Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7](=O)[CH2:8][CH2:9][C:10](=O)[CH:11]([C:19]2[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][N:20]=2)[CH2:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[N:4][CH:3]=1.C([O-])(=O)C.[NH4+:33].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[S:6][C:5]([C:7]2[NH:33][C:10]([CH:11]([C:19]3[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][N:20]=3)[CH2:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:9][CH:8]=2)=[N:4][CH:3]=1
Reactant: CSc1ccc(C(CC2CCOCC2)C(=O)CCC(=O)c2ncc(Cl)s2)nc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CSc1ccc(C(CC2CCOCC2)c2ccc(-c3ncc(Cl)s3)[nH]2)nc1
Temperature: 110 °C
Reaction time: 1 h
Yield: 104.5 %

Procedure:
To a solution of 1-(5-chloro-1,3-thiazol-2-yl)-5-[5-(methylsulfanyl)pyridin-2-yl]-6-(tetrahydro-2H-pyran-4-yl)hexane-1,4-dione (83.9 mg) in acetic acid (1.8 mL) was added ammonium acetate (278 mg), and the mixture was stirred at 110° C. for 1 hr. After cooling to room temperature, the mixture was neutralized with saturated aqueous sodium hydrogen carbonate solution. The reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (83.9 mg, yield 89%) was obtained as a pale-yellow amorphous solid from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: CC[O-].[Na+].[C:5]([CH2:7][C:8]([NH:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)=[O:9])#[N:6].[NH2:22][C:23]1[C:28]([CH:29]=O)=[CH:27][CH:26]=[CH:25][N:24]=1>CCO>[NH2:6][C:5]1[C:7]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:20])([F:19])[F:21])[CH:13]=2)=[O:9])=[CH:29][C:28]2[C:23](=[N:24][CH:25]=[CH:26][CH:27]=2)[N:22]=1
Reactant: N#CCC(=O)NCc1cccc(C(F)(F)F)c1
Reactant: Nc1ncccc1C=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Nc1nc2ncccc2cc1C(=O)NCc1cccc(C(F)(F)F)c1
Yield: 57.4 %

Procedure:
To a solution of NaOEt prepared by dissolving Na (50 mg, 1.47 mmol) in EtOH (2.5 ml), was added 2-cyano-N-(3-(trifluoromethyl)benzyl)acetamide (297.5 mg, 1.23 mmol) and 2-amino-3-pyridine-carboxaldehyde (150.0 mg, 1.23 mmol). The mixture was refluxed for 30 minutes. The solvent was removed under reduced pressure and the residue chromatographed CH2Cl2/MeOH 95:5→92:8, yielding 244.5 mg (57%) of the title compound.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[CH:11][C:10]2[NH:9][C:8]3[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][C:7]=3[C:6]=2[CH:5]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([CH3:29])[CH2:28][O:27]2)=[CH:22][CH:21]=1.O>CN(C=O)C>[Cl:3][C:4]1[CH:12]=[CH:11][C:10]2[N:9]([CH2:29][C:26]([C:23]3[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=3)([OH:27])[CH3:28])[C:8]3[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][C:7]=3[C:6]=2[CH:5]=1
Reactant: CC1(c2ccc(F)cc2)CO1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCc2c(n(CC(C)(O)c3ccc(F)cc3)c3ccc(Cl)cc23)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 45.5 %

Procedure:
The title compound was prepared by following general procedure 5. To a stirred suspension of sodium hydride (61 mg, 0.254 mmol) in 5 mL of DMF, 9-chloro-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.2 g, 0.852 mmol) was added and stirred at RT for 5 min. 2-(4-Fluorophenyl)-2-methyloxirane (194 mg, 1.27 mmol) was added slowly dropwise and stirred at RT for 14 h. The reaction was monitored by TLC and LCMS. After completion of the reaction, water was added, extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, evaporated under reduced pressure and purified by reverse phase chromatography to afford 150 mg of (1-(9-chloro-3-methyl-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-2-(4-fluorophenyl)propan-2-ol) as the TFA salt. 1H NMR (DMSO-d6, TFA salt) δ (ppm): 7.40 (s, 1H), 7.30-7.18 (m, 3H), 7.0-6.80 (m, 3H), 4.40-4.25 (d, 2H), 4.25-4.15 (d, 2H), 3.40-3.20 (d, 2H), 3.20-3.00 (m, 4H), 2.90 (s, 3H), 1.50 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[NH:11][CH:12]=[CH:13][N:14]=2)=[N:8][CH:9]=1)([OH:3])=[O:2].[CH2:15](O)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>S(Cl)(Cl)=O.N1C=CC=CC=1>[NH:14]1[CH:13]=[CH:12][N:11]=[C:10]1[C:7]1[CH:6]=[CH:5][C:4]([C:1]([O:3][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH3:15])=[O:2])=[CH:9][N:8]=1
Reactant: CCCCCCCCCCCCCCCCO
Reactant: O=C(O)c1ccc(-c2ncc[nH]2)nc1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCCCCCCCCCCCCCCCOC(=O)c1ccc(-c2ncc[nH]2)nc1
Reaction time: 17 h

Procedure:
5-Carboxy-2-(2-imidazolyl)-pyridine (1.89 g, 0.01 mol) is refluxed in 10 ml of thionyl chloride for 2 h. The solution is evaporated to dryness and the residue dissolved in 20 ml of dichloromethane. The latter solution is added dropwise to a mixture of 1-hexadecanol (2.68 g, 0.011 mol) in 1.6 ml of pyridine. After 17 h at room temperature, the precipitate is filtered off and the filtrate evaporated to dryness. The resulting residue is crystallized in toluene to yield the title compound, m.p. 97°-98°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])=[N:10][N:11]3[C:16](O)=[CH:15][CH:14]=[N:13][C:12]=23)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.O=P(Cl)(Cl)[Cl:36]>C1(C)C=CC=CC=1>[Cl:36][C:16]1[N:11]2[N:10]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[Cl:24])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[C:12]2[N:13]=[CH:14][CH:15]=1
Reactant: Oc1ccnc2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)nn12
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: Clc1ccc(-c2c(-c3ccccc3Cl)nn3c(Cl)ccnc23)cc1
Temperature: 100 °C

Procedure:
To a slurry of 3-(4-chlorophenyl)-2-(2-chlorophenyl)-pyrazolo[1,5-a]pyrimidin-7-ol (I-12A-1a; 2.00 g, 5.61 mmol) and diisopropylethylamine (4.0 ml, 22 mmol) in toluene (60 ml) at room temperature was added POCl3 (2.1 ml, 22 mmol), dropwise. The mixture was heated at 100° C. for 7 hours, concentrated, in vacuo, and the purified by silica gel chromatography using 10% hexanes in methylene chloride as eluant to afford I-13A-1a (1.72 g, 82%) as a solid: +APcI MS (M+1) 374.1; 1H NMR (400 MHz, CD2Cl2) δ 8.49 (d, J=4.6 Hz, 1H), 7.54–7.38 (m, 6H), 7.28 (d, J=8.7 Hz, 2H), 7.12 (d, J=4.2 Hz, 1H).
Reaction SMILES: Br[CH:2]1[CH2:19][CH2:18][C:5]2=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:7][C:8]([S:9][CH:10]([CH3:12])[CH3:11])=[C:4]2[C:3]1=[O:20].[N-:21]=[N+:22]=[N-:23].[Na+]>CN(C)C=O.O>[N:21]([CH:2]1[CH2:19][CH2:18][C:5]2=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:7][C:8]([S:9][CH:10]([CH3:12])[CH3:11])=[C:4]2[C:3]1=[O:20])=[N+:22]=[N-:23]
Reactant: CCOC(=O)c1sc(SC(C)C)c2c1CCC(Br)C2=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(SC(C)C)c2c1CCC(N=[N+]=[N-])C2=O
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 74.1 %

Procedure:
Ethyl 5-bromo-4,5,6,7-tetrahydro-3-isopropylthio-4-oxobenzo[c]thiophene-1-carboxylate (2.55 g) was dissolved in N,N-dimethylformamide (30 ml); a solution of sodium azide (0.88 g) in water (5 ml) was added at 0° C. After the reaction mixture was stirred at room temperature for 50 minutes, it was poured over water and extracted with ethyl acetate. The organic layer was washed with water and dried (MgSO4), after which the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:9, v/v) to yield ethyl 5-azido-4,5,6,7-tetrahydro-3-isopropylthio-4-oxobenzo[c]thiophene-1-carboxylate (1.70 g, 74.2%), which was then recrystallized from ethyl acetate-hexane. Colorless prisms. Melting point 118-119° C.
Reaction SMILES: C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl:47][C:48]1[CH:49]=[C:50](B(O)O)[CH:51]=[CH:52][C:53]=1[F:54].CO.[CH2:60]([N:67]1[CH2:71][CH:70]=[C:69]([C:72](=[O:74])[CH3:73])[CH2:68]1)[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>O>[CH2:60]([N:67]1[CH2:71][C@H:70]([C:50]2[CH:51]=[CH:52][C:53]([F:54])=[C:48]([Cl:47])[CH:49]=2)[C@@H:69]([C:72](=[O:74])[CH3:73])[CH2:68]1)[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: CC(=O)C1=CCN(Cc2ccccc2)C1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: O
Solvent: CO
Product: CC(=O)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(F)c(Cl)c1
Temperature: 60 °C
Yield: 22 %

Procedure:
A two necked flask was charged under argon with rhodium(acac)bis ethylene (31 mg, 0.05 eq.), (R)-BINAP (76 mg, 0.05 eq.) and 3-chloro-4-fluoro-phenylboronic acid (850 mg, 2.0 eq.). 60 mL of MeOH and 6.0 mL of H2O were added followed by 1-(1-benzyl-2,5-dihydro-1H-pyrrol-3-yl)-ethanone. The reaction mixture was heated at 60° C. for 2 hours, cooled down to RT and concentrated under vacuo. Purification by flash chromatography (SiO2, EtOAc/Heptane 2/1) afforded 180 mg (22%) of the title product as a light yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8].S(=O)(=O)(O)O.[CH3:18]O>>[F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:18])=[O:11])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: CO
Reactant: Cc1ccc(CC(=O)O)cc1F
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc(C)c(F)c1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
(3-Fluoro-4-methylphenyl)acetic acid (105.3 g) was dissolved in methanol (740 ml). Concentrated sulfuric acid (9.9 ml) was added and the mixture was stirred at 85° C. for 1 hr. The reaction mixture was allowed to return to room temperature, and concentrated under reduced pressure. Water was added to the obtained residue and the mixture was extracted with ethyl acetate (1 L). The organic layer was washed successively with water, saturated aqueous sodium hydrogencarbonate solution, water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (114.2 g).
Reaction SMILES: [C-:1]#[N:2].[Na+].[Cl:4][C:5]1[CH:6]=[C:7]([CH:22](Br)[CH3:23])[CH:8]=[CH:9][C:10]=1[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]21[O:21][CH2:20][CH2:19][O:18]2>O.CS(C)=O>[Cl:4][C:5]1[CH:6]=[C:7]([CH:22]([CH3:23])[C:1]#[N:2])[CH:8]=[CH:9][C:10]=1[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]21[O:21][CH2:20][CH2:19][O:18]2
Reactant: CC(Br)c1ccc(CC2CCCCC23OCCO3)c(Cl)c1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C#N)c1ccc(CC2CCCCC23OCCO3)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.9 %

Procedure:
7.35 g of sodium cyanide were dissolved in 10 ml of water under heat, incorporated with 60 ml of dimethylsulfoxide, cooled to room temperature and then incorporated with a solution of 51 g of 1-[3-chloro-4-(2,2-ethylenedioxycyclohexane-1-yl methyl)phenyl]ethyl bromide in 90 ml of dimethylsulfoxide. The reaction mixture obtained was agitated at 70° C. for one hour, thereafter incorporated with water and extracted with ethyl acetate. The extract was washed with water, dried and then freed of the solvent at a reduced pressure to obtain a residue. The thus obtained residue was adhered to a silica gel-packed column and then eluted with isopropyl ether hexane (2/1). The eluate obtained was freed of the solvent thereby to obtain 32.7 g of 2-[3-chloro-4-(2,2-ethylenedioxycyclohexane-1-yl methyl)phenyl]propionitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]([CH3:11])[NH2:10].Cl[C:13]1[C:18]([C:19]#[N:20])=[CH:17][CH:16]=[CH:15][N:14]=1.N>CN(C)C(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]([NH:10][C:13]1[C:18]([C:19]#[N:20])=[CH:17][CH:16]=[CH:15][N:14]=1)[CH3:11]
Reactant: N#Cc1cccnc1Cl
Reactant: CC(N)c1c(Cl)cccc1Cl
Agent: N
Solvent: CC(=O)N(C)C
Product: CC(Nc1ncccc1C#N)c1c(Cl)cccc1Cl
Temperature: 90 °C
Reaction time: 20 h
Yield: 41.1 %

Procedure:
A mixture of 2,6-dichloro-α-methylbenzenemethanamine (0.03 mol) and 2-chloro-3-pyridinecarbonitrile (0.03 mol) in N,N-dimethylacetamide (few drops) was stirred for 20 hours at 90° C. The reaction mixture was cooled and poured out into aqueous ammonia. The mixture was extracted twice with CH2Cl2. The organic layer was separated, washed with water, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /hexane 50/50). The pure fractions were collected and the solvent was evaporated, yielding 3.6 g (±)-2-[[1-(2,6-dichlorophenyl)ethyl]amino]-3-pyridinecarbonitrile (41.4%); mp. 84.4° C. (comp. 9).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23]>ClCCl>[CH2:25]([O:24][C:22]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)[CH2:9][CH2:10]1)=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Brc1ccc(N2CCNCC2)cc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCN(c2ccc(Br)cc2)CC1

Procedure:
5 g of 4-bromophenylpiperazine are placed in a 500 ml three-necked flask under a nitrogen atmosphere. 4.34 ml of triethylamine are added. The mixture is cooled in an ice bath and 3.24 ml of benzyl chloroformate are added. The mixture is allowed to return to ambient temperature. It is diluted with dichloromethane and then gentle hydrolysis is carried out. The aqueous phase is extracted with dichloromethane. The organic phases are combined, washed with a saturated NaCl solution, dried over sodium sulphate, then filtered through a sintered glass filter and concentrated under vacuum. 8.43 g of 4-(4-bromophenyl)piperazine-1-carboxylic acid benzyl ester are obtained.
Reaction SMILES: Cl[C:2]1[C:7]([C:8](=[O:10])[CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.O1CCOCC1.CC1(C)[C@]2(CS(O)(=O)=O)C(C[C@H]1CC2)=O.[NH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(OCC)(=O)C>[C:33]1([NH:32][C:2]2[C:7]([C:8](=[O:10])[CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Nc1ccccc1
Reactant: CC(=O)c1cccnc1Cl
Agent: CC1(C)[C@@H]2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(=O)c1cccnc1Nc1ccccc1
Temperature: 75 °C
Reaction time: 3 h
Yield: 35.8 %

Procedure:
A solution of 1-(2-chloro-pyridin-3-yl)-ethanone (6.42 g, 41.3 mmol) and 1,4-dioxane (70 mL, 0.59M) in a large sealed tube vessel was treated with DL-10-camphorsulfonic acid (23.96 g, 103 mmol). The vessel was tightly sealed, placed behind a blast shield, and warmed to 75° C. At this time, the reaction vessel was removed from the oil bath, carefully opened, treated quickly with aniline (5.6 mL, 61.5 mmol), resealed, and lowered back into the oil bath. The reaction was then warmed to 80° C., where it was stirred for 3 h. At this time, the reaction was cooled to 25° C., diluted with ethyl acetate (250 mL) and washed with a saturated aqueous sodium bicarbonate solution (3×250 mL), water (150 mL) and a saturated aqueous sodium chloride solution (150 mL). The organics were dried over magnesium sulfate, filtered, rinsed with ethyl acetate, and concentrated in vacuo. Flash chromatography (AnaLogix Intelliflash 280, 220 g silica gel column, 1-20% ethyl acetate/hexanes) afforded 1-(2-phenylamino-pyridin-3-yl)-ethanone (3.14 g, 36%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.CC1C([N+]([O-])=O)=C2C(=CC=1)N=CC=C2.[NH2:27][C:28]1[N:33]=[C:32]([NH2:34])[C:31]([CH2:35]O)=[CH:30][N:29]=1.[ClH:37]>C(O)(=O)C>[ClH:37].[ClH:37].[NH2:27][C:28]1[N:33]=[C:32]([NH2:34])[C:31]([CH2:35][C:9]2[CH:10]=[C:11]([CH3:12])[C:2]([NH2:1])=[C:3]3[C:8]=2[N:7]=[CH:6][CH:5]=[CH:4]3)=[CH:30][N:29]=1
Reactant: Nc1ncc(CO)c(N)n1
Reactant: Cc1ccc2ncccc2c1N
Agent: Cc1ccc2ncccc2c1[N+](=O)[O-]
Agent: Cl
Solvent: CC(=O)O
Product: Cc1cc(Cc2cnc(N)nc2N)c2ncccc2c1N
Yield: 40 %

Procedure:
A mixture of 5-amino-6-methylquinoline (2.16 g, 13.7 mmol), prepared by reduction of 6-methyl-5-nitroquinoline (R. Long and K. Schofield, J. Chem. Soc. 1953, 2350), 2,4-diamino-5-hydroxymethylpyrimidine (1.91 g, 13.6 mmol), concentrated hydrochloric acid (1.9 mL), and glacial acetic acid was refluxed for 2 hr. The cooled reaction mixture was filtered and the precipitate washed with ether and dried (4.17 g). Recrystallization from aqueous ethanol with hydrochloric acid gave title compound as red-orange solid (2.08 g, 40%); mp >290° dec. Anal. Calcd for C15H16N6.2HCl.2H2O: C, 46.28; H, 5.70; N, 21.59; Cl, 18.21. Found: C, 46.13; H, 5.61; N, 21.66; Cl, 18.25.
Reaction SMILES: [CH2:1]([SH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:14]([O:18][CH3:19])(=[O:17])[CH:15]=[CH2:16]>O[Li].O>[CH2:1]([S:13][CH2:16][CH2:15][C:14]([O:18][CH3:19])=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCS
Reactant: C=CC(=O)OC
Agent: [Li]O
Solvent: O
Product: CCCCCCCCCCCCSCCC(=O)OC
Reaction time: 0.33 h
Yield: 100.8 %

Procedure:
Into the same type of equipment used in Example 1 was charged 405 grams of 98% 1-dodecanethiol with stirring to 1.0 grams of LiOH·H2O and 181 grams of 99% methyl acrylate. The addition was over a period of 20 minutes and the temperature increased to 80°-85° C. The reaction was stirred an extra 2 hours at 85°-95° C. The reaction mixture was then stripped at 122° C. and 10 mm pressure. 582 grams of product was obtained. Product analysis by GC indicated a purity of 92.1%.
Reaction SMILES: C([O:8][C:9]1[CH:31]=[CH:30][C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[S:19]2(=[O:21])=[O:20])=[CH:11][CH:10]=1)C1C=CC=CC=1.C1CC=CCC=1>CCO.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[S:19]2(=[O:21])=[O:20])=[CH:30][CH:31]=1
Reactant: O=C1c2ccccc2S(=O)(=O)N1CCCCOc1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCC=CC1
Product: O=C1c2ccccc2S(=O)(=O)N1CCCCOc1ccc(O)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 55.1 %

Procedure:
To a stirred solution of 83.3 (0.1 g, 0.23 mmol) in EtOH (5 mL) was added 10% Pd/C (0.1 g, 100% w/w) and 1,4-cyclohexadiene (92 mg, 1.15 mmol) and the resulting suspension was stirred vigorously at 50° C. for 2 hours. The reaction mixture was cooled to room temperature, the catalyst was removed by filtration through Celite, and the filtrate was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel (60% diethyl ether-hexane) to give 84 (0.044 g, 56% yield) as a white solid (m p 107-109° C.). 1H NMR (500 MHz, CDCl3) δ 8.06 (d, J=7.0 Hz, 1H), 7.92 (d, J=7.0 Hz, 1H), 7.87 (td, J=7.0 Hz, J=1.2 Hz, 1H), 7.83 (td, J=7.0 Hz, J=1.2 Hz, 1H), 6.79 (d, J=9.0 Hz, 2H), 6.74 (d, J=9.0 Hz, 2H), 4.38 (br s, 1H), 3.96 (t, J=6.4 Hz, 2H), 3.89 (t, J=7.2 Hz, 2H), 2.05 (quintet, J=6.9 Hz, 2H), 1.89 (quintet, J=6.9 Hz, 2H).
Reaction SMILES: O.C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]3[C:29](=[O:30])[C:28]([C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)=[CH:27][N:26]([CH2:38][CH2:39][F:40])[CH:25]=3)=[O:23])=[CH:17][CH:16]=2)=[CH:13][C:12](Br)=[CH:11][N:10]=1.CC1(C)C(C)(C)OB([C:50]2[CH:51]=[N:52][N:53]([CH:55]3[CH2:60][CH2:59][N:58]([C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[CH2:57][CH2:56]3)[CH:54]=2)O1>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:8][C:9]1[N:10]=[CH:11][C:12]([C:50]2[CH:51]=[N:52][N:53]([CH:55]3[CH2:56][CH2:57][N:58]([C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])[CH2:59][CH2:60]3)[CH:54]=2)=[CH:13][C:14]=1[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]2[C:29](=[O:30])[C:28]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)=[CH:27][N:26]([CH2:38][CH2:39][F:40])[CH:25]=2)=[O:23])=[CH:17][CH:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Nc1ncc(Br)cc1-c1ccc(NC(=O)c2cn(CCF)cc(-c3ccc(F)cc3)c2=O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4ccc(NC(=O)c5cn(CCF)cc(-c6ccc(F)cc6)c5=O)cc4)c3)cn2)CC1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 120.8 %

Procedure:
Water (0.5 ml), cesium carbonate (60 mg) and tetrakis(triphenylphosphine)palladium (16 mg) were added to a solution of the compound obtained in Step 1 of Example 43 (75 mg) and tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]piperidine-1-carboxylate (59 mg) in dimethoxyethane (4 ml). The mixture was stirred under microwave irradiation at 100° C. for 10 minutes. After leaving to cool, the reaction product was purified by silica gel column chromatography [chloroform:methanol=99:1->9:1 (v/v)]. Further, the resulting crude purified product was crystallized from ethyl acetate to give 120 mg of the title compound as a solid.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[OH:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([CH2:27][NH:28][CH2:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][N:31]2[CH2:36][CH2:37][NH:38][CH3:39])[CH2:23][CH2:22]1.Cl>CC(C)=O.C(O)(C)C>[OH:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([CH2:27][NH:28][CH2:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][N:31]2[CH2:36][CH2:37][N:38]([CH3:39])[C:2]([N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[NH:7][C:6]3[CH:16]=[CH:17][CH:18]=[N:19][C:5]2=3)=[O:3])[CH2:23][CH2:22]1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: CNCCN1CCCCC1CNC[C@H]1CC[C@H](O)CC1
Agent: Cl
Solvent: CC(C)=O
Solvent: CC(C)O
Product: CN(CCN1CCCCC1CNC[C@H]1CC[C@H](O)CC1)C(=O)N1c2ccccc2C(=O)Nc2cccnc21
Yield: 24 %

Procedure:
Prepared analogously to Example 2 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and trans-2-[2-[[(4-hydroxy-cyclohexyl)methylamino]methyl]-piperidin-1-yl]-N-methyl-ethanamine in a yield of 24% of theory. Colourless, substantially amorphous solid substance with an approximate m.p. 105°-120° C. M.p. of the hydrochloride 210°-213° C. (D.) (acetone/isopropanol).
Reaction SMILES: [CH2:1]([N:8]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2B2OC(C)(C)C(C)(C)O2)[O:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:36]1[CH:41]=[CH:40][N:39]=[N:38][CH:37]=1>>[CH2:1]([N:8]([CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[C:36]2[CH:41]=[CH:40][N:39]=[N:38][CH:37]=2)[O:11][CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OB(c2cccc3c2C[C@H](N(Cc2ccccc2)Cc2ccccc2)CO3)OC1(C)C
Reactant: Brc1ccnnc1
Product: c1ccc(CN(Cc2ccccc2)[C@@H]2COc3cccc(-c4ccnnc4)c3C2)cc1
Yield: 62 %

Procedure:
The title compound was synthesized as described for Intermediate example I-48 in 62% yield starting from (3S)-N,N-dibenzyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan -2-yl)chroman-3-amine and 4-bromopyridazine (1.2 equiv). The reaction was irradiated in microwave at 140° C. for 45 min: 1H NMR (400 MHz, CDCl3) δ ppm 9.26 (dd, 1 H), 9.19-9.22 (m, 1 H), 7.38 (dd, 1 H), 7.26-7.34 (m, 8 H), 7.16-7.25 (m, 3 H), 6.91 (d, 1 H), 6.78 (dd, 1 H), 4.36-4.43 (m, 1 H), 4.06 (t, 1 H), 3.64-3.77 (m, 4 H), 3.15-3.25 (m, 1 H), 2.86 (dd, 1 H), 2.57 (ddd, 1 H); MS (ESI) m/z 408[M+H+].