixture of 2-(3-methoxy-phenyl)-pyrimidine-5-carboxylic acid (135 mg, 0.58 mmol), 4-amino-6-methyl-4,5-dihydro-2H-[1,2,4]triazin-3-one (76 mg, 0.58 mmol), DMTMM (171 mg, 0.6 mmol) and DMF (3 mL) is stirred at rt for 2 days. Water (3 ml) is added, and the precipitated product is filtered, washed with water and dried to afford 2-(3-methoxy-phenyl)-pyrimidine-5-carboxylic acid (6-methyl-3-oxo-2,5-dihydro-3H-[1,2,4]triazin-4-yl)-amide (127 mg). MS: 341 (M+H); 1H NMR (DMSO-d6): δ 1.91 (s, 3H), 4.23 (s, 3H), 4.62 (s, 2H), 7.53 (m, 2H), 8.34 (m, 1H), 8.46 (s, 1H), 9.27 (s, 2H), 9.97 (s, 1H), 11.08 (s, 1H). IC50=174.5 nM.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][CH2:27][NH2:28].CCN(C(C)C)C(C)C>>[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][CH2:27][NH:28][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1
Reactant: NCCc1ccccn1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(NCCc2ccccn2)S/C1=C\c1ccc2ncccc2c1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, 2-pyridin-2-yl-ethylamine and DIEA to give 2-(2-pyridin-2-yl-ethylamino)-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 361 (MH+).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[CH:2]1.[H-].[Na+].[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17](Cl)[N:16]=1>CN(C=O)C>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:1]2[CH:5]=[CH:4][C:3]([C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=3)=[CH:2]2)[N:16]=1
Reactant: c1ccc(-c2cc[nH]c2)nc1
Reactant: Clc1cccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1cccc(-n2ccc(-c3ccccn3)c2)n1
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-(1H-pyrrol-3-yl)pyridine (432 mg, 3.0 mmol) in DMF (15 mL) at 50° C. was added NaH (3.15 mmol, 60% suspension in oil). After 10 min, 2,6-dichloropyridine (1.33 g, 9.0 mmol) was added, and the reaction was warmed to 120° C., stirred for 18 h, then quenched with water (100 mL) and partitioned with EtOAc (100 mL). The aqueous layer was washed with additional EtOAc (2×75 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by liquid chromatography on SiO2 eluting with 1:1 hexanes:EtOAc to afford 2-chloro-6-(3-pyridin-2-yl-1H-pyrrol-1-yl)pyridine as a tan solid. H-NMR (CDCl3, 500 MHz) δ 8.60 (d, 1H), 8.13 (dd, 1H), 7.66-7.79 (m, 2H), 7.57-7.61 (m, 2H), 7.31 (d, 1H), 7.16 (d, 1H), 7.11 (dd, 1H), 6.88 (m, 1H).
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:42])[CH2:15][C@H:16]([C:37]1[CH:41]=[CH:40][O:39][N:38]=1)[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[CH:19][CH:18]=1)C1C=CC=CC=1.[OH:43]O.[OH-].[Li+].Cl>C1COCC1.O>[O:39]1[CH:40]=[CH:41][C:37]([C@H:16]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][O:26][C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:35])([F:34])[F:36])=[CH:29][CH:28]=3)=[CH:19][CH:18]=2)[CH2:15][C:14]([OH:42])=[O:43])=[N:38]1
Reactant: O=C(C[C@@H](c1ccc(OCCOc2ccc(C(F)(F)F)cc2)cc1)c1ccon1)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: OO
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C[C@@H](c1ccc(OCCOc2ccc(C(F)(F)F)cc2)cc1)c1ccon1
Reaction time: 1 h
Yield: 56 %

Procedure:
To a solution of the oxazolidinone 47.2 (58.0 mg, 0.1 mmol) dissolved in THF (5 mL), was added a 30% hydrogen peroxide solution (113 μL, 1 mmol) followed by a 2 M lithium hydroxide solution (250 μL, 0.5 mmol). The resulting slurry was stirred for one hour. The reaction mixture was then diluted with water and acidified with hydrochloric acid to pH ˜3. The mixture was then extracted with EtOAc (1×20 mL), and the organic layer was washed with an acidic sodium sulfite solution (2×15 mL) and brine (1×15 mL), and dried over magnesium sulfate. The filtrate was concentrated under reduced pressure, and the residue was purified by reverse phase HPLC to give 47 (23.6 mg). MS ESI (pos.) m/e: 422.0 (M+H). 1H NMR (400 MHz, CD3CN) δ ppm 8.34 (1 H, s), 7.53 (2 H, d, J=8.6 Hz), 7.14 (2 H, d, J=8.6 Hz), 7.00 (2 H, d, J=8.6 Hz), 6.83 (2 H, d, J=8.6 Hz), 6.16 (1 H, d), 4.45 (1 H, t, J=7.8 Hz), 4.25-4.31 (2 H, m), 4.20-4.24 (2 H, m), 3.09 (1 H, dd, J=16.4, 8.2 Hz), 2.84 (1 H, dd, J=16.4, 7.4 Hz).
Reaction SMILES: [OH:1][CH2:2][CH:3]([C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=1)[CH2:4][O:5][C:6]1[CH:19]=[CH:18][C:9]([CH2:10][CH:11]2[S:15][C:14](=N)[NH:13][C:12]2=[O:17])=[CH:8][CH:7]=1.C([OH:29])C>Cl>[OH:1][CH2:2][CH:3]([C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=1)[CH2:4][O:5][C:6]1[CH:19]=[CH:18][C:9]([CH2:10][CH:11]2[S:15][C:14](=[O:29])[NH:13][C:12]2=[O:17])=[CH:8][CH:7]=1
Reactant: CCO
Reactant: Cc1cccnc1C(CO)COc1ccc(CC2SC(=N)NC2=O)cc1
Agent: Cl
Product: Cc1cccnc1C(CO)COc1ccc(CC2SC(=O)NC2=O)cc1

Procedure:
5-{4-[3-hydroxy-2-(3-methyl-2-pyridyl)propoxy]benzyl}-2-imino-4-thiazolidinone (2.3 g) was dissolved in a mixture of 2N-hydrochloric acid and ethanol (20 ml), and the solution was heated under reflux for 4 hours. After neutralization with aqueous sodium hydrogencarbonate solution, the solution was extracted with chloroform, and the chloroform layer was washed with water and dried (MgSO4). The solvent was distilled off to give 5-{4-[3-hydroxy-2-(3-methyl-2-pyridyl)propoxy]-benzyl}-2,4-thiazolidinedione in the form of crystals. Yield of 1.9 g. Recrystallization from ethanol produced colorless prisms. m.p. 182°-183° C.
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH2:3][CH2:2]1.[Cl:7][C:8]1[C:13]2[C:14](=[O:29])[N:15]3[CH2:28][CH2:27][CH2:26][C@H:16]3[C:17]3[N:18]([CH:19]=[N:20][C:21]=3[C:22](=[N:24]O)[NH2:23])[C:12]=2[CH:11]=[CH:10][CH:9]=1>CN(C)C=O>[Cl:7][C:8]1[C:13]2[C:14](=[O:29])[N:15]3[CH2:28][CH2:27][CH2:26][C@H:16]3[C:17]3[N:18]([CH:19]=[N:20][C:21]=3[C:22]3[N:24]=[C:4]([CH:1]4[CH2:3][CH2:2]4)[O:6][N:23]=3)[C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)C1CC1
Reactant: NC(=NO)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Solvent: CN(C)C=O
Product: O=C1c2c(Cl)cccc2-n2cnc(-c3noc(C4CC4)n3)c2[C@@H]2CCCN12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
17.0 g (105 mmol) of N,N'-carbonyldiimidazole are added portionwise to a solution of 8.61 g (100 mmol) of cyclopropanecarboxylic acid in 30 ml of N,N-dimethylformamide. The mixture is stirred at room temperature for 1 hour and then heated rapidly to 50°. The solution obtained is added to a suspension of 33.1 g (100 mmol) of (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxamidoxime in 100 ml of N,N-dimethylformamide and the mixture is heated to 90° for 2.5 hours. The solvent is removed on a rotary evaporator and is replaced by 100 ml of acetic acid. After stirring at 120° for 2.5 hours the mixture is again evaporated, the residue is dissolved in methylene chloride and washed with saturated sodium bicarbonate solution. The organic phase is dried over magnesium sulphate and concentrated. By chromatography of the oily residue on silica gel while eluting with ethyl acetate and recrystallization from alcohol and a small amount of methylene chloride there is obtained (S)-8-chloro-1-[5-(cyclopropyl)-1,2,4-oxadiazol-3-yl]-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one of melting point 236°-237°
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.[CH2:23]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][O:30][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: BrCCCCCCOCc1ccccc1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCCOCc2ccccc2)CC1
Yield: 34.2 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.00 g) as starting compound and 6-benzyloxyhexyl bromide (0.75 g) were reacted and treated in the same manner as in Example 168 to give 0.45 g of 4-amino-N-((1-(6-benzyloxyhexyl)piperidin-4-yl)methyl)-5-chloro-2-methoxybenzamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:12][C:11]3([N:16]([CH3:17])[CH2:15][CH2:14][CH2:13]3)[CH2:10]2)[C:6]([N+:18]([O-])=O)=[CH:5][C:4]=1[NH:21][C:22]1[N:27]=[C:26]([C:28]2[CH:29]=[N:30][N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][C:32]=23)[CH:25]=[CH:24][N:23]=1.[NH4+].[Cl-].O>C(O)C.[Fe]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N:9]2[CH2:10][C:11]3([N:16]([CH3:17])[CH2:15][CH2:14][CH2:13]3)[CH2:12]2)[C:6]([NH2:18])=[CH:5][C:4]=1[NH:21][C:22]1[N:27]=[C:26]([C:28]2[CH:29]=[N:30][N:31]3[CH2:36][CH2:35][CH2:34][CH2:33][C:32]=23)[CH:25]=[CH:24][N:23]=1
Reactant: COc1cc(N2CC3(CCCN3C)C2)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1cc(N2CC3(CCCN3C)C2)c(N)cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Yield: 83.8 %

Procedure:
N-[2-Methoxy-4-(8-methyl-2,8-diazaspiro[3.4]octan-2-yl)-5-nitrophenyl]-4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine (Intermediate 142, 320 mg, 0.65 mmol), iron (219 mg, 3.91 mmol) and NH4Cl (26.2 mg, 0.49 mmol) were heated at reflux in ethanol (18 mL) and water (6 mL) for 4 h. The mixture was then cooled, filtered and concentrated in vacuo. The resulting residue was triturated in 10% CH3OH in CH2Cl2 (15 mL) for 15 minutes and the mixture was then filtered. The residues were re-triturated with 10% CH3OH in CH2Cl2 (15 mL) and the mixture was then filtered. The combined filtrates were washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification by FCC, eluting with 2% 7N methanolic ammonia in CH2Cl2 gave the title compound (251 mg, 84%) as a brown gum which crystallised on standing; 1H NMR: 1.64-1.76 (2H, m), 1.75-1.87 (2H, m), 1.91-2.03 (2H, m), 2.08 (2H, dd), 2.39 (3H, s), 2.63 (2H, t), 3.06 (2H, t), 3.56 (2H, d), 3.72 (3H, s), 3.82 (2H, d), 4.01 (2H, s), 4.10 (2H, t), 6.25 (1H, s), 6.91 (1H, d), 7.21 (1H, s), 7.67 (1H, s), 8.04 (1H, s), 8.23 (1H, d); m/z: ES+ MH+ 461.37.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11](C)[CH2:10][CH:9]2[O:15][CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:34]([O:36][CH2:37][C:38]([Cl:41])([Cl:40])[Cl:39])=[O:35]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:34]([O:36][CH2:37][C:38]([Cl:41])([Cl:40])[Cl:39])=[O:35])[CH2:10][CH:9]2[O:15][CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CN1CCC(c2ccc(Cl)cc2)C(OCc2ccc3ccccc3c2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(OCC(Cl)(Cl)Cl)N1CCC(c2ccc(Cl)cc2)C(OCc2ccc3ccccc3c2)C1
Reaction time: 12 h
Yield: 57 %

Procedure:
A solution of 0.526 g (1.43 mmol) of (3RS,4RS)-4-(4-chloro-phenyl)-1-methyl-3-(naphthalen-2-ylmethoxy)-piperidine in 12 ml of toluene was treated with 100 mg of potassium carbonate and heated to 100°. Subsequently, 0.423 g (0.288 ml, 2 mmol) of 2,2,2-trichloroethyl chloroformate was added thereto and the mixture was stirred at 100° for 12 hours. The reaction solution was evaporated, taken up in 50 ml of ethyl acetate and washed with 20 ml of water and 20 ml of saturated sodium hydrogen carbonate solution. Drying over magnesium sulphate, filtration (sic) and evaporation yielded a colourless oil which was chromatographed on silica gel using a 3:2 mixture of hexane and ethyl acetate as the eluent. There was obtained 0.426 9 (57% of theory) of 2,2,2-trichloroethyl 4-(4-chloro-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless oil; Rf: 0.31 (silica gel, hexane/ethyl acetate: 3/2).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[N:17]=[C:16]4[C:12]([N:13]=[C:14]([C:19]([OH:21])=O)[N:15]4[CH3:18])=[C:11]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[N:10]=3)[C:7]3[CH:28]=[CH:29][CH:30]=[CH:31][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.[NH:32]1[CH2:37][CH2:36][CH:35]([C:38]([OH:41])([CH3:40])[CH3:39])[CH2:34][CH2:33]1.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>C(Cl)Cl>[CH:1]1([C:4]2[N:8]([C:9]3[N:17]=[C:16]4[C:12]([N:13]=[C:14]([C:19]([N:32]5[CH2:37][CH2:36][CH:35]([C:38]([OH:41])([CH3:40])[CH3:39])[CH2:34][CH2:33]5)=[O:21])[N:15]4[CH3:18])=[C:11]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[N:10]=3)[C:7]3[CH:28]=[CH:29][CH:30]=[CH:31][C:6]=3[N:5]=2)[CH2:3][CH2:2]1
Reactant: Cn1c(C(=O)O)nc2c(N3CCOCC3)nc(-n3c(C4CC4)nc4ccccc43)nc21
Reactant: CC(C)(O)C1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(C(=O)N2CCC(C(C)(C)O)CC2)nc2c(N3CCOCC3)nc(-n3c(C4CC4)nc4ccccc43)nc21
Temperature: 25 °C
Reaction time: 19 h
Yield: 52.8 %

Procedure:
A mixture of 2-(2-cyclopropylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carboxylic acid (200 mg, 0.48 mmol), 2-piperidin-4-ylpropan-2-ol (78 mg, 0.55 mmol), HATU (205 mg, 0.54 mmol) and DIPEA (96 μL, 0.55 mmol) in DCM (5 mL) was allowed to stir at r.t. for 19 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The resulting residue was purified by column chromatography (Si-PCC, MeOH:DCM, 0-3%) then (Si-PCC, MeOH:EtOAc, 0-5%) affording 798 as a white solid (138 mg, 53%). LCMS (method G): RT 7.50 min, [M+H]+ 545.4. 1H NMR (CDCl3, 400 MHz): δ 7.97-7.96 (1 H, m), 7.68-7.67 (1 H, m), 7.28-7.20 (2 H, s), 4.91-4.82 (1 H, m), 4.68-4.65 (1 H, m), 4.40 (4 H, brd s), 3.97 (3 H, s), 3.86 (4 H, t, J=4.70 Hz), 3.18-3.10 (1 H, m), 2.84-2.83 (2 H, m), 1.94-1.92 (2 H, m), 1.64-1.62 (1 H, m), 1.44-1.43 (2 H, m), 1.35-1.34 (2 H, m), 1.24-1.22 (7 H, m), 1.06-1.05 (2 H, m)
Reaction SMILES: [C:1]([C:3]1[CH:14]=[CH:13][C:6]([CH2:7][CH:8]([C:11]#[N:12])[C:9]#[N:10])=[CH:5][CH:4]=1)#[N:2].[H-].[Na+].Br[CH2:18][CH2:19][F:20]>CN(C)C=O>[C:1]([C:3]1[CH:14]=[CH:13][C:6]([CH2:7][C:8]([CH2:18][CH2:19][F:20])([C:11]#[N:12])[C:9]#[N:10])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(CC(C#N)C#N)cc1
Reactant: FCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(CC(C#N)(C#N)CCF)cc1
Yield: 24.9 %

Procedure:
Using 0.32 g of (4-cyanobenzyl)malononitrile, 7 ml of N,N-di-methylformamide, 0.12 g of sodium hydride (60% in oil), and 0.25 g of 1-bromo-2-fluoroethane, and according to the process described in the Production Example 1, there was obtained 0.10 g of 2-(4-cyanobenzyl)-2-(2-fluoroethyl)malononitrile (the present compound (46)).