Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[C:12]([S-:14])#[N:13].[K+].BrBr.O>C(O)(=O)C>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]=[C:12]([NH2:13])[S:14][C:10]=2[CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: N#C[S-]
Reactant: CCCCc1ccc(N)cc1
Agent: BrBr
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CCCCc1ccc2nc(N)sc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Step-1: To a mixture of 4-butylaniline 67 mmol) and KSCN (26 g, 268 mmol) in acetic acid was added Br2 in acetic acid (70 mL) dropwise over 6 min at RT. The mixture was stirred at RT overnight and poured into water (2 L). The precipitate was collected, washed with water and dried to afford 6-butylbenzo[d]thiazol-2-amine. MS (ESI+) m/z 207.20 [M+H]+
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@H:9](OS(C)(=O)=O)[CH2:8][C@H:7]1[C:16]([N:18]1[CH2:22][CH2:21][C:20]([F:24])([F:23])[CH2:19]1)=[O:17])=[O:5])[CH3:2].[Cl:25][C:26]1[CH:31]=[C:30]([Br:32])[CH:29]=[CH:28][C:27]=1[SH:33]>>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@@H:9]([S:33][C:27]2[CH:28]=[CH:29][C:30]([Br:32])=[CH:31][C:26]=2[Cl:25])[CH2:8][C@H:7]1[C:16]([N:18]1[CH2:22][CH2:21][C:20]([F:23])([F:24])[CH2:19]1)=[O:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1C[C@H](OS(C)(=O)=O)C[C@H]1C(=O)N1CCC(F)(F)C1
Reactant: Sc1ccc(Br)cc1Cl
Product: CCOC(=O)[C@@H]1C[C@@H](Sc2ccc(Br)cc2Cl)C[C@H]1C(=O)N1CCC(F)(F)C1

Procedure:
The title compound was prepared in analogy to example 68/69 step 8 using (1R,2R,4R)-2-(3,3-Difluoro-pyrrolidine-1-carbonyl)-4-methanesulfonyloxy-cyclopentanecarboxylic acid ethyl ester (example 186 step 3) and 2-chloro-4-bromothiophenol. Light yellow oil (89%). MS (EI): 498.0 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:13]3[N:14]([CH3:30])[C:15](=[O:29])[CH:16]=[C:17]([O:18][S:19]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)(=[O:21])=[O:20])[C:12]=3[C:11](=[O:31])[N:10]([CH:32]3[CH2:34][CH2:33]3)[C:9]2=[O:35])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>C(Cl)(Cl)Cl>[CH:32]1([N:10]2[C:11](=[O:31])[C:12]3[C:17]([O:18][S:19]([C:22]4[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=4)(=[O:21])=[O:20])=[CH:16][C:15](=[O:29])[N:14]([CH3:30])[C:13]=3[N:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][S:43]([CH3:42])(=[O:45])=[O:44])[CH:3]=3)[C:9]2=[O:35])[CH2:33][CH2:34]1
Reactant: Cc1ccc(S(=O)(=O)Oc2cc(=O)n(C)c3c2c(=O)n(C2CC2)c(=O)n3-c2cccc(N)c2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)Oc2cc(=O)n(C)c3c2c(=O)n(C2CC2)c(=O)n3-c2cccc(NS(C)(=O)=O)c2)cc1
Yield: 95 %

Procedure:
To toluene-4-sulfonic acid 1-(3-aminophenyl)-3-cyclopropyl-8-methyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-yl ester 13 (5 g) obtained in Step 7 was added pyridine (40 ml), a solution of methanesulfonyl chloride 14 (0.9 ml) in chloroform (10 ml) was added dropwise with stirring under ice-cooling, and the mixture was stirred for 3 hrs in an ice bath. The reaction mixture was concentrated under reduced pressure, 2N hydrochloric acid was added and the mixture was extracted with chloroform. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resultant solid was suspended in diethyl ether:hexane=1:1, and filtered by suction to give toluene-4-sulfonic acid 3-cyclopropyl-1-(3-methanesulfonylaminophenyl)-8-methyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-yl ester 15 (5.5 g, 95%) as a white solid.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[C:6]([O:11][CH2:12][CH2:13][CH2:14][OH:15])(=[O:10])[C:7]([CH3:9])=[CH2:8]>N1C=CC=CC=1>[C:6]([O:11][CH2:12][CH2:13][CH2:14][O:15][C:3](=[O:4])[CH2:2][Cl:1])(=[O:10])[C:7]([CH3:9])=[CH2:8]
Reactant: O=C(Cl)CCl
Reactant: C=C(C)C(=O)OCCCO
Solvent: c1ccncc1
Product: C=C(C)C(=O)OCCCOC(=O)CCl

Procedure:
Chloroacetoxypropyl methacrylate (CAPM) was prepared by condensation of chloroacetyl chloride with hydroxypropyl methacrylate in pyridine (cf Chem. Abs. 68, 105913 g) b.p. 92°-4° C./0.2 mm.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH2:7][CH2:8][CH2:9][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:11][C:5]2=[C:4]([C:19](O)=[O:20])[N:3]=1.[CH3:22][NH:23][C:24](=[O:31])[C@H:25]([CH2:27][CH:28]([CH3:30])[CH3:29])[NH2:26].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[N:6]2[CH2:7][CH2:8][CH2:9][N:10]([C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])[CH2:11][C:5]2=[C:4]([C:19](=[O:20])[NH:26][C@@H:25]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:24]([NH:23][CH3:22])=[O:31])[N:3]=1
Reactant: CNC(=O)[C@@H](N)CC(C)C
Reactant: CC(C)(C)OC(=O)N1CCCn2c(Br)nc(C(=O)O)c2C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNC(=O)[C@H](CC(C)C)NC(=O)c1nc(Br)n2c1CN(C(=O)OC(C)(C)C)CCC2
Reaction time: 8 h
Yield: 51 %

Procedure:
To a solution of 3-bromo-8-(tert-butoxycarbonyl)-6,7,8,9-tetrahydro-5H-imidazo[1,5-a][1,4]diazepine-1-carboxylic acid (33E) (1.08 g, 3.0 mmol), H-Leu-NHMe (20B) (0.62 g, 4.30 mmol) and DIEA (0.52 mL, 3.0 mmol) in DMF (25 mL) was added TBTU (1.46 g, 4.55 mmol) in two batches over 10 min at 0° C. After stirring from 0° C. to room temperature overnight, the reaction was quenched with water and evaporated under vacuum. The residue was extracted between saturated aqueous NaHCO3 and EtOAc. The organic layer was dried over anhydrous Na2SO4 and evaporated to dryness. The crude mixture was purified by column chromatography with 60% to 100% EtOAc/Hex to give an oily product 55A at 51% yield. LCMS (+ESI) m/z 486.1, 489.1 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[O:6][C@H:5]([C:7]([OH:9])=[O:8])[C@H:4]([C:10]([OH:12])=[O:11])[CH2:3]1.[CH2:13](O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CC(C)=O>[CH2:13]([O:8][C:7]([C@@H:5]1[C@H:4]([C:10]([OH:12])=[O:11])[CH2:3][C:2](=[O:1])[O:6]1)=[O:9])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1C[C@@H](C(=O)O)[C@@H](C(=O)O)O1
Reactant: OCc1ccccc1
Solvent: CC(C)=O
Product: O=C1C[C@@H](C(=O)O)[C@@H](C(=O)OCc2ccccc2)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5.2 g of (2S,3R)-5-oxotetrahydrofuran-2,3-dicarboxylic acid was dissolved in 88 ml of acetone, and 6.5 g of 1,1'-dicyclohexylcarbodiimide was added thereto, followed by stirring at room temperature for 2 hours. 3.26 ml of benzyl alcohol was added to the reaction solution, and stirred at the same temperature for 12 hours. Insoluble mattes were filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1→chloroform/methanol=50/1) to obtain 7.93 g of the above-identified compound as yellow solid.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].C(=O)([O-])[O-].[Na+].[Na+].Br[CH:18]1[CH2:23][CH2:22][O:21][C:19]1=[O:20].Cl>O>[C:1]([C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[S:4][CH:18]1[CH2:23][CH2:22][O:21][C:19]1=[O:20])([OH:10])=[O:9]
Reactant: O=C1OCCC1Br
Reactant: O=C(O)c1ccccc1S
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccccc1SC1CCOC1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.1 %

Procedure:
In 250 ml of water are dissolved 25 g of thiosalicylic acid and 60 g of sodium carbonate. Then, under ice-cooling, 38 g of α-bromo-γ-butyrolactone is added dropwise. The mixture is stirred at room temperature for 3 hours. The reaction mixture is made acidic with dilute hydrochloric acid and the resultant precipitate is recovered by filtration, rinsed with water and recrystallized from ethanol. By the above procedure there is obtained 32.5 g of α-[(2-carboxyphenyl)thio]-γ-butyrolactone as colorless prisms melting at 180°-182° C.
Reaction SMILES: [C:1]([C:3]([C:11]1[S:12][CH:13]=[CH:14][C:15]=1[C:16]#[N:17])([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6]I)#[N:2].C(N(CC)CC)C.[C:25]([C:27]1[CH:28]=[C:29]([CH:39]=[CH:40][CH:41]=1)[O:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)#[N:26]>C(#N)C>[C:1]([C:3]([C:11]1[S:12][CH:13]=[CH:14][C:15]=1[C:16]#[N:17])([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6][N:36]1[CH2:35][CH2:34][N:33]([CH2:32][CH2:31][O:30][C:29]2[CH:39]=[CH:40][CH:41]=[C:27]([C:25]#[N:26])[CH:28]=2)[CH2:38][CH2:37]1)#[N:2]
Reactant: CC(C)C(C#N)(CCCI)c1sccc1C#N
Reactant: N#Cc1cccc(OCCN2CCNCC2)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)C(C#N)(CCCN1CCN(CCOc2cccc(C#N)c2)CC1)c1sccc1C#N
Reaction time: 72 h

Procedure:
In 1.5 ml of acetonitrile was dissolved 111 mg (0.31 mmol) of 4-cyano-5-methyl-4-(3-cyano-2-thienyl)hexyl iodide. To the mixture were added 56.2 μl (0.40 mmol) of triethylamine and 109 mg (0.47 mmol) of 1-(3-cyanophenoxyethyl)piperazine, followed by stirring for 3 days. The organic layer separated by adding ethyl acetate and brine to the reaction solution was dried over magnesium sulfate, and then evaporated, to give a crude product. The crude product was subjected to 12.5 g of Cromatorex NH silica gel (ethyl acetate/hexane-1/2), to give 144 mg (quantitative) of the title compound as a yellow syrup.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10](=[O:19])[O:9][N:8]=2)=[N:4][O:5][N:6]=1.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:12]([N:11]1[C:10](=[O:19])[O:9][N:8]=[C:7]1[C:3]1[C:2]([NH:1][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:6][O:5][N:4]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nonc1-c1noc(=O)n1Cc1ccccc1
Reactant: BrCc1ccccc1
Product: O=c1onc(-c2nonc2NCc2ccccc2)n1Cc1ccccc1
Reaction time: 16 h
Yield: 14.9 %

Procedure:
A solution of 3-(4-amino-1,2,5-oxadiazol-3-yl)-4-benzyl-1,2,4-oxadiazol-5(4H)-one (60.0 mg, 0.231 mmol) and benzyl bromide (28 μL, 0.23 mmol) was heated at 150° C. for 5 h. Additional benzyl bromide (28 μL) was added to the incomplete reaction and heating was continued for another 16 h. Purification of the crude reaction mixture by preparative HPLC gave the desired product (12 mg, 15%). LCMS for C18H16N5O3 (M+H)+: m/z=349.9.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[C:15]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH:14]=[C:13]([CH3:33])[N:12]=1>O1CCCC1>[CH3:33][C:13]1[N:12]=[C:11]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:16]([N+:17]([O-:19])=[O:18])=[C:15]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH:14]=1
Reactant: Oc1ccccc1
Reactant: Cc1cc(NCCCCNC(=O)OC(C)(C)C)c([N+](=O)[O-])c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(NCCCCNC(=O)OC(C)(C)C)c([N+](=O)[O-])c(Oc2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 64.5 %

Procedure:
Phenol (9.45 g, 100 mmol) was added over a period of 10 minutes to a chilled (0° C.) suspension of sodium hydride (4.24 g of 60%, 106 mmol) in anhydrous tetrahydrofuran (100 mL). The reaction mixture was allowed to stir at 0° C. for 30 minutes. A solution of tert-butyl 4-[(2-chloro-6-methyl-3-nitropyridin-4-yl)amino]butylcarbamate (33.92 g, 94.5 mmol) in anhydrous tetrahydrofuran (250 mL) was added over a period of 50 minutes while maintaining the reaction mixture at 0° C. The reaction mixture was allowed to warm to ambient temperature and stirred overnight before being concentrated under reduced pressure. The residue was dissolved in ethyl acetate (500 mL), washed with 1N sodium hydroxide (300 mL), dried over magnesium sulfate and then concentrated to dryness. The crude product was purified by column chromatography (400 g silica gel eluting with 7:3 hexanes:ethyl acetate to provide 25.4 g of tert-butyl 4-[(6-methyl-3-nitro-2-phenoxypyridin-4-yl)amino]butylcarbamate.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:15]=2)=[O:12])[N:7]([C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[CH2:33][NH:32][CH:31]([C:37](OC)=[O:38])[CH2:30]3)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:41][CH2:42][CH:43]([OH:46])[CH2:44][OH:45]>Cl.CO>[OH:46][CH:43]([CH2:44][OH:45])[CH2:42][NH:41][C:37]([CH:31]1[CH2:30][C:29]2[C:34](=[CH:35][CH:36]=[C:27]([N:7]3[C:8]([NH:10][C:11]([NH:13][C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)[CH:15]=4)=[O:12])=[CH:9][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[N:6]3)[CH:28]=2)[CH2:33][NH:32]1)=[O:38]
Reactant: COC(=O)C1Cc2cc(-n3nc(C(C)(C)C)cc3NC(=O)Nc3cccc(Oc4cccnc4)c3)ccc2CN1
Reactant: NCC(O)CO
Agent: Cl
Solvent: CO
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Oc3cccnc3)c2)n(-c2ccc3c(c2)CC(C(=O)NCC(O)CO)NC3)n1
Reaction time: 8 h
Yield: 102.6 %

Procedure:
Using the same method as for Example 184, a solution of methyl 6-(3-t-butyl-5-(3-(3-(pyridin-3-yloxy)phenyl)ureido)-1H-pyrazol-1-yl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate (0.017 g, 0.026 mmol, available in Example 179) in 3N HCl in MeOH (2 mL) was stirred at RT overnight. The solvent was evaporated and the residue was dissolved in MeOH (0.5 mL). 3-Amino-1,2-dihydroxypropane (0.200 g, 2.20 mmol) was added and the solution was kept at RT overnight. The mixture was directly loaded on to a reverse phase column and purified to yield 1-(1-(3-((2,3-dihydroxypropyl)carbamoyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)-3-t-butyl-1H-pyrazol-5-yl)-3-(3-(pyridin-3-yloxy)phenyl)urea (16 mg, 97% yield) as a yellow solid. 1H-NMR (MeOH-d4): δ 8.66 (s, 1H), 8.60 (d, 1H, J=−5.6 Hz), 8.23-8.20 (m, 1H), 8.05 (dd, 1H, J=8.8, 5.6 Hz), 7.57 (t, 1H, J=2.0 Hz), 7.52-7.40 (m, 4H), 7.23 (d, 1H, J=8.4 Hz), 6.89 (dd, 1H, J=7.6, 1.6 Hz), 6.54 (s, 1H), 4.56 (d, 1H, J=16.8 Hz), 4.51 (d, 1H, J=16.8 Hz), 4.29 (dd, 1H, J=12.0, 4.4 Hz), 3.78-3.72 (m, 1H), 3.54-3.45 (m, 5H), 1.36 (s, 9H), one proton is buried under the MeOH peak, urea, amide, amine and hydroxy protons not visible. MS expected 600.3 found 600.2
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][CH3:12])=[O:10].[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH:26]=[C:25]([S:30]([O-:32])=[O:31])[CH:24]=[CH:23]3)=[CH:16][CH:15]=1.[Na+]>>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH:26]=[C:25]([S:30]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH:8][C:9]([NH:11][CH3:12])=[O:10])(=[O:32])=[O:31])[CH:24]=[CH:23]3)=[CH:16][CH:15]=1
Reactant: O=S([O-])c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Reactant: CNC(=O)Nc1ccccc1I
Agent: [Na+]
Product: CNC(=O)Nc1ccccc1S(=O)(=O)c1ccc2cc(-c3ccc(F)cc3)ccc2c1

Procedure:
Prepared according to the method of Example 6 Step 4 using N-(2-iodophenyl)-N′-methylurea and sodium 6-(4-fluorophenyl)naphthalene-2-sulfinate, to give the title compound as a white solid (81 mg). 1H NMR (500 MHz, d6-DMSO): δ 8.81 (1H, s), 8.34 (2H, s), 8.18 (2H, dd, J=8.6, 21.9 Hz), 8.08-8.02 (2H, m), 7.97 (1H, d, J=8.3 Hz), 7.90 (2H, dd, J=5.5, 8.7 Hz), 7.84 (1H, dd, J=1.7, 8.6 Hz), 7.61-7.57 (1H, m), 7.52 (1H, s), 7.37 (2H, t, J=8.8 Hz), 7.25 (1H, t, J=7.6 Hz), 2.56 (3H, d, J=4.4 Hz); m/z (ES+) 411 [MH+].
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:15][O:16][P:17]([O:20]C)[O:18][CH3:19]>C1(C)C=CC=CC=1>[CH3:15][O:16][P:17]([CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:20])[O:18][CH3:19]
Reactant: BrCc1ccccc1-c1ccccc1
Reactant: COP(OC)OC
Solvent: Cc1ccccc1
Product: COP(=O)(Cc1ccccc1-c1ccccc1)OC
Yield: 96.9 %

Procedure:
A solution of 2-(bromomethyl)biphenyl (4.94 g, 0.020 M) and trimethylphosphite (5.0 mL, 5.26 g, 0.042 M) in toluene (25 mL) is heated at reflux temperature for 24 hours Toluene and excess trimethylphosphite are removed under reduced pressure and the oily residue is chromatographed over silica gel (195 g, 40-63 pm, EtOAc, 50 mL fractions) using EtOAc to elute the column. The title compound (5.35 g, 0.0194 M, 97%) is obtained in fractions 10-19 and is a colorless viscous oil.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH3:15].C[O:17][C:18](=[O:43])[CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]OS(C)(=O)=O)=[C:23]([CH2:38][CH2:39][C:40]([OH:42])=[O:41])[CH:22]=1>>[O:10]=[C:6]1[C:5]2[CH:11]=[CH:12][C:2]([O:1][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][O:27][C:24]3[CH:25]=[CH:26][C:21]([CH2:20][CH2:19][C:18]([OH:43])=[O:17])=[CH:22][C:23]=3[CH2:38][CH2:39][C:40]([OH:42])=[O:41])=[C:3]([CH2:13][CH2:14][CH3:15])[C:4]=2[O:9][CH2:8][CH2:7]1
Reactant: COC(=O)CCc1ccc(OCCCCCOS(C)(=O)=O)c(CCC(=O)O)c1
Reactant: CCCc1c(O)ccc2c1OCCC2=O
Product: CCCc1c(OCCCCCOc2ccc(CCC(=O)O)cc2CCC(=O)O)ccc2c1OCCC2=O

Procedure:
Using the procedure of example 126, 2,3-dihydro-7-hydroxy-8-propyl-4H-1-benzopyran-4-one was converted into the title compound by alkylation with 4-[5-(methylsulfonyl)oxypentyloxy]-1,3-benzenedipropanoic acid methyl ester from the preceding exapmle, followed by saponification, in 8% overall yield. The product was a colorless solid, mp 108°-109° C., recrystallized from hexane-ethyl acetate.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].[CH3:16][C:17]1[CH:22]=[C:21](Cl)[CH:20]=[CH:19][N:18]=1>C(O)(=O)C>[CH3:16][C:17]1[CH:22]=[C:21]([NH:1][C:2]2[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=2[C:4]([N:6]2[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]2)=[O:5])[CH:20]=[CH:19][N:18]=1
Reactant: Cc1cc(Cl)ccn1
Reactant: Nc1ccccc1C(=O)N1CCCCC1
Solvent: CC(=O)O
Product: Cc1cc(Nc2ccccc2C(=O)N2CCCCC2)ccn1
Reaction time: 8 h
Yield: 9.8 %

Procedure:
A mixture of 18.2 g of 1-(2-aminobenzoyl)piperidine and 12.2 g of 2-methyl-4-chloropyridine in 5.0 ml of acetic acid was heated at reflux for six hours and then kept at room temperature overnight. The reaction mixture was concentrated in vacuo, and the residue treated with dilute acid to pH 2 and extracted with methylene dichloride. The aqueous layer was made basic with potassium carbonate and extracted with chloroform. Further work-up of this solution afforded 2.58 g of 1-[2-(2-methyl-4-pyridinylamino)benzoyl]piperidine, m.p. 93°-95° C. when recrystallized from ethyl acetate--ether--hexane.
Reaction SMILES: Br[CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH:15]1[CH2:23][CH2:22][CH2:21][CH:17]([C:18]([NH2:20])=[O:19])[CH2:16]1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.CC#N>[C:3]1([CH:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:15]2[CH2:23][CH2:22][CH2:21][CH:17]([C:18]([NH2:20])=[O:19])[CH2:16]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NC(=O)C1CCCNC1
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC#N
Product: NC(=O)C1CCCN(C(c2ccccc2)c2ccccc2)C1

Procedure:
Step 1): A solution of bromodiphenylmethane (48.2 g, 195 mmol) in DMSO (30 ml) was added dropwise to a solution of nipecotamide (25 g, 195 mmol) and K2CO3 (27 g, 195 mmol) in CH3CN (100 ml) and DMSO (50 ml) under stirring and cooling in an ice-bath for 1 hour. After the addition was complete, the mixture was stirred overnight at room temperature. The insoluble precipitates were filtered off and then the filtrate was evaporated. To the residue was added H2O and AcOEt, and agitated. The organic layer was washed with H2O, dried over MgSO4 and evaporated to give 1-diphenylmethylpiperidin-3-carboxamide, 33 g (57.5%): mp 86°-87° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[Cl:7][C:8]1[CH:18]=[C:17](F)[CH:16]=[CH:15][C:9]=1[C:10](OCC)=[O:11]>>[Cl:7][C:8]1[CH:18]=[C:17]([N:3]2[CH:4]=[CH:5][N:6]=[C:2]2[CH3:1])[CH:16]=[CH:15][C:9]=1[CH2:10][OH:11]
Reactant: CCOC(=O)c1ccc(F)cc1Cl
Reactant: Cc1ncc[nH]1
Product: Cc1nccn1-c1ccc(CO)c(Cl)c1

Procedure:
Prepared from 2-methylimidazole and ethyl 2-chloro-4-fluorobenzoate.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[N:8]1.Br[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:28][C:25]1[CH:26]=[C:27]([C:11]2[N:7]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[N:8]=[CH:9][CH:10]=2)[CH:22]=[CH:23][C:24]=1[Cl:29]
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Reactant: Clc1ccc(Br)cc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(-c2ccnn2C2CCCCO2)cc1Cl
Temperature: 50 °C
Reaction time: 3 h

Procedure:
1-(Tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester (6.16 g, 22.13 mmol) and 4-Bromo-1,2-dichloro-benzene (2.84 ml, 22.13 mmol) were dissolved in DMF (20 ml) under nitrogen atmosphere. Bis(triphenylphosphine)-palladium(II) chloride (0.777 g, 1.107 mmol) was added along with sodium carbonate (22.13 ml, 44.3 mmol) and the resulting mixture was stirred at 50° C. for 3 h. DMF was evaporated, water was added (15 ml) and extracted with ethyl acetate. Combined organic phases were dried with Na2SO4, filtered and dried with vacuum at 40° C. The product was purified by recrystallization from diethyl ether and diethyl ether/heptane, respectively. 1H-NMR (400 MHz; DMSO-d6): δ 1.50-1.69 (m, 3H), 1.77-1.84 (m, 1H), 1.91-2.00 (m, 1H), 2.31-2.44 (m, 1H), 3.54-3.62 (m, 1H), 3.96-4.02 (m, 1H), 5.23 (dd, 1H), 6.89 (d, 1H), 7.53 (dd, 1H), 7.60 (d, 1H), 7.77-7.82 (m, 2H).
Reaction SMILES: Br.[C:2]([CH:4]([NH:14][CH2:15][C:16]([NH2:18])=[NH:17])[C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[C:6]=1[Cl:13])#[N:3].O.[OH-].[Li+]>CO>[NH2:3][C:2]1[C:4]([C:5]2[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]([Cl:12])[C:6]=2[Cl:13])=[N:14][CH:15]=[C:16]([NH2:18])[N:17]=1
Reactant: N#CC(NCC(=N)N)c1cc(Cl)cc(Cl)c1Cl
Agent: Br
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1cnc(-c2cc(Cl)cc(Cl)c2Cl)c(N)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2{[Cyano-(2,3,5-trichlorophenyl)-methyl]-amino}-acetamidine hydrobromide (95.36 g, 0.256 mole) was added in portions to a solution of lithium hydroxide monohydrate (16.11 g, 0.384 mole) in methanol (1.9 litres) at room temperature. The resulting solution was stirred at room temperature for 3 hours before being evaporated to dryness in vacuo. The resulting solid was slurried in water (1.15 litres) and collected by filtration. After drying at 50° C. in vacuo the crude material was purified by recrystallisation from toluene to give the desired product. Yield 69.51 g (93.8%), M.p. 178-180° C.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[CH:12]1([NH2:16])[CH2:15][CH2:14][CH2:13]1.C(N(CC)CC)C>ClCCl>[CH:12]1([NH:16][C:2](=[O:3])[O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:15][CH2:14][CH2:13]1
Reactant: NC1CCC1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NC1CCC1)OCc1ccccc1
Temperature: 25 °C

Procedure:
Benzyl chloroformate (5.2 mL, 36.4 mmol) was added dropwise to an ice-cold solution of cyclobutylamine (2 g, 28.1 mmol) in dichloromethane (20 mL), with stirring. Triethylamine (4.7 mL, 33.7 mmol) was added dropwise to the ice-cold solution, and once the addition was complete the reaction was allowed to warm to room temperature and stirred for 18 hours. The reaction was washed with saturated sodium bicarbonate solution (×2), dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using dichloromethane as eluant to afford the title compound, 3.72 g. 1H NMR (CDCl3, 300 MHz) δ: 1.68 (m, 2H), 1.82 (m, 2H), 2.35 (m, 2H), 4.19 (m, 1H), 4.92 (m, 1H), 5.14 (s, 2H), 7.25-7.39 (m, 5H). MS TSP+ m/z 223.2 [MH]+