Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.C([Mg]Cl)(C)C.Br[C:14]1[C:15]([O:22][CH3:23])=[N:16][CH:17]=[C:18]([Cl:21])[C:19]=1[CH3:20].ClC1C(C)=C([Mg]Cl)C(OC)=NC=1.[CH3:36][O:37][C:38]1[C:45]([O:46][CH3:47])=[C:44]([O:48][CH3:49])[CH:43]=[C:42]([CH3:50])[C:39]=1[CH:40]=[O:41]>O1CCCC1.O>[CH3:36][O:37][C:38]1[C:45]([O:46][CH3:47])=[C:44]([O:48][CH3:49])[CH:43]=[C:42]([CH3:50])[C:39]=1[CH:40]([C:14]1[C:15]([O:22][CH3:23])=[N:16][CH:17]=[C:18]([Cl:21])[C:19]=1[CH3:20])[OH:41]
Reactant: COc1ncc(Cl)c(C)c1Br
Reactant: COc1cc(C)c(C=O)c(OC)c1OC
Agent: CC(C)[Mg]Cl
Agent: COc1ncc(Cl)c(C)c1[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc(C)c(C(O)c2c(OC)ncc(Cl)c2C)c(OC)c1OC
Temperature: 0 °C
Reaction time: 3 h
Yield: 71.2 %

Procedure:
4 ml of tetrahydrofuran and 0.62 ml (4.4 mmol) of triethylamine were added to 2.2 ml (4.4 mmol) of isopropylmagnesium chloride (2.0 mol/l tetrahydrofuran solution), the mixture was cooled to 0° C., and a solution having 1.0 g (4.2 mmol) of 3-bromo-5-chloro-2-methoxy-4-methylpyridine dissolved in 5 ml of tetrahydrofuran was dropwise added, followed by stirring for 3 hours to prepare 5-chloro-2-methoxy-4-methyl-3-pyridylmagnesium chloride. A solution having 0.89 g (4.2 mmol) of 2,3,4-trimethoxy-6-methylbenzaldehyde dissolved in 5 ml of tetrahydrofuran was dropwise added to the reaction solution, followed by stirring for 1 hour, and then the temperature was increased to room temperature, followed by stirring further for 1 hour. Water was added to the reaction solution to terminate the reaction, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate and subjected to filtration, and the solvent was distilled off under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 1.1 g (yield: 70%) of (2,3,4-trimethoxy-6-methylphenyl)(5-chloro-2-methoxy-4-methyl-3-pyridyl)methanol (pale yellow oily substance).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[C:12]([N+:24]([O-:26])=[O:25])=[CH:13][C:14]2[NH:19][C:18](=[O:20])[O:17][C:16]([CH3:22])([CH3:21])[C:15]=2[CH:23]=1)(=O)=O.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([SH:34])=[CH:30][CH:29]=1>>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([S:34][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]2[C:12]([N+:24]([O-:26])=[O:25])=[CH:13][C:14]3[NH:19][C:18](=[O:20])[O:17][C:16]([CH3:21])([CH3:22])[C:15]=3[CH:23]=2)=[CH:30][CH:29]=1
Reactant: CC1(C)OC(=O)Nc2cc([N+](=O)[O-])c(OCCCCOS(C)(=O)=O)cc21
Reactant: Sc1ccc(Cl)cc1
Product: CC1(C)OC(=O)Nc2cc([N+](=O)[O-])c(OCCCCSc3ccc(Cl)cc3)cc21

Procedure:
Prepared analogously to Example 210 from 6-(4-methanesulfonyloxy-butoxy)-7-nitro-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-chloro-thiophenol.
Reaction SMILES: O1CCCCC1[O:7][C@@H:8]1[CH2:12][C@H:11]([O:13]C2CCCCO2)[C@H:10]([CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][C:25](=[O:31])[CH2:26][O:27][C:28](=[O:30])[CH3:29])[C@H:9]1/[CH:32]=[CH:33]/[C@@H:34]([O:40]C1CCCCO1)[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>CO>[OH:7][C@@H:8]1[CH2:12][C@H:11]([OH:13])[C@H:10]([CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][C:25](=[O:31])[CH2:26][O:27][C:28](=[O:30])[CH3:29])[C@H:9]1/[CH:32]=[CH:33]/[C@@H:34]([OH:40])[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCC[C@@H](/C=C/[C@@H]1[C@@H](C/C=C\CCC(=O)COC(C)=O)[C@@H](OC2CCCCO2)C[C@H]1OC1CCCCO1)OC1CCCCO1
Solvent: CO
Product: CCCCC[C@H](O)/C=C/[C@@H]1[C@@H](C/C=C\CCC(=O)COC(C)=O)[C@@H](O)C[C@H]1O
Temperature: 25 °C
Yield: 82.5 %

Procedure:
A solution of the acetate of Example 25 (36 mg, 0.055 mmol) and PPTs (2 mg) in MeOH (1.0 mL) was stirred at 45° C. for 4 h. The reaction was cooled to room temperature and the solvent was removed in vacuo. The residue was diluted with EtOAc and washed with 1N HCl, saturated aqueous NaHCO3 and brine. The organic portion was dried (MgSO4), filtered and concentrated it vacuo. FCC (silica gel, 50%-100% EtOAc/hex) afforded 18 mg of the named compound.
Reaction SMILES: [C:1]1([N:7]=[C:8]=S)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:10]([C:12]1[N:17]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:16](=[O:27])[N:15]([CH3:28])[C:14](=[O:29])[CH:13]=1)[NH2:11]>CN(C=O)C>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][N:17]2[C:12]3[NH:10][N:11]=[C:8]([NH:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:13]=3[C:14](=[O:29])[N:15]([CH3:28])[C:16]2=[O:27])=[CH:24][CH:23]=1
Reactant: COc1ccc(Cn2c(NN)cc(=O)n(C)c2=O)cc1
Reactant: S=C=Nc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)n(C)c(=O)c3c(Nc4ccccc4)n[nH]c32)cc1
Temperature: 120 °C
Reaction time: 48 h
Yield: 414 %

Procedure:
Phenyl isothiocyanate (3.9 mL, 32.7 mmol) is added to a suspension of 6-hydrazinyl-1-(4-methoxybenzyl)-3-methylpyrimidine-2,4(1H,3H)-dione (0.45 g, 1.6 mmol) in DMF (12 mL). The reaction mixture is heated at 120° C. for 40 hours, and then evaporated to remove solvent under reduced pressure. The residue is washed with hexanes, and then treated with MeOH (125 mL), and stored at −15° C. for 2 days to give a crystalline solid. The solid is recrystallized from CH3OH-EtOAc to afford 2.5 g of product (Yield: 61%). 1H NMR (400 MHz, DMSO-d6) δ 3.21 (s, 3H), 3.73 (s, 3H), 5.01 (s, 2H), 6.88-7.36 (m, 9H). MS (FAB) m/z 378.3 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[C:4]([C:13]([OH:15])=O)=[C:3]1[CH3:16].C(Cl)(=O)C(Cl)=O.[CH:23]1([NH2:26])[CH2:25][CH2:24]1>>[CH:23]1([NH:26][C:13]([C:4]2[C:5]3[C:10](=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=3)[N:2]([CH3:1])[C:3]=2[CH3:16])=[O:15])[CH2:25][CH2:24]1
Reactant: NC1CC1
Reactant: COc1ccc2c(C(=O)O)c(C)n(C)c2c1
Agent: O=C(Cl)C(=O)Cl
Product: COc1ccc2c(C(=O)NC3CC3)c(C)n(C)c2c1
Yield: 80.8 %

Procedure:
This material was prepared from 1,2-dimethyl-6-methoxy1H-indole-3-carboxylic acid 16c (500 mg, 2.3 mmole), oxalyl chloride (0.4 ml, 4.6 mmole) and cyclopropylamine (1.6 ml, 23 mmole) in a manner as previously described for example 16d to give 480 mg (82%) of a white solid. 1H NMR (DMSO-d6 δ7.57 (1H, d, J=3.8 Hz), 7.50 (1H, d, J=8.8 Hz), 6.99 (1H, d, J=2.3 Hz), 6.71 (1H, dd, J=2.3, 8.8 Hz), 3.78 (3H, s), 3.63 (3H, s), 2.83-2.80 (1H, m), 2.51 (3H, s), 0.68-0.62 (2H, m), 0.57-0.53 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[C:11]([C:14]#[N:15])([CH3:13])[CH3:12].CN(C)C=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:39]=[CH:40][C:41]=1[F:42])[O:25][C:26]1[N:31]=[C:30]2[S:32][C:33]([NH:35][C:36](=[O:38])[CH3:37])=[N:34][C:29]2=[CH:28][CH:27]=1.O>C(Cl)(=O)C(Cl)=O.CN(C)C(=O)C>[C:36]([NH:35][C:33]1[S:32][C:30]2[C:29]([N:34]=1)=[CH:28][CH:27]=[C:26]([O:25][C:24]1[CH:39]=[CH:40][C:41]([F:42])=[C:22]([NH:21][C:6](=[O:8])[C:5]3[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([C:11]([C:14]#[N:15])([CH3:13])[CH3:12])[CH:4]=3)[CH:23]=1)[N:31]=2)(=[O:38])[CH3:37]
Reactant: CC(C)(C#N)c1cc(C(=O)O)ccc1Cl
Reactant: CC(=O)Nc1nc2ccc(Oc3ccc(F)c(N)c3)nc2s1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1nc2ccc(Oc3ccc(F)c(NC(=O)c4ccc(Cl)c(C(C)(C)C#N)c4)c3)nc2s1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 21.4 %

Procedure:
To a solution of 4-chloro-3-(1-cyano-1-methylethyl)benzoic acid (0.11 g, 0.5 mmol) in oxalyl chloride (0.5 mL) was added N,N-dimethylformamide (40 μL), and the mixture was stirred at room temperature for 30 min, and concentrated to dryness under reduced pressure. This was dissolved in a mixture of N,N-dimethylacetamide (1 mL) and tetrahydrofuran (1 mL), and a solution was added dropwise to a solution of N-[5-(3-amino-4-fluorophenoxy)[1,3]thiazolo[5,4-b]pyridin-2-yl]acetamide (0.11 g, 0.33 mmol) produced in Example C64(ii) in N,N-dimethylacetamide (1 mL) under ice-cooling. The reaction mixture was stirred at room temperature for 3 hr, and poured into water (100 mL), and the mixture was extracted with ethyl acetate (100 mL×2). The ethyl acetate layers were combined, and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane=0/100→100/0), and recrystallized from methanol to give the title compound (37 mg, 21%) as colorless crystals.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10](=O)[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].OC1C(OS(C2C=CC(C)=CC=2)(=O)=O)=C(I)C=CC=1.[NH2:37][C:38]([NH2:40])=[S:39]>C(#N)C>[NH2:40][C:38]1[S:39][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:37]=1
Reactant: CCOC(=O)CC(=O)c1cccc([N+](=O)[O-])c1
Reactant: NC(N)=S
Agent: Cc1ccc(S(=O)(=O)Oc2c(O)cccc2I)cc1
Solvent: CC#N
Product: CCOC(=O)c1sc(N)nc1-c1cccc([N+](=O)[O-])c1
Temperature: 65 °C
Reaction time: 1 h
Yield: 70.5 %

Procedure:
To a solution of ethyl 3-(3-nitrophenyl)-3-oxopropionate (3.45 g, 14.5 mmol) in 100 mL of acetonitrile was added hydroxy(tosyloxy)iodobenzene (6.3 g, 16.0 mmol). The resulting suspension was stirred at 65° C. for 1 h at which time the reaction was a homogeneous solution. Thiourea (1.22 g, 16.0 mmol) was added and stirring was continued at 65° C. for 2 h. The mixture was cooled and concentrated, and the residue was taken up in ethyl acetate, washed with saturated aq Na2CO3 and brine, dried (MgSO4) and concentrated. The residue was triturated with ethyl ether to afford 3.0 g (71%) of the title compound as a yellow solid. 1H NMR (DMSO-d6) δ: 8.47 (t, 1H, J=1.9 Hz); 8.24 (m, 1H) ; 8.21 (m, 1H); 7.97 (broad s, 2H); 7.65 (t, 1H, J=8.1 Hz); 4.08 (q, 2H, J=7.1 Hz); 1.11 (t, 3H, J=7.1 Hz).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[NH2:11].[F:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1.C(Cl)(=O)C(Cl)=O.CN([CH:31]=[O:32])C>C(Cl)Cl>[F:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]2[O:1][C:2]3[C:3](=[C:4]([C:5]([OH:7])=[O:6])[CH:8]=[CH:9][CH:10]=3)[N:11]=2)=[CH:15][CH:14]=1.[F:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]2[O:18][C:2]3[C:3](=[C:4]([C:5]([O:32][CH3:31])=[O:6])[CH:8]=[CH:9][CH:10]=3)[N:11]=2)=[CH:15][CH:14]=1
Reactant: CN(C)C=O
Reactant: Nc1c(O)cccc1C(=O)O
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COC(=O)c1cccc2oc(-c3ccc(F)cc3)nc12
Product: O=C(O)c1cccc2oc(-c3ccc(F)cc3)nc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 26 %

Procedure:
2-(4-fluorophenyl)benzoxazole-4-carboxylic acid was prepared from 3-hydroxyanthranilic acid and 4-fluorobenzoyl chloride as described in Step A of Example 1. The crude product was dissolved in methylene chloride (20 mL) and the resulting solution treated with oxalyl chloride (1 mL) and DMF (0.05 mL). After stirring at room temperature for 6 h, the reaction was quenched by the addition of methanol (10 mL) and stirred at room temperature for a further 71 h. The reaction was then re-concentrated and the resulting solid purified by column chromatography to afford a 26% yield of methyl 2-(4-fluorophenyl)benzoxazole-4-carboxylate as a white solid: 1H NMR (500 MHz, CDCl3) δ 8.36 (dd, J=14.7, 11.8 Hz, 2H), 8.03 (d, J=14.7 Hz, 1H), 7.78 (d, J=15.2 Hz, 1H), 7.42 (t, J=13.2 Hz, 1H), 7.18 (m, 2H), 4.06 (m, 3H).
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:7]=[CH:6][C:4]=1N.[C:14](#[N:17])[CH:15]=[CH2:16].N([O-])=O.[Na+]>O.[Cu]=O.ClCCl>[Cl:1][CH:15]([CH2:16][C:4]1[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([F:13])([F:12])[F:11])[C:3]=1[CH3:2])[C:14]#[N:17]
Reactant: C=CC#N
Reactant: Cl
Reactant: Cc1c(N)cccc1C(F)(F)F
Agent: O=[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1c(CC(Cl)C#N)cccc1C(F)(F)F
Temperature: 20 °C
Reaction time: 0.08 h
Yield: 90.1 %

Procedure:
20 mol of concentrated hydrochloric acid is added at 0°-5° C. to a suspension of 16.7 g of 2-methyl-3-trifluoromethylaniline (0.095 mol) in 50 ml of water and the mixture is then briefly warmed to 60°-80° C. until a clear solution has formed. The solution is cooled very rapidly to 0°-5° C. with vigorous stirring, 22.4 ml (0.286 mol) of acrylonitrile are added dropwise to the fine suspension at 0°-5° C. and a solution of 6.75 g of sodium nitrite in 10 ml of water is then rapidly added, and the mixture is kept at 5° C. for a further 5 minutes and stirred at 20° C. for 1 hour. After cooling, 0.8 g of copper(II) oxide powder is added to the reaction mixture at 0°-10° C. in portions, a vigorous evolution of nitrogen gas occurring. After completion of the evolution of gas, the mixture is stirred for a further 2 hours at 0°-10° C., then for 15 hours at room temperature, dichloromethane is added, and the mixture is washed with water, dried over sodium sulphate and concentrated in vacuo. 21.2 g (90% of theory) of 2-chloro-3-(2-methyl-3-trifluoromethylphenyl)-propionitrile are obtained as a brown oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([CH2:14][C:15]#[C:16][C:17]3[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=3)[CH:5]=[CH:4][C:3]1=2.[CH2:27]([NH2:29])[CH3:28].C([NH-])C>>[CH2:27]([NH:29][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][C:17]([C:16]#[C:15][CH2:14][C:6]2[CH:5]=[CH:4][C:3]3[C:2]([CH3:1])([CH3:26])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=3[CH:7]=2)=[CH:18][CH:19]=1)[CH3:28]
Reactant: CCN
Reactant: CC1(C)CCC(C)(C)c2cc(CC#Cc3ccc(C(=O)Cl)cc3)ccc21
Agent: CC[NH-]
Product: CCNC(=O)c1ccc(C#CCc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1

Procedure:
In a similar manner to Example 17(b), by reaction of 3 g (8.3 mmol) of 4-[3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)-1-propynyl]benzoyl chloride with 650 μl (10 mmol) of ethylamine (70%), 1.84 g (59.4%) of the expected ethyl amide are obtained, with a melting point of 128-9° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)=O)=O)=[CH:4][CH:3]=1.[C:19]1([NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH2:25]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:10]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[N:26][C:19]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:25]=2)=[CH:4][CH:3]=1
Reactant: O=C(C(=O)c1ccc(F)cc1)c1ccc(F)cc1
Reactant: Nc1ccccc1N
Solvent: ClC(Cl)Cl
Product: Fc1ccc(-c2nc3ccccc3nc2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Yield: 99 %

Procedure:
First, 3.71 g of 4,4′-difluorobenzil and 1.71 g of o-phenylenediamine were stirred on heating in a solvent (200 mL of chloroform) for 6 hours. The reaction solution was cooled to a room temperature, washed with 1 mol/L hydrochloric acid and a saturated aqueous solution of sodium chloride, and dried with magnesium sulfate. The solvent was removed to obtain a ligand 2,3-bis(4-fluorophenyl)quinoxaline) (abbreviation: HFdpq) (pale yellow powder, yield: 99%). A synthetic scheme (b-1) of Step 1 is shown below.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7](B(O)O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br:12][C:13]1[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=1>>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:7]2[S:8][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=2)=[CH:15][CH:14]=1
Reactant: CC(=O)c1ccc(B(O)O)s1
Reactant: Brc1ccc(I)cc1
Product: CC(=O)c1ccc(-c2ccc(Br)cc2)s1

Procedure:
1-(5-(4-Bromophenyl)thien-2-yl)ethanone is prepared from 5-acetyl-2-thiopheneboronic acid and 1-bromo-4-iodobenzene according to general procedure A.
Reaction SMILES: OC(C(F)(F)F)=O.[O:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[N:16]([C:20]([CH:35]4[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]4)=[C:21]([C:23]#[C:24][C:25]4[CH:34]=[CH:33][C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[N:26]=4)[N:22]=3)[N:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1.CCN(C(C)C)C(C)C.Br[CH2:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53]>C(Cl)Cl>[O:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15]3[N:16]([C:20]([CH:35]4[CH2:40][CH2:39][N:38]([CH2:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:37][CH2:36]4)=[C:21]([C:23]#[C:24][C:25]4[CH:34]=[CH:33][C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[N:26]=4)[N:22]=3)[N:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: C(#Cc1nc2c(N3CCOCC3)ccnn2c1C1CCNCC1)c1ccc2ccccc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CN1CCC(c2c(C#Cc3ccc4ccccc4n3)nc3c(N4CCOCC4)ccnn23)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of compound 41f (0.15 g, 0.27 mmol) in DCM (3 mL), DIEA (54 mg, 0.42 mmol) was added. The resulting mixture was stirred for 15 min before the addition of tert-butyl 2-bromoacetate (65 mg, 0.33 mmol). The reaction mixture was stirred at rt for 2 h, and concentrated under reduced pressure. The residue obtained was purified by flash column chromatography on silica gel (ethyl acetate:petroleum ether (1:2)) to obtain compound 41g as a yellow solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C32H36N6O3: 553.3 (M+H). found: 553.1.
Reaction SMILES: [ClH:1].[OH:2][CH:3]1[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]1[NH2:5].O.[S:15]([O-:19])([O-:18])(=[O:17])=[O:16].[Mn+2:20]>O>[Cl-:1].[Mn+3:20].[S:15]([O-:19])([O-:18])(=[O:17])=[O:16].[OH:2][CH:3]1[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]1[NH2:5]
Reactant: [Mn+2]
Reactant: Cl
Agent: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Product: [Cl-]
Product: [Mn+3]

Procedure:
Example 1 was repeated using 450 g of purified water, 107.8 g (0.5 mole) of glucosamine hydrochloride and 42.3 g (0.25 mole) of manganese sulfate monohydrate instead of the sodium sulfate. After freeze drying, glucosamine sulfate manganese chloride was obtained as a white powder in a yield of 144 g (98% of theoretical).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].N1C=CN=C1.CN(C)C=O>CCCCCC>[Si:14]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6])([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)c1ccc(OC)c(O)c1
Agent: c1c[nH]cn1
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)c(O[Si](C)(C)C(C)(C)C)c1

Procedure:
A mixture of methyl 3-hydroxy-4-methoxybenzoate (120 mg, 0.66 mmol, prepared in Step 1, above), tert-butyldimethylsilyl chloride: (109 mg, 0.72 mmol), imidazole (98 mg, 1.24 mmol) and dimethylformamide (DMF, 2 ml) was stirred at room temperature over night. Extractive workup with hexane gave 90 mg of methyl 3-tert-butyldimethylsilyloxy-4-methoxybenzoate. NMR(δ): 0.18 (s, 3H), 1.00 (s, 9H),3.88 (s, 3H), 3.89 (s, 3 H).
Reaction SMILES: [Cl-].[CH3:2][O:3]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].O=[C:35]1[CH:40]2[CH2:41][CH2:42][CH:36]1[CH2:37][CH:38]([C:43]1[NH:51][C:50]3[C:49](=[O:52])[N:48]([CH2:53][CH2:54][CH3:55])[C:47](=[O:56])[N:46]([CH2:57][CH2:58][CH3:59])[C:45]=3[N:44]=1)[CH2:39]2>C1(C)C=CC=CC=1>[O:56]=[C:47]1[N:46]([CH2:57][CH2:58][CH3:59])[C:45]2[N:44]=[C:43]([CH:38]3[CH2:37][CH:36]4[CH:35]([CH:2]=[O:3])[CH:40]([CH2:41][CH2:42]4)[CH2:39]3)[NH:51][C:50]=2[C:49](=[O:52])[N:48]1[CH2:53][CH2:54][CH3:55]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCn1c(=O)c2[nH]c(C3CC4CCC(C3)C4=O)nc2n(CCC)c1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCCn1c(=O)c2[nH]c(C3CC4CCC(C3)C4C=O)nc2n(CCC)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
(Methoxymethyl)triphenylphosphonium chloride (296 mg 0.86 mmol) in toluene was cooled in an ice-bath. Potassium bis(trimethylsilyl)amide (2.5 ml, 0.5M in toluene) was added dropwise through a syringe. The mixture was stirred at 0° C. for 1 h. 8-(8-Oxo-bicyclo[3.2.1]oct-3-yl)-1,3-dipropyl-3,7-dihydro-purine-2,6-dione (100 mg) was then added to the mixture, and the mixture was allowed to warm to room temperature and was stirred overnight. Toluene was evaporated off, and the residue was treated with 1N HCl in THF at 70° C. for 3 h. Ethyl acetate was used to extract the product. Column chromatography gave 94 mg of 3-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[3.2.1]octane-8-carbaldehyde as a mixture of cis and trans yield (90%)
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=2[N+:19]([O-])=O)[CH2:4][CH2:3]1>[Pd].CO.O1CCOCC1>[NH2:19][C:10]1[CH:11]=[C:12]([C:15]([F:16])([F:17])[F:18])[CH:13]=[CH:14][C:9]=1[NH:8][C@H:5]1[CH2:6][CH2:7][C@H:2]([OH:1])[CH2:3][CH2:4]1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1N[C@H]1CC[C@H](O)CC1
Agent: [Pd]
Solvent: CO
Solvent: C1COCCO1
Product: Nc1cc(C(F)(F)F)ccc1N[C@H]1CC[C@H](O)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 4-(trans-4-hydroxycyclohexylamino)-3-nitrobenzotrifluoride (4.0 g) and 10% palladium on activated carbon (400 mg) in a mixture of methanol (20 mL) and dioxane(20 mL) was stirred under hydrogen atmosphere (3 atm) at ambient temperature for 4 hours. The reaction mixture was filtered through a celite pad, and the filtrate was concentrated in vacuo. The residue was subjected to a silica gel column chromatography eluting with a mixture of chloroform and methanol (20:1). The obtained substance was triturated with petroleum ether to give 3-amino-4-(trans-4-hydroxycyclohexylamino)benzotrifluoride (3.5 g) as a pale orange solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([C:16]=1[C:17]1[CH:18]=[CH:19][C:20]([NH:23][NH2:24])=[N:21][CH:22]=1)[CH:14]=[CH:13][O:12]2.[CH3:25][CH:26]([CH3:29])[CH:27]=O.C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1>CO>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]2[N:15]([C:16]=1[C:17]1[CH:18]=[CH:19][C:20]3[N:21]([C:25]([CH:26]([CH3:29])[CH3:27])=[N:24][N:23]=3)[CH:22]=1)[CH:14]=[CH:13][O:12]2
Reactant: CC(C)C=O
Reactant: NNc1ccc(-c2c(-c3ccc(F)cc3F)nc3occn23)cn1
Solvent: CO
Solvent: CC(=O)O
Solvent: Ic1ccccc1
Product: CC(C)c1nnc2ccc(-c3c(-c4ccc(F)cc4F)nc4occn34)cn12
Temperature: 60 °C
Reaction time: 1 h
Yield: 18 %

Procedure:
In a round bottom flask {5-[6-(2,4-difluorophenyl)-imidazo[2,1-b]oxazol-5-yl]-pyridin-2-yl}-hydrazine (0.35 g, 1.1 mmol) and 2-methylpropionaldehyde (0.1 mL, 1.1 mmol) was dissolved in MeOH (5 mL) followed by heating to about 60° C. for about 1 h. The reaction was allowed to cool to ambient temperature and then iodobenzene diacetate (0.35 g, 1.1 mmol) was added followed by stirring for about 1 h. The reaction was then purified directly by flash chromatography using DCM/MeOH (90:10) as eluent followed by titration with Et2O to provide the title compound (0.075 g, 18%) as an off-white solid: LC/MS (Table 1, Method a) Rt, =2.12 min; MS m/z: 380.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:13])[CH:12]=1)[C@H:5]([OH:9])[C:6]([OH:8])=O.Cl.[NH2:15][C@H:16]([C:20]([NH:22][N:23]1[C:29](=[O:30])[CH:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:27]2[CH:37]=[CH:38][CH:39]=[CH:40][C:26]=2[C:25]2[CH:41]=[CH:42][CH:43]=[CH:44][C:24]1=2)=[O:21])[CH:17]([CH3:19])[CH3:18]>>[F:13][C:11]1[CH:10]=[C:4]([CH:3]=[C:2]([F:1])[CH:12]=1)[C@H:5]([OH:9])[C:6]([NH:15][C@H:16]([C:20]([NH:22][N:23]1[C:29](=[O:30])[CH:28]([CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])[C:27]2[CH:37]=[CH:38][CH:39]=[CH:40][C:26]=2[C:25]2[CH:41]=[CH:42][CH:43]=[CH:44][C:24]1=2)=[O:21])[CH:17]([CH3:18])[CH3:19])=[O:8]
Reactant: CCCCCCC1C(=O)N(NC(=O)[C@@H](N)C(C)C)c2ccccc2-c2ccccc21
Reactant: O=C(O)[C@@H](O)c1cc(F)cc(F)c1
Agent: Cl
Product: CCCCCCC1C(=O)N(NC(=O)[C@@H](NC(=O)[C@@H](O)c2cc(F)cc(F)c2)C(C)C)c2ccccc2-c2ccccc21

Procedure:
Following General Procedure D and using (S)-3,5-difluoromandelic acid (Example L) and 5-(L-valinyl)-amino-7-hexyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride (Example 7-V), the title compound was prepared. The product was purified by chromatography (silica, 5% MeOH/CHCl3).