Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[CH:14][C:13]=1[C:20]1[N:25]=[CH:24][CH:23]=[CH:22][N:21]=1)=[O:11].Cl[C:27]1[N:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][N:28]=1>>[F:19][C:15]1[C:16]([F:18])=[CH:17][C:12]([C:10]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:9])[C@H:3]2[CH2:2][NH:1][C:27]2[N:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][N:28]=2)=[O:11])=[C:13]([C:20]2[N:21]=[CH:22][CH:23]=[CH:24][N:25]=2)[CH:14]=1
Reactant: C[C@@H]1CCCN(C(=O)c2cc(F)c(F)cc2-c2ncccn2)[C@@H]1CN
Reactant: FC(F)(F)c1cnc(Cl)nc1
Product: C[C@@H]1CCCN(C(=O)c2cc(F)c(F)cc2-c2ncccn2)[C@@H]1CNc1ncc(C(F)(F)F)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(4,5-difluoro-2-(pyrimidin-2-yl)phenyl)methanone and 2-chloro-5-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 493 [M+1]+. 1H NMR (500 MHz, DMSO-d6) δ 8.95-6.75 (m, 8H), 4.95-2.85 (m, 5H), 1.95-0.65 (m, 8H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C:10](=[O:21])[N:11]([S:13]([C:16]3[NH:20][N:19]=[CH:18][N:17]=3)(=[O:15])=[O:14])[N:12]=2)=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[F:40][C:41]([F:51])([F:50])[C:42]1[CH:49]=[CH:48][CH:47]=[CH:46][C:43]=1[CH2:44]Br>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C:10](=[O:21])[N:11]([S:13]([C:16]3[N:20]([CH2:44][C:43]4[CH:46]=[CH:47][CH:48]=[CH:49][C:42]=4[C:41]([F:40])([F:50])[F:51])[N:19]=[CH:18][N:17]=3)(=[O:15])=[O:14])[N:12]=2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccccc1CBr
Reactant: COc1ccc(Cn2c(-c3ccc(Cl)cc3)nn(S(=O)(=O)c3ncn[nH]3)c2=O)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cn2c(-c3ccc(Cl)cc3)nn(S(=O)(=O)c3ncnn3Cc3ccccc3C(F)(F)F)c2=O)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
334 mg (0.75 mmol) of the compound from Example 94A were dissolved in 5 ml of dichloromethane, and 154 μl (0.93 mmol) of N,N-diisopropylethylamine were added. 223 mg (0.93 mmol) of 2-(trifluoromethyl)benzyl bromide dissolved in 0.5 ml of dichloromethane were then added, and the mixture was stirred at RT for 20 h. For work-up, the mixture was concentrated under reduced pressure and the crude product was purified chromatographically [Method 19]. This gave 245 mg (54% of theory) of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[C:6]([C:13]#[N:14])=[C:5]2[CH3:15].[N-:16]=[N+:17]=[N-:18].[NH4+]>CCO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[C:6]([C:13]1[NH:18][N:17]=[N:16][N:14]=1)=[C:5]2[CH3:15]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1c(C#N)c(=O)oc2ccc(Cl)cc12
Agent: [NH4+]
Solvent: CCO
Product: Cc1c(-c2nnn[nH]2)c(=O)oc2ccc(Cl)cc12

Procedure:
The reaction of 6-Chloro-3-cyano-4-methyl coumarin with ammonium azide as described in Example 1 yielded the title product, m.p. (EtOH) 219°-223° C. (Found: C, 50.30; H, 2.69; N, 21.33; C11H7ClN4O2 requires; C, 50.04; H, 2.84; N, 21.63%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:12][CH:13]([CH3:15])[CH3:14])[C:4]([NH:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])=[O:5].[C:16]([O:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29](O)=[O:30])=[O:22])([CH3:19])([CH3:18])[CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1>[CH2:12]([C@@H:3]([C:4](=[O:5])[NH:6][CH2:7][C:8]([O:10][CH3:11])=[O:9])[NH:2][C:29](=[O:30])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][NH:23][C:21](=[O:22])[O:20][C:16]([CH3:17])([CH3:18])[CH3:19])[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)O
Reactant: COC(=O)CNC(=O)[C@@H](N)CC(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)CCCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (S)-methyl 2-(2-amino-4-methylpentanamido)acetate hydrochloride (4w) in THF was added 6-((tert-butoxycarbonyl)amino) hexanoic acid, HATU and DIPEA. The reaction was stirred at room temperature for 18 h. The mixture was then filtered through Celite. The filtrate was concentrated under reduced pressure and the crude residue was purified by column chromatography (silica gel, CH2Cl2/MeOH=50/1) to give (S)-methyl 13-isobutyl-2,2-dimethyl-4,11,14-trioxo-3-oxa-5,12,15-triazaheptadecan-17-oate (6w) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl:16][C:17]1[CH:29]=[CH:28][C:20]([O:21][CH:22]([CH2:26][CH3:27])[C:23](Cl)=[O:24])=[CH:19][C:18]=1[C:30]([F:33])([F:32])[F:31]>C1(C)C=CC=CC=1>[N:6]1[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:23](=[O:24])[CH:22]([O:21][C:20]2[CH:28]=[CH:29][C:17]([Cl:16])=[C:18]([C:30]([F:32])([F:33])[F:31])[CH:19]=2)[CH2:26][CH3:27])=[CH:4][CH:5]=1
Reactant: NCc1ccncc1
Reactant: CCC(Oc1ccc(Cl)c(C(F)(F)F)c1)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCC(Oc1ccc(Cl)c(C(F)(F)F)c1)C(=O)NCc1ccncc1
Yield: 42.9 %

Procedure:
In 50 ml of toluene were dissolved 1.3 g (0.012 mole) of 4-(aminomethyl)pyridine and 1.0 g (0.010 mole) of triethylamine. Thereto was added dropwise a solution of 3.0 g (0.010 mole) of 2-(4-chloro-3-trifluoromethylphenoxy)-butyroyl chloride in 30 ml of toluene at room temperature with stirring, and the mixture was treated according to the same procedure as in Synthesis Example 10. The resultant oily substance was subjected to silica gel column chromatography by eluting with toluene to obtain 1.6 g of N-(4-pyridylmethyl)-2-(4-chloro-3-trifluoromethylphenoxy)-butyramide showing nD19 1.5228 as pale yellow oil.
Reaction SMILES: [F:1][C:2]1[C:11]([NH:12][C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])=[CH:10][CH:9]=[C:8]([F:19])[C:3]=1[C:4]([O:6]C)=O.[Cl:20][C:21]1[N:26]=[C:25]([CH3:27])[CH:24]=[CH:23][N:22]=1>>[Cl:20][C:21]1[N:26]=[C:25]([CH2:27][C:4]([C:3]2[C:2]([F:1])=[C:11]([NH:12][C:13](=[O:14])[O:15][CH2:16][CH:17]=[CH2:18])[CH:10]=[CH:9][C:8]=2[F:19])=[O:6])[CH:24]=[CH:23][N:22]=1
Reactant: C=CCOC(=O)Nc1ccc(F)c(C(=O)OC)c1F
Reactant: Cc1ccnc(Cl)n1
Product: C=CCOC(=O)Nc1ccc(F)c(C(=O)Cc2ccnc(Cl)n2)c1F
Yield: 60.2 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 11 using methyl 2,6-difluoro-3-{[(2-propen-1-yloxy)carbonyl]amino}benzoate (80 g, 295 mmol) and 2-chloro-4-methylpyrimidine (41.6 g, 324 mmol) the title compound of Step E was obtained (65 g, 60.2% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.49-9.60 (m, 1H), 8.72-8.77 (m, 0.3H), 8.58-8.64 (m, 0.6H), 7.57-7.83 (m, 2H), 7.15-7.25 (m, 1H), 5.89-6.01 (m, 1H), 5.75-5.82 (m, 0.6H), 5.20-5.40 (m, 2H), 4.55-4.62 (m, 2H), m/z (ES+): 368 [M+H]+.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=2[O:23][CH3:24])(=O)=O)=CC=1.[CH:26]([NH2:29])([CH3:28])[CH3:27]>O1CCOCC1>[CH:26]([NH:29][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=1[O:23][CH3:24])([CH3:28])[CH3:27]
Reactant: COc1cc([N+](=O)[O-])ccc1OCCOS(=O)(=O)c1ccc(C)cc1
Reactant: CC(C)N
Solvent: C1COCCO1
Product: COc1cc([N+](=O)[O-])ccc1OCCNC(C)C
Temperature: 73 °C
Reaction time: 9 h
Yield: 68.8 %

Procedure:
2-(2-Methoxy-4-nitrophenoxy)ethyl p-toluenesulfonate (19.5 g) and 70% aqueous isopropylamine solution (15.7 g) were dissolved into dioxane (100 ml) and the mixture was stirred for 9 hours at 73° C. After being concentrated under vacuum, the reaction mixture was dissolved into 2N HCl (50 ml) and washed with ethyl acetate (50 ml) two times. Resulting aqueous layer was neutralized with 2N sodium hydroxide (50 ml) and then extracted with ethyl acetate (100 ml). The organic layer was dehydrated with anhydrous sodium sulfate and then concentrated under vacuum to almost dryness to obtain N-isopropyl-2-(2-methoxy-4-nitrophenoxy)ethylamine (9.29 g) as yellowish oil.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH:15]=2)[C:10]([OH:12])=O)=[CH:4][CH:3]=1.[CH2:23]([O:25][C:26](=[O:35])[CH2:27][S:28][C:29]1[S:33][C:32]([NH2:34])=[N:31][CH:30]=1)[CH3:24]>>[CH2:23]([O:25][C:26](=[O:35])[CH2:27][S:28][C:29]1[S:33][C:32]([NH:34][C:10](=[O:12])[C:9]2[CH:13]=[C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH:15]=[C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:22][CH:21]=3)[CH:8]=2)=[N:31][CH:30]=1)[CH3:24]
Reactant: CC(C)COc1cc(Oc2ccc(F)cc2)cc(C(=O)O)c1
Reactant: CCOC(=O)CSc1cnc(N)s1
Product: CCOC(=O)CSc1cnc(NC(=O)c2cc(OCC(C)C)cc(Oc3ccc(F)cc3)c2)s1

Procedure:
The title compound was prepared from 3-(4-fluoro-phenoxy)-5-isobutoxy-benzoic acid and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester following general procedure A
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[C:6]([C:15](=[O:17])[CH3:16])[CH:5]=[C:4]([Cl:18])[C:3]=1[CH3:19].Cl[CH2:21][CH2:22][CH2:23][C:24](Cl)=[O:25].CC(C)([O-])C.[K+]>CN(C)C1C=CN=CC=1.O1CCCC1>[C:15]([C:6]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[C:2]([N:1]2[CH2:21][CH2:22][CH2:23][C:24]2=[O:25])[C:3]([CH3:19])=[C:4]([Cl:18])[CH:5]=1)(=[O:17])[CH3:16]
Reactant: O=C(Cl)CCCCl
Reactant: CC(=O)c1cc(Cl)c(C)c(N)c1-c1cccc(F)c1
Agent: CC(C)(C)[O-]
Agent: CN(C)c1ccncc1
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)c1cc(Cl)c(C)c(N2CCCC2=O)c1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.9 %

Procedure:
To a mixture of 1-(6-amino-4-chloro-3′-fluoro-5-methylbiphenyl-2-yl)ethanone (100 mg, 0.4 mmol) and 4-dimethylaminopyridine (52.8 mg, 0.432 mmol) in tetrahydrofuran (1 mL) was added 4-chlorobutanoyl chloride (0.044 mL, 0.40 mmol). The reaction was stirred at room temperature for 1 hour. Potassium tert-butoxide (1.0 M) in tetrahydrofuran (0.79 mL, 0.79 mmol) was added and the resulting mixture was stirred at room temperature for 2 hours, then quenched with aq. ammonium chloride and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried and evaporated. The resulting residue was purified on silica gel, eluting with 0 to 50% ethyl acetate in hexane, to give the product (40 mg, 30%). LCMS calculated for C19H18ClFNO2 (M+H)+: m/z=346.1. found: 346.1.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[CH:4]=[C:5]([CH3:9])[C:6]=1[C:7]#[N:8].[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(O)(=O)C>[C:7]([C:6]1[C:5]([CH3:9])=[CH:4][N:3]([C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[C:2]=1[NH:1][C:19](=[O:21])[CH3:20])#[N:8]
Reactant: Cc1cc(C)c(-n2cc(C)c(C#N)c2N)c(C)c1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1c(C#N)c(C)cn1-c1c(C)cc(C)cc1C
Yield: 105.2 %

Procedure:
A mixture of the purified compound of step A (3.000 g, 12.54 mmol) and acetic anhydride (1.410 g, 1.31 ml, 13.82 mmol) in 3 ml of acetic acid was refluxed for 45 minutes, cooled and poured onto crushed ice and extracted with ethyl acetate. The organic layer was neutralized, dried and concentrated to give 3.71 g (105%) of dark-pink glass foam. 1H NMR (CDCl3) □ 1.95(s, 6H), 2.2(s, 3H), 2.32 (s, 3H), 6.2(s, 1H), 6.8(brs, 1H, NH), 6.9(s, 2H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([C:12]2[C:17]([Cl:18])=[CH:16][C:15]([N+:19]([O-])=O)=[CH:14][C:13]=2[Cl:22])[C:10]#[N:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[H][H]>CO.[Ni]>[Cl:18][C:17]1[CH:16]=[C:15]([CH:14]=[C:13]([Cl:22])[C:12]=1[CH:9]([C:10]#[N:11])[C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[NH2:19]
Reactant: N#CC(c1ccc(Cl)c(Cl)c1)c1c(Cl)cc([N+](=O)[O-])cc1Cl
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: N#CC(c1ccc(Cl)c(Cl)c1)c1c(Cl)cc(N)cc1Cl
Yield: 95 %

Procedure:
In 100 ml of methanol were dissolved 7.6 g of α-(3,4-dichlorophenyl)-α-(2,6-dichloro-4-nitrophenyl)acetonitrile and 0.8 g (50%) of Raney's nickel. The solution was subjected to reduction with three times as much mol. of hydrogen gas. Insolubles were removed from the reaction mixture, then the remaining solution was concentrated to give the titled compound in a yield of 95%, m.p. 191-194° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[Si]([C:15]([F:18])([F:17])[F:16])(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:7]([OH:8])[C:15]([F:18])([F:17])[F:16])[CH:9]=1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1cc(Br)ccc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1cc(Br)ccc1F)C(F)(F)F
Reaction time: 0.17 h
Yield: 48 %

Procedure:
A solution of 5-bromo-2-fluorobenzaldehyde (5.05 g, 24.9 mmol) in THF (200 mL) was cooled in a wet ice bath and treated dropwise with TMS-CF3 over five minutes. After stirring for 10 minutes, a solution of tetrabutylammonium fluoride (TBAF) in THF (1.0 mL, 1.0M) was added dropwise over 5 minutes. After stirring for 10 minutes, the ice bath was removed and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was treated with 1N HCl (50 mL) and allowed to stir for 2 hours. The mixture was diluted with 1N HCl (50 mL) and extracted with EtOAc (200 mL). The organic layer was washed with saturated aqueous NaHCO3 (2×50 mL) and brine (50 mL), dried over Na2SO4, filtered and concentrated. Purification by flash column chromatography (silica gel, hexanes/EtOAc, 100:0 to 95:5) provided the title compound (3.28 g, 48%) as a colorless liquid. 1H NMR (500 MHz, CDCl3) δ 7.76 (dd, J=6.0, 2.0 Hz, 1H), 7.50 (ddd, J=8.5, 4.5, 2.5 Hz, 1H), 7.00 (overlapping dd, J=9.0, 9.0 Hz, 1H), 5.39 (overlapping dq, J=6.0, 6.0 Hz, 1H), 2.86 (d, J=5.5 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][CH2:7][CH2:8][N:9]3[C:13]2=[N:12][C:11]([C:16](/[N:18]=[CH:19]/[N:20](C)C)=O)=[CH:10]3)=[CH:4][CH:3]=1.Cl.[CH:24]([NH:27]N)([CH3:26])[CH3:25]>CC(O)=O>[Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][CH2:7][CH2:8][N:9]3[C:13]2=[N:12][C:11]([C:16]2[N:27]([CH:24]([CH3:26])[CH3:25])[N:20]=[CH:19][N:18]=2)=[CH:10]3)=[CH:4][CH:3]=1
Reactant: CC(C)NN
Reactant: CN(C)/C=N/C(=O)c1cn2c(n1)-c1cc(Br)ccc1OCC2
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(Br)ccc1OCC2
Temperature: 100 °C

Procedure:
To a solution of 13-bromo-N-[(1E)-(dimethylamino)methylidene]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaene-4-carboxamide (2.2 g, 6.1 mmol) in AcOH (20 mL) was added isopropylhydrazine hydrochloride (0.73 g, 6.6 mmol). The mixture was heated at 100° C. for 1 h. Most of the solvent was removed and water (50 mL) was added. The solid was collected by filtration, washed with water and dried in vacuo to afford 13-Bromo-4-[1-(propan-2-yl)-1H-1,2,4-triazol-5-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca1(14),2,4,10,12-pentaene, also named as 10-bromo-2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine (1.8 g, 74% yield) as a yellow solid. LCMS (ESI) m/z: 376.1 [M+H+].