Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH3:3][CH:4]([CH3:11])[CH2:5][CH2:6][CH2:7][C@@H:8]([OH:10])[CH3:9].[CH2:12](Br)[CH:13]=[CH2:14].O>CN(C)C=O>[CH3:9][C@H:8]([O:10][CH2:14][CH:13]=[CH2:12])[CH2:7][CH2:6][CH2:5][CH:4]([CH3:11])[CH3:3]
Reactant: C=CCBr
Reactant: CC(C)CCC[C@H](C)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCO[C@@H](C)CCCC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 2.9 g, 72 mmol) and dimethylformamide (100 mL) were charged to a 250 mL three-necked flask fitted with thermocouple, magnetic stirrer, condenser and dropping funnel. To the reaction mixture was added a solution of (2S)-6-methylheptan-2-ol (3.1 g, 24 mmol) in dimethylformamide (10 mL). This reaction mixture was stirred at room temperature for 1 hr then allyl bromide (8.6 g, 72 mmol) was added dropwise over 10 minutes ensuring the reaction temperature did not rise significantly (41° C. was observed). The reaction mixture was stirred for a further 20 minutes until the reaction was complete. To the reaction mixture was added water (10 mL) and the resultant mixture was extracted with methyltert-butyl ether (2×100 mL). The combined organic phase was dried over magnesium sulphate and the solvent remove in vacuo to yield a yellow oil which was chromatographed over silica gel (hexane/methyltert-butyl ether) to give 3-{[(1S)-1,5-dimethylhexyl]oxy}prop-1-ene as a sl. yellow oil (2.7 g, 15.8 mmol, chemical yield 66%).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][NH2:18].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C(=O)C>[N+:8]([C:7]1[C:2]([NH:18][CH2:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: NCc1ccccn1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=[N+]([O-])c1cccnc1NCc1ccccn1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 50 parts of 2-chloro-3-nitropyridine, 32.5 parts of 2-pyridinemethanamine, 53 parts of sodium carbonate and 675 parts of N,N-dimethylacetamide was stirred for 1 hour at 100° C. The reaction mixture was cooled and filtered over Hyflo. The filtrate was poured onto 1000 parts of water and the whole was stirred overnight at room temperature. The product was filtered off and dried, yielding 56.4 parts of N-(3-nitro-2-pyridinyl)-2-pyridinemethanamine; mp. 113.6° C. (intermediate 3).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:5]=[C:4]([N:16]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[S:17]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)(=[O:19])=[O:18])[CH:3]=1.[NH2:34][C@@H:35]([CH2:37][OH:38])[CH3:36]>CN1C(=O)CCC1>[CH2:9]([S:8][C:6]1[N:5]=[C:4]([N:16]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[S:17]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)(=[O:19])=[O:18])[CH:3]=[C:2]([NH:34][C@H:35]([CH3:36])[CH2:37][OH:38])[N:7]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C[Si](C)(C)CCOCN(c1cc(Cl)nc(SCc2ccccc2)n1)S(=O)(=O)N1CCOCC1
Reactant: C[C@@H](N)CO
Solvent: CN1CCCC1=O
Product: C[C@H](CO)Nc1cc(N(COCC[Si](C)(C)C)S(=O)(=O)N2CCOCC2)nc(SCc2ccccc2)n1

Procedure:
The subtitle compound was prepared as a yellow oil by the method of Example 43 step by reacting the subtitle product of step i) (11.75 g) with (R)-alaninol (3.4 ml) in NMP (30 ml). Yield: 12.2 g.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[I:12].[OH-].[Li+]>O1CCOCC1.O>[NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[I:12]
Reactant: COC(=O)c1ccc(N)c(I)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: Nc1ccc(C(=O)O)cc1I
Yield: 98.6 %

Procedure:
A solution of 3.00 g (10.8 mmol) of methyl 4-amino-3-iodobenzoate and 1.30 g (54.1 mmol) of lithium hydroxide in 150 ml of a dioxane/water mixture (1:1) was stirred at room temperature for 6 h. The dioxane was distilled off in vacuo, and the remaining aqueous phase was adjusted to pH 5 with 1 M hydrochloric acid. The precipitate was filtered off with suction and washed with water. 2.80 g (98%) of the title compound were obtained as a solid.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH3:4].C([Li])CCC.[Cl:29][C:30]1[CH:31]=[C:32]([CH:35]=[C:36]([O:42][CH2:43][C:44]#[CH:45])[C:37]=1[O:38][CH2:39][C:40]#[CH:41])[CH:33]=O>C(OCC)C>[Cl:29][C:30]1[CH:31]=[C:32]([CH:33]=[CH:2][CH2:3][CH3:4])[CH:35]=[C:36]([O:42][CH2:43][C:44]#[CH:45])[C:37]=1[O:38][CH2:39][C:40]#[CH:41]
Reactant: C#CCOc1cc(C=O)cc(Cl)c1OCC#C
Reactant: CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCOCC
Product: C#CCOc1cc(C=CCC)cc(Cl)c1OCC#C
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.5 %

Procedure:
n-Propyltriphenylphosphonium bromide (4.66 g) was dissolved in dry diethyl ether (50 ml), and n-butyl lithium (7.6 ml; 1.6N) was added thereto at 0° C. under nitrogen stream, followed by stirring at room temperature for 3 hours. A solution of 3-chloro-4,5-dipropargyloxybenzaldehyde (3.0 g) in dry diethyl ether (50 ml) was dropwise added to the resultant mixture, which was stirred at room temperature overnight, poured into ice-water and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using toluene as an eluent to give 1-(3-chloro-4,5-dipropargyloxyphenyl)butene (2.7 g). nD25.0 1.5602.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([C:14](O)=[O:15])=[C:12]([CH3:17])[O:11][N:10]=1.S(Cl)(Cl)=O.[CH3:22][NH:23][CH3:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([C:14]([N:23]([CH3:24])[CH3:22])=[O:15])=[C:12]([CH3:17])[O:11][N:10]=1
Reactant: Cc1onc(-c2c(Cl)cccc2Cl)c1C(=O)O
Reactant: CNC
Solvent: O=S(Cl)Cl
Product: Cc1onc(-c2c(Cl)cccc2Cl)c1C(=O)N(C)C
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 41.8 %

Procedure:
To 3-(2,6-dichlorophenyl)-5-methylisoxazol-4-carboxylic acid (25 mg, 0.10 mmol) was added thionyl chloride (1 mL) and the neat solution allowed to stir 60° C. After 30 min, excess thionyl chloride was evaporated and dimethyl amine (40 μL, 0.08 mmol, 2M in tetrahydrofuran) was added and allowed to stir overnight at ambient temperature. The residue was purified using reversed phase HPLC to afford the title compound (10 mg). HRMS (ESI, pos. ion) m/z calcd for C13H12Cl2N2O2: 298.0276, found 298.0276.
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[H-].[Na+].[CH3:13][Si:14]([CH3:21])([CH3:20])[CH2:15][CH2:16][O:17][CH2:18]Cl.O>CN(C=O)C>[Cl:1][C:2]1[N:6]([CH2:18][O:17][CH2:16][CH2:15][Si:14]([CH3:21])([CH3:20])[CH3:13])[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCn1c(Cl)nc2ccccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-chloro-1H-benzimidazole (3.8 g) in DMF (25 ml) was added sodium hydride (60% in oil, 1.1 g) at 0° C. in several portions. The reaction mixture was stirred at 0° C. for 30 min, 2-(trimethylsilyl)ethoxymethyl chloride (4.7 ml) was added dropwise, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate) to give the title compound (6.3 g).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH2:8].C(N(CC)CC)C.[Cl:16][C:17]1[CH:18]=[C:19]([CH:37]=[CH:38][C:39]=1[CH3:40])[CH2:20][N:21]1[C:25]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)=[CH:24][C:23]([C:34](Cl)=[O:35])=[N:22]1>C(Cl)Cl>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH:8][C:34]([C:23]1[CH:24]=[C:25]([C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[C:28]([Cl:33])[CH:27]=2)[N:21]([CH2:20][C:19]2[CH:37]=[CH:38][C:39]([CH3:40])=[C:17]([Cl:16])[CH:18]=2)[N:22]=1)=[O:35]
Reactant: Cc1ccc(Cn2nc(C(=O)Cl)cc2-c2ccc(Cl)c(Cl)c2)cc1Cl
Reactant: CC1CCCCC1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(Cn2nc(C(=O)NC3CCCCC3C)cc2-c2ccc(Cl)c(Cl)c2)cc1Cl

Procedure:
This compound is prepared by the procedure described in step B of EXAMPLE 36 from 1 ml of 2-methylcyclohexylamine, 1 ml of triethylamine in 15 ml of DCM and 1.5 g of the compound obtained in step A of EXAMPLE 36 in 15 ml of DCM. The compound is purified by chromatography on silica using a DCM/MeOH mixture (98/2; v/v) as the eluent to give 0.27 g of the expected product. M.p.=165° C.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([F:11])=[CH:5][C:4]=1[C:12]1[CH:20]=[C:19]2[C:15]([C:16]([I:21])=[N:17][NH:18]2)=[CH:14][CH:13]=1)[CH3:2].CC1C=CC(S(O)(=O)=O)=CC=1.[O:33]1[CH:38]=[CH:37][CH2:36][CH2:35][CH2:34]1>C(Cl)Cl>[CH2:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([F:11])=[CH:5][C:4]=1[C:12]1[CH:20]=[C:19]2[C:15]([C:16]([I:21])=[N:17][N:18]2[CH:34]2[CH2:35][CH2:36][CH2:37][CH2:38][O:33]2)=[CH:14][CH:13]=1)[CH3:2]
Reactant: C1=COCCC1
Reactant: CCc1cc(OC)c(F)cc1-c1ccc2c(I)n[nH]c2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CCc1cc(OC)c(F)cc1-c1ccc2c(I)nn(C3CCCCO3)c2c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
To a solution of 6-(2-ethyl-5-fluoro-4-methoxy-phenyl)-3-iodo-1H-indazole (Preparation 16, 1.94 g, 4.9 mmol) in DCM (10 mL) was added p-TsOH (187 mg, 982 μmol) and the mixture was cooled to 0° C. 3,4-Dihydro-2H-pyran (660 μL, 7.4 mmol) was added dropwise to the solution and the reaction was stirred at room temperature overnight. The reaction mixture was diluted with DCM (5 mL) and washed with saturated sodium hydrogen carbonate aqueous solution (20 mL). The organic layer was dried over MgSO4 and concentrated in vacuo to yield a black oil. The residue was purified by column chromatography (Biotage SNAP 10 g) eluting with a gradient of 20% EtOAc in heptane to give the title compound as a colourless oil (2.09 g) in an 89% yield.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:26][C@H:25]([CH2:27][O:28]CC4C=CC(Cl)=CC=4Cl)[C@@H:14]([O:15]CC4C=CC(Cl)=CC=4Cl)[C@@:12]3([CH2:38][OH:39])[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1>CO.ClCCl.[Pd]>[NH2:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[O:26][C@H:25]([CH2:27][OH:28])[C@@H:14]([OH:15])[C@@:12]3([CH2:38][OH:39])[OH:13])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Nc1ncnc2c1ccn2[C@@H]1O[C@H](COCc2ccc(Cl)cc2Cl)[C@@H](OCc2ccc(Cl)cc2Cl)[C@]1(O)CO
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: Nc1ncnc2c1ccn2[C@@H]1O[C@H](CO)[C@@H](O)[C@]1(O)CO
Reaction time: 12 h
Yield: 84.4 %

Procedure:
The compound from Step B (120 mg, 0.2 mmol) was dissolved in 1:1 methanol/dichloromethane, 10% Pd-C was added, and the suspension stirred under an H2 atmosphere for 12 h. The catalyst was removed by filtration through a celite pad and washed with copious amounts of methanol. The combined filtrate was evaporated in vacuo and the residue was purified by flash chromatography (SiO2, 10% methanol in EtOAc containing 0.1% triethylamine) to give the title compound (50 mg) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=2[CH:13](Cl)Cl.Cl.[NH2:17]O.C([O-])=O.[Na+]>C(O)=O.O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[C:6]=2[C:13]#[N:17]
Reactant: NO
Reactant: Clc1cnc2c(C(Cl)Cl)c(Cl)ccc2c1
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: N#Cc1c(Cl)ccc2cc(Cl)cnc12
Yield: 78.5 %

Procedure:
28.1 parts by weight of the 3,7-dichloro-8-dichloromethylquinoline thus obtained, 6.95 parts by weight of hydroxylamine hydrochloride and 13.6 parts by weight of sodium formate in 200 ml of formic acid and 60 ml of water were stirred for 12 hours at 100° C., the reaction solution was poured onto ice, the precipitated solid was filtered off under suction, washed neutral with water and dried. 19 parts by weight of 3,7-dichloro-8-cyanoquinoline of melting point 222° C. were obtained. Yield: 78.5% of theory.
Reaction SMILES: CO.[CH3:3][S:4][C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:21][CH2:20][CH2:19][O:18]2)[CH:12]=1)([CH3:10])[C:6]([O:8]C)=[O:7].[OH-].[Na+]>O>[CH3:3][S:4][C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:21][CH2:20][CH2:19][O:18]2)[CH:12]=1)([CH3:10])[C:6]([OH:8])=[O:7]
Reactant: COC(=O)C(C)(SC)c1cccc(C2(c3ccccc3)OCCO2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CSC(C)(C(=O)O)c1cccc(C2(c3ccccc3)OCCO2)c1
Yield: 97.7 %

Procedure:
Methanol (4 ml) and 1 ml of water were added to 1.277 g of methyl α-methylthio-α-[m-(2-phenyl-1,3-dioxa-2-cyclopentyl)phenyl]propionate. Furthermore, 350 mg of sodium hydroxide was added, and the mixture was heated under reflux for 2 hours. After cooling, 30 ml of water was added, and the mixture was washed twice with 10 ml of diethyl ether. To the aqueous layer was added about 6 ml of 3.5% hydrochloric acid to adjust its pH to 3. It was then extracted four times with 20 ml of diethyl ether. The organic layer was washed twice with 10 ml of water, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to afford 1.199 g of α-methylthio-α-[m-(2-phenyl-1,3-dioxa-2-cyclopentyl)phenyl]propionic acid as colorless crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Br[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[CH2:10][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1]
Reactant: BrCC1CCCCC1
Reactant: Oc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccccc1OCC1CCCCC1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
5.00 ml of 2-bromophenol was dissolved in 90 ml of N,N-dimethylformamide, 7.21 ml of (bromomethyl)cyclohexane and 7.15 g of potassium carbonate were added thereto, and the mixture was stirred at 100° C. for 5 hours. Water was added to the reaction solution, and the mixture was extracted with n-hexane. The organic layer was washed with water, 5N-sodium hydroxide and brine, and then dried over anhydrous magnesium sulfate. The mixture was filtered through alumina, and the solvent was evaporated, to give 10.47 g of the title compound as a slight yellow oil.
Reaction SMILES: [CH3:1][CH:2]([OH:9])[CH2:3][NH:4][CH2:5][CH:6]([OH:8])[CH3:7].[C:10](O)(=O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>O>[CH3:1][CH:2]1[O:9][C:21]2([CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH3:10])[O:8][CH:6]([CH3:7])[CH2:5][N:4]2[CH2:3]1
Reactant: CC(O)CNCC(C)O
Reactant: CCCCCCCCCCCC(=O)O
Solvent: O
Product: CCCCCCCCCCCC12OC(C)CN1CC(C)O2
Temperature: 186 °C
Reaction time: 1.85 h

Procedure:
To a 1 liter stirred reactor, equipped with a distillation column, condenser, and graduated receiver, the following constituents were added: 166.5 g of diisopropanol amine (DIPA) and 200.0 9 (98%) of lauric acid. The contents were heated to 186° C. under a nitrogen blanket. After 111 minutes, 15 ml of water had come overhead. The batch temperature was allowed to drop to 172° C. while the pressure was dropped to 10,531 Pa. The batch temperature was then raised to 195° C. and the pressure was raised to 13,330 Pa. The batch temperature was slowly raised to 220° C. while the batch pressure was increased to 19,800 Pa. An additional 13 ml of a mixture of water and DIPA came overhead. The temperature was then allowed to drop to 182° C. while the pressure was dropped to 280 Pa. During the pressure reduction, 31.2 g of DIPA came overhead. As the pressure was dropped to 227 Pa and the temperature increased to 221° C., a total of 93.4 g of the amide acetal of lauric acid was collected.
Reaction SMILES: [C:1]1([O:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:14](Cl)(=[O:24])[C:15]1[CH:23]=[CH:22][CH:21]=[C:17]([C:18](Cl)=[O:19])[CH:16]=1.C(Cl)Cl.[Cl-].[Al+3].[Cl-].[Cl-]>O>[O:7]([C:1]1[CH:2]=[CH:3][C:4]([C:14]([C:15]2[CH:23]=[CH:22][CH:21]=[C:17]([C:18](=[O:19])[C:11]3[CH:12]=[CH:13][C:8]([O:7][C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:9][CH:10]=3)[CH:16]=2)=[O:24])=[CH:5][CH:6]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: O=C(Cl)c1cccc(C(=O)Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: O=C(c1ccc(Oc2ccccc2)cc1)c1cccc(C(=O)c2ccc(Oc3ccccc3)cc2)c1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
Into a 2 liter flask equipped with a mechanical stirrer, thermometer, and nitrogen inlet and outlet, were charged 210 g (1.2338 moles) of diphenyl ether, 83.9 g (0.4132 moles) of isophthaloyl chloride, and 970 ml of methylene chloride. The solution was cooled to -5° C. by means of and acetone ice bath and then aluminum chloride (240 g, 1.8005 mole) was added in six 40 g portions. The temperature rose slightly during the addition of aluminum chloride and after the final addition the temperature was stabilized and held at 0° C. for thirty minutes. The solution was subsequently warmed to room temperature and held there for 1 hour. Afterwards, the solution was very slowly poured into agitated chilled demineralized water to deactivate the aluminum chloride (maximum water temperature reached was 28° C.). After stirring for 10 minutes, stirring was stopped and the very acidic upper layer was decanted off. The organic layer was subsequently washed several times with fresh dimeneralized water to remove the acid and filtered to remove solid impurities, e.g., elemental aluminum). Afterwards, methanol was slowly added to the organic layer (about 1/1 on a volume basis) with stirring and the product precipitated as short, white needles. Further purification was undertaken by slurrying 3X in isopropanol followed by filtration and drying. The short needles gave a DSC melting point (20° C./min) of 124° C.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][C:5]2([CH2:11][CH2:10][N:9]([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[N:20]=4)[N:15]=[CH:14][CH:13]=3)[CH2:8][CH2:7]2)[CH2:4][C@H:3]1[OH:24].[O-]S([O-])(=O)=O.[Na+].[Na+].[O:32]=[C:33]1[CH2:38][S:37][C:36]2[CH:39]=[CH:40][C:41]([CH:43]=O)=[N:42][C:35]=2[NH:34]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CCO>[OH:24][C@@H:3]1[CH2:4][C:5]2([CH2:11][CH2:10][N:9]([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[N:20]=4)[N:15]=[CH:14][CH:13]=3)[CH2:8][CH2:7]2)[CH2:6][C@@H:2]1[NH:1][CH2:43][C:41]1[CH:40]=[CH:39][C:36]2[S:37][CH2:38][C:33](=[O:32])[NH:34][C:35]=2[N:42]=1
Reactant: COc1ccc2nccc(N3CCC4(CC3)C[C@@H](O)[C@@H](N)C4)c2n1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc2nccc(N3CCC4(CC3)C[C@@H](O)[C@@H](NCc3ccc5c(n3)NC(=O)CS5)C4)c2n1
Reaction time: 12 h
Yield: 46.9 %

Procedure:
To a solution of (2R,3S)-3-amino-8-[6-(methyloxy)-1,5-naphthyridin-4-yl]-8-azaspiro[4.5]decan-2-ol (40 mg, 0.122 mmol) in DCM-EtOH (1.5 mL, 1:1) at 25° C. were added Na2SO4 (35 mg, 0.244 mmol) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde (24 mg, 0.122 mmol). After 12 h, NaBH(OAc)3 was added and after stirring an additional 2 h the solution was partitioned between NaHCO3 (sat)-DCM. The aqueous phase was extracted several times with DCM and the combined organic fractions were dried (Na2SO4), concentrated and purified via column chromatography (silica, 2% MeOH in DCM (1% NH4OH)) yielding the title compound (29 mg, 47%) as a yellow foam: LCMS (ES) m/e 507 (M+H)+; 1H NMR (400 MHz, CDCl3) δ 8.51 (d, J=5.2 Hz, 1H), 8.17 (d, J=9.0 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.07 (d, J=9.0 Hz, 1H), 6.95 (d, J=7.8 Hz, 1H), 6.83 (d, J=5.3 Hz, 1H), 4.12-4.19 (m, 1H), 4.03 (s, 3H), 3.92 (AB quart., 2H), 3.52-3.67 (m, 4H), 3.47 (s, 2H), 3.21-3.27 (m, 1H), 1.91-2.10 (m, 4H), 1.75-1.78 (m, 4H).
Reaction SMILES: F[C:2](F)(F)C([O-])=O.[CH2:8]([NH2+:15][CH:16]1[CH2:21][CH2:20][CH:19]([C@H:22]([CH3:40])[C@H:23]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:24]([N:26]2[CH2:30][CH2:29][C@H:28]([F:31])[CH2:27]2)=[O:25])[CH2:18][CH2:17]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.C(OCC)(=O)C>[C:36]([O:35][C:33](=[O:34])[NH:32][C@H:23]([C:24]([N:26]1[CH2:30][CH2:29][C@H:28]([F:31])[CH2:27]1)=[O:25])[C@H:22]([CH:19]1[CH2:20][CH2:21][CH:16]([N:15]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH3:2])[CH2:17][CH2:18]1)[CH3:40])([CH3:39])([CH3:38])[CH3:37]
Reactant: O=C([O-])C(F)(F)F
Reactant: C[C@@H](C1CCC([NH2+]Cc2ccccc2)CC1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: C[C@@H](C1CCC(N(C)Cc2ccccc2)CC1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1

Procedure:
To a solution of the material prepared in Step A (0.25 g, 0.54 mmol) in methanol (6 mL) was added a 37% aqueous solution of formaldehyde (0.10 mL, 1.62 mmol), followed by sodium triacetoxyborohydride (0.46 g, 2.16 mmol). After 3 h at ambient temperature the reaction was diluted with 100 mL of ethyl acetate, and the organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried (magnesium sulfate) and concentrated in vacuo, affording the title compound as a clear oil. This material was used without further purification. LC/MS 476.5 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH:4]=O.[N:12]1C=CC=[CH:14][CH:13]=1.C(OC(=O)C)(=O)C>C1(C)C=CC=CC=1>[CH3:11][O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:2]2[C:3]=1[CH:4]=[N:12][C:13]([CH3:14])=[N:1]2
Reactant: c1ccncc1
Reactant: COc1cccc(N)c1C=O
Solvent: Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: COc1cccc2nc(C)ncc12
Yield: 85.4 %

Procedure:
To a stirred solution of 2-amino-6-methoxybenzaldehyde [K. Tsuda et al., Chem. Pharm. Bull. 1962, 10, 856] (1.3 g, 8.6 mmol), pyridine (0.81 g, 10.3 mmol) and toluene (60 mL) was added acetic anhydride (0.97 g, 9.5 mmol). The resulting mixture was heated at reflux for 18 h, cooled, then partitioned between saturated aqueous NaHCO3 (100 mL) and ether (50 mL). The organic phase was dried (Na2SO4) and evaporated in vacuo to give a solid which was purified by chromatography on silica with 0-50% ether in hexane gradient elution to give a colourless solid (1.28 g). The latter was dissolved in 2 M methanolic ammonia (100 mL) and the solution heated at reflux for 3 h, cooled, then evaporated in vacuo. Chromatography of the residue on silica with 0-100% ether in dichloromethane gradient elution gave the title compound (0.92 g, 62%) as a colourless solid.