Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:16][OH:17].[OH-].[Na+]>C(O)C>[N:16](=[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[OH:17]
Reactant: NO
Reactant: O=C(O)CCCC(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CCCC(=NO)c1ccccc1
Temperature: 120 °C

Procedure:
4-benzoylbutyric acid (4.26 g, 22.2 mmol), a 5 mL solution of aqueous hydroxylamine hydrochloride (1.80 g, 25.9 mmol), and a 2.0M solution of aqueous sodium hydroxide (14 mL, 28.0 mmol) were combined in 15 mL of absolute ethanol. The mixture was refluxed at 120° C. for 1 hour, then evaporated in vacuo to remove ethanol. A few drops of a 2.0M solution of aqueous hydrochloric acid were added to the solution to achieve a pH of 6. Then more water was added, and the slurry was filtered to isolate the title compound as a solid.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:10]=2[C:9](=[O:17])[NH:8][C:7]2[CH:18]=[CH:19][CH:20]=[N:21][C:6]1=2)=[O:4].[CH2:22]([N:24]([CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]1)[CH2:25][CH3:26])[CH3:23].C(OC(C)C)(C)C>C(#N)C>[CH2:22]([N:24]([CH2:27][CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][N:29]1[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][C:14]([CH3:16])=[CH:15][C:10]=2[C:9](=[O:17])[NH:8][C:7]2[CH:18]=[CH:19][CH:20]=[N:21][C:6]1=2)=[O:4])[CH2:25][CH3:26])[CH3:23]
Reactant: CCN(CC)CC1CCCCN1
Reactant: Cc1ccc2c(c1)C(=O)Nc1cccnc1N2C(=O)CCl
Solvent: CC#N
Solvent: CC(C)OC(C)C
Product: CCN(CC)CC1CCCCN1CC(=O)N1c2ccc(C)cc2C(=O)Nc2cccnc21
Yield: 54 %

Procedure:
Prepared in analogy to Example 2 from 11-(chloroacetyl)-5,11-dihydro-8-methyl-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[(diethylamino)methyl]piperidine, but using acetonitrile as solvent, in a yield of 54% of theory. M.p. 173-174° C. (diisopropylether).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].Br[CH2:11][CH2:12][CH2:13][Cl:14].C(N(CC)CC)C.Cl>C(C(C)=O)C.O>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH:5][CH2:11][CH2:12][CH2:13][Cl:14]
Reactant: ClCCCBr
Reactant: Cc1ccc(N)cc1Cl
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCC(C)=O
Product: Cc1ccc(NCCCCl)cc1Cl
Temperature: 26.5 °C
Reaction time: 24 h
Yield: 157.1 %

Procedure:
3-Chloro-4-methylaniline (10.0 g, 70.6 mmol), 1-bromo-3-chloropropane (34.7 mL, 55.6 g, 353 mmol) and triethylamine (21.4 g, 212 mmol) were charged. The mixture was stirred at 25-28° C. for 24 hrs. Water (50 mL) and methyl ethyl ketone (25 mL) were added for partitioning. The organic layer was washed twice with water (50 mL). Conc. hydrochloric acid (35 mL, 5.7 eq) was dropwise added to the organic layer under ice-cooling. The mixture was stirred at room temperature for 1 hr. The crystals were collected by filtration, washed with diisopropyl ether (10 mL) and dried in vacuo at 50° C. to give the title compound (14.12 g, yield 78.5%) as pale-yellow crystals.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])=[CH:4][CH:3]=1.[O:16]1[C:20]2([CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]2)[O:19][CH2:18][CH2:17]1>>[C:10]([Si:7]([CH3:9])([CH3:8])[O:6][C:5]1[CH:14]=[CH:15][C:2]([C:23]2([OH:26])[CH2:24][CH2:25][C:20]3([O:19][CH2:18][CH2:17][O:16]3)[CH2:21][CH2:22]2)=[CH:3][CH:4]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(Br)cc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C2(O)CCC3(CC2)OCCO3)cc1

Procedure:
The title compound was prepared as a white solid from (4-bromo-phenoxy)-tert-butyl-dimethyl-silane (Aldrich) and 1,4-dioxa-spiro[4.5]decan-8-one using the procedure described in Step A of Example 1.
Reaction SMILES: Br[CH:2]([CH3:13])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])=O.[CH:14]1([CH:17]([N:25]([CH2:29][CH2:30][CH3:31])[C:26]([NH2:28])=[S:27])[C:18]2[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][CH:19]=2)[CH2:16][CH2:15]1.C(N(CC)CC)C>C(O)C>[Cl:12][C:6]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=1[C:3]1[N:28]=[C:26]([N:25]([CH:17]([CH:14]2[CH2:16][CH2:15]2)[C:18]2[CH:19]=[CH:20][C:21]([Br:24])=[CH:22][CH:23]=2)[CH2:29][CH2:30][CH3:31])[S:27][C:2]=1[CH3:13]
Reactant: CC(Br)C(=O)c1ccc(Cl)cc1Cl
Reactant: CCCN(C(N)=S)C(c1ccc(Br)cc1)C1CC1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCCN(c1nc(-c2ccc(Cl)cc2Cl)c(C)s1)C(c1ccc(Br)cc1)C1CC1
Temperature: 65 °C

Procedure:
14 g of 2-bromo-1-(2,4-dichlorophenyl)-1-propanone (Compound 1), 17.1 g of N-(α-cyclopropyl-4-bromobenzyl)-N-propylthiourea (Compound 64) and 7.6 ml of triethylamine are dissolved in 200 ml of ethanol and the solution is heated to 65° C. The reaction is monitored by TLC. At the end of the reaction, the ethanol is removed and the residue is hydrolysed with water and extracted with methylene chloride. The organic phases are washed and dried. The product is purified on a column of silica, using a mixture of cyclohexane and ethyl acetate (20:1 v/v) as eluent.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[F:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][C:21]([O:23]C(C)(C)C)=O)=[CH:14][CH:13]=1.ClC(OCC)=O.Cl[CH:35](F)[F:36]>C(O)(=O)C.O1CCCC1>[F:36]/[CH:35]=[C:20](\[CH2:19][CH2:18][C:15]1[CH:14]=[CH:13][C:12]([F:11])=[CH:17][CH:16]=1)/[CH2:21][OH:23]
Reactant: FC(F)Cl
Reactant: CC(C)(C)OC(=O)CCCc1ccc(F)cc1
Agent: CCOC(=O)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: OC/C(=C/F)CCc1ccc(F)cc1
Reaction time: 0.25 h

Procedure:
Cool a tetrahydrofuran solution of sodium bis(trimethylsilyl)amide (545 kg, 2M, 877 mol) to -10° C. Slowly add, t-butyl 4-(p-fluorophenyl)butyrate (84.1 kg, 80% by weight in toluene, 353 mol). After 15 minutes, slowly add ethyl chloroformate (38.6 kg, 356 mol) at such a rate that the reaction temperature is maintained at or below -5° C. After 20 minutes, warm the reaction mixture to 40° C.-45° C. Seal the reaction vessel and add chlorodifluoromethane (38.15 kg, 445 mol) to the head space. After 1 hour, cool to 15° C.-20° C. and vent the reaction vessel. Add a solution of acetic acid (421 kg, 20% in water) and stir. After 30 minutes, separate the aqueous layer and evaporate the organic layer in vacuo to obtain a residue. Add toluene (45 kg) and evaporate in vacuo until the internal temperature of the reaction vessel is 55° C. to obtain the title compound as a toluene solution.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][OH:23])[CH:17]=2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:5]([F:24])=[CH:4][N:3]=1.[C:25](Cl)(=[O:28])[CH:26]=[CH2:27].CCCCCC.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>O>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N:22]([OH:23])[C:25](=[O:28])[CH:26]=[CH2:27])[CH:17]=2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:5]([F:24])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N(c1cccc(NO)c1)c1nc(Cl)ncc1F
Reactant: C=CC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: CCOC(C)=O
Product: C=CC(=O)N(O)c1cccc(N(C(=O)OC(C)(C)C)c2nc(Cl)ncc2F)c1
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
In a 25 ml 3-neck RBF was equipped with a magnetic stirrer and CaCl2 guard tube was added tert-butyl (2-chloro-5-fluoropyrimidin-4-yl)(3-(hydroxyamino)phenyl)carbamate (0.409 g in 5 ml DCM). The reaction was cooled to −40° C. and acryloyl chloride (0.114 g in 3 ml DCM) was slowly added. The reaction mixture was warmed to room temperature and stirred at room temperature for 30 min. The reaction was monitored on TLC using hexane:ethyl acetate (7:3) as mobile phase. The reaction was complete after 30 min and was poured in water (100 ml) and basified using sodium bicarbonate solution. The reaction mixture was extracted with DCM (2×25 ml) and the combined organic layer was washed with brine solution, dried over sodium sulfate and concentrated completely under reduced pressure at 40° C. Crude material was purified by using column chromatography. Product was eluted with 14% ethyl acetate in hexane to give, after concentration, 0.250 g of tert-butyl (2-chloro-5-fluoropyrimidin-4-yl)(3-(N-hydroxyacrylamido)phenyl)carbamate
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:14](=[O:15])[C:13]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([C@@H:25]3[O:42][C@H:41]([CH2:43][O:44][C:45](=[O:47])[CH3:46])[C@@H:36]([O:37][C:38](=[O:40])[CH3:39])[C@H:31]([O:32][C:33](=[O:35])[CH3:34])[C@H:26]3[O:27][C:28](=[O:30])[CH3:29])[CH:17]=2)=[C:12]([C:48]2[C:56]3[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=3)[NH:50][CH:49]=2)[C:11]1=[O:57])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.II>C1C=CC=CC=1.C(OCC)(=O)C.[Hg]>[CH2:1]([O:8][CH2:9][N:10]1[C:11](=[O:57])[C:12]2[C:48]3[C:56]4[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=4)[NH:50][C:49]=3[C:17]3[N:18]([C@@H:25]4[O:42][C@H:41]([CH2:43][O:44][C:45](=[O:47])[CH3:46])[C@@H:36]([O:37][C:38](=[O:40])[CH3:39])[C@H:31]([O:32][C:33](=[O:35])[CH3:34])[C@H:26]4[O:27][C:28](=[O:30])[CH3:29])[C:19]4[N:20]=[CH:21][CH:22]=[CH:23][C:24]=4[C:16]=3[C:13]=2[C:14]1=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(C3=C(c4c[nH]c5ccccc45)C(=O)N(COCc4ccccc4)C3=O)c3cccnc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: II
Agent: [Hg]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](n2c3ncccc3c3c4c(c5c6ccccc6[nH]c5c32)C(=O)N(COCc2ccccc2)C4=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 0.5 h

Procedure:
To a solution of the compound of Example 1b (0.409 mmol), dissolved in 500 ml of benzene, there is added iodine (4.90 mmol). The mixture is irradiated in a quartz reactor equipped with an immersible medium-pressure mercury-vapour U.V. lamp of 400 W for 1 hour 30 minutes. The solvent is evaporated off; the crude reaction product is taken up in ethyl acetate and washed with aqueous sodium thiosulphite solution and then with saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate and filtered, and the solvent is evaporated off. After purification by chromatography on silica gel (cyclohexane/ethyl acetate: 3/2), the expected product is isolated.
Reaction SMILES: C(O[CH:4]=[C:5]([C:10]#[N:11])[CH:6](O)C#N)C.[CH:12]([NH:15][NH2:16])([CH3:14])[CH3:13].C([N:19](CC)CC)C>C(O)C>[NH2:11][C:10]1[N:15]([CH:12]([CH3:14])[CH3:13])[N:16]=[CH:4][C:5]=1[C:6]#[N:19]
Reactant: CCOC=C(C#N)C(O)C#N
Reactant: CCN(CC)CC
Reactant: CC(C)NN
Solvent: CCO
Product: CC(C)n1ncc(C#N)c1N
Temperature: 150 °C

Procedure:
A mixture of ethoxymethylenemalonitrile (0.55 g, 4.5 mmol) and iso-propylhydrazine (0.50 g, 4.5 mmol) in ethanol (10 mL) in a 10-20 mL Smith process vial was treated with triethylamine (0.88 mL). The vial was capped and heated in the microwave reactor for one hour at 150° C. Following cooling of the vial, the mixture was concentrated to dryness under reduced pressure. The residue was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness under reduced pressure to provide 5-amino-1-isopropyl-1H-pyrazole-4-carbonitrile as a slowly solidifying syrup (0.72 g, >100%). MS (ES+): 151.2 (M+H)+
Reaction SMILES: CN([Si:9]([CH3:12])([CH3:11])[CH3:10])C(=O)C(F)(F)F.[CH:13]([NH:15][CH:16]1[C:28](=[O:29])[N:18]2[C:19]([C:25]([OH:27])=[O:26])=[C:20]([CH3:24])[CH2:21][S:22](=[O:23])[C@H:17]12)=[O:14].NS(O)(=O)=O.[Br:35]N1C(=O)CCC1=O>ClCCl>[Br:35][CH2:24][C:20]1[CH2:21][S:22](=[O:23])[C@@H:17]2[CH:16]([NH:15][CH:13]=[O:14])[C:28](=[O:29])[N:18]2[C:19]=1[C:25]([O:27][Si:9]([CH3:12])([CH3:11])[CH3:10])=[O:26]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC=O)[C@H]2S(=O)C1
Reactant: CN(C(=O)C(F)(F)F)[Si](C)(C)C
Agent: NS(=O)(=O)O
Solvent: ClCCl
Product: C[Si](C)(C)OC(=O)C1=C(CBr)CS(=O)[C@@H]2C(NC=O)C(=O)N12
Yield: 52 %

Procedure:
325 mg (1.63 mmoles) of N-methyl-N-trimethylsilyltrifluoroacetamide were added at room temperature to a suspension of 280.7 mg (1.09 mmoles) of 7-formamido-3-methyl-3-cephem-4-carboxylic acid-1-oxide in 40 ml of dichloromethane and the mixture was stirred for half an hour, after which an almost clear solution was obtained. This was cooled in an ice-bath and 69.5 mg (0.71 mmole) of amidosulfonic acid were added to it. Bromination was carried out in half an hour using 275.8 mg (1.55 mmoles) of N-bromosuccinimide as the brominating agent to obtain a 52% yield of trimethylsilyl 3-bromomethyl-7-formamido-3-cephem-4-carboxylate-1-oxide.
Reaction SMILES: [C:1]([C:4]1[C:9](/[CH:10]=[CH:11]/[C:12]([O:14]C(C)(C)C)=[O:13])=[C:8]([F:19])[C:7]([Cl:20])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]>C(Cl)Cl.C(O)(C(F)(F)F)=O>[C:1]([C:4]1[C:9](/[CH:10]=[CH:11]/[C:12]([OH:14])=[O:13])=[C:8]([F:19])[C:7]([Cl:20])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(Cl)c(F)c1/C=C/C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1ccc(Cl)c(F)c1/C=C/C(=O)O
Reaction time: 1.5 h
Yield: 95.7 %

Procedure:
A solution of Intermediate 12D (25 g, 84 mmol) in DCM (330 mL) and TFA (330 mL) was stirred at rt. After 1.5 h, the solvent was concentrated to give Intermediate 12 (19.5 g, 97.0% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ: 12.69 (bs, 1 H), 7.80-7.76 (m, 2 H), 7.62 (d, J=12.1 Hz, 1 H), 6.30 (dd, J=2.4, 2.0 Hz, 1 H), 2.6 (s, 3H) ppm. MS (ESI) m/z: 241 (M−H)+.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([OH:8])=O.S(Cl)(Cl)=O.[C:13]([N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[OH-].[Na+]>C1(C)C=CC=CC=1.O>[O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([N:23]1[CH2:22][CH2:21][N:20]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:25][CH2:24]1)=[O:8]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)[C@H]1CCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)[C@H]2CCCO2)CC1
Temperature: 90 °C
Reaction time: 2 h
Yield: 80.6 %

Procedure:
To a solution of (R)-tetrahydro-2-furoic acid (5 g, 43.06 mmol) in toluene (75 mL) was added thionyl chloride (7.68 g, 64.6 mmol). The mixture was stirred at 90° C. for 2 h, then slowly cooled to 0° C. To a separate flask was charged a solution of N-Boc piperazine (8.02 g, 43.06 mmol) in toluene (40 mL), and aqueous sodium hydroxide (10.3 g, 258 mmol) in water (80 mL). This biphasic solution was cooled in an ice bath, followed by the addition of the cold acid chloride prepared above. The mixture was stirred vigorously for 2 h. The organic phase was collected, and washed with 1M H3PO4, dried and evaporated, to provide the title intermediate (9.87 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:12][C:13]#[N:14])[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22](Cl)(=[O:24])=[O:23]>N1C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1([CH2:12][C:13]#[N:14])[CH2:7][CH2:8][N:9]([S:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[Cl:15])(=[O:24])=[O:23])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(CC#N)CCNCC1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Solvent: c1ccncc1
Product: CCOC(=O)C1(CC#N)CCN(S(=O)(=O)c2ccccc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.7 %

Procedure:
4-Cyanomethyl-piperidine-4-carboxylic acid ethyl ester (14.2 g) was dissolved in pyridine (150 ml), 2-chlorobenzenesulfonyl chloride (16.83 g) was added and the reaction mixture was stirred overnight at RT. Then, most of pyridine was evaporated off in vacuo, the residue was dissolved in AcOEt, washed with 0.5M aqueous HCl and brine. The organic layer was dried over magnesium sulphate and concentrated in vacuo. The residue (crude oil) was chromatographed over silica (AcOEt/Heptanes, gradient from 0 to 25%) to give the desired material (8.5 g) as viscous brown oil. MS (ESI): 388.1 (M+NH4)+.
Reaction SMILES: [CH:1](=O)[CH2:2][CH3:3].O=O.C(O[CH2:11][CH3:12])(=O)C>>[CH:2]12[C:3]([CH3:12])([CH3:11])[CH:3]1[CH2:2][CH:1]=[C:11]([CH3:12])[CH2:1]2
Reactant: CCOC(C)=O
Reactant: CCC=O
Agent: O=O
Product: CC1=CCC2C(C1)C2(C)C
Reaction time: 4 h

Procedure:
Δ-3-carene was epoxidized by the above-described procedure, using Di(acetate)3 as catalyst (1% based on the weight of Δ-3-carene) and ethyl acetate as solvent (volume ratio solvent to Δ-3-carene 3:1). The final mol ratio propionaldehyde to Δ-3-carene was 1.5:1, oxygen was bubbled through at a rate of 8 liters/hour, and reaction time was 4 hours.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C@@H:14]2[CH2:16][C@@H:15]2[CH:17]2[CH2:22][CH2:21][N:20]([C:23]3[N:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=3)[CH2:19][CH2:18]2)(=O)=O)=CC=1.COC1C=CC(C[N:37]2[C:45]3[C:40](=[CH:41][C:42]([NH:46]C(=O)OC(C)(C)C)=[CH:43][CH:44]=3)[CH:39]=[N:38]2)=CC=1.COC1C=CC(CN2C3C(=CC(NC(=O)OC(C)(C)C)=CC=3)CN2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1.O>[Cl:29][C:26]1[CH:27]=[N:28][C:23]([N:20]2[CH2:19][CH2:18][CH:17]([C@H:15]3[CH2:16][C@H:14]3[CH2:13][CH2:12][NH:46][C:42]3[CH:41]=[C:40]4[C:45](=[CH:44][CH:43]=3)[NH:37][N:38]=[CH:39]4)[CH2:22][CH2:21]2)=[N:24][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)OCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)cc1
Reactant: COc1ccc(Cn2ncc3cc(NC(=O)OC(C)(C)C)ccc32)cc1
Agent: COc1ccc(CN2NCc3cc(NC(=O)OC(C)(C)C)ccc32)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Clc1cnc(N2CCC([C@H]3C[C@H]3CCNc3ccc4[nH]ncc4c3)CC2)nc1
Temperature: 70 °C
Reaction time: 24 h

Procedure:
2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethyl 4-methylbenzenesulfonate from step 1 of Example 5 (100 mg, 0.23 mmol) was dissolved in NMP (1.1 ml). The mixture of tert-butyl [1-(4-methoxybenzyl)-1H-indazol-5-yl]carbamate and tert-butyl [1-(4-methoxybenzyl)-2H-indazol-5-yl]carbamate (81 mg, 0.23 mmol) from step 2 of this example and cesium carbonate (0.224 mg, 0.69 mmol) were added and the slurry stirred at 70° C. for 24 h. The mixture was diluted with 4:1 water:saturated sodium bicarbonate (30 ml), extracted with EtOAc (3×30 ml), the organic fractions combined, washed with brine, dried over Na2SO4, filtered, and the volatiles removed in vacuum. The material was dissolved in TPA at RT and the solution stirred for 5 minutes. The solution was heated to 70° C. for 2 hours. The volatiles were removed in vacuum. The residue was dissolved in DCM (30 ml), shaken with a solution of saturated bicarbonate (30 ml), the layers separated, and the aqueous phase extracted with DCM (2×30 ml). The organic fractions were combined, washed with brine, dried over Na2SO4, filtered, and the volatiles removed in vacuum. The product was purified by chromatography on SiO2 eluting with 20% acetone:DCM to give the titled compound. LRMS calc: 396.18; obs: 397.27 (M+1). Compounds reported in Table 6 are prepared by a general procedure analogous to that described in Example 42 above.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:16]C(CCCC[C@H]1[C@@H]2[C@@H](NC(N2)=O)CS1)=O>CS(C)=O>[CH:10]1([NH:9][C:8](=[O:16])[NH:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CS(C)=O
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
One molar equivalent (1.97 g) of HNSA was mixed together with one molar equivalent (1.85 g) of dicyclohexylcarbodiimide and one molar equivalent (2.0 g) of biotin in 50 ml of dimethylsulfoxide at room temperature overnight. The reaction resulted in the formation of dicyclohexyl urea as a precipitate. The precipitate was filtered off and 400 ml of dichloromethane was added to the mother liquor. After several hours a solid precipitate was formed. The yield of this crude ester was 59% of theoretical. This precipitate was analyzed spectroscopically as described in Example IA and found to contain 38% biotin-HNSA ester together with 68% of free HNSA. The solid was then purified by column chromatography on LH20 Sephadex in DMF and positively identified as described above for the preparation of mal-sac HNSA ester. The purification yielded biotin-HNSA ester of greater than 99% purity.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:5]([C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)=[O:7])=[CH:14][CH:13]=1
Reactant: O=C(O)c1cccc(F)c1
Reactant: Nc1ccccc1
Product: Nc1ccc(C(=O)c2cccc(F)c2)cc1
Reaction time: 1 h
Yield: 299.2 %

Procedure:
To stirred 90° C. polyphosphoric acid (150 g) was added 10.72 g (7.65 mmol) of 3-fluorobenzoic acid and 6.98 g (7.5 mmol) of aniline and the bath temperature raised to 180°-190° C. and held there for 1 hour. A solution was obtained at about 130° C. The heating bath was removed and the stirred mixture (sublimate above the solution) was treated cautiously with 60 mL of water. The mixture was stirred at 140°-155° C. for 1 hour, the heating bath removed, 50 mL of 3N HCl added, the mixture poured into 750 mL of water and filtered through a pad of Celite. The filtrate was basified with 15% sodium hydroxide and the resulting solid extracted with methylene chloride. The dried (MgSO4) solution was filtered and the solvent removed to yield a brown solid. Recrystallization from ethanol-hexane (1:3) returned a greenish yellow solid that was chromatographed on silica gel (methylene chloride) to yield 4.83 g (30%) of yellow 4-amino-3'-fluorobenzophenone, mp 98°-100° C. 1H NMR (300 MHz, CDCl3): 4.21 (s, 2H, NH2) 6.66-6.70 (m, 2H, aromatic) 7.23-7.26 (m, 1H, aromatic) 7.39-7.51 (m, 3H, aromatic) 7.69-7.72 (m, 2H, aromatic). MS (CI, CH4): 216 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[CH:8]=1.C([O:16][CH:17](O)[C:18]([F:21])([F:20])[F:19])C.O>C(OCC)(=O)C>[F:19][C:18]([F:21])([F:20])[CH:17]([C:12]1[N:7]=[CH:8][C:9]([OH:13])=[CH:10][CH:11]=1)[OH:16]
Reactant: Oc1cccnc1
Reactant: CCOC(O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: Oc1ccc(C(O)C(F)(F)F)nc1
Temperature: 100 °C
Reaction time: 4 h
Yield: 19.2 %

Procedure:
Potassium carbonate (4.66 g, 36.3 mmol) was added to the mixture of pyridin-3-ol (2.00 g, 21.0 mmol) and 1-ethoxy-2,2,2-trifluoroethanol (3.30 g, 23.1 mmol), and the mixture was stirred for 4 hours at 100° C. under nitrogen atmosphere. This reaction solution was cooled to room temperature, followed by adding water and ethyl acetate to the reaction solution, washing the organic layer with a saturated saline solution, drying the layer with anhydrous sodium sulfate, and thereafter concentration under reduced pressure. The obtained residue was purified by silica gel column chromatography (Purif-Pack SI200, hexane:ethyl acetate:=40:60) to obtain the title compound (780 mg, yield: 19%) as a white amorphous.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][N:7]=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>ClCCl.C(N(CC)CC)C.O>[CH3:18][S:19]([O:1][CH2:2][C:3]1[N:4]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][N:7]=1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)n2ccnc2CO)cc1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)n2ccnc2COS(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
The alcohol described in (b) above (12.6 mg) was dissolved in dichloromethane (2.5 ml) and triethylamine (0.07 ml). This solution was cooled to 0° C. Methanesulfonyl chloride (0.04 ml) was added to the solution dropwise. After stirring for 10 mins the solution was diluted with water and the organic layer was separated, dried (MgSO4), filtered and the solvent removed in vacuo to yield a white solid which was used in the following reaction without further purification. 1H NMR (250 MHz, CDCl3) d 2.44 (3H, s, ArH), 2.94 (3H, s, SO2CH3), 5.51 (2H, s, CH2SO2), 7.08 (1H, d, J=1.5 Hz, imidazole-H), 7.40 (2H, d, J=8.0 Hz, ArH), 7.49 (1H, d, J=1.5 Hz, imidazole-H), 7.92 (2H, d, J=8.0 Hz, ArH).