Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]2[C@H:15]([CH3:16])[CH2:14][CH2:13][C@H:12]([C:17]([NH:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[O:18])[CH2:11]2)[CH:3]=1.[C:26]([C:28]1[C:33]([F:34])=[CH:32][C:31](B(O)O)=[CH:30][C:29]=1[F:38])#[N:27].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.O1CCOCC1>[C:26]([C:28]1[C:33]([F:34])=[CH:32][C:31]([C:2]2[N:7]=[C:6]([NH:8][CH3:9])[N:5]=[C:4]([N:10]3[C@H:15]([CH3:16])[CH2:14][CH2:13][C@H:12]([C:17]([NH:19][CH:20]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]4)=[O:18])[CH2:11]3)[CH:3]=2)=[CH:30][C:29]=1[F:38])#[N:27]
Reactant: CNc1nc(Cl)cc(N2C[C@@H](C(=O)NC3CCCCC3)CC[C@H]2C)n1
Reactant: N#Cc1c(F)cc(B(O)O)cc1F
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CNc1nc(-c2cc(F)c(C#N)c(F)c2)cc(N2C[C@@H](C(=O)NC3CCCCC3)CC[C@H]2C)n1
Temperature: 100 °C
Yield: 63.8 %

Procedure:
(3S,6R)-1-[6-Chloro-2-(methylamino)-4-pyrimidinyl]-N-cyclohexyl-6-methyl-3-piperidinecarboxamide (600 mg, 1.64 mmol) and (4-cyano-3,5-difluorophenyl)boronic acid (390 mg, 2.13 mmol, 1.3 equiv), Pd2(dba)3 (113 mg, 0.12 mmol, 0.075 equiv), tricyclohexylphosphine (69 mg, 0.246 mmol, 0.15 equiv), and K3PO4 (592 mg, 2.79 mmol, 1.7 equiv) were charged to a seal tube, followed by addition of 1,4-dioxane (12 mL) and water (4 mL). The mixture was bubbled with argon for 10 minutes, capped and heated at 100° C. for 20 hours. The mixture was filtered through celite, and the filtrate was concentrated in vacuo. The resulting residue was partitioned between EtOAc (50 mL) and brine (15 mL), and the organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel column chromatography using gradient elution of 1% EtOAc in CHCl3 to 100% EtOAc afforded the title compound (490 mg). LC-MS (ES) m/z=469 [M+H]+.
Reaction SMILES: C1(C[N:8]2[CH2:12][C@H:11]([CH2:13][OH:14])[C@H:10]([CH2:15][OH:16])[CH2:9]2)C=CC=CC=1.Cl>CO.[OH-].[OH-].[Pd+2]>[NH:8]1[CH2:12][C@H:11]([CH2:13][OH:14])[C@H:10]([CH2:15][OH:16])[CH2:9]1
Reactant: OC[C@@H]1CN(Cc2ccccc2)C[C@@H]1CO
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Product: OC[C@@H]1CNC[C@@H]1CO
Reaction time: 48 h
Yield: 65.5 %

Procedure:
To a solution of crude [(cis)-1-(phenylmethyl)-3,4-pyrrolidinediyl]dimethanol (2.5 g) in MeOH (50 mL) was added conc HCl (0.2 mL) followed by Pearlmans catalyst (700 mg). The resulting suspension was hydrogenated for 48 hours at 50 psi on a Parr shaker, after which time a further 700 mg of the catalyst was added. Hydrogenation for another 72 hours at 50 psi resulted in completion of the reaction. Removal of the catalyst by filtration and evaporation of the solvents under reduced pressure yielded (cis)-3,4-pyrrolidinediyldimethanol (970 mg, 7.4 mmol). LCMS: (M+H)+: Not detected.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C:3]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:2]1.[CH2:22]([C@@H:29]1[CH2:31][O:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[OH:30][C@H:29]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:31][N:1]1[CH2:6][CH2:5][CH2:4][C:3]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:2]1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCCNC1)O2
Reactant: c1ccc(C[C@@H]2CO2)cc1
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCCN(C[C@H](O)Cc3ccccc3)C1)O2

Procedure:
Compound 195 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,3′-piperidine]-5,6-dione, (2R)-2-benzyloxirane and conditions outlined in procedure Y. M.p.=65-67° C., 400 MHz 1H NMR (CDCl3) δ: 8.04-8.03 (br d, J=7.82 Hz, 1H), 7.73-7.60 (m, 2H), 7.49-7.44 (m, 1H), 7.31-7.18 (m, 5H), 3.95-3.91 (m, 1H), 3.18-2.91 (m, 3H), 2.78-2.53 (m, 5H), 2.45-2.33 (m, 2H), 2.03-1.70 (m, 4H); LCMS: 436 [M+H].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([OH:12])=[CH:7][CH:6]=[CH:5]2.[C:13]1([CH3:23])[C:14]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:16]=[CH:17][CH:18]=1>>[NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([O:12][S:19]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH3:23])(=[O:21])=[O:20])=[CH:7][CH:6]=[CH:5]2
Reactant: Nc1ccc2c(O)cccc2c1
Reactant: Cc1ccccc1S(=O)(=O)Cl
Product: Cc1ccccc1S(=O)(=O)Oc1cccc2cc(N)ccc12

Procedure:
Additional substituents can be added to the naphthol ring by reacting a 6-aminonaphth-1-ol (SM11) with toluene sulfonyl chloride in the manner disclosed above to yield the 6-amino-1-(methylphenylsulfonyloxy)naphthalene (NN). The 6-amino-1-(methylphenylsulfonyloxy)naphthalene (NN) was then reacted with t-butyl nitrite in a solvent, for example at 0° C. followed by a copper (II) halide, for example, copper (II) chloride, to yield the appropriate 6-halo-1-(methylphenylsulfonyloxy)naphthalene (PP). The 6-amino-1-(methylphenylsulfonyloxy)naphthalene (NN) was also reacted with an excess of a copper (II) halide, for example, copper (II) chloride, in a solvent followed by t-butylnitrite in the manner disclosed above to form the appropriate 5,6-dihalo-1-(methylphenylsulfonyloxy)naphthalene (QQ). The appropriately substituted naphthalene (QQ) or (PP) can then reacted with a base, for example, potassium hydroxide, and an alcohol, for example, ethanol, in a mixture of a solvent, for example, THF, and water to yield the appropriately substituted. naphthol (RR), for example 5,6-dichloronaphthol. When the naphthol was a 5,6-dihalonaphthol (RR) it was reacted with either the appropriately substituted benzaldehyde (BB), alcohol (CC), toluene (DD), or hydrochloride (EE) and a borane-pyridine complex under acidic conditions, or a base, for example, sodium hydride or triethylamine, in a solvent, for example DMF, or a phosphine complex, for example n-butylphosphine, and DPAD in a solvent, for example, THF, to form the targeted 1-substitutedalkylthio or alkoxy-4-((5,6-substituted naphth-1-yl)oxyalkyl)benzene (Ia), for example, (2-(4-((5,6-dichloronaphthyloxy)methyl)phenoxy)ethyl)diethylamine.
Reaction SMILES: Cl[CH2:2][C:3](=O)[C:4](=[N:21][O:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:5]([NH:7][CH:8]1[C:19](=[O:20])[N:10]2[C:11]([C:16]([OH:18])=[S:17])=[C:12]([CH3:15])[CH2:13][S:14][C@H:9]12)=[O:6].[CH3:29][NH:30][C:31]([NH2:33])=[S:32].C([O-])(=O)C.[Na+]>O.O1CCCC1>[CH3:29][NH:30][C:31]1[S:32][CH:2]=[C:3]([C:4](=[N:21][O:22][CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:5]([NH:7][CH:8]2[C:19](=[O:20])[N:10]3[C:11]([C:16]([OH:18])=[S:17])=[C:12]([CH3:15])[CH2:13][S:14][C@H:9]23)=[O:6])[N:33]=1
Reactant: COC(=O)CON=C(C(=O)CCl)C(=O)NC1C(=O)N2C(C(O)=S)=C(C)CS[C@H]12
Reactant: CNC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CNc1nc(C(=NOCC(=O)OC)C(=O)NC2C(=O)N3C(C(O)=S)=C(C)CS[C@H]23)cs1
Reaction time: 2.5 h
Yield: 69 %

Procedure:
A mixture of 7-[4-chloro-2-(methoxycarbonylmethoxyimino)-3-oxobutyramido]-3-methylthio-3-cephem-4-carboxylic acid (syn isomer) (4.3 g), N-methylthiourea (1.8 g) and sodium acetate (4.1 g) in water (20 ml) and tetrahydrofuran (40 ml) was stirred at 38° to 42° C. for 2.5 hours. Water (50 ml) was added to the reaction mixture and the resultant solution was washed with ethyl acetate. The separated aqueous layer was acidified to pH 2.3 with 10% hydrochloric acid and then extracted with ethyl acetate. The ethyl acetate layer was washed with brine and dried over magnesium sulfate. The solution was evaporated and the residue was triturated with ether to give 7-[2-(2-methylaminothiazol-4-yl)-2-(methoxycarbonylmethoxyimino)acetamido]-3-methylthio-3-cephem-4-carboxylic acid (syn isomer) (3.2 g).
Reaction SMILES: O=S(Cl)[Cl:3].[CH3:5][C:6]1[O:10][C:9]([C:11]([OH:13])=O)=[CH:8][CH:7]=1>C1C=CC=CC=1>[CH3:5][C:6]1[O:10][C:9]([C:11]([Cl:3])=[O:13])=[CH:8][CH:7]=1
Reactant: Cc1ccc(C(=O)O)o1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: Cc1ccc(C(=O)Cl)o1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
A solution of 0.31 g of SOCl2 in 2 ml of benzene was added dropwise at 0° C. under nitrogen atmosphere to a solution of 0.22 g of 5-methylfuran-2-carboxylic acid, prepared following the method described by Robert et al., Eur. J. Med. Chem. 30, 915-924 (1995), in 5 ml of benzene. The mixture was stirred at 80° C. for 1 hour and the excess SOCl2 was then distilled off. The residue (0.24 g, 97% of theory) was utilized for the next step without further purification.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].C(N(CC)CC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:26]([O:33][C:34](=[O:51])[CH:35]([NH2:50])[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[CH:39][CH:38]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl>[CH2:26]([O:33][C:34](=[O:51])[CH:35]([NH:50][C:1](=[O:3])[CH3:2])[CH2:36][C:37]1[CH:38]=[CH:39][C:40]([C:43]([O:45][C:46]([CH3:48])([CH3:47])[CH3:49])=[O:44])=[CH:41][CH:42]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)c1ccc(CC(N)C(=O)OCc2ccccc2)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC(Cc1ccc(C(=O)OC(C)(C)C)cc1)C(=O)OCc1ccccc1
Reaction time: 2 h
Yield: 88.9 %

Procedure:
Acetic anhydride (1.0 mL, 10.8 mmol) and triethylamine (2.4 g, 24 mmol) were added sequentially to a solution of rac.-2-amino-3-[4-[(1,1-dimethylethoxy)carbonyl]phenyl]propanoic acid benzyl ester p-toluenesulfonic acid salt (5.0 g, 9 mmol) in dichloromethane (100 ml) at 0° C. After 2 h, the reaction mixture was diluted with dichloromethane (250 mL) and washed with 1N HCl (2×20 mL), saturated aqueous sodium bicarbonate (2×20 mL) and dried (Na2SO4). Filtration and concentration provided the crude product which was purified by HPLC on silica gel eluting with a mixture of hexanes and ethyl acetate to give rac.-2-acetamido-3-[4-[(1,1-dimethylethoxy)carbonyl]phenyl]propanoic acid benzyl ester (3.3 g, 8 mmol) in 91% yield.
Reaction SMILES: I[C:2]1[C:3]([NH2:9])=[N:4][C:5]([NH2:8])=[CH:6][CH:7]=1.[CH3:10][Si:11]([C:14]#[CH:15])([CH3:13])[CH3:12].C(N(CC)C(C)C)(C)C.CN1C(=O)CCC1>[Cu]I.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:10][Si:11]([C:14]#[C:15][C:2]1[C:3]([NH2:9])=[N:4][C:5]([NH2:8])=[CH:6][CH:7]=1)([CH3:13])[CH3:12]
Reactant: Nc1ccc(I)c(N)n1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)C#Cc1ccc(N)nc1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 3-iodo-pyridin-2,6-diamine (20 g) described in Manufacturing Example 4-1, trimethylsilyl acetylene (24 mL), copper(I) iodide (3.3 g), N,N-diisopropylethylamine (19 g), and NMP (290 mL) was added tetrakis(triphenylphosphine)palladium(0) (9.8 g), which was stirred for 30 minutes at room temperature under an argon atmosphere. Water was added to the reaction solution, which was then extracted with ethyl acetate. The ethyl acetate layer thus obtained was washed with water 4 times and dried over sodium sulfate. The sodium sulfate was filtered off, the solvent was evaporated under a reduced pressure, and the residue was purified by NH silica gel chromatography (heptane:ethyl acetate=4:1, then 1:1). The eluate was concentrated under a reduced pressure, and the resulting solids were washed with heptane containing a small amount of ethyl acetate to obtain the titled compound (11 g).
Reaction SMILES: C([O:4][C:5]1[C:6]([O:11][CH:12]([C:14]([O:16][CH3:17])=[O:15])[CH3:13])=[N:7][CH:8]=[CH:9][CH:10]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+].CO>O>[OH:4][C:5]1[C:6]([O:11][CH:12]([C:14]([O:16][CH3:17])=[O:15])[CH3:13])=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)C(C)Oc1ncccc1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)C(C)Oc1ncccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
A mixture of 0.34 g of 3-acetoxy-2-{1-(methoxycarbonyl)ethoxy}pyridine, 0.11 g of potassium carbonate, and 2 ml of methanol was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then concentrated. The residue was subjected to silica gel column chromatography to give 198 mg of 3-hydroxy-2-{1-(methoxycarbonyl)ethoxy}pyridine.
Reaction SMILES: C([NH:5][C:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([NH:18][C:19]3[CH:24]=[C:23]([NH:25][C:26](=[O:37])[C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=4)[CH:22]=[CH:21][C:20]=3[CH3:38])=[O:17])[C:10]=2[CH:9]=[CH:8][N:7]=1)(C)(C)C.C(O)(C(F)(F)F)=O.C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C>[NH2:5][C:6]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([C:16]([NH:18][C:19]3[CH:24]=[C:23]([NH:25][C:26](=[O:37])[C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:35])([F:34])[F:36])[CH:28]=4)[CH:22]=[CH:21][C:20]=3[CH3:38])=[O:17])[C:10]=2[CH:9]=[CH:8][N:7]=1
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1NC(=O)c1cccc2c(NC(C)(C)C)nccc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1NC(=O)c1cccc2c(N)nccc12
Temperature: 70 °C
Reaction time: 4 h
Yield: 8.6 %

Procedure:
1-(t-Butylamino)-N-(2-methyl-5-(3-(trifluoromethyl)benzamido)phenyl)isoquinoline-5-carboxamide (0.13 g, 0.25 mmol) obtained in Step (3) above was dissolved in tetrahydrofuran (1 mL), slowly added with TFA (3 mL) at 0° C., and stirred for about 4 hours at 70° C. The reaction mixture was cooled to room temperature, and adjusted to have a pH value in a range of 10˜11 by adding a saturated aqueous sodium bicarbonate solution. The reaction mixture was diluted with ethyl acetate, followed by washing with distilled water. The organic layer thus obtained was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The concentrated compound was purified using silica gel chromatography to obtain the title compound (10 mg, 8%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][CH:11]1[CH2:16][C:15](=[O:17])[O:14][C:13](=[O:18])[CH2:12]1>C1COCC1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][C:15](=[O:17])[CH2:16][CH:11]([CH3:10])[CH2:12][C:13]([OH:18])=[O:14])=[CH:3][CH:4]=1)#[N:7]
Reactant: CC1CC(=O)OC(=O)C1
Reactant: N#Cc1ccc(N)cc1
Solvent: C1CCOC1
Product: CC(CC(=O)O)CC(=O)Nc1ccc(C#N)cc1
Yield: 64.8 %

Procedure:
A solution of 4-aminobenzonitrile (4.61 g, 39.02 mmol) and 4-methyldihydro-2H-pyran-2,6(3H)-dione (5.0 g, 39.02 mmol) in THF (50 mL) was stirred at 90° C. for 14 hr. The reaction solution was concentrated, and the precipitate was washed with ethyl acetate to give 5-(4-cyanophenylamino)-3-methyl-5-oxopentanoic acid (6.23 g, 25.3 mmol, 64.8%).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C:11]#[N:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[OH:13][NH:14][C:15](=N)[CH2:16][CH2:17][CH3:18]>>[CH2:16]([C:15]1[N:12]=[C:11]([N:8]2[CH2:7][CH2:6][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:10][CH2:9]2)[O:13][N:14]=1)[CH2:17][CH3:18]
Reactant: CCCC(=N)NO
Reactant: N#CN1CCC2(CC1)OCCO2
Product: CCCc1noc(N2CCC3(CC2)OCCO3)n1

Procedure:
The title compound is prepared from 1,4-dioxa-8-aza-spiro[4.5]decane-8-carbonitrile and N-hydroxy-butyramidine following a procedure analogous to that described in Intermediate 2. LC (method 14): tR=1.16 min; Mass spectrum (ESI+): m/z=254 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35](Cl)=[O:36])[C:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:38]1[CH2:43][CH2:42][NH:41][CH2:40][C:39]1=[O:44]>>[C:1]([C:5]1[N:10]=[C:9]([O:11][CH2:12][CH3:13])[C:8]([C:14]2[N:15]([C:35]([N:41]3[CH2:42][CH2:43][NH:38][C:39](=[O:44])[CH2:40]3)=[O:36])[C@@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)([CH3:27])[C@@:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)([CH3:19])[N:18]=2)=[CH:7][N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOc1nc(C(C)(C)C)ncc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: O=C1CNCCN1
Product: CCOc1nc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCNC(=O)C1

Procedure:
In a manner analogous to the method described in example 3, rac-(4S*,5R*)-2-(2-tert-butyl-4-ethoxy-pyrimidin-5-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 2-piperazinone (Avocado Organics) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 35% methanol in carbon dioxide). HR-MS (ES, m/z) calculated for C32H37N6O3Cl2 [(M+H)+] 623.2299, observed 623.2298.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:13]2[CH2:12][CH2:11][NH:10][CH2:9][CH:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]=2[CH:6]=[C:5]([OH:20])[C:4]=1[OH:21]>CO>[CH3:1][S:2][C:3]1[C:4](=[O:21])[C:5](=[O:20])[CH:6]=[C:7]2[C:13]=1[CH2:12][CH2:11][NH:10][CH2:9][CH:8]2[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CSc1c(O)c(O)cc2c1CCNCC2c1ccccc1
Solvent: CO
Product: CSC1=C2CCNCC(c3ccccc3)C2=CC(=O)C1=O

Procedure:
6-Methylthio-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (5 g) is oxidized with 2,3-dichloro-4,5-dicyano-1,4-benzoquinone in methanol at room temperature as in Example 1 to give 6-methylthio-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-dione which (1 g) is reacted with methylmercaptan in methanol to give 6,9-dimethylthio-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:19]([N:20]([CH3:24])[CH:21]([CH3:23])[CH3:22])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:25](O)=[O:26])[CH:16]=4)[N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C(N(CC)CC)C.[CH3:35][C:36]([NH2:39])([CH3:38])[CH3:37].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>ClCCl.O>[C:36]([NH:39][C:25]([C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:6]1[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=1)[NH:1][N:2]=[CH:3]3)[C:19]([N:20]([CH3:24])[CH:21]([CH3:23])[CH3:22])=[N:18]2)=[O:26])([CH3:38])([CH3:37])[CH3:35]
Reactant: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccc2[nH]ncc2c1
Reactant: CC(C)(C)N
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)N(C)c1nc2cc(C(=O)NC(C)(C)C)ccc2nc1-c1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(1H-indazol-5-yl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxylic acid (200 mg, 0.55 mmol) in dichloromethane (30 ml) was added triethylamine (210 mg, 2.08 mmol), 2-methylpropan-2-amine (121 mg, 1.65 mmol), and T3P (396 mg, 1.25 mmol), and the resulting mixture was stirred for 1 h at room temperature. The solution was diluted with water (150 ml), extracted with dichloromethane (3×50 ml), dried over anhydrous magnesium, and concentrated in vacuo to get N-tert-butyl-2-(1H-indazol-5-yl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxamide as a yellow solid (311 mg, crude).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[C:6]([F:8])[CH:7]=1.[Mg].C[O:12][B:13](OC)[O:14]C.Cl>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([B:13]([OH:14])[OH:12])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: COB(OC)OC
Reactant: Fc1cc(F)cc(Br)c1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: OB(O)c1cc(F)cc(F)c1
Temperature: 40 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
In a nitrogen atmosphere, a solution prepared by dissolving 100 g of 3,5-difluorobromobenzene in 150 mL of THF was added dropwise at a rate that caused gentle reflux to a mixed solution of 13.85 g of magnesium and 55 mL of THF. After dropwise addition, the mixture was stirred at 40° C. for 1 hour and cooled with ice. Then, a solution prepared by dissolving 64.59 g of trimethoxyborane in 130 mL of THF was slowly added dropwise under ice cooling, followed by stirring at room temperature for 1 hour. Then, 10% hydrochloric acid was added until the reaction system became acidic, and the mixture was stirred at room temperature for 30 minutes. Then, an organic layer was separated from the mixture, and an aqueous layer was subjected to extraction with hexane. The hexane extract was combined with the organic layer and washed with saturated brine. The resultant mixture was dried by adding sodium sulfate, and then the solvent was distilled off under reduced pressure to yield 71.65 g of 3,5-difluorophenylboronic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]([F:23])([F:22])[F:21])=[C:6]([CH:19]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16](I)=[CH:17][C:9]1=2.[CH3:24][N:25]1[CH:29]=[C:28](B2OC(C)(C)C(C)(C)O2)[CH:27]=[N:26]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]([F:23])([F:22])[F:21])=[C:6]([CH:19]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:28]3[CH:27]=[N:26][N:25]([CH3:24])[CH:29]=3)=[CH:17][C:9]1=2
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: FC(F)(F)c1ccc(Cl)cc1CN1CCNc2ncc(I)cc21
Product: Cn1cc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cn1
Yield: 74 %

Procedure:
1-[5-Chloro-2-(trifluoromethyl)benzyl]-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (112 mg) was reacted with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole as in General Procedure 4B to give the title compound as a brown solid (74% yield). m.p.=156° C., LCMS: m/z=408.25 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 3.48 (2H, m), 3.65 (2H, m), 3.87 (3H, s), 4.58 (2H, s), 5.06 (1H, s), 6.45 (1H, s), 7.36 (2H, m), 7.49 (2H, m), 7.63 (2H, m).
Reaction SMILES: [CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH:16]=O)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[O:25]=[S:26]1(=[O:32])[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH:1]1([N:7]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:8]([NH:10][C:11]2[S:12][C:13]([CH2:16][N:29]3[CH2:30][CH2:31][S:26](=[O:32])(=[O:25])[CH2:27][CH2:28]3)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S1(=O)CCNCC1
Reactant: O=Cc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Product: O=C(Nc1ncc(CN2CCS(=O)(=O)CC2)s1)N(C1CCCCC1)C1CCCCC1
Yield: 17.6 %

Procedure:
Prepared as described in general procedure (P) using 1,1-dicyclohexyl-3-(5-formyl-thiazol-2-yl)-urea (67 mg, 0.20 mmol), 1,1-dioxo-thiomorpholine hydrochloride (52 mg, 0.30 mmol) and sodium triacetoxyborohydride (51 mg, 0.24 mmol) to afford 16 mg (18%) of the desired product after purification.
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C@:3]21[CH2:26][C:25]1[C:20](=[CH:21][CH:22]=[C:23]([SH-:27]C(=S)OCC)[CH:24]=1)[CH2:19]2.[OH-].[Na+].O>CCO>[SH:27][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[CH2:19][C@:3]1([C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:16])([CH3:17])[CH3:18])[C:2]1=[O:1])[CH2:26]2
Reactant: CCOC(=S)[SH-]c1ccc2c(c1)C[C@@]1(C2)C(=O)N(COCC[Si](C)(C)C)c2ncccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C[Si](C)(C)CCOCN1C(=O)[C@@]2(Cc3ccc(S)cc3C2)c2cccnc21
Temperature: 60 °C

Procedure:
To a stirred solution of O-ethyl S-[(2R)-2′-oxo-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl]carbonodithioate from Step B (740 mg, 1.52 mmol) in EtOH (4 mL) was added 1 N NaOH (3.0 mL, 3.0 mmol). The resulting suspension was heated at 60° C. for 90 min, then cooled and poured into H2O (50 mL). The mixture was extracted with EtOAc (2×70 mL), and the combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo to yield the title compound. MS: m/z=462 (M+Na+CH3CN).