Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][C:3]1[N:8]=[N:7][C:6]([N:9]2[CH:17]=[C:12]3[CH2:13][NH:14][CH2:15][CH2:16][C:11]3=[N:10]2)=[CH:5][CH:4]=1.Cl[CH2:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([CH:28]2[CH2:31][CH2:30][CH2:29]2)[CH2:24][CH2:23]1)=[O:21].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH:28]1([N:25]2[CH2:26][CH2:27][N:22]([C:20](=[O:21])[CH2:19][N:14]3[CH2:15][CH2:16][C:11]4=[N:10][N:9]([C:6]5[N:7]=[N:8][C:3]([CH3:2])=[CH:4][CH:5]=5)[CH:17]=[C:12]4[CH2:13]3)[CH2:23][CH2:24]2)[CH2:31][CH2:30][CH2:29]1
Reactant: Cc1ccc(-n2cc3c(n2)CCNC3)nn1
Reactant: O=C(CCl)N1CCN(C2CCC2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(-n2cc3c(n2)CCN(CC(=O)N2CCN(C4CCC4)CC2)C3)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(6-methylpyridazin-3-yl)-2,4,6,7-tetrahydro-5H-pyrazolo[4,3-c]pyridine hydrochloride (920 mg, 3.65 mmol), 1-(chloroacetyl)-4-cyclobutylpiperazine (791 mg, 3.65 mmol), K2CO3 (2.52 g, 18.3 mmol) and KI (66 mg, 0.4 mmol) in CH3CN (20 ml) is stirred at rt overnight. The solvent is removed in vacuo and the residue is partitioned between water (20 mL) and EtOAc (20 mL). The layers are separated and the aqueous layer is extracted with EtOAc (3×20 mL). The combined extracts are washed with brine (30 mL), dried and evaporated. The resulting oil is purified by flash column with DCM/MeOH/NH4OH (100:5:0.5) to give the title compound as a light yellow solid. 1H NMR (δ, CDCl3): 8.43 (s, 1H), 8.01 (d, 1H), 7.41 (d. 1H), 3.64-3.67 (m, 6H), 3.40 (s, 2H), 2.88 (s, 4H), 2.66-2.72 (m, 4H), 2.29 (q, 4H), 1.59-2.05 (m, 6H). MS (M+1): 396.2.
Reaction SMILES: N([O-])=O.[Na+].[N+]([O-])(O)=O.[Cl:9][C:10]1[CH:11]=[C:12]([CH2:16][CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28]([C:37]4[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=4)([OH:36])[C:29]4[N:33]([CH3:34])[C:32](S)=[N:31][N:30]=4)[CH:26]=3)[N:21]([CH3:44])[C:20](=[O:45])[CH:19]=2)[CH:13]=[CH:14][CH:15]=1>O.C1COCC1>[Cl:9][C:10]1[CH:11]=[C:12]([CH2:16][CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28]([C:37]4[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=4)([OH:36])[C:29]4[N:33]([CH3:34])[CH:32]=[N:31][N:30]=4)[CH:26]=3)[N:21]([CH3:44])[C:20](=[O:45])[CH:19]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: Cn1c(S)nnc1C(O)(c1ccc(Cl)cc1)c1ccc2c(c1)c(CCc1cccc(Cl)c1)cc(=O)n2C
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: O=[N+]([O-])O
Product: Cn1cnnc1C(O)(c1ccc(Cl)cc1)c1ccc2c(c1)c(CCc1cccc(Cl)c1)cc(=O)n2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
Sodium nitrite (0.0007 mol) was added at 0° C. to a mixture of nitric acid (0.0007 mol) in water (1 ml). A solution of 4-[2-(3-chlorophenyl)ethyl]-6-[(4-chlorophenyl)hydroxy(5-mercapto-4-methyl-4H-1,2,4-triazol-3-yl)methyl]-1-methyl-2(1H)-quinolinone, obtained in Example B19 (0.0007 mol) in THF (3 ml) was added dropwise (very exothermic reaction). The mixture was stirred at room temperature for 30 minutes, poured out into ice water and extracted with DCM. The organic layer was separated, washed with K2CO3 10%, dried (MgSO4), filtered and the solvent was evaporated. The residue was purified by column chromatography over kromasyl (eluent: CH2Cl2/CH3OH/NH4OH 96/4/0.4; 5 μm). The pure fractions were collected and the solvent was evaporated. The residue (0.25 g) was crystallized from CH3CN. The precipitate was filtered off and dried, yielding 0.12 g (32%) of 4-[2-(3-chlorophenyl)ethyl]-6-[(4-chlorophenyl)hydroxy(4-methyl-4H-1,2,4-triazol-3-yl)methyl]-1-methyl-2(1H)-quinolinone, melting point 200° C.
Reaction SMILES: [OH-].[K+:2].[C:3]([NH:13][NH2:14])(=[O:12])[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1.[C:15](=[S:17])=[S:16]>C(O)C>[C:3]([NH:13][NH:14][C:15]([S-:17])=[S:16])(=[O:12])[C:4]1[CH:11]=[CH:10][C:8]([OH:9])=[C:6]([OH:7])[CH:5]=1.[K+:2]
Reactant: NNC(=O)c1ccc(O)c(O)c1
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(NNC(=S)[S-])c1ccc(O)c(O)c1
Yield: 75.3 %

Procedure:
10 g (178 mmol) of potassium hydroxide was dissolved in 400 ml of ethanol, and 20 g (119 mmol) of protocatechuhydrazide was added thereto under stirring at a temperature of at most 5° C. To this solution, 28.0 ml of carbon disulfide was dropwise added over a period of 10 minutes at a temperature of at most 10° C., and the mixture was stirred at a temperature of from 0° to 10° C. for 30 minutes. Then, the precipitates were collected by filtration, washed with ethanol and dried to obtain 25.3 g (yield: 75.3%) of potassium 3-protocatechuoyldithiocarbazate.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][C:6]([N+:13]([O-])=O)=[CH:5][N:4]=1)#[N:2].[C:16](Cl)(Cl)=[S:17]>O>[N:13]([C:6]1[CH:7]=[C:8]([C:9]([F:12])([F:11])[F:10])[C:3]([C:1]#[N:2])=[N:4][CH:5]=1)=[C:16]=[S:17]
Reactant: N#Cc1ncc([N+](=O)[O-])cc1C(F)(F)F
Reactant: S=C(Cl)Cl
Solvent: O
Product: N#Cc1ncc(N=C=S)cc1C(F)(F)F
Reaction time: 2 h

Procedure:
To a heterogeneous mixture of 2-cyano-3-(trifluoromethyl)-5-nitropyridine A11 (0.075 g, 0.4 mmol) in water (2 ml) was added thiophosgene (50 μl). The mixture was stirred for 2 hours and then washed with water and extracted with chloroform. The organic layer was dried over MgSO4 and concentrated to yield compound A12 (0.087 g, 0.38 mmol, 95%). 1H NMR (400 MHz, CDCl3) δ 7.85 (d, J=2.4 Hz, 1H), 8.72 (d, J=2.4 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 113.61, 121.04 (q, J=273.1 Hz), 127.41, 130.38 (q, J=4.3 Hz), 131.44 (q, J=34.4 Hz), 133.55, 144.75, 150.30.
Reaction SMILES: [CH3:1][C:2](=[O:5])[CH2:3][CH3:4].C([N-]C(C)C)(C)C.[Li+].[CH2:14]([O:21][CH2:22][C:23]([O:25]C)=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[C:15]1([CH2:14][O:21][CH2:22][C:23](=[O:25])[CH2:1][C:2](=[O:5])[CH2:3][CH3:4])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)COCc1ccccc1
Reactant: CCC(C)=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(=O)CC(=O)COCc1ccccc1
Temperature: 25 °C

Procedure:
2-Butanone (32.7 ml) in dry THF (120 ml) was added to lithium diisopropylamide (1.5M in THF; 250 ml) at -78° C. Methyl benzyloxyacetate (30,0 g) was added with stirring and the mixture allowed to warm to room temperature and was then heated at 45° overnight. After cooling the reaction was quenched with saturated ammonium chloride solution, acidified and extracted with ether (3×100 ml). After drying and evaporation, the title compound was obtained as a brown oil (45.6 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10](Cl)(=[O:12])=[O:11])=[C:7]([CH3:14])[C:6]=2[CH:15]=1.[O:16]1[C:20]([C:21]2[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=2)[NH2:24])=[CH:19][N:18]=[CH:17]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:24][C:23]3[CH:25]=[CH:26][CH:27]=[C:21]([C:20]4[O:16][CH:17]=[N:18][CH:19]=4)[CH:22]=3)(=[O:12])=[O:11])=[C:7]([CH3:14])[C:6]=2[CH:15]=1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Reactant: Nc1cccc(-c2cnco2)c1
Product: Cc1c(S(=O)(=O)Nc2cccc(-c3cnco3)c2)sc2ccc(Cl)cc12
Yield: 28.2 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, starting with 5-chloro-3-methyl-benzothiophene-2-sulfonyl chloride (15.5 mg, 0.055 mmol) and 3-(1,3-oxazol-5-yl)-aniline (8 mg, 0.05 mmol) yielding 5.7 mg (26%) of the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.06 (d, 1 H) 7.29 (t, 1 H) 7.39 (d, 1 H) 7.45 (br. s., 1 H) 7.49 (d, 1 H) 7.54 (s, 1 H) 7.93 (s, 1 H) 8.00 (d, 1 H) 8.36 (s, 1 H) 10.87 (br. s., 1 H) (Note; CH3 in DMSO-peak).
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[N:8]=[CH:9][C:10]([CH:13]=[O:14])=[N:11][CH:12]=2)=[CH:4][CH:3]=1.[CH2:17](O)[CH2:18][OH:19].C(=O)([O-])O.[Na+].C(OCC)(=O)C>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:12]=[N:11][C:10]([CH:13]3[O:19][CH2:18][CH2:17][O:14]3)=[CH:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: OCCO
Reactant: O=Cc1cnc(Oc2ccc(Br)cc2)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Brc1ccc(Oc2cnc(C3OCCO3)cn2)cc1
Temperature: 140 °C
Yield: 92.6 %

Procedure:
To a solution in toluene (20 mL) of the compound (1.66 g) obtained in step (1) above, ethylene glycol (1.11 g) and p-toluenesulfonic acid monohydrate (56.6 mg) were added and, thereafter, the mixture was stirred at 140° C. for an hour using a Dean-Stark apparatus. After cooling the reaction mixture to room temperature, a saturated aqueous solution of sodium hydrogencarbonate was added to it under cooling with ice and extraction was conducted with ethyl acetate. The combined organic layers were washed with saturated brine and dried over anhydrous magnesium sulfate. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. Purification by silica gel column chromatography (n-hexane:ethyl acetate=100:0-60:40) gave 2-(4-bromophenoxy)-5-(1,3-dioxolan-2-yl)pyrazine as a colorless solid (1.78 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].[C:14]([O:18][C:19]([CH2:21][O:22][NH2:23])=[O:20])([CH3:17])([CH3:16])[CH3:15].C[O-].[Na+]>CO>[C:14]([O:18][C:19]([CH2:21][O:22][N:23]=[C:9]([C:4]1[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([Cl:1])[CH:3]=1)[C:10]([OH:12])=[O:11])=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)CON
Reactant: O=C(O)C(=O)c1ccc(O)c(Cl)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)CON=C(C(=O)O)c1ccc(O)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.1 %

Procedure:
A mixture of 2-(3-chloro-4-hydroxyphenyl)glyoxylic acid (2.0 g.), O-t-butoxycarbonylmethylhydroxylamine (1.62 g.) and methanol (20 ml.) was adjusted to pH 5 to 6 by adding an 1N methanol solution of sodium methoxide and stirred for 3 hours at ambient temperature. The reaction mixture was concentrated to dryness under reduced pressure and the residue was dissolved in an 1N aqueous solution of sodium hydroxide to adjust to pH 7.0. The aqueous solution was washed with ether, adjusted to pH 2.0 with 10% hydrochloric acid under ice-cooling and extracted with ether. The extract was washed with water and dried over magnesium sulfate. The solution was concentrated to dryness under reduced pressure to give crystals of 2-t-butoxycarbonylmethoxyimino-2-(3-chloro-4-hydroxyphenyl)acetic acid (syn isomer) (2.6 g.), mp 116° to 118° C. (dec.).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([C:21]4[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=4)=[O:20])[CH2:15][CH2:14]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1.[S:28]1(=[O:35])(=[O:34])[CH2:33][CH2:32][CH2:31][CH2:30][NH:29]1>>[CH:1]1([C:4]2[C:5]([N:13]3[CH2:18][CH2:17][N:16]([C:19]([C:21]4[CH:26]=[CH:25][C:24]([N:29]5[CH2:30][CH2:31][CH2:32][CH2:33][S:28]5(=[O:35])=[O:34])=[CH:23][CH:22]=4)=[O:20])[CH2:15][CH2:14]3)=[N:6][CH:7]=[C:8]([CH:10]3[CH2:12][CH2:11]3)[CH:9]=2)[CH2:3][CH2:2]1
Reactant: O=C(c1ccc(I)cc1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Reactant: O=S1(=O)CCCCN1
Product: O=C(c1ccc(N2CCCCS2(=O)=O)cc1)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Yield: 72.4 %

Procedure:
Using [4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (446 mg) described in Preparation Example 186 and [1,2]thiazinane 1,1-dioxide (176 mg) and by the reaction and treatment in the same manner as in Example 262, the title compound (328 mg) was obtained.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[CH:8]1[CH2:17][CH2:16][C:15]2[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11][C:10]=2[CH2:9]1.[CH3:20][O:21][C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=1[CH2:31][CH:32]=O>>[CH3:20][O:21][C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=1[CH2:31][CH2:32][N:6]1[CH2:5][CH2:4][N:3]([CH:8]2[CH2:17][CH2:16][C:15]3[CH:14]=[C:13]([C:18]#[N:19])[CH:12]=[CH:11][C:10]=3[CH2:9]2)[C:2](=[O:1])[CH2:7]1
Reactant: N#Cc1ccc2c(c1)CCC(N1CCNCC1=O)C2
Reactant: COc1cc([N+](=O)[O-])ccc1CC=O
Product: COc1cc([N+](=O)[O-])ccc1CCN1CCN(C2CCc3cc(C#N)ccc3C2)C(=O)C1

Procedure:
The title compound was prepared from 6-(2-Oxopiperazin-1-yl)-5,6,7,8-tetrahydronaphthalene-2-carbonitrile and (2-Methoxy-4-nitrophenyl)acetaldehyde following essentially the same procedure as Example 6. The product was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 435 [M+1]+.
Reaction SMILES: [CH3:1][CH2:2][N:3](C(C)C)C(C)C.Cl[C:11]([Cl:21])(OC(=O)OC(Cl)(Cl)Cl)Cl.ClC1[C:28](Cl)=[CH:27][CH:26]=[CH:25][C:24]=1[NH:30][C:31]([N:33]1[CH2:38][CH2:37][N:36]2[C:39](=[O:52])[N:40]([C@H:43]3[CH2:45][C@@H:44]3[C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:41](=[O:42])[C@@H:35]2[CH2:34]1)=[O:32].Cl.C1([C@H]2C[C@@H]2N2C(=O)[C@@H]3CNCCN3C2=O)C=CC=CC=1>C(Cl)Cl.ClCCCl>[Cl:21][C:11]1[CH:1]=[CH:2][N:3]=[C:25]([CH:26]2[CH2:28][CH2:27]2)[C:24]=1[NH:30][C:31]([N:33]1[CH2:38][CH2:37][N:36]2[C:39](=[O:52])[N:40]([C@H:43]3[CH2:45][C@@H:44]3[C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:41](=[O:42])[C@@H:35]2[CH2:34]1)=[O:32]
Reactant: O=C(Nc1cccc(Cl)c1Cl)N1CCN2C(=O)N([C@H]3C[C@@H]3c3ccccc3)C(=O)[C@@H]2C1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Agent: O=C1[C@@H]2CNCCN2C(=O)N1[C@H]1C[C@@H]1c1ccccc1
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(Nc1c(Cl)ccnc1C1CC1)N1CCN2C(=O)N([C@H]3C[C@@H]3c3ccccc3)C(=O)[C@@H]2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
L1 (1.0 eq.) and DIPEA (5.0 eq.) in DCM (0.1M) was slowly added to an ice cooled solution of triphosgene (0.33 eq.) in DCM (0.1M). The reaction mixture was stirred 30 min at RT and slowly added to a solution of Example 4, D2 (0.5 eq) and DIPEA (0.5 eq) in DCE (0.1M). The reaction mixture was stirred 3 h at RT, volatiles were removed under reduced pressure and the crude product was purified by preparative RP-HPLC using H2O (0.1% TFA) and MeCN (0.1% TFA) as eluents. The desired fractions were lyophilized to afford the title compound as a white powder. 1H-NMR (400 MHz, DMSO-d6, 300K) δ 8.80 (1H, br. s), 8.24 (1H, d, J=5.1 Hz), 7.34 (1H, d, J=5.1 Hz), 7.32-7.26 (2H, m), 7.25-7.17 (3H, m), 4.39 (1H, dd, J=4.1 and 13.0 Hz), 4.17-4.06 (2H, m), 3.97-3.90 (1H, m), 3.12-2.88 (3H, m), 2.72-2.65 (1H, m), 2.43-2.35 (1H, m), 2.30-2.20 (1H, m), 1.55-1.47 (1H, m), 1.45-1.38 (1H, m), 0.98-0.90 (4H, m). MS (ES) C24H24ClN5O3 requires: 465, found: 466, 468 (M+H)+.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1.[CH2:24]([NH2:27])[CH2:25][CH3:26]>C(O)C>[CH2:24]([NH:27][C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1)[CH2:25][CH3:26]
Reactant: CCCN
Reactant: CCCOc1ccccc1-c1nc2nc(SC)ncc2c(=O)[nH]1
Solvent: CCO
Product: CCCNc1ncc2c(=O)[nH]c(-c3ccccc3OCCC)nc2n1

Procedure:
In a similar manner to Example 34 reaction of 7-methylthio-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (0.60 g) and n-propylamine (1.44 g) in ethanol (20 ml) yielded the title compound, 0.46 g, m.p. 185.7° C. (recrystallized from ethanol).
Reaction SMILES: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)C1N2N=CC=C2N=C(C2CCC(=[CH:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])CC2)C=1.C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)C1N2N=CC=C2N=C(C2CCCC(=O)C2)C=1.[CH3:72][Si:73]([CH3:104])([CH3:103])[CH2:74][CH2:75][O:76][CH2:77][N:78]([CH2:95][O:96][CH2:97][CH2:98][Si:99]([CH3:102])([CH3:101])[CH3:100])[C:79]1[N:84]2[N:85]=[CH:86][CH:87]=[C:83]2[N:82]=[C:81]([CH:88]2[CH2:93][CH2:92][C:91](=O)[CH2:90][CH2:89]2)[CH:80]=1>>[CH3:101][Si:99]([CH3:100])([CH3:102])[CH2:98][CH2:97][O:96][CH2:95][N:78]([CH2:77][O:76][CH2:75][CH2:74][Si:73]([CH3:72])([CH3:103])[CH3:104])[C:79]1[N:84]2[N:85]=[CH:86][CH:87]=[C:83]2[N:82]=[C:81]([CH:88]2[CH2:93][CH2:92][CH2:91][C:90](=[CH:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:89]2)[CH:80]=1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCC(=O)CC2)nc2ccnn12
Reactant: CCOC(=O)C=C1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1
Agent: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCCC(=O)C2)nc2ccnn12
Product: CCOC(=O)C=C1CCCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)C1

Procedure:
Ethyl 2-(3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexylidene)acetate was synthesized in a manner similar to the synthesis of ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexylidene)acetate, but with 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexanone substituted for 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexanone.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][CH:7]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[S:22][C:21]3[C:16](=[N:17][CH:18]=[CH:19][C:20]=3[Cl:23])[CH:15]=2)=[O:13])[CH2:8]1>>[Cl:23][C:20]1[CH:19]=[CH:18][N:17]=[C:16]2[CH:15]=[C:14]([C:12]([N:9]3[CH2:10][CH2:11][CH:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:8]3)=[O:13])[S:22][C:21]=12
Reactant: NC1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)NC1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1

Procedure:
The title compound was prepared from methanesulfonyl chloride and (3-amino-pyrrolidin-1-yl)-(7-chloro-thieno[3,2-b]pyridin-2yl)-methanone by a procedure analogous to Example 64C. MS: 360/362 (MH+); HPLC Rf: 3.22 min.; HPLC purity 98%.
Reaction SMILES: CO[CH2:3][C:4]([OH:6])=[O:5].[CH2:7]([OH:13])[CH2:8][CH2:9][CH2:10]CC.[CH3:14]O>>[OH:13][CH2:7][CH2:8][CH2:9][CH2:10][CH2:3][C:4]([O:6][CH3:14])=[O:5]
Reactant: CO
Reactant: COCC(=O)O
Reactant: CCCCCCO
Product: COC(=O)CCCCCO
Temperature: 300 °C

Procedure:
Nylon 6 (0.1 g), methoxyacetic acid as a carboxylic acid (0.45 g) and methanol (3.0 g) were added to a 10 mL volume reactor equipped with a tube (outer diameter: ⅜ inches, inner diameter: 7.53 mm, length: 23 cm), nitrogen substitution was conducted at room temperature, and the reactor was sealed. The reactor was put into an electric furnace heated to 300° C. (pressure: 16.3 MPa), and the change over time was measured. In the measurement, the obtained reaction mixture and 1-hexanol as an internal standard substance were weighed and used as analysis samples for a gas chromatography analysis. An integral value was calculated by a gas chromatography analysis, and a table of a standard curve was prepared and the yield of methyl 6-hydroxycaproate was obtained therefrom. The result is shown in Table 3.
Reaction SMILES: O=[O+][O-].[C:4]([N:11]1[CH2:16][CH2:15][CH:14]([O:17][CH2:18][CH:19]=C)[CH2:13][CH2:12]1)([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C[OH:22].C(Cl)Cl.[BH4-].[Na+]>CCOC(C)=O>[C:4]([N:11]1[CH2:12][CH2:13][CH:14]([O:17][CH2:18][CH2:19][OH:22])[CH2:15][CH2:16]1)([O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:5]
Reactant: C=CCOC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CO
Agent: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(OCCO)CC1
Reaction time: 0.08 h

Procedure:
Ozone was bubbled into a solution of 21-3 (1.5 g, 6.4 mmol) in 2:1 CH3OH/CH2Cl2 (102 mL) at -78° C. After 5 min no starting material remained so oxygen was bubbled through the solution for 15 min to remove excess ozone. NaBH4 (1.7 g, 45 mmol) was added and the cooling bath removed. After 1 h the reaction mixture was concentrated. The residue was diluted with H2O (30 mL) and then extracted with CHCl3 (300 mL). The organic phase was washed with brine (30 mL), dried (MgSO4), and concentrated. Flash chromatography (silica, EtOAc) gave 21-4 as a nearly colorless oil. Rf 0.42 (silica, EtOAc).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:28][C:29]1[N:30]=[CH:31][N:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[Cl:40])[CH:33]=1.O>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:10](=[O:13])[N:11]([CH2:28][C:29]3[N:30]=[CH:31][N:32]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[Cl:40])[CH:33]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Reactant: Clc1ccccc1-n1cnc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=c1n(Cc2cn(-c3ccccc3Cl)cn2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Temperature: 65 °C
Reaction time: 2 h

Procedure:
19 mg (0.06 mmol) of the compound from Example 5A were dissolved in 5 ml of acetonitrile, and 17 mg (0.13 mmol) of potassium carbonate and 17 mg (0.06 mmol) of the compound from Example 42A were added. The mixture was stirred at 65° C. for 2 h and then stirred at RT for 20 h. For work-up, 5 ml of water were added and the mixture was extracted twice with in each case 10 ml of ethyl acetate. The organic phase was washed once with 5 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified chromatographically [Method 19]. This gave 4 mg (12% of theory) of the target compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)([CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])[O:12][C:11]2=[O:28])[CH3:9])=[CH:4][CH:3]=1.[CH3:29][O:30][C:31]1[N:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1>>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C@:13]2([CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])[O:12][C:11](=[O:28])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:34]4[CH:35]=[N:36][C:31]([O:30][CH3:29])=[CH:32][CH:33]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:22][CH:23]=1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccc(F)cc2)OC1=O
Reactant: COc1ccc(B(O)O)cn1
Product: COc1ccc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccc(F)cc4)OC3=O)cc2)cn1

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-1,3-oxazinan-2-one and 6-methoxypyridine-3-boronic acid following a procedure analogous to that described in Example 75. Step 1. LC-MS Method 3 tR=1.111 min, m/z=478.23; 1H NMR (CDCl3) 1.15 (d, 6H), 1.55 (d, 3H), 2.17-2.29 (m, 4H), 2.42 (m, 1H), 2.91 (m, 1H), 3.95 (s, 3H), 5.70 (m, 1H) 6.80 (d, 1H), 7.03 (m, 4H), 7.30 (m, 4H), 7.71 (m, 1H), 8.30 (s, 1H).
Reaction SMILES: Br[C:2]1[O:3][C:4]([CH3:7])=[N:5][N:6]=1.C([Mg]Cl)(C)C.[CH:13]1([CH2:16]/[C:17](=[N:19]\[S:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[O:21])/[CH3:18])[CH2:15][CH2:14]1.C[Al](C)C.CCCCCCC>C1COCC1.C1(C)C=CC=CC=1>[CH:13]1([CH2:16][C:17]([NH:19][S:20]([C:22]([CH3:23])([CH3:25])[CH3:24])=[O:21])([CH3:18])[C:2]2[O:3][C:4]([CH3:7])=[N:5][N:6]=2)[CH2:14][CH2:15]1
Reactant: C/C(CC1CC1)=N/S(=O)C(C)(C)C
Reactant: Cc1nnc(Br)o1
Agent: CC(C)[Mg]Cl
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: Cc1nnc(C(C)(CC2CC2)NS(=O)C(C)(C)C)o1
Temperature: -15 °C
Reaction time: 0.5 h
Yield: 59.5 %

Procedure:
To a solution of 2-bromo-5-methyl-1,3,4-oxadiazole (CAN 864750-58-3, 0.5 g, 3.07 mmol) in dry THF (8 ml) cooled down to −15° C. under an argon atmosphere was added isopropyl magnesium chloride, lithium chloride complex (2.36 ml, 3.07 mmol). (During the addition the temperature was kept below −12° C.). The reaction was then stirred at −15° C. for 30 minutes followed by slow addition of a solution of (Z)—N-(1-cyclopropylpropan-2-ylidene)-2-methylpropane-2-sulfinamide (CAN 1426426-70-1, 618 mg, 3.07 mmol) and a 2M solution of trimethylaluminum in heptane (1.53 ml, 3.07 mmol) in dry toluene (8 ml). The reaction was allowed to warm up to room temperature overnight. The reaction was cooled down to 0° C. and quenched by addition of water (slow addition because reaction very exothermic). The reaction medium was diluted with ethylacetate and the organic phase was extracted with a saturated aqueous solution of ammonium chloride. The organic phase was collected and the aqueous phase was back-extracted with ethylacetate. The combined organic phases were dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a dichloromethane/methanol gradient to yield the title compound (521 mg, purity: 90%, 54%). MS (ESI, m/z): 286.5 (M+H+).