Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([N:16]1[CH2:21][CH2:20][N:19]2[C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=[C:18]2[CH2:17]1)/[CH:3]=[C:4](\[NH2:15])/[CH2:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([F:13])=[CH:8][C:7]=1[F:14].FC(F)(F)CO.[H][H]>[B-](F)(F)(F)F.C1C2C=CC1C=C2.C1C2C=CC1C=C2.[Rh].CO>[O:1]=[C:2]([N:16]1[CH2:21][CH2:20][N:19]2[C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=[C:18]2[CH2:17]1)[CH2:3][C@H:4]([NH2:15])[CH2:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([F:13])=[CH:8][C:7]=1[F:14]
Reactant: N/C(=C\C(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Reactant: [H][H]
Agent: [Rh]
Agent: C1=CC2C=CC1C2
Agent: F[B-](F)(F)F
Solvent: OCC(F)(F)F
Solvent: CO
Product: N[C@@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Temperature: 50 °C
Reaction time: 17 h

Procedure:
Into a flask were charged bis(norbornadiene)rhodium(I) tetrafluoroborate {[Rh(nbd)2]BF4}(41.55 mg, 0.1 mmol), Ligand D (69.73 mg, 0.1 mmol) and the enamine amide 2-4 (45 g, 111.1 mmol) under a nitrogen atmosphere. To this mixture a solvent mixture of 37.5 mL methanol (extra dry and degassed) and 112.5 mL 2,2,2-trifluoroethanol (distilled and degassed) were added. The slurry was then transferred under nitrogen into an stainless steel autoclave and sealed. The autoclave was then heated to 50° C. and pressurized to 500 psig with hydrogen. A sample taken after 17 hours was analyzed using HPLC, which confirmed the end of the reaction giving 94% assay yield and 94% ee.
Reaction SMILES: Cl[CH2:2][CH:3]1[CH:5]([C:6]([O:8]CC)=O)[C:4]1([CH3:20])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1.C(=O)([O-])O.[Na+].[C:26]1([CH2:32][CH2:33][CH2:34][NH2:35])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CN(C)C=O>[CH3:20][C:4]1([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[CH:5]2[CH:3]1[CH2:2][N:35]([CH2:34][CH2:33][CH2:32][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:6]2=[O:8]
Reactant: NCCCc1ccccc1
Reactant: CCOC(=O)C1C(CCl)C1(C)c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(c2cccc([N+](=O)[O-])c2)C2CN(CCCc3ccccc3)C(=O)C21
Temperature: 150 °C

Procedure:
To a solution of ethyl 3-(chloromethyl)-2-methyl-2-(3-nitrophenyl)cyclopropane carboxylate (Preparation 5, 14.4 g, 48.6 mmol), in N,N-dimethylformamide (120 ml) was added sodium hydrogen carbonate (12 g, 143 mmol) and 3-phenylpropylamine (38.8 g, 41 ml, 290 mmol). The mixture was heated to 150° C. for 7 h, then cooled to room temperature and poured onto water (1000 ml). The mixture was extracted with diethyl ether (2×500 ml), and the combined extracts were washed with water (2×250 ml), dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by silica (1000 g) column chromatography eluting with dichloromethane then dichloromethane/ethyl acetate 4:1. Product-containing fractions were combined and concentrated in vacuo to give the title compound as a very pale yellow oil (6.2 g, 36%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.CS(O[C:40]1[CH:45]=[CH:44][C:43]([C:46](=[NH:48])[NH2:47])=[CH:42][C:41]=1[C:49](=[O:56])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)(=O)=O>N1C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][C:40]1[CH:45]=[CH:44][C:43]([C:46](=[NH:47])[NH2:48])=[CH:42][C:41]=1[C:49](=[O:56])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[O:18])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Oc1ccc(C(=N)N)cc1C(=O)c1ccccc1
Reactant: O=C(O)CCCCCNC(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: N=C(N)c1ccc(OC(=O)CCCCCNC(=O)OCc2ccccc2)c(C(=O)c2ccccc2)c1
Reaction time: 0.5 h
Yield: 36.7 %

Procedure:
Into 50 ml of anhydrous pyridine, was dissolved 4.0 g of 6-benzyloxycarbonylaminocaproic acid. To the solution, while being cooled in ice, was added 3.7 g of DCC. After having been stirred for 30 minutes, the mixture was admixed with 5.0 g of 4-amidino-2-benzoylphenol methanesulfonate and stirred overnight at room temperature. The precipitate which was formed was separated by filtration and washed with pyridine. Ethyl ether was added to the filtrate to precipitate white crystals. The crystals were collected by filtration, washed with ethyl ether, dissolved in DMF, and admixed with ethyl ether to precipitate colorless crystals which were collected by filtration and dried to obtain 5.7 g of an anhydrous substance. This substance was recrystallized from ethanol to obtain 2.7 g of colorless needle crystals of 4-amidino 2-benzoylphenyl 6-benzyloxycarbonylaminocaproate methanesulfonate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:9]([C:14]([OH:16])=O)=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[Br:17][C:18]1[CH:19]=[N:20][C:21]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]2)=[N:22][CH:23]=1>>[Br:17][C:18]1[CH:19]=[N:20][C:21]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][N:27]([C:14]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[O:16])[CH2:26]2)=[N:22][CH:23]=1
Reactant: Brc1cnc(N[C@@H]2CCCNC2)nc1
Reactant: O=C(O)c1ccccc1-c1cccc(F)c1
Product: O=C(c1ccccc1-c1cccc(F)c1)N1CCC[C@@H](Nc2ncc(Br)cn2)C1

Procedure:
prepared by reaction of 3′-fluoro-biphenyl-2-carboxylic acid with (R)-(5-bromo-pyrimidin-2-yl)-piperidine-3-yl-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][NH2:11])=[CH:7][C:6]=2[CH:12]=1.C(N(CC)CC)C.Cl[C:21](=[O:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][NH:11][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:27])=[CH:7][C:6]=2[CH:12]=1
Reactant: NCc1cc2cc(Cl)ccc2o1
Reactant: CCOC(=O)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(=O)NCc1cc2cc(Cl)ccc2o1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
To a solution of (5-chloro-1-benzofuran-2-yl)methanamine (420 mg, crude) in dichloromethane (50 ml) was added triethylamine (315 mg, 3.12 mmol). Then ethyl 2-chloro-2-oxoacetate (378 mg, 2.77 mmol) was added dropwise and the contents were stirred for 30 minutes at 0° C. The resulting solution was quenched with water (100 ml) and extracted with dichloromethane (3×70 ml). The organic fractions were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography eluting with 20% ethyl acetate in petroleum ether to afford ethyl [[(5-chloro-1-benzofuran-2-yl)methyl]carbamoyl]formate as an off-white solid (600 mg). (ES, m/z): [M+H]+ 282.0; 1H NMR (400 MHz, CDCl3): δ 7.52 (s, 2H), 7.38 (d, J=8.4 Hz, 1H), 7.26 (d, J=8.8 Hz, 1H), 6.64 (s, 1H), 4.68 (d, J=4.2 Hz, 2H), 4.39 (q, J=7.2 Hz, 2H), 1.37 (t, J=7.2 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:28]=[CH:27][C:7]([CH:8]=[CH:9][C:10]2[N:11]=[N:12][C:13]([CH:16]=[CH:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].ClC1C=CC=C(C(OO)=[O:37])C=1>ClCCCl>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([CH:17]=[CH:16][C:13]2[N:12]=[N+:11]([O-:37])[C:10]([CH:9]=[CH:8][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:28][CH:27]=3)=[CH:15][CH:14]=2)=[CH:19][CH:20]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1ccc(C=Cc2ccc(C=Cc3ccc([N+](=O)[O-])cc3)nn2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCCl
Product: O=[N+]([O-])c1ccc(C=Cc2ccc(C=Cc3ccc([N+](=O)[O-])cc3)[n+]([O-])n2)cc1

Procedure:
33 g of this nitro compound (K') is reacted, with 15g of m-chloroperbenzoic acid in halogen-containing solvent (such as 1,2-dichloroethane) to obtain 27 g of 3,6-di(p-nitrostyryl)pyridazine-N-oxide (L'). The nitro group in the N-oxide compound (L') is selectively reduced under a neutral or basic condition to obtain 20 g of vermilion crystals of 3,6-di(p-aminostyryl)pyridazine-N-oxide (M').
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[C:16]([O:25][CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])(=[O:24])[C:17]1[C:18](=[CH:20][CH:21]=[CH:22][CH:23]=1)[OH:19]>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:19][C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[C:16]([O:25][CH2:26][CH2:27][CH:28]([CH3:29])[CH3:30])=[O:24]
Reactant: CC(C)CCOC(=O)c1ccccc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: COc1cc2nccc(Oc3ccccc3C(=O)OCCC(C)C)c2cc1OC
Temperature: 140 °C
Reaction time: 3 h
Yield: 62.2 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (100 mg), isoamyl salicylate (416 mg), and 4-dimethylaminopyridine (244 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120° C. overnight and at 140° C. for 3 hr. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (110 mg, yield 56%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:23]([N:26](CC2C=CC(OC)=CC=2OC)[C:27]2[CH:32]=[CH:31][N:30]=[CH:29][N:28]=2)(=[O:25])=[O:24])[CH:6]=[CH:7][C:8]=1[O:9][C@H:10]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]1[C:17]1[N:21]([CH3:22])[N:20]=[CH:19][CH:18]=1)#[N:2].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([S:23]([NH:26][C:27]2[CH:32]=[CH:31][N:30]=[CH:29][N:28]=2)(=[O:24])=[O:25])[CH:6]=[CH:7][C:8]=1[O:9][C@H:10]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]1[C:17]1[N:21]([CH3:22])[N:20]=[CH:19][CH:18]=1)#[N:2]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(O[C@H]3CCCCC[C@@H]3c3ccnn3C)c(C#N)c2)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@H]1CCCCC[C@@H]1Oc1ccc(S(=O)(=O)Nc2ccncn2)cc1C#N
Yield: 70.4 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using 3-cyano-N-(2,4-dimethoxybenzyl)-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cycloheptyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (195 mg, 0.32 mmol) prepared in Example 55a, triethylsilane (0.10 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (4.0 mL), to yield the title compound (102 mg, 70%) as a colorless solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH:16]=O)=[C:4]([O:14][CH3:15])[C:5]2[C:10]([C:11]=1[O:12][CH3:13])=[CH:9][CH:8]=[CH:7][CH:6]=2.CO[C:20]1C2C(=CC=CC=2)C(OC)=C[C:21]=1/[CH:32]=[C:33](\C)/[C:34]([O:36][CH2:37][CH3:38])=[O:35]>CCOCC>[Br:1][C:2]1[C:3](/[CH:16]=[C:33](\[CH2:32][CH2:21][CH3:20])/[C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:4]([O:14][CH3:15])[C:5]2[C:10]([C:11]=1[O:12][CH3:13])=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: COc1c(Br)c(C=O)c(OC)c2ccccc12
Reactant: CCOC(=O)/C(C)=C/c1cc(OC)c2ccccc2c1OC
Solvent: CCOCC
Product: CCC/C(=C\c1c(Br)c(OC)c2ccccc2c1OC)C(=O)OCC

Procedure:
Compound 98f was prepared from 38 (0.514 g, 1.75 mmol) as described above for 28a to give 0.346 g (0.849 mmol, 49%) of the product as a yellow solid following flash chromatography (1:19 Et2O:hexanes) and recrystallization from Et2O/hexanes. (0.291 g E; 0.055 g Z)
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[CH2:4]/[CH:5]=[CH:6]\[Sn:7]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][CH2:10][CH3:11])[CH3:2].BrC/C=C\[Sn](CCCC)(CCCC)CCCC.N1CCCC1>>[CH2:8]([Sn:7]([CH2:16][CH2:17][CH2:18][CH3:19])([CH2:12][CH2:13][CH2:14][CH3:15])/[CH:6]=[CH:5]\[CH2:4][N:3]1[CH2:1][CH2:2][CH2:21][CH2:20]1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCC[Sn](/C=C\CN(CC)CC)(CCCC)CCCC
Agent: CCCC[Sn](/C=C\CBr)(CCCC)CCCC
Solvent: C1CCNC1
Product: CCCC[Sn](/C=C\CN1CCCC1)(CCCC)CCCC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 3, starting from ((Z)-3-bromoprop-1-enyl)tributylstannane (Intermediate 2) and pyrrolidine.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][CH:12]2[C:20]3[C:15](=[CH:16][C:17]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[O:35](C(OC(C)(C)C)=O)[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:39]([O:38][C:36]([N:11]([C@H:8]1[CH2:9][CH2:10][C@H:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:6][CH2:7]1)[CH:12]1[C:20]2[C:15](=[CH:16][C:17]([C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])=[CH:18][CH:19]=2)[CH2:14][CH2:13]1)=[O:35])([CH3:42])([CH3:41])[CH3:40]
Reactant: CCCCOC(=O)c1ccc2c(c1)CCC2N[C@H]1CC[C@H](C(C)(C)C)CC1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCOC(=O)c1ccc2c(c1)CCC2N(C(=O)OC(C)(C)C)[C@H]1CC[C@H](C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of butyl 1-[(trans-4-tert-butylcyclohexyl)amino]indane-5-carboxylate (1.0 g, 2.8 mmol) in CH2Cl2 (50 mL) was added Et3N (2.0 mL, 14.3 mmol), BOC2O (3.1 mL, 13.5 mmol) and catalytic amount of DMAP. After stirring at room temperature for 18 h, the reaction was quenched with saturated aqueous NaHCO3 (50 mL). The layers were separated and the aqueous layer was extracted once with EtOAc (50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated. Chromatography (5% EtOAc in Hexane) gave butyl 1-[(tert-butoxycarbonyl)(trans-4-tert-butylcyclohexyl)amino]indane-5-carboxylate. HPLC/MS: m/z=416.3 (M−56+1), 438.3 (M−56+23), Rt=3.07 min. 1H NMR (CDCl3): δ 7.90 (1H, d, J=8.5 Hz), 7.89 (1H, s), 7.16 (1H, m), 4.75 (1H, br s), 4.35 (2H, t, J=6.5 Hz), 4.19 (1H, br s), 3.10-3.05 (1H, m), 2.97-2.87 (1H, m), 2.36 (2H, m), 1.91-1.77 (5H, m), 1.52 (2H, m), 1.07-1.00 (8H, m), 0.90 (9H, s), 0.89 (9H, s).
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:15][CH:16](Br)[CH3:17])=[CH:10][C:11]=2[C:13]#[N:14])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[N-:19]=[N+:20]=[N-:21].[Na+]>C(OCCOCCO)C.O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([CH2:15][CH:16]([N:19]=[N+:20]=[N-:21])[CH3:17])=[CH:10][C:11]=2[C:13]#[N:14])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2cc(CC(C)Br)cc(C#N)c21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOCCOCCO
Solvent: O
Product: CC(=O)N1CCc2cc(CC(C)N=[N+]=[N-])cc(C#N)c21
Yield: 88.5 %

Procedure:
1-Acetyl-5-(2-bromopropyl)indoline-7-carbonitrile (1.42 g) and sodium azide (0.30 g) were dissolved in diethylene glycol monoethyl ether (1.4 ml) and water (3.2 ml), and the mixture was stirred at 90° C. for 9.5 hours.-To the reaction mixture was added water, and the mixture was extracted with methylene chloride. The extract was washed with water, dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on silica gel using a mixture of ethyl acetate and hexane (3/1) as eluent to give 1.10 g of 1-acetyl-5-(2-azidopropyl)indoline-7-carbonitrile as an oil.
Reaction SMILES: CCCCCC.Br[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[CH:10][C:9]=1[CH3:17].[CH2:18]([O:25][C@@H:26]1[C@@H:32]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@H:31]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C@@H:30]([CH2:49][O:50][CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[S:29][C:27]1([C:58]1[CH:63]=[CH:62][C:61]([Cl:64])=[C:60]([CH:65]=[O:66])[CH:59]=1)[OH:28])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:18]([O:25][C@@H:26]1[C@@H:32]([O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C@H:31]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C@@H:30]([CH2:49][O:50][CH2:51][C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)[S:29][C:27]1([C:58]1[CH:63]=[CH:62][C:61]([Cl:64])=[C:60]([CH:65]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[CH:10][C:9]=2[CH3:17])[OH:66])[CH:59]=1)[OH:28])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=Cc1cc(C2(O)S[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1Cl
Reactant: CCOc1ccc(Br)c(C)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOc1ccc(C(O)c2cc(C3(O)S[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)c(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
Then, 2.6 M n-butylithium hexane solution (1.6 mL) was added to a mixture of 1-bromo-4-ethoxy-2-methylbenzene (0.94 g, 4.37 mmol) and tetrahydrofuran (12 mL) at −78° C. After stirred for one hour, the mixture was added with a tetrahydrofuran (10 mL) solution of 2,3,4,6-tetra-O-benzyl-1-C-(4-chloro-3-formylphenyl)-5-thio-D-glucopyranose (1.52 g, 2.18 mmol), and, further stirred for 20 minutes, and the reaction mixture was warmed to room temperature. After the reaction mixture was added with a saturated ammonium chloride aqueous solution and extracted with ethyl acetate, the organic phase was washed with brine and dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain 2,3,4,6-tetra-O-benzyl-1-C-{4-chloro-3-[(4-ethoxy-2-methylphenyl)(hydroxy)methyl]phenyl}-5-thio-D-glucopyranose (1.72 g, 95%) as a yellow amorphous diastereomer mixture.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:21]([C:24]4[CH:29]=[CH:28][N:27]=[C:26](S(C)=O)[N:25]=4)=[CH:22][N:23]=3)[CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH2:34]([NH2:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:21]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH:41][CH2:34][C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[N:25]=4)=[CH:22][N:23]=3)[CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCc1ccccc1
Reactant: CS(=O)c1nccc(-c2cnc3c(NC4CCC(NC(=O)OC(C)(C)C)CC4)nccn23)n1
Product: CC(C)(C)OC(=O)NC1CCC(Nc2nccn3c(-c4ccnc(NCc5ccccc5)n4)cnc23)CC1
Temperature: 140 °C
Reaction time: 2 h

Procedure:
The mixture of {4-[3-(2-methanesulfinyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (from Example 48 supra) (130 mg, 0.276 mmol) and benzylamine (118.2 mg, 1.104 mmol) was heated at 140° C. with stirring for 2 hours. The oil was purified by chromatography (silica gel, 10 g, 200-300 mesh, eluting with dichloromethane:methanol, 50:1 to 30:1) to afford crude {4-[3-(2-benzylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester. (Yield 80 mg). LC-MS: [M+H]+ 515.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH:14](OS(C)(=O)=O)[CH2:13][CH2:12][CH:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:25]=[N+:26]=[N-:27].[Na+]>CS(C)=O.C(OCC)(=O)C>[N:25]([CH:14]1[CH2:13][CH2:12][CH:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:10][CH:9]1[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[N+:26]=[N-:27]
Reactant: CCOC(=O)C1CCC(OS(C)(=O)=O)C(NC(=O)OC(C)(C)C)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCC(N=[N+]=[N-])C(NC(=O)OC(C)(C)C)C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 43.8 %

Procedure:
To a solution of Racemate-ethyl 3-(tert-butoxycarbonylamino)-4-(methylsulfonyloxy)cyclohexanecarboxylate (11.0 g, 30 mmol) in dimethyl sulfoxide (110 mL) was added sodium azide (20 g, 300 mmol), and the mixture was stirred at 90° C. overnight under N2. The solution was cooled to ˜30° C., dissolved in ethyl acetate (˜500 mL), washed with water (500 mL×5) and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=4:1˜2:1) to thereby give the title compound (4.1 g, 44%) as an colorless oil. MS (ES+) C14H24N4O4 requires: 312, found: 213 [M+H−100]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([OH:19])[CH:18]=1)[C:12]([O:14][CH3:15])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([O:19][CH3:20])[CH:18]=1)[C:12]([O:14][CH3:15])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(O)cc(OCc2ccccc2)c1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1cc(OC)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
A suspension of 4.0 g (0.0165 mmol) methyl 3-(benzyloxy)-5-hydroxybenzoate (160), 6.84 g (0.0495 mmol) potassium carbonate, and 11.71 g (0.0825 mmol) iodomethane in the 200 mL of acetone was stirred at room temperature for 24 h. After the mixture was filtered and evaporated, the residue was washed with water. The methyl 3-(benzyloxy)-5-methoxybenzoate (161) was obtained as a white solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([F:8])[C:5]2[O:9][C:10]3[C:15]([C:16](=O)[C:4]=2[CH:3]=1)=[CH:14][C:13]([C:18]1[C:19]([F:24])=[N:20][CH:21]=[CH:22][CH:23]=1)=[CH:12][CH:11]=3.[CH3:25][Mg]Br.Cl>C1COCC1>[Br:1][C:2]1[N:7]=[C:6]([F:8])[C:5]2[O:9][C:10]3[C:15]([C:16](=[CH2:25])[C:4]=2[CH:3]=1)=[CH:14][C:13]([C:18]1[C:19]([F:24])=[N:20][CH:21]=[CH:22][CH:23]=1)=[CH:12][CH:11]=3
Reactant: C[Mg]Br
Reactant: O=c1c2cc(-c3cccnc3F)ccc2oc2c(F)nc(Br)cc12
Agent: Cl
Solvent: C1CCOC1
Product: C=C1c2cc(-c3cccnc3F)ccc2Oc2c1cc(Br)nc2F
Temperature: 40 °C
Reaction time: 0.17 h
Yield: 58.9 %

Procedure:
3-Bromo-1-fluoro-7-(2-fluoropyridin-3-yl)-5H-chromeno[2,3-c]pyridin-5-one (3.75 g, 9.64 mmol) was suspended in dry THF (100 mL) and cooled in an ice bath under nitrogen. Methylmagnesium bromide (3.0 M in diethyl ether, 10 mL, 30.0 mmol) was added dropwise and the mixture stirred for an additional 10 min before removing from the ice bath. Additional THF (300 mL) and methylmagnesium bromide (15 mL, 4.5 eq) was added slowly. Once the solids had completely dissolved the reaction was stirred for 5 min. It was quenched by careful addition of 5 N HCl. Water (600 mL) and EtOAc (500 mL) were added and the phases mixed and separated. The organic was dried with magnesium sulfate and evaporated to dryness under reduced pressure. The crude alcohol was dissolved in dry THF (200 mL) and treated with hydrogen chloride (4.0 M solution in 1,4-dioxane, 7 mL, 28.0 mmol). The solution was heated to 40° C. for 1 h. The solution was evaporated to dryness under reduced pressure and further dried under high vacuo. The crude 3-bromo-1-fluoro-7-(2-fluoropyridin-3-yl)-5-methylene-5H-chromeno[2,3-c]pyridine (2.20 g, 5.68 mmol, 59.0% yield) was used without purification. It was dissolved in dry THF (80 mL) and cooled in an ice bath under nitrogen. Silver cyanate (2.5 g, 16.68 mmol) was added and the mixture stirred. A solution of iodine (1.45 g, 5.71 mmol) in dry THF (20 mL) was added dropwise. After 30 min the colour of iodine had been consumed and the supernatant was clear. Diethyl ether (200 mL) was added and the mixture filtered through a pad of celite. The filtrate was treated with ammonia (2.0 M solution in methanol, 80 mL, 160 mmol) and the flask sealed. It was stirred overnight. The solution was evaporated to dryness under reduced pressure. The crude solids were triturated with diethyl ether and filtered through a sintered glass frit. The solids were dried under high vacuo to give the desired 3-bromo-1-fluoro-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine (2.25 g, 5.05 mmol, 89% yield). MS m/z=445.0, 446.9 [M+H]+. Calculated for C19H11BrF2N4O2: 444.0. Separation of the stereoisomers using SCF gave optically pure (5R)-3-bromo-1-fluoro-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine (MS m/z=445.0, 447.0 [M+H]) and (5S)-3-bromo-1-fluoro-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-oxazol]-2′-amine