Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:15][CH2:14][C@H:13]([CH2:16][OH:17])[O:12][C:8]3=2)[N:3]=1.[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([Br:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19].C(N(CC)CC)C.O>C1(C)C=CC=CC=1.C(O)(C)C.CN(C1C=CC=CN=1)C>[Br:25][C:24]1[CH:26]=[CH:27][C:21]([S:18]([O:17][CH2:16][C@@H:13]2[O:12][C:8]3=[C:9]4[C:4](=[CH:5][CH:6]=[C:7]3[O:15][CH2:14]2)[N:3]=[C:2]([CH3:1])[CH:11]=[CH:10]4)(=[O:20])=[O:19])=[CH:22][CH:23]=1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](CO)O3
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Agent: CN(C)c1ccccn1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(Br)cc1)O3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
A solution of [(2S)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]-methanol (4.0 g, 17.3 mmol), brosyl chloride (4.86 g, 19.0 mmol), dimethylamino pyridine (20 mg, 0.16 mmol) and triethylamine (3.62 mL, 25.8 mmol) in toluene (40 mL) was stirred at 60° C. for 6 h. The reaction mixture was cooled to room temperature then water (20 mL) was added. After 30 min, the two layers were separated. The organic layer was extracted with 8% NaHCO3 (20 mL) and H2O (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The solid obtained was dissolved in isopropyl alcohol (50 mL) and toluene (10 mL) at 80° C., cooled to room temperature over 1 h then filtered, washed with (5:1) IPA: toluene (2×5 mL) and dried in a vacuum oven to give 5.99 g (76.9%) of the title compound as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C(O)(=O)[CH2:12][C:13]([OH:15])=[O:14]>>[CH3:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[CH:12][C:13]([OH:15])=[O:14]
Reactant: Cc1ccc(C=O)c(C)c1
Reactant: O=C(O)CC(=O)O
Product: Cc1ccc(C=CC(=O)O)c(C)c1

Procedure:
According to the previously described general procedure (GP1), Knoevenagel condensation (75° C.; 3h30) between 2,4-dimethyl-benzaldehyde (10.000 g; 74.528 mmol) and malonic acid (14.735 g; 141.607 mmol) gave the product 3-(2,4-dimethyl-phenyl)-acrylic acid as a colorless solid (9.720 g; 74%). LC-MS: tR=0.86 min; [M+H]+: no ionisation.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:17]=[CH:18][C:19]4[N:20]([C:22]([C@@H:25]5[CH2:27][C@H:26]5[C:28]([O:30]CC)=[O:29])=[N:23][N:24]=4)[CH:21]=2)[CH:13]=[CH:12][O:11]3)=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[N:14]([C:15]=2[C:16]2[CH:17]=[CH:18][C:19]4[N:20]([C:22]([C@@H:25]5[CH2:27][C@H:26]5[C:28]([OH:30])=[O:29])=[N:23][N:24]=4)[CH:21]=2)[CH:13]=[CH:12][O:11]3)=[CH:4][CH:3]=1
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1nnc2ccc(-c3c(-c4ccc(F)cc4)nc4occn34)cn12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)[C@@H]1C[C@H]1c1nnc2ccc(-c3c(-c4ccc(F)cc4)nc4occn34)cn12
Temperature: 60 °C
Reaction time: 3 h
Yield: 99.2 %

Procedure:
A solution of (1R,2R)-ethyl 2-(6-(6-(4-fluorophenyl)imidazo[2,1-b]oxazol-5-yl)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)cyclopropanecarboxylate (0.15 g, 0.35 mmol; Example #K.1.1.17) in 1,4-dioxane (10 mL) was treated with 1N NaOH solution (6 mL, 6 mmol). The reaction mixture was stirred at about 60° C. for about 3 h. The organic solvent was removed under reduced pressure. The aqueous layer was acidified to about pH 6 using 1N HCl. The precipitate was filtered, dried in a heated vacuum oven at about 60° C., to give the title compound (0.140 g, 99%) LC/MS (Table 1, Method a) Rt, =1.72 min; MS m/z: 404.1 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[C:16]([O:17][CH2:18][CH3:19])=[CH:15][C:12]([CH:13]=[O:14])=[C:11]([N+:20]([O-:22])=[O:21])[CH:10]=1)C1C=CC=CC=1.Cl>C(O)(=O)C>[CH2:18]([O:17][C:16]1[C:9]([OH:8])=[CH:10][C:11]([N+:20]([O-:22])=[O:21])=[C:12]([CH:15]=1)[CH:13]=[O:14])[CH3:19]
Reactant: CCOc1cc(C=O)c([N+](=O)[O-])cc1OCc1ccccc1
Agent: Cl
Solvent: CC(=O)O
Product: CCOc1cc(C=O)c([N+](=O)[O-])cc1O

Procedure:
4-Benzyloxy-5-ethoxy-2-nitro-benzaldehyde (23 g) was dissolved in acetic acid (93 ml) and concentrated hydrochloric acid (10 ml). The reaction solution was refluxed for 24 hours. Then the solution was evaporated to dryness and the residue was dissolved in diethyl ether. The product was extracted into 1M sodium hydroxide and acidified with 6M hydrochloric acid. The resultant solid was filtered and dried under vacuum.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][N:6]1[C@H:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][C@H:8]([CH2:18][CH2:19][C:20](=O)[CH3:21])[C:7]1=[O:23])[CH3:2].[NH2:25][C:26]1[C:31]([CH:32]=O)=[CH:30][CH:29]=[CH:28][N:27]=1.N1CCC[C@H]1C(O)=O>C(O)C>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][N:6]1[C@H:10]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:9][C@H:8]([CH2:18][CH2:19][C:20]2[CH:21]=[CH:32][C:31]3[C:26](=[N:27][CH:28]=[CH:29][CH:30]=3)[N:25]=2)[C:7]1=[O:23])[CH3:2]
Reactant: Nc1ncccc1C=O
Reactant: CCOC(=O)CN1C(=O)[C@@H](CCC(C)=O)C[C@H]1Cc1ccccc1
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CCOC(=O)CN1C(=O)[C@@H](CCc2ccc3cccnc3n2)C[C@H]1Cc1ccccc1

Procedure:
A mixture of 12-5 (230 mg, 0.6940 mmol), 1-4, (2-amino-3-formylpyridine, 110 mg, 0.9022 mmol) and proline (80 mg, 0.6940 mmol) in absolute ethanol (10 mL) was heated at reflux for 18 h. Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 70:28:2 chloroform/ethyl acetate/MeOH) to give 12-6 as a yellow oil.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:13][O:12][CH:10]1O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C=O)C.O[Br:38]>ClCCl>[CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:13][O:12][CH:10]1[Br:38])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OBr
Reactant: OC1OC[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: BrC1OC[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2,3,4-tri-O-benzyl-xylopyranose was dissolved in dry dichloromethane (50 mL) and dry DMF (3.0 mL) was added. The reaction mixture was cooled at 0° C. and added dropwise oxayl bromide (1.4 mL). The reaction mixture was stirred for 1 hour at 0° to 5° C. and then diluted with dichloromethane (250 mL), washed with water (2×250 mL), dried over Na2SO4, filtered and evaporated to provide the title compound. The yield was quantitative for this step.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([O:9][CH:10]2[CH2:15][C:14]([CH3:17])([CH3:16])[NH:13][C:12]([CH3:19])([CH3:18])[CH2:11]2)=[O:8])=[CH:5][CH:4]=1.[NH2:22][OH:23]>>[CH3:16][C:14]1([CH3:17])[CH2:15][CH:10]([O:9][C:7]([C:6]2[CH:20]=[CH:21][C:3]([CH2:2][N:22]([CH2:2][C:3]3[CH:4]=[CH:5][C:6]([C:7]([O:9][CH:10]4[CH2:15][C:14]([CH3:17])([CH3:16])[NH:13][C:12]([CH3:19])([CH3:18])[CH2:11]4)=[O:8])=[CH:20][CH:21]=3)[OH:23])=[CH:4][CH:5]=2)=[O:8])[CH2:11][C:12]([CH3:19])([CH3:18])[NH:13]1
Reactant: CC1(C)CC(OC(=O)c2ccc(CCl)cc2)CC(C)(C)N1
Reactant: NO
Product: CC1(C)CC(OC(=O)c2ccc(CN(O)Cc3ccc(C(=O)OC4CC(C)(C)NC(C)(C)C4)cc3)cc2)CC(C)(C)N1

Procedure:
from 2,2,6,6-tetramethylpiperidin-4-yl 4-chloromethylbenzoate and hydroxylamine
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.ClCCl.[N:21]1([C:27]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:28]=2[NH2:29])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>O>[N:21]1([C:27]2[CH:33]=[CH:32][C:31]([C:34]([F:36])([F:37])[F:35])=[CH:30][C:28]=2[NH:29][C:2](=[O:9])[C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: O=C(Cl)c1ccncc1
Reactant: Nc1cc(C(F)(F)F)ccc1N1CCCCC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1cc(C(F)(F)F)ccc1N1CCCCC1)c1ccncc1
Yield: 86.3 %

Procedure:
Isonicotinoyl chloride hydrochloride (6.48 g, 36.4 mmol, commercially available product) and triethylamine (5.57 ml, 54.6 mmol) were sequentially added at 0° C. to a dichloromethane (10 ml) solution of 2-(1-piperidinyl)-5-(trifluoromethyl)aniline (4.45 g, 18.2 mmol) obtained as described in Referential Example 1-2B. The mixture was stirred for half an hour. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (200 g, hexane/ethyl acetate=1/1) and recrystallization. Thus, N-[2-(1-piperidinyl)-5-(trifluoromethyl) phenyl]isonicotinamide (SRPIN-1, GIF-0340) (5.49 g, 86.3%) was yielded as a colorless solid.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][C:20]1[O:21][C:22]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)=[C:23]([C:25](O)=[O:26])[N:24]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:25]([C:23]3[N:24]=[C:20]([CH3:19])[O:21][C:22]=3[C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)=[O:26])[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Reactant: Cc1ccc(-c2oc(C)nc2C(=O)O)cc1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)c3nc(C)oc3-c3ccc(C)cc3)cn2)o1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and 2-methyl-5-p-tolyl-oxazole-4-carboxylic acid.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]([O:11]CC)=[O:10])[CH:4]=1)[CH3:2].[OH-].[Na+]>C(O)C.O>[CH2:1]([C:3]1[N:7]([CH3:8])[N:6]=[C:5]([C:9]([OH:11])=[O:10])[CH:4]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(CC)n(C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCc1cc(C(=O)O)nn1C

Procedure:
Ethyl 5-ethyl-1-methylpyrazole-3-carboxylate (6.86 g) in ethanol (70 ml) was treated with sodium hydroxide (1.58 g) in water (30 ml) and heated under reflux for 6 h. The solution was concentrated and the aqueous phase washed with ethyl acetate before adding dichloromethane (50 ml). The solution was acidified with 5M hydrochloric acid, and the mixture exhaustively extracted with dichloromethane. The remaining undissolved solid was filtered off suspended in water and the pH adjusted to 6 with saturated sodium hydrogen carbonate. The solution was again extracted with dichloromethane. The combined organic layers were dried over anhydrous magnesium sulphate and concentrated to give the title compound as a white solid. (2.72 g, 47%); (Found: M+, 154.0742. C7H10N2O2 requires M, 154.0742); nmax (CH2Cl2) 3689 and 1760 cm−1; dH(CDCl3) 1.30 (3H, t, J7.4 Hz), 2.64 (2H, q, J7.4 Hz), 3.88 (3H, s) and 6.65 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[CH:23][CH:24]=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.O[C:27]1[CH:36]=[CH:35][C:30]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:28]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[CH3:34][O:33][C:31](=[O:32])[C:30]1[CH:35]=[CH:36][C:27]([O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:22]=[CH:23][CH:24]=[CH:25][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:28][CH:29]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2ccccc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Product: COC(=O)c1ccc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3ccccc32)cc1

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-benzoimidazol-1-yl]-2-cyclohexyl-ethanol and methyl 4-hydroxy-benzoate (commercially available) and replacing di-ethyl azodicarboxylate by di-tert-butyl azodicarboxylate. White solid (58%). MS (Turbo Spray): m/z=489.3 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:29]=[CH:28][C:17]4[O:18][CH2:19][C:20]5[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=5[CH:22](O)[C:16]=4[CH:15]=3)=[N:9]2)=[CH:4][CH:3]=1.[SH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34]>>[C:33]([CH2:32][CH2:31][S:30][CH:22]1[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[CH2:19][O:18][C:17]2[CH:28]=[CH:29][C:14]([O:13][CH2:12][C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=3)=[CH:15][C:16]1=2)([OH:35])=[O:34]
Reactant: O=C(O)CCS
Reactant: OC1c2ccccc2COc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc21
Product: O=C(O)CCSC1c2ccccc2COc2ccc(OCc3ccc4ccc(Cl)cc4n3)cc21

Procedure:
2-(7-Chloroquinolin-2-yl)methoxy-11-hydroxy-6,11-dihydrodibenz[b,e]oxepine and 3-mercaptopropionic acid were used and reacted in the same manner as in Example 1 to obtain the title compound.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.[CH3:13][N:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[NH2:15]>Cl.C(O)C>[CH3:13][N:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[N:15]=[CH:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1
Reactant: O=Cc1ccc2ccccc2c1
Reactant: CN(N)c1ccccc1
Agent: Cl
Solvent: CCO
Product: CN(N=Cc1ccc2ccccc2c1)c1ccccc1

Procedure:
3.1 g of 2-naphthaldehyde and 2.4 g of 1-methyl-1-phenylhydrazine were added to 50 ml of ethanol. To the mixture, two or three drops of 1 N hydrochloric acid were added. The mixture was heated and refluxed for about one hour. The reaction mixture was cooled and the crystals then separated, which were then collected on a suction funnel. The thus obtained crude 2-naphthaldehyde 1-methyl-1-phenylhydrazone was recrystallized from ethyl acetate. The yield was 3.5 g (67.3%) of white needle-like crystals which melt at 172.5°-174.5° C.
Reaction SMILES: COP([CH2:7][C:8](=[O:17])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)OC.[OH-].[Na+].[C:20]([O:23][CH2:24][CH3:25])(=[O:22])[CH3:21]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.ClCCl>[O:22]=[C:20]1[O:23][CH:24]2[CH2:7][CH2:8][CH:9](/[CH:10]=[CH:7]/[C:8](=[O:17])[CH2:9][CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:25]2[CH2:21]1
Reactant: COP(=O)(CC(=O)CCc1ccccc1)OC
Reactant: CCOC(C)=O
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: O=C(/C=C/C1CCC2OC(=O)CC12)CCc1ccccc1
Reaction time: 0.67 h

Procedure:
To a solution of dimethyl(2-oxo-4-phenylbutyl)phosphonate (1.40 g, 5.46 mmol), [3aα,4β,5α]-hexahydro-2-oxo-cyclopenta[b]furan-4-carboxaldehyde (4) (0.765 mg, 4.96 mmol) and triethylbenzyl ammonium chloride (110 mg 0.48 mmol) in dichloromethane (10 mL) at room temperature was added a 10M aqueous solution sodium hydroxide (0.55 mL, 5.5 mmol) and the resulting mixture was vigorously stirred for 40 min. The reaction was then diluted with ethyl acetate and washed with water (2×10 mL) and brine (1×10 mL) and concentrated in vacuo. Column chromatography (1:2 ethyl acetate-hexanes through silica gel) provided the title compound 5 as a clear, colorless oil (1.29 g, 4.53 mmol). Rf =0.42 in ethyl acetate-hexanes, 1:1.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.[H-].[Na+].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C1COCC1>[CH2:19]([C:5]1([CH2:13][CH2:14][CH2:2][CH2:3][CH2:4][CH2:12][CH2:11][CH3:10])[C:4]2[CH:3]=[C:2]([Br:1])[CH:14]=[CH:13][C:12]=2[C:11]2[C:6]1=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: Brc1ccc2c(c1)Cc1cc(Br)ccc1-2
Reactant: CCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCC1(CCCCCCCC)c2cc(Br)ccc2-c2ccc(Br)cc21
Temperature: 60 °C
Yield: 150.4 %

Procedure:
To a solution of 28.5 g (88 mmol) 2,7-dibromofluorene in 800 mL THF was added 8.8 g (220 mmol) sodium hydride (60%) in several portions at room temperature. The mixture was heated at 60° C. and 43 g (220 mmol) bromooctane in 200 mL THF was added dropwisely into the mixture and refluxed overnight. The mixture was concentrated and diluted with water, and then extracted with diethyl ether. After washing with brine, the ether solution was dried over anhydrous MgSO4 and the ether was then removed by evaporation. This crude solid was purified by a silica chromography with hexane and recrystallized from ethanol to give white solid (36.3 g, yield 75.3%, mp. 52˜54° C.). 1H NMR (500 MHz, CDCl3), δ (ppm): 7.51 (2H, d), 7.44 (2H, d), 7.41 (2H, s), 1.89 (4H, m), 1.02˜1.20 (20H, m), 0.81 (6H, t), 0.56 (4H, m).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[N:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([O:22][Si](C)(C)C)[C:20]#N)[CH:14]=1.BrC[C:29]1[CH:41]=[CH:40][C:32]([CH:33]=[CH:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:31][CH:30]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[Na+]>O1CCCC1.CCCCCC>[O:22]=[C:19]([C:15]1[CH:14]=[N:13][CH:18]=[CH:17][CH:16]=1)[CH2:20][C:29]1[CH:41]=[CH:40][C:32]([CH:33]=[CH:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:31][CH:30]=1
Reactant: CCOC(=O)C=Cc1ccc(CBr)cc1
Reactant: C[Si](C)(C)OC(C#N)c1cccnc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Product: CCOC(=O)C=Cc1ccc(CC(=O)c2cccnc2)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 43.6 %

Procedure:
In argon atmosphere, 4.88 g of diisopropylamine was dissolved in 100 ml of dry tetrahydrofuran, followed by dropwise addition of 1.55M n-butyl lithium in 31.1 ml of hexane in solution at -20° C. After stirring at the same temperature for 10 minutes and then cooling down to -78° C., 9.96 g of 2-(3-pyridyl)-2-(trimethylsiloxy)acetonitrile dissolved in 100 ml of dry tetrahydrofuran was added dropwise. After stirring at the same temperature for one hour, 12.99 g of ethyl 4-bromomethylcinnamate dissolved in 100 ml of dry tetrahydrofuran was added, followed by gradual temperature rise from -78° C. to room temperature and stirring overnight. 1.0M Tetra-n-butylammonium fluoride in 48.3 ml of tetrahydrofuran in solution was added and stirred for 3.5 hours. To the reaction mixture was added saturated aqueous sodium chloride solution, and the organic phase was separated, which was then extracted with ethyl acetate from aqueous phase. The organic phases were combined and washed with saturated aqueous sodium chloride solution, followed by drying over magnesium sulfate. Then, the solvent was distilled off under reduced pressure. The residue obtained was subjected to chromatography on a silica gel column, and 6.21 g of ethyl 4-[2-oxo-2-(3-pyridyl)ethyl]cinnamate was obtained from a fraction eluted with methanol-methylene chloride (2:98 v/v) .
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[N:15]=[C:14]([C:16]3[S:20][C:19]([NH:21][CH3:22])=[N:18][C:17]=3[CH3:23])[CH:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1.[F:24][C:25]([F:31])([F:30])[S:26](Cl)(=[O:28])=[O:27]>CC#N>[F:24][C:25]([F:31])([F:30])[S:26]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][C:10]2[N:15]=[C:14]([C:16]3[S:20][C:19]([NH:21][CH3:22])=[N:18][C:17]=3[CH3:23])[CH:13]=[CH:12][N:11]=2)[CH:4]=1)(=[O:28])=[O:27]
Reactant: CNc1nc(C)c(-c2ccnc(Nc3cccc(CN)c3)n2)s1
Reactant: O=S(=O)(Cl)C(F)(F)F
Solvent: CC#N
Product: CNc1nc(C)c(-c2ccnc(Nc3cccc(CNS(=O)(=O)C(F)(F)F)c3)n2)s1

Procedure:
By treatment of (3-aminomethyl-phenyl)-[4-(4-methyl-2-methylamino-thiazol-5-yl)-pyrimidin-2-yl]-amine with trifluoro-methanesulfonyl chloride. Yellow solid. Anal. RP-HPLC: tR=11.6 min (0-60% MeCN, purity ˜90%). 1H-NMR (CD3OD) δ: 2.53 (s, 3H, CH3), 2.97 (s, 3H, CH3), 4.39 (s, 2H, CH2), 6.94 (d, 1H, J=5.5 Hz, pyrimidinyl-H), 7.01 (d, 1H, J=7.5 Hz, Ph-H), 7.31 (d, 1H, J=8.0 Hz, Ph-H), 7.60 (d, 1H, J=7.5 Hz, Ph-H), 7.67 (s, 1H, Ph-H), 8.28 (d, 1H, J=5.5 Hz, pyrimidinyl-H). MS (ESI+) m/z 459.33 [M+H]+ (C17H17F3N6O2S requires 458.48).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.C(=O)([O-])O.[Na+].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].Cl>O1CCCC1.O>[F:9][C:4]1[CH:3]=[C:2]([NH:1][C:16](=[O:17])[O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:7]=[CH:6][C:5]=1[OH:8]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1ccc(O)c(F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(O)c(F)c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.9 %

Procedure:
To a suspension of 4-amino-2-fluorophenol (60 g, 472 mmol) in tetrahydrofuran/water (=1/1, 600 mL) was added sodium hydrogen carbonate (43.6 g, 519 mmol), and benzyl chloroformate (74.1 mL, 519 mmol) was added dropwise at 0° C. The mixture was stirred at room temperature for 16 hr, 2N hydrochloric acid (150 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, the residue was washed with hexane/diethyl ether (=1/1) and collected by filtration to give the title compound (82.5 g, 67%). The solvent of the filtrate was evaporated under reduced pressure, and the residue was washed with hexane/diethyl ether (=1/1) and collected by filtration to give the title compound (17.7 g, 14%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[C:10](=[CH:13]N(C)C)[CH:9]([CH3:17])[C:8](=[O:18])[N:7]([CH3:19])[C:6]=2[CH:20]=1.[NH:21]([C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=1)[C:22]([NH2:24])=[NH:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:23]=[C:22]([NH:21][C:25]4[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=4)[N:24]=[CH:13][C:10]=3[CH:9]([CH3:17])[C:8](=[O:18])[N:7]([CH3:19])[C:6]=2[CH:20]=1
Reactant: CC1C(=O)N(C)c2cc(Cl)ccc2C(=O)C1=CN(C)C
Reactant: N=C(N)Nc1ccc(C(=O)O)cc1
Product: CC1C(=O)N(C)c2cc(Cl)ccc2-c2nc(Nc3ccc(C(=O)O)cc3)ncc21

Procedure:
In a manner similar to that described for method I, 8-chloro-4-dimethylaminomethylene-1,3-dimethyl-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-o) and 4-guanidinobenzoic acid were converted to I-68 (6%) after purification by C-18 RP LC-MS chromatography: HRMS Calcd. for C21H17ClN4O3: 409.1067, Found 409.1052.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[F:13]>CO.[B-](F)(F)(F)F.CC[C@H]1P(C2C(P3[C@H](CC)CC[C@H]3CC)=CC=CC=2)[C@H](CC)CC1.C1[CH][CH]CC[CH][CH]C1.[Rh]>[CH3:1][O:2][C:3](=[O:22])[C@H:4]([NH:14][C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH2:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[F:13]
Reactant: COC(=O)C(=Cc1cc(F)ccc1F)NC(=O)OC(C)(C)C
Agent: [Rh]
Agent: CC[C@@H]1CC[C@@H](CC)P1c1ccccc1P1[C@H](CC)CC[C@H]1CC
Agent: F[B-](F)(F)F
Solvent: CO
Product: COC(=O)[C@@H](Cc1cc(F)ccc1F)NC(=O)OC(C)(C)C
Reaction time: 20 h
Yield: 98.1 %

Procedure:
To a solution of 2-tert-butoxycarbonylamino-3-(2,5-difluorophenyl)-acrylic acid methyl ester (4.9 g, 15.7 mmol) in methanol (49 mL) is added (−)-1,2-bis((2R,5R)-2,5-diethylphospholano)benzene(cyclooctadiene)rhodium(I) tetrafluoroborate (113 mg, 0.15 mmol), and is shaken for 20 h under an atmosphere of H2 at 75 psi. The suspension is filtered through Celite to remove catalyst and concentrated under reduced pressure to afford a light yellow solid. The solid is triturated in cold methanol to afford the title compound as a white solid (4.75 g, 15.4 mmol)