Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:64][CH:65]([CH2:68][OH:69])[CH2:66][OH:67]>CN(C=O)C>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[CH:16][C:17]([C:18]([NH:64][CH:65]([CH2:68][OH:69])[CH2:66][OH:67])=[O:20])=[CH:21][CH:22]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2]
Reactant: NC(CO)CO
Reactant: CC(=O)N1c2ccc(-c3ccc(C(=O)O)cc3)cc2[C@H](Nc2ccccn2)C[C@@H]1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(-c3ccc(C(=O)NC(CO)CO)cc3)cc2[C@H](Nc2ccccn2)C[C@@H]1C
Yield: 20.55 %

Procedure:
To a flask charged with 4-((2S,4R)-1-acetyl-2-methyl-4-(pyridin-2-ylamino)-1,2,3,4-tetrahydroquinolin-6-yl)benzoic acid (for a preparation see Intermediate 23) (70 mg, 0.174 mmol) and HATU (80 mg, 0.209 mmol) was added DMF (3 mL) and the resulting solution was treated with DIPEA (0.091 mL, 0.523 mmol) and after 5 min by 2-aminopropane-1,3-diol (31.8 mg, 0.349 mmol). The reaction was concentrated in vacuo, residue partitioned between water and EtOAc. the phases were separated and the aqueous extracted with EtOAc (×2). The combined organic layers were washed with saturated NaHCO3 (3×) then brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by MDAP (HpH) and the residue triturated with Et2O to give 4-((2S,4R)-1-acetyl-2-methyl-4-(pyridin-2-ylamino)-1,2,3,4-tetrahydroquinolin-6-yl)-N-(1,3-dihydroxypropan-2-yl)benzamide (17 mg, 0.036 mmol, 20.55% yield) as a very pale yellow solid. LCMS (HpH, 2 min), Rt=0.74 min, MH+=475.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[S:3]([C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:31][O:32][C:33]1[C:34](=[O:57])[C:35]([CH3:56])=[C:36]([CH2:42][C:43]2[CH:44]=[CH:45][C:46]([O:52][C:53](=[O:55])[CH3:54])=[C:47]([CH:51]=2)[C:48](O)=[O:49])[C:37](=[O:41])[C:38]=1[O:39][CH3:40]>C(Cl)Cl>[CH3:31][O:32][C:33]1[C:34](=[O:57])[C:35]([CH3:56])=[C:36]([CH2:42][C:43]2[CH:44]=[CH:45][C:46]([O:52][C:53](=[O:55])[CH3:54])=[C:47]([CH:51]=2)[C:48]([NH:10][C:9]2[CH:11]=[CH:12][C:6]([S:3]([C:2]([F:13])([F:1])[F:14])(=[O:4])=[O:5])=[CH:7][CH:8]=2)=[O:49])[C:37](=[O:41])[C:38]=1[O:39][CH3:40]
Reactant: Nc1ccc(S(=O)(=O)C(F)(F)F)cc1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(S(=O)(=O)C(F)(F)F)cc3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 36.1 %

Procedure:
4-(Trifluoromethylsulfonyl)aniline (0.452 g, 2.005 mmol), triethylamine (0.203 g, 2.005 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.339 g, 2.005 mmol) were added to a methylene chloride solution (70 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.250 g, 0.668 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.140 g, 0.241 mmol, 36%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:28])[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)(=[O:20])=[O:19])=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+].I[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(OCCCC)CCC.[Cu]>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([C:9](=[O:28])[CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([S:18]([N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)(=[O:20])=[O:19])=[CH:16][CH:17]=2)=[C:2]([NH:1][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:7]=1
Reactant: Ic1ccccc1
Reactant: CN1CCN(S(=O)(=O)c2ccc(CCC(=O)c3ccc(Cl)cc3N)cc2)CC1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCOCCCC
Product: CN1CCN(S(=O)(=O)c2ccc(CCC(=O)c3ccc(Cl)cc3Nc3ccccc3)cc2)CC1
Temperature: 160 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
A mixture of 1-(2-amino-4-chlorophenyl)-3-[4-(4-methylpiperazine-1-sulfonyl)-phenyl]-propan-1-one (1.268 g), copper powder (38 mg), KI (99 mg), K2CO3 (829 mg) and iodobenzene (1.35 mL) in dibutyl ether (25 mL) was heated to 160° C. (oil bath temperature) overnight. Additional copper powder (38 mg), KI (99 mg), K2CO3 (829 mg) and iodobenzene (1.35 mL) were added, and the resulting mixture was again stirred at 160° C. overnight. The reaction mixture was then cooled and concentrated under reduced pressure. The residue was partitioned between water and EtOAc, the organic layer was separated, and the aqueous layer was extracted 2× with EtOAc (50 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4, filtered, and evaporated under reduced pressure. The crude residue was purified by flash chromatography (DCM/MeOH, 100/0 for 5 minutes, 98/2 from minute 8 to 20) to give 1-(4-chloro-2-phenylaminophenyl)-3-[4-(4-methylpiperazine-1-sulfonyl)-phenyl]-propan-1-one (1.02 g; 68% yield). MS=498.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[N:14]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:13]=[C:12]([CH3:25])[C:11]=2[C:10](=O)[CH2:9]1.[C:27]([NH:30][NH2:31])([NH2:29])=[NH:28].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[N:14]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:13]=[C:12]([CH3:25])[C:11]=2[C:10](=[N:31][NH:30][C:27]([NH2:29])=[NH:28])[CH2:9]1
Reactant: N=C(N)NN
Reactant: Cc1nn(CCc2ccccc2)c2c1C(=O)CC(c1ccccc1Cl)C2
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1nn(CCc2ccccc2)c2c1C(=NNC(=N)N)CC(c1ccccc1Cl)C2
Yield: 74.5 %

Procedure:
A mixture of 6-(2-chlorophenyl)-3-methyl-1-(2-phenylethyl)-4,5,6,7-tetrahydroindazol-4-one (0.15 g), aminoguanidine hydrochloride (0.055 g), concentrated hydrochloric acid (0.1 ml), water (0.1 ml) and ethanol (15 ml) was refluxed for 12 hours. Under reduced pressure, the solvent was evaporated, and the resulting crystals were recrystallized from ethanol to give 6-(2-chlorophenyl)-4-guanidinoimino-3-methyl-1-(2-phenylethyl)-4,5,6,7-tetrahydroindazole hydrochloride (Compound 151) (0.07 g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:9][CH2:10][NH:11]C(=O)OC(C)(C)C)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[C:3]([CH2:9][CH2:10][NH2:11])=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCc1ncc(Cl)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCCc1ncc(Cl)cc1Cl
Reaction time: 2 h
Yield: 100 %

Procedure:
Tert-butyl 2-(3,5-dichloropyridin-2-yl)ethylcarbamate (50 mg, 0.17 mmol) was diluted with DCM (500 uL) followed by the addition of TFA (500 μl). After stirring for 2 hours, the reaction was concentrated and placed under vacuum to yield the desired compound (32 mg, 0.17 mmol, 98% yield).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11].[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[C:21]([N:23]1[CH2:28][C:27]2([CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[O:26][CH2:25][CH2:24]1)=[O:22].C(N(CC)CC)C>C(#N)C>[S:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[C:13]1[C:21]([N:23]1[CH2:28][C:27]2([CH2:33][CH2:32][N:31]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH2:30][CH2:29]2)[O:26][CH2:25][CH2:24]1)=[O:22]
Reactant: OCCCCCCCCCBr
Reactant: O=C(c1nc2ccccc2s1)N1CCOC2(CCNCC2)C1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(c1nc2ccccc2s1)N1CCOC2(CCN(CCCCCCCCCO)CC2)C1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A solution of 9-bromo-1-nonanol (0.335 g) in acetonitrile (3 mL) was added to a solution of benzo[d]thiazol-2-yl(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone (example 106, step b) (0.34 g) and triethylamine (0.278 mL) in acetonitrile (7 mL). The resulting mixture was stirred at 60° C. overnight. The reaction mixture was evaporated in vacuo and the residue was taken up into DCM (30 mL), washed with brine (2×15 mL), dried over sodium sulphate, filtered and evaporated in vacuo. Purification was by silica gel chromatography eluting with 0-10% methanol in dichloromethane to give the subtitled compound as a white solid. Yield 0.34 g.
Reaction SMILES: [C:1]([C:4]1[CH2:9][CH2:8][CH2:7][NH:6][CH:5]=1)(=[O:3])[CH3:2].Br[CH2:11][CH2:12][CH3:13]>>[CH2:11]([N:6]1[CH2:7][CH2:8][CH2:9][C:4]([C:1]([CH3:2])=[O:3])=[CH:5]1)[CH2:12][CH3:13]
Reactant: CC(=O)C1=CNCCC1
Reactant: CCCBr
Product: CCCN1C=C(C(C)=O)CCC1

Procedure:
Methyl 1-propyl-1,4,5,6-tetrahydro-3-pyridyl ketone was prepared from 3-acetyl-1,4,5,6-tetrahydropyridine and 1-bromopropane according to the procedure of Part b) of Example 1. The product distilled as a pale yellow (b.pt 98°-100° C./0.5 mm Hg).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:29]=1[CH:30]=[CH:31][NH:32]2.CC#N>O>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:24][CH2:25][CH2:26][O:27][C:28]4[CH:36]=[CH:35][CH:34]=[C:33]5[C:29]=4[CH:30]=[CH:31][NH:32]5)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: ClCCCOc1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Fc1ccc2c(C3CCN(CCCOc4cccc5[nH]ccc45)CC3)noc2c1
Reaction time: 68 h
Yield: 103.5 %

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.5 g, 16 mmol), K2CO3 (2.2 g, 16 mmol), KI (200 mg), 4-(3-chloropropoxy)indole (3.0 g, 14 mmol) and CH3CN (100 ml) was stirred at reflux under N2 for 7 hours and then at ambient temperature for 68 hours. Reflux was resumed for an additional 6 hours whereupon a TLC revealed incomplete reaction. K2CO3 (0.5 g, 4 mmol) was added and the reaction was stirred at reflux for 17 hours. The cooled reaction was poured into H2O and the aqueous mixture was extracted with EtOAc. The organic extract was washed with H2O and saturated NaCl and after drying over MgSO4 the solvent was removed to afford 5.7 g of a beige solid. The product was purified by preparative HPLC (Water's Associates Prep LC/System 500 using 2 silica gel columns and 4% MeOH—CH2Cl2 as eluent) to yield 3.4 g (61%) of a beige solid. Two consecutive recrystallizations from EtOH provided 2.3 g (41%) of a white powder, m.p.=129°-131° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([CH:16]([C:18](C)=[O:19])[CH3:17])[C:10]1=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[OH:23].[OH-].[Na+]>O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:15][CH2:14][CH2:13][CH2:12][N:11]([CH:16]([C:18]([OH:19])=[O:23])[CH3:17])[C:10]1=[O:21])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CO
Reactant: CC(=O)C(C)N1CCCC[C@H](NC(=O)OC(C)(C)C)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C(=O)O)N1CCCC[C@H](NC(=O)OC(C)(C)C)C1=O
Reaction time: 2 h

Procedure:
Dissolve 2.59 g 3-(S)-t-butoxycarbonylamino-1-(1-methylcarbonylethyl)perhydroazepin-2-one in 10 ml. methanol and 10 ml water and add 0.5 ml 50% NaOH solution. Store the mixture at room temperature for 2 hours and then concentrate at aspirator pressure to a syrup. Dissolve the syrup in water and chill the solution in an ice bath. Add 6N hydrochloric acid to pH 2 then extract the solution several times with ethyl acetate. Dry the combined extracts over MgSO4, filter and concentrate the filtrate at aspirator pressure and isolate 3-(S)-t-butoxycarbonylamino-1-(1-carboxyethyl)perhydroazepin-2-one as an oil (2.04 g) which is a mixture of diastereomers. Separate the isomers on a column of XAD2 resin at 50° C. using 0.1N NH4OH containing 6% acetonitrile as eluent. Isolate the ammonium salt of the desired isomer as the one which elutes first (u.v. and refractive index detection).
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:11][CH2:12][CH3:13])[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].Br[CH2:15][C:16]1[S:20][C:19]([C:21]2[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=2[C:23]#[N:24])=[CH:18][CH:17]=1.Cl>O1CCCC1>[C:23]([C:22]1[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=1[C:19]1[S:20][C:16]([CH2:15][CH:5]([C:4](=[O:3])[CH2:11][CH2:12][CH3:13])[C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:17][CH:18]=1)#[N:24]
Reactant: CCCC(=O)CC(=O)OCC
Reactant: N#Cc1ccccc1-c1ccc(CBr)s1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)s1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.7 %

Procedure:
To a mixture of 60% sodium hydride in oil (0.71 g) and tetrahydrofuran (20 mL) was added dropwise a mixture of ethyl 3-oxohexanoate (3.65 g) in tetrahydrofuran (10 mL) at 0° C., and the mixture was stirred at room temperature for 30 min. Then, 2-[5-(bromomethyl)thiophen-2-yl]benzonitrile (3.20 g) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 1 M hydrochloric acid (50 mL), and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless oil (3.30 g, 81%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]([CH:15]=[CH:16][CH:17]=2)[C:10]([O:12]CC)=O)[O:4][N:3]=1.C(C1C=C(C=CC=1)C(OCC)=O)#C.C1C(=O)N(Cl)C(=O)C1.C(=NO)C.[C:43]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])(=[O:45])[CH3:44].[Li]>C(Cl)(Cl)Cl.N1C=CC=CC=1.CCN(CC)CC>[C:47]([O:46][C:43](=[O:45])[CH2:44][C:10]([C:9]1[CH:15]=[CH:16][CH:17]=[C:7]([C:5]2[O:4][N:3]=[C:2]([CH3:1])[CH:6]=2)[CH:8]=1)=[O:12])([CH3:50])([CH3:49])[CH3:48]
Reactant: CC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1cccc(-c2cc(C)no2)c1
Agent: C#Cc1cccc(C(=O)OCC)c1
Agent: O=C1CCC(=O)N1Cl
Agent: [Li]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CC=NO
Product: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)on1

Procedure:
The title compound was prepared from ethyl 3-(3-methyl-isoxazol-5-yl)-benzoate [prepared by reaction of ethyl 3-ethynylbenzoate [CAS-No. 178742-95-5] with a mixture of NCS, acetaldoxime, Et3N and cat. amount of pyridine in CHCl3 at 50° C. according to Tetrahedron 1984, 40, 2985-2988] by treatment with lithium tert.-butyl acetate according to general procedure K (method b). Obtained as a yellow solid (2.54 g).
Reaction SMILES: Cl.[CH2:2]([C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]([NH2:15])=[NH:14])[CH2:9][CH2:8]1)[CH2:3][CH2:4][CH2:5][CH3:6].[CH3:16][O:17][CH:18]([C:23](OC)=[O:24])[C:19](OC)=[O:20].C[O-].[Na+].Cl>CO>[CH2:2]([C@H:7]1[CH2:8][CH2:9][C@H:10]([C:13]2[N:15]=[C:23]([OH:24])[C:18]([O:17][CH3:16])=[C:19]([OH:20])[N:14]=2)[CH2:11][CH2:12]1)[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC[C@H]1CC[C@H](C(=N)N)CC1
Reactant: COC(=O)C(OC)C(=O)OC
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCCC[C@H]1CC[C@H](c2nc(O)c(OC)c(O)n2)CC1
Reaction time: 5 h

Procedure:
This trans-4-pentylcyclohexanecarboxamidine hydrochloride (69 g, 0.30 mol) and dimethyl methoxymalonate (48 g, 0.30 mol) were added to a solution of sodium methylate (56 g, 1.0 mol) dissolved in anhydrous methanol (1 l), followed by heating the mixture under reflux with stirring for 5 hours, thereafter cooling the resulting material, mixing it with 6N-hydrochloric acid (500 ml), agitating the mixed liquid at room temperature for 20 minutes, filtering the liquid under suction through a filter, washing the resulting residue on the filter with water and methanol and drying it under reduced pressure to obtain 2-(trans-4-pentylcyclohexyl)-4,6-dihydroxy-5-methoxypyrimidine (67 g, 0.23 mol).
Reaction SMILES: [CH2:1]1[O:5][C:4]2[CH:6]=[C:7]([CH2:10][C:11](O)=[O:12])[CH:8]=[CH:9][C:3]=2[O:2]1.C1COCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C(OCC)C>[O:2]1[C:3]2[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][OH:12])=[CH:6][C:4]=2[O:5][CH2:1]1
Reactant: O=C(O)Cc1ccc2c(c1)OCO2
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCCc1ccc2c(c1)OCO2

Procedure:
A solution of 3,4-(methylenedioxy)phenylacetic acid (Intermediate D1) (commercially available from Aldrich) (2 g, 11 mmol) in diethyl ether (40 mL) and THF (60 mL) was treated with lithium aluminum hydride: LiAlH4 (24 mL, 1 M in ether) at rt for 16 h. Rochelle's salt solution was added to quench the reaction mixture. The aqueous layer was extracted with ether (3×100 mL). The combined organic fractions were dried over MgSO4, filtered and evaporated to give 1.8 g of 2-benzo[1,3]dioxol-5-yl-ethanol (Intermediate D2) that was sufficiently pure to be used in the next synthetic step.
Reaction SMILES: [CH3:1][C:2]([SH:5])([CH3:4])[CH3:3].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].CC1C=CC(S([O-])(=O)=O)=CC=1.[CH2:27]([C@@:30]1([CH3:57])[CH2:35][C@H:34]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[C@@H:33]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[C:45]([F:50])[CH:44]=2)[N+:32]2[C@@H:51]([CH:54]3[CH2:56][CH2:55]3)[CH2:52][O:53][C:31]1=2)[CH:28]=[CH2:29]>O1CCCC1>[CH2:27]([C@@:30]1([CH3:57])[CH2:35][C@H:34]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[C@@H:33]([C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[C:45]([F:50])[CH:44]=2)[N:32]([C@@H:51]([CH:54]2[CH2:55][CH2:56]2)[CH2:52][S:5][C:2]([CH3:4])([CH3:3])[CH3:1])[C:31]1=[O:53])[CH:28]=[CH2:29]
Reactant: CC(C)(C)S
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)c(F)c2)[N+]2=C1OC[C@@H]2C1CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)c(F)c2)N([C@H](CSC(C)(C)C)C2CC2)C1=O
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
2-Methyl-2-propanethiol (15.25 mL, 135 mmol, dried over activated 4 Å molecular sieves) was added to a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (1.0 M, 135 mL, 135 mmol) at room temperature under argon in a 500 mL round-bottomed flask. The reaction mixture was heated to 60° C. After 30 minutes, a solution of (3S,5S,6R,8S)-8-allyl-5-(4-chloro-3-fluorophenyl)-6-(3-chlorophenyl)-3-cyclopropyl-8-methyl-2,3,5,6,7,8-hexahydrooxazolo[3,2-60 ]pyridin-4-ium 4-methylbenzenesulfonate (78 g, 123 mmol, Example 4, Step H) in anhydrous tetrahydrofuran (100 mL) was added via cannula. The reaction mixture was heated at 60° C. for 3 hours and then cooled to room temperature. The reaction mixture was quenched with water and extracted thrice with ethyl acetate. The organics were pooled, washed with brine, dried over magnesium sulfate, filtered and concentrated under a vacuum to provide a yellow foam. Purification by flash column chromatography (1.5 kg SiO2 column, gradient elution with 5% to 30% ethyl acetate in hexanes provided the title compound as an off-white foam.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].CCN(C(C)C)C(C)C>CC#N>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:2]2[CH:7]=[N:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Temperature: 25 °C
Yield: 60.1 %

Procedure:
To a stirred solution of 5-bromo-2-nitropyridine (4.93 g, 24.3 mmol) and piperazine-1-carboxylic acid tert-butyl ester (4.97 g, 26.7 mmol) in CH3CN (60 ml) is added DIPEA (4.65 mL, 26.7 mmol). The mixture is heated at reflux for 72 hours then cooled to room temperature and the precipitated product collected by filtration. The filtrate is concentrated and purified by flash column chromatography eluting with 30% EtOAc/petrol. The combined products are re-crystallized from EtOAc/petrol to give 4-(6-nitro-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester, (4.50 g, 80% yield). MS (ESI) m/z 308 (M+H)+
Reaction SMILES: C(O)C.Cl.[NH2:5][OH:6].[C:7]([CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]1)#[N:8].C[O-].[Na+]>O>[NH2:8][C:7](=[N:5][OH:6])[CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]1
Reactant: CCOC(=O)N1CCC(C#N)CC1
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)N1CCC(C(N)=NO)CC1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
Ethanol (150 ml) was added to a solution of hydroxylamine hydrochloride (17.25 g) in water (48 ml). Ethyl 4-cyano-1-piperidinecarboxylate (45 g) was added and the mixture was cooled. Sodium methoxide (44.4 g) was added dropwise at RT and the reaction mixture was stirred for 30 minutes at 60° C. The reaction mixture was cooled, filtered and the filtrate evaporated. The residue was purified by column chromatography on silica gel (eluent: CH2Cl2 /CH3OH 95/5). The pure fractions were collected and the solvent evaporated, yielding 25 g (40%) of ethyl 4-[amino(hydroxyimino)methyl]-1-piperidinecarboxylate. This fraction was redissolved in 2-propanone and converted into the hydrochloric acid salt (1:1) with HCl/2-propanol. The precipitate was filtered off and dried, yielding 22 g (35%) of ethyl 4-[amino(hydroxyimino)methyl]-1-piperidine-carboxylate hydrochloride (intermediate 2).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:15]3([CH:19]([CH2:20][O:21][CH3:22])[S:18][C:17]([NH2:23])=[N:16]3)[C:14]3[CH:13]=[C:12]([Cl:24])[N:11]=[CH:10][C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[F:33][C:34]1[C:39](B(O)O)=[CH:38][CH:37]=[CH:36][N:35]=1.O1CCOCC1>O.C(C1C(C(C)(C)C)=C([Pd]Cl)C=CC=1N(C)C)(C)(C)C>[Cl:24][C:12]1[N:11]=[CH:10][C:9]2[O:8][C:5]3[C:4]([C:15]4([CH:19]([CH2:20][O:21][CH3:22])[S:18][C:17]([NH2:23])=[N:16]4)[C:14]=2[CH:13]=1)=[CH:3][C:2]([C:39]1[C:34]([F:33])=[N:35][CH:36]=[CH:37][CH:38]=1)=[CH:7][CH:6]=3
Reactant: OB(O)c1cccnc1F
Reactant: COCC1SC(N)=NC12c1cc(Br)ccc1Oc1cnc(Cl)cc12
Agent: CN(C)c1ccc([Pd]Cl)c(C(C)(C)C)c1C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COCC1SC(N)=NC12c1cc(-c3cccnc3F)ccc1Oc1cnc(Cl)cc12
Temperature: 100 °C
Yield: 66.8 %

Procedure:
To a microwave vessel was added 7-bromo-3-chloro-5′-(methoxymethyl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-thiazol]-2′-amine (1.50 g, 3.52 mmol, prepared as described in Method CC27), potassium phosphate (2.24 g, 10.55 mmol), (2-fluoropyridin-3-yl)boronic acid (1.14 g, 8.09 mmol), 1,1-bis[(di-t-butyl-p-dimethylaminophenyl]palladium(ii) chloride (0.25 g, 0.35 mmol), dioxane (13.2 mL), and water (4.4 mL). The resulting mixture was then heated at 100° C. in a microwave for 10 min. The reaction mixture was diluted with water and extracted with EtOAc. The organic extract was washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give the crude material as an orange solid. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a gold Redi-Sep pre-packed silica gel column (80 g), eluting with a gradient of 30% to 45% to 60% DCM/MeOH/NH4OH (90/10/1) in 40% EtOAc in Heptane, to provide 3-chloro-7-(2-fluoropyridin-3-yl)-5′-(methoxymethyl)-5′H-spiro[chromeno[2,3-c]pyridine-5,4′-thiazol]-2′-amine (1.04 g, 2.35 mmol, 66.8% yield) as off-white solid.