Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[OH:12].[CH:13]([C:15]1[O:19][C:18](B(O)O)=[CH:17][CH:16]=1)=[O:14].C(=O)([O-])[O-].[Na+].[Na+].COCCOC>C(OC)(C)(C)C.O>[C:8]([C:6]1[CH:5]=[CH:4][C:3]([OH:12])=[C:2]([C:18]2[O:19][C:15]([CH:13]=[O:14])=[CH:16][CH:17]=2)[CH:7]=1)([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)c1ccc(O)c(Br)c1
Reactant: O=Cc1ccc(B(O)O)o1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: COC(C)(C)C
Solvent: O
Product: CC(C)(C)c1ccc(O)c(-c2ccc(C=O)o2)c1
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 7.4 %

Procedure:
A reaction flask was flushed with nitrogen and charged with 2-bromo-4-tert-butyl-phenol (2.019 g, 8.81 mmol), 5-formyl-furan-2-boronic acid (1.831 g, 13.09 mmol) and sodium carbonate (2.783 g, 26.26 mmol). A mixture of 1,2-dimethoxyethane (40 mL) and water (13 mL) was added and the reaction mixture was stirred for 10 min under a nitrogen atmosphere. Dichlorobis(triphenylphosphine) palladium(II) (0.193 g, 0.27 mmol) was added and the mixture was stirred and heated to 65° C. for 17 h. The mixture was cooled to room temperature, diluted with methyl tert-butyl ether (MTBE) (250 mL) and washed successively with 5% aq. potassium carbonate (100 mL), water (100 mL) and brine. The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on flash Silica (100 g, 5 to 10% ethyl acetate in hexanes) to afford 5-(5-tert-butyl-2-hydroxy-phenyl)-furan-2-carbaldehyde (160 mg, 7%). 1H NMR (400 MHz, CDCl3): δ 1.33 (9H, s) 6.51 (1H, bs), 6.90 (1H, d, J=8.8 Hz), 7.03 (1H, d, J=4.0 Hz), 7.32 (1H, dd, J=8.8, 2.4 Hz), 7.36 (1H, d, J=3.6 Hz), 7.73 (1H, d, J=3.2 Hz), 9.64 (1H, s). ESI-MS: 243.0.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[N:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:33]=[CH:32][C:28](C(O)=O)=[CH:27][CH:26]=2)=[CH:21][CH:20]=1.[NH2:34][C@@H:35]([CH2:44][OH:45])[C@H:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[OH:37]>>[OH:37][C@@H:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C@@H:35]([NH:34][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6](=[O:7])[C:28]1[CH:27]=[CH:26][C:25]([C:22]2[CH:21]=[CH:20][N:19]=[CH:24][CH:23]=2)=[CH:33][CH:32]=1)=[O:18])[CH2:44][OH:45]
Reactant: O=C(O)c1ccc(-c2ccncc2)cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: N[C@@H](CO)[C@@H](O)c1ccccc1
Product: CON=C1C[C@@H](C(=O)N[C@@H](CO)[C@@H](O)c2ccccc2)N(C(=O)c2ccc(-c3ccncc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 4-(4-pyridinyl)benzoic acid, and (1S,2S)-2-amino-1-phenyl-1,3-propanediol, the title compound was obtained in 64% purity by HPLC. MS(ESI+): m/z=489.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:8]([C:12]([NH:14][CH2:15][CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:13])=[C:7]([Cl:22])[CH:6]=[CH:5][C:4]=2[N:3]=1.Cl.[C:24]([CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)#[N:25]>>[Cl:22][C:7]1[CH:6]=[CH:5][C:4]2[N:3]=[C:2]([N:29]3[CH2:30][CH2:31][CH:26]([C:24]#[N:25])[CH2:27][CH2:28]3)[CH:11]=[CH:10][C:9]=2[C:8]=1[C:12]([NH:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:13]
Reactant: O=C(NCC1CCCCC1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: N#CC1CCNCC1
Agent: Cl
Product: N#CC1CCN(c2ccc3c(C(=O)NCC4CCCCC4)c(Cl)ccc3n2)CC1

Procedure:
Prepared according to the method of example 51, using 2,6-dichloro-N-(cyclohexylmethyl)-5-quinolinecarboxamide Example 43(a)) (0.25 g), and 4-cyanopiperidine hydrochloride (0.25 g) to afford the title compound (0.27 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:11]([F:14])([F:13])[F:12])[C:5]([CH2:8][C:9]#[N:10])=[N:6][CH:7]=1.[CH2:15]([O:17][C:18]1[C:23](=[O:24])[NH:22][CH:21]=[C:20]([C:25]2[CH:30]=[CH:29][C:28]([CH2:31][C:32](O)=[O:33])=[C:27]([F:35])[CH:26]=2)[CH:19]=1)[CH3:16].C1C=CC2N(O)N=NC=2C=1.C(Cl)C[Cl:48].CCN(CC)CC>CN(C=O)C>[ClH:48].[C:9]([CH2:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][C:32](=[O:33])[CH2:31][C:28]2[CH:29]=[CH:30][C:25]([C:20]3[CH:19]=[C:18]([O:17][CH2:15][CH3:16])[C:23](=[O:24])[NH:22][CH:21]=3)=[CH:26][C:27]=2[F:35])=[CH:3][C:4]=1[C:11]([F:14])([F:12])[F:13])#[N:10]
Reactant: N#CCc1ncc(N)cc1C(F)(F)F
Reactant: ClCCCl
Reactant: CCOc1cc(-c2ccc(CC(=O)O)c(F)c2)c[nH]c1=O
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1cc(-c2ccc(CC(=O)Nc3cnc(CC#N)c(C(F)(F)F)c3)c(F)c2)c[nH]c1=O
Product: Cl
Yield: 2.3 %

Procedure:
A suspension of 2-(5-amino-3-(trifluoromethyl)pyridin-2-yl)acetonitrile (16.00 mg, 0.080 mmol) in DMF (5 mL) was added to a solution of 2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetic acid (46.33 mg, 0.080 mmol) in DMF (5 mL). HOBt (18.27 mg, 0.119 mmol), EDC (22.87 mg, 0.119 mmol) and Et3N (0.033 mL, 0.239 mmol) and the mixture was at 50° C. for 12 h. Then the solution was concentrated and distributed between EA and saturated NaHCO3 solution. The combined organic extract was washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by preparative HPLC (MeCN/H2O as eluants, acidic condition) to yield a yellow solid of N-(6-(cyanomethyl)-5-(trifluoromethyl)pyridin-3-yl)-2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetamide, hydrochloride (0.96 mg, 1.879 μmol, 2.4% yield). TLC (DCM/MeOH=10:1, Rf=0.3): 1H NMR (400 MHz, CD3OD) δ: 8.87-8.96 (m, 1H), 8.56 (d, J=2.21 Hz, 1H), 7.19-7.50 (m, 5H), 4.08-4.18 (m, 2H), 3.85 (s, 3H), 3.58 (s, 2H), 1.29-1.35 (m, 3H); ES-LCMS m/z 475.0 (M+H).
Reaction SMILES: [CH2:1]1[O:5][CH2:4][O:3][CH2:2]1.[C:6]([Cl:9])(=[O:8])C.[CH3:10]COCC>>[C:4]([O:5][CH2:1][CH2:2][O:8][CH2:6][Cl:9])(=[O:3])[CH3:10]
Reactant: C1COCO1
Reactant: CCOCC
Reactant: CC(=O)Cl
Product: CC(=O)OCCOCCl
Temperature: 23 °C
Reaction time: 8 h

Procedure:
A 5 L three-neck flask was fitted with mechanical stirrer, thermometer, 500 mL additional funnel and argon purged. 1,3-Dioxalane (140 mL, 2.00 mol) in anhydrous Et2O (800 mL) and 1.0 M ZlnCl2/Et2O (7.5 mL, 0.007 mol) were added. A solution of acetyl chloride (157 mL, 2.20 mol) in Et2O (200 mL) was added dropwise through an additional funnel over 20 min. A cold water bath was used to maintain temperature between 19-27° C. throughout. Continue stirring without external cooling for 4 h, reaction self heating at 20-25° C. for about 1 h. A clear, colorless solution retained under argon overnight. Stood for 3 days and formed an orange solution. Strip Et2O on rotavap (water aspirator) until no more distilled at 35° C. bath. A quantitative yield of product 318 g (theoretical yield 306 g) was obtained.
Reaction SMILES: Cl.[CH:2]1([NH:7][NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH2:9]([O:11][C:12](=[O:24])[C:13](=[CH:20]N(C)C)[C:14](=O)[C:15]([F:18])([F:17])[F:16])[CH3:10].C([O-])(=O)C.[Na+]>C(O)C>[CH2:9]([O:11][C:12]([C:13]1[CH:20]=[N:8][N:7]([CH:2]2[CH2:6][CH2:5][CH2:4][CH2:3]2)[C:14]=1[C:15]([F:16])([F:17])[F:18])=[O:24])[CH3:10]
Reactant: NNC1CCCC1
Reactant: CCOC(=O)C(=CN(C)C)C(=O)C(F)(F)F
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cnn(C2CCCC2)c1C(F)(F)F
Temperature: 70 °C
Yield: 52.6 %

Procedure:
Cyclopentyl-hydrazine hydrochloride (0.250 g, 1.83 mmol, Example 64, Step 2), 2-dimethylaminomethylene-4,4,4-trifluoro-3-oxo-butyric acid ethyl ester (0.403 g, 1.68 mmol) and anhydrous sodium acetate (0.163 g, 1.99 mmol) were combined in ethanol (2.5 mL) and heated at 70° C. for 17 hours. After cooling to room temperature, the reaction mixture was partitioned between methylene chloride and water. The organic phase was washed with water and brine. Each aqueous phase was back extracted with a second portion of methylene chloride. The two organic phases were combined, dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography, eluting with a 10-40% ethyl acetate-hexanes gradient, yielded 1-cyclopentyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid ethyl ester (0.244 g, 52%). Mass spectrum: m/z: 277.1 (M+H).
Reaction SMILES: [C:1]1([C:7]2[S:8][C:9]3[CH2:15][CH2:14][C:13]4=[C:16]([C:23]([O:25]CC)=[O:24])[S:17][C:18]([S:19][CH2:20][CH2:21][CH3:22])=[C:12]4[C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.[OH-].[Na+].Cl>O.O1CCCC1>[C:1]1([C:7]2[S:8][C:9]3[CH2:15][CH2:14][C:13]4=[C:16]([C:23]([OH:25])=[O:24])[S:17][C:18]([S:19][CH2:20][CH2:21][CH3:22])=[C:12]4[C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCSc1sc(C(=O)OCC)c2c1-c1nc(-c3ccccc3)sc1CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCCSc1sc(C(=O)O)c2c1-c1nc(-c3ccccc3)sc1CC2
Temperature: 50 °C
Reaction time: 3 h
Yield: 98.6 %

Procedure:
Ethyl 4,5-dihydro-2-phenyl-8-propylthiothieno[3,4-e]benzothiazole-6-carboxylate (3.62 g) was suspended in a mixed solvent of ethanol (25 ml) and tetrahydrofuran (15 ml); a 2 N aqueous solution of sodium hydroxide (13.3 ml) was added at 50° C. After the reaction mixture was stirred at 50° C. for 3 hours, the solution obtained was poured over water (400 ml), acidified with concentrated hydrochloric acid, and extracted with ethyl acetate-tetrahydrofuran (3:1, v/v). The organic layer was washed with water and dried (MgSO4), after which the solvent was distilled off to yield 4,5-dihydro-2-phenyl-8-propylthiothieno[3,4-e]benzothiazole-6-carboxylic acid (3.33 g, 98.5%), which was then recrystallized from chloroform-methanol. Light-yellow prisms. Melting point 236-237° C. (decomposed).
Reaction SMILES: [CH3:1][N:2]([CH3:8])[C@@H:3]1[CH2:7][CH2:6][NH:5][CH2:4]1.F[C:10]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([NH:19][C:20]2[N:25]=[C:24]([C:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]([CH3:35])[CH:27]=3)[C:23]([CH3:36])=[CH:22][N:21]=2)=[C:12]([O:37][CH3:38])[CH:11]=1>CC(N(C)C)=O>[CH3:1][N:2]([CH3:8])[C@@H:3]1[CH2:7][CH2:6][N:5]([C:10]2[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:13]([NH:19][C:20]3[N:25]=[C:24]([C:26]4[C:34]5[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=5)[N:28]([CH3:35])[CH:27]=4)[C:23]([CH3:36])=[CH:22][N:21]=3)=[C:12]([O:37][CH3:38])[CH:11]=2)[CH2:4]1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(C)c(-c2cn(C)c3ccccc23)n1
Reactant: CN(C)[C@@H]1CCNC1
Solvent: CC(=O)N(C)C
Product: COc1cc(N2CC[C@@H](N(C)C)C2)c([N+](=O)[O-])cc1Nc1ncc(C)c(-c2cn(C)c3ccccc23)n1
Temperature: 140 °C
Yield: 64.5 %

Procedure:
(3R)—N,N-dimethylpyrrolidin-3-amine (255 mg, 2.24 mmol) was added to a suspension of N-(4-fluoro-2-methoxy-5-nitrophenyl)-5-methyl-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 79, 414 mg, 1.02 mmol) in DMA (4 mL) and the mixture was heated in a microwave at 140° C. for 0.5 h. The mixture was then concentrated in vacuo and the residue was dissolved in EtOAc (50 mL). Purification by ion exchange chromatography, using an SCX column and eluting with 0.35M methanolic ammonia provided semi-purified material after concentration of appropriate fractions in vacuo. Purification by FCC, eluting with 1-8% CH3OH in CH2Cl2 gave the title compound (330 mg, 65%) as an orange dry film; 1H NMR: 1.75-1.86 (1H, m), 2.13-2.19 (1H, m), 2.21 (6H, s), 2.37 (3H, s), 2.75 (1H, s), 3.10-3.20 (2H, m), 3.21-3.27 (1H, m), 3.46 (1H, td), 3.90 (3H, s), 3.94 (3H, s), 6.56 (1H, s), 7.03 (1H, t), 7.21-7.26 (1H, m), 7.49 (1H, d), 7.94 (1H, s), 8.05 (1H, s), 8.23 (1H, s), 8.37 (1H, d), 8.39 (1H, s); m/z: ES+ MH+ 502.33.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([C:13]#[N:14])[CH2:10][C@H:9]1[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[C:20]([F:27])=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][NH2:23].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([C:13]#[N:14])[CH2:10][C@H:9]1[C:15](=[O:17])[NH:23][CH2:22][C:21]1[CH:24]=[CH:25][CH:26]=[C:19]([Cl:18])[C:20]=1[F:27])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](C#N)C[C@H]1C(=O)O
Reactant: NCc1cccc(Cl)c1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1C[C@@H](C#N)C[C@H]1C(=O)NCc1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of (2S,4S)-4-cyano-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (700 mg, 2.91 mmol), 3-chloro-2-fluorobenzylamine (558 mg, 3.50 mmol), HBTU (1.66 g, 4.37 mmol) in DMF (15 mL) was added DIPEA (1.5 mL, 8.74 mmol) and the resolution mixture was stirred at RT under nitrogen for 48 h. The mixture was poured in water and extracted with EtOAc (2×). The combined organic extracts were washed with water (1×), dried (Na2SO4), filtered and concentrated. The crude material was purified by flash column chromatography (c-hexane to c-hexane/EtOAc 1:1) to give the desired compound. TLC, Rf (c-hexane/EtOAc 1:1)=0.40; MS: 404.0 [M+Na]+, 380.0 [M−H]−, tR (HPLC conditions a): 3.45 min.
Reaction SMILES: C1(N2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)C=CC=CC=1.NC1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.[CH3:49][O:50][C:51]1[CH:52]=[C:53]([CH:55]=[CH:56][C:57]=1[O:58][CH3:59])[NH2:54]>C(O)(=O)C>[CH3:49][O:50][C:51]1[CH:52]=[C:53]([N:54]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:55]=[CH:56][C:57]=1[O:58][CH3:59]
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: COc1ccc(N)cc1OC
Agent: COC(=O)c1scc(-c2ccccc2)c1N
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: COc1ccc(-n2cnc3c(-c4ccccc4)csc3c2=O)cc1OC
Yield: 59 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (52 mg, 0.22 mmol), triethyl orthoformate (0.45 ml), 3,4-dimethoxyaniline (62.8 mg, 0.41 mmol), and acetic acid (0.06 ml) were used to give 48 mg (0.13 mmol, 59% yield) of the title compound.
Reaction SMILES: [C:1]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([C:12](Cl)=[O:13])[N:9]=[CH:8]2)[CH:2]=1.C(N(CC)CC)C.Cl.[CH3:29][NH:30][O:31][CH3:32]>ClCCl>[CH3:32][O:31][N:30]([CH3:29])[C:12]([C:10]1[N:9]=[CH:8][N:7]([C:3]2[CH:2]=[C:1]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:6]=[CH:5][CH:4]=2)[CH:11]=1)=[O:13]
Reactant: O=C(Cl)c1cn(-c2cccc(-c3ccccc3)c2)cn1
Reactant: CNOC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3)c2)cn1

Procedure:
The above product (11a) was dissolved in dichloromethane (20 ml). Triethylamine (10 ml) and N,O-dimethylhydroxylamine hydrochloride (0.83 g, 8.3 mmol) were added and the resultant mixture was stirred at ambient conditions overnight. The reaction mixture was concentrated under reduced pressure and the concentrate was purified by column chromatography on silica gel using a mixture of 0.8% methanol in chloroform as the eluent to afford 12a (1.2 g).