Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].N12CCCN=C1CCCCC2.[O:20]([CH2:24][CH2:25]Br)[CH2:21][CH2:22]Br.O>CN(C=O)C>[C:1]([C:3]1([C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:25][CH2:24][O:20][CH2:21][CH2:22]1)#[N:2]
Reactant: BrCCOCCBr
Reactant: CCOC(=O)CC#N
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C1(C#N)CCOCC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 89.1 %

Procedure:
A solution of ethyl cyanoacetate (7.0 g) and 1,8-diazabicyclo[5,4,0]undec-7-ene (19 mL) in DMF (310 mL) was stirred at room temperature for 10 min, and cooled to 0° C. To this mixture was added 1,1′-oxybis(2-bromoethane) (15.8 g) at 0° C., and the mixture was stirred at 80° C. for 4 hr and cooled to room temperature. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried and concentrated under reduced pressure to give ethyl 4-cyanotetrahydro-2H-pyran-4-carboxylate (10.1 g, 89%) as a deep brown oil.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].N1C=CC=CC=1.[CH3:14][C:15]1[CH:16]=C(O)C=[CH:19][CH:20]=1.Cl>ClCCl>[C:5]([O:4][C:1]1[CH:14]=[C:15]([CH3:16])[CH:20]=[CH:19][CH:2]=1)(=[O:7])[CH3:6]
Reactant: Cc1cccc(O)c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Oc1cccc(C)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 84 %

Procedure:
Acetic anhydride (519 mg) and pyridine (439 mg) were added to a solution of 3-methylphenol (500 mg) in dichloromethane (10 mL), and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into 1 mol/L hydrochloric acid, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and water successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane=1/8) to give the title compound (583 mg).
Reaction SMILES: [Sn].C[Sn](C)(C)[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[CH3:14].C(Cl)[Cl:18]>>[Cl:18][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][C:5]=1[CH3:14]
Reactant: Cc1ccc2ccccc2c1[Sn](C)(C)C
Reactant: ClCCl
Agent: [Sn]
Product: Cc1ccc2ccccc2c1Cl
Reaction time: 8 h
Yield: 80 %

Procedure:
To the tin compound 20 (1 g, 3.3 mmole) in CH2Cl2 (50 ml) was added N-chlorosuccimimide NCIS (931 mg, 7 mmole). The mixture was stirred overnight. The mixture was washed with saturated solution of NaHCO3, water, brine, dried with anhydrous magnesium sulfate, and concentrated in vacuo to yield 0.7 g of a crude yellowish semi-solid. The crude yellow semi-solid was purified by column chromatography (silica, 100% hexane) to afford 1.2 g of 21 (80%) as a white powder. A simple component was detected by TLC (100%) hexane) Rf, 0.69; NMR (CDCl3) d 2.3 (3H, S, CH3), d 7.2-8.2 (m, 6H, naphthyl).
Reaction SMILES: [CH:1]([S:3]([N:6]1[CH2:15][CH2:14][C:9]2([O:13][CH2:12][CH2:11][O:10]2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])=[CH2:2].Br[C:17]1[C:22]([CH3:23])=[CH:21][C:20]([N:24]2[C:28]([CH3:30])([CH3:29])[C:27](=[O:31])[NH:26][C:25]2=[O:32])=[CH:19][C:18]=1[CH3:33].F[B-](F)(F)F.[H+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.CN(C1CCCCC1)C1CCCCC1>CN1CCCC1=O>[O:13]1[C:9]2([CH2:8][CH2:7][N:6]([S:3](/[CH:1]=[CH:2]/[C:17]3[C:18]([CH3:33])=[CH:19][C:20]([N:24]4[C:28]([CH3:30])([CH3:29])[C:27](=[O:31])[NH:26][C:25]4=[O:32])=[CH:21][C:22]=3[CH3:23])(=[O:4])=[O:5])[CH2:15][CH2:14]2)[O:10][CH2:11][CH2:12]1
Reactant: C=CS(=O)(=O)N1CCC2(CC1)OCCO2
Reactant: Cc1cc(N2C(=O)NC(=O)C2(C)C)cc(C)c1Br
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CN(C1CCCCC1)C1CCCCC1
Agent: F[B-](F)(F)F
Solvent: CN1CCCC1=O
Product: Cc1cc(N2C(=O)NC(=O)C2(C)C)cc(C)c1/C=C/S(=O)(=O)N1CCC2(CC1)OCCO2
Temperature: 110 °C
Reaction time: 2 h
Yield: 68.1 %

Procedure:
A mixture of 8-(vinylsulfonyl)-1,4-dioxa-8-azaspiro[4.5]decane (431 mg, 1.85 mmol), 1-(4-bromo-3,5-dimethylphenyl)-5,5-dimethylimidazolidine-2,4-dione (575 mg, 1.85 mmol), tris(dibenzylidineacetone)palladium(0) (508 mg, 0.55 mmol), tri-tert-butylphosphine tetrafluoroboric acid (165 mg, 0.55 mmol), and methyldicyclohexylamine (2.1 mL, 9.25 mmol) in N-methyl-2-pyrrolidone (18.5 mL) was stirred under nitrogen atmosphere at 110° C. for two hours. The reaction mixture was cooled, quenched with water, and then extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by amino-silica gel column chromatography (dichloromethane-methanol) to afford (E)-1-(4-(2-(1,4-dioxa-8-azaspiro[4.5]decan-8-ylsulfonyl)vinyl)-3,5-dimethylphenyl)-5,5-dimeth ylimidazolidine-2,4-dione (584 mg, 68%).
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:8][C:9]([O:11]C)=O)[C:4]([Cl:7])=[CH:5][CH:6]=1.I.[NH2:14][C:15]1[NH:16][CH2:17][CH2:18][N:19]=1.[O-]CC.[Na+]>C(O)C>[Cl:7][C:4]1[N:3]([CH2:8][C:9]([N:14]=[C:15]2[NH:19][CH2:18][CH2:17][NH:16]2)=[O:11])[C:2]([Cl:1])=[CH:6][CH:5]=1
Reactant: COC(=O)Cn1c(Cl)ccc1Cl
Reactant: NC1=NCCN1
Agent: CC[O-]
Agent: I
Agent: [Na+]
Solvent: CCO
Product: O=C(Cn1c(Cl)ccc1Cl)N=C1NCCN1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.8 %

Procedure:
Methyl (2,5-dichloro-1H-pyrrol-1-yl)acetate (2.08 g.) was added to a solution of 2-aminoimidazoline hydroiodide (3.2 g.) and sodium ethoxide (from 0.35 g. of sodium) in ethanol (10 cm3). The solution was stirred at room temperature for 3 hr. and the precipitated title product collected by filtration (1.9 g.) m.p. 225°-227° C. The base was suspended in ethanol (25 cm3) and acidified with ethanolic hydrogen chloride to give the hydrochloride of the title compound (1.9 g.) m.p. 225° C.(d).
Reaction SMILES: Cl.[C:2](O)(=[O:4])[CH3:3].[NH2:6][C@@H:7]([CH2:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=1)[C:8]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)=[O:9]>>[C:2]([NH:6][C@@H:7]([CH2:25][O:26][CH2:27][C:28]1[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=1)[C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[CH:15][CH:16]=1)=[O:9])(=[O:4])[CH3:3]
Reactant: N[C@@H](COCc1ccc(F)cc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Reactant: CC(=O)O
Agent: Cl
Product: CC(=O)N[C@@H](COCc1ccc(F)cc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 60 %

Procedure:
Proceeding as in Example 1, but substituting acetic acid hydrochloride and (S)-2-amino-3-(4-fluorobenzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide, gave Compound 164, (S)-2-acetamido-3-(4-fluorobenzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide (35 mg, 60%). 1H-NMR (400 MHz, CDCl3): δ 8.40 (s, 1H), 7.40-7.25 (m, 5H), 7.10-6.90 (m, 7H), 6.45-6.40 (m, 1H), 4.80-4.45 (m, 3H), 4.00-3.90 (m, 1H), 3.60 (m, 1H), 1.60 (s, 3H). MS (EI) for C24H22F2N2O4 found 441 (MH+).
Reaction SMILES: [C:1]12[C:14](=[O:15])[O:13][C:11](=[O:12])[C:2]=1[CH2:3][CH2:4][C:5]1[C:10]2=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:16][C:17]([CH3:22])([CH2:20][NH2:21])[CH2:18][OH:19].O>C1(C)C=CC=CC=1>[OH:19][CH2:18][C:17]([CH3:22])([CH3:16])[CH2:20][N:21]=[C:14]([C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]=1[C:11]([OH:13])=[O:12])[OH:15]
Reactant: CC(C)(CN)CO
Reactant: O=C1OC(=O)C2=C1CCc1ccccc12
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(CO)CN=C(O)C1=C(C(=O)O)CCc2ccccc21

Procedure:
20.0 g (0.1 mol) of 3,4-dihydronaphthalene-1,2-dicarboxylic acid anhydride and 10.3 g (0.1 mol) of 2,2-dimethyl-3-aminopropanol are dissolved in 60 ml of toluene and the solution is refluxed for 2 hours, the water formed being separated off by means of a water separator. After the reaction has ended, the reaction mixture is concentrated to dryness in vacuo at 60° C. The residue is recrystallised from ethanol. This yields 25.1 g (87.9% of theory) of N-(3'-hydroxy-2',2'-dimethylpropyl)-3,4-dihydronaphthalene-1,2-dicarboxylic acid imide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:12]=[C:13](I)[C:14]4[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[NH:17][C:15]=4[N:16]=3)=[N:9][N:8]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])[C:5]2=[N:6][CH:7]=1.C(N(CC)C(C)C)(C)C.Cl.[F:42][C:43]1([F:49])[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1.O>CN1CCCC1=O>[F:42][C:43]1([F:49])[CH2:48][CH2:47][N:46]([C:13]2[C:14]3[C:19]([CH3:21])([CH3:20])[C:18](=[O:22])[NH:17][C:15]=3[N:16]=[C:11]([C:10]3[C:4]4[C:5](=[N:6][CH:7]=[C:2]([F:1])[CH:3]=4)[N:8]([CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[F:31])[N:9]=3)[N:12]=2)[CH2:45][CH2:44]1
Reactant: FC1(F)CCNCC1
Reactant: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncc(F)cc34)nc(I)c21
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncc(F)cc34)nc(N3CCC(F)(F)CC3)c21
Temperature: 150 °C
Reaction time: 6 h
Yield: 66.6 %

Procedure:
100 mg (0.18 mmol) of 2-[5-fluoro-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example 16A) was dissolved in 1-methyl-2-pyrrolidone (3.1 ml) in a reaction vessel suitable for a microwave, and 0.19 ml (1.07 mmol) of N,N-diisopropyl ethylamine and 140 mg (0.89 mmol) of 4,4-difluoropiperidine hydrochloride were added. Then the reaction vessel was sealed with a septum and was heated in the microwave for 5 h at 150° C. Then the same amounts of N,N-diisopropyl ethylamine and 4,4-difluoropiperidine hydrochloride were added again to the reaction solution and the reaction mixture was stirred for 6 h at 150° C. in the microwave. Water was added to the reaction mixture, the precipitated solid was stirred for 30 min at room temperature and then filtered off. The precipitated solid was stirred with 1 ml acetonitrile, the solid was filtered off and was washed with 0.5 ml acetonitrile. 63 mg of the target compound (64% of theor.) was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[C:16]3[O:15][CH2:14][CH:13]([C:17]4[CH:22]=[CH:21][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:19][CH:18]=4)[C:12]=3[C:11]([CH3:26])=[C:10]([NH:27][C:28](=[O:34])[CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:9]=2[CH3:35])[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:43](Cl)(=[O:45])[CH3:44]>C1COCC1.C(=O)(O)[O-].[Na+]>[C:43]([NH:1][C:2]1[N:7]=[C:6]([C:8]2[C:16]3[O:15][CH2:14][CH:13]([C:17]4[CH:22]=[CH:21][C:20]([CH:23]([CH3:24])[CH3:25])=[CH:19][CH:18]=4)[C:12]=3[C:11]([CH3:26])=[C:10]([NH:27][C:28](=[O:34])[CH2:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:9]=2[CH3:35])[CH:5]=[CH:4][CH:3]=1)(=[O:45])[CH3:44]
Reactant: CC(=O)Cl
Reactant: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1-c1cccc(N)n1)OCC2c1ccc(C(C)C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1cccc(-c2c(C)c(NC(=O)CC(C)(C)C)c(C)c3c2OCC3c2ccc(C(C)C)cc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.6 %

Procedure:
To a solution of N-(7-(6-aminopyridine-2-yl)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (94.3 mg, 0.2 mmol) and triethylamine (0.042 mL, 0.3 mmol) in THF (1 mL) was added acetyl chloride (0.015 mL, 0.22 mmol) at 0° C. and the resulting mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate. The extracts were washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain 51 mg (yield: 50%) of the title compound. Melting point: 205-208° C. (ethyl acetate-hexane).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[S:38][CH:39]=[CH:40][N:41]=1>>[OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:37]3[S:38][CH:39]=[CH:40][N:41]=3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: Brc1nccs1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2nccs2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-[(S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl]-1,3-oxazinan-2-one and 2-bromo-thiazole following a procedure analogous to that described in Example 171. Mass spectrum (ESI+): m/z=437 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[CH:7][O:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:9][N:10]([CH3:13])[CH:11]=O>>[CH3:9][N:10]([CH3:13])[CH:11]=[CH:2][C:1]([C:4]1[CH:8]=[CH:7][O:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccoc1
Reactant: CN(C)C=O
Product: CN(C)C=CC(=O)c1ccoc1

Procedure:
A mixture of 50.0 g. of 3-acetylfuran and 60 ml. of N,N-dimethylformamide is heated at reflux temperature for 16 hours. The solvent is removed in vacuo and hexane is added to the residue to give 3-dimethylamino-1-(3-furyl)-2-propen-1-one. A mixture of 0.01 mole of the preceding compound and 0.01 mole of 3-aminopyrazole in glacial acetic acid is refluxed for 8 hours and the solvent removed in vacuo. The residue is purified as described in Example 1 to give the product of the example.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[S:12][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:9]=2)[CH2:4][C@H:3]1[O:17][CH3:18].[Cl:19][C:20]1[N:21]=[C:22]([C:27](O)=[O:28])[NH:23][C:24]=1[CH2:25][CH3:26].CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>>[Cl:19][C:20]1[N:21]=[C:22]([C:27]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[S:12][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:9]=3)[CH2:4][C@H:3]2[O:17][CH3:18])=[O:28])[NH:23][C:24]=1[CH2:25][CH3:26]
Reactant: COC(=O)c1ccc(N2CC[C@H](N)[C@H](OC)C2)s1
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3ccc(C(=O)OC)s3)C[C@H]2OC)nc1Cl
Yield: 50.2 %

Procedure:
The same operation as in Example (221c) was performed using methyl cis(±)-5-(4-amino-3-methoxypiperidin-1-yl)thiophene-2-carboxylate obtained in Example (244c) (76 mg, 0.28 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (54 mg, 0.31 mmol), WSC hydrochloride (162 mg, 0.84 mmol), 1-hydroxybenzotriazole (38 mg, 0.28 mmol) and N-methylmorpholine (0.06 mL, 0.56 mmol), to obtain 60 mg of the title compound as a pale brown solid (50%).
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][CH:8]([C:11]2[N:12]([CH3:19])[N:13]=[CH:14][C:15]=2[N+:16]([O-:18])=[O:17])[O:7][CH2:6][CH:5]1O)=[N+:2]=[N-:3].COCCN(S(F)(F)[F:31])CCOC.C([O-])(O)=O.[Na+]>C(Cl)Cl.C1COCC1>[N:1]([CH:4]1[CH:5]([F:31])[CH2:6][O:7][CH:8]([C:11]2[N:12]([CH3:19])[N:13]=[CH:14][C:15]=2[N+:16]([O-:18])=[O:17])[CH2:9][CH2:10]1)=[N+:2]=[N-:3]
Reactant: Cn1ncc([N+](=O)[O-])c1C1CCC(N=[N+]=[N-])C(O)CO1
Reactant: COCCN(CCOC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cn1ncc([N+](=O)[O-])c1C1CCC(N=[N+]=[N-])C(F)CO1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-azido-7-(2-methyl-4-nitro-pyrazol-3-yl)oxepan-3-ol (660 mg, 2.34 mmol, intermediate 57) in DCM (12 mL) was added deoxo-Fluor® (50% in THF, 2.12 mL) and the mixture was stirred at room temperature for 18 hr. The mixture was diluted with DCM (22 mL), cooled to 0° C. and saturated aqueous NaHCO3 (20 mL) was carefully added. The aqueous layer was extracted with DCM (3×20 mL) and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (0-30% EtOAc/isohexane) gave 5-(5-azido-6-fluorooxepan-2-yl)-1-methyl-4-nitro-1H-pyrazole as an oil (440 mg). A solution of this oil (440 mg, 1.54 mmol) in THF/water (15 mL/2.8 mL) was treated with triphenylphosphine (487 mg, 1.86 mmol) and the reaction mixture was heated at 70° C. behind a blast shield for 18 hr. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in dry DCM (15 mL), cooled to 0° C. and di-tert-butyl-dicarbonate (402 mg, 1.84 mmol) was added followed by DIPEA (0.8 mL, 4.62 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 18 hr. Water (20 mL) was added and the mixture extracted with DCM (100 mL). The organic layer was separated, dried over MgSO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (0-35% EtOAc/isohexane) followed by chiral prep SFC gave tert-butyl N-[(3S,4R,7S)-3-fluoro-7-(2-methyl-4-nitro-pyrazol-3-yl)oxepan-4-yl]carbamate as a white solid (223 mg, 27% over three steps). 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 5.37 (dd, J=10.5, 3.0 Hz, 1H), 4.89 (br s, 1H), 4.61 (ddd, J=49.1, 7.7, 3.2 Hz, 1H), 4.44 (dd, J=22.2, 15.0 Hz, 1H), 4.07 (s, 3H), 3.98-3.80 (m, 1H), 3.49 (d, J=5.3 Hz, 1H), 2.15-1.90 (m, 4H), 1.47 (s, 9H).
Reaction SMILES: [C:1]([C:3]1[CH:36]=[CH:35][C:6]([CH2:7][N:8]2[C:12]([CH2:13][CH2:14][NH:15][C:16]([C@@H:18]3[CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][N:19]3C(OC(C)(C)C)=O)=[O:17])=[CH:11][N:10]=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].[C:37]([C:41]([OH:43])=[O:42])([F:40])([F:39])[F:38]>C(Cl)Cl>[F:38][C:37]([F:40])([F:39])[C:41]([OH:43])=[O:42].[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]([CH2:13][CH2:14][NH:15][C:16]([C@@H:18]3[CH2:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:20][NH:19]3)=[O:17])=[CH:11][N:10]=[CH:9]2)=[CH:35][CH:36]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C(=O)NCCc1cncn1Cc1ccc(C#N)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(Cn2cncc2CCNC(=O)[C@@H]2Cc3ccccc3CN2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-(t-butyloxycarbonyl)-1,2,3,4-tetrahydro-isoquinoline-3(S)-carboxylic acid {2-[3-(4-cyanobenzyl)-3H-imidazol-4-yl]-ethyl}-amide (1.18 g, 2.4 mmol) in CH2Cl2 (6 mL) was added CF3CO2H (4 mL). The reaction was stirred for 0.75 hr at 25° C. Evaporation in vacuo yielded the title compound.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5]1([C:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)Cl)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl.C(CN)O>C(O)(C)C>[C:11]([NH:4][CH2:3][CH2:1][OH:2])([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NCCO
Agent: Cl
Solvent: CC(C)O
Product: OCCNC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 99.4 %

Procedure:
A mixture of ethanolamine (2-aminoethanol) (98%, 1.750 kg, 28.0 moles) in isopropanol (7.0 l) was stirred to yield a homogeneous solution. Thereto triphenylchloromethane (97%, 2.020 kg, 7.03 moles) was added slowly within 1 h at room temperature with stirring, whereat the temperature was not to exceed 30° C. After completed dissolution of triphenylchloromethane (whereat ethanolamine hydrochloride separated as a white precipitate) the reaction mixture was stirred for another hour and cooled to room temperature. The precipitate, which separated, was filtered off and the filtrate was poured into ice-cold water (8.0 l). The precipitate, which separated, was filtered off and dried in vacuo at a temperature not exceeding 50° C. Thus there were obtained 2.120 kg (98%) of the desired compound.
Reaction SMILES: [OH-].[Na+].C([O:6][CH2:7][C:8]1[CH:13]=[C:12]([C:14]([O:16]C)=[O:15])[CH:11]=[CH:10][C:9]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24])(=O)C>CCO>[OH:6][CH2:7][C:8]1[CH:13]=[C:12]([C:14]([OH:16])=[O:15])[CH:11]=[CH:10][C:9]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24]
Reactant: COC(=O)c1ccc(-c2ccccc2C)c(COC(C)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccccc1-c1ccc(C(=O)O)cc1CO
Temperature: 60 °C
Reaction time: 2 h
Yield: 71.4 %

Procedure:
Sodium hydroxide (5M; 12.1 mL; 60.3 mmol; 3 eq.) was added to a solution of methyl 2-[(acetyloxy)methyl]-2′-methylbiphenyl-4-carboxylate (6 g; 20 mmol; 1 eq.) in EtOH (180 mL) and the reaction mixture was stirred at 60° C. for 2 hours. After concentration in vacuo, the residue was taken up in water (500 mL) and washed with Ethyl acetate (2×100 mL). The aqueous phase was acidified to pH 2 with conc. HCl and extracted with Ethyl acetate (2×100 mL). The combined organic layer was dried over MgSO4 and concentrated in vacuo to afford the title compound (3.46 g, 71%) as a yellow solid.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([C:18]([F:21])([F:20])[F:19])=[N:16][N:17]=2)[N:14]=1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=O>>[Cl:22][C:23]1[CH:24]=[C:25]([CH2:26][N:7]2[CH2:8][CH:4]3[CH:5]([CH2:1][N:2]([C:9]4[CH:10]=[CH:11][C:12]5[N:13]([C:15]([C:18]([F:20])([F:21])[F:19])=[N:16][N:17]=5)[N:14]=4)[CH2:3]3)[CH2:6]2)[CH:28]=[CH:29][CH:30]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CC4CNCC4C3)nn12
Reactant: O=Cc1cccc(Cl)c1
Product: FC(F)(F)c1nnc2ccc(N3CC4CN(Cc5cccc(Cl)c5)CC4C3)nn12

Procedure:
Reductive amination of 6-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 3-chlorobenzaldehyde was carried out according to General Synthetic Method 10. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[2-[(3-chlorophenyl)methyl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1F.[CH2:12]([O:15][C:16]([N:18]1[CH2:22][CH2:21][C@@H:20]([NH2:23])[CH2:19]1)=[O:17])[CH:13]=[CH2:14].C(N(CC)CC)C>C(OCC)(=O)C>[CH2:12]([O:15][C:16]([N:18]1[CH2:22][CH2:21][C@@H:20]([NH:23][C:7]2[CH:6]=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[CH:3][C:2]=2[F:1])[CH2:19]1)=[O:17])[CH:13]=[CH2:14]
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: C=CCOC(=O)N1CC[C@@H](N)C1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C=CCOC(=O)N1CC[C@@H](Nc2ccc([N+](=O)[O-])cc2F)C1

Procedure:
A solution of 5.01 g of 3,4-difluoro nitrobenzene, 5.1 g (3R)-1-allyloxycarbonyl-3-amino pyrrolidine (30 mmol) and 6,27 ml of triethylamine (31.5 mmol) in 100 ml of ethyl acetate was stirred at reflux. The reaction was monitored by HPLC. The reaction was diluted with ethyl acetate, washed with water and brine, the org. layer dried over Mg sulfate, filtered and evaporated. The residue crystallized from an ether/hexane mixture.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]1[N:7]=[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:9][C:10]=1[CH:11]=[O:12].C(P(CCCC)CCCC)CCC.[CH3:32][C:33]1[O:37][C:36]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[N:35][C:34]=1[CH2:44][O:45][C:46]1[CH:51]=[CH:50][C:49](O)=[CH:48][CH:47]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH3:1][O:2][CH2:3][O:4][CH2:5][C:6]1[N:7]=[C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:9][C:10]=1[CH2:11][O:12][C:49]1[CH:48]=[CH:47][C:46]([O:45][CH2:44][C:34]2[N:35]=[C:36]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[O:37][C:33]=2[CH3:32])=[CH:51][CH:50]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(O)cc1
Reactant: COCOCc1nc(-c2ccccc2)oc1C=O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COCOCc1nc(-c2ccccc2)oc1COc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Reaction time: 15 h
Yield: 57.1 %

Procedure:
To a mixture of 4-[(methoxymethoxy)methyl]-2-phenyl-1,3-oxazole-5-carbaldehyde (0.45 g), tributylphosphine (0.73 g), 4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenol (0.50 g) and tetrahydrofuran (50 mL) was added 1,1′-(azodicarbonyl)dipiperidine (0.91 g) at room temperature, and the mixture was stirred for 15 hrs. The precipitated crystals were removed by filtration and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give 4-[(methoxymethoxy)methyl]-5-({4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenoxy}methyl)-2-phenyl-1,3-oxazole as colorless crystals (0.52 g, yield 57%) from a fraction eluted with ethyl acetate-hexane (1:2, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 74-75° C.