Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[NH4+].[OH2:3].C([C:8]1[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][C:9]=1[C:10]#[N:11])C(C)C>[Fe].C(O)C>[NH2:16][C:13]1[CH:14]=[CH:15][C:8]([O:3][CH2:8][CH:9]([CH3:12])[CH3:10])=[C:9]([CH:12]=1)[C:10]#[N:11]
Reactant: O
Reactant: CC(C)Cc1ccc([N+](=O)[O-])cc1C#N
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CC(C)COc1ccc(N)cc1C#N
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
Ammonium chloride (5.6 g) and iron powder (21 g) were added to a mixed solvent of water (80 ml) and ethanol (240 ml), and the mixture was heated to 65° C. Then, 2-isobutyl-5-nitrobenzonitrile (20 g) was added in parts over 20 min and the mixture was stirred at a refluxing temperature for 30 min. The reaction mixture was ice-cooled and filtrated. The solvent was evaporated under reduced pressure. To the residue was added aqueous sodium hydroxide solution and the mixture was extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization. The crystals were recrystallized from a mixed solvent of ethyl acetate-n-hexane to give the title compound (17 g), melting point: 88–93° C.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5](=[S:18])[NH:6][C:7]=1[C:8](=O)[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[CH:10]=1)[CH3:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:20]>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[NH:4][C:5](=[S:18])[NH:6][C:7]=1[C:8](=[S:20])[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[CH:10]=1)[CH3:2]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCc1[nH]c(=S)[nH]c1C(=O)c1ccc(F)c(F)c1
Solvent: Cc1ccccc1
Product: CCc1[nH]c(=S)[nH]c1C(=S)c1ccc(F)c(F)c1

Procedure:
Ten grams of 1,3-dihydro-4-ethyl-5-(3,4-difluorobenzoyl)-2H-imidazole-2-thione in toluene and phosphorus pentasulfide was heated at reflux temperature for 5 hours. Evaporation of the solvent provides the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][C@@H:11]([CH3:14])[C@@H:10]([N:15]3[C:19]4=[C:20]5[CH:26]=[CH:25][NH:24][C:21]5=[N:22][CH:23]=[C:18]4[NH:17][C:16]3=[O:27])[CH2:9]2)[CH:5]=[CH:4][N:3]=1.[C-]#N.[Na+].[N:31]12CCN(CC1)C[CH2:32]2.O>CS(C)=O>[CH3:14][C@@H:11]1[CH2:12][CH2:13][N:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:32]#[N:31])[N:7]=2)[CH2:9][C@@H:10]1[N:15]1[C:19]2=[C:20]3[CH:26]=[CH:25][NH:24][C:21]3=[N:22][CH:23]=[C:18]2[NH:17][C:16]1=[O:27]
Reactant: C[C@@H]1CCN(c2ccnc(Cl)n2)C[C@@H]1n1c(=O)[nH]c2cnc3[nH]ccc3c21
Reactant: C1CN2CCN1CC2
Agent: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C[C@@H]1CCN(c2ccnc(C#N)n2)C[C@@H]1n1c(=O)[nH]c2cnc3[nH]ccc3c21
Temperature: 80 °C
Reaction time: 7 h
Yield: 245.7 %

Procedure:
To a solution of rel-1-[(3R,4R)-1-(2-chloro-4-pyrimidinyl)-4-methyl-3-piperidinyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]-pyridin-2(1H)-one (60 mg) and sodium cyanide (38 mg) in DMSO (1 mL), 1,4-diazabicyclo[2.2.2]octane (5 mg) was added at ambient temperature. The temperature was raised to 80° C. and stirred for 7 hours. After cooling down to ambient temperature, water (15 mL) was added to the mixture and resulting precipitate was collected by filtration. The filtrate was purified by pre-packed column (chloroform:methanol=95:1 to 80:20) to afford rel-4-[(3R,4R)-4-methyl-3-(2-oxo-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-1(2H)-yl)-1-piperidinyl]-2-pyrimidinecarbonitrile (41 mg) as white powder.
Reaction SMILES: [N:1]1C=CC=C[CH:2]=1.[NH2:7][C:8]1[C:9](Br)=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:12][CH:13]=1.[C-]#N.[Na+].O>C1C=CC=CC=1>[C:2]([C:9]1[C:10]([C:14]([F:17])([F:16])[F:15])=[CH:11][CH:12]=[CH:13][C:8]=1[NH2:7])#[N:1]
Reactant: c1ccncc1
Reactant: Nc1cccc(C(F)(F)F)c1Br
Agent: [C-]#N
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: N#Cc1c(N)cccc1C(F)(F)F

Procedure:
To 21 g. of dry pyridine is added slowly with stirring 23 g. (0.26 mol.) of cuprous cyanide. The mixture rapidly solidifies and is then heated to 125°. Excess pyridine is boiled off and the temperature is decreased to 110°. 3-Amino-2-bromobenzotrifluoride (48 g., 0.20 mol.) is added with stirring and the reaction mixture is heated to 165°-170° for 75 minutes. The mixture is then cooled to 90° and a solution of 75 g. (1.05 mol.) of sodium cyanide in 75 ml. of water is added followed by 250 ml. of benzene. The resulting mixture is stirred for one hour, the layers are separated and the benzene layer is washed with water, dried and evaporated to give 2-cyano-3-trifluoromethylaniline.
Reaction SMILES: [SH:1][CH2:2][C:3]([CH2:5][SH:6])=[CH2:4].[CH3:7][C:8]([CH3:10])=O.[Cl-].[Al+3].[Cl-].[Cl-].O>ClCCl>[CH3:7][C:8]1([CH3:10])[S:6][CH2:5][C:3](=[CH2:4])[CH2:2][S:1]1
Reactant: CC(C)=O
Reactant: C=C(CS)CS
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: C=C1CSC(C)(C)SC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-(Mercaptomethyl)-3-mercapto-1-propene (Z Chem. 1975, 15, 302)(0.83 g, 6.9 mmoles) and acetone (0.51 mL) were placed in about 15 mL of dichloromethane. Then anhydrous aluminium chloride (0.32 g) was added portionwise over one minute at room temperature. The solution was stirred at room temperature for 30 minutes. The reaction was worked up by addition of 20 mL of water followed by extraction with dichloromethane. The extracts were dried and evaporated to give 0.89 g clear oil with a penetrating smell. The oil was chromatographed to give 400 mg (40%) of clear oil.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:16][C:17](=[CH2:19])[CH3:18].C(=O)(O)[O-].[Na+]>O1CCOCC1>[C:17]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([I:1])=[CH:3][CH:4]=1)([CH3:19])([CH3:18])[CH3:16]
Reactant: O=C(O)c1ccc(I)cc1
Reactant: C=C(C)C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
4-Iodobenzoic Acid (25 g, 0.10M) was suspended in 200 ml of anhydrous dioxane containing 14 ml of concentrated sulfuric acid. Isobutylene (200 ml) was condensed and added to the suspension. The reaction vessel was sealed and stirred at room temperature for 3 days, during which time most of the material dissolved. The reaction mixture was cautiously poured into saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was dried with anhydrous sodium carbonate, filtered and evaporated to a colorless oil (18 g, (60%). 1H NMR (CDCl3) δ 1.59 (s, 9H), 7.68 (d, J=8 Hz, 2H), 7.75 (d, J=8 Hz, 2H).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:10]=2[C:11]#[N:12])[CH2:3]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].CN(C)C=O>O>[N+:17]([C:14]1[CH:15]=[CH:16][C:9]([N:4]2[CH2:3][C@@H:2]([CH3:1])[N:7]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C@@H:6]([CH3:8])[CH2:5]2)=[C:10]([C:11]#[N:12])[CH:13]=1)([O-:19])=[O:18]
Reactant: CCOC(=O)CBr
Reactant: C[C@@H]1CN(c2ccc([N+](=O)[O-])cc2C#N)C[C@H](C)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN1[C@H](C)CN(c2ccc([N+](=O)[O-])cc2C#N)C[C@@H]1C
Temperature: 60 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
Then, cis-2-(3,5-dimethylpiperazin-1-yl)-5-nitrobenzonitrile (14.3 g), potassium carbonate (4.9 g) and ethyl bromoacetate (6 g) were added to dimethylformamide (35 ml), and the mixture was stirred at 60° C. for 1 h. The reaction mixture was added to water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (mobile phase: chloroform) to give ethyl cis-4-(4-nitro-2-cyanophenyl)-2,6-dimethylpiperazin-1-ylacetate (10.8 g) as an oily substance.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[C:11]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH3:22])[CH:14]=2)[N:10]([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[NH:25][CH:24]=2)[C:9]1=[O:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:34][CH2:35][CH2:36][CH2:37][N:38]1[C:42](=[O:43])[C:41]2=[CH:44][CH:45]=[CH:46][CH:47]=[C:40]2[C:39]1=[O:48].[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH:12]=[C:11]([C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([CH3:22])[CH:14]=2)[N:10]([C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH2:34][CH2:35][CH2:36][CH2:37][N:38]3[C:42](=[O:43])[C:41]4[C:40](=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:39]3=[O:48])[CH:24]=2)[C:9]1=[O:32])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1cc(-c2cn(C(=O)OC(C)(C)C)c(=O)n2-c2c[nH]c3ccccc23)c2ccccc21
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cc(-c2cn(C(=O)OC(C)(C)C)c(=O)n2-c2cn(CCCCN3C(=O)c4ccccc4C3=O)c3ccccc23)c2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 38 %

Procedure:
The product of step e) (0.034 g, 0.080 mmol), N-(4-bromobutyl)phthalimide (0.028 g, 0.10 mmol) and sodium hydride (95%, 0.0024 g, 0.10 mmol) was dissolved in dry DMF (0.5 ml). After stirring at room temperature for 1.5 hour HPLC shows complete reaction. The reaction was quenched by addition of aqueous acetic acid (1 M, 2 ml) and ethyl acetate (2 ml), the phases were separated and the organic phase washed with water (1×2 ml). Solvent removal followed by chromatographic purification on silica, eluting with heptane—ethyl acetate (20:80), furnishes the sub-title product (0.019 g, 38%) as a slightly brown solid.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[C:11]2[CH2:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=2[O:25][CH3:26])=[CH:6][CH:5]=1)(O)=[O:2].Cl.CN(C)CCCN=C=NCC.[CH2:39]([CH:41]([CH2:44][CH3:45])[CH2:42][NH2:43])[CH3:40].CN(C)C=O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:39]([CH:41]([CH2:44][CH3:45])[CH2:42][NH:43][C:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[C:11]2[CH2:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][C:16]=2[O:25][CH3:26])=[CH:6][CH:5]=1)=[O:2])[CH3:40]
Reactant: COC(=O)c1ccc(Cc2cccc3ccc(C(=O)O)cc23)c(OC)c1
Reactant: CCC(CC)CN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCC(CC)CNC(=O)c1ccc2cccc(Cc3ccc(C(=O)OC)cc3OC)c2c1
Yield: 77 %

Procedure:
A mixture of methyl 4-(7-carboxynaphth-1-ylmethyl)-3-methoxybenzoate (342 mg), 4-dimethylaminopyridine (358 mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (560 mg), and 2-ethylbutylamine (198 mg), was dissolved in 3:1 methylene chloride:dimethylformamide (distilled over CaH2) (4 ml) and stirred for 18 h. Methylene chloride was added and the solution was washed (1N hydrochloric acid, brine), dried (MgSO4) and evaporated to give a yellow foam. Recrystallization from 1:2 methylene chloride:hexane (30 ml) gave methyl 4-[7-(2-ethylbutylcarbamoyl)naphth-1-ylmethyl]-3-methoxybenzoate (326 mg, 77%) as a colorless solid; mp 129.5°-130.5° C.
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=O)=[CH:12][CH:11]=2)[CH:2]=1.[C:20]([C:24]1[CH:25]=[C:26]([NH2:42])[N:27]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[CH:30]=2)[N:28]=1)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:24]1[CH:25]=[C:26]([NH:42][C:17](=[O:19])[CH2:16][C:13]2[CH:12]=[CH:11][C:10]([N:3]3[C:4]4=[N:5][CH:6]=[CH:7][CH:8]=[C:9]4[N:1]=[CH:2]3)=[CH:15][CH:14]=2)[N:27]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35][N:36]3[CH2:37][CH2:38][O:39][CH2:40][CH2:41]3)[CH:30]=2)[N:28]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)c1cc(N)n(-c2cccc(CN3CCOCC3)c2)n1
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1
Product: CC(C)(C)c1cc(NC(=O)Cc2ccc(-n3cnc4cccnc43)cc2)n(-c2cccc(CN3CCOCC3)c2)n1

Procedure:
The title compound is prepared as described in Example 28 but using 2-(4-imidazo[4,5-b]pyridine-3-yl-phenyl)-acetic acid and 5-tert-butyl-2-(3-morpholin-4-ylmethyl-phenyl)-2H-pyrazol-3-ylamine. Title compound: ES-MS: 550.41 [M-H]+; RT=1.40 min (HPLC System 3).
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]([NH:5][C:6]1[S:7][C:8](=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][C:22](=O)[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[C:9](=[O:11])[N:10]=1)=[NH:4].[NH2:27][CH2:28][C@H:29]([OH:39])[CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1>>[OH:39][C@H:29]([CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[CH2:28][NH:27][CH:22]1[CH2:23][CH2:24][N:19]([C:16]2[CH:17]=[CH:18][C:13]([CH:12]=[C:8]3[S:7][C:6]([NH:5][C:3](=[NH:4])[N:2]([CH3:1])[CH3:26])=[N:10][C:9]3=[O:11])=[CH:14][CH:15]=2)[CH2:20][CH2:21]1
Reactant: NC[C@H](O)COc1ccc(O)cc1
Reactant: CN(C)C(=N)NC1=NC(=O)C(=Cc2ccc(N3CCC(=O)CC3)cc2)S1
Product: CN(C)C(=N)NC1=NC(=O)C(=Cc2ccc(N3CCC(NC[C@H](O)COc4ccc(O)cc4)CC3)cc2)S1

Procedure:
The title compound was prepared from N,N-dimethyl-N′-{4-oxo-5-[4-(4-oxo-piperidin-1-yl)-benzylidene]-4,5-dihydro-thiazol-2-yl}-guanidine(which was obtained in Intermediate 23) and 4-((2S)-3-amino-2-hydroxy-propoxy)-phenol (which was obtained in Intermediate 5) according to the procedure of Example 1 as a yellowish solid; 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2 H), 1.75-1.95 (m, 2 H), 2.50-3.30 (m, 9 H), 3.70-3.90 (m, 7 H), 4.90 (brs, 1 H), 6.66 (d, J=6.8 Hz, 1 H), 6.74 (d, J=6.8 Hz, 1 H), 7.01 (d, J=8.8 Hz, 2 H), 7.41 (d, J=8.8 Hz, 2 H), 7.47 (s, 1 H); MS (ES) m/z: 270.0 ((M+2H)2+, 100%); 539.1 (MH+, 10%); HRMS Calcd. for C27H35N6O4S (MH+): 539.2441. Found: 539.2422.
Reaction SMILES: [H-].[Na+].[C:3]1([C@H:9]([N:11]2[C@H:15]3[CH2:16][O:17][C:18](=[O:19])[C@H:14]3[NH:13][C:12]2=[O:20])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(COC)OC>[C:3]1([C@H:9]([N:11]2[C@H:15]3[CH2:16][O:17][C:18](=[O:19])[C@H:14]3[N:13]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:12]2=[O:20])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: BrCc1ccccc1
Reactant: C[C@H](c1ccccc1)N1C(=O)N[C@@H]2C(=O)OC[C@@H]21
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: C[C@H](c1ccccc1)N1C(=O)N(Cc2ccccc2)[C@@H]2C(=O)OC[C@@H]21
Reaction time: 0.5 h

Procedure:
48 ml of dimethoxyethane and 0.39 g (16.2 mmol) of sodium hydride were placed in a 100-ml three-neck flask equipped with a magnetic stirrer under argon and with complete exclusion of moisture. Then 3.24 g (13.2 mmol) of (3aS,6aR)-1-[(R)-(1-phenylethyl)]-dihydro-1H-furo-[3,4-d]imidazol-2,4(3H,3aH)-dione was added. After a stirring time of 10 min., 2.76 g (16.2 mmol) of benzyl bromide was added and the suspension was stirred for 30 min. Then the reaction mixture was evaporated. The residue was dissolved with 25 ml of dichloromethane and 25 ml of water. The phases were separated and the aqueous phase was washed three times, each time with 15 ml of dichloromethane. The organic phases were combined, dried with 5 g of magnesium sulfate and evaporated. (3aS,6aR)-1-[(R)-(1-phenylethyl)]-3-benzyl-dihydro-1H-furo[3,4-d]imidazol-2,4(3H,3aH)-dione was obtained as a beige product in a yield of 3.56 g (80.5 percent). Concerning the product:
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][CH:5]([OH:8])[CH2:6][CH3:7].Cl[C:10]1[N:15]2[N:16]=[C:17]([CH3:28])[C:18]([C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[CH3:27])=[C:14]2[N:13]=[C:12]([CH3:29])[CH:11]=1>CS(C)=O>[CH2:4]([CH:5]([O:8][C:10]1[N:15]2[N:16]=[C:17]([CH3:28])[C:18]([C:19]3[C:20]([CH3:27])=[CH:21][C:22]([CH3:26])=[CH:23][C:24]=3[CH3:25])=[C:14]2[N:13]=[C:12]([CH3:29])[CH:11]=1)[CH2:6][CH3:7])[CH3:3]
Reactant: Cc1cc(C)c(-c2c(C)nn3c(Cl)cc(C)nc23)c(C)c1
Reactant: CCC(O)CC
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCC(CC)Oc1cc(C)nc2c(-c3c(C)cc(C)cc3C)c(C)nn12
Temperature: 88 °C

Procedure:
To a suspension of 60% Sodium hydride in oil (160 mg) in 4 ml of DMSO was added 3-pentanol (853 mg), and then 7-chloro-2,5-dimethyl-3-(2,4,6-trimethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (580 mg) at room temperature. The mixture was heated at 88° C. overnight. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was dried and concentrated and purified through silica gel column chromatography using 10% hexane in chloroform as eluent to give the title compound as an orange oil. 1H NMR (CDCl3) ä 6.96(s, 2H), 5.95(s, 1H), 4.52(m, 1H), 2.48(s, 3H), 2.33(s, 3H), 2.27(s, 3H), 2.03(s, 6H), 1.75-2.00(m, 4H), 1.08(t, 6H)ppm.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30]C(=O)OC(C)(C)C)[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.[CH3:38][O-:39].[Na+]>[Cu](I)I>[CH3:38][O:39][C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH2:30])[CH2:27][CH2:28][CH2:29]2)=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(Br)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Reactant: C[O-]
Agent: I[Cu]I
Agent: [Na+]
Product: COc1nc2n(c1-c1ccc(C3(N)CCC3)cc1)-c1cccnc1Nc1ccccc1-2
Temperature: 100 °C
Yield: 11 %

Procedure:
A mixture of tert-butyl {1-[4-(2-bromo-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (50 mg, 0.09 mmol) and copper iodide (1.7 mg, 0.01 mmol) in sodium methoxide solution (1 M, 5 mL) was heated at 100° C. for 24 hour. After cooling to room temperature, the precipitate was collected and purified by HPLC to give the title compound as a white solid (5 mg, 11%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([NH2:12])=[S:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)=O.O>CN(C=O)C>[CH2:1]([O:8][CH2:9][C:10]1[S:11][CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: NC(=S)COCc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc(-c2csc(COCc3ccccc3)n2)cc1
Temperature: 130 °C
Yield: 49.2 %

Procedure:
To the solution of 2-Benzyloxy-thioacetamide (3.0 g, 16.57 mmol) in 3 ml of DMF was added 2-Bromo-1-(4-chloro-phenyl)-ethanone (3.0 g, 12.87 mmol). The reaction mixture was heated at 130° C. for 24 h under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), water (25 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified over silica gel (230-400 M, 2% EtOAc-Hexane) to get the desired product (2.0 g, 49%). The corresponding cyano derivative was also prepared by the same general method.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]=[C:5]=[O:6].[NH2:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1>C1(C)C=CC=CC=1>[Cl:1][CH2:2][CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)=[O:6]
Reactant: Nc1ccncc1
Reactant: O=C=NCCCl
Solvent: Cc1ccccc1
Product: O=C(NCCCl)Nc1ccncc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 88.3 %

Procedure:
2-Chloroethylisocyanate (10.0 g, 94 mmol) was added dropwise to a mixture of 4-aminopyridine (6.0 g, 63 mmol) and toluene (40 mL) at 0° C., and the mixture was stirred at room temperature for 6 hrs. The precipitates were collected by filtration and washed with diisopropyl ether to give the titled compound (11.1 g, 87%) as white crystals.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:14][CH:15]([CH3:28])[CH2:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=O)=[CH:20][C:19]=1[O:26][CH3:27].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C([O-])(O)=O.[Na+]>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:22][C:21]2[CH:24]=[CH:25][C:18]([O:17][CH2:16][CH:15]([CH3:14])[CH3:28])=[C:19]([O:26][CH3:27])[CH:20]=2)[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: COc1cc(C=O)ccc1OCC(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cc(CN2CCN(C(=O)OC(C)(C)C)CC2)ccc1OCC(C)C
Temperature: 20 °C
Reaction time: 12 h

Procedure:
The synthesis is carried out in argon condition. 2.2 g (11.8 mmol) of N-Boc-piperazine and 2.5 g (about 12 mmol) of crude 4-(2-methylpropyloxy)-3-methoxybenzaldehyde are mixed in 50 ml of dry of dichloromethane. After dissolution 2 drops of acetic acid is added, then 4.25 g (20 mmol) of NaBH(OAc)3 is added and the mixture is stirred for 12 h at 20° C. Then 20 ml of 5% NaHCO3 aqueous solution is added dropwise with care to the reaction mixture. The organic layer is separated, washed with 5% Na2CO3 solution, dried over sodium sulfate, filtered off, concentrated in vacuum at 50÷80° C. The residue (3.3 g of oil)-crude N-(tert-butyloxycarbonyl)-N′-(4-(2-methylpropyloxy)-3-methoxybenzyl)piperazine is used on the next step without further purification.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:13][CH:12]([OH:14])[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].CS(O[CH2:20][C:21]1[CH:22]=[N:23][C:24]([C:27]2[S:35][C:34]3[C:29](=[N:30][CH:31]=[CH:32][C:33]=3[O:36][C:37]3[CH:42]=[CH:41][C:40]([NH:43][C:44]([NH:46][CH:47]4[CH2:49][CH2:48]4)=[O:45])=[CH:39][C:38]=3[F:50])[CH:28]=2)=[CH:25][CH:26]=1)(=O)=O>CN(C=O)C>[CH:47]1([NH:46][C:44](=[O:45])[NH:43][C:40]2[CH:41]=[CH:42][C:37]([O:36][C:33]3[CH:32]=[CH:31][N:30]=[C:29]4[CH:28]=[C:27]([C:24]5[N:23]=[CH:22][C:21]([CH2:20][O:14][CH:12]6[CH2:13][N:10]([C:8]([O:7][C:3]([CH3:6])([CH3:4])[CH3:5])=[O:9])[CH2:11]6)=[CH:26][CH:25]=5)[S:35][C:34]=34)=[C:38]([F:50])[CH:39]=2)[CH2:49][CH2:48]1
Reactant: CS(=O)(=O)OCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1
Reactant: CC(C)(C)OC(=O)N1CC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC(OCc2ccc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)nc2)C1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
To a stirred suspension of NaH (271 mg, 60% dispersion in mineral oil, 6.72 mmol) in DMF (2 mL) at 0° C. was added tert-butyl-3-hydroxyazetidine-1-carboxylate (1.0 g, 5.65 mmol). After 30 min, a solution of 403 (1.13 mmol) in DMF (6 mL) and KI (183 mg, 1.13 mmol) were added at 0° C. The reaction mixture was heated to 80° C. for 30 min. The reaction was then quenched by addition of water and the mixture was extracted with AcOEt/MeOH. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified via Biotage [linear gradient 0-10%, (methanol/dichloromethane: SiliaFlash 25 g cartridge]. Title compound 404 was obtained as a beige solid (221 mg, 32% yield for 2 steps). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.71 (s, 1H), 8.62 (d, J=2.4 Hz, 1H), 8.52 (d, J=5.2 Hz, 1H), 8.37 (s, 1H), 8.28 (d, J=8.0 Hz, 1H), 7.94 (dd, J=8.0, 2.0 Hz, 1H), 7.73 (dd, J=13.6, 2.4 Hz, 1H), 7.38 (t, J=9.0 Hz, 1H), 7.23-7.18 (m, 1H), 6.64 (d, J=5.2 Hz, 1H), 6.57 (brd, 1H), 4.53 (s, 2H), 4.42-4.36 (m, 1H), 4.09-4.00 (m, 2H), 3.77-3.68 (m, 2H), 2.59-2.50 (m, 1H), 1.37 (s, 9H), 0.68-0.62 (m, 2H), 0.47-0.41 (m, 2H). MS (m/z): 606.48 (M+H).