Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8]C(C)C)=[CH:6][C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]3[CH2:19][CH2:20][CH2:21][N:14]3[C:13]2=[O:22])=[C:4]([F:23])[CH:3]=1.ClC1C(O)=CC(N2C(=O)N3CCCCN3C2=S)=C(F)C=1>>[Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]3[CH2:19][CH2:20][CH2:21][N:14]3[C:13]2=[O:22])=[C:4]([F:23])[CH:3]=1
Reactant: CC(C)Oc1cc(-n2c(=O)cc3n(c2=O)CCC3)c(F)cc1Cl
Agent: O=c1n(-c2cc(O)c(Cl)cc2F)c(=S)n2n1CCCC2
Product: O=c1cc2n(c(=O)n1-c1cc(O)c(Cl)cc1F)CCC2
Yield: 86 %

Procedure:
This was synthesized from 2-(4-chloro-2-fluoro-5-isopropyloxyphenyl)-6,7-dihydropyrrolo[1,2-c]pyrimidine-1,3(2H,5H)-dione in 86% yield under similar conditions as described below for the preparation of 2-(4-chloro-2-fluoro-5-hydroxyphenyl)hexahydro-3-thioxo-1H-[1,2,4]triazolo[1,2-a]pyridazin-1-one (Example 10.2). 1H NMR (CDCl3, TMS): 2.22(2H, m), 3.06(2H, t, J=7.5 Hz), 3.13(1H, br), 4.01(2H, t, J=6.5 Hz), 5.71(1H, s), 6.87(1H, d, J=6.9 Hz), 7.18(1 H, d, J=9.3 Hz).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].[Cl:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][CH2:14][C:13]1[CH:16]=[CH:17][C:10]([Cl:9])=[CH:11][CH:12]=1)[CH3:3]
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CCOC(=O)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CCOC(=O)CNCc1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
To a suspension of glycine ethyl ester hydrochloride (1.2 eq.) in DCE was added TEA (2 eq.) The reaction was stirred for 10 min at 20° C. then 4-chlorobenzaldehyde (1 eq.), acetic acid (4 eq.) and sodium triacetoxyborohydride (2 eq.) were added. The reaction was stirred for 15 h at 20° C. The crude was partitioned between DCM and a saturated aqueous solution of NaHCO3. The aqueous layer was then extracted twice with DCM. The organic layers were combined, washed with brine, dried on MgSO4, filtered and concentrated under reduced pressure to afford (4-chloro-benzylamino)-acetic acid ethyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:18]1[N:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)=[CH:20][N:19]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:18]2[N:19]=[CH:20][C:21]([C:24]3[CH:25]=[CH:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=3)=[CH:22][N:23]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(-c2cnc(Cl)nc2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cnc(NC3CCN(C(=O)OC(C)(C)C)CC3)nc2)cc1
Temperature: 25 °C
Yield: 9 %

Procedure:
To a solution of 4-amino-piperidine-1-carboxylic acid tert-butyl ester (4.0 g, 20.0 mmol, 1.3 equiv; commercially available) in dry DMF (100 mL) under Ar was added sodium hydride (1.01 g, 23.1 mmol, 1.5 equiv; 55% free-flowing powder moistened with oil) and the reaction mixture stirred at rt. After 2 h 2-chloro-5-(4-methoxy-phenyl)-pyrimidine (3.39 g, 15.4 mmol, 1.0 equiv; commercially available from Peakdale Molecular, UK) was added and the mixture stirred at rt for 48 h. The solvent was removed under reduced pressure and the crude reaction product extracted from a solution of 1 M NaOH (100 mL) with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO4, concentrated by evaporation under reduced pressure and the crude material purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate to provide 0.55 g (9%) of the title compound. MS (ISP): 385.4 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[C:5]([O:23][CH3:24])=[C:6]([CH:12]([OH:22])[CH2:13][NH:14][C:15](=O)[O:16]C(C)(C)C)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)(=[O:3])[CH3:2].Cl.C(N(CC)CC)C.[Cl:33][CH2:34]C(Cl)=O>O1CCOCC1.C(Cl)Cl>[C:1]([C:4]1[C:5]([O:23][CH3:24])=[C:6]([CH:12]([OH:22])[CH2:13][NH:14][C:15](=[O:16])[CH2:34][Cl:33])[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: O=C(Cl)CCl
Reactant: COc1c(C(C)=O)cc(Cl)c(C)c1C(O)CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1c(C(C)=O)cc(Cl)c(C)c1C(O)CNC(=O)CCl
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
tert-Butyl [2-(3-acetyl-5-chloro-2-methoxy-6-methylphenyl)-2-hydroxyethyl]carbamate (170 mg, 0.47 mmol) (Peak 1 from step 2) was treated with 4.0 M hydrogen chloride in 1,4-dioxane (12 mL) for 15 minutes. The solvents were evaporated, methylene chloride (6 mL) and triethylamine (200 μL, 1.4 mmol) were added and the mixture cooled to 0° C. Chloroacetyl chloride (45 μL, 0.56 mmol) was added slowly and was stirred for 10 minutes at 0° C. The solvents were evaporated to dryness. Water was added and the mixture was extracted with ethyl acetate. The combined extracts were washed with brine, dried over sodium sulfate, and concentrated to give the crude residue as a single enantiomer. LCMS calculated for C14H17Cl2NO4Na (M+Na)+: m/z=356.1; found: 356.1.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH:7]2[CH2:8][CH:3]1[CH2:4][CH:5]=[C:6]2[C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=1.[CH:19]1[CH:20]=[CH:21][N:22]2[CH2:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[NH:25][CH2:24][C:23]=12>>[CH:19]1[CH:20]=[CH:21][N:22]2[CH2:28][C:27]3[CH:29]=[CH:30][CH:31]=[CH:32][C:26]=3[N:25]([C:13]([C:12]3[CH:16]=[CH:17][C:9]([C:6]4[CH:7]5[CH2:8][CH:3]([CH2:4][CH:5]=4)[C:2]5([CH3:18])[CH3:1])=[CH:10][CH:11]=3)=[O:14])[CH2:24][C:23]=12
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: CC1(C)C2CC=C(c3ccc(C(=O)O)cc3)C1C2
Product: CC1(C)C2CC=C(c3ccc(C(=O)N4Cc5cccn5Cc5ccccc54)cc3)C1C2
Yield: 74.2 %

Procedure:
4-(6,6-Dimethyl-bicyclo[3.1.1]hept-2-en-2-yl)-benzoic acid of Step B (0.160 g, 0.66 mmol) and 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.134 g, 0.726 mmol) were reacted in the manner of Example 15, Step D. Purification by flash column chromatography on silica gel, eluting with 20% ethyl acetate in hexane, followed by recrystallization from petroleum ether afforded the title compound (0.200 g) as white crystals, m.p. 118–119° C.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=1)[CH:11]([OH:21])[CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:37][CH2:38][C:39](Cl)=[O:40].O>C1COCC1>[CH2:1]([N:8]([CH2:9][CH:10]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=1)[CH:11]([OH:21])[CH2:12][O:13][Si:14]([C:17]([CH3:19])([CH3:20])[CH3:18])([CH3:16])[CH3:15])[C:39](=[O:40])[CH2:38][Cl:37])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)CCl
Reactant: CC(C)(C)[Si](C)(C)OCC(O)C(CNCc1ccccc1)c1ccc(Cl)c(Cl)c1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCC(O)C(CN(Cc1ccccc1)C(=O)CCl)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of (2RS,3RS)-4-(benzylamino)-1-{[tert-butyl(dimethyl)silyl]oxy}-3-(3,4-dichlorophenyl)butan-2-ol (6.40 g) and triethylamine (2.16 mL) in THF (50 mL) was added dropwise chloroacetyl chloride (1.23 mL) at 0° C. The mixture was stirred at 0° C. for 20 min, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate (0%-30%)) to give the title compound (6.83 g) as a pale-yellow oil.
Reaction SMILES: Cl.[CH3:2][CH:3]([CH:5]1[NH:9][C:8](=[O:10])[CH2:7][NH:6]1)[CH3:4].N1C2(CCCCC2)NC[C:12]1=O.C(=O)([O-])[O-].[K+].[K+].[O:28]1[CH2:35][CH:29]1[CH2:30][C:31]([O:33]C)=[O:32]>CC(C)=O.O>[CH3:12][N:6]1[CH2:7][C:8](=[O:10])[NH:9][CH:5]1[CH:3]([CH3:4])[CH3:2].[OH:28][CH:29]([CH3:35])[CH2:30][C:31]([O-:33])=[O:32]
Reactant: CC(C)C1NCC(=O)N1
Reactant: COC(=O)CC1CO1
Reactant: O=C1CNC2(CCCCC2)N1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)C1NC(=O)CN1C
Product: CC(O)CC(=O)[O-]
Temperature: 70 °C
Reaction time: 45 h

Procedure:
12 g 2-(1-methylethyl)-4-imidazolidinone hydrochloride ((5); R4 =H, R5 =isopropyl) (0.073 moles) are shaken with 20 ml water and treated with 5 g potassium carbonate (0.036 moles). 8.5 g methyl 3,4-epoxybutanoate (0.073 moles) and 12 ml acetone are added. The mixture is stirred for 45 h at 70° C. After evaporating, the residue is chromatographed on silica, eluting with 8:2 ethyl acetate/methanol. The main fractions are combined and evaporated. 2.5 g of methyl 2-(1-methylethyl)-4-oxoimidazolidine-β-hydroxybutanoate, m.p. 109°-122° C., are obtained as a white powder (14.4%). 2.0 g of this compound (0.0082 mole) are heated to boiling for 15 h with 8.8 ml DMF and 2.2 ml water. After evaporation in vacuo, the residue is taken up with methanol, and filtered. 0.74 g oxiracetam is obtained as a white crystalline powder, m.p. 167°-70° C. (57.4%).
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]Br)=[CH:9][CH:8]=1)C.[OH:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[C:24]#[N:25].CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[C:24]([C:23]1[CH:22]=[C:21]([CH:28]=[CH:27][CH:26]=1)[O:20][CH2:15][CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:17][CH3:18])[C:4]([OH:3])=[O:19])=[CH:12][CH:11]=1)#[N:25]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Reactant: N#Cc1cccc(O)c1
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCOc2cccc(C#N)c2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 283, Step 2) and 3-hydroxy-benzonitrile via the same procedure used for the preparation of (2S)-2-methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1), to produce a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[CH2:10][N:9]([C:11](=[O:13])[CH3:12])[CH2:8][C:6]=2[N:7]=1.Cl.Cl[C:22]1N=C(N2CCOC[C@@H]2C)C2CNCC=2N=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][C@@H:19]2[CH3:22])[C:5]2[CH2:10][N:9]([C:11](=[O:13])[CH3:12])[CH2:8][C:6]=2[N:7]=1
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CNC2
Reactant: CC(=O)N1Cc2nc(Cl)nc(N3CCOCC3)c2C1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1Cc2nc(Cl)nc(N3CCOC[C@@H]3C)c2C1

Procedure:
Method as described for 1-(2-chloro-4-morpholino-5H-pyrrolo[3,4-d]pyrimidin-6(7H)-yl)ethanone (intermediate 23) using (S)-4-(2-chloro-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-4-yl)-3-methylmorpholine (intermediate 6) as a TFA salt to yield a dark brown oil, which was used without further purification.
Reaction SMILES: ClC1C=C([N:8]2N=[N:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:9]2)C=CC=1.[NH2:19][C:20]1[C:21]([Cl:26])=[N:22][CH:23]=[CH:24][CH:25]=1.N1C=CC=CC=1C=O>>[Cl:26][C:21]1[C:20]([N:19]2[N:8]=[N:9][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:11]2)=[CH:25][CH:24]=[CH:23][N:22]=1
Reactant: Clc1cccc(-n2nnc(-c3ccccn3)n2)c1
Reactant: Nc1cccnc1Cl
Agent: O=Cc1ccccn1
Product: Clc1ncccc1-n1nnc(-c2ccccn2)n1

Procedure:
Following the procedure described in EXAMPLE 1 for the synthesis of 2-[2-(3-chlorophenyl)-2H-tetrazol-5-yl]pyridine, 3-amino-2-chloropyridine (38.6 mg, 0.3 mmol) and 2-pyridinecarboxaldehyde (32.1 mg, 0.3 mmol) were employed to obtain 2-[2-(2-chloro-3-pyridyl)-2H-tetrazol-5-yl]pyridine as an orange solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[CH2:18][CH2:19][CH2:20][CH2:21][C:22]=4[CH:23]=[CH:24][C:9]2=3)=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:27]=1[CH2:28][S:29](Cl)(=[O:31])=[O:30]>>[Cl:25][C:26]1[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:27]=1[CH2:28][S:29]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[CH2:18][CH2:19][CH2:20][CH2:21][C:22]=4[CH:23]=[CH:24][C:9]2=3)=[CH:6][CH:7]=1)(=[O:31])=[O:30]
Reactant: O=S(=O)(Cl)Cc1c(Cl)cccc1Cl
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2c3CCCC2)cc1
Product: O=C1CC(=O)N(c2ccc(NS(=O)(=O)Cc3c(Cl)cccc3Cl)cc2)c2ccc3c(c2N1)CCCC3
Yield: 29.4 %

Procedure:
By using 5-(4-aminophenyl)-1,5,8,9,10,11-hexahydronaphtho[1,2-b][1,4]diazepine-2,4-dione (50 mg, 0.156 mmol) obtained in Example 55, and 2,6-dichlorobenzylsulfonyl chloride (81 mg, 0.312 mmol), the title compound (25 mg, yield 29%) was obtained in the same manner as that of Example 145.
Reaction SMILES: [Na].[N+:2]([C:5]1[CH:6]=[C:7]([CH:26]=[CH:27][CH:28]=1)[CH:8]=[C:9]([C:23]([CH3:25])=O)[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:11])([O-:4])=[O:3].Cl.[C:30]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])(=[NH:32])[NH2:31]>C(O)C>[NH2:31][C:30]1[NH:32][C:23]([CH3:25])=[C:9]([C:10]([O:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[O:11])[CH:8]([C:7]2[CH:26]=[CH:27][CH:28]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=2)[C:33]=1[C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: CCCCCCCCCCOC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Reactant: CCOC(=O)CC(=N)N
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: CCCCCCCCCCOC(=O)C1=C(C)NC(N)=C(C(=O)OCC)C1c1cccc([N+](=O)[O-])c1
Reaction time: 0.25 h

Procedure:
A solution of 1.15 g (50 mmol) of sodium in 100 ml of ethanol was added dropwise at room temperature, with stirring, to a solution of 18.8 g (50 mmol) of decyl 2-(3-nitrobenzylidene)acetoacetate and 8.3 g (50 mmol) of ethyl amidinoacetate hydrochloride in 250 ml of ethanol. The mixture was then heated to boiling for 15 minutes. After standing overnight, the precipitated sodium chloride was filtered off, the filtrate was evaporated in vacuo and the oily residue was brought to crystallization by trituration with ether/petroleum ether. The crude product was filtered off with suction and recrystallized from ethanol, melting point: 190°-191° C.
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]2[O:13][C:12]([CH2:14][O:15]C(=O)C)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO>[C:1]1([NH:7][CH2:8][C:9]2[O:13][C:12]([CH2:14][OH:15])=[CH:11][CH:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)OCc1ccc(CNc2ccccc2)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Nc1ccccc1
Solvent: CO
Product: OCc1ccc(CNc2ccccc2)o1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
Then, the resulting mixture of acetic acid 5-phenylaminomethyl-furan-2-ylmethyl ester and aniline (2.91 g) as well as potassium carbonate (3.28 g, 23.7 mmol) were suspended in methanol (60 mL), and the solution was stirred overnight at room temperature. The reaction solution was evaporated in vacuo, water and ethyl acetate were added to the residue, the organic layer was partitioned, washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated in vacuo, the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate=1:1), and the title compound (1.99 g, 9.79 mmol, 82%) was obtained as a colorless oil.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:12]([CH3:34])[CH2:13][CH2:14][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:7]=[C:8]([O:10][CH3:11])[CH:9]=1.[N:35]1[CH:40]=[CH:39][C:38]([CH:41]=O)=[CH:37][CH:36]=1.[H-].[Na+]>CS(C)=O.O1CCCC1>[CH3:11][O:10][C:8]1[CH:7]=[C:6]([CH:12]([CH3:34])[CH2:13][CH:14]=[CH:41][C:38]2[CH:39]=[CH:40][N:35]=[CH:36][CH:37]=2)[CH:5]=[C:4]([O:3][CH3:2])[CH:9]=1
Reactant: COc1cc(OC)cc(C(C)CC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Reactant: O=Cc1ccncc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C(C)CC=Cc2ccncc2)c1
Reaction time: 1 h
Yield: 70.8 %

Procedure:
A mixture of 3-(3,5-dimethoxyphenyl)butyl triphenylphosphonium bromide (19.0 g., 35.4 mmoles) in dimethylsulfoxide (50 ml.) is added to 4-pyridinecarboxaldehyde (3.79 g., 35.4 mmoles) in tetrahydrofuran (40 ml.). The resulting mixture is then added dropwise to a slurry of 50% sodium hydride (1.87 g., 39 mmoles) in tetrahydrofuran (20 ml.) under a nitrogen atmosphere at 0°-5° C. Following completion of addition, the mixture is stirred for one hour at 0°-5° and then concentrated under reduced pressure. The concentrate is diluted with water (200 ml.) and then acidified with 6N HCl. The aqueous acid solution is extracted with benzene (4 × 50 ml.). It is then made basic and extracted with ethyl acetate (3 × 50 ml.). Evaporation of the combined extracts after drying (MgSO4) affords 4-(3,5-dimethoxyphenyl)-1-(4-pyridyl)-1-pentene (7.1 g., 70%) as an oil.
Reaction SMILES: F[C:2]1[CH:7]=[C:6](F)[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:15]([OH:19])[C:16]#[C:17][CH3:18].[CH3:20][C@H:21]1[CH2:27][CH2:26][CH2:25][C@@H:24]([CH3:28])[CH2:23][NH:22]1>O.C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH2:15]([O:19][C:6]1[N:5]=[CH:4][N:3]=[C:2]([N:22]2[CH2:23][C@H:24]([CH3:28])[CH2:25][CH2:26][CH2:27][C@@H:21]2[CH3:20])[CH:7]=1)[C:16]#[C:17][CH3:18]
Reactant: CC#CCO
Reactant: Fc1cc(F)ncn1
Reactant: C[C@@H]1CCC[C@H](C)NC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: CC#CCOc1cc(N2C[C@H](C)CCC[C@@H]2C)ncn1
Temperature: 30 °C

Procedure:
To a mixture obtained by adding 110.0 g of 4,6-difluoropyrimidine, 132.3 g of potassium carbonate and 19.2 g of triethylamine to 220.0 g of toluene, 69.8 g of 2-butyn-1-ol is added dropwise at 25 to 30° C. over one hour, followed by stirring at 30° C. Then, 220.0 g of water is added dropwise into the reaction mixture, followed by stirring. Then, 126.6 g of cis-2,6-dimethylhexahydroazepine is added dropwise and, after the mixture is stirred at 30° C., the reaction mixture is allowed to stand. After separating into the organic layer and the aqueous layer, the aqueous layer is removed and the organic layer is washed once with 220.0 g of 5% hydrochloric acid and then washed once with 220.0 g of water. The organic layer is concentrated to obtain 1-(6-(2-butynyloxy)pyrimidin-4-yl)-cis-2,6-dimethylhexahydroazepine (hereinafter referred to as the present compound (4)).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][CH2:15][C@H:14]3[CH2:18][O:19][CH3:20])=[O:12])[S:10][C:3]=12.[CH:21]1([NH:24][C:25]([C:27]2[C:28]3[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][C:29]=3[S:30][C:31]=2[CH3:32])=[O:26])[CH2:23][CH2:22]1.C([O-])([O-])=O.[Cs+].[Cs+]>>[CH:21]1([NH:24][C:25]([C:27]2[C:28]3[CH:36]=[CH:35][C:34]([O:37][C:2]4[CH:7]=[CH:6][N:5]=[C:4]5[CH:8]=[C:9]([C:11]([N:13]6[CH2:17][CH2:16][CH2:15][C@H:14]6[CH2:18][O:19][CH3:20])=[O:12])[S:10][C:3]=45)=[CH:33][C:29]=3[S:30][C:31]=2[CH3:32])=[O:26])[CH2:23][CH2:22]1
Reactant: COC[C@@H]1CCCN1C(=O)c1cc2nccc(Cl)c2s1
Reactant: Cc1sc2cc(O)ccc2c1C(=O)NC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC[C@@H]1CCCN1C(=O)c1cc2nccc(Oc3ccc4c(C(=O)NC5CC5)c(C)sc4c3)c2s1
Yield: 70 %

Procedure:
This material was prepared by the reaction of 7-chloro-2-{[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridine 2a (124 mg, 0.40 mmole) with 6-hydroxy-2-methylbenzo[b]thiophene-3-carboxylic acid cyclopropylamide 8c (119 mg, 0.48 mmole) and Cs2CO3 (391 mg, 1.2 mmole) in a manner as previously described for example 1 to give a yellow solid (146 mg, 70%). 1H NMR (DMSO-d6, 300 MHz) δ8.58 (1H. d, J=5.27 Hz), 8.46 (1H, d, J=4.33 Hz), 8.03 (1H, s), 7.96 (1H, d, J=2.26 Hz), 7.80 (1H, d, J=8.67 Hz), 7.32 (1H, dd, J=2.17, 8.76 Hz), 6.75 (1H, d, J=5.27 Hz), 4.30 (1H, m), 3.84 (2H, m), 3.53 (1H, m) 3.42 (1H, m), 3.27 (3H, s), 2.89 (1H, m), 2.57 (3H, s), 2.09-1.81 (4H, m) 0.72 (2H, m), 0.59 (2H, m).
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@:5]2([C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]#[C:21][C:22]([CH3:25])([OH:24])[CH3:23])[CH:18]=3)[O:13][C:12]3[C:7]2=[CH:8][C:9]([C:26]2[CH:27]=[N:28][CH:29]=[N:30][CH:31]=2)=[CH:10][CH:11]=3)[N:6]=1.CO.[CH3:34]S(O)(=O)=O>C(=O)(O)[O-].[Na+]>[CH3:34][O:24][C:22]([CH3:25])([CH3:23])[C:21]#[C:20][C:17]1[CH:18]=[C:19]2[C@:5]3([CH2:4][O:3][C:2]([NH2:1])=[N:6]3)[C:7]3[C:12](=[CH:11][CH:10]=[C:9]([C:26]4[CH:27]=[N:28][CH:29]=[N:30][CH:31]=4)[CH:8]=3)[O:13][C:14]2=[N:15][CH:16]=1
Reactant: CC(C)(O)C#Cc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cncnc3)ccc1O2
Reactant: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(C)(C)C#Cc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cncnc3)ccc1O2

Procedure:
To a solution of (S)-4-(2′-amino-7-(pyrimidin-5-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazole]-3-yl)-2-methylbut-3-yn-2-ol (58 mg, 0.140 mmol) in MeOH (1703 μL, 42.1 mmol) was added methane sulfonic acid (91 μL, 1.403 mmol) in a vial. The vial was sealed and placed in a 70° C. oil bath for 3 hours. The mixture was poured into saturated aqueous sodium bicarbonate solution (20 mL) and extracted with DCM (3×10 mL). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was purified by chromatography on a 25-g SNAP column, eluting with 0-70% of a 90:10:1 mixture of DCM/MeOH/NH4OH in DCM to give (S)-3-(3-methoxy-3-methylbut-1-ynyl)-7-(pyrimidin-5-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine as a white solid after evaporation from DCM/hexane.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][C:18]=3[C:19]([F:22])([F:21])[F:20])[C:9]2=[O:12])=[CH:4][C:3]=1[CH3:23].[C:24]([O-:27])(=O)[CH3:25].[K+].C(OC(=O)C)(=O)C.C1OCCOCCOCCOCCOCCOC1.C(O[N:60]=O)CC(C)C>C(Cl)(Cl)Cl>[C:24]([N:1]1[C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH2:7][N:8]([C:13]4[CH:14]=[N:15][CH:16]=[CH:17][C:18]=4[C:19]([F:22])([F:21])[F:20])[C:9]3=[O:12])=[CH:4][C:3]=2[CH:23]=[N:60]1)(=[O:27])[CH3:25]
Reactant: Cc1cc2c(cc1N)C(=O)N(c1cnccc1C(F)(F)F)CC2
Reactant: CC(C)CCON=O
Reactant: CC(=O)[O-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: CC(=O)n1ncc2cc3c(cc21)C(=O)N(c1cnccc1C(F)(F)F)CC3
Yield: 19.3 %

Procedure:
7-Amino-6-methyl-2-(4-(trifluoromethyl)pyridin-3-yl)-3,4-dihydroisoquinolin-1(2H)-one (I-72b: 300 mg, 1.11 mmol) in chloroform (10 mL) was reacted with potassium acetate (153 mg, 1.56 mmol), acetic anhydride (0.213 mL, 2.23 mmol), 18-crown-6-ether (59 mg, 0.223 mmol) and isoamylnitrite (0.33 mL, 2.46 mmol) for 24 hours to afford the crude product. Purification by column chromatography on silica gel (100% ethyl acetate) afforded 80 mg of the product (16.7% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10][C:9]=2[N:15]([CH3:33])[C:16](=[O:32])[C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19](SC3COC3)[CH:18]=2)=[C:4]([O:34][CH3:35])[CH:3]=1.O[O:37][S:38]([O-:40])=O.[K+].[O-]S([O-])(=S)=O.[Na+].[Na+].C[CH2:50][O:51][C:52]([CH3:54])=O>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10][C:9]=2[N:15]([CH3:33])[C:16](=[O:32])[C:17]2[CH:22]=[C:21]([C:23]([F:25])([F:24])[F:26])[CH:20]=[C:19]([S:38]([CH:54]3[CH2:50][O:51][CH2:52]3)(=[O:40])=[O:37])[CH:18]=2)=[C:4]([O:34][CH3:35])[CH:3]=1
Reactant: CCOC(C)=O
Reactant: O=S([O-])OO
Reactant: COc1cc(F)ccc1-c1cc(C)ncc1N(C)C(=O)c1cc(SC2COC2)cc(C(F)(F)F)c1
Agent: O=S([O-])([O-])=S
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(F)ccc1-c1cc(C)ncc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)C2COC2)c1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To an ice-cold solution of N-(4-(4-fluoro-2-methoxyphenyl)-6-methylpyridin-3-yl)-N-methyl-3-(oxetan-3-ylthio)-5-(trifluoromethyl)benzamide (0.045 g, 88.8 μmol, example 310) in MeOH (2 mL) and water (0.5 mL) was added Oxone® (137 mg, 222 μmol) and stirring was continued at room temperature for 2.5 hours. The reaction mixture was poured on 10% aqueous Na2S2O3 solution and EtOAc and the layers were separated. The aqueous layer was saturated with sodium chloride, extracted three times with EtOAc. The organic layers were washed once with brine, dried over MgSO4, filtered and evaporated. The compound was purified by silica gel chromatography on a 10 g column using an MPLC (ISCO) system eluting with a gradient of n-heptane:EtOAc (100:0 to 0:100). The product was purified by preparative HPLC (Gemini NX column) using a gradient of MeOH:water (containing 0.1% formic acid) (20:80 to 98:2). Light brown foam (0.038 g; 79%). MS (ESI): m/z=539.13 [M+H]+.