Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[C:2]1([CH2:8][CH2:9][CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][O:31][C:32](=[O:41])[C:33]1[CH:38]=[CH:37][C:36]([CH:39]=O)=[CH:35][CH:34]=1>C1COCC1.O>[C:2]1([CH2:8][CH2:9][CH:10]=[CH:39][C:36]2[CH:37]=[CH:38][C:33]([C:32]([O:31][CH3:30])=[O:41])=[CH:34][CH:35]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(C=CCCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 0° solution of phenylpropyl triphenylphosphonium bromide (3.55 g, 1.25 eq) in 30 ml of dry THF under argon was added K-t-amylate (3.9 ml, 1.1 eq). After stirring for 30 minutes at 0° C. then allowing to warm to room temperature, a solution of 4-formylbenzoic acid methyl ester (1.0 g, 6.1 mmol) in ~8 ml of dry THF was added dropwise. This solution was stirred for 3 hours at room temperature, then diluted with ~1 ml of H2O, and concentrated to remove most of the THF. EtOAc (~200 ml) was added and the mixture was washed with H2O, 1N HCl (2×) and brine. After drying over anhydrous MgSO4, the solvent was removed in vacuo to yield a yellow oil which solidified soon after. Column purification of this crude product was done on a 50 mm column on silica gel eluted with 95:5 hexane/EtOAc. Product containing fractions were combined to yield after concentration title compound, 1.5 g (93%) as a clear oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20](S(C)(=O)=O)[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[C:28](Cl)(=[O:30])[CH3:29]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20]([C:28](=[O:30])[CH3:29])[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(=O)Cl
Reactant: CS(=O)(=O)N1CC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Product: CC(=O)N1CC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Yield: 18 %

Procedure:
According to the procedure for compound 398 using acetyl chloride (45 uL, 0.64 mmol) afforded 4.2 mg (18% yield) of 480, as a solid.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[NH2:11][C:12]1[CH:13]=[C:14]([C:18]#[CH:19])[CH:15]=[CH:16][CH:17]=1>N1C=CC=CC=1>[C:18]([C:14]1[CH:13]=[C:12]([NH:11][C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH:17]=[CH:16][CH:15]=1)#[CH:19]
Reactant: C#Cc1cccc(N)c1
Reactant: Clc1ncnc2nc[nH]c12
Solvent: c1ccncc1
Product: C#Cc1cccc(Nc2ncnc3[nH]cnc23)c1
Temperature: 85 °C
Yield: 3.3 %

Procedure:
To 6-chloropurine (1.0 g, 6.5 mmol) in dry pyridine (10 ml) was added m-aminophenyl acetylene (0.91 g, 7.8 mmol). The mixture was heated in an 85° C. oil bath for 23 hours. The mixture was cooled to ambient temperature and concentrated in vacuo. The oily residue was partitioned between CH2Cl2 and H2O then filtered to afford the title compound as a light orange solid (50 mg, 3.3%). LC-MS: 236 (MH+); anal. RP18-HPLC RT: 3.25 min.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:15][Mg]Br.[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[C:11]([CH:12]([OH:13])[CH3:15])=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: C[Mg]Br
Reactant: Cc1cccc2cc(C=O)c(Cl)nc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cccc2cc(C(C)O)c(Cl)nc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
To a suspension of 2-chloro-8-methylquinoline-3-carboxaldehyde (10 g, 48.6 mmol) in dry THF (100 mL) under nitrogen cooled to −78° C. was added dropwise over 1 h methylmagnesium bromide (40 mL, 121.6 mmol, 3.0M solution in Et2O). The reaction was allowed to warm to r.t. and stirred for a further 1 h before being poured slowly into NH4Cl solution (100 mL). The mixture was extracted with EtOAc (2×200 mL) and the organic layers were combined, dried (MgSO4), filtered and concentrated in vacuo to afford the title compound as an off-white solid (8.0 g, 74%). δH (CDCl3) 8.33 (s, 1H), 7.68 (d, J 8.0 Hz, 1H), 7.55 (d, J 7.2 Hz, 1H), 7.44 (t, J 7.6 Hz, 1H), 5.34-5.40 (m, 1H), 2.77 (s, 3H), 1.61 (d, J 6.4 Hz, 3H). LCMS (ES+) 222, 224 (M+H)+, RT 3.01 minutes (Method 5).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][NH2:14]>>[CH3:13][NH:14][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: CN
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Product: CNc1ccc(C=O)cc1[N+](=O)[O-]

Procedure:
4-Chloro-3-nitro-benzaldehyde is reacted with methylamine to yield 4-(methylamino)-3-nitrobenzaldehyde (8) which is then reduced by NaBH4 to N-methyl-4-hydroxymethyl-2-nitroaniline (9). Reaction of SOCl2 with 8 will give N-methyl-4-chloromethyl-2-nitroaniline (10). Structures of 8, 9 and 10 may be characterized by 1H NMR and elemental analysis. 10 is used as an electrophile to react with sodium CD alkoxide (11) to yield 2-O-(4-methylamino-3-nitro) benzyl-β-CD (12). The addition of 10 to 11 is a novel method for mono-functionalizing the 2-position of CD's (Rong, P., and D'Souza, V. T., Tetrahedron Lett., 31:4275 (1990)). 12 is hydrogenated by agents such as H2 /Pd, H2 /Pt, H2 /Ni, Sn/HCl, Fe/HCl and Zn/HCl, and then condensed with alloxan monohydrate to yield 2-flavo-CD (13). Compounds 11 and 12 can be characterized by 1H and 13C NRM. 2-Flavo-α-CD, β-CD and γ-CD may be synthesized by the same method. ##STR12##
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:7]([O:8][CH3:9])=[C:5]([OH:6])[CH:4]=1.C[C:13]1[CH:18]=[CH:17][C:16](S(OCCC#CCC)(=O)=O)=[CH:15][CH:14]=1>>[CH2:17]([O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:7]=1[O:8][CH3:9])[CH:2]=[O:1])[CH2:18][C:13]#[C:14][CH2:15][CH3:16]
Reactant: CCC#CCCOS(=O)(=O)c1ccc(C)cc1
Reactant: COc1ccc(C=O)cc1O
Product: CCC#CCCOc1cc(C=O)ccc1OC
Yield: 49.9 %

Procedure:
Isovanillin (0.76 g, 5.0 mmol) was alkylated with hex-3-ynyl 4-methylbenzenesulfonate (1.9 g, 7.53 mmol) according to Procedure 4. The crude product was recrystallised from EtOAc/petrol to provide 3-(hex-3-ynyloxy)-4-methoxybenzaldehyde (0.58 g, 50%) as a colourless crystalline solid; mp 86.5-87.5° C.; δH (400 MHz, CDCl3) 1.13 (t, J=7.6 Hz, 3H, CH3), 2.17 (tq, J=7.6, 2.4 Hz, 2H, CH3CH2), 2.72 (tt, J=7.6, 2.4 Hz, 2H, OCH2CH2C), 3.95 (s, 3H, OCH3), 4.17 (t, J=7.6 Hz, 2H, OCH2), 6.98 (d, J5,6=8.0 Hz, 1H, H5), 7.44 (d, J2,6=1.6 Hz, 1H, H2), 7.47 (dd, J5,6=8.0, J2,6=1.6 Hz, 1H, H6), 9.85 (s, 1H, CHO); δC (100 MHz, CDCl3) 12.4, 14.1, 19.6, 56.2, 67.6, 74.5, 83.9, 110.8, 111.0, 126.9, 130.1, 148.6, 154.8, 190.8; vmax 1019, 1134, 1265, 1586, 1683, 2841, 2977 cm−1.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C@H:8]([NH:10][C:11]2[N:16]=[C:15]([C:17]3[C:25]4[C:20](=[N:21][CH:22]=[C:23]([C:26]([F:29])([F:28])[F:27])[CH:24]=4)[N:19]([S:30]([C:33]4[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=4)(=[O:32])=[O:31])[CH:18]=3)[C:14]([C:40]#[N:41])=[CH:13][N:12]=2)[CH3:9])[CH2:4][CH2:3]1.C([O-])(=O)C.[NH4+:46].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.ClCCl>[NH2:46][CH:2]1[CH2:7][CH2:6][CH:5]([C@H:8]([NH:10][C:11]2[N:16]=[C:15]([C:17]3[C:25]4[C:20](=[N:21][CH:22]=[C:23]([C:26]([F:29])([F:28])[F:27])[CH:24]=4)[N:19]([S:30]([C:33]4[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=4)(=[O:32])=[O:31])[CH:18]=3)[C:14]([C:40]#[N:41])=[CH:13][N:12]=2)[CH3:9])[CH2:4][CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(N[C@H](C)C4CCC(=O)CC4)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Reactant: [NH4+]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nc(N[C@H](C)C4CCC(N)CC4)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.3 %

Procedure:
2-((R)-1-(4-oxocyclohexyl)ethylamino)-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile (105 mg, 0.1802 mmol) was disolved in methanol (5 mL) and dichloromethane (5 mL). Ammonium acetate (138.9 mg, 118.7 μL, 1.802 mmol), followed by sodium triacetoxyborohydride (38.19 mg, 0.1802 mmol) were added and the reaction mixture was stirred for 4 hours at room temperature. The mixture was partitioned between dichloromethane and a saturated solution of sodium bicarbonate. The aqueous phase was extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered and concentrated to dryness to afford the desired product as a yellow solid (95 mg, 90% yield).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[C:7]([O:10][NH:11][S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Br:21])(=[O:14])=[O:13])(=[O:9])[CH3:8]>>[C:7]([O:10][N:11]([S:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Br:21])(=[O:14])=[O:13])[C:2](=[O:3])[O:4][CH2:5][CH3:6])(=[O:9])[CH3:8]
Reactant: CCOC(=O)Cl
Reactant: CC(=O)ONS(=O)(=O)c1ccccc1Br
Product: CCOC(=O)N(OC(C)=O)S(=O)(=O)c1ccccc1Br

Procedure:
Ethyl (acetyloxy)[(2-bromophenyl)sulfonyl]carbamate (49) is prepared from ethyl chloroformate and N-(acetyloxy)-2-bromobenzenesulfonamide according to Scheme 3. δH (250 MHz, CHLOROFORM-d) δ 8.23-8.37 (1H, m), 7.74-7.85 (1H, m), 7.45-7.60 (2H, m), 4.21 (2H, q, 7.2 Hz), 2.34 (3H, s), 1.19 (3H, t, 7.2 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12](/[CH:13]=[CH:14]/[C:15]3[S:16][C:17]([C:21]([OH:23])=O)=[C:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1.[NH2:25][C:26]([CH3:30])([CH3:29])[CH2:27][OH:28]>CO.O>[OH:28][CH2:27][C:26]([NH:25][C:21]([C:17]1[S:16][C:15](/[CH:14]=[CH:13]/[C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)=[N:9][O:10][C:11]=2[CH3:24])=[N:19][C:18]=1[CH3:20])=[O:23])([CH3:30])[CH3:29]
Reactant: Cc1nc(/C=C/c2c(-c3ccc(F)cn3)noc2C)sc1C(=O)O
Reactant: CC(C)(N)CO
Solvent: CO
Solvent: O
Product: Cc1nc(/C=C/c2c(-c3ccc(F)cn3)noc2C)sc1C(=O)NC(C)(C)CO
Yield: 30 %

Procedure:
As described for example 71d, 2-{(E)-2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-vinyl}-4-methyl-thiazole-5-carboxylic acid (69 mg, 0.2 mmol) was converted, using 2-amino-2-methyl-1-propanol instead of isopropylamine, to the title compound (25 mg, 30%) which was obtained as a white solid after trituration from methanol/water. MS: m/e=417.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]3[CH2:14][CH2:15][CH2:16][CH2:17][C:10]=3[C:9]2=[O:18])=[CH:4][C:3]=1[OH:19].Br[CH:21]([CH2:27][CH2:28][CH3:29])[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9](=[O:18])[C:10]3[CH2:17][CH2:16][CH2:15][CH2:14][C:11]=3[C:12]2=[O:13])=[CH:4][C:3]=1[O:19][CH:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:27][CH2:28][CH3:29]
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1ccc(Br)c(O)c1
Reactant: CCCC(Br)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCC(Oc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Br)C(=O)OCC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 15.0 g. of N-(4-bromo-3-hydroxyphenyl)-3,4,5,6-tetrahydrophthalimide, 12.0 g. of ethyl α-bromovalerate, 7.7 g. of potassium carbonate, 2.5 g. of potassium iodide and 50 ml. of acetone was refluxed with stirring for 3 hours and then, the reaction mixture was cooled to room temperature and the salt was separated by a filtration. The filtrate was concentrated under a reduced pressure and 2N-HCl was added to the residue to crystallize the product. The crystal was separated by a filtration and washed with water and dried. The residue was purified by a chromatography on a column of silica gel (developing solvent: ethyl acetate: n-hexane of 1:3) to obtain 17.6 g. of Compound No. 90 shown in table 1.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([C:10]3[C:19]4[C:14](=[CH:15][C:16]5[O:22][CH2:21][O:20][C:17]=5[CH:18]=4)[NH:13][C:12](=O)[N:11]=3)=[CH:4][C:3]=2[O:2]1.P(Cl)(Cl)([Cl:26])=O.[OH-].[Na+]>CN(C=O)C>[Cl:26][C:12]1[N:11]=[C:10]([C:5]2[CH:6]=[CH:7][C:8]3[O:9][CH2:1][O:2][C:3]=3[CH:4]=2)[C:19]2[C:14](=[CH:15][C:16]3[O:22][CH2:21][O:20][C:17]=3[CH:18]=2)[N:13]=1
Reactant: O=c1nc(-c2ccc3c(c2)OCO3)c2cc3c(cc2[nH]1)OCO3
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Clc1nc(-c2ccc3c(c2)OCO3)c2cc3c(cc2n1)OCO3
Temperature: 25 °C
Yield: 111.1 %

Procedure:
4-(3,4-Methylenedioxyphenyl)-6,7-methylenedioxyquinazolin-2(1H)-one (1 g, 3.23 mmol) was treated with DMF (one drop) and phosphorous oxychloride (7 mL, 75 mmol) and the suspension was heated to reflux for 4 h. Upon cooling to rt, the reaction mixture was poured into ice and the pH was adjusted to ˜8 with 3N NaOH solution. The precipitate was vacuum filtered and dried to give the title compound as a brown granular solid (1.18 g). 1H NMR (DMSO-d6) 6.16 (s, 2H), 6.32 (s, 2H), 6.85-7.41 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][C:15](O)=[O:16])[CH:12]=2)[C:7]([CH3:18])=[N:6]1.[C:24]([O:28][C:29](=[O:32])[NH:30][NH2:31])([CH3:27])([CH3:26])[CH3:25].O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH2:14][C:15]([NH:31][NH:30][C:29]([O:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:32])=[O:16])[CH:12]=2)[C:7]([CH3:18])=[N:6]1
Reactant: CC(C)(C)OC(=O)NN
Reactant: Cc1nn(Cc2c(Cl)cccc2Cl)c2cc(CC(=O)O)ccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1nn(Cc2c(Cl)cccc2Cl)c2cc(CC(=O)NNC(=O)OC(C)(C)C)ccc12
Reaction time: 18 h
Yield: 86.5 %

Procedure:
To a solution of the compound [97] (73.2 mg) in chloroform (1.1 mL) were added tert-butylcarbazate (222.0 mg), 1-hydroxybenzotriazole monohydrate (113.5 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (161.0 mg) at room temperature, and then the reaction mixture was stirred for 18 hours. The reaction mixture was quenched with water, and extracted with ethyl acetate. The obtained organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the titled compound (84.0 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.Cl[CH2:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH3:39])=[CH:33][CH:32]=2)[CH:26]=1>>[C:19]([O:18][C:16]([N:13]1[CH2:14][CH2:15][CH:10]([N:9]([CH2:24][C:25]2[CH:30]=[CH:29][N:28]=[C:27]([C:31]3[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH3:39])=[CH:33][CH:32]=3)[CH:26]=2)[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[CH2:11][CH2:12]1)=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CCOc1ccc(-c2cc(CCl)ccn2)cc1
Reactant: COc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Product: CCOc1ccc(-c2cc(CN(c3ccc(OC)cc3)C3CCN(C(=O)OC(C)(C)C)CC3)ccn2)cc1

Procedure:
4-(p-Anisidino)-1-(tert-butoxycarbonyl)piperidine (306 mg) and 4-chloromethyl-2-(4-ethoxyphenyl)pyridine (248 mg) were condensed in the same manner as described in Example 9 to give the title compound.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:13]=[C:12]([Br:14])[CH:11]=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6].[S-:15][C:16]#[N:17].[NH4+].BrBr>C(O)(=O)C>[NH2:2][C:3]1[CH:13]=[C:12]([Br:14])[C:11]([S:15][C:16]#[N:17])=[CH:10][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)c1ccc(Br)cc1N
Reactant: N#C[S-]
Agent: BrBr
Agent: Cl
Agent: [NH4+]
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(SC#N)c(Br)cc1N
Temperature: 25 °C

Procedure:
In a 100 ml three-neck round bottom flask equipped with an internal thermometer and magnetic stirrer, a solution of 3.26 g (0.0116 mol) of ethyl 2-amino-4-bromobenzoate hydrochloride, 2.12 g (0.0279 mol) of ammonium thiocyanate and 30 ml of acetic acid was cooled to 15° C. Bromine (1.86 g, 0.0116 mol) was then added dropwise with stirring. A precipitate formed. When the addition was complete, the solution was allowed to warm to room temperature, and to stir for an hour. The product was filtered, dried under nitrogen, and recrystallized from hexane and ethyl acetate to furnish crystalline ethyl 2-amino-4-bromo-5-thiocyanatobenzoate: yield 2.05 g (59%); m.p. 149°-150° C.; ir(KBr) 3487 cm, 3453, 3375, 3346, 2980, 2146, 1697, 1614 among others; 1H--NMR(CDCl3) 1.4 ppm (triplet, 3H, CH2CH3), 4.3 (quartet, 2H, CH2CH3), 6.0 (broad singlet), 6.9 (singlet, 1H, aromatic H), 8.1 (singlet, 1H aromatic H).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][C:5]2=[N:6][O:7][N:8]=[C:4]2[CH:3]=1.[CH2:11](O)[CH3:12]>>[CH:11]([C:2]1[CH:10]=[CH:9][C:5]2=[N:6][O:7][N:8]=[C:4]2[CH:3]=1)=[CH2:12]
Reactant: CCO
Reactant: Brc1ccc2nonc2c1
Product: C=Cc1ccc2nonc2c1

Procedure:
5-Bromo-2,1,3-benzoxadiazole (5.5 g, 27.6 mmol)), potassium vinylfluoroborate (7.40 g, 55.3 mmol), and PdCl2(dppf)-CH2Cl2Adduct (1.088 g, 1.332 mmol) were suspended in ethanol (75 ml) then added TEA (7.70 ml, 55.3 mmol). The reaction mixture was then degassed and heated to reflux for 3 hrs. The reaction was diluted with ethyl acetate and washed with brine. The organic layer was dried over Na2SO4, filtered and evaporated to dryness. The residue was purified through a 330 g ISCO Redi-Sep silica gel plug and eluted with 20% ETOAc/hexane to yield 5-ethenyl-2,1,3-benzoxadiazole.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.CC1C=CC(C[O:18][C:19](=O)[O:20][N:21]2[C:25](=[O:26])[CH2:24][CH2:23][C:22]2=[O:27])=CC=1>>[O:27]=[C:22]1[CH2:23][CH2:24][C:25](=[O:26])[N:21]1[O:20][C:19](=[O:18])[O:11][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:3][CH2:2]2)=[CH:9][CH:8]=1
Reactant: Cc1ccc(COC(=O)ON2C(=O)CCC2=O)cc1
Reactant: OCc1ccc(C2CC2)cc1
Product: O=C(OCc1ccc(C2CC2)cc1)ON1C(=O)CCC1=O

Procedure:
The title compound was prepared from (4-cyclopropyl-phenyl)-methanol as described for similar compounds previously (Chem. Pharm. Bull., 38(1):110–115(1990) and INTERMEDIATE 1A).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][O:6][C:7]1[S:11][C:10]([NH2:12])=[N:9][N:8]=1>C(OCC)(=O)C>[CH3:5][O:6][C:7]1[S:11][C:10]([N:12]=[C:1]=[O:2])=[N:9][N:8]=1
Reactant: COc1nnc(N)s1
Reactant: O=C(Cl)Cl
Solvent: CCOC(C)=O
Product: COc1nnc(N=C=O)s1
Reaction time: 16 h

Procedure:
A saturated solution of phosgene in ethyl acetate (100 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer. A slurry of 5-methoxy-2-amino-1,3,4-thiadiazole (40 grams) in ethyl acetate (300 ml) is added to the reaction vessel, and the resulting mixture is stirred for a period of about 16 hours, resulting in the formation of a precipitate. The reaction mixture is then purged with nitrogen as to remove unreacted phosgene. The purged mixture is then filtered to recover the precipitate. The precipitate is then recrystallized to yield the desired product 5-methoxy-1,3,4-thiadiazol-2-yl isocyanate dimer.
Reaction SMILES: [Br:1]Br.[C:3]1([CH2:9][CH2:10][CH:11]=[O:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(=O)(O)[O-].[Na+]>ClCCl>[Br:1][CH:10]([CH2:9][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH:11]=[O:12]
Reactant: O=CCCc1ccccc1
Reactant: BrBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=CC(Br)Cc1ccccc1
Reaction time: 2 h
Yield: 70.1 %

Procedure:
A solution of bromine (15.2 g, 95.1 mmol) in 30 mL of dichloromethane was added to a solution of 3-phenyl-propionaldehyde (13.4 g, 100 mmol) in dichloromethane (150 mL) at 0° C. over 20 minutes. The reaction mixture was allowed to stir for 2 hours and then a saturated aqueous solution of sodium bicarbonate (100 mL) was added to the mixture. The organic layer was separated and the aqueous layer was washed with dichloromethane (50 mL). The combined organic layers were washed with water, a saturated aqueous solution of sodium chloride, and then evaporated to dryness to give an orange oil (14.2 g), which was used directly in the next step.
Reaction SMILES: [NH2:1][C@H:2]([C:11]([NH:13][C@H:14]([C:19]([OH:21])=[O:20])[C@H:15]([CH2:17][CH3:18])[CH3:16])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.CN1CCOCC1.ClC1C=C(Cl)C(Cl)=CC=1[O:38][C:39](=O)[C@H:40]([CH:52]([CH3:54])[CH3:53])[NH:41][C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43].Cl>CS(C)=O>[NH:41]([C:42]([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43])[C@H:40]([C:39]([NH:1][C@H:2]([C:11]([NH:13][C@H:14]([C:19]([OH:21])=[O:20])[C@H:15]([CH2:17][CH3:18])[CH3:16])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1)=[O:38])[CH:52]([CH3:54])[CH3:53]
Reactant: CC[C@H](C)[C@H](NC(=O)[C@@H](N)Cc1ccc(O)cc1)C(=O)O
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1cc(Cl)c(Cl)cc1Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CS(C)=O
Product: CC[C@H](C)[C@H](NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Tyrosylisoleucine (29.4 parts) is suspended in 300 parts by volume of dimethyl sulfoxide and 10.1 parts of N-methylmorpholine added. Carbobenzoxyvaline-2,4,5-trichlorophenyl ester is added and the mixture stirred 48 hours at room temperature. The clear solution is poured into 6000 parts by volume of 0.1 N hydrochloric acid and the mixture is stirred until the initially oily product solidifies. The crude product, after washing with water and drying, is boiled with 1 l. of ether. The desired tri-peptide, Z-Val-Tyr-Ile, is obtained as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.[S-:11][C:12]#[N:13].[K+]>Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:12](=[S:11])[NH2:13])[CH2:6][CH2:5]2
Reactant: N#C[S-]
Reactant: Brc1ccc2c(c1)CCN2
Agent: Cl
Agent: [K+]
Product: NC(=S)N1CCc2cc(Br)ccc21
Temperature: 25 °C
Yield: 73.1 %

Procedure:
A solution of 5-bromoindoline (14.8 g, 75 mmol) in 200 mL of 1N aqueous hydrochloric acid was treated with potassium thiocyanate (34.0 g, 350 mmol) in portions. The mixture was heated at reflux for 1 h and was then cooled to room temperature. The precipitate was collected, washed with water, and recrystallized from 2-propanol to afford (in two crops) 14.1 g (73%) of 5-bromoindoline-1-thiocarboxamide as a light yellow, fluffy solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@@H:9]1[C:21]([OH:23])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:48][CH:49]([CH3:52])[CH2:50][NH2:51].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:48][CH:49]([CH3:52])[CH2:50][NH:51][C:21]([C@H:9]1[CH2:10][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:12][CH2:13][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[O:23]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)O)C1
Reactant: CC(C)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CNC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 118.4 %

Procedure:
A 20 mL vial was charged with ((2R)-1,4-bis(tert-butoxycarbonyl)-2-piperazinecarboxylic acid (1.52 g, 4.60 mmol, ASW MedChem Inc., New Brunswick, N.J.), HATU (2.10 g, 5.52 mmol, ChemImpex International Inc., Wood Dale, Ill.), 2-methylpropan-1-amine (0.457 mL, 4.60 mmol, Sigma-Aldrich, St. Louis, Mo.), DIPEA (1.60 mL, 9.19 mmol) and DMF (8 mL). The mixture was stirred at room temperature for 2.5 h. and then partitioned between water (80 mL) and EtOAc (50 mL). The aqueous phase was extracted with EtOAc (50 mL). The combined organic extracts were washed with saturated aqueous NaHCO3 (100 mL), water (100 mL) then brine (100 mL). The organics were dried over sodium sulfate, filtered and concentrated in vacuo to afford di-tert-butyl (2R)-2-((2-methylpropyl)carbamoyl)-1,4-piperazinedicarboxylate (2.10 g) as a light brown foam.