Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([NH:20][NH2:21])=[O:19])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:22]([C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)([O-:24])=[O:23]>C(Cl)Cl.CCN(CC)CC>[CH2:1]([CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([NH:20][NH:21][C:29](=[O:30])[C:28]2[CH:27]=[CH:26][C:25]([N+:22]([O-:24])=[O:23])=[CH:33][CH:32]=2)=[O:19])[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNC(=O)CCCCN1CCC(Cc2ccccc2)CC1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCCCN1CCC(Cc2ccccc2)CC1)NNC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 92.4 %

Procedure:
To a solution of 5-(4-benzylpiperidin-1-yl)valerhydrazide (289 mg, 1.00 mmol) in 10 mL of CH2Cl2 and 0.21 mL of Et3N was added 4-nitrobenzoyl chloride (278 mg, 1.50 mmol). The resulting solution was allowed to stir at rt for 12 hr. The mixture was poured into ice water (10 g). The organic layer was separated and the water phase was extracted with CH2Cl2 (2×15 mL). The combined organic extracts were dried over Na2SO4. Evaporation of solvent gave the title product as a brown oil (405 mg, 92%): 1H NMR (CDCl3) 1.25 (m, 2 H), 1.60 (m, 6 H), 1.90 (m, 2 H), 2.29 (m, 4 H), 2.48 (d, J=6.6 Hz, 2 H), 2.90 (m, 2 H), 3.42 (s, 1 H), 7.07-7.24 (m 5 H), 7.70 (bs, 2 H), 7.96 (d, J=7.8 Hz, 2 H), 8.08 (d, J=7.8 Hz, 2 H).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[CH2:9]([C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)[CH2:10][CH2:11][CH2:12][CH3:13].Cl>C(Cl)Cl>[C:5]([C:29]1[CH:30]=[CH:31][C:26]([C:23]2[CH:22]=[CH:21][C:20]([C@H:17]3[CH2:18][CH2:19][C@H:14]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:15][CH2:16]3)=[CH:25][CH:24]=2)=[CH:27][CH:28]=1)(=[O:7])[CH3:6]
Reactant: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccccc3)cc2)CC1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCC[C@H]1CC[C@H](c2ccc(-c3ccc(C(C)=O)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
First, 23.6 g of anhydrous aluminum chloride and 120 ml of methylene chloride were put in a 300 ml flask. After 14.0 g of acetyl chloride was dropped into the mixture at 5° C. or less, the resultant mixture was stirred keeping the same temperature for 30 minutes. Then, 45.2 g of 4-(trans-4-pentylcyclohexyl)biphenyl was added to resultant mixture at 5° C. or less and stirred for 30 minutes at room temperature. After the reaction, the reaction solution was poured into dilute hydrochloric acid, and an organic layer was separated. The organic layer was then washed with water and dried with sodium sulfate. The solvent was then distilled off. The residue was recrystallized from acetone to obtain 24.0 g (Y: 46.0%) of 4-acetyl-4′-(trans-4-pentylcyclohexyl)biphenyl. The purity of the resultant compound was 99.7% as measured by GC.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]([OH:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:14]([OH:16])=O)=[N:7]2.C1(N=C=NC2CCCCC2)CCCCC1.O.ON1C2C=CC=CC=2N=N1.Cl.Cl.[NH2:45][CH2:46][CH2:47][C:48]1[N:52]=[CH:51][NH:50][CH:49]=1>C(N(CC)CC)C>[NH:50]1[CH:49]=[C:48]([CH2:47][CH2:46][NH:45][C:14]([C:6]2[CH:5]=[CH:4][C:3]3[C:8](=[C:9]([OH:13])[C:10]([Cl:12])=[CH:11][C:2]=3[Cl:1])[N:7]=2)=[O:16])[N:52]=[CH:51]1
Reactant: NCCc1c[nH]cn1
Reactant: O=C(O)c1ccc2c(Cl)cc(Cl)c(O)c2n1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(NCCc1c[nH]cn1)c1ccc2c(Cl)cc(Cl)c(O)c2n1

Procedure:
According to the procedure described in Example 1,5,7-dichloro-8-hydroxyquinoline-2-carboxylic acid 19 (597 mg, 2.31 mmol), dicyclohexylcarbodiimide (483 mg, 2.31 mmol), 1-hydroxybenzotriazole hydrate (316 mg, 2.31 mmol), histamine dihydrochloride (425 mg, 2.31 mmol) and triethylamine (0.5 mL) gave, after column purification (silica gel, ethyl acetate/isopropanol/water (12:4:1)), 5,7-dichloro-8-hydroxyquinoline-2-carboxylic acid [2-(1H-imidazol-4-yl)-ethyl]-amide (PBT 1038) as a pale straw-coloured solid (276 mg, 34%). 1H NMR (DMSO-d6, 400 MHz): δ 11.40 (br, 2 H), 9.74 (m, 1 H), 8.64 (d, J=8.6, 1 H), 8.28 (d, J=8.6, 1 H), 7.92 (s, 1 H), 7.53 (s, 1 H), 6.83 (s, 1 H), 3.59 (m, 2 H), 2.81 (m, 2 H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([CH3:10])=[N:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=[O:4].C1C(=O)N([Br:26])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]([CH2:10][Br:26])=[N:7][C:6]=1[C:11]1[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1)=[O:4]
Reactant: COC(=O)c1sc(C)nc1-c1ccc(OC)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1sc(CBr)nc1-c1ccc(OC)cc1
Temperature: 100 °C
Yield: 24.2 %

Procedure:
To the solution of 4-(4-Methoxy-phenyl)-2-methyl-thiazole-5-carboxylic acid methyl ester (0.25 g, 0.94 mmol) in the 20 ml of CCl4 was added NBS (0.16 g, 0.94 mmol) and AlBN 0.015 g, 0.094 mmol). The reaction mixture was heated at 100° C. for 2 h under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), the reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (230-400 M) using 10% ethyl acetate/hexane as a eluent to give the desired product (0.078 g, 24%).
Reaction SMILES: Cl.[NH2:2][C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[CH2:4][OH:5].[CH2:13]([O:20][C:21](ON1C(=O)CCC1=O)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C1COCC1>[OH:5][CH2:4][C:3]([NH:2][C:21](=[O:22])[O:20][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:6]
Reactant: CC(N)(CO)c1ccccc1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(CO)(NC(=O)OCc1ccccc1)c1ccccc1
Reaction time: 1 h

Procedure:
2-Amino-2-phenylpropan-1-ol hydrochloride (0.5 g, 2.7 mmol) was reacted with N-(benzyloxycarbonyloxy)-succinimide (0.73 g, 2.9 mmol) and triethylamine (0.82 mL, 5.9 mmol) in THF (25 mL) at 0° C. for 1.0 hours and then at room temperature for 1 hour. The reaction was concentrated and extracted with ethyl acetate (25 mL). The extract was washed with water (2×) and brine, dried over MgSO4, and concentrated to give the crude title compound and used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[C@@H:7]1[CH2:11][CH2:10][CH2:9][NH:8]1)([CH3:4])([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.C([S:31][CH2:32][CH:33]([CH3:37])[C:34](O)=[O:35])(=O)C>ClCCl>[C:1]([O:5][C:6](=[O:12])[C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:34](=[O:35])[CH:33]([CH3:37])[CH2:32][SH:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)SCC(C)C(=O)O
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(CS)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
L-Proline tert-butyl ester (5.1 g.) is dissolved in dichloromethane (40 ml.) and the solution stirred and chilled in an ice bath. Dicyclohexylcarbodiimide (6.2 g.) dissolved in dichloromethane (15 ml.) is added followed immediately by a solution of 3-acetylthio-2-methylpropanoic acid (4.9 g.) in dichloromethane (5 ml.). After 15 minutes stirring in the ice bath and 16 hours at room temperature, the precipitate is filtered off and the filtrate is concentrated to dryness in vauco. The residue is dissolved in ethyl acetate and washed neutral. The organic phase is dried over magnesium sulfate and concentrated to dryness in vacuo. The residue, N-(3-acetylthio-2-methylpropanoyl)-L-proline tert-butyl ester, is purified by column chromatography (silica gel, chloroform), yield 7.9 g. The named product is obtained by following the procedure of Example 17.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[CH:2]1.[Li]CCCC.[I:14]I.O>O1CCCC1>[I:14][C:2]1[O:1][CH:5]=[CH:4][C:3]=1[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1ccoc1
Reactant: II
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccoc1I
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.5 %

Procedure:
To a stirring solution of furan-3-carboxylic acid (5 g, 44.6 mmol) in anhydrous tetrahydrofuran (200 ml) under a nitrogen atmosphere at −78° C. was added BuLi (44.6 ml, 112 mmol) dropwise. After stirring for 0.5 h, cooling was switched off and the mixture allowed to warm to room temperature. During warming, iodine (12.5 g, 49.1 mmol) as a solution in anhydrous tetrahydrofuran (30 ml) and added dropwise to the stirring mixture. Water was added (100 ml) and the organic solvents were removed in vacuo. The aqueous solution was acidified to ca pH 1 using 2M hydrochloric acid (aq) solution (ca 10-20 ml). The precipitated solid was collected by filtration and dried under vacuum and flowing nitrogen for 16 h to afford the title compound (6.21 g, 59%) that was used in the next step without further purification. LCMS RT=0.78 min, M−H−=236.8.
Reaction SMILES: [CH3:1][C:2]1[C:9]([F:10])=[C:8]([F:11])[C:5]([CH2:6][OH:7])=[C:4]([F:12])[C:3]=1[F:13].[C:14]([C:16]([CH3:26])=[CH:17][C@@H:18]1[C@@H:20]([C:21](O)=[O:22])[C:19]1([CH3:25])[CH3:24])#[N:15]>CN(C)C1C=CN=CC=1.ClCCl>[C:14]([C:16]([CH3:26])=[CH:17][C@@H:18]1[C@@H:20]([C:21]([O:7][CH2:6][C:5]2[C:4]([F:12])=[C:3]([F:13])[C:2]([CH3:1])=[C:9]([F:10])[C:8]=2[F:11])=[O:22])[C:19]1([CH3:25])[CH3:24])#[N:15]
Reactant: CC(C#N)=C[C@@H]1[C@@H](C(=O)O)C1(C)C
Reactant: Cc1c(F)c(F)c(CO)c(F)c1F
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C#N)=C[C@@H]1[C@@H](C(=O)OCc2c(F)c(F)c(C)c(F)c2F)C1(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.5 %

Procedure:
Under a nitrogen atmosphere, 0.59 g of N,N-dicyclohexyl carbodiimide was added to a mixture of 0.55 g of 4-methyl-2,3,5,6-tetrafluorobenzyl alcohol, 0.51 g of (1R)-trans-3-(2-cyano-1-propenyl)-2,2-dimethylcyclopropanecarboxylic acid, 0.10 g of 4-dimethylaminopyridine and 7 ml of anhydrous dichloromethane, and the mixture was stirred at room temperature for 3 hours. Thereafter, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 0.72 g of 4-methyl-2,3,5,6-tetrafluorobenzyl(1R)-trans-3-(2-cyano-1-propenyl)-2,2-dimethylcyclopropanecarboxylate represented by the following formula:
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].C(O)(=O)C(O)=O.[NH2:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][NH:22][C:23]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH:34]([CH3:36])[CH3:35])[N:26]=2)=[O:24])[CH2:16][CH2:15]1.C(N(CC)CC)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>O1CCCC1>[C:1]([OH:6])(=[O:5])[C:2]([OH:4])=[O:3].[CH3:44][S:45]([NH:13][CH:14]1[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][NH:22][C:23]([C:25]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH:34]([CH3:36])[CH3:35])[N:26]=2)=[O:24])[CH2:18][CH2:19]1)(=[O:47])=[O:46]
Reactant: CC(C)n1nc(C(=O)NCCN2CCC(N)CC2)c2ccccc21
Reactant: CS(=O)(=O)Cl
Agent: O=C(O)C(=O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)n1nc(C(=O)NCCN2CCC(NS(C)(=O)=O)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The product from Example 23, as the free base (0.330 g, 1 mmol) and triethylamine (0.15 mL, 1.05 mmol) were stirred in 10.0 mL tetrahydrofuran and cooled briefly in an ice bath. To the mixture was added dropwise methanesulfonyl chloride (0.08 mL, 1 mmol) and the resulting mixture was stirred 18 h at room temperature. The mixture was filtered and the filtrate was evaporated to 0.401 g oil. Flash chromatography [silica gel, methylene chloride/methanol (90/10)] yielded 0.147 g oil. Crystallization as the oxalate salt from ethyl acetate/methanol provided 0.149 g colorless crystals. Mp 204° C. Mass spectrum, m+ =407. Exact mass theory, 408.2069; found, 408.2066.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:41])=[C:4]([S:20]([N:23](CC2C=CC(OC)=CC=2OC)[C:24]2[CH:29]=[CH:28][N:27]=[CH:26][N:25]=2)(=[O:22])=[O:21])[CH:5]=[CH:6][C:7]=1[O:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@@H:10]1[C:14]1[N:18]([CH3:19])[N:17]=[CH:16][CH:15]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([F:41])=[C:4]([S:20]([NH:23][C:24]2[CH:29]=[CH:28][N:27]=[CH:26][N:25]=2)(=[O:21])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@@H:10]1[C:14]1[N:18]([CH3:19])[N:17]=[CH:16][CH:15]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(O[C@H]3CCC[C@@H]3c3ccnn3C)c(Cl)c2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1CCC[C@@H]1Oc1ccc(S(=O)(=O)Nc2ccncn2)c(F)c1Cl
Yield: 162 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 3-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (344 mg, 0.31 mmol) prepared in Example 80a, triethylsilane (0.50 mL), trifluoroacetic acid (5.0 mL) and dichloromethane (5.0 mL), to yield the title compound (227 mg, 88%) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[C:4]([C:6]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9])=[O:5].[Cl:21][CH2:22][CH:23]1[O:25][CH2:24]1.[OH-].[NH4+]>C1(C)C=CC=CC=1>[CH3:11][O:10][C:8](=[O:9])[C:7]1[CH:12]=[CH:13][C:14]([Cl:16])=[CH:15][C:6]=1[C:4]1([C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=2[F:1])[O:25][CH:23]([CH2:22][Cl:21])[CH2:24][O:5]1
Reactant: COC(=O)c1ccc(Cl)cc1C(=O)c1ccccc1F
Reactant: ClCC1CO1
Agent: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(Cl)cc1C1(c2ccccc2F)OCC(CCl)O1
Reaction time: 0.5 h

Procedure:
To a solution of 47 g (0.16 mol) of the end product of Example 6 in 350 ml of dry toluene was added 21.4 ml (0.18 mol) of stannic chloride, and after 5 hrs a solution of 24 ml (0.308 mol) of 1-chloro-2,3-epoxypropane in 25 ml of toluene was added with stirring over a 30 min period. After 18 hrs an additional 12 ml (0.154 mol) of 1-chloro-2,3-epoxypropane was added over a 15 min period. After 4 hrs the reaction was cooled in an ice bath and made basic with concentrated ammonium hydroxide. The reaction was filtered through celite, and the celite was washed with toluene. The combined filtrates were washed with 200 ml of water, dried over sodium sulfate, and evaporated. The resulting oil was dissolved in 100 ml of dichloromethane and chromatographed through 500 g of alumina. The column was eluted with 4 l of dichloromethane/petrol (2/1 ) to give an oil, which was about 90-95% pure by TLC. A sample was crystallized and recrystallized from ether/petrol to give white prisms: mp 117°-122° C.
Reaction SMILES: Cl.[C:2]([NH2:10])(=[NH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C[O-].[Na+].O1[CH2:18][CH2:17][CH2:16][CH2:15]1>>[C:3]1([C:2]2[NH:9][CH:15]=[C:16]([C:17]3[C:18]4[C:18](=[CH:2][CH:3]=[CH:4][CH:5]=4)[CH:17]=[CH:16][CH:15]=3)[N:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C1CCOC1
Reactant: N=C(N)c1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: c1ccc(-c2nc(-c3cccc4ccccc34)c[nH]2)cc1
Temperature: 25 °C

Procedure:
A suspension consisting of 31.3 g (0.20 mol) of benzamidine hydrochloride, 10.8 g (0.20 mol) of sodium methylate, and 150 mL of tetrahydrofuran was heated under reflux for one hour. After cooling to 25° C., a solution consisting of 49.8 g (0.2 mol) of ω-bromo-1-acetonaphthone and 100 mL of tetrahydrofuran was added dropwise such that the internal temperature did not exceed 30° C. After completion of addition, 10.8 g (0.20 mol) of sodium methylate was added, and the mixture was heated under reflux for one hour. Next, the reaction mixture was cooled to room temperature, insoluble matters were filtered off, and the filtrate was evaporated to dryness in vacuo. The residual solid was successively washed with water and acetonitrile and then dried to obtain a crude crystal as a desired material. This crude crystal was recrystallized from acetonitrile to obtain 18.0 g (yield: 33.3%) of a grayish blue crystal.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[O:24]1[CH:28]=[CH:27][C:26]([C:29](Cl)=[O:30])=[CH:25]1>>[O:24]1[CH:28]=[CH:27][C:26]([C:29]([NH:1][C:2]2[N:7]=[C:6]3[C:8]([CH:11]4[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]4)=[CH:9][NH:10][C:5]3=[CH:4][CH:3]=2)=[O:30])=[CH:25]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1ccoc1
Product: O=C(Nc1ccc2[nH]cc(C3CCNCC3)c2n1)c1ccoc1

Procedure:
Beginning with 0.015 gm (0.047 mMol) 5-amino-3-(1-tert-butoxycarbonylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.008 mL (0.062 mMol) 3-furoyl chloride, the title compound was prepared.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]#[N:29])=[CH:18][CH:17]=2)[C:7]2[N:8]([C:10]([CH3:14])=[C:11]([CH3:13])[N:12]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4].C[Sn]([N:34]=[N+:35]=[N-:36])(C)C>>[CH2:1]([C:5]1[N:6]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[C:28]3[NH:36][N:35]=[N:34][N:29]=3)=[CH:20][CH:21]=2)[C:7]2[N:8]([C:10]([CH3:14])=[C:11]([CH3:13])[N:12]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CCCCc1nn2c(C)c(C)nc2n1Cc1ccc(-c2ccccc2C#N)cc1
Product: CCCCc1nn2c(C)c(C)nc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 40 %

Procedure:
Reaction of 2-butyl-3-[(2'-cyanobiphenyl-4-yl)methyl]-5,6-dimethyl-3H-imidazo[1,2-b][1,2,4]triazole (from Step B) with trimethyltin azide according to the procedure of Example 1, Step G, furnished a 40% yield of the title compound as a light tan solid, mp 138°-141° C.; homogeneous by TLC in 90:10:0.1 CH2Cl2 -MeOH-AcOH.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:17]3[CH:25]=[C:24]([C:26]4[O:30][C:29]([CH:31]=O)=[CH:28][CH:27]=4)[N:23]=[CH:22][C:18]=3[N:19]=[CH:20][N:21]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33][S:34]([CH2:36][CH2:37][NH2:38])=[O:35]>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]2[C:17]3[CH:25]=[C:24]([C:26]4[O:30][C:29]([CH2:31][NH:38][CH2:37][CH2:36][S:34]([CH3:33])=[O:35])=[CH:28][CH:27]=4)[N:23]=[CH:22][C:18]=3[N:19]=[CH:20][N:21]=2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccc(-c2cc3c(Nc4ccc(OCc5ccccc5)cc4)ncnc3cn2)o1
Reactant: CS(=O)CCN
Product: CS(=O)CCNCc1ccc(-c2cc3c(Nc4ccc(OCc5ccccc5)cc4)ncnc3cn2)o1

Procedure:
In an analogous manner to Example 1, 5-(4-(4-Benzyloxy-phenylamino)-pyrido[3,4-d]pyrimidin-6-yl)-furan-2-carbaldehyde and [2-(methanesulphinyl)ethyl]amine were converted into the title compound; δH [2H6]-DMSO 10.20 (1H, b), 9.11 (1H, s), 8.67 (1H, s), 8.59 (1H, s), 7.72 (2H, d), 7.53−7.30 (5H, m), 7.17−7.04 (3H, m), 6.52 (1H, d), 5.15 (2H, s), 3.87 (2H, s), 3.08−2.75 (4H, m), 2.55 (3H, s); m/z 514 (M+1)+.
Reaction SMILES: N[C:2]1[C:11]2[C:6](=[CH:7][C:8](OC)=[C:9](OC)[CH:10]=2)[N:5]=[C:4](N2CCNCC2)[N:3]=1.C(N(CC)CC)C>C(COC)OC>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:2]=[N:3][CH:4]=1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Solvent: COCCOC
Solvent: CCN(CC)CC
Product: c1ccc2ncncc2c1

Procedure:
In accordance with the foregoing reaction scheme, a 4-nitrophenylalkanoic acid (1) is reacted with phosphorous trichloride, such as by heating at reflux in a suitable solvent, to obtain the corresponding acid chloride (2). The latter is reacted with 4-amino-6,7-dimethoxy-2-(1-piperazinyl) quinazoline (3) and triethyl amine (TEA) in dimethoxy ethane (DME) to obtain the 4-amino-6,7-dimethoxy-2-[4-[4-nitrophenyl]-alkanoyl)-1-piperazinyl] quinazoline intermediate (4). The 4-nitrophenyl intermediate (4) is then subjected to catalytic hydrogenation, such as in the presence of a palladium-on-carbon (Pd/C) catalyst, to obtain the desired 4-aminophenyl product (5).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH:8][NH2:9])=[C:4]([CH3:10])[CH:3]=1.[F:11][CH:12]([F:16])[C:13](O)=O.CCOCC>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]2[N:6]([C:13]([CH:12]([F:16])[F:11])=[N:9][N:8]=2)[N:7]=1
Reactant: O=C(O)C(F)F
Reactant: Cc1cc(Cl)nnc1NN
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cc1cc(Cl)nn2c(C(F)F)nnc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a beige suspension of 6-chloro-3-hydrazinyl-4-methylpyridazine (step 195.1) (22.44 g, 127 mmol) in dioxane (250 mL) was added difluoroacetic acid (Aldrich) (9.40 mL, 146 mmol) and the reaction mixture was stirred at rt for 5 min, then heated-up to 120° C. for 2.5 hr. With heating the suspension turned into a red-orange solution. The reaction mixture was cooled to rt. Et2O (80 mL) was added and the suspension was stirred for 2 hours at 0° C. Precipitated solids were isolated by filtration, suspended in hexanes and filtered again. After repeated washings with hexanes the tittle compound was obtained as an orange solid.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.[Cl:10][C:11]1[CH:19]=[C:18]([C:20](=[O:22])[NH2:21])[CH:17]=[C:16]([Cl:23])[C:12]=1[C:13](O)=[O:14]>>[Cl:10][C:11]1[CH:19]=[C:18]([CH:17]=[C:16]([Cl:23])[C:12]=1[C:13]([N:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1)=[O:14])[C:20]([NH2:21])=[O:22]
Reactant: NC(=O)c1cc(Cl)c(C(=O)O)c(Cl)c1
Reactant: c1cc2[nH]ccc2cn1
Product: NC(=O)c1cc(Cl)c(C(=O)n2ccc3cnccc32)c(Cl)c1

Procedure:
3,5-Dichloro-4-(1H-pyrrolo[3,2-c]pyridin-1-ylcarbonyl)benzamide was prepared using 1H-pyrrolo[3,2-c]pyridine and 2,6-dichloro-4-carbamoyl benzoic acid.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7]([CH2:10][C:11](O)=O)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[Br:16][C:17]1[CH:24]=[CH:23][C:20](C=O)=[CH:19][CH:18]=1>>[Br:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][S:7](/[CH:10]=[CH:11]/[C:20]2[CH:23]=[CH:24][C:17]([Br:16])=[CH:18][CH:19]=2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: O=C(O)CS(=O)(=O)Cc1ccc(Br)cc1
Reactant: O=Cc1ccc(Br)cc1
Product: O=S(=O)(/C=C/c1ccc(Br)cc1)Cc1ccc(Br)cc1
Yield: 88 %

Procedure:
A solution of 4-bromobenzyl sulfonylacetic acid (0.01 mol) and 4-bromobenzaldehyde (0.01 mol) was subjected to Procedure 1. The title compound was obtained in 88% yield.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:8][CH:9]=1.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21](Br)[CH3:22])=[C:17]([CH2:24]Br)[CH:16]=1>CN(C=O)C>[Br:14][C:15]1[CH:16]=[C:17]2[C:18](=[CH:19][CH:20]=1)[CH:21]([CH3:22])[N:13]([S:10]([C:7]1[CH:6]=[CH:5][C:4]([CH3:3])=[CH:9][CH:8]=1)(=[O:12])=[O:11])[CH2:24]2
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Reactant: CC(Br)c1ccc(Br)cc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2Cc3cc(Br)ccc3C2C)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 77.8 %

Procedure:
3.97 g of about 60% sodium hydride was suspended in 70 ml of DMF, and 50 ml of DMF solution of 8.49 g of p-toluene sulfonamide in was added thereto, and the resulting mixture was stirred at 60° C. for 1 hour, and 50 ml of DMF solution of 17.70 g of 1-bromo-4-(1-bromoethyl)-3-bromomethylbenzene (3-7) was dropped thereto, which was stirred at the same temperature for 2 hours. The reaction solution was poured into ice water and extracted with chloroform and the resulting organic layer was dried over anhydrous magnesium sulfate, and thereafter, the solvent was distilled off under reduced pressure and the resulting residue was purified by chromatopraphy (eluent; hexane:chloroform=1:1) to obtain 14.13 g of 5-bromo-1-methyl-2-(p-toluene sulfonyl)isoindoline (3-8).