Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [K:1].Br[CH2:3][B-:4]([F:7])([F:6])[F:5].[N:8]1([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1>O1CCCC1>[K:1].[C:17]([O:16][C:14]([N:8]1[CH2:13][CH2:12][N:11]([CH2:3][B-:4]([F:7])([F:6])[F:5])[CH2:10][CH2:9]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: F[B-](F)(F)CBr
Agent: [K]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C[B-](F)(F)F)CC1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
5.00 g potassium-bromomethyl-trifluoroborate are added to a solution of 4.87 g tert-butyl piperazine-1-carboxylate in 25 ml of tetrahydrofuran. The mixture is stirred for 3 h at 80° C. and then cooled to ambient temperature. The solvent is removed, and the residue is suspended in 50 ml acetone and combined with 3.44 g potassium carbonate. The mixture is stirred overnight at ambient temperature. Then the mixture is filtered and the filtrate is evaporated down. The oil remaining is combined with diisopropylether and the colourless precipitate formed after a while is separated off and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[CH:13][C:12]([CH2:15]O)=[CH:11][N:10]=2)=[CH:4][CH:3]=1.CCN(CC)CC.CS([Cl:28])(=O)=O>C(Cl)Cl>[Cl:28][CH2:15][C:12]1[CH:11]=[N:10][C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:14][CH:13]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cnc(Nc2ccc(Cl)cc2)nc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: ClCc1cnc(Nc2ccc(Cl)cc2)nc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 61.9 %

Procedure:
A suspension of (2-(4-chlorophenylamino)pyrimidin-5-yl)methanol (0.15 g, 0.636 mmol) and Et3N (0.177 ml, 1.273 mmol) in DCM (6.4 mL) was cooled to 0° C. and methanesulfonyl chloride (0.099 mL, 1.273 mmol) was added. The reaction was stirred for 1.5 h while warming to room temperature. The mixture was diluted with DCM and quenched with sat. NaHCO3. The organic layer was isolated and dried over Na2SO4, then concentrated to give crude 5-(chloromethyl)-N-(4-chlorophenyl)pyrimidin-2-amine as a yellow solid (0.1 g, 62%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.46 (2H, s), 7.58 (2H, d, J=8.78 Hz), 7.31 (2H, d, J=8.78 Hz), 7.25 (1H, br. s.), 4.53 (2H, s).
Reaction SMILES: Cl.[CH:2]1([NH:8][C:9]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([S:21](=[O:30])(=[O:29])[NH:22][CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[CH:13][CH:12]=2)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C.Cl[C:39]([O:41][CH2:42][CH3:43])=[O:40]>ClCCl>[CH2:42]([O:41][C:39]([N:26]1[CH2:25][CH2:24][CH:23]([NH:22][S:21]([C:14]2[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:11]([C:9](=[O:10])[NH:8][CH:2]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]3)=[CH:12][CH:13]=2)(=[O:30])=[O:29])[CH2:28][CH2:27]1)=[O:40])[CH3:43]
Reactant: O=C(NC1CCCCC1)c1ccc(S(=O)(=O)NC2CCNCC2)c2ccccc12
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1CCC(NS(=O)(=O)c2ccc(C(=O)NC3CCCCC3)c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-(Piperidin-4-ylsulfamoyl)-naphthalene-1-carboxylic acid cyclohexylamide hydrochloride F-2 (87 mg, 0.19 mmol) was dissolved and stirred in dichloromethane (2 mL). Triethylamine (58 mg, 0.08 mL, 0.57 mmol) was added followed by ethyl chloroformate (41 mg, 0.037 mL, 0.39 mmol). The reaction was stirred overnight at room temperature, then charged directly to a flash column. Elution with 99:1 dichloromethane:methanol afforded the titled compound the title compound as a white solid. Wt.: 60 mg (65%). 1H NMR (300 MHz, CDCl3) δ 8.59 (m, 1H), 8.28 (m, 1H), 8.19 (d, 1H), 7.64 (m, 2H), 7.54 (d, 1H), 4.10 (m, 1H), 4.03 (q, 2H), 3.80 (m, 2), 3.64 (m, 1H), 3.18 (m, 1H), 2.68 (m, 2H), 2.12 (m, 2H), 1.79 (m, 2H), 1.68 (m, 1H), 1.58 (m, 2H), 1.47 (m, 2H), 1.24 (m, 6H), 1.18 (t, 3H); LC/MS m/z 488 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:4]=1[C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]2[O:15][CH2:16][O:17][C:11]=2[CH:10]=1)=[O:6].[C:23](Cl)(=[O:25])[CH3:24].C(N(C(C)C)CC)(C)C>O1CCCC1>[C:23]([NH:2][C:3]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:4]=1[C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]2[O:15][CH2:16][O:17][C:11]=2[CH:10]=1)=[O:6])(=[O:25])[CH3:24]
Reactant: CC(=O)Cl
Reactant: Nc1ccc(Cl)cc1C(=O)NCc1ccc2c(c1)OCO2
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc(Cl)cc1C(=O)NCc1ccc2c(c1)OCO2
Yield: 84 %

Procedure:
2-Amino-5-chloro-N-(3,4-methylenedioxybenzyl)benzamide hydrochloride (100 mg) was reacted with 40 μl of acetyl chloride in 5 ml of tetrahydrofuran in the presence of 150 μl of diisopropylethylamine. The reaction mixture was subjected to extraction with ethyl acetate and water and recrystallization from ethyl acetate/hexane to give 85 mg of 2-acetamido-5-chloro-N-(3,4-methylenedioxybenzyl)benzamide (yield: 84%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH:13]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([S:23](Cl)(=[O:25])=[O:24])[C:17]=2[CH:16]=[CH:15][N:14]=1.C(Cl)(Cl)Cl>C(Cl)Cl>[CH:13]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([S:23]([N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)(=[O:25])=[O:24])[C:17]=2[CH:16]=[CH:15][N:14]=1
Reactant: O=S(=O)(Cl)c1cccc2cnccc12
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=S(=O)(c1cccc2cnccc12)N1CCNCC1
Reaction time: 15 h
Yield: 87.8 %

Procedure:
In 100 ml of methylene chloride were added 6.0 g of piperazine and 1.2 g of anhydrous potassium carbonate, and to the mixture was added dropwise 30 ml of a methylene chloride solution containing 2.0 g of 5-isoquinolinesulfonyl chloride under cooling with ice. After the dropwise addition of the methylene chloride solution, the mixed solution was stirred at a temperature of 15° C. to 25° C. for 15 hours, and then the reaction solution was washed with water, dried with anhydrous magnesium sulfate, and the methylene chloride was distilled therefrom. The residue thus obtained was subjected to a silica gel column chromatography (silica gel: 70 g; solvent: chloroform) to give 2.14 g of 1-(5-isoquinolinesulfonyl)piperazine, i.e., Compound (35) in a yield of 89%.
Reaction SMILES: [NH2:1][C:2](=[S:13])[C:3]1[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=1[CH3:8].[C:14]([C:18]1[O:22][C:21]([CH3:23])=[C:20]([C:24](=O)[CH2:25]Br)[CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>>[C:14]([C:18]1[O:22][C:21]([CH3:23])=[C:20]([C:24]2[N:1]=[C:2]([C:3]3[CH:4]=[C:5]([C:9]([O:11][CH3:12])=[S:10])[S:6][C:7]=3[CH3:8])[S:13][CH:25]=2)[CH:19]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: Cc1oc(C(C)(C)C)cc1C(=O)CBr
Reactant: COC(=S)c1cc(C(N)=S)c(C)s1
Product: COC(=S)c1cc(-c2nc(-c3cc(C(C)(C)C)oc3C)cs2)c(C)s1
Yield: 66.1 %

Procedure:
Methyl 4-{4-[S-(tert-butyl)-2-methyl(3-furyl)](1,3-thiazol-2-yl)}-5-methylthiothiophene-2-carboxylate: A solution of 955 mg (3.86 mmol) of methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge, Cornwall, UK) was reacted with 1 g (3.86 mmol) of 1-[5-(tert-butyl)-2-methyl(3-furyl)]-2-bromoethan-1-one (1 g) in a manner similar to Example 8, step (a) to give methyl 4-{4-[5-(tert-butyl)-2-methyl(3-furyl)](1,3-thiazol-2-yl)}-5-methylthiothiophene-2-carboxylate (999 mg, 64%) as a red-brown solid. 1H-NMR (DMSO-d6; 300 MHz) δ 8.14 (s, 1H), 7.74 (s, 1H), 6.46 (s, 1H), 3.86 (s, 3H), 2.74 (s, 3H), 2.66 (s, 3H), 1.27 (s, 9H). Mass spectrum (MALDI-TOF, CHCA matrix, m/z): Calcd. for C19H21NO3S3, 408.1 (M+H), found 408.0.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:10]([C:11]([C:13]2[N:14]=[C:15]([CH3:25])[S:16][C:17]=2[C:18]2[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=2)=[O:12])[CH2:9][C@H:8]2[C@@H:4]1[CH2:5][C:6]([F:27])([F:26])[CH2:7]2.[N:28]1[CH:29]=[C:30]([C:37](O)=[O:38])[N:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=12>>[F:26][C:6]1([F:27])[CH2:5][C@H:4]2[C@H:8]([CH2:9][N:10]([C:11]([C:13]3[N:14]=[C:15]([CH3:25])[S:16][C:17]=3[C:18]3[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=3)=[O:12])[C@@H:3]2[CH2:2][NH:1][C:37]([C:30]2[N:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]3=[N:28][CH:29]=2)=[O:38])[CH2:7]1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(F)(F)C[C@@H]3[C@H]2CN)c1
Reactant: O=C(O)c1cnc2ccccn12
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3CC(F)(F)C[C@@H]3[C@H]2CNC(=O)c2cnc3ccccn23)c1

Procedure:
prepared by reaction of (1S,2S,5R)-(2-aminomethyl-7,7-difluoro-3-aza-bicyclo[3.3.0]-oct-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with imidazo[1,2-a]pyridine-3-carboxylic acid.
Reaction SMILES: [O:1]1[C:8]2[CH:7]=[C:6]([C:9]([O:11][CH3:12])=[O:10])[NH:5][C:4]=2[CH:3]=[CH:2]1.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1C(=O)N([Br:38])C(=O)C1>C(Cl)Cl>[Br:38][C:7]1[C:8]2[O:1][CH:2]=[CH:3][C:4]=2[NH:5][C:6]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)c1cc2occc2[nH]1
Reactant: O=C1CCC(=O)N1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: ClCCl
Product: COC(=O)c1[nH]c2ccoc2c1Br
Reaction time: 8 h

Procedure:
To a cold solution (ice-water bath) of methyl 4H-furo[3,2-b]pyrrole-5-carboxylate (1.0 g, 6.05 mmol) in DCM (10 mL) was added TBAF (1.0 M in THF, 9.0 mL, 9.0 mmol) and NBS (1.5 g, 7.9 mmol). The resulting dark colored solution was stirred from 0° C. to rt overnight. The reaction mixture was diluted with 50 mL of CH2Cl2 and washed with water (100 mL) and brine (100 mL) and dried (Na2SO4). After filtration, the filtrate was concentrated by evaporation and the crude product was purified by silica gel chromatography (0-5% EtOAc/hexane) to afford a white solid. 1H NMR (400 MHz, CDCl3) δ (ppm) 8.84 (broad, 1H, NH), 7.54 (d, J=2.2 Hz, 1H), 6.48 (d, J=1.83 Hz, 1H), 3.92 (s, 3H) ppm; m+/z 244 (100%), 246 (100%).
Reaction SMILES: [Na].[C:2]([O:6][C:7]([N:9]([C:17]1[C:22]([CH3:23])=[CH:21][C:20]([CH2:24][C:25]2([CH3:35])[C:30](=[O:31])[O:29][C:28](C)([CH3:32])[O:27][C:26]2=[O:34])=[CH:19][N:18]=1)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:8])([CH3:5])([CH3:4])[CH3:3].C(Cl)Cl>C(O)C>[CH2:28]([O:27][C:26](=[O:34])[C:25]([CH2:24][C:20]1[CH:19]=[N:18][C:17]([N:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:7]([O:6][C:2]([CH3:5])([CH3:3])[CH3:4])=[O:8])=[C:22]([CH3:23])[CH:21]=1)([CH3:35])[C:30]([OH:31])=[O:29])[CH3:32]
Reactant: Cc1cc(CC2(C)C(=O)OC(C)(C)OC2=O)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: [Na]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C(C)(Cc1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(C)c1)C(=O)O
Reaction time: 1 h
Yield: 101.8 %

Procedure:
A solution of sodium metal (184 mg, 8.0 mmol) in ethanol (20 mL) was added to a solution of crude 2-[N,N-bis(tert-butoxycarbonyl)amino]-3-methyl-5-(2,2,5-trimethyl-4,6-dioxo-[1,3]dioxan-5-ylmethyl)-pyridin (2.06 g, ˜4.0 mmol) in ethanol (20 mL) under argon. The reaction was stirred for 60 min. and methylene chloride was then added. The mixture was washed with 0.5 M HCl and brine, dried and concented under reduced pressure to give crude 2-(6-[N,N-bis(tert-butoxycarbonyl)amino]-5-methyl-pyridin-3-ylmethyl)-2-methyl-malonic acid monoethyl ester (1.9 g)
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]#[N:12])=[C:4]([C:8]([OH:10])=O)[NH:5][C:6]=1[CH3:7].[NH2:13][C@@H:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][C@@H:15]1[O:25][CH2:26][CH3:27].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>ClCCl>[Cl:1][C:2]1[C:3]([C:11]#[N:12])=[C:4]([C:8]([NH:13][C@@H:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][C@@H:15]2[O:25][CH2:26][CH3:27])=[O:10])[NH:5][C:6]=1[CH3:7]
Reactant: Cc1[nH]c(C(=O)O)c(C#N)c1Cl
Reactant: CCOC(=O)N1CC[C@@H](N)[C@@H](OCC)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCOC(=O)N1CC[C@@H](NC(=O)c2[nH]c(C)c(Cl)c2C#N)[C@@H](OCC)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
To a solution of 4-chloro-3-cyano-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 16, 1.01 g, 5.55 mmol) and ethyl (3S,4R)-4-amino-3-ethoxypiperidine-1-carboxylate (Intermediate 24, 1.2 g, 5.55 mmol) in dichloromethane (480 mL) were added HOBt (850 mg, 5.55 mmol) and N-methyl morpholine (1.82 mL, 16.66 mmol). The reaction mixture was stirred for 1 h at room temperature and EDC HCl (1.9 g, 9.99 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with 2N hydrochloric acid (120 mL). The organic layer was washed with sodium bicarbonate (150 mL), water (150 mL) and brine, dried over anhydrous sodium sulphate, filtered, concentrated under vacuum. Purification by flash column chromatography (silica, 35% ethylacetate in pet ether) afforded ethyl (3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidine-1-carboxylate 1.5 g (71%) as solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[CH:26]([NH:27][C:28](=[O:60])/[C:29](=[N:55]\[O:56][CH2:57][C:58]#[CH:59])/[C:30]3[N:31]=[C:32]([NH:35][C:36]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[S:33][CH:34]=3)[C:25](=[O:61])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[Na+].[I-:63]>CC(C)=O>[CH2:57]([O:56]/[N:55]=[C:29](/[C:30]1[N:31]=[C:32]([NH:35][C:36]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[S:33][CH:34]=1)\[C:28]([NH:27][CH:26]1[C:25](=[O:61])[N:7]2[C:8]([C:9]([O:11][CH:12]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[O:10])=[C:3]([CH2:2][I:63])[CH2:4][S:5][C@H:6]12)=[O:60])[C:58]#[CH:59]
Reactant: C#CCO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: C#CCO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 1 h
Yield: 100.1 %

Procedure:
A mixture of diphenylmethyl 3-chloromethyl-7-[(Z)-2-propargyloxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (VI-f) (2.0 g, 2.3 mmoles) and NaI (1.04 g, 6.9 mmoles) in acetone (40 ml) was stirred for 1 hour. The mixture was filtered and the filtrate was poured into water and extracted with ethyl acetate. The organic layer was washed with 5% aqueous Na2S2O3, water and a saturated aqueous NaCl, successively. It was then dried over MgSO4 and evaporated to give 2.2 g (98%) of the title compound [VII-f].
Reaction SMILES: [N:1]1([C@@H:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[CH:16]=2)[C@H:11]([OH:14])[CH2:12][OH:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1>ClCCl.C(OCC)(=O)C.[O-2].[O-2].[Mn+4]>[F:21][C:17]1[CH:16]=[C:15]([C@H:10]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)[C@H:11]([OH:14])[CH2:12][OH:13])[CH:20]=[CH:19][CH:18]=1
Reactant: OC[C@@H](O)[C@H](c1cccc(F)c1)N1CCc2ccccc21
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: OC[C@@H](O)[C@H](c1cccc(F)c1)n1ccc2ccccc21
Temperature: 20 °C
Reaction time: 3 h
Yield: 70.5 %

Procedure:
A mixture of (2S,3S)-3-(2,3-dihydro-1H-indol-1-yl)-3-(3-fluorophenyl)propane-1,2-diol (2.00 g, 6.96 mmol) and activated manganese dioxide (20.0 g, 230 mmol) in dichloromethane (30 mL) was stirred at 20° C. for 3 hours. The mixture was diluted with ethyl acetate (15 mL), filtered through a pad of silica gel, and concentrated. The crude product was purified by Biotage chromatography (FlasH40i, silica, 0-70% EtOAc/hexane) to give 1.40 g (71%) of (2S,3S)-3-(3-fluorophenyl)-3-(1H-indol-1-yl)propane-1,2-diol as a colorless oil. MS (ESI) m/z 286.0 ([M+H]+). HRMS: calcd for C17H16FNO2+H+, 286.1238; found (ESI, [M+H]+), 286.1239.
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[CH:20]2[CH2:29][CH2:28][C:27]3[CH:26]=[C:25]([O:30]C(=O)C(C)(C)C)[CH:24]=[CH:23][C:22]=3[CH2:21]2)=O)=[CH:4][CH:3]=1.Cl[CH2:40][C:41]([N:43]([CH2:48][CH2:49][O:50][CH3:51])[CH2:44][CH2:45][O:46][CH3:47])=O>>[CH3:47][O:46][CH2:45][CH2:44][N:43]([CH2:48][CH2:49][O:50][CH3:51])[CH2:41][CH2:40][O:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][CH2:8][CH2:9][CH2:10][NH:11][C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[CH:20]2[CH2:29][CH2:28][C:27]3[CH:26]=[C:25]([OH:30])[CH:24]=[CH:23][C:22]=3[CH2:21]2)=[CH:4][CH:3]=1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCC(=O)c2ccc(O)cc2)c1
Reactant: COCCN(CCOC)C(=O)CCl
Product: COCCN(CCOC)CCOc1ccc(CCCCNc2cc(OC)ccc2C2CCc3cc(O)ccc3C2)cc1
Yield: 15.8 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)propylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (21 mg) and 2-chloro-N,N-bis(2-methoxyethyl)acetamide (17 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (3.7 mg) was obtained.
Reaction SMILES: C1C2C(CO[C:16]([NH:18][C@H:19]([C:26]([NH:28][CH2:29][CH2:30][C:31]3[CH:38]=[CH:37][C:35]([OH:36])=[C:33]([OH:34])[CH:32]=3)=[O:27])[CH2:20][O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:17])C3C(=CC=CC=3)C=2C=CC=1.C(O)(=O)[C:40]1[CH:48]=[C:46]([OH:47])[C:44]([OH:45])=[C:42]([OH:43])[CH:41]=1>>[OH:43][C:42]1[CH:41]=[C:40]([CH:48]=[C:46]([OH:47])[C:44]=1[OH:45])[C:16]([NH:18][C@H:19]([C:26]([NH:28][CH2:29][CH2:30][C:31]1[CH:38]=[CH:37][C:35]([OH:36])=[C:33]([OH:34])[CH:32]=1)=[O:27])[CH2:20][O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:17]
Reactant: O=C(O)c1cc(O)c(O)c(O)c1
Reactant: CC(C)(C)OC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCc1ccc(O)c(O)c1
Product: CC(C)(C)OC[C@H](NC(=O)c1cc(O)c(O)c(O)c1)C(=O)NCCc1ccc(O)c(O)c1

Procedure:
The title compound was prepared from N-[Nα-(9-fluorenylmethoxycarbonyl)-O-tert-butyl-L-seryl]dopamine (1.16 g, 2.24 mmol, example 42, step A) as described for example 42 (step B) using gallic acid (571 mg, 3.36 mmol) instead of caffeic acid. The crude material was purified by flash chromatography using successively 30%, 40% and 70% EtOAc/CH2Cl2/1% AcOH as the eluent. The title compound was obtained as a white powder (300 mg, 30%).
Reaction SMILES: [OH:1][N:2]1[C:8]([CH3:10])([CH3:9])[CH2:7][C:6](=[O:11])[NH:5][CH2:4][C:3]1([CH3:13])[CH3:12].[C:14]1([N:20]=[C:21]=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:14]1([NH:20][C:21]([N:5]2[C:6](=[O:11])[CH2:7][C:8]([CH3:9])([CH3:10])[N:2]([OH:1])[C:3]([CH3:13])([CH3:12])[CH2:4]2)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C=Nc1ccccc1
Reactant: CC1(C)CNC(=O)CC(C)(C)N1O
Product: CC1(C)CC(=O)N(C(=O)Nc2ccccc2)CC(C)(C)N1O

Procedure:
Using the same conditions as in Example 4, 3.6 parts of 1-oxyl-2,2,7,7-tetramethyl-1,4-diazacycloheptan-5-one and 2.6 parts of phenyl isocyanate were reacted together and afforded 6.0 parts of a red oil which was purfied by column chromatography on alumina to give 4-phenylcarbamoyl-1-oxyl-2,2,7,7-tetramethyl-1,4-diazacycloheptan-5-one as a red solid of melting point 112° to 114°C. This material gave the following elemental analysis by weight:
Reaction SMILES: F[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][N:11]=1)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]2[NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1.[N:25]1([CH2:31][CH2:32][NH2:33])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[N:25]1([CH2:31][CH2:32][NH:33][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][N:11]=2)[N:8]=[CH:7][C:6]([C:12]#[N:13])=[C:5]3[NH:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=2)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(C(F)(F)F)cc1
Reactant: NCCN1CCOCC1
Product: N#Cc1cnc2cnc(NCCN3CCOCC3)cc2c1Nc1ccc(C(F)(F)F)cc1
Yield: 55 %

Procedure:
Following the procedure described above in Example 34, 6-fluoro-4-{[4-(trifluoromethyl)phenyl]amino}-1,7-naphthyridine-3-carbonitrile was reacted with 2-morpholin-4-yl-ethylamine. The crude product was purified by flash column chromatography (2% methanol in methylene chloride) to give a yellow solid (0.14 g, 55%). 1H NMR (400 MHz, DMSO-D6) δ ppm 2.4 (m, 4 H) 3.4 (m, 2 H) 3.4 (m, 2 H) 3.6 (m, 4 H) 6.8 (m, 1 H) 6.9 (s, 1 H) 7.4 (d, J=8.3 Hz, 2 H) 7.7 (d, J=8.6 Hz, 2 H) 8.4 (s, 1 H) 8.9 (s, 1 H) 9.8 (s, 1 H).
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>C1COCC1>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][C:7]([C:8]#[N:9])([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:26]
Reactant: N#CCc1ccccc1
Reactant: CCOC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Combined phenylacetonitrile (5.85 g, 50.0 mmol) and THF (30 mL). Cooled in a dry-ice/acetone bath. Added dropwise, sodium bis-(trimethylsilyl)amide (100 mL, 1.0M in THF, 100 mmol, 2 eq.). After the addition was complete, allowed to warm to ambient temperature. Cooled in a dry-ice/acetone bath. Added dropwise, ethyl bromoacetate (11 mL, 99 mmol). After the addition was complete, warmed to ambient temperature and stir for 3 h. Partitioned the reaction mixture between diethyl ether (200 mL) and water (200 mL). The organic layer was extracted with H2O (3×150 mL), 1N HCl (2×100 mL), 5% NaHCO3 (2×100 mL), and brine (1×150 mL). Dried over MgSO4, filtered, and concentrated in vacuo to obtain a residue. Chromatographed on silica gel eluting with 20% ethyl acetate in hexane to obtain the title compound:
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH3:6][C:7]1[CH:16]=[C:15]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=[CH:14]2)[CH:8]=1.CN(C)[CH:19]=[O:20]>>[CH3:6][C:7]1[CH:8]=[C:9]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=[CH:10]2)[C:16]=1[CH:19]=[O:20]
Reactant: Cc1cc2cccccc-2c1
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc2cccccc-2c1C=O

Procedure:
POCl3 (3.86 mL, 42.2 mmol) was added slowly to a stirring dimethylformamide (DMF) solution at 0° C. The mixture was cooled for 1 h before a DMF solution of 2-methyl azulene (2.0 g, 14.1 mmol) was added drop-wise. The reaction was mixed for 2 h at 0° C., and then quenched with cold 10% NaOH. The organic layer was extracted into ethyl acetate after which the extracts were washed with water and brine, dried with MgSO4 and purified using flash chromatography (ethyl acetate and hexane). The purified material was dried down into a dark red solid. Yield: 2.389 g, 89%. 1H NMR (400 MHz, CDCl3) δ 10.50 (s, 1H), 9.44 (d, J=9.73 Hz, 1H), 8.29 (d, J=9.72 Hz, 1H), 7.72 (t, J=9.82 Hz, 1H), 7.56 (t, J=9.82 Hz, 1H), 7.46 (t, J=9.67 Hz, 1H), 7.08 (s, 1H), 2.84 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 185.8, 154.9, 144.4, 142.1, 137.9, 136.4, 129.7, 128.5, 122.5, 120.3, 15.1. HRMS (ES) calcd. MH+(C12H11O) 171.0732 found 171.0804.
Reaction SMILES: [NH3:1].[NH4+].[C:3](=[O:6])([OH:5])[O-:4].[C:7](=[O:10])([O-])[O-:8].C(=O)=O>O>[C:3](=[O:4])([OH:6])[O-:5].[C:7](=[O:10])([O-:8])[NH2:1].[NH4+:1]
Reactant: N
Reactant: O=C([O-])[O-]
Agent: O=C([O-])O
Agent: O=C=O
Agent: [NH4+]
Solvent: O
Product: NC(=O)[O-]

Procedure:
For the ammonia process, the solvent solution consists of ammonium, bicarbonate ions and to a lesser extent, carbonate, in equilibrium with dissolved ammonia (aqueous), and dissolved CO2 (aqueous). In the absorber, water and ammonia react with CO2 (aqueous) to form bicarbonate ions or ammonium carbamate ions, with the reaction reversed in the stripper by the application of energy. The relevant aqueous phase reactions can be summarized by the following overall equations: CO2+H2O+NH3HCO3−+NH4+  (eqn. 1) CO2+2NH3NH2COO−+NH4+  (eqn. 2) HCO3−+NH3CO32−+NH4+  (eqn. 3) CO32−+H2O+CO22HCO3−  (eqn. 4)