Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:8][O:7][C:6]2[CH:9]=[CH:10][C:11]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=3)=[CH:12][C:5]=2[O:4][CH2:3]1.[CH3:23][O:24][CH2:25][CH2:26]Br>>[CH3:23][O:24][CH2:25][CH2:26][O:21][C:18]1[CH:17]=[CH:16][C:15]([C:14]#[C:13][C:11]2[CH:10]=[CH:9][C:6]3[O:7][CH2:8][C:2]([CH3:22])([CH3:1])[CH2:3][O:4][C:5]=3[CH:12]=2)=[CH:20][CH:19]=1
Reactant: CC1(C)COc2ccc(C#Cc3ccc(O)cc3)cc2OC1
Reactant: COCCBr
Product: COCCOc1ccc(C#Cc2ccc3c(c2)OCC(C)(C)CO3)cc1

Procedure:
The title compound was prepared according to the general procedure described in example 18 by alkylation of 4-(3,3-dimethyl-3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-ylethynyl)-phenol (Example 6) with 2-methoxyethyl bromide as brownish solid, MS (ESI) 353.3 (M+H)+.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:15][F:16])[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd]>[C:17]([N:13]([CH:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[CH2:14][CH2:15][F:16])([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18]
Reactant: CC(C)(C)OC(=O)N(CCF)C1CCN(Cc2ccccc2)C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Product: CC(C)(C)OC(=O)N(CCF)C1CCNC1

Procedure:
A 225 mg sample of the compound from step 448a was treated with ammonium formate and 10% Pd/C according to the procedure of step 445b for 1 hour, and the title compound was isolated (190 mg).
Reaction SMILES: [NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[NH:26][C:25](=[O:30])[CH2:24][CH2:23]3)[C:14]([C:17]#[N:18])=[N:15][CH:16]=1.[OH-].[Na+].OO.CC(O)=[O:37]>CCO.CS(C)=O>[NH2:1][C@H:2]1[C:7]([F:9])([F:8])[CH2:6][CH2:5][CH2:4][C@H:3]1[NH:10][C:11]1[N:12]=[C:13]([NH:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[NH:26][C:25](=[O:30])[CH2:24][CH2:23]3)[C:14]([C:17]([NH2:18])=[O:37])=[N:15][CH:16]=1
Reactant: N#Cc1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Nc1ccc2c(c1)CCC(=O)N2
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: NC(=O)c1ncc(N[C@@H]2CCCC(F)(F)[C@@H]2N)nc1Nc1ccc2c(c1)CCC(=O)N2
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
The compound 5-((1R,2R)-2-amino-3,3-difluorocyclohexylamino)-3-(2-oxo-1,2,3,4-tetrahydroquinolin-6-ylamino)pyrazine-2-carbonitrile (45 mg, 0.108 mmol) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (30%, 1.0 mL) were added. The mixture was stirred at room temperature for 20 min. HOAc (0.1 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (24 mg). MS 432.3 (M+H); UV 209.6, 308.9 nm; t 0.422 min.
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[N:13]=[C:12]([O:14][CH2:15][CH3:16])[S:11][N:10]=1.[CH:17]([N:19]=[C:20]=[O:21])=[CH2:18]>C(OC(C)C)(C)C>[CH:17]([NH:19][C:20]([N:10]1[C:9](=[O:8])[N:13]=[C:12]([O:14][CH2:15][CH3:16])[S:11]1)=[O:21])=[CH2:18]
Reactant: C=CN=C=O
Reactant: CCOc1nc(O)ns1
Solvent: CC(C)OC(C)C
Solvent: CCN(CC)CC
Product: C=CNC(=O)n1sc(OCC)nc1=O
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 69.8 %

Procedure:
1 ml of triethylamine was added to a solution of 14.6 g of 3-hydroxy-5-ethoxy-1,2,4-thiadiazole in 250 ml of isopropyl ether and after 5 minutes, 8 g of vinyl isocyanate were added. The mixture was stirred for 30 minutes at 20° C and was vacuum filtered and the recovered precipitate was washed, dried and crystallized from ethyl acetate to obtain 15 g of 2-(N-vinylcarbamoyl)-5-ethoxy-1,2,4-thiadiazole-3-one melting at 123° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([OH:8])[CH2:3]1.[H-].[Na+].F[C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[C:15]#[N:16]>CN(C=O)C>[CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][C:12]2[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=2)[C:15]#[N:16])[CH2:3]1
Reactant: CN1CCCC(O)C1
Reactant: N#Cc1cccc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCCC(Oc2cccc(C#N)c2)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1-Methylpiperidin-3-ol (500 mg, 4.341 mmol) was dissolved in DMF (10 ml) and cooled to 0° C. NaH (312 mg, 6.52 mmol) was added in small portions, stirred for 30 minutes and 3-fluorobenzonitrile (557 μl, 5.21 mmol) was subsequently added. The mixture was allowed to reach r.t. over 1 h and stirred for a further 16 h. Cooled to 0° C. and quenched with water. The reaction mixture was separated between water (150 ml) and DCM (2×150 ml). The combined organics were washed with water (150 ml), dried through a phase separator and evaporated in vacuo. Purification by flash silica gel chromatography using a 40 g Biotage column with a gradient of 10-100% EtOAc/MeOH/TEA 100:10:1 in heptane yielded the title compound as a colorless oil. Yield: 0.628 g (56%). 1H NMR (400 MHz, CDCl3) δ 7.32 (dt, 1H, J=7.6 Hz, J=0.9 Hz), 7.19 (m, 1H), 7.16-7.11 (m, 2H), 4.36 (m, 1H, J=4.0 Hz), 2.84 (m, 1H), 2.55 (m, 1H), 2.30-2.11 (m, 5H), 1.94 (m, 1H), 1.82 (m, 1H), 1.67-1.43 (m, 2H).
Reaction SMILES: Br[CH:2]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[C:10]([F:28])[CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].C1CCN2C(=NCCC2)CC1.Cl>C1(C)C=CC=CC=1>[CH3:6][O:5][C:3](=[O:4])[CH:2]=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[O:19][C:20]=2[CH3:21])=[C:10]([F:28])[CH:9]=1
Reactant: COC(=O)C(Br)Cc1ccc(OCc2nc(-c3ccccc3)oc2C)c(F)c1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: COC(=O)C=Cc1ccc(OCc2nc(-c3ccccc3)oc2C)c(F)c1
Temperature: 85 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
A mixture of methyl 2-bromo-3-[3-fluoro-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]propionate (14.2 g), 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) (4.83 g) and toluene (150 ml) was stirred at 80 to 90° C. for 2 hours, and then poured into 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure to give methyl3-fluoro-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)-cinnamate (10.0 g, 86%). This product was recrystallized from dichloromethane-methanol. Colorless prisms, mp: 167-168° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[C:4]([CH2:10][CH3:11])[CH:3]=1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:4]([CH2:10][CH3:11])[CH:3]=1
Reactant: CCc1cc(Br)ccc1CBr
Reactant: C1CCNC1
Solvent: ClCCl
Product: CCc1cc(Br)ccc1CN1CCCC1
Reaction time: 15 h
Yield: 67.4 %

Procedure:
To a solution of 4-bromo-1-bromomethyl-2-ethyl-benzene (2.00 g, 7.19 mmol) in CH2Cl2 (30 mL) was added dropwise pyrrolidine (1.19 mL, 14.4 mmol). The mixture was stirred for 15 hours, and then partitioned between Et2O and H2O. The organic layer was washed with brine, dried over MgSO4, and concentrated to yield a yellow oil (1.3 g, 68%). 1H NMR (300 MHz, CDCl3): δ 1.19 (t, J=7.5 Hz, 3 H), 1.76 (m, 4 H), 2.47 (m, 4 H), 2.69 (q, J=7.5 Hz, 2 H), 3.54 (s, 2 H), 7.19 (m, 1 H), 7.25 (m, 1 H), 7.29 (d, J=1.9 Hz, 1 H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([C:6]([S:20][C:21]3[C:22]([F:32])=[C:23]([CH:29]=[CH:30][CH:31]=3)[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:7][N:8]2[C:12]2[CH:13]=[N:14][N:15]([CH2:17][CH2:18][CH3:19])[CH:16]=2)=[CH:4][CH:3]=1.C1C(=O)N([Br:40])C(=O)C1>C(Cl)(Cl)(Cl)Cl.O>[Br:40][C:7]1[N:8]([C:12]2[CH:13]=[N:14][N:15]([CH2:17][CH2:18][CH3:19])[CH:16]=2)[C:9]2[C:5]([C:6]=1[S:20][C:21]1[C:22]([F:32])=[C:23]([CH:29]=[CH:30][CH:31]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:4][CH:3]=[C:2]([Cl:1])[C:10]=2[F:11]
Reactant: CCCn1cc(-n2cc(Sc3cccc(C(=O)OCC)c3F)c3ccc(Cl)c(F)c32)cn1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CCCn1cc(-n2c(Br)c(Sc3cccc(C(=O)OCC)c3F)c3ccc(Cl)c(F)c32)cn1
Reaction time: 16 h
Yield: 42.9 %

Procedure:
To a stirred solution of compound 2 (200 mg, 0.42 mmol) in CCl4 (3 mL) under inert atmosphere was added NBS (150 mg, 0.84 mmol) at RT and stirred for 16 h. The reaction was monitored by TLC and LC-MS; after completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with CH2Cl2 (2×20 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. This was purified by silica gel column chromatography using 10-15% EtOAc/Hexanes to afford compound 3 (100 mg, 43%) as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 7.71-7.67 (m, 1H), 7.66 (s, 1H), 7.64 (s, 1H), 7.31 (d, J=8.8 Hz, 1H), 7.18-7.15 (m, 1H), 7.00-6.96 (m, 2H), 4.40 (q, J=7.2 Hz, 2H), 4.18 (t, J=7.2 Hz, 2H), 2.02-1.93 (m, 2H), 1.40 (t, J=7.2 Hz, 3H), 0.97 (t, J=7.2 Hz, 3H); LC-MS (ESI): 98.1%; m/z 556.2 (M+2); (column: X Select CSH C-18, 50×3.0 mm, 3.5 μm); RT 4.94 min; 5 mM NH4OAc: ACN; 0.8 mL/min).
Reaction SMILES: CC(C)([O-])C.[K+:6].[CH2:7]([O:9][CH2:10][CH2:11][SH:12])[CH3:8].[C:13](=[S:15])=[S:14]>O1CCCC1>[C:13](=[S:14])([S-:15])[S:12][CH2:11][CH2:10][O:9][CH2:7][CH3:8].[K+:6]
Reactant: CCOCCS
Reactant: S=C=S
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOCCSC(=S)[S-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 6.79 g potassium t-butoxide in 300 ml of anhydrous tetrahydrofuran cooled to 0° C. under a nitrogen atmosphere was added 6.42 g of 2-mercaptoethyl ethyl ether. The resulting slurry was stirred at 25° C. for 1 hour, then 4.4 ml. of carbon disulfide was added dropwise at 0° C. The resulting solution was stirred at 25° C. for 30 min., then concentrated in vacuo. Diethyl ether (300 ml) was added and the mixture was filtered, washed with ether and dried under nitrogen to yield 12.6 g of the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:19]2[C:14](=[CH:15][N:16]=[C:17](F)[CH:18]=2)[N:13]=[CH:12][C:11]=1[C:21]#[N:22].[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][O-:27].[Na+].O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:19]2[C:14](=[CH:15][N:16]=[C:17]([O:27][CH2:26][CH2:25][N:24]([CH3:28])[CH3:23])[CH:18]=2)[N:13]=[CH:12][C:11]=1[C:21]#[N:22]
Reactant: CN(C)CC[O-]
Reactant: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(Cl)cc1Cl
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)CCOc1cc2c(Nc3ccc(Cl)cc3Cl)c(C#N)cnc2cn1
Yield: 59 %

Procedure:
To 250 mg of 4-(2,4-dichloro-phenylamino)-6-fluoro-[1.7]naphthyridine-3-carbonitrile under an inert atmosphere was added 8 mL of 1 M sodium (2-dimethylamino-ethoxide) in tetrahydrofuran. After refluxing for 2 hours, the reaction was stripped of tetrahydrofuran and water was added. The product was filtered, washed with water, dried, and recrystallized from chloroform/ether/hexanes to give 186 mg (59%) of 4-(2,4-dichloro-phenylamino)-6-(2-dimethylamino-ethoxy)-[1.7]naphthyridine-3-carbonitrile as a yellow solid: melting point 75-9° C.; mass spectrum (m/e): M+H 401.9.