Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=2[N:11]([C:19](=[O:32])[C:20]2[CH:25]=[CH:24][C:23]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[CH2:10][CH2:9][CH2:8]1)=[O:5])C.[OH-].[Na+].Cl>C(O)C>[C:4]([CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:12]=2[N:11]([C:19](=[O:32])[C:20]2[CH:25]=[CH:24][C:23]([CH:26]3[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]3)=[CH:22][CH:21]=2)[CH2:10][CH2:9][CH2:8]1)([OH:5])=[O:3]
Reactant: CCOC(=O)CC1CCCN(C(=O)c2ccc(C3CCCCC3)cc2)c2ccc(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CC1CCCN(C(=O)c2ccc(C3CCCCC3)cc2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.9 %

Procedure:
To a solution of 5-ethoxycarbonylmethyl-7-chloro-1-(4-cyclohexylbenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (2 g) in ethanol (20 ml) is added a 5N aqueous sodium hydroxide solution (5 ml), and the mixture is stirred at room temperature overnight. The reaction solution is acidified with hydrochloric acid, and the mixture is extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated to remove the solvent to give 5-carboxymethyl-7-chloro-1-(4-cyclohexylbenzoyl)-2,3,4,5-tetrahydro-1H-benzazepine (1.8 g) in colorless amorphous.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([NH:9][CH:10]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:17][C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:4]1)[CH3:2].C(OCC)C.[C:29]([OH:38])(=[O:37])[C@H:30]([C@@H:32]([C:34]([OH:36])=[O:35])[OH:33])[OH:31]>O1CCCC1>[CH2:1]([N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([NH:9][CH:10]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:17][C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:4]1)[CH3:2].[C:34]([CH:32]([CH:30]([C:29]([O-:38])=[O:37])[OH:31])[OH:33])([O-:36])=[O:35]
Reactant: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Agent: CCN1CCCC(NC2c3ccccc3Oc3ccccc32)C1
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C([O-])C(O)C(O)C(=O)[O-]
Reaction time: 1 h

Procedure:
To a solution of 1.1 g. of N-(N-ethyl-3-piperidinyl)-9-xanthenylamine in 8 ml. of tetrahydrofuran and 50 ml. of diethyl ether at -5° C. was added 538 mg. of levo tartaric acid in 32 ml. of tetrahydrofuran. The resulting precipitate was allowed to stand one hour, filtered off, washed twice with 100 ml. portions of ether and air-dried to give N-(N-ethyl-3-piperidinyl)-9-xanthenylamine, tartrate, hydrate m.p. 146°-148° C. (dec.)
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:13](=[O:14])[C:12]2[C:7](=[N:8][C:9]([C:15]([F:18])([F:17])[F:16])=[CH:10][CH:11]=2)[N:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]=1[C:25]([O:27][CH3:28])=[O:26].[Cl:29][C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][C:38]=1[Cl:39])[C:33](O)=[O:34]>>[CH3:28][O:27][C:25]([C:5]1[N:6]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:7]2[C:12]([C:13](=[O:14])[C:4]=1[CH2:3][NH:2][C:33](=[O:34])[C:32]1[CH:36]=[CH:37][C:38]([Cl:39])=[C:30]([Cl:29])[CH:31]=1)=[CH:11][CH:10]=[C:9]([C:15]([F:16])([F:17])[F:18])[N:8]=2)=[O:26]
Reactant: COC(=O)c1c(CN)c(=O)c2ccc(C(F)(F)F)nc2n1-c1ccccc1
Reactant: O=C(O)c1ccc(Cl)c(Cl)c1
Agent: Cl
Product: COC(=O)c1c(CNC(=O)c2ccc(Cl)c(Cl)c2)c(=O)c2ccc(C(F)(F)F)nc2n1-c1ccccc1

Procedure:
3-[(3,4-Dichloro-benzoylamino)-methyl]-4-oxo-1-phenyl-7-trifluoromethyl-1,4-dihydro-[1,8]-naphthyridine-2-carboxylic acid methyl ester was prepared starting from intermediate J and 3,4-dichlorobenzoic acid. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.90 (d, J=8.06 Hz, 1H) 8.80 (t, J=4.63 Hz, 1H) 8.04 (d, J=1.81 Hz, 1H) 7.97 (d, J=8.06 Hz, 1H) 7.67-7.83 (m, 2H) 7.51-7.60 (m, 3H) 7.35-7.47 (m, 2H) 4.44 (d, J=4.83 Hz, 2H) 3.39 (s, 3H). MS calcd. for C25H16Cl2F3N3O4 [(M+H)+] 549.0, obsd. 549.9.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10](=O)[CH2:11][CH2:12][CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.B.CO>O1CCCC1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1cccc(C)c1NC(=O)CCCc1cccnc1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cccc(C)c1NCCCCc1cccnc1

Procedure:
A solution of 13.9 g of N-(2,6-dimethylphenyl)-3-pyridinebutanamide in dry tetrahydrofuran was added dropwise with stirring to an excess of 1 molar borane in tetrahydrofuran and the resulting solution was heated to reflux for two hours. After cooling, excess methanol was added to decompose the remaining borane and the solution was evaporated to dryness. The residue was acidified by the cautious addition of 2N hydrochloric acid and was warmed on the steam bath for 20 minutes. The resulting solution was cooled, made strongly basic with sodium hydroxide solution and was extracted with dichloromethane. The combined layers were dried with potassium carbonate and concentrated to give N-(2,6-dimethylphenyl)-3-pyridinebutanamine as an oil. A solution of the free base in methanol was treated with an excess of fumaric acid in methanol and the resulting solution was diluted with ether. The resulting difumarate was crystallized from 200 ml of 2-propanol to give 20.6 g of N-(2,6-dimethylphenyl)-3-pyridinebutanamine (E)-2-butenedioate(1:2) salt, mp 138°-140° C. (decomposition). Recrystallization from 2-propanol gave the analytical sample, mp 140°-142° C. (decomposition).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)[C:4](=[O:21])[C:3]=1[C:22]#[N:23].Cl.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][NH2:34].C(N(CC)CC)C.C(O)C>O>[NH2:23][C:22]1[N:33]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[O:26][CH3:25])[N:34]=[C:2]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:5]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)[C:4](=[O:21])[C:3]=12
Reactant: COc1ccccc1NN
Reactant: COc1ccc(Cn2c(=O)c(C#N)c(Cl)c3ccccc32)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2c(=O)c3c(N)n(-c4ccccc4OC)nc3c3ccccc32)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 64.1 %

Procedure:
A mixture of 4-chloro-1-(4-methoxybenzyl)-2-oxo-1,2-dihydroquinoline-3-carbonitrile (500 mg), 2-methoxyphenylhydrazine hydrochloride (321 mg), triethylamine (627 μl) and ethanol (5 ml) was stirred at room temperature for 1 hour and at 90° C. for 2 hours. After cooling, water was added to the mixture and the precipitated solid was collected by filtration, washed with water-ethanol and dried to obtain the target compound (421 mg).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:5](=[O:14])[O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1.[CH3:15][C:16]1[O:20][C:19]([CH2:21][N:22]2[C:26]3=[N:27][CH:28]=[CH:29][CH:30]=[C:25]3[N:24]=[C:23]2[NH:31][CH:32]2[CH2:36][CH2:35][NH:34][CH2:33]2)=[CH:18][CH:17]=1.[C:37](=[O:40])([O-:39])O.[Na+].[I-].[K+]>C(O)C>[C:5]([OH:14])(=[O:6])/[CH:4]=[CH:3]/[C:37]([OH:39])=[O:40].[CH3:15][C:16]1[O:20][C:19]([CH2:21][N:22]2[C:26]3=[N:27][CH:28]=[CH:29][CH:30]=[C:25]3[N:24]=[C:23]2[NH:31][CH:32]2[CH2:36][CH2:35][N:34]([CH2:2][CH2:3][C:4]3[C:5](=[O:14])[O:6][C:7]4[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=4[CH:9]=3)[CH2:33]2)=[CH:18][CH:17]=1
Reactant: Cc1ccc(Cn2c(NC3CCNC3)nc3cccnc32)o1
Reactant: O=c1oc2ccccc2cc1CCBr
Reactant: O=C([O-])O
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc(Cn2c(NC3CCN(CCc4cc5ccccc5oc4=O)C3)nc3cccnc32)o1
Product: O=C(O)/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 25.6 %

Procedure:
A mixture of 7.6 parts of 3-(2-bromoethyl)-2H-1-benzopyran-2-one, 6.0 parts of 3-[(5-methyl-2-furanyl)methyl]-N-(3-pyrrolidinyl)-3H-imidazo[4,5-b]pyridin-2-amine, 8.4 parts of sodium hydrogen carbonate, 0.1 parts of potassium iodide and 160 parts of ethanol was stirred for 4 hours at reflux temperature. After cooling to room temperature, the precipitated product was filtered off and the filtrate was evaporated. The residue was stirred in ethyl acetate. The precipitate was filtered off and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane, hexane, methanol and ammonium hydroxide (45:45:9:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the (E)-2-butenedioate salt in 2-propanone. The salt was filtered off and crystallized twice from ethanol. The product was filtered off, washed with ethanol and dried in vacuo at 50° C., yielding 3 parts (25.6%) of 3-[2-[3-[[3-[(5-methyl-2-furanyl) methyl]-3H-imidazo[4,5-b]pyridin-2-yl]amino]-1-pyrrolidinyl]ethyl]-2H-1-benzopyran-2-one (E)-2-butenedioate(1:1); mp. 194.2° C. (compound 130).
Reaction SMILES: CC(C)(OC([NH:7][C@H:8]([C:24]([NH:26][C@@H:27]([CH2:44][CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1)[C@@H:28]([OH:43])[C:29]1[N:30](COCC2C=CC=CC=2)[CH:31]=[CH:32][N:33]=1)=[O:25])[CH2:9][C:10]1[N:14](COCC2C=CC=CC=2)[CH:13]=[N:12][CH:11]=1)=O)C.[H][H]>[OH-].[OH-].[Pd+2].CO.Cl>[CH:45]1([CH2:44][C@H:27]([NH:26][C:24](=[O:25])[C@H:8]([CH2:9][C:10]2[N:14]=[CH:13][NH:12][CH:11]=2)[NH2:7])[C@@H:28]([OH:43])[C:29]2[NH:33][CH:32]=[CH:31][N:30]=2)[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cncn1COCc1ccccc1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)c1nccn1COCc1ccccc1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)c1ncc[nH]1
Reaction time: 2 h

Procedure:
A mixture of [(1,1-dimethylethoxy)carbonyl]-N-[(1S,2R)-1-(cyclohexylmethyl)-2-hydroxy-2-[1-[(phenylmethoxy)methyl]-1H-imidazol-2-yl]ethyl]-N3 -[(phenylmethoxy)methyl]-L-histidinamide (1.46 g., 2.0 mmole) [prepared as set forth in Example 11 (d)], 20% palladium hydroxide on carbon catalyst (350 mg.), and 1.0 N hydrochloric acid (4 ml., 4 mmole) in methanol (15 ml.) is hydrogenated under a slow stream of hydrogen for 20 hours at 25°, after which it is filtered and concentrated to dryness. The residue (1.1 g.) is dissolved in acetic acid (30 ml.) and dry HCl gas is bubbled through the solution for 30 minutes at 25°. The mixture is then stirred at 25° for 2 hours, after which is is concentrated in vacuo. The residue is triturated with acetonitrile to give 833 mg. of a white solid. The solid is dissolved in excess 1N hydrochloric acid and concentrated to dryness. The process is repeated three times to give N-[(1S,2R)-1-(cyclohexylmethyl)-2-hydroxy-2-(1H-imidazol-2-yl)ethyl]-L-histidinamide as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:17]([O:19][CH3:20])=[O:18])([C:14](O)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.ClC(OC)=O.[BH4-].[Na+]>C1COCC1.CO>[OH:15][CH2:14][C:11]1([C:17]([O:19][CH3:20])=[O:18])[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:13][CH2:12]1
Reactant: COC(=O)C1(C(=O)O)CCN(C(=O)OC(C)(C)C)CC1
Agent: COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)C1(CO)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Yield: 45.3 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-(methoxycarbonyl)piperidine-4-carboxylic acid (6 g, 21 mmol) and DIEA (7.3 mL, 42 mmol, 2.0 equiv.) in THF (60 mL) was added methyl chloroformate (1.94 mL, 25 mmol, 1.2 equiv.) at 0° C. The mixture was stirred at 0° C. until the reaction was complete. NaBH4 (3.16 g, 84 mmol, 4.0 equiv.) was added at 0° C. MeOH (10 mL) was then added. The mixture was stirred at 0° C. for 90 min. The reaction mixture was then quenched by saturated NaHCO3 and concentrated to dryness. The residue was dissolved in ethyl acetate, washed with saturated NaHCO3, water and brine, dried over Na2SO4, and concentrated. The resulting residue was purified by column chromatography to give 1-tert-butyl 4-methyl 4-(hydroxymethyl)piperidine-1,4-dicarboxylate (2.6 g, 46%). LRMS (M-Boc+H+) m/z 174.1.
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6]([O:8][CH3:9])=[O:7])#[N:4].Br[CH:11]([CH3:24])[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]([F:23])([F:22])[F:21])=[O:13]>C1COCC1>[CH3:9][O:8][C:6](=[O:7])[CH:5]([C:3]#[N:4])[CH:11]([CH3:24])[C:12](=[O:13])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]([F:21])([F:22])[F:23]
Reactant: COC(=O)CC#N
Reactant: CC(Br)C(=O)c1ccccc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(C#N)C(C)C(=O)c1ccccc1C(F)(F)F
Temperature: 20 °C
Reaction time: 3 h
Yield: 92.6 %

Procedure:
To a suspension of NaH (60%, 2.88 g, 72 mmol) in anhyd THF (200 mL) was added methyl cyanoacetate (4.5 mL, 50 mmol). After this mixture was stirred for 3 h at 20° C., a solution of 2-bromo-1-(2-trifluoromethyl-phenyl)-propan-1-one (13.5 g, 48 mmol) was added and the mixture was stirred overnight at 20° C. The mixture was quenched with water and the organic layer was separated. The aqueous layer was extracted with EtOAc. The combined extracts were washed with brine, dried (anhyd Na2SO4) and concentrated under reduced pressure to afford the title compound as an oil (13.3 g, 93%), which was used in the next step without purification. MS (ES): 300 (MH+).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:18](=[O:31])[C:19]([C:28](O)=[O:29])=[CH:20][N:21]([CH2:23][C:24]([F:27])([F:26])[F:25])[CH:22]=2)=[CH:13][CH:12]=1.CCOC(C(C#N)=NOC(N1CCOCC1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.[NH2:59][C:60]1[CH:65]=[CH:64][C:63]([C:66]2[C:67]([NH2:73])=[N:68][CH:69]=[C:70]([Br:72])[CH:71]=2)=[CH:62][CH:61]=1>CN(C=O)C.O>[NH2:73][C:67]1[C:66]([C:63]2[CH:62]=[CH:61][C:60]([NH:59][C:28]([C:19]3[C:18](=[O:31])[C:17]([C:14]4[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=4)=[CH:22][N:21]([CH2:23][C:24]([F:26])([F:25])[F:27])[CH:20]=3)=[O:29])=[CH:65][CH:64]=2)=[CH:71][C:70]([Br:72])=[CH:69][N:68]=1
Reactant: O=C(O)c1cn(CC(F)(F)F)cc(-c2ccc(F)cc2)c1=O
Reactant: Nc1ccc(-c2cc(Br)cnc2N)cc1
Agent: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncc(Br)cc1-c1ccc(NC(=O)c2cn(CC(F)(F)F)cc(-c3ccc(F)cc3)c2=O)cc1
Reaction time: 0.42 h
Yield: 89.9 %

Procedure:
DIPEA (414 μl) was added to a solution of the compound obtained in Step 2 of Example 9 (500 mg) and COMU (883 mg) in DMF (8.0 ml) at room temperature, and the mixture was stirred for 25 minutes. The compound obtained in Step 1 of Example 1 (440 mg) was added at room temperature. The mixture was stirred for 19 hours, followed by the addition of water. The precipitated solid was collected by filtration, suspended in chloroform/diisopropyl ether and then collected by filtration to give 800 mg of the title compound.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([CH:19]3[CH2:24][NH:23][CH2:22][CH2:21][NH:20]3)=[O:18])[CH2:13][CH2:12]2)[CH:7]=[CH:8][C:9]=1[Cl:10].C(N(CC)C(C)C)(C)C.[CH:34](=O)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH2:34]([N:23]1[CH2:22][CH2:21][NH:20][CH:19]([C:17]([N:14]2[CH2:13][CH2:12][N:11]([C:6]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:4]([Cl:3])[CH:5]=3)[CH2:16][CH2:15]2)=[O:18])[CH2:24]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(C1CNCCN1)N1CCN(c2ccc(Cl)c(Cl)c2)CC1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(C1CN(Cc2ccccc2)CCN1)N1CCN(c2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C

Procedure:
A mixture of 1-(3,4-dichlorophenyl)-4-(piperazin-2-ylcarbonyl)piperazine dihydrochloride (150 mg), N,N-di-iso-propylethylamine (0.189 mL) and dichloromethane (10 ml) was stirred at room temperature under argon. After 5 minutes benzaldehyde (0.04 ml) was added followed by sodium triacetoxyborohydride (153 mg). The mixture was stirred overnight at room temperature and then filtered through a SCX-2 column eluting with methanol and then a 7M solution NH3 in methanol. The basic fraction was concentrated at reduced pressure. The residue was purified using reverse phase HPLC eluting with a mixture of 5-95% acetonitrile in water and then was filtered through a SCX-2 column eluting with methanol and then a 7M solution NH3 in methanol. The basic fraction was concentrated at reduced pressure. This gave 1-benzyl-3-{[4-(3,4-dichlorophenyl)piperazin-1-yl]carbonyl}piperazine as a colourless gum (125 mg).
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[NH:5][CH2:4][CH:3]1[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[C:22](Cl)(=[O:24])[CH3:23].N1C=CC=CC=1.O>ClCCCl>[O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[N:5]([C:22](=[O:24])[CH3:23])[CH2:4][CH:3]1[NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]
Reactant: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2
Reactant: CC(=O)Cl
Solvent: ClCCCl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)N1CC(NC(=O)OC(C)(C)C)C(=O)Nc2cc(C)ccc21

Procedure:
2-Oxo-3-tert-butoxycarbonylamino-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (2.00 g) obtained from Referential Example 7 was suspended in 1,2-dichloroethane (40 ml), acetyl chloride (0.56 ml) and pyridine (0.64 ml) were added thereto, the mixture was refluxed for 2 hours. Water (100 ml) was added, extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and diisopropyl ether was added to the residue for trituration, collectedly filtration, to thereby obtain 1.33 g of the titled compound.
Reaction SMILES: [C@@H:1]12[N:8](C)[C@@H:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH2:2]2.C(=O)([O-])OCC[Cl:14].O>C1(C)C=CC=CC=1>[ClH:14].[CH:5]12[NH:8][CH:1]([CH2:7][CH2:6]1)[CH2:2][CH2:3][CH2:4]2
Reactant: CN1[C@@H]2CCC[C@H]1CC2
Reactant: O=C([O-])OCCCl
Solvent: Cc1ccccc1
Solvent: O
Product: C1CC2CCC(C1)N2
Product: Cl
Temperature: 80 °C
Reaction time: 24 h

Procedure:
Tropane (11.0 mL, 7.44 mmol) was dissolved in toluene (10 mL), chloroethyl carbonate (2.2 mL, 23 mmol) was added slowly, and the mixture stirred at 80° C. for 24 hours. Distilled water was added to the reaction mixture, and the mixture extracted with ethyl acetate. The organic phase was dried and concentrated by anhydrous magnesium sulfate. The obtained oily residue was dissolved in concentrated hydrochloric acid (10 mL), and heated with stirring at 100° C. for 2 hours. The solvent was distilled off under reduced pressure, toluene was added to the residue, and the mixture distilled under reduced pressure to obtain the target substance (820 mg, 72%) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:5]([N:15]=[CH:16][C:17]=2[C:18]#[C:19][CH:20]2[CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]2)[CH:6]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[CH:8]=1.[F:31][C:32]([F:37])([F:36])[C:33](O)=[O:34].C(OCC)(=[O:40])C>ClCCl>[CH3:1][O:2][C:3]1[C:4]2[N:5]([N:15]=[CH:16][C:17]=2[C:18](=[O:40])[CH2:19][CH:20]2[CH2:23][N:22]([C:33](=[O:34])[C:32]([F:37])([F:36])[F:31])[CH2:21]2)[CH:6]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)[CH:8]=1
Reactant: COc1cc(-c2cnn(C)c2)cn2ncc(C#CC3CN(C(=O)OC(C)(C)C)C3)c12
Reactant: O=C(O)C(F)(F)F
Reactant: CCOC(C)=O
Solvent: ClCCl
Product: COc1cc(-c2cnn(C)c2)cn2ncc(C(=O)CC3CN(C(=O)C(F)(F)F)C3)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 3-{[4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl]ethynyl}azetidine-1-carboxylate (24 mg, 0.059 mmol) in dichloromethane (0.5 ml), was added trifluoroacetic acid (0.50 ml, 6.49 mmol) at 0° C. The reaction mixture was warmed to room temperature and stirred for 30 mins. The reaction was diluted with ethyl acetate, and washed with saturated aqueous sodium bicarbonate. The organic layer was separated, and the aqueous layer was back extracted two times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (methanol/dichloromethane gradient) to afford 1-[4-methoxy-6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl]-2-[1-(trifluoroacetyl)azetidin-3-yl]ethanone. 1H NMR (500 MHz, CDCl3) δ 8.35 (s, 1H), 8.32 (s, 1H), 7.77 (s, 1H), 7.67 (s, 1H), 6.81 (s, 1H), 4.68 (app t, 1H), 4.39 (app t, 1H), 4.10-4.16 (m, 1H), 4.06 (s, 3H), 3.98 (s, 3H), 3.85-3.91 (m, 1H), 3.36-3.53 (m, 2H), 3.23-3.33 (m, 1H). LRMS (ESI) calculated for C19H19F3N5O3 [M+H]+, 422.1; found 422.0.
Reaction SMILES: [OH-].[Na+].[CH2:3]([NH:7][C:8](=[O:13])[O:9][CH2:10][C:11]#[CH:12])[CH2:4][CH2:5][CH3:6].[I:14]I.ClCl>CO.O>[CH2:3]([NH:7][C:8](=[O:13])[O:9][CH2:10][C:11]#[C:12][I:14])[CH2:4][CH2:5][CH3:6]
Reactant: C#CCOC(=O)NCCCC
Reactant: II
Agent: ClCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCNC(=O)OCC#CI
Reaction time: 1 h
Yield: 166.2 %

Procedure:
At 8° C., 10.1 g of sodium hydroxide (0.244 mol) and 19.0 g of propargyl butylcarbamate (0.122 mol) are introduced as initial charge in 48 g of methanol and 50 g of water. At this temperature, 15.5 g of iodine (0.061 mol) are added in portions. Chlorine (5.6 g, 0.079 mol) is then slowly introduced into the reaction mixture so that the temperature still remains below 8° C. When the metered addition is complete, the mixture is stirred for 1 h at this temperature and then 105 g of water are added. The precipitated solid is isolated by filtration, washed with water and dried in vacuo. This gives 28.5 g of 3-iodo-2-propynyl N-butylcarbamate (purity: 95.0% (HPLC), polyiodized compounds: 0.3% (HPLC), yield: 79%).
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:20]1[N:29]=[C:28]([NH:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]3[O:38][CH2:39][O:40][C:34]=3[CH:33]=2)[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:41]#[N:42])[CH:26]=2)[N:21]=1>CC(O)C>[CH2:8]([O:7][C:5]([CH:4]1[CH2:3][CH2:2][N:1]([C:20]2[N:29]=[C:28]([NH:30][CH2:31][C:32]3[CH:37]=[CH:36][C:35]4[O:38][CH2:39][O:40][C:34]=4[CH:33]=3)[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:41]#[N:42])[CH:26]=3)[N:21]=2)[CH2:11][CH2:10]1)=[O:6])[CH3:9]
Reactant: N#Cc1ccc2nc(Cl)nc(NCc3ccc4c(c3)OCO4)c2c1
Reactant: CCOC(=O)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CCOC(=O)C1CCN(c2nc(NCc3ccc4c(c3)OCO4)c3cc(C#N)ccc3n2)CC1
Temperature: 25 °C
Yield: 83 %

Procedure:
3.71 g of ethyl isonipecotate, 2.38 g of triethylamine and 10 ml of 2-propanol were added to 1 g of 2-chloro-4-(3,4-methylenedioxybenzyl)amino-6-cyanoquinazoline. The obtained mixture was refluxed for 1 hour and cooled to room temperature. The crystals thus precipitated were recovered by filtration and washed with water and ether successively to give 1.126 g of the title compound.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:7]2=[N:8][CH:9]=[N:10][C:11]([NH2:12])=[C:6]2[CH:5]=[N:4]1.[C:13]1([C:19]2[C:20]3[CH:33]=[CH:32][CH:31]=[CH:30][C:21]=3[S:22][C:23]=2[CH2:24]OS(C)(=O)=O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C>[C:13]1([C:19]2[C:20]3[CH:33]=[CH:32][CH:31]=[CH:30][C:21]=3[S:22][C:23]=2[CH2:24][N:3]2[C:7]3=[N:8][CH:9]=[N:10][C:11]([NH2:12])=[C:6]3[CH:5]=[N:4]2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1ncnc2[nH]ncc12
Reactant: CS(=O)(=O)OCc1sc2ccccc2c1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1ncnc2c1cnn2Cc1sc2ccccc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
NaH (60% in mineral oil, 13 mg, 0.314 mmol) was added in one portion to a mixture of 1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (42 mg, 0.314 mmol) in DMF (5 mL) at RT. After 5 min stirring a solution of methanesulfonic acid 3-phenylbenzo[b]thiophen-2-ylmethyl ester from Example 26 (100 mg, 0.314 mmol) in DMF (1 mL) was added dropwise and stirring at RT was continued for 30 min. The reaction mixture was then quenched by addition of water and diluted with EtOAc. The aqueous phase was further extracted with EtOAc (2×100 mL) and the combined organic layers were washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in EtOAc) and triturated from MeOH with water affording 164 as an off-white solid (17 mg, 15%). LCMS: RT 4.13 min [M+H]+ 358.1. 1H NMR (DMSO, 400 MHz): δ 8.23 (1H, s), 8.16 (1H, s), 7.95-7.90 (1H, m), 7.70-7.59 (4H, m), 7.56-7.49 (2H, m), 7.42-7.35 (2H, m), 5.72 (2H, s)