Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:7]([NH:9][NH2:10])=O)[S:5][CH:6]=1.[CH3:11][C:12]([N:14]([CH3:16])C)=O.[CH:17]1(N)CC1.CC(O)=O>CN(C=O)C.C1(C)C=CC=CC=1>[Br:1][C:2]1[N:3]=[C:4]([C:7]2[N:14]([CH:12]3[CH2:11][CH2:17]3)[CH:16]=[N:10][N:9]=2)[S:5][CH:6]=1
Reactant: CC(=O)N(C)C
Reactant: NNC(=O)c1nc(Br)cs1
Reactant: NC1CC1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Brc1csc(-c2nncn2C2CC2)n1
Temperature: 150 °C
Reaction time: 0.08 h

Procedure:
4-bromothiazole-2-carbohydrazide (620 mg, 2.8 mmol) and toluene (9 mL) were added to a sealable vial, DMF.DMA (920 μL, 6.9 mmol) was added and the reaction was stirred for 5 minutes. Cyclopropyl amine (770 μL, 11 mmol), and AcOH (160 μL, 2.8 mmol) were added and the reaction was heated in a microwave reactor at 150° C. for 30 minutes. The reaction was concentrated and purified by flash chromatography (1→7% MeOH in CH2Cl2) to afford 4-bromo-2-(4-cyclopropyl-4H-1,2,4-triazol-3-yl)thiazole (contaminated with DMF.DMA for next step).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C:8]([C:10]1[S:11][C:12]([S:32][CH3:33])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=3[NH2:31])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.Cl[C:42](OC1C=CC([N+]([O-])=O)=CC=1)=[O:43].[C:54]([N:73]1[N:77]=[N:76][C:75]([CH2:78][CH2:79][CH2:80][CH2:81][NH2:82])=[N:74]1)([C:67]1[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=1)([C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:34])[NH:7][C:8](=[NH:9])[C:10]1[S:11][C:12]([S:32][CH3:33])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=3[NH:31][C:42]([NH:82][CH2:81][CH2:80][CH2:79][CH2:78][C:75]3[N:76]=[N:77][N:73]([C:54]([C:55]4[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=4)([C:61]4[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=4)[C:67]4[CH:68]=[CH:69][CH:70]=[CH:71][CH:72]=4)[N:74]=3)=[O:43])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2N)c1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCCCCc1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cccc2NC(=O)NCCCCc2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 13.9 %

Procedure:
To a solution of {[4-(2′-amino-6′-methyl-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (60 mg, 0.116 mmol), as prepared according to the procedure of step c of Example 25, and pyridine (10 mg, 0.128 mmol) in DCM (1.1 mL) was added 4-nitrophenyl chloroformate (23 mg, 0.116 mmol), and stirred at ambient temperature for 4 h. To the above mixture was added a solution of 4-(2-trityl-2H-tetrazol-5-yl)-butylamine (65 mg, 0.151 mmol) in DCM (0.65 mL), and stirred for 48 h. The mixture was concentrated and purified on a preparative TLC plate (1000 μm), developing with EtOAc/DCM (5 and 20%) to give the title compound (15 mg, 14% yield) as a yellow solid.
Reaction SMILES: [NH2:1][C@H:2]([C:4]([N:6]1[C:12](=[O:13])[CH:11]([CH3:14])[C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=2[C:8]2[C:19]([NH2:23])=[CH:20][CH:21]=[CH:22][C:7]1=2)=[O:5])[CH3:3].N1C=CC=CC=1.[CH2:30]([S:38](Cl)(=[O:40])=[O:39])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>CN(C=O)C>[CH2:30]([S:38]([NH:1][C@H:2]([C:4]([N:6]1[C:12](=[O:13])[CH:11]([CH3:14])[C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=2[C:8]2[C:19]([NH2:23])=[CH:20][CH:21]=[CH:22][C:7]1=2)=[O:5])[CH3:3])(=[O:40])=[O:39])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CC1C(=O)N(C(=O)[C@H](C)N)c2cccc(N)c2-c2ccccc21
Reactant: CCCCCCCCS(=O)(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCCCCCCCS(=O)(=O)N[C@@H](C)C(=O)N1C(=O)C(C)c2ccccc2-c2c(N)cccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 341.8 %

Procedure:
To 5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one (Example 7B) (0.1500 g, 0.0485 mmol) in DMF (4 ml) were added pyridine (0.059 ml, 0.728 mmol) and 1-octanesulfonyl chloride (Aldrich) (0.095 ml, 0.485 mmol), stirred at RT overnight. The reaction mixture was evaporated to dryness. Water was added, extracted with EtOAc, washed with brine, dried over MgSO4. Evaporation and flash chromatography (silica, 5% MeOH/CH2Cl2), gave the title compound (0.0805 g, 34%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[C:11]#[N:12].N1C=CC=CC=1.C([O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1)(=O)C>CCOCC>[C:11]([C:10]1[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=1[S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][C:31](=[O:32])[C:30]1[CH:34]=[CH:35][C:27]([OH:26])=[CH:28][CH:29]=1)#[N:12]
Reactant: N#Cc1ccccc1Sc1ccccc1N
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Solvent: CCOCC
Solvent: c1ccncc1
Product: N#Cc1ccccc1Sc1ccccc1NC(=O)c1ccc(O)cc1
Yield: 82.9 %

Procedure:
In 60 ml of ether were dissolved 2.6 g of 2-(2-aminophenylthio)benzonitrile (prepared in accordance with Reference Example 5, Step 4) and 2.8 g of pyridine, followed by dropwise addition of a solution of 2.7 g of 4-acetoxybenzoyl chloride in ether with ice-cooling and stirring. After completion of dropwise addition, the mixture was stirred at room temperature for 10 hours. The ether was then distilled off and ethanol was added to the residue. The resulting crystals were collected by filtration and washed with ethanol. The crystals were then suspended in 70 ml of ethanol, and after 7 ml of 10% aqueous sodium hydroxide solution was added, the mixture was stirred at room temperature for 1 hour. The reaction mixture was acidified with concentrated hydrochloric acid and diluted with water. The crystals separated out therefrom were collected by filtration and dried to give 3.3 g of the title compound as white crystals.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([CH3:11])(=[O:10])=[O:9].Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:20][CH:21]=2)[N:16]=[CH:15][C:14]=1[N+:29]([O-:31])=[O:30].C(N(CC)CC)C.O>CN1C(=O)CCC1>[N+:29]([C:14]1[CH:15]=[N:16][C:17]2[C:22]([C:13]=1[NH:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([CH3:11])(=[O:10])=[O:9])=[CH:21][CH:20]=[C:19]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH:18]=2)([O-:31])=[O:30]
Reactant: O=[N+]([O-])c1cnc2cc(-c3ccccc3)ccc2c1Cl
Reactant: CS(=O)(=O)NCCCCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN1CCCC1=O
Product: CS(=O)(=O)NCCCCNc1c([N+](=O)[O-])cnc2cc(-c3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
N-(4-aminobutyl)methanesulfonamide hydrochloride (7.8 g, 39 mmol) was added to a suspension of 4-chloro-3-nitro-7-phenylquinoline (35 mmol) and triethylamine (8.0 g, 79 mmol) in NMP (80 mL), and the reaction was stirred at ambient temperature overnight. The resulting solution was poured into water (350 mL) to form a solid, which was isolated by filtration, washed with water, air-dried, and recrystallized from acetonitrile to provide 12.0 g of N-[4-(3-nitro-7-phenylquinolin-4-ylamino)butyl]methanesulfonamide as yellow plates.
Reaction SMILES: [F:1][C:2]1[C:11](S(C(F)(F)F)(=O)=O)=[C:10]([F:19])[C:9]([F:20])=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[CH2:21]([Sn](CCCC)(CCCC)C=C)[CH2:22]CC.[Cl-].[Li+]>O1CCOCC1.CCOCC>[CH:21]([C:11]1[C:2]([F:1])=[C:3]([CH:8]=[C:9]([F:20])[C:10]=1[F:19])[C:4]([OH:6])=[O:5])=[CH2:22]
Reactant: COC(=O)c1cc(F)c(F)c(S(=O)(=O)C(F)(F)F)c1F
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: CCOCC
Product: C=Cc1c(F)c(F)cc(C(=O)O)c1F
Temperature: 98 °C
Reaction time: 4 h
Yield: 73.1 %

Procedure:
To a solution of 2,4,5-trifluoro-3-trifluoro methanesulfonyl benzoic acid, methyl ester (22.0 g, 0.065 mol) in dioxane (100 mL) was added tri-n-butyl vinyl tin (21.6 g, 0.068 mol), lithium chloride (16.7 g, 0.37 mL) 2,6-di-t-butyl-4-methylphenol (0.08 g) and palladium-tetra-triphenyl phosphine (1.1 g). The mixture was heated at 98° C. for 12 hours, cooled, diluted with ether and filtered through celite. The ether layer was concentrated and the resulting residue suspended in hexane and filtered. The filtrate was concentrated to a yellow oil which was immediately dissolved in methanol (250 mL) and 1 N sodium hydroxide (150 mL). The mixture was stirred at room temperature for 4 hours, diluted with water and ether. The aqueous layer was acidified (pH ~2) with 6 N HCl and extracted with methylene chloride. The organic layer was dried and concentrated to provide the desired product (9.6 g, 77%); mp 108°-110° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[O-2].[Ca+2:7].[Ca]>O>[NH2:1][CH2:2][C:3]([O-:5])=[O:4].[NH2:1][CH2:2][C:3]([O-:5])=[O:4].[Ca+2:7]
Reactant: NCC(=O)O
Agent: [Ca+2]
Agent: [Ca]
Agent: [O-2]
Solvent: O
Product: NCC(=O)[O-]

Procedure:
About 250 grams of glycine was dissolved into 937.8 grams of water. Once the glycine was significantly dissolved, about 95 grams of calcium oxide was added. The solution was continually stirred for about 15 minutes until all of the calcium was dissolved. The resulting reaction formed a calcium bisglycinate chelate or complex and water.
Reaction SMILES: [H-].[Na+].[C:3]1(O)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[O:10]1[CH2:12][CH:11]1[CH:13]1[CH2:22][CH2:21][C:16]2([O:20][CH2:19][CH2:18][O:17]2)[CH2:15][CH2:14]1.[OH2:23]>CN(C)C=O>[O:17]1[C:16]2([CH2:15][CH2:14][CH:13]([CH:11]([OH:23])[CH2:12][O:10][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH2:22][CH2:21]2)[O:20][CH2:19][CH2:18]1
Reactant: C1COC2(CCC(C3CO3)CC2)O1
Reactant: Oc1ccccc1
Reactant: O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OC(COc1ccccc1)C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A 60% strength dispersion of sodium hydride in mineral oil (834 mg, 20.7 mmol) was taken up in anhydrous N,N-dimethylformamide (10 ml), and phenol (1.96 g, 20.8 mmol) was added. The mixture was stirred at room temperature for 15 min and a solution of 8-oxiranyl-1,4-dioxaspiro[4.5]decane (2.62 g, content approx. 30%, approx. 4 mmol) in N,N-dimethylformamide (6 ml) was then added. The reaction mixture was stirred at 120° C. for 5.5 h and then cooled to room temperature, water (1 ml) was added and the mixture was concentrated in vacuo. Toluene was repeatedly added to the residue and the mixture was concentrated again in vacuo each time. The crude product (2.9 g) was purified by flash chromatography (200 g, 20×5.6 cm) with cyclohexane/ethyl acetate (4:1).
Reaction SMILES: [CH3:1][CH:2]([CH3:30])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22](=O)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[C:32]1([NH:42]N)[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1>>[CH3:1][CH:2]([CH3:30])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]3[C:33]4[C:32](=[C:41]5[CH:40]=[CH:39][CH:38]=[CH:37][C:36]5=[CH:35][CH:34]=4)[NH:42][C:22]=3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: NNc1cccc2ccccc12
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3)CC2)c1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccccc4)[nH]c4c3ccc3ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-{3-[1-(5-oxo-5-phenylpentyl)-4-piperidinyl]phenyl}propanamide and 1-(1-naphthyl)hydrazine hydrochloride: ESMS m/e: 530.2 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[C:24]1([N:30]2[CH:34]=[N:33][C:32]([C:35](Cl)=[O:36])=[N:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:35]([C:32]2[N:33]=[CH:34][N:30]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[N:31]=2)=[O:36])[CH:10]([CH3:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=C(Cl)c1ncn(-c2ccccc2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC1CN(C(=O)OC(C)(C)C)CCN1C(=O)c1ncn(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of 2.19 g (10.5 mmol) 3-methyl-piperazine-1-carboxylic acid tert-butyl ester and 2.50 mL (14.6 mmol) DIPEA in 15 mL DCM was added a solution of 2.18 g (10.5 mmol) 1-phenyl-1H-[1,2,4]-triazole-3-carbonyl chloride in 15 mL DCM. The reaction mixture was stirred at RT for 3 days, then washed with water. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8](OS(C)(=O)=O)[CH2:7][N:6]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:4].[N-:22]=[N+:23]=[N-:24].[Na+]>CS(C)=O>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([N:22]=[N+:23]=[N-:24])[CH2:7][N:6]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:4]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)[C@@H]1C[C@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Temperature: 90 °C
Reaction time: 16 h

Procedure:
(2S,4R)-4-Methanesulfonyloxypyrrolidine-1,2-dicarboxylic acid 1-t-butyl ester 2-methyl ester (11.9 g, 37 mmol) and NaN3 (2 equiv) were mixed in DMSO (160 mL) and stirred at 90° C. for 16 hours. The mixture was cooled then partitioned between water (200 mL) and EtOAc (400 mL). The aqueous layer was discarded, the organics washed with water (200 mL) and saturated aqueous NaCl (200 mL), then dried over Na2SO4. The solvent was evaporated to afford the title compound (8.5 g, 31 mmol), which was used without further purification. MS m/z: [M+H]+ calcd for C11H18N4O4, 270.3. found 271.3.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:11]=[CH:10][C:9]=2[N+:20]([O-:22])=[O:21])[N:5]=[CH:4][N:3]=1.[CH3:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][NH2:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27][NH:28][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH:11]=[CH:10][C:9]=2[N+:20]([O-:22])=[O:21])[N:5]=[CH:4][N:3]=1
Reactant: Cc1cccc(CN)c1
Reactant: O=[N+]([O-])c1ccc(N2CCCCC2)cc1-c1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(CNc2cc(-c3cc(N4CCCCC4)ccc3[N+](=O)[O-])ncn2)c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of 4-chloro-6-(2-nitro-5-(piperidin-1-yl)phenyl)pyrimidine 3.1b (500 mg, 1.57 mmol, 1.00 equiv) in N,N-dimethylformamide (10 mL), m-methylbenzylamine (285 mg, 2.36 mmol, 1.50 equiv), and potassium carbonate (650 mg, 4.71 mmol, 3.00 equiv). The resulting solution was stirred overnight at 80° C. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was dissolved in 50 mL of ethyl acetate. The resulting mixture was washed with 2×50 mL of water. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:5). This resulted in 0.5 g (79%) of N-(3-methylbenzyl)-6-(2-nitro-5-(piperidin-1-yl)phenyl)pyrimidin-4-amine. as yellow oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CN(C)C=O>O>[NH2:1][C:2]1[S:3][C:4]([S:7][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:5][N:6]=1
Reactant: Nc1nnc(S)s1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1nnc(SCc2ccccc2)s1

Procedure:
A mixture of 2-amino-5-mercapto-1,3,4-thiadiazole (39.9 g), potassium carbonate (41.4 g), α-chlorotoluene (38.0 g), and N,N-dimethylformamide (180 ml) is heated for 1.5 hours on a steam bath. The reaction mixture is drowned into water (1,000 ml) and the product collected by filtration and air dried. The crude product is recrystallized from ethanol and melts at 154°-156° C.
Reaction SMILES: [C:1]([CH:3]=[C:4]1[CH2:7][N:6](C(OC(C)(C)C)=O)[CH2:5]1)#[N:2].Cl.C(N(C(C)C)CC)(C)C.[CH2:25]([S:27](Cl)(=[O:29])=[O:28])[CH3:26]>C(#N)C>[CH2:25]([S:27]([N:6]1[CH2:5][C:4](=[CH:3][C:1]#[N:2])[CH2:7]1)(=[O:29])=[O:28])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CC(=CC#N)C1
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCS(=O)(=O)N1CC(=CC#N)C1
Temperature: 2.5 °C
Reaction time: 8 h
Yield: 91.1 %

Procedure:
A solution of tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (9, 1000 g, 5.2 mol) in acetonitrile (7 L) and a 3 N aqueous HCl solution (7 L) was stirred at room temperature for 18 h. When HPLC showed that all the starting material (9) was consumed, the reaction mixture was concentrated under reduced pressure to dryness. The residue, which contains the crude desired deprotection product (10), was then suspended in acetonitrile (12 L) and the resulting suspension was cooled to 0-5° C. Diisopropyethylamine (DIEA, 3.14 L, 18.03 mol, 3.5 equiv) was then slowly added while keeping the internal temperature below 5° C. The resulting homogeneous solution was allowed to cool down to 0° C. and ethane sulfonyl chloride (EtSO2Cl, 730 mL, 7.73 mol, 1.5 equiv) was added over 1 h while keeping the internal temperature below 5° C. The resulting reaction mixture was allowed to gradually warm to room temperature and stirred at room temperature for overnight. When HPLC showed that the reaction was complete, the reaction mixture was concentrated under reduced pressure to a volume of approximately 2 L. The bath temperature of the rotary evaporator is set to not exceed 45° C. The concentrated residue was then diluted with dichloromethane (CH2Cl2, 10 L) and the resulting dichloromethane solution was washed with aqueous sodium chloride solution (10 L). The aqueous phase was back extracted with dichloromethane (CH2Cl2, 5 L). The combined organic layers were dried over anhydrous sodium sulfate (Na2SO4) and the residue was absorbed onto silica gel (SiO2, 1 Kg) under reduced pressure. The bath temperature of the rotary evaporator was set to not exceed 45° C. The material was then loaded onto a silica gel column (SiO2, 2.5 Kg) and eluted with 20-60% ethyl acetate in heptane to afford 2-(1-(ethylsulfonyl)azetidin-3-ylidene)acetonitrile (11, 882 g, 968.4 g theoretical, 91% yield) as off-white solids. For 11: 1H NMR (CDCl3, 300 MHz) δ 5.46 (m, 1H), 4.77 (m, 2H), 4.70 (m, 2H), 3.05 (q, 2H), 1.39 (t, 3H) ppm; C7H10N2O2S (MW, 186.23), LCMS (EI) m/e 187 (M++H).
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([CH2:9][N:10]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])=[CH:5][CH:4]=1)#[N:2].Cl.CCOCC>[Pd].CO>[NH2:2][CH2:1][C:3]1[N:8]=[CH:7][C:6]([CH2:9][N:10]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:11](=[O:16])[C:12]([F:13])([F:14])[F:15])=[CH:5][CH:4]=1
Reactant: N#Cc1ccc(CN(C(=O)C(F)(F)F)C2CCCCC2)cn1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: NCc1ccc(CN(C(=O)C(F)(F)F)C2CCCCC2)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 105.7 %

Procedure:
Add 6-cyano-3-[N-(cyclohexyl)-N-(2,2,2-trifluoroacetyl)-aminomethyl]-pyridine (1.5 g, 4.8 mmol), 2M hydrogen chloride in ether (7.2 mL, 14.4 mmol) and 10% Pd/C (0.3 g) to methanol (30 mL) in a pressure vessel. Flush the vessel three times with hydrogen and charge to 50 psi with hydrogen. Stir at room temperature for 4 h. Filter the mixture through Whatman® GF/B glass microfiber filter paper, and concentrate in vacuo. Purify the residue by chromatography on silica gel (100 g) eluting with a gradient of DCM to 4:1 DCM/(chloroform:methanol:concentrated NH4OH 80:18:2) to obtain the title compound as a clear oil (1.6 g, 99%). MS (ES+) m/z: 316 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[C:10](=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].ClC[C:20](OCC)=[O:21].CC(C)([O-])C.[K+].[Na]>O.C(O)C.C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[CH:10]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:20]=[O:21]
Reactant: CCCCCCC(=O)c1cc(C)ccc1OC
Reactant: CCOC(=O)CCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Na]
Solvent: c1ccccc1
Solvent: O
Solvent: CCO
Product: CCCCCCC(C=O)c1cc(C)ccc1OC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.6 %

Procedure:
1-(2-Methoxy-5-methylphenyl)heptan-1-one (81.6 g, 0.348 mol), ethyl chloroacetate (64 g, 0.522 mol) and benzene (100 ml) were mixed, and this solution was cooled to 0° C. Potassium t-butoxide (58.6 g, 0.522 mol) was added, and the mixture was stirred at room temperature for 0.5 hour. This solution was cooled again to 0° C. Then ethyl chloroacetate (32 g, 0.261 mol) and potassium t-butoxide (29.3 g, 0.261 mol) were added, and the mixture was stirred at room temperature for 0.5 hour. The reaction mixture was poured onto ice (200 g) to stop the reaction and the aqueous layer was extracted 3 times with toluene (120 ml). The organic layer was washed successively with water, an aqueous acetic acid solution (water/acetic acid=50/1) and water (100 ml each), and dried over anhydrous magnesium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure. To the obtained residue were added ethanol (90 ml) and sodium ethoxide previously prepared from sodium (13.1 g, 0.567 mol) and ethanol (260 ml), and the mixture was stirred at room temperature for 1.5 hours. Water (17 ml) was added to the reaction mixture, and the mixture was stirred for 0.5 hour. Ethanol was evaporated under reduced pressure. To this residue, water (350 ml) and conc. hydrochloric acid (63 ml) were added, and the mixture was refluxed under heating for 1.5 hours. The aqueous layer was extracted 3 times with ether (200 ml). The organic layers were combined, washed successively with water, a saturated aqueous sodium hydrogencarbonate solution and saturated brine (100 ml each), and dried over anhydrous magnesium sulfate. The drying agent was filtered off, the filtrate was concentrated under reduced pressure, and the obtained residue was distilled under reduced pressure (450 pa, 155-160° C.) to give 2-(2-methoxy-5-methylphenyl)octanal (64.5 g, 74.6%/) as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([C:25]4[O:26][C:27]([C:30]5[N:35]=[C:34]([C:36]([O:38]C)=[O:37])[CH:33]=[CH:32][CH:31]=5)=[CH:28][N:29]=4)=[O:24])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[Li+].[OH-].Cl>C1COCC1.O.C(Cl)Cl>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][C:23]([C:25]4[O:26][C:27]([C:30]5[N:35]=[C:34]([C:36]([OH:38])=[O:37])[CH:33]=[CH:32][CH:31]=5)=[CH:28][N:29]=4)=[O:24])=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)[CH2:6][CH2:7]1
Reactant: COC(=O)c1cccc(-c2cnc(C(=O)CCc3ccc(-c4ccc(CN5CCN(C)CC5)cc4)cc3)o2)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN1CCN(Cc2ccc(-c3ccc(CCC(=O)c4ncc(-c5cccc(C(=O)O)n5)o4)cc3)cc2)CC1
Yield: 20.6 %

Procedure:
Methyl 6-(2-(3-(4′-((4-methylpiperazin-1-yl)methyl)biphenyl-4-yl)propanoyl)oxazol-5-yl)pyridine-2-carboxylate (10 mg, 0.019 mmol) was dissolved in THF/H2O (3:2, 2 mL) and LiOH (1 mg, 0.06 mmol) was added. The reaction solution was stirred at room temperature under an atmosphere of Ar for 40 min before the addition of aqueous 1 N HCl to pH 4. The reaction solution was diluted with CH2Cl2 and the organic and aqueous layers were separated. The aqueous layer was made basic to pH 8 with the addition of saturated aqueous NaHCO3 and extracted with CH2Cl2. The organic phases were combined, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by tritration in ether to provide 6-(2-(3-(4′-((4-methylpiperazin-1-yl)methyl)biphenyl-4-yl)propanoyl)oxazol-5-yl)pyridine-2-carboxylic acid as a white solid (2 mg, 21%): 1H NMR (CDCl3, 600 MHz) δ 8.17 (s, 1H), 7.93 (s, 3H), 7.48 (d, 2H, J=7.8 Hz), 7.44 (d, 2H, J=7.8 Hz), 7.31-7.27 (m, 4H), 3.68 (s, 2H), 3.47 (t, 2H, J=6.9 Hz), 3.15 (t, 2H, J=6.9 Hz), 2.82 (bs, 4H), 2.69 (s, 3H), 2.10-2.00 (m, 4H); HR ESI-TOF m/z 511.2334 (M+H+, C30H30N4O4, requires 511.2340).