Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20](F)=[CH:19][N:18]=1>>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:13]2[CH:14]=[C:10]([C:9]#[C:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:11]=[C:12]2[CH3:15])=[CH:19][N:18]=1
Reactant: Fc1ccc(Cl)nc1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)c[nH]1
Product: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1ccc(Cl)nc1

Procedure:
The title compound, MS: m/e=328.1 (M+), was prepared in accordance with the general method of example 1 from 4-(3-chloro-phenylethynyl)-2-methyl-1H-imidazole and 2-chloro-5-fluoro-pyridine.
Reaction SMILES: C([O:5][C:6](=O)[NH:7][C@H:8]([C:13](=[O:33])[NH:14][CH:15]1[CH2:21][CH:20]([CH3:22])[CH2:19][N:18]([S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)(=[O:25])=[O:24])[CH2:17][CH:16]1[OH:32])[CH2:9][CH:10]([CH3:12])[CH3:11])(C)(C)C.Cl.O1CCOCC1.Cl.[CH3:43][O:44][C:45]1[CH:46]=[CH:47][C:48]2[O:52][C:51](C(O)=O)=[CH:50][C:49]=2[CH:56]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>>[OH:32][CH:16]1[CH:15]([NH:14][C:13]([C@@H:8]([NH:7][C:6]([C:51]2[O:52][C:48]3[CH:47]=[CH:46][C:45]([O:44][CH3:43])=[CH:56][C:49]=3[CH:50]=2)=[O:5])[CH2:9][CH:10]([CH3:11])[CH3:12])=[O:33])[CH2:21][CH:20]([CH3:22])[CH2:19][N:18]([S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)(=[O:25])=[O:24])[CH2:17]1
Reactant: COc1ccc2oc(C(=O)O)cc2c1
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)NC1CC(C)CN(S(=O)(=O)c2ccccn2)CC1O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCO1
Solvent: CN1CCOCC1
Product: COc1ccc2oc(C(=O)N[C@@H](CC(C)C)C(=O)NC3CC(C)CN(S(=O)(=O)c4ccccn4)CC3O)cc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
To {(S)-1-[3-hydroxy-6-methyl-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-3-methyl-butyl}-carbamic acid tert-butyl ester (0.13 g, 0.28 mmol) was added HCl/dioxane (4M, 2.8 ml, 11.2 mmol). The mixture was stirred at RT for 2 h before solvents and excess amount of HCl was removed on rotavapor. The result white solid was dissolved in 5 ml DMF. To the solution was added 5-methoxy-benzofuran-2-carboxylic acid (63.4 mg, 0.33 mmol), HBTU (125 g, 0.33 mmol) and NMM (0.14 g, 1.34 mmol). The mixture was stirred at RT overnight. DMF was then removed and the residue was re-dissolved in EtOAc (50 ml), washed with 10% NaHCO3 (50 ml×2) and brine (50 ml). The combined organics were concentrated by rotary evaporation. Purification by column chromatograghy gave the title compound (110 mg in 69% yield, 2 steps): MS (M+H+):573.4; 1H-NMR (400 Hz, CDCl3): d=8.74–8.66(dd, 1H), 7.96–6.97(m, 9H), 4.72(m, 1H), 4.18–3.21(m, 7H), 2.81(m, 1H), 2.04–1.74(m, 6H), 1.25(m, 2H), 0.99–0.87(m, 9H).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([C:17]([CH3:21])([CH3:20])[CH2:18][NH2:19])(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:34](Cl)(=[O:36])[CH3:35]>ClCCl>[CH:1]1([CH2:4][N:5]2[C:9]3[CH:10]=[CH:11][C:12]([S:14]([C:17]([CH3:20])([CH3:21])[CH2:18][NH:19][C:34](=[O:36])[CH3:35])(=[O:16])=[O:15])=[CH:13][C:8]=3[N:7]=[C:6]2[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:2][CH2:3]1
Reactant: CC(=O)Cl
Reactant: CC(C)(C)Cc1nc2cc(S(=O)(=O)C(C)(C)CN)ccc2n1CC1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCC(C)(C)S(=O)(=O)c1ccc2c(c1)nc(CC(C)(C)C)n2CC1CC1
Reaction time: 0.25 h
Yield: 76.9 %

Procedure:
To a solution of 2-{[1-(cyclopropylmethyl)-2-(2,2-dimethylpropyl)-1H-benzimidazol-5-yl]sulfonyl}-2-methylpropan-1-amine (Step K, 132 mg, 0.350 mmol) and triethylamine (98 μL, 0.700 mmol) in dichloromethane (4 mL) was added acetyl chloride (0.03 mL, 0.420 mmol) at room temperature. After stirring for 15 min, the mixture was concentrated under reduced pressure. The residue was purified by HPLC (ODS, gradient elution with Acetonitrile/0.01% aq. NH3=4:96 to 96:4, by volume; flow rate 40 mL/min) to afford the title compound (113 mg, 77%) as an amorphous.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][C:11]1[C:12]([OH:18])=[CH:13][C:14](=[O:17])[NH:15][CH:16]=1>N1C=CC=CC=1>[Cl:10][C:11]1[C:12]([O:18][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:13][C:14]([O:17][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[N:15][CH:16]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=c1cc(O)c(Cl)c[nH]1
Solvent: c1ccncc1
Product: O=C(Oc1cc(OC(=O)c2ccccc2)c(Cl)cn1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
A 1.76 ml quantity of benzoyl chloride was added to a suspension of 1.00 g of 5-chloro-4-hydroxy-2-pyridone in 30 ml of pyridine, and the mixture was stirred at room temperature for two hours. The solvent was distilled off and the residue was dissolved in a mixture solution of 60 ml of ethyl acetate and 30 ml of water. The ethyl acetate layer was separated, washed twice with 30 ml of water, dried on anhydrous sodium sulfate and concentrated. The concentrate was further washed with a small amount of ethanol, giving 2.11 g of the title compound in a yield of 86.8%.
Reaction SMILES: Br[C:2]1[CH:11]=[N:10][C:5]2[O:6][CH2:7][CH2:8][NH:9][C:4]=2[CH:3]=1.[O:12]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(#N)C>[O:12]1[CH:16]=[CH:15][C:14]([C:2]2[CH:11]=[N:10][C:5]3[O:6][CH2:7][CH2:8][NH:9][C:4]=3[CH:3]=2)=[CH:13]1
Reactant: Brc1cnc2c(c1)NCCO2
Reactant: OB(O)c1ccoc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: O
Product: c1cc(-c2cnc3c(c2)NCCO3)co1

Procedure:
To 2.0 ml of acetonitrile/0.5 ml of distilled water, 7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (80 mg, 0.372 mmol), 3-furan boronic acid (45.7 mg, 0.409 mmol), palladium acetate (8.3 mg, 0.0372 mmol), triphenylphosphine (19.5 mg, 0.0744 mmol) and potassium carbonate (102.8 mg, 0.744 mmol) were added and reacted at 100□ for 10 min using microwave (50 W) apparatus. After completion of the reaction, the mixture was extracted with ethyl acetate, and the combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by preparative TLC eluting a solvent of dichloromethane:methanol=20:1. Silica gels containing the product were eluted with dichloromethane and the solvent was evaporated to obtain 7-furan-3-yl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine in oil form (18 mg, 24%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[N:8][N:7]2[CH:10]=[C:11]([C:13]3[O:17][N:16]=[C:15]([CH3:18])[CH:14]=3)[CH:12]=[C:6]2[C:5]=1[NH:19][C@H:20]1[C@@H:24]([CH2:25][CH3:26])[CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]1)(=[O:3])[NH2:2].Cl.O1CCOCC1>ClCCl>[CH2:25]([C@H:24]1[CH2:23][NH:22][CH2:21][C@H:20]1[NH:19][C:5]1[C:6]2[N:7]([CH:10]=[C:11]([C:13]3[O:17][N:16]=[C:15]([CH3:18])[CH:14]=3)[CH:12]=2)[N:8]=[CH:9][C:4]=1[C:1]([NH2:2])=[O:3])[CH3:26]
Reactant: CC[C@H]1CN(C(=O)OC(C)(C)C)C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3cc(C)no3)cc12
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC[C@H]1CNC[C@H]1Nc1c(C(N)=O)cnn2cc(-c3cc(C)no3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 107.9 %

Procedure:
To a solution of (3S,4S)-tert-butyl 3-((3-carbamoyl-6-(3-methylisoxazol-5-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-4-ethylpyrrolidine-1-carboxylate (62 mg, 0.136 mmol) in dichloromethane (1 mL) was added 4N HCl in 1,4-dioxane (0.512 mL, 2.046 mmol). After stirring at room temperature overnight, the deprotection was complete. The volatile were removed in vacuo to afford the hydrochloride salt of the title compound (52 mg, 98% yield) as an off-white solid. MS (ES+) m/z: 355.1 (M+H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([NH:10][C@H:11]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[CH2:12][C:13]([OH:15])=[O:14])=[O:9])[CH:5]=[CH:4][C:3]=1[O:23][CH3:24].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.C1(B(O)O)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C@@H:11]([NH:10][C:8]([C:6]1[CH:5]=[CH:4][C:3]([O:23][CH3:24])=[C:2]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:7]=1)=[O:9])[CH2:12][C:13]([OH:15])=[O:14]
Reactant: COc1ccc(C(=O)N[C@@H](CC(=O)O)c2ccccc2F)nc1Br
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: OB(O)c1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N[C@@H](CC(=O)O)c2ccccc2F)nc1-c1ccccc1
Temperature: 100 °C
Yield: 63.4 %

Procedure:
50 mg (0.12 mmol) of (S)-3-[(6-Bromo-5-methoxy-pyridine-2-carbonyl)-amino]-3-(2-fluoro-phenyl)-propionic acid are dissolved in 3 ml of DMF, 120 mg (0.16 mmol, 1.35 eq) phenylboronic acid, 10 mg of bis(triphenylphosphine)palladium(II)chloride as catalyst and 1 ml of 1N Na2CO3 solution are added and the resulting mixture is heated to 100° C. for 6 hours. The mixture is filtrated via a pad of celite and subjected to preparative HPLC chromatography to yield 15 mg (31%) of product.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7](B(O)O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Br[C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1>>[F:21][C:20]([F:22])([F:23])[O:19][C:16]1[CH:17]=[CH:18][C:13]([C:7]2[S:8][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=2)=[CH:14][CH:15]=1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Reactant: CC(=O)c1ccc(B(O)O)s1
Product: CC(=O)c1ccc(-c2ccc(OC(F)(F)F)cc2)s1

Procedure:
1-(5-(4-(Trifluoromethoxy)phenyl)thien-2-yl)ethanone is prepared from 5-acetyl-2-thiopheneboronic acid and 1-bromo-4-(trifluoromethoxy)benzene according to general procedure A.
Reaction SMILES: Cl.C([O:4][CH:5](OCC)[CH2:6][O:7][C:8]1[CH:21]=[CH:20][C:11]([CH2:12][CH:13]2[S:17][C:16](=[O:18])[NH:15][C:14]2=[O:19])=[CH:10][CH:9]=1)C>O1CCCC1>[O:4]=[CH:5][CH2:6][O:7][C:8]1[CH:21]=[CH:20][C:11]([CH2:12][CH:13]2[S:17][C:16](=[O:18])[NH:15][C:14]2=[O:19])=[CH:10][CH:9]=1
Reactant: CCOC(COc1ccc(CC2SC(=O)NC2=O)cc1)OCC
Agent: Cl
Solvent: C1CCOC1
Product: O=CCOc1ccc(CC2SC(=O)NC2=O)cc1
Reaction time: 8 h
Yield: 75.2 %

Procedure:
20 ml of 6N aqueous hydrochloric acid were added to a solution of 10.07 g of 5-[4-(2,2-diethoxyethoxy)-benzyl]thiazolidine-2,4-dione (prepared as described in Preparation 46) in 80 ml of tetrahydrofuran, and the resulting mixture was allowed to stand overnight at room temperature. At the end of this time, the reaction mixture was freed from the solvent by distillation under reduced pressure. The residue was diluted with water, after which it was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through silica gel, using a 2:3 by volume mixture of hexane and ethyl acetate as the eluent, to give 5.92 g of the title compound having Rf=0.37 (on silica gel thin layer chromatography using a 1:2 by volume mixture of hexane and ethyl acetate as the developing solvent).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]2[C:11]([C:12](=O)[CH3:13])=[CH:10][C:9]([C:15]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[O:16])=[CH:8][CH:7]=2)=[CH:4][CH:3]=1.C[O:25][C:26](=[O:36])[C:27]1[CH:32]=[CH:31][C:30]([NH2:33])=[C:29]([CH:34]=O)[CH:28]=1.[OH-].[K+].Cl>CCO.O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2[C:11]([C:12]3[CH:13]=[CH:34][C:29]4[C:30](=[CH:31][CH:32]=[C:27]([C:26]([OH:25])=[O:36])[CH:28]=4)[N:33]=3)=[CH:10][C:9]([C:15]([N:17]3[CH2:18][CH2:19][CH2:20][CH2:21]3)=[O:16])=[CH:8][CH:7]=2)=[CH:22][CH:23]=1
Reactant: COC(=O)c1ccc(N)c(C=O)c1
Reactant: CC(=O)c1cc(C(=O)N2CCCC2)ccc1-c1ccc(Cl)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: C1COCCO1
Product: O=C(O)c1ccc2nc(-c3cc(C(=O)N4CCCC4)ccc3-c3ccc(Cl)cc3)ccc2c1
Temperature: 75 °C
Reaction time: 16 h

Procedure:
To a mixture of Compound 259a (0.388 g, 1.184 mmol) and Compound 7 (0.223 g, 1.243 mmol) was added a solution of KOH (0.234 g, 3.55 mmol) in EtOH (18 mL). The reaction mixture was stirred under Ar at 75° C. for 16 h. EtOH (10 mL) was added to make a clean solution, which was neutralized by adding 4 N HCl in dioxane (about 1 mL) to pH 3. After evaporation of solvent, H2O (15 mL) was added and the precipitates were collected by filtration, washed with water and dried. Yield 0.125 g, 89%. MS: 457.12, 458.13 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[CH2:5][CH:4]([C:6]2[NH:7][N:8]=[C:9]3[C:14]=2[CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][C:11](=[O:21])[NH:10]3)[CH2:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[OH:1][CH:2]1[CH2:5][CH:4]([C:6]2[NH:7][N:8]=[C:9]3[C:14]=2[CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][C:11](=[O:21])[NH:10]3)[CH2:3]1
Reactant: O=C1CC(c2[nH]nc3c2C(c2ccccc2)CC(=O)N3)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1CC(c2ccccc2)c2c(n[nH]c2C2CC(O)C2)N1
Temperature: 0 °C
Reaction time: 1 h
Yield: 54.6 %

Procedure:
To 3-(3-oxo-cyclobutyl)-4-phenyl-2,4,5,7-tetrahydro-pyrazolo[3,4-b]pyridin-6-one (0.91 g, 3.23 mmol) in THF (20 mL) at 0° C. (ice water bath) was added slowly down the side of the flask a solution of LAH (6.4 mL, 1 M hexanes). After one hr, the reaction was quenched with H2O, 15% NaOH, H2O (0.24 □L:0.24 □L:0.71 □L) and then diluted with EtOAc. To this slurry was added 5 g of silica gel and this mixture was concentrated and dried under reduced pressure. Purification of this material was accomplished by MPLC using 40 g ISCO column (dry pack condition), eluting with a gradient of 5%, 10%, 20% MeOH/CH2Cl2. The product-containing fractions were collected and concentrated to give the title compound (0.50 g, 55%) as a colorless solid. Rf=0.42 (20% MeOH/CH2Cl2). 400 MHz 1H NMR (DMSO-d6) d 11.90 (s, 1H), 10.29 (s, 1H), 7.28-7.23 (m, 2H), 7.20-7.15 (m, 2H), 7.10-7.06 (m, 1H), 5.04 (d, J=6.2 Hz, 1H), 4.16 (dd, J=7.0,4.1 Hz, 1H), 3.86-3.76 (m, 1H), 2.84 (dd, J=15.7, 7.5 Hz, 1H), 2.52 (dddd, J=10.4, 10.4, 7.5, 7.5 Hz, 1H), 2.50-2.48 (dd, J=masked by DMSO, 4.1 Hz, 1H), 2.29-2.12 (m, 2H), 1.89-1.72 (m, 2H). 100 MHz 13C NMR (DMSO-d6) d 170.0, 149.6, 145.0, 142.2, 129.2, 127.5, 127.2, 101.7, 62.4, 41.4, 34.4, 21.2. LRMS m/z (APCI+) 284 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:9])=[N:4][CH:5]=[N:6][C:7]=1Cl.CCN(CC)CC.[CH2:17]([NH2:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>C(O)CCC>[Cl:9][C:3]1[N:4]=[CH:5][N:6]=[C:7]([NH:22][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:2]=1[NH2:1]
Reactant: Nc1c(Cl)ncnc1Cl
Reactant: CC(C)(C)CN
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: CC(C)(C)CNc1ncnc(Cl)c1N
Reaction time: 12 h

Procedure:
A solution of 5-amino-4,6-dichloropyrimidine (1 mmol) in nBuOH was treated with Et3N (1.2 mmol) and neopentylamine (1.05 mmol) at 80° C. After 12 h, the cooled reaction mixture was evaporated under vacuum and the residue was chromatographed to give 6-chloro-5-amino-4-(neopentylamino)-pyrimidine as a yellow solid. Step B. The 6-chloro-5-amino-4-(2-neopentylamino)pyrimidine (1 mmol) in DMSO was treated with 5-diethylphosphono-2-furaldehyde (1.5 mmol) and FeCl3-silica (2.0 mmol) at 80° C. for 12 h. The cooled reaction mixture was filtered and the filtrate was evaporated under vacuum. Chromatography afforded 6-chloro-N9-neopentyl-8-(2-(5-diethyl-phosphono)furanyl)purine as a yellow solid. Step C. 6-Chloro-N9-neopentyl-8-(2-(5-diethylphosphono)furanyl)purine (1 mmol) in THF-DMSO was treated with liquid ammonia (2 mL) in a steel bomb. After 12 h, the reaction was evaporated under vacuum and the residue was purified through chromatography to give N9-neopentyl-8-(2-(5-diethylphosphono)furanyl)adenine as a yellow solid. Step D. A solution of N9-neopentyl-8-(2-(5-diethylphosphono)furanyl)-adenine (1 mmol) in acetonitrile was treated with bromotrimethylsilane (10 mmol). After 12 h, the reaction was evaporated under vacuum and the residue was treated with a mixture of water and acetonitrile. The solid was collected through filtration.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[N:10][N:11]2[CH3:14])=[CH:7][CH:6]=1)[OH:4].[Cl:15][CH2:16][C:17](Cl)=[O:18].CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:15][CH2:16][C:17]([NH:1][CH2:2][CH:3]([OH:4])[C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[N:10][N:11]2[CH3:14])=[CH:7][CH:6]=1)=[O:18]
Reactant: O=C(Cl)CCl
Reactant: Cn1ncc2ccc(C(O)CN)cc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc2ccc(C(O)CNC(=O)CCl)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To the crude material 2-amino-1-(1-methyl-1H-indazol-6-yl)ethanol (390.8 mg, ˜50%, ˜1 mmol)in DMF was then added 2-chloroacetyl chloride (138.7 mg, 1.2 mmol) and iPr2NEt (0.347 mL, 2 mmol). The resulting mixture was stirred at room temperature for 2 hr. The mixture was then taken into partition between EtOAc and brine. The organic layer was separated and the aqueous layer was extracted with EtOAc twice. The combined organic layers were dried dried (Na2SO4), filtered and evaporated to dryness. The residue was purified on CombiFlash (50% EtOAc/Hex) to give 2-chloro-N-(2-hydroxy-2-(1-methyl-1H-indazol-6-yl)ethyl)acetamide. LCMS-ESI+: calc'd for C12H14ClN3O2: 268.1, 270.1 (M+H+); found: 268.2, 270.2 (M+H+).
Reaction SMILES: [C:1]([S:9][CH2:10][CH:11]([CH3:31])[C:12]([N:14]1[C@H:23]([C:24]([O:26]C(C)(C)C)=[O:25])[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15]1)=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[C:1]([S:9][CH2:10][CH:11]([CH3:31])[C:12]([N:14]1[C@H:23]([C:24]([OH:26])=[O:25])[CH2:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15]1)=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(CSC(=O)c1ccccc1)C(=O)N1Cc2ccccc2C[C@H]1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(CSC(=O)c1ccccc1)C(=O)N1Cc2ccccc2C[C@H]1C(=O)O
Reaction time: 1 h
Yield: 97.4 %

Procedure:
A solution of 5.18 g of tert.-butyl (3S)-2-(3-benzoylthio-2-methylpropionyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate in 20 ml of trifluoroacetic acid is allowed to stand at room temperature for one hour. The reaction solution is distilled under reduced pressure to remove solvent. Ethyl acetate and an aqueous sodium bicarbonate solution is added to the residue. After shaking the mixture, the aqueous layer is collected therefrom and is made acidic with diluted hydrochloric acid. Then, the aqueous solution is extracted with ethyl acetate. The extract is washed with water, dried and then distilled to remove solvent. 4.4 g of (3S)-2-(3-benzoylthio-2-methylpropionyl)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid are thereby obtained as pale yellow oil. Yield: 97.2 % 4.4 g of this product are dissolved in about 20 ml of ether, and 2.1 g of dicyclohexylamine are added thereto. Said mixture is distilled to remove ether. After the residue is washed with n-hexane, ether is added to said residue. Crystalline precipitates are collected by filtration, whereby 2.15 g of (3S)-2-[(2S)-3-benzoylthio-2-methylpropionyl]-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.dicyclohexylamine salt are obtained as colorless crystals. Yield: 32.2 % M.p. 164°-166° C.(recrystallized from ethyl acetate-ether)
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=O)[C:4]([NH2:6])=[O:5].[C:10]1([C@H:16]([NH2:18])[CH3:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=[N:18][C@@H:16]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:17])[C:4]([NH2:6])=[O:5]
Reactant: CC(C)(C)C(=O)C(N)=O
Reactant: C[C@@H](N)c1ccccc1
Product: C[C@@H](N=C(C(N)=O)C(C)(C)C)c1ccccc1
Yield: 66.7 %

Procedure:
The procedure described under n) was carried out using 5.0 g of 3,3-dimethyl-2-oxo-butyramide and 10.0 g of (R)-1-phenylethylamine. After a single crystallization from hexane there were isolated 6.0 g (67%) of (R)-3,3-dimethyl-2-(1-phenylethylimino)-butyramide of melting point 100°-101° C. [α]=+61.4 (c=0.8, CHCl3).
Reaction SMILES: [BH4-].[Na+].[C:3]([O:6][C@@H:7]1[CH2:14][C@H:13]2[C@H:9]([CH2:10][C@H:11]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[O:12]2)[C@H:8]1/[CH:23]=[CH:24]/[C:25](=[O:32])[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])(=[O:5])[CH3:4].CO>C1COCC1>[C:3]([O:6][C@@H:7]1[CH2:14][C@H:13]2[C@H:9]([CH2:10][C@H:11]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[O:12]2)[C@H:8]1/[CH:23]=[CH:24]/[C@@H:25]([OH:32])[CH2:26][CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])(=[O:5])[CH3:4]
Reactant: COC(=O)CCCC[C@H]1C[C@@H]2[C@@H](/C=C/C(=O)CCC=C(C)C)[C@H](OC(C)=O)C[C@@H]2O1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)CCCC[C@H]1C[C@@H]2[C@@H](/C=C/[C@@H](O)CCC=C(C)C)[C@H](OC(C)=O)C[C@@H]2O1
Reaction time: 1 h

Procedure:
At -40°, 230 mg. of sodium borohydride is added in incremental portions to a solution of 470 mg. of (1S,5R,6R,7R,3S)-7-acetoxy-6-[(1E)-7-methyl-3-oxo-1,6-octadienyl]-3-(4-methoxycarbonyl-1-butyl)-2-oxabicyclo[3,3,0]octane in 14 ml. of methanol and 4 ml. of THF. The mixture is stirred for 1 hour at -40° and then combined with 0.6 ml. of glacial acetic acid, concentrated under vacuum, combined with methylene chloride, the organic extract shaken in 4% sodium bicarbonate solution, washed neutral with water, dried over magnesium sulfate, and evaporated under vacuum. After separation by chromatography on silica gel, ether/pentane (1+1) yields 120 mg. of the corresponding β-configured compound and 160 mg. of the title compound as a colorless oil.
Reaction SMILES: [OH:1][NH:2][C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[H-].[Na+].Cl[CH2:13][CH2:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:16]>C1COCC1>[O:16]=[C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:14][CH2:13][O:1][NH:2][C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)NO
Reactant: O=C(CCCl)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NOCCC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 69.7 %

Procedure:
To a cooled (0° C.) solution of tert-butyl hydroxycarbamate (1.90 g, 14.2 mmol) in THF (30 mL) was added NaH (0.285 g, 11.9 mmol). After stirring at 0° C. for 5 minutes and at room temperature for 10 minutes, the mixture was added to a solution of 3-chloro-1-phenylpropan-1-one (2.00 g, 11.9 mmol) in THF (10 mL). After stirring at room temperature for 30 minutes, the mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was chromatographed (20% ethyl acetate in hexanes) to provide the product (2.20 g, 69%) as a white solid.
Reaction SMILES: [C:1]([OH:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([OH:11])=[O:10])([C:5]([OH:7])=[O:6])[OH:4].[Cu:14].C(=O)([O-])[O-].[S:19]([O-:23])([O-:22])(=[O:21])=[O:20].[Cl-].[N+]([O-])([O-])=O.P([O-])([O-])([O-])=O>>[S:19]([O-:23])([O-:22])(=[O:21])=[O:20].[Cu+2:14].[C:1]([OH:13])(=[O:12])[CH2:2][C:3]([CH2:8][C:9]([OH:11])=[O:10])([C:5]([OH:7])=[O:6])[OH:4]
Reactant: [Cu]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: O=P([O-])([O-])[O-]
Product: [Cu+2]

Procedure:
This example presents a synopsis of biocidal solution design calculations for a biocidal solution comprised of citric acid (the ligand, or complexing agent) and copper. One gallon of sewage effluent containing bacteria could be treated with one drop of stock solution prepared as follows. For this example, a biocide solution of copper sulfate and citric acid is prepared. Other chemical species present in sewage effluent are carbonate, sulfate, chloride, nitrate and especially phosphate, all of which have the potential for decreasing copper effectiveness via precipitation of copper (carbonate, and phosphate), or increasing copper complexation thereby increasing the total available copper.