Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3N=N2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>P(=O)(O)(O)O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:3]=1[C:11]1[CH:16]=[CH:15][CH:14]=[N:13][C:12]=1[NH:8]2
Reactant: Brc1cccc(-n2nnc3cccnc32)c1
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Brc1cccc2[nH]c3ncccc3c12
Temperature: 150 °C
Yield: 7.1 %

Procedure:
Compound 3 (2.8 g, 10.2 mmol) was dissolved in ortho-phosphoric acid (40 ml). The mixture was heated to 150° C. for 18 hours, and the intended product confirmed by LC-MS. The mixture was cooled to 0° C. and the acid neutralized with concentrated NaOH. Extraction with methylene chloride afforded a mixture of Compounds 4 and 4′, which was then purified by HPLC to provide Compound 4 (180 mg, 9%). 1H NMR (400 MHz, CD3OD) δ 9.16 (d, J=7.8 Hz 1 H) 8.48 (s, 1 H) 7.62 (d, J=7.8 Hz 1 H) 7.52 (d, J=6.8 Hz 1 H) 7.44 (m, 2 H). [M+H] calc'd for C17H12N2, 245; found 245.
Reaction SMILES: [C:1]([CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[C:15]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:25][CH:24]=3)[CH:16]=[CH:17][C:18]=2[CH2:19][CH2:20][CH2:21]Br)=[CH:9][C:8]=1[C:34]([CH3:37])([CH3:36])[CH3:35])(=[O:3])[CH3:2].[CH:38]1([NH2:41])[CH2:40][CH2:39]1>>[C:1]([CH2:4][CH2:5][NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[C:15]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:25][CH:24]=3)[CH:16]=[CH:17][C:18]=2[CH2:19][CH2:20][CH2:21][NH:41][CH:38]2[CH2:40][CH2:39]2)=[CH:9][C:8]=1[C:34]([CH3:37])([CH3:36])[CH3:35])(=[O:3])[CH3:2]
Reactant: NC1CC1
Reactant: CCOC(=O)c1ccc(-c2ccc(CCCBr)c(-c3ccc(NCCC(C)=O)c(C(C)(C)C)c3)c2)cc1
Product: CCOC(=O)c1ccc(-c2ccc(CCCNC3CC3)c(-c3ccc(NCCC(C)=O)c(C(C)(C)C)c3)c2)cc1
Yield: 57.4 %

Procedure:
In a manner similar to that of Example 38b, by reacting 490 mg of ethyl 4″-(acetylethylamino)-4′-(3-bromopropyl)-3″-tert-butyl[1,1′;3′,1″]terphenyl-4-carboxylate (0.87 mmol) with 0.6 mL of cyclopropylamine (9 mmol). 270 mg of ethyl 4″-(acetylethylamino)-3″-tert-butyl-4′-(3-cyclopropylaminopropyl)-[1,1′;3′,1″]terphenyl-4-carboxylate are obtained (yield=57%) in the form of an orange-colored oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](I)[CH:5]=[C:4]([Cl:9])[N:3]=1.[Li]CCCC.CON(C)[C:18](=[O:33])[CH2:19][CH:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:18](=[O:33])[CH2:19][CH:20]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: CON(C)C(=O)CC(c1ccccc1)c1ccccc1
Reactant: Clc1cc(I)cc(Cl)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(CC(c1ccccc1)c1ccccc1)c1cc(Cl)nc(Cl)c1
Temperature: -70 °C
Reaction time: 1 h
Yield: 175.8 %

Procedure:
At −70° C. to a solution of 2,6-dichloro-4-iodopyridine (1.02 g) in THF (20 mL) was added n-BuLi (1.6 M in hexane, 2.3 mL) dropwise. The mixture was stirred for additional 15 min at which timepoint a solution of N-methoxy-N-methyl-3,3-diphenyl-propionamide (200 mg) in THF (10 mL) was added. The reaction mixture was stirred for 1 hour at −70° C. A saturated aqueous solution of NH4Cl was added, the phases were separated and the inorganic one was extracted with EtOAc (2×). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (EtOAc/n-heptane 1:10) to yield 1-(2,6-dichloro-pyridin-4-yl)-3,3-diphenyl-propan-1-one (465 mg, 88%) as a yellow oil, which was directly subjected to the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:20]([NH:23][C:24](=[O:37])[C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH2:32][CH2:33][NH:34][CH2:35][CH:36]=3)=[CH:27][CH:26]=2)(=[O:22])=[O:21])[CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH2:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O-:3])=[O:2].[BH3-]C#N.[Na+].[OH-].[Na+].[N:44]1[CH:49]=[CH:48][CH:47]=[C:46]([CH:50]=O)[CH:45]=1>C(O)(=O)C.CO>[N+:1]([C:4]1[CH:5]=[C:6]([S:20]([NH:23][C:24](=[O:37])[C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH2:36][CH2:35][N:34]([CH2:50][C:46]4[CH:45]=[N:44][CH:49]=[CH:48][CH:47]=4)[CH2:33][CH:32]=3)=[CH:27][CH:26]=2)(=[O:21])=[O:22])[CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH2:12][S:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O-:3])=[O:2]
Reactant: O=Cc1cccnc1
Reactant: O=C(NS(=O)(=O)c1ccc(NCCSc2ccccc2)c([N+](=O)[O-])c1)c1ccc(C2=CCNCC2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(NS(=O)(=O)c1ccc(NCCSc2ccccc2)c([N+](=O)[O-])c1)c1ccc(C2=CCN(Cc3cccnc3)CC2)cc1

Procedure:
A mixture of Example 340A (65 mg, 0.1 mmol), NaBH3CN (48 mg, 0.75 mmol), 2N NaOH (0.15 mL), and 3-pyridinecarboxaldehyde (214 mg, 2 mmol) in acetic acid (0.5 mL) and methanol (1 mL) was stirred for 16 hours. The reaction mixture was concentrated, dissolved in 1:1 DMSO/methanol (1.0 mL) and purified by reverse phase preparative HPLC using 20-90% acetonitrile/water containing 0.1% TFA to provide the desired product. MS (ESI(−)) m/e 628 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ8.78 (br t, 1H), 8.70 (d, 1H), 8.70 (dd, 1H), 8.60 (d, 1H), 8.05 (m, 1H), 7.95 (d, 2H), 7.62 (d, 2H), 7.60 (dd, 1H), 7.40-7.15 (m, 6H), 6.35 (m, 1H), 4.52 (d, 2H), 3.92 (m, 4H), 3.45 (t, 4H), 2.82 (m, 2H).
Reaction SMILES: C[O:2][C:3](=[O:33])[C@@H:4]([NH:22][C:23](=[O:32])[C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=1[Cl:31])[CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][C:11]([C:14]2([O:20][CH3:21])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1.O.O.O.O.O.O.O.O.[OH-].[Ba+2].[OH-]>C1COCC1.O>[Cl:31][C:25]1[CH:26]=[CH:27][CH:28]=[C:29]([Cl:30])[C:24]=1[C:23]([NH:22][C@@H:4]([CH2:5]/[CH:6]=[CH:7]/[C:8]1[CH:13]=[CH:12][C:11]([C:14]2([O:20][CH3:21])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][CH:9]=1)[C:3]([OH:33])=[O:2])=[O:32]
Reactant: COC(=O)[C@H](C/C=C/c1ccc(C2(OC)CCOCC2)cc1)NC(=O)c1c(Cl)cccc1Cl
Agent: [Ba+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COC1(c2ccc(/C=C/C[C@H](NC(=O)c3c(Cl)cccc3Cl)C(=O)O)cc2)CCOCC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
In a mixed solvent of THF (250 ml) and water (125 ml), (S,E)-2-(2,6-dichlorobenzamido)-5-[4-(4-methoxytetrahydropyran-4-yl)-phenyl]pent-4-enoic acid methyl ester (9.80 g) was dissolved, and the resulting mixture was cooled to 0° C. Barium hydroxide octahydrate (3.14 g) was added thereto and the resulting mixture was stirred at 0° C. for 8 hours. The reaction solution was concentrated to remove THF, and water (150 ml) was added thereto, followed by washing the resulting mixture with ether. Aqueous layer was acidified by adding 1N hydrochloric acid in small portions thereto and extracted 3 times with ethyl acetate. Organic layers were washed with saturated brine and dried over anhydrous sodium sulfate. After removing anhydrous sodium sulfate by filtration, the filtrate was concentrated. The residue was purified by column chromatography (silica gel, eluent:chloroform/methanol=10/1). The obtained crudely purified product was further purified by column chromatography (silica gel, eluent:cyclohexane/ethyl acetate=ethyl acetate) to obtain (S,E)-2-(2,6-dichlorobenzamido)-5-[4-(4-methoxytetrahydropyran-4-yl)-phenyl]pent-4-enoic acid (6.15 g).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.[NH2:15]O>P(Cl)(Cl)(Cl)=O>[Cl:1][C:2]1[C:11]([C:12]#[N:15])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=Cc1cc2ccccc2nc1Cl
Reactant: NO
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cc2ccccc2nc1Cl
Yield: 71.1 %

Procedure:
A mixture was prepared from 10 g of 2-chloro-3-quinolinecarboxaldehyde, 5.2 g of hydroxylamine hydrochloride and 100 ml of phosphoryl chloride and heated with a heat lamp. The mixture was heterogeneous until the temperature reached 90° C. and there was no noticeable exotherm or gas evolution. After heating at reflux for 30 minutes, the mixture was cooled for 16 hours. It was then quenched in 700 ml of water. The tan solid which formed was separated by filtration and dried to give 7 g of crude 2-chloro-3-cyanoquinoline.
Reaction SMILES: C([NH:4][C:5]1[C:13]([Cl:14])=[CH:12][C:8]([C:9]([OH:11])=O)=[C:7]([O:15][CH3:16])[CH:6]=1)(=O)C.S(Cl)(Cl)=O.[NH2:21][CH:22]1[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23]1>>[NH2:4][C:5]1[C:13]([Cl:14])=[CH:12][C:8]([C:9]([NH:21][CH:22]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23]2)=[O:11])=[C:7]([O:15][CH3:16])[CH:6]=1
Reactant: CN1CCC(N)C1
Reactant: COc1cc(NC(C)=O)c(Cl)cc1C(=O)O
Solvent: O=S(Cl)Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NC1CCN(C)C1
Reaction time: 1 h

Procedure:
A suspension of 5.3 g. (0.022 mole) of 4-acetamido-5-chloro-2-methoxybenzoic acid in 30 ml. of thionyl chloride was refluxed for two hours and then concentrated. To the concentrate was added 100 ml. of chloroform and the solution was again concentrated. The residue was again dissolved in chloroform and added at a rapid drop to a chloroform solution containing 2.4 g. (0.024 mole) of 3-amino-1-methylpyrrolidine. The solution was stirred for one hour and concentrated. The residue was dissolved in 100 ml. of 4N hydrochloric acid and the solution was refluxed for 10 minutes, cooled in an ice bath and basified with sodium hydroxide. The mixture was extracted with chloroform and the extract dried and concentrated. The crystalline residue was recrystallized from isopropyl ether-isopropyl alcohol followed by another recrystallization from ethyl acetate. The yield of product was 1.4 g. (22 %); m.p. 185°-187°C.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:13]C(=O)OC(C)(C)C)[CH2:9][N:10]([CH3:12])[CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCOCC1.[ClH:27]>O>[ClH:27].[ClH:27].[CH:1]1([CH2:7][C@H:8]([NH2:13])[CH2:9][N:10]([CH3:12])[CH3:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(C)C[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CN(C)C[C@@H](N)CC1CCCCC1
Reaction time: 2 h
Yield: 100 %

Procedure:
Solid (S)-tert-butyl 1-cyclohexyl-3-(dimethylamino)propan-2-ylcarbamate (263 mg, 0.97 mmol) was dissolved in 4 M HCl in dioxane (10 mL, 40 mmol) and H2O (1 mL). After 2 h, the solvent was removed (50° C., 150 mm) and the residual solvent was azeotroped with toluene (2×10 mL) to afford (S)-3-Cyclohexyl-N1,N1-dimethylpropane-1,2-diamine dihydrochloride (245.3 mg, 100%) as a white solid. MS ESI +ve m/z 185 (M(−BOC)+1)+.
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[H-].C([Al+]CC(C)C)C(C)C.Cl>C1(C)C=CC=CC=1>[C:6]([NH:5][C@H:4]([CH:3]=[O:2])[CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([O:8][C:9]([CH3:11])([CH3:10])[CH3:12])=[O:7]
Reactant: COC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@H](C=O)COCc1ccccc1
Temperature: -70 °C

Procedure:
N-Boc-O-benzylserine methyl ester (9.5 g, 32 mmol) was dissolved in dry toluene (distilled from sodium) (100 ml). The solution was cooled to -70° C., and a solution of diisobutylaluminium hydride in toluene (1.2M, 53 ml, 64 mmol) was added dropwise over a period of 45 minutes under vigorous stirring under nitrogen. The mixture was stirred for an additional 20 minutes and was then allowed to reach -50° C. Hydrochloric acid (2M, 150 ml) was carefully added and the resulting reaction mixture was allowed to reach -10° C. The organic layer was separated and the aqueous layer was extracted with ethylacetate (2×100 ml). The combined organic solution was dried with sodium sulphate and evaporated to dryness below 40° C. (bath temperature). The N-Boc-O-benzylserinal was isolated as a colourless oil. Yield 8 6 g (96%). The structure was confirmed by 1HNMR and 13CNMR.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][C:27]1[NH:31][N:30]=[C:29]([CH2:32][C:33](O)=[O:34])[N:28]=1>>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[C:33](=[O:34])[CH2:32][C:29]1[NH:30][N:31]=[C:27]([CH3:26])[N:28]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CC1
Reactant: Cc1nc(CC(=O)O)n[nH]1
Product: COc1ccc(N2CCN(C(=O)Cc3nc(C)n[nH]3)[C@@H](Cc3ccccc3)C2)cc1OC1CC1
Yield: 40 %

Procedure:
Prepared using the same procedure described in Example 189 from (S)-3-benzyl-1-(3-cyclopropoxy-4-methoxy-phenyl)-piperazine and (5-methyl-1H-[1,2,4]triazol-3-yl)-acetic acid to afford the title compound as colorless solid (53 mg, 40%). LC/MS (Method B) 3.02 min, [M+1]+ 462.
Reaction SMILES: Br[C:2]1[C:3]([F:12])=[C:4]([C:8]([F:11])=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[N:13]1([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[C:22]([O:21][C:19]([N:13]1[CH2:18][CH2:17][N:16]([C:2]2[C:3]([F:12])=[C:4]([C:8]([F:11])=[CH:9][CH:10]=2)[C:5]([OH:7])=[O:6])[CH2:15][CH2:14]1)=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: O=C(O)c1c(F)ccc(Br)c1F
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(F)c(C(=O)O)c2F)CC1

Procedure:
3-(4-(tert-butoxycarbonyl)piperazin-1-yl)-2,6-difluorobenzoic acid was prepared as in Example 162 (Step ii) using 3-bromo-2,6-difluorobenzoic acid and tert-butyl piperazine-1-carboxylate.
Reaction SMILES: [Cl:1]C1C2C(=CC=C(C=O)C=2)NC=1.C([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][CH2:28][CH2:29][N:30]2[C:38]3[C:33](=[C:34]([CH:39]=[O:40])[CH:35]=[CH:36][CH:37]=3)[CH:32]=[CH:31]2)[CH2:22][CH2:21]1)=[O:19])(C)(C)C>>[Cl:1][C:32]1[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][C:34]=2[CH:39]=[O:40])[N:30]([CH2:29][CH2:28][CH2:27][CH2:26][CH:23]2[CH2:24][CH2:25][N:20]([C:18]([OH:17])=[O:19])[CH2:21][CH2:22]2)[CH:31]=1
Reactant: O=Cc1ccc2[nH]cc(Cl)c2c1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCCn2ccc3c(C=O)cccc32)CC1
Product: O=Cc1cccc2c1c(Cl)cn2CCCCC1CCN(C(=O)O)CC1

Procedure:
The title compound was prepared using methods analogous to those described for Intermediate 1 from 4-[4-(4-formyl-indol-1-yl)-butyl]-piperidine-1-carboxylic acid tert-butyl ester. MS: mass calcd. for C23H31ClN2O3, 418.20; m/z found, 441.3 [M+Na]+.
Reaction SMILES: CC(O[C:6](=[O:22])[NH:7][C@@H:8]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([C:15](=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17])[C:9]1=[O:21])(C)C.C(O)(C(F)(F)F)=O.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+].[Cl:47][C:48]1[CH:57]=[C:56]2[C:51]([C:52]([N:59]3[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]3)=[CH:53][C:54]([NH2:58])=[N:55]2)=[CH:50][CH:49]=1>>[NH2:58][C:54]1[CH:53]=[C:52]([N:59]2[CH2:60][CH2:61][N:62]([C:6]([NH:7][C@H:8]3[CH2:14][CH2:13][CH2:12][CH2:11][N:10]([C:15](=[O:20])[C:16]([CH3:17])([CH3:18])[CH3:19])[C:9]3=[O:21])=[O:22])[CH2:63][CH2:64]2)[C:51]2[C:56](=[CH:57][C:48]([Cl:47])=[CH:49][CH:50]=2)[N:55]=1
Reactant: Nc1cc(N2CCNCC2)c2ccc(Cl)cc2n1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCCN(C(=O)C(C)(C)C)C1=O
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C(=O)N1CCCC[C@H](NC(=O)N2CCN(c3cc(N)nc4cc(Cl)ccc34)CC2)C1=O

Procedure:
As described for example 213, [(3R)-1-(2,2-dimethyl-1-oxopropyl)hexahydro-2-oxo-1H-azepin-3-yl]-carbamic acid-1,1-dimethylethyl ester, TFA, triphosgene, NaHCO3 (sat.), and 7-chloro-4-(1-piperazinyl)-2-quinolinamine are reacted to afford the product as a light yellow solid. LC-MS: 501 (M++1). 1H NMR (CDCl3) δ 1.30 (s, 9H), 1.50˜1.70 (m, 1H), 1.80˜2.08 (m, 3H), 2.10–2.20 (m, 1H), 3.05˜3.20 (m, 4H), 3.45 (dd, 1H), 3.60–3.74 (m, 4H), 3.80 (br.dd, 1H), 4.66 (m, 1H), 4.94 (br.s, 2H), 5.96 (d, 1H), 6.15 (s, 1H), 7.16 (dd, 1H), 7.60 (d, 1H), 7.71 (d, 1H).
Reaction SMILES: Cl[CH:2]([C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][CH:4]=1.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][C:18]1=[O:23].C(N(CC)CC)C>CC#N>[Cl:9][C:6]1[CH:7]=[CH:8][C:3]([CH:2]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[N:20]2[CH2:21][CH2:22][NH:17][C:18](=[O:23])[CH2:19]2)=[CH:4][CH:5]=1
Reactant: O=C1CNCCN1
Reactant: Clc1ccc(C(Cl)c2ccc(Cl)cc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)CCN1
Temperature: 25 °C
Yield: 83.5 %

Procedure:
To a solution of chlorobis(4-chlorophenyl)methane (407 mg, 1.5 mmol) in MeCN was added piperazin-2-one (601 mg, 6.0 mmol) followed by triethylamine (626 μl, 4.5 mmol) and the resulting mixture was refluxed overnight. After cooling to rt, the solvent was evaporated to dryness and the residue was submitted to column chromatography (SiO2, DCM to DCM/MeOH=100:5) to give 4-(bis(4-chlorophenyl)methyl)piperazin-2-one (420 mg) as a white solid.
Reaction SMILES: [C:1]([OH:30])(=[O:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].[Sn].[OH:32][CH2:33][CH:34]([CH2:36]O)[OH:35]>>[C:1]([O:30][CH2:36][CH:34]([CH2:33][OH:32])[OH:35])(=[O:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)O
Reactant: OCC(O)CO
Agent: [Sn]
Product: CCCCCCCCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO

Procedure:
400 g montanic acid (Hoechst-Wachs S), 97 g glycerol (5% excess) and 0.5 g tin powder were reacted as in Example 1. A yellow, brown-tinged hard wax having a dropping point of 84.2° C. was obtained.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]([C:13]3[C:14]([F:34])=[C:15]([NH:20][S:21]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=4)(=[O:23])=[O:22])[CH:16]=[CH:17][C:18]=3[F:19])=[O:12])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.CS(C)=O.[C-:39]#[N:40].[K+]>O>[C:39]([C:2]1[C:3]2[C:10]([C:11]([C:13]3[C:14]([F:34])=[C:15]([NH:20][S:21]([C:24]4[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=4)(=[O:22])=[O:23])[CH:16]=[CH:17][C:18]=3[F:19])=[O:12])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1)#[N:40]
Reactant: O=C(c1c(F)ccc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)c1F)c1c[nH]c2ncnc(Cl)c12
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ncnc2[nH]cc(C(=O)c3c(F)ccc(NS(=O)(=O)c4ccc(C(F)(F)F)cc4)c3F)c12
Temperature: 150 °C
Yield: 13.1 %

Procedure:
To N-[3-(4-chloro-7H-pyrrolo[2,3-d]pyrimidine-5-carbonyl)-2,4-difluoro-phenyl]-4-trifluoromethyl-benzenesulfonamide (P-1016, 62 mg, 0.12 mmol), 1.00 mL of dimethyl sulfoxide is added, followed by potassium cyanide (39.0 mg, 0.60 mmol). The reaction is heated at 150° C. in an oil bath for 4 hours, then at 150° C. overnight. The reaction is poured into water and extracted with ethyl acetate. The organic layer is concentrated under vacuum and purified by silica gel column chromatography, eluting with a gradient of 10-60% ethyl acetate in hexanes. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (P-1023, 8 mg). MS (ESI) [M+H+]+=508.1.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].C([O-])([O-])=O.[K+].[K+].Cl[CH2:21][C:22]([CH3:24])=[CH2:23]>CN(C=O)C>[CH3:13][O:12][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[O:1][CH2:23][C:22]([CH3:24])=[CH2:21])[C:6]([O:8][CH3:9])=[O:7]
Reactant: C=C(C)CCl
Reactant: COC(=O)c1ccc(O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=C(C)COc1ccc(C(=O)OC)cc1OC
Temperature: 60 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a suspension of methyl 4-hydroxy-3-methoxybenzoate (100 g, 0.55 mol) and K2CO3 (92 g, 0.66 mol) in DMF (800 ml) was added drop wise 3-chloro-2-methyl-propene (55 g, 0.60 mol). The mixture was stirred at 60° C. overnight. TLC (EtOAc/petroleum ether=1/3) showed no starting material was present. The reaction mixture was filtered and the filtrate was added water (400 ml). The mixture was extracted with EtOAc (400 ml×3). The combined organic phase was washed with brine (400 mL), dried (Na2SO4) and concentrated to give the product (130 g, 100%) as yellow oil. The oil was used directly to the next step without further purification. 1H NMR (400 MHz, CDCl3): δ 7.54 (d, 1H), 7.19 (s, 1H), 6.80 (d, 1H), 5.00(d, 2H), 4.50 (s, 2H), 3.83 (d, 6H), 1.76 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].[OH2:10]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]([NH2:6])=[O:10]
Reactant: O
Reactant: N#Cc1cccc(Br)c1
Solvent: C1COCCO1
Product: NC(=O)c1cccc(Br)c1
Temperature: 80 °C
Yield: 80 %

Procedure:
To a solution of 3-bromobenzonitrile (0.91 g, 5 mmol) in dioxane (19 mL), NaBO3.4H2O (2.12 g, 13.78 mmol) and H2O (19 mL) were added. The mixture was stirred at 80° C. 16 hours (h), cooled, added of H2O and extracted with CH2Cl2. The combined organic layers were dried over Na2SO4 and evaporated. Purification of the residue by column chromatography (hexane/EtOAc 2:8) and recrystallization gave the desired product as colorless tablets. Yield 80% (EtOH). Mp: 156-7° C. (lit. 156° C.) (Pearson, D. E. et al., J. Org. Chem., 28: 3147-3149, (1963)). MS (EI): m/z 199 (M+); 183 (100%).
Reaction SMILES: [Li+].CC([N-][CH:6]([CH3:8])[CH3:7])C.[CH3:9][O:10][C:11](=[O:25])[CH2:12][CH:13]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=1)[CH2:14][C:15]([OH:17])=[O:16].C(Br)C=C.CCN=C=NCCCN(C)C>C1COCC1.CN(C1C=CN=CC=1)C>[CH3:9][O:10][C:11](=[O:25])[CH:12]([CH2:8][CH:6]=[CH2:7])[CH:13]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=1)[CH2:14][C:15]([OH:17])=[O:16]
Reactant: COC(=O)CC(CC(=O)O)c1cccc(F)c1
Reactant: CC(C)[N-]C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: [Li+]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCC(C(=O)OC)C(CC(=O)O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a cooled (-78° C.) solution of LDA (7.1 mL, 2.0 M, 14.2 mmol) in 50 mL THF was added a solution of 3-(3-fluoro-phenyl)-pentanedioic acid monomethyl ester (2-4) (1.58 g, 6.58 mmol) in 10 mL THF gradually. The mixture was stirred for 40 min, treated with allyl bromide (1.71 mL, 19.7 mmol) at -78° C. and stirred overnight while it was warmed to room temperature. It was then concentrated and diluted with 20 mL CH2Cl2 and 15 mL EtOH. To the resulting solution was added EDAC (1.88 g, 9.87 mmol) and DMAP (25 mg, 0.02 mmol). After stirring for 5 hr, the reaction was quenched with 20 mL 10% NaHCO3 and extracted with EtOAc (×3). The combined organic layers were washed with brine, dried (Na2SO4) and concentrated to provide 2-5 as an oil, which was further purified using flash silica chromatography (Hexane/EtOAc, 4:1).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH:5]([C:13]([NH:15][S:16](/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:18])=[O:17])=[O:14])[C:6]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])=[O:7])#[N:2].C(N[C:30]1[CH:35]=CC=[CH:32][CH:31]=1)C>>[C:1]([CH2:3][CH2:4][CH:5]([C:13]([NH:15][S:16](/[CH:19]=[CH:20]/[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:17])=[O:18])=[O:14])[C:6]([N:8]([CH2:9][CH3:10])[C:11]1[CH:32]=[CH:31][CH:30]=[CH:35][CH:12]=1)=[O:7])#[N:2]
Reactant: CCN(CC)C(=O)C(CCC#N)C(=O)NS(=O)(=O)/C=C/c1ccccc1
Reactant: CCNc1ccccc1
Product: CCN(C(=O)C(CCC#N)C(=O)NS(=O)(=O)/C=C/c1ccccc1)c1ccccc1

Procedure:
In the same manner as in Example 1 (4), a crude product was obtained using the compound (300 mg) obtained in Example 216 (2) and N-ethylaniline (123 μL). This was purified by silica gel column chromatography to give the title compound (145 mg) as a white powder.