Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]2[O:13][C:14](=[O:32])[N:15]([CH:17]3[CH2:23][CH:22]4[N:24](C(OC(C)(C)C)=O)[CH:19]([CH2:20][CH2:21]4)[CH2:18]3)[N:16]=2)[C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[NH:33][C:34](=[O:43])[O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:11]=[C:10]([C:12]2[O:13][C:14](=[O:32])[N:15]([CH:17]3[CH2:18][CH:19]4[NH:24][CH:22]([CH2:21][CH2:20]4)[CH2:23]3)[N:16]=2)[C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[NH:33][C:34](=[O:43])[O:35][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(n1nc(-c3cc(Cl)c(NC(=O)OCc4ccccc4)c4c3OCCO4)oc1=O)C2
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1c(Cl)cc(-c2nn(C3CC4CCC(C3)N4)c(=O)o2)c2c1OCCO2)OCc1ccccc1
Reaction time: 19 h

Procedure:
13.75 g (0.022 mol) of phenylmethyl [6-chloro-8-[4-[8-[(1,1-dimethylethoxy)carbonyl]-8-azabicyclo[3.2.1]oct-3-yl]-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl]-2,3-dihydro-1,4-benzodioxin-5-yl)carbamate dissolved in 150 ml of chloroform are introduced into a 500 ml three-necked round-bottomed flask, 17.05 ml (0.221 mol) of trifluoroacetic acid are added slowly, over 20 min, and the mixture is stirred for 19 h. A further 17.05 ml (0.221 mol) of trifluoroacetic acid are added and the mixture is stirred for 5 h.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[C:12]([O:14]C)=[O:13].Cl.O>CO.C1COCC1.[OH-].[Na+]>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[C:12]([OH:14])=[O:13]
Reactant: COC(=O)c1c[nH]c2ccc(C(F)(F)F)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1c[nH]c2ccc(C(F)(F)F)cc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 74.6 %

Procedure:
To a solution of 1.01 g of methyl 5-(trifluoromethyl)-1H-indole-3-carboxylate in 12 mL of MeOH and 12 mL of THF, 6 mL of 1 M aqueous sodium hydroxide solution was added, and the resulting mixture was stirred at 80° C. overnight. To the solution, 3 mL of 1 M aqueous sodium hydroxide solution was further added, and the resulting mixture was stirred at 80° C. for 6 hours. To the solution, 9 mL of 1 M hydrochloric acid and 60 mL of water were added, the precipitated solid was collected by filtration, and the solid obtained was purified by silica gel column chromatography (chloroform-methanol=100:1 →150:1→20:1) and then washed with hexane to obtain 0.71 g of 5-(trifluoromethyl)-1H-indole-3-carboxylic acid as a cream-colored solid. FAB−: 228
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10]CC)=[O:9])[N:6]=1.C(Cl)(Cl)Cl.[C:17](Cl)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>O.C(N(CC)CC)C>[C:17]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[N:6]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)Cc1csc(N)n1
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(O)Cc1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reaction time: 3 h
Yield: 66.5 %

Procedure:
A mixture of 930 mg of ethyl 2-amino-4-thiazolyl-acetate, 25 ml of dry chloroform, 0.8 ml of triethylamine and 1.65 g of trityl chloride was stirred for 3 hours and then 3 ml of N hydrochloric acid and 5 ml of water were added thereto. The mixture was stirred and decanted and 5 ml of N hydrochloric acid and 5 ml of water were again added. The mixture was decanted and the organic phase was dried and evaporated to dryness. The residue was added to 10 ml of dioxane and 6 ml of N sodium hydroxide and the mixture was stirred at 50° C and then stood overnight at room temperature. The mixture was evaporated to dryness and the residue was diluted with water. The solution was washed with ether and was acidified with 0.5 ml of acetic acid. The mixture was allowed to crystallize and was then vacuum filtered to obtain 1.33 g of 2-tritylamino-4-thiazolyl-acetic acid which after empasting with ether melted at 220° C.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[C:24]([CH3:30])=[N:25][N:26]([CH2:28][CH3:29])[CH:27]=4)=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:31].[CH3:32][N:33]1[CH2:38][CH2:37][N:36]([C:39]2[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=2)[CH2:35][CH2:34]1>C1COCC1>[CH3:32][N:33]1[CH2:34][CH2:35][N:36]([C:39]2[CH:44]=[CH:43][C:42]([NH:45][CH:2]=[C:3]3[C:11]4[C:6](=[CH:7][C:8]([C:12]([C:14]5[CH:15]=[C:16]([NH:20][C:21]([C:23]6[C:24]([CH3:30])=[N:25][N:26]([CH2:28][CH3:29])[CH:27]=6)=[O:22])[CH:17]=[CH:18][CH:19]=5)=[O:13])=[CH:9][CH:10]=4)[NH:5][C:4]3=[O:31])=[CH:41][CH:40]=2)[CH2:37][CH2:38]1
Reactant: CCn1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CO)c2)c(C)n1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: C1CCOC1
Product: CCn1cc(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4=CNc3ccc(N4CCN(C)CC4)cc3)c2)c(C)n1
Temperature: 65 °C
Reaction time: 24 h
Yield: 58 %

Procedure:
A small screw cap test tube was charged with 1-Ethyl-3-methyl-1H-pyrazole-4-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (prepared below, 100 mg, 0.2401 mmol) and THF (2.5 mL). To the resulting solution was added 4-(4-methyl-piperazin-1-yl)-phenylamine (45.7 mg, 0.240 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The solid residue was redissolved in EtOAc (˜5 mL) and Hexane (˜40 mL) was added to the solution. The precipitate that formed was collected by filtration and washed with 0° C. iPrOH (10 mL) to afford the title compound in 58% yield (0.0821 g, 0.139 mmol).
Reaction SMILES: [OH:1][CH:2]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][CH:7]=[C:8]2[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])[CH3:3].[C:22](OC(=O)C)(=[O:24])[CH3:23]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[C:22]([O:1][CH:2]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][CH:7]=[C:8]2[C:12]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:13])[CH3:3])(=[O:24])[CH3:23]
Reactant: CC(O)C1C(=O)N2C(C(=O)OCc3ccccc3)=CCC12
Reactant: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)OC(C)C1C(=O)N2C(C(=O)OCc3ccccc3)=CCC12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Benzyl 6-(α-Hydroxyethyl)-7-oxo-1-azabicyclo [3.2.0]hept-2-ene-2-carboxylate (I) (18 mg) is dissolved in 1 ml of pyridine (Py) and 0.2 ml of acetic anhydride (Ac2O). The mixture is stirred at 25° C. for 3 hours and then evaporated to dryness to give oily residue. The residue is dissolved in 0.2 ml chloroform and chromatographed on two 20×20 cm, 250μ silica gel TLC plates (Rf 0.56, 20% ethylacetate/chloroform) to give 4 mg. of the desired product (II) which shows nmr (CDCl3, 60 MHZ) resonances at 2.02 (s, OAc), 6.48 (t, vinyl proton) and 7.40 ppm (m, aromatic protons) and ir (CHCl3) carbonyl vibrations at 1780 (β-lactam) and 1740 cm-1 (esters).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].N1C=CC=CC=1.[F:13][C:14]([F:49])([F:48])[C:15]1[CH:16]=[C:17]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[CH2:18][N:19]([CH:25]1[CH2:31][CH2:30][CH2:29][NH:28][C:27]2[CH:32]=[C:33]([C:37]([F:40])([F:39])[F:38])[C:34]([CH3:36])=[CH:35][C:26]1=2)[C:20]1[NH:24][N:23]=[N:22][N:21]=1>ClCCl>[CH2:5]([O:4][C:2]([N:28]1[CH2:29][CH2:30][CH2:31][CH:25]([N:19]([CH2:18][C:17]2[CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=[C:15]([C:14]([F:13])([F:49])[F:48])[CH:16]=2)[C:20]2[NH:24][N:23]=[N:22][N:21]=2)[C:26]2[CH:35]=[C:34]([CH3:36])[C:33]([C:37]([F:39])([F:38])[F:40])=[CH:32][C:27]1=2)=[O:3])[CH3:6]
Reactant: Cc1cc2c(cc1C(F)(F)F)NCCCC2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn[nH]1
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)N1CCCC(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn[nH]2)c2cc(C)c(C(F)(F)F)cc21
Reaction time: 14 h
Yield: 20.5 %

Procedure:
Add ethyl chloroformate (0.24 mmol) and pyridine (0.24 mmol) to a dichloromethane (5 mL) solution of (3,5-bis-trifluoromethyl-benzyl)-(7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-(1H-tetrazol-5-yl)-amine (0.045 g, 0.08 mmol). After stirring 14 h, wash the reaction with 5% HCl (3 mL), water (3 mL) and brine (3 mL). Dry the organic portion over sodium sulfate and filter. Chromatograph the crude product, eluting with ethyl acetate/hexane (20-60%), to provide the title compound (0.01 g, 20%) as an oil: MS (ES+): 611 (M+H).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][NH:6][C:7](=[O:29])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:18][C:17]=2[CH3:28])=[CH:10][CH:9]=1.[OH-].[Na+].Cl>C1COCC1>[CH3:28][C:17]1[CH:18]=[C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:21][C:16]=1[CH2:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:30])=[O:2])=[O:29])=[CH:13][CH:12]=1
Reactant: COC(=O)CCNC(=O)c1ccc(OCc2ccc(-c3ccccc3)cc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(-c2ccccc2)ccc1COc1ccc(C(=O)NCCC(=O)O)cc1
Temperature: 70 °C
Yield: 25.7 %

Procedure:
A mixture of 3-[4-(3-methyl-biphenyl-4-ylmethoxy)-benzoylamino]-propionic acid methyl ester (0.17 g, 0.42 mmol) and 5M NaOH (2 mL) in THF (4 mL) is heated at 70° C. for 5 h. The mixture is acidified with 5M HCl, and extracted with EtOAc. The organics are washed with water and brine, and dried with MgSO4 to yield the title compound (42 mg, 26%). MS (ES): 390 (M+). The structure is also confirmed by 1H NMR.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:13][CH:14]=[CH:15][CH2:16][C:17]2[CH:22]=[C:21]([CH3:23])[C:20]([OH:24])=[C:19]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:18]=2)[CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[C:25]([C:19]1[CH:18]=[C:17]([CH2:16][CH2:15][CH2:14][CH2:13][C:7]2[CH:8]=[C:9]([CH3:12])[C:10]([OH:11])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=2)[CH:22]=[C:21]([CH3:23])[C:20]=1[OH:24])([CH3:26])([CH3:28])[CH3:27]
Reactant: Cc1cc(CC=CCc2cc(C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1cc(CCCCc2cc(C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
8.55 g (22.5 mmol) of 1,4-bis(3'-tert-butyl-5'-methyl-4'-hydroxyphenyl)but-2-ene in 100 ml of ethyl acetate are hydrogenated over 1 g of Pd/C (5%) at room temperature under atmospheric pressure. After 30 minutes, the uptake of hydrogen has ended. The reaction mixture is filtered over Celite and the resulting filtrate is concentrated. Crystallization of the crude product from acetonitrile gives 6.6 g (77% of theory) of 1,4-bis(3'-tert-butyl-5'-methyl-4'-hydroxyphenyl)butane of melting point 106°-107° C.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[CH3:6][C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1>C1COCC1>[CH3:5][O:4][N:3]([CH3:2])[C:11](=[O:12])[C:10]1[CH:14]=[CH:15][C:7]([CH3:6])=[CH:8][CH:9]=1
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CNOC
Agent: Cl
Solvent: C1CCOC1
Product: CON(C)C(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 100.9 %

Procedure:
To a mixture of N,O-dimethylhydroxylamine hydrochloride (8.20 g) in THF (dry) (75 mL) was added TEA (23.4 mL) at 0° C. After being stirred at 0° C. for 20 min, 4-methylbenzoyl chloride (10 g) in THF (dry) (20 mL) was added to the reaction mixture. The mixture was stirred at room temperature for 2 days. The mixture was quenched with water at room temperature and extracted with EtOAc. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give N-methoxy-N, 4-dimethylbenzamide (11.7 g) as a yellow oil. n-Butyllithium (1.6 M in hexane) (25.1 mL) was added dropwise to a mixture of 1,4-dibromobenzene (8.29 g) in THF (dry) (105 mL) at −78° C. for 10 min. The mixture was stirred at the same temperature under nitrogen for 30 min to form white precipitates. A solution of N-methoxy-N, 4-dimethylbenzamide (6 g) in THF (dry) (20 mL) was added to the reaction mixture at −78° C. and the mixture was stirred at the same temperature under nitrogen for 30 min and then at room temperature under a dry atmosphere with anhydrous calcium chloride tube overnight. The mixture was quenched with sat. NH4Cl aq. at room temperature and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with EtOAc in hexane) to give the title compound (7.18 g) as a pale yellow solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=2[CH:4]=[N:3]1.[Cl:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:16][N:17]=[C:18]=[O:19]>C1(C)C=CC=CC=1>[Cl:12][C:13]1[CH:14]=[C:15]([CH:20]=[CH:21][C:22]=1[Cl:23])[CH2:16][NH:17][C:18]([NH:11][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[N:3][N:2]2[CH3:1])=[O:19]
Reactant: O=C=NCc1ccc(Cl)c(Cl)c1
Reactant: Cn1ncc2c(N)cccc21
Solvent: Cc1ccccc1
Product: Cn1ncc2c(NC(=O)NCc3ccc(Cl)c(Cl)c3)cccc21
Temperature: 80 °C

Procedure:
1-Methyl-1H-indazol-4-amine (390 mg, 2.65 mmol) and 3,4-dichlorobenzyl isocyanate (0.39 mL, 2.65 mmol) were combined in toluene (20 mL) and heated overnight at 80° C. The mixture was allowed to cool to ambient temperature, filtered, and the filter cake was allowed to air-dry to provide the title compound. The corresponding hydrochloride salt was prepared by treatment with methanolic HCl. 1H NMR (300 MHz, d6-DMSO) δ 8.86 (s, 1H), 8.06 (d, J=1.0 Hz, 1H), 7.59-7.64 (m, 3H), 7.33 (m, 1H), 7.25 (m, 1H), 7.15 (m, 1H), 6.91 (t, J=6.0 Hz), 4.35 (d, J=5.8 Hz, 2H), 3.99 (s, 3H); MS (ESI+) m/z 349/351 (M+H, 35Cl/37Cl)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH2:33]Cl)[CH:26]=3)[CH:16]=2)=[CH:11][C:10]=1[CH3:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:36]1[CH:40]=[CH:39][N:38]=[C:37]1[Na]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][CH2:33][N:36]4[CH:40]=[CH:39][N:38]=[CH:37]4)[CH:26]=3)[CH:16]=2)=[CH:11][C:10]=1[CH3:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(-c2cn(-c3cccc(OCCCl)c3)c3ncnc(N)c23)ccc1OCc1ccccc1
Reactant: [Na]c1ncc[nH]1
Solvent: CN(C)C=O
Product: Cc1cc(-c2cn(-c3cccc(OCCn4ccnc4)c3)c3ncnc(N)c23)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
0.7 g of 5-(4-benzyloxy-3-methylphenyl)-7-[3-(2-chloro-1-ethoxy)phenyl]-4-aminopyrrolo-[2,3-d]pyrimidine and 0.2 g of imidazolyl sodium are heated to 80° C. in 30 ml of DMF and the mixture is stirred for 5 h. It is then cooled to RT and concentrated. After chromatography on silica gel, 5-(4-benzyloxy-3-methylphenyl)-7-[3-(2-(1-imidazolyl)ethoxy)phenyl]-4-amino-pyrrolo[2,3-d]pyrimidine having an m.p. of 158°-160° C. is obtained.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][CH2:15][OH:16])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:17](Cl)([Cl:19])=[O:18]>C1(C)C=CC=CC=1>[Cl:19][C:17]([O:16][CH2:15][CH2:14][CH:12]1[C:13]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:18]
Reactant: O=C(Cl)Cl
Reactant: OCCC1c2ccccc2-c2ccccc21
Solvent: Cc1ccccc1
Product: O=C(Cl)OCCC1c2ccccc2-c2ccccc21
Reaction time: 0.5 h

Procedure:
N-[9H-(Fluorenyl-9-ethoxycarbonyl)]amino-4-benzoic acid was prepared from a solution of 2-(9-fluorenyl) ethanol (1.5 g, 7.1 mmol) in 10 ml of toluene to which was added dropwise with stirring a solution of phosgene in toluene (12.4 ml, 1.93M). After 0.5 hours, the solution was put under vacuum to remove excess phosgene, and concentrated to yield 2-(9-fluorenyl)ethyl chloroformate. This was then dissolved in 10 ml of dioxane and add to a solution of 4-aminobenzoic acid (1.0 g, 7.3 mmol) in 15 ml water. After 5 hours, the dioxane was evaporated, the solution diluted with an equal amount of water, rendered basic with sodium carbonate solution, and filtered to remove insoluble materials. Acidification with 10% HCl yielded a white precipitate, which was filtered and dried. Crystallization from aqueous DMF gave a white solid (1.22 g, 46%), mp 202° C. IR(KBr) 3342, 2964, 2666, 2543, 2363, 1699, 1676, 1609, 1594, 1524, 1509, 1477, 1414, 1313, 1293, 1266, 1177, 1069, 1049, 938, 853, 768, 750, 735 cm-1. 1H NMR (300 MHz, DMSO) δ 2.3(q, 2H, J=7.0), 400(t, 2H, J=7.0), 4.12(t, 1H, J=6.0), 7.29-7.88(m, 13H, 9.97(s, 1H). Anal. calcd for C23H19NO4 0.25H2O: C, 73:10; H, 5.20; N, 3.71. Found: C, 73.32; H, 5.23; H, 3.70.
Reaction SMILES: O=C1CCC(=O)N1[C:8]1[C:16]2[C:11](=[CH:12][C:13]([C:26]([O-])=[O:27])=[C:14]([O:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[F:25])[CH:15]=2)[N:10]([CH2:29][C:30]([F:33])([CH3:32])[CH3:31])[N:9]=1.[NH2:34][C@H:35]1[CH2:40][CH2:39][CH2:38][NH:37][C:36]1=[O:41]>ClCCl.C(OCC)(=O)C>[F:25][C:19]1[CH:20]=[C:21]([F:24])[CH:22]=[CH:23][C:18]=1[O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][C:13]=1[C:26]([NH:34][C@H:35]1[CH2:40][CH2:39][CH2:38][NH:37][C:36]1=[O:41])=[O:27])[N:10]([CH2:29][C:30]([F:33])([CH3:31])[CH3:32])[N:9]=[CH:8]2
Reactant: N[C@H]1CCCNC1=O
Reactant: CC(C)(F)Cn1nc(N2C(=O)CCC2=O)c2cc(Oc3ccc(F)cc3F)c(C(=O)[O-])cc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(F)Cn1ncc2cc(Oc3ccc(F)cc3F)c(C(=O)N[C@H]3CCCNC3=O)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 1000.8 %

Procedure:
To a solution of 2,5-dioxopyrrolidin-1-yl-5-(2,4-difluorophenoxy)-1-(2-fluoro-2-methylpropyl)-1H-indazole-6-carboxylate (100 mg, 0.217 mmol; prepared according to Example 26) in dichloromethane (1 mL) was added (S)-3-aminopiperidin-2-one (prepared according to Example 3; 521 mg, 4.56 mmol), and the reaction mixture was allowed to stir overnight at ambient temperature. The reaction mixture was diluted with ethyl acetate and washed with 1M hydrochloric acid, 1M sodium hydroxide, saturated sodium bicarbonate, and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel, eluting with 50% acetone/hexanes to yield (S)-5-(2,4-difluorophenoxy)-1-(2-fluoro-2-methylpropyl)-N-(2-oxopiperidin-3-yl)-1H-indazole-6-carboxamide (Ik) (1.00 g, 99%). Mass spec: 461 (M+1). 1H NMR (CDCl3) δ 8.53 (s, 1H), 8.40 (s, 1H), 7.90 (s, 1H), 7.15 (m, 1H), 7.03 (s, 1H), 6.99 (m, 1H), 6.90 (m, 1H), 6.09 (br, 1H), 4.56 (d, 1H), 4.53 (m, 1H), 3.36 (m, 2H), 2.70 (m, 1H), 1.97 (m, 1H), 1.66 (m, 1H), 1.39 (d, 3H), 1.38 (d, 3H).
Reaction SMILES: [H-].[Na+].[C:3]1([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11](=[O:19])[CH2:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:20]I>C1COCC1>[CH3:20][N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:10][C:11]1=[O:19]
Reactant: CI
Reactant: O=C1CC(c2ccccc2)c2ccccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1C(=O)CC(c2ccccc2)c2ccccc21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a suspension of NaH (1.2 eq., 0.537 g of 60% dispersion in mineral oil) in THF (50 mL) under N2 at 0° C. was added the product from Step A (1.0 eq., 2.50 g) in THF (50 mL) via cannula over a period of 5 minutes. The resulting pale yellow mixture was stirred at 0° C. for 10 minutes, then MeI (2.0 eq., 1.39 mL) was added. The opaque yellow mixture was allowed to slowly (ice bath not removed) warm to ambient temperature with stirring for 15 hours. 1M Aq. HCl (50 mL) and EtOAc (250 mL) were added and the phases partitioned. The organic phase was washed with dilute NaHCO3 (1×100 mL), brine (1×100 mL), then dried over MgSO4, filtered, concentrated, and the residue purified by flash chromatography eluting with CH2Cl2/EtOAc (19:1 gradient to 15:1) to provide 1-methyl-4-phenyl-3,4-dihydrocarbostyril.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][CH:6]([CH:9]=[O:10])[CH2:5][CH2:4]1)#[CH:2].[SH:11][CH2:12][CH:13]([CH:16]([CH3:18])[CH3:17])[CH2:14]O>>[C:1]([CH:3]1[CH2:8][CH2:7][CH:6]([CH:9]2[S:11][CH2:12][CH:13]([CH:16]([CH3:18])[CH3:17])[CH2:14][O:10]2)[CH2:5][CH2:4]1)#[CH:2]
Reactant: CC(C)C(CO)CS
Reactant: C#CC1CCC(C=O)CC1
Product: C#CC1CCC(C2OCC(C(C)C)CS2)CC1

Procedure:
Using the method described in Example 1(v) and starting from 4-ethynyl cyclohexanecarboxaldehyde (European Patent Application No. 88305107) and 2-mercaptomethyl-3-methylbutan-1-ol, 2-(4-ethynylcyclohexyl)-5-isopropyl-1,3-oxathiane was obtained as a mixture of isomers.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=2)=[CH:6][CH:5]=1)([O-])=O>CO.[Pt]>[F:18][C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[O:11][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(COc2cccc(F)c2)cc1
Agent: [Pt]
Solvent: CO
Product: Nc1ccc(COc2cccc(F)c2)cc1
Yield: 112.8 %

Procedure:
g (4 mmol) of 1-Nitro-4-(3-fluoro-phenoxymethyl)-benzene in 40 ml methanol is treated with 0.25 g of 5% platinum on charcoal and hydrogenated for 1 h at room temperature and normal pressure. The catalyst is filtered and the solution evaporated to yield 0.98 g of the crude title compound as yellow oil. MS: m/e=218.3 (M++H).
Reaction SMILES: [C:1]12([CH2:11][O:12][C:13]3[C:25](/[CH:26]=[CH:27]/[CH3:28])=[CH:24][C:16]([C:17]([O:19]C(C)(C)C)=[O:18])=[C:15]([F:29])[CH:14]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.FC(F)(F)C(O)=O>ClCCl>[C:1]12([CH2:11][O:12][C:13]3[C:25](/[CH:26]=[CH:27]/[CH3:28])=[CH:24][C:16]([C:17]([OH:19])=[O:18])=[C:15]([F:29])[CH:14]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: C/C=C/c1cc(C(=O)OC(C)(C)C)c(F)cc1OCC12CC3CC(CC(C3)C1)C2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C/C=C/c1cc(C(=O)O)c(F)cc1OCC12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Following the procedure as described in Example 305/306 Step 2 and making variations as required to replace tert-butyl 4-(1,4-dioxaspiro[4.5]decan-8-ylmethoxy)-5-chloro-2-fluorobenzoate with tert-butyl 4-(adamantan-1-ylmethoxy)-5-chloro-2-fluorobenzoate and to replace cyclopropylboronic acid with trans-propenylboronic acid pinacol ester, tert-butyl 4-(adamantan-1-ylmethoxy)-2-fluoro-5-((E)-prop-1-en-1-yl)benzoate was obtained as a yellowish oil (1.20 g, quant.). To a mixture of tert-butyl 4-(adamantan-1-ylmethoxy)-2-fluoro-5-((E)-prop-1-en-1-yl)benzoate (0.30 g, 0.75 mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL) and the reaction mixture was stirred at ambient temperature for 2 hours. Concentration in vacuo gave the title compound as a yellowish residue (0.260 g, quant.) which was used without further purification: MS (ES+) m/z 345.2 (M+1).