Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:23][C:22]3[C:17](=[C:18]([O:30][CH3:31])[C:19]([O:28][CH3:29])=[C:20]([O:26][CH3:27])[C:21]=3[O:24][CH3:25])[C:16]2=[O:32])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)C.[BH4-].[Na+].Cl>O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:23][C:22]3[C:17](=[C:18]([O:30][CH3:31])[C:19]([O:28][CH3:29])=[C:20]([O:26][CH3:27])[C:21]=3[O:24][CH3:25])[CH:16]2[OH:32])=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1(c2ccc(OCc3ccccc3)cc2)Cc2c(OC)c(OC)c(OC)c(OC)c2C1=O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C1(c2ccc(OCc3ccccc3)cc2)Cc2c(OC)c(OC)c(OC)c(OC)c2C1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 79.6 %

Procedure:
Ethyl 2-(4-benzyloxyphenyl)-4,5,6,7-tetramethoxy-1-oxo-2-indancarboxylate (3.78 g, 7.46 mmols) was dissolved in ethanol (40 mmols), and sodium borohydride (564 mg, 14.9 mmols) was added thereto with cooling with ice. The reaction mixture was warmed to room temperature, and then stirred for further 6 hours. Water was added to the reaction mixture, which was neutralized with 10% hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, and then dried. The solvent was evaporated out in vacuo, and the resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate=4:1 to 2:1) to obtain ethyl 2-(4-benzyloxyphenyl)-1-hydroxy-4,5,6,7-tetramethoxy-2-indancarboxylate (3.02 g).
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]2[C:13]([N:14]3[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]([CH3:25])[C:15]3=[O:26])=[CH:12][CH:11]=[C:10]([Cl:27])[C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:28]N(Cl)C(OCC)=O.O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C.Cl>[C:1]([C:5]1[O:6][C:7]2[C:13]([N:14]3[C:19](=[O:20])[C:18]([Cl:28])=[C:17]([C:21]([F:23])([F:22])[F:24])[N:16]([CH3:25])[C:15]3=[O:26])=[CH:12][CH:11]=[C:10]([Cl:27])[C:8]=2[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)N(Cl)Cl
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c3nc(C(C)(C)C)oc23)c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cn1c(C(F)(F)F)c(Cl)c(=O)n(-c2ccc(Cl)c3nc(C(C)(C)C)oc23)c1=O
Reaction time: 0.25 h
Yield: 130.7 %

Procedure:
A stirred solution of 0.84 gram (2.1 mmole) of 3-(2-t-butyl-4-chlorobenzoxazol-7-yl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)pyrimidinedione (prepared as described in Example 2) in 20 mL of acetic acid had 0.16 gram (1.0 mmole) of N,N-dichlorourethane added via syringe. Upon completion of the addition the clear reaction mixture was stirred for 15 minutes, then one drop of concentrated hydrochloric acid was added, and the reaction mixture was stirred at ambient temperature for 72 hours. After this time the reaction mixture was poured into 100 mL of water, and 10 grams of sodium carbonate were added. The mixture was extracted with three 50 mL portions of methylene chloride. The organic extracts were combined and washed with one 50 mL portion of an aqueous 5% sodium carbonate solution. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrate under reduced pressure, yielding a pale yellow oil which was subjected to column chromatography on silica gel. Elution was accomplished with 9:1 heptane:ethyl acetate, followed by 2:1 heptane:ethyl acetate. The product-containing fractions were combined and concentrated under reduced pressure, yielding 0.57 gram of 3-(2-t-butyl-4-chlorobenzoxazol-7-yl)-1-methyl-5-chloro-6-trifluoromethyl-2,4-(1H,3H)pyrimidinedione, m.p. 83°-86° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: Cl[C:2]1[C:3]([CH3:14])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.C(=O)([O-])[O-:16].[Na+].[Na+]>Cl.O>[CH3:13][O:12][C:8]1[CH:9]=[C:10]2[C:5]([N:4]=[C:3]([CH3:14])[C:2](=[O:16])[NH:11]2)=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc2nc(C)c(Cl)nc2c1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: COc1ccc2nc(C)c(=O)[nH]c2c1
Temperature: 110 °C
Yield: 71 %

Procedure:
A suspension of 3-chloro-6-methoxy-2-methylquinoxaline (Intermediate 162, 1.5 g, 7.21 mmol) in 5M HCl (30 mL) was heated to 110° C. for 1 hour. The reaction mixture was neutralized with saturated sodium carbonate solution, diluted with water and extracted with ethyl acetate (3 times). The combined organic phases were dried over magnesium sulfate and concentrated to a small volume under reduced pressure. The precipitate was collected by filtration to give 1.0 g (71%) of product as an off-white solid.
Reaction SMILES: Cl.[NH2:2][N:3]=[CH:4][C:5]1[CH:29]=[CH:28][C:8]([C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]3[O:20][CH:19]([CH2:21][C:22]([O:24]CC)=[O:23])[CH2:18][CH2:17][C:16]=3[CH:27]=2)=[O:10])=[C:7]([Cl:30])[CH:6]=1.C(O)C.[OH-].[Na+]>C(O)(=O)C>[NH2:2][N:3]=[CH:4][C:5]1[CH:29]=[CH:28][C:8]([C:9]([NH:11][C:12]2[CH:13]=[CH:14][C:15]3[O:20][CH:19]([CH2:21][C:22]([OH:24])=[O:23])[CH2:18][CH2:17][C:16]=3[CH:27]=2)=[O:10])=[C:7]([Cl:30])[CH:6]=1
Reactant: CCOC(=O)CC1CCc2cc(NC(=O)c3ccc(C=NN)cc3Cl)ccc2O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: NN=Cc1ccc(C(=O)Nc2ccc3c(c2)CCC(CC(=O)O)O3)c(Cl)c1

Procedure:
0.3 g (0.66 mmol) of the ester from Example 75 were stirred overnight at room temperature with a mixture of 5 ml ethanol and 0.5 ml 2 N aqueous sodium hydroxide solution. It was brought to pH 5 with 2 N acetic acid. The precipitate of the title compound was filtered with suction, washed successively with water and with acetone, and dried in vacuo. Yield: 0.19 g (74%) of a white powder, m.p. 269-270° C.(dec.).
Reaction SMILES: C[O:2][C:3](=[O:26])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:14]=2)=O)[C:5]=1[OH:25].[OH-].[Na+]>>[C:16]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:17]=[CH:18][C:13]([C:11]2[O:25][C:5]3[C:4]([C:3]([OH:2])=[O:26])=[CH:9][CH:8]=[CH:7][C:6]=3[N:10]=2)=[CH:14][CH:15]=1
Reactant: COC(=O)c1cccc(NC(=O)c2ccc(-c3ccccc3)cc2)c1O
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cccc2nc(-c3ccc(-c4ccccc4)cc3)oc12
Temperature: 170 °C
Yield: 39.6 %

Procedure:
3-[(biphenyl-4-carbonyl)-amino]-2-hydroxy-benzoic acid methyl ester (100 mg, 0.28 mmol) was suspended in PPA (500 mg) and heated at 170° C. for 4 h. The reaction was monitored by TLC. After completion of the reaction, the crude mixture was cooled to room temperature and ice water was added. The pH was adjusted to 5 with an aq. solution of 5N NaOH and was extracted with ethyl acetate (3×50 mL). The combined organic phases were dried over sodium sulphate and concentrated under reduced pressure. The crude mixture was purified by column chromatography to get 35 mg of the required product as a pale pink coloured solid.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[CH:14]([NH:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1)[C:15]#[N:16]>>[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=1[CH:14]([NH:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=1)[C:15]([NH2:16])=[O:2]
Reactant: N#CC(Nc1ccc2ccccc2c1)c1c(Cl)cccc1Cl
Reactant: O=S(=O)(O)O
Product: NC(=O)C(Nc1ccc2ccccc2c1)c1c(Cl)cccc1Cl
Reaction time: 8 h

Procedure:
To 360 parts of concentrated sulfuric acid are added portionwise 30 parts of 2,6-dichloro-α-[(2-naphthalenyl)amino]benzeneacetonitrile and the whole is stirred till all solid enters solution. The reaction solution is allowed to stand overnight at room temperature and then poured onto 1000 parts of crushed ice. The precipitated product is filtered off and extracted with 1500 parts of chloroform. The organic phase is washed with water, dried, filtered and evaporated. The oily residue solidifies on triturating in 2-propanol. The solid product is filtered off and crystallized from 200 parts of 2-propanol at 0° C., yielding 11.3 parts of 2,6-dichloro-α-[(2-naphthalenyl)amino]benzeneacetamide; mp. 157.9° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:12][CH:13]([C:17]([CH3:21])([CH3:20])[CH2:18][CH3:19])[C:14](O)=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.CCN=C=NCCCN(C)C.Cl.OC1C2N=NNC=2C=CC=1.C(N(C(C)C)CC)(C)C.Cl.[NH2:54][OH:55]>CN(C=O)C.ClCCl>[OH:55][NH:54][C:14](=[O:15])[CH:13]([NH:12][S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])[C:17]([CH3:21])([CH3:20])[CH2:18][CH3:19]
Reactant: NO
Reactant: CCC(C)(C)C(NS(=O)(=O)c1ccc(OC)cc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(C)(C)C(NS(=O)(=O)c1ccc(OC)cc1)C(=O)NO
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.1 %

Procedure:
The product of step 1 (0.116 g), EDC hydrochloride (0.076 g, 1.1 equivalent), hydroxybenzotriazole (0.054 g, 1.1 equivalent), and diisopropylethylamine (0.143 g, 3 equivalent) are mixed with dichloromethane (20 mL) to give a homogeneous solution. Hydroxylamine hydrochloride (0.051 g, 2 equivalent) is added as a solid. DMF (3 mL) is added to solubilize the hydroxylamine hydrochloride. The reaction is allowed to stir at room temperature overnight. The solvents are then removed under reduced pressure and the residue partitioned between ethyl acetate and 1N HCl. The organic phase is separated and the aqueous phase re-extracted with ethyl acetate. The combined organic phases are dried (MgSO4), filtered, and concentrated under reduced pressure. The crude product is loaded onto a reverse phase column as a DMSO solution. The column is eluted with a step gradient, starting at 20% acetonitrile/water, and raised in 10% increments. The appropriate fractions are combined to give 22 mg of the title compound. 1H NMR (DMSO, 300 MHz): 10.4, 7.69-7.65, 7.43, 7.01-6.98, 3.80, 1.20-1.17, 0.77, 0.75, 0.69 .
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:5]([CH2:6][O:7][C:8](=[O:10])[NH2:9])[N:4]([S:11]([OH:14])(=[O:13])=[O:12])[C:3]1=[O:15].[NH2:16][C:17]1[S:18][CH:19]=[C:20](/[C:22](=[N:26]/[O:27][CH2:28][CH2:29][N:30]=[N+:31]=[N-:32])/[C:23](O)=[O:24])[N:21]=1>>[NH2:16][C:17]1[S:18][CH:19]=[C:20](/[C:22](=[N:26]/[O:27][CH2:28][CH2:29][N:30]=[N+:31]=[N-:32])/[C:23]([NH:1][C@H:2]2[C@@H:5]([CH2:6][O:7][C:8](=[O:10])[NH2:9])[N:4]([S:11]([OH:14])(=[O:12])=[O:13])[C:3]2=[O:15])=[O:24])[N:21]=1
Reactant: NC(=O)OC[C@@H]1[C@H](N)C(=O)N1S(=O)(=O)O
Reactant: [N-]=[N+]=NCCO/N=C(\C(=O)O)c1csc(N)n1
Product: [N-]=[N+]=NCCO/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1COC(N)=O)c1csc(N)n1
Yield: 59 %

Procedure:
In the same manner as described in Example 9, from 1.87 g of (3S,4S)-3-amino-4-carbamoyloxymethyl-2-oxo-1-azetidinesulphonic acid and 2 g of 2-(2-amino-4-thiazolyl)-2-[(Z)-(2-azidoethoxy)imino]-acetic acid there are obtained 2.2 g of (3S,4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[(2-azidoethoxy)imino]acetamido]-4-carbamoyloxymethyl-2-oxo-1-azetidinesulphonic acid.
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[C:9]([CH2:11][N:12]3[CH2:16][CH2:15][C@H:14]([NH:17][S:18]([C:21]4[S:25][C:24]5[CH:26]=[C:27]([Cl:30])[CH:28]=[CH:29][C:23]=5[CH:22]=4)(=[O:20])=[O:19])[C:13]3=[O:31])[NH:10][C:6]=2[CH:5]=[CH:4][N:3]=1>[Pd].C(O)C>[O:31]=[C:13]1[C@@H:14]([NH:17][S:18]([C:21]2[S:25][C:24]3[CH:26]=[C:27]([Cl:30])[CH:28]=[CH:29][C:23]=3[CH:22]=2)(=[O:19])=[O:20])[CH2:15][CH2:16][N:12]1[CH2:11][C:9]1[NH:10][C:6]2[CH:5]=[CH:4][N:3]=[CH:2][C:7]=2[CH:8]=1
Reactant: O=C1[C@@H](NS(=O)(=O)c2cc3ccc(Cl)cc3s2)CCN1Cc1cc2c(Cl)nccc2[nH]1
Agent: [Pd]
Solvent: CCO
Product: O=C1[C@@H](NS(=O)(=O)c2cc3ccc(Cl)cc3s2)CCN1Cc1cc2cnccc2[nH]1
Temperature: 65 °C

Procedure:
Palladium on carbon (0.01 g) is added to a solution of 6-chloro-benzo[b]thiophene-2-sulfonic acid [1-(4-chloro-1H-pyrrolo[3,2-c]pyridin-2-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide in 95% ethanol (5 mL) and charged with H2 gas. The mixture is heated at 65° C. overnight then cooled to room temperature and filtered through Celite. The solvent is removed and the crude product is purified by RP-HPLC eluting with a gradient of 10% CH3CN/H2O (0.1% TFA) to 100% CH3CN. The appropriate product fractions are lyophilized to give the title compound as a white solid.
Reaction SMILES: C([Li])CCC.[C:6](#[N:8])[CH3:7].[CH3:9][O:10][CH2:11][CH2:12][C:13](OC)=[O:14]>C1COCC1>[CH3:9][O:10][CH2:11][CH2:12][C:13](=[O:14])[CH2:7][C:6]#[N:8]
Reactant: CC#N
Reactant: COCCC(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCCC(=O)CC#N
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A flame-dried flask was charged with 5 ml (8.0 mmol) n-butyllithium (1.6 M solution in hexanes) in dry THF (25 ml) under inert gas atmosphere and cooled to −78° C. Next, 0.368 ml (7 mmol) acetonitrile were slowly added, and the resulting mixture was stirred for 1 h at −70° C. Then, 0.585 ml (5.0 mmol) methyl 3-methoxypropanoate were slowly added maintaining the temperature below −66° C. The reaction mixture was stirred for 2 h at −45° C. and then quenched by addition of hydrochloric acid (2 M, 16 ml) keeping the temperature below −35° C. The resulting clear solution was allowed to warm to room temperature and then concentrated under reduced pressure, and the residue was dried under high vacuum. The crude product thus obtained (1.51 g) was used in the next step without further purification.
Reaction SMILES: CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[C:31]1([C:37]2[NH:41][N:40]=[C:39]([C:42]([NH:44][CH2:45][C:46]([OH:48])=O)=[O:43])[CH:38]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.Cl.[Cl:50][C:51]1[CH:61]=[CH:60][CH:59]=[CH:58][C:52]=1[O:53][CH:54]1[CH2:57][NH:56][CH2:55]1>CN(C=O)C>[Cl:50][C:51]1[CH:61]=[CH:60][CH:59]=[CH:58][C:52]=1[O:53][CH:54]1[CH2:57][N:56]([C:46](=[O:48])[CH2:45][NH:44][C:42]([C:39]2[CH:38]=[C:37]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[NH:41][N:40]=2)=[O:43])[CH2:55]1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)[nH]n1
Reactant: Clc1ccccc1OC1CNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CC(Oc2ccccc2Cl)C1)c1cc(-c2ccccc2)[nH]n1
Reaction time: 0.03 h
Yield: 42.8 %

Procedure:
DIPEA (143 mg, 1.1 mmol) followed by HOBt (39 mg, 0.29 mmol) and EDCI (56 mg, 0.29 mmol) was added to a stirred solution of [(5-phenyl-1H-pyrazole-3-carbonyl)-amino]-acetic acid (67 g, 0.27 mmol) in DMF (2 mL). After 2 minutes of stirring, 3-(2-chloro-phenoxy)-azetidinehydrochloride (prepared by the method used for the synthesis of Intermediate 71) (60 mg, 0.27 mmol) was added and the resulting mixture was stirred at room temperature overnight. The reaction mixture was partitioned between cold water and ethyl acetate. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. Purification by preparative HPLC afforded 48 mg (42.8% Yield) of 5-phenyl-1H-pyrazole-3-carboxylic acid {2-[3-(2-chloro-phenoxy)-azetidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 411, 99.1%. 1H NMR (300 MHz, DMSO-d6): δ 13.7 (s, 1H), 8.2 (t, 1H), 7.54 (m, 2H), 7.28 (m, 5H), 7.08 (d, 1H), 7.0 (t, 1H), 6.86 (d, 1H), 5.1 (m, 1H), 4.64 (m, 1H), 4.36 (m, 1H), 4.2 (m, 1H), 3.84 (m, 3H).
Reaction SMILES: Cl[Si:2]([CH3:17])([CH3:16])[CH:3]1[C:14]2[C:6](=[CH:7][C:8]3[CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=2)[CH:5]=[C:4]1[CH3:15].CCN(CC)CC.[CH:25]1([NH2:31])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CCCCCC>[CH:25]1([NH:31][Si:2]([CH3:17])([CH3:16])[CH:3]2[C:14]3[C:6](=[CH:7][C:8]4[CH2:9][CH2:10][CH2:11][C:12]=4[CH:13]=3)[CH:5]=[C:4]2[CH3:15])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: NC1CCCCC1
Reactant: CC1=Cc2cc3c(cc2C1[Si](C)(C)Cl)CCC3
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CC1=Cc2cc3c(cc2C1[Si](C)(C)NC1CCCCC1)CCC3
Reaction time: 16 h
Yield: 94.1 %

Procedure:
Chlorodimethyl(1,5,6,7-tetrahydro-2-methyl-s-indacen-1-yl) silane (5.67 g, 0.0216 moles) was stirred in hexane (50 mL) as NEt3 (2.18 g, 0.0216 moles) and cyclohexylamine (2.13 g, 0.0216 moles) were added. This mixture was allowed to stir 16 hours. After the reaction period the mixture was filtered and the volatiles removed resulting in the isolation of the desired product as a yellow oil (6.62 g, 94.3 percent).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[CH:3]2[CH2:7][CH:8]=[CH:9][CH2:10][CH:2]12.[K].S(C1C=CC(C)=CC=1)(O)(=O)=O.O[CH2:25][CH2:26][N:27]1[C:31]([N+:32]([O-:34])=[O:33])=[CH:30][N:29]=[C:28]1[CH3:35]>>[CH3:35][C:28]1[N:27]([CH2:26][CH2:25][N:5]2[C:1](=[O:11])[CH:2]3[CH2:10][CH:9]=[CH:8][CH2:7][CH:3]3[C:4]2=[O:6])[C:31]([N+:32]([O-:34])=[O:33])=[CH:30][N:29]=1
Reactant: O=C1NC(=O)C2CC=CCC12
Reactant: Cc1ncc([N+](=O)[O-])n1CCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [K]
Product: Cc1ncc([N+](=O)[O-])n1CCN1C(=O)C2CC=CCC2C1=O

Procedure:
1,2,3,6-Tetrahydrophthalimide is converted to the potassium salt and reacted with 1-(2-hydroxyethyl)-2-methyl-5-nitroimidazole tosylate according to the procedure described in Example 13. The crude reaction mixture obtained is concentrated and the concentrate distributed between water and toluene. The toluene layer is separated and the solvent is evaporated to leave a residue which is recrystallized from 2-propanol, affording N-[2-(2-methyl-5-nitro-1-imidazolyl)ethyl]-1,2,3,6-tetrahydrophthalimide melting at about 118°-123° C.
Reaction SMILES: FC1C=C(C=CC=1[N+]([O-])=O)OCC1C=CC(C)=CN=1.[CH3:20][C:21]1[CH:44]=[C:43]([O:45][C:46]([F:49])([F:48])[F:47])[CH:42]=[CH:41][C:22]=1[CH2:23][NH:24][C:25]1[C:26]([NH2:40])=[CH:27][CH:28]=[C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][N:34]=2)[CH:30]=1.[C:50]1(=[O:60])[C@@H:58]2[C@@H:53]([CH2:54][CH2:55][CH2:56][CH2:57]2)[C:52](=O)[O:51]1>>[CH3:39][C:36]1[CH:37]=[CH:38][C:33]([CH2:32][O:31][C:29]2[CH:28]=[CH:27][C:26]3[N:40]=[C:52]([C@H:53]4[CH2:54][CH2:55][CH2:56][CH2:57][C@H:58]4[C:50]([OH:60])=[O:51])[N:24]([CH2:23][C:22]4[CH:41]=[CH:42][C:43]([O:45][C:46]([F:48])([F:49])[F:47])=[CH:44][C:21]=4[CH3:20])[C:25]=3[CH:30]=2)=[N:34][CH:35]=1
Reactant: Cc1ccc(COc2ccc(N)c(NCc3ccc(OC(F)(F)F)cc3C)c2)nc1
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Agent: Cc1ccc(COc2ccc([N+](=O)[O-])c(F)c2)nc1
Product: Cc1ccc(COc2ccc3nc([C@H]4CCCC[C@H]4C(=O)O)n(Cc4ccc(OC(F)(F)F)cc4C)c3c2)nc1

Procedure:
The title compound was prepared using analogous conditions described in Example 92 using 2-((3-fluoro-4-nitrophenoxy)methyl)-5-methylpyridine in Step B and N1-(2-methyl-4-(trifluoromethoxy)benzyl)-5-((5-methylpyridin-2-yl)methoxy)benzene-1,2-diamine and cis-hexahydroisobenzofuran-1,3-dione in Step D. MS (ESI): mass calcd. for C30H30F3N3O4, 553.20; m/z found, 553.9 [M+H]+. 1H NMR (300 MHz, DMSO-d6) δ 8.34 (s, 1H), 7.66 (s, 1H), 7.60 (d, J=7.3, 1H), 7.37 (d, J=8.2, 1H), 7.32 (s, 1H), 7.15 (s, 2H), 6.95 (d, J=7.9, 1H), 6.36 (d, J=8.3, 1H), 5.60 (s, 2H), 5.11 (s, 2H), 3.59 (s, 1H), 2.71 (s, 1H), 2.50 (s, 3H), 2.28 (s, 3H), 1.75 (brs, 4H), 1.60-1.30 (m, 4H).
Reaction SMILES: C([C:3]1([C:16]([O-:18])=O)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)C.O.[NH2:20][NH2:21]>CCO.C(Cl)Cl.C(#N)C>[NH:20]([C:16]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=[O:18])[NH2:21]
Reactant: CCC1(C(=O)[O-])CCN(C(=O)OC(C)(C)C)CC1
Reactant: NN
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NN)CC1
Temperature: 25 °C
Yield: 90.7 %

Procedure:
To a stirred solution of 1-tert-butyl 4-ethylpiperidine-1,4-dicarboxylate (10 g, 38.9 mmol, 1.0 eq) in EtOH (100 mL) was added hydrazine hydrate (18.67 g, 389 mmol, 10 eq.) and the mixture was refluxed for 8 h. The reaction was cooled to room temperature and upon evaporation of the solvent gave a viscous liquid which was redissolved in CH2Cl2, washed with water (3×50 mL), then brine (50 mL). The organic layers were combined, dried over Na2SO4 and the solvent evaporated, leaving an yellowish oil, which upon addition of a few drops of ACN and re-evaporated yielded the title compound (8.6 g, 35.3 mmol). 1H NMR (400 MHz, MeOD) δ ppm 4.09 (d, J=13.14 Hz, 2H) 2.70-2.85 (br. s., 2H) 2.23-2.43 (m, 1H) 1.66-1.77 (m, 2H) 1.49-1.66 (m, 2H) 1.40-1.49 (m, 9H). MS (m/z, MH−): 242.2
Reaction SMILES: O(C)[Na].[N:4]1[CH:9]=[CH:8][CH:7]=[N:6][C:5]=1[C:10]#[N:11].CO[CH:14](OC)[CH2:15][NH2:16].Cl.C([O-])([O-])=O.[Na+].[Na+]>CO.CC(O)=O>[NH:11]1[CH:14]=[CH:15][N:16]=[C:10]1[C:5]1[N:6]=[CH:7][CH:8]=[CH:9][N:4]=1
Reactant: COC(CN)OC
Reactant: N#Cc1ncccn1
Agent: CO[Na]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: CC(=O)O
Product: c1cnc(-c2ncc[nH]2)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of NaOCH3 (270 mg) in 50 mL of MeOH, pyrimidine-2-carbonitrile (1-Im-3, 50 mmol) was added. The mixture was stirred at rt for 1 h, then 2,2-dimethoxyethanamine (50 mmol) was added followed by 2 mL of AcOH. This mixture was stirred for 1 h, then 6N HCl was added to adjust pH=1. The resulting acidic solution was heated at reflux for 18 h. After cooling to rt, the reaction was poured into a mixture of ice and aqueous Na2CO3 solution, then extracted with EtOAc and the organic layer was concentrated to give 2-(1H-imidazol-2-yl)pyrimidine (Imidazole 3). LCMS (0.01% Ammonia): 147.2 m/z (M+H)+; 1H-NMR (DMSO-d6, 500 MHz): δ: 13.04 (bs, 1H), 8.87 (d, 2H, J=5.0 Hz), 7.44 (t, 1H, J=5.0 Hz), 7.24 (s, 2H).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([CH2:23][O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:12][C@H:11]([CH2:32]I)[C@@H:10]1[O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[P:42]([O:49]CC)([O:46][CH2:47][CH3:48])[O:43][CH2:44][CH3:45]>>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([CH2:23][O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:12][C@H:11]([CH2:32][P:42](=[O:49])([O:46][CH2:47][CH3:48])[O:43][CH2:44][CH3:45])[C@@H:10]1[O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOP(OCC)OCC
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H]1CI
Product: CCOP(=O)(C[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1O[Si](C)(C)C(C)(C)C)OCC
Yield: 83 %

Procedure:
A solution of (((2S,3R,4S,5R,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-2-(iodomethyl)tetrahydro-2H-pyran-3-yl)oxy)(tert-butyl)dimethylsilane (4.0 g, 5.8 mmol, 1.0 equiv) in anhydrous triethyl phosphite (40 mL) was heated to 160° C. in a 100 mL sealed tube for 16 hours. The solvent was removed in vacuo and the resulting product was purified by silica gel chromatography, eluting with 30% EtOAc in petroleum ether, to give diethyl (((2S,3R,4S,5R,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-3-((tert-butyldimethylsilyl)oxy)tetrahydro-2H-pyran-2-yl)methyl)phosphonate as a pale yellow oil (3.36 g, 83%). 1H NMR (300 MHz, CDCl3) δ 7.37-7.22 (m, 13H), 7.06 (dd, J=6.6, 3.0 Hz, 2H), 4.90-4.72 (m, 3H), 4.67-4.61 (m, 1H), 4.49 (d, J=4.3 Hz, 1H), 4.46 (d, J=2.9 Hz, 1H), 4.40 (d, J=7.1 Hz, 1H), 4.17-4.03 (m, 4H), 3.93-3.85 (m, 1H), 3.77 (d, J=9.9 Hz, 1H), 3.72-3.61 (m, 3H), 3.55-3.47 (m, 1H), 2.27-2.13 (m, 2H), 1.29 (td, J=7.1, 1.2 Hz, 6H), 0.90 (s, 9H), 0.09 (s, 3H), 0.07 (s, 3H). ESI (M+1) 699.2; calc for C38H55O8PSi 698.3.