Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([CH2:24][OH:25])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:26]([F:29])([F:28])[F:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][C:31]1[CH:36]=[CH:35][C:34]([CH3:37])=[CH:33][C:32]=1O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][O:25][C:32]3[CH:33]=[C:34]([CH3:37])[CH:35]=[CH:36][C:31]=3[CH3:30])[CH:19]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:26]([F:29])([F:27])[F:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: Cc1ccc(C)c(O)c1
Product: Cc1ccc(C)c(OCc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}methanol and 2,5-dimethylphenol according to the procedure of Example 69. MS (ESI) m/z 498.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:15][C:16]([OH:18])=O)[CH:12]([CH3:14])[CH3:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.Cl.[F:21][C:22]([F:38])([F:37])[C:23]1[CH:24]=[CH:25][C:26]([N:29]2[CH2:34][CH2:33][O:32][CH:31]([CH2:35][NH2:36])[CH2:30]2)=[N:27][CH:28]=1.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH:12]([CH3:13])[CH3:14])[CH2:15][C:16]([NH:36][CH2:35][CH:31]2[O:32][CH2:33][CH2:34][N:29]([C:26]3[CH:25]=[CH:24][C:23]([C:22]([F:38])([F:37])[F:21])=[CH:28][N:27]=3)[CH2:30]2)=[O:18])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C)N(CC(=O)O)S(=O)(=O)c1ccc(F)cc1
Reactant: NCC1CN(c2ccc(C(F)(F)F)cn2)CCO1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CC(C)N(CC(=O)NCC1CN(c2ccc(C(F)(F)F)cn2)CCO1)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 79.1 %

Procedure:
2-(4-Fluoro-N-isopropylphenylsulfonamido)acetic acid (108 mg, 0.39 mmol), (4-(5-(trifluoromethyl)pyridin-2-yl)morpholin-2-yl)methylamine dihydrochloride (131 mg, 0.39 mmol) and TEA (0.22 mL) were combined in dichloromethane (6 mL). To this stirred solution was added BOP reagent (174 mg, 0.39 mmol). The mixture was stirred at room temperature for 6 h. Solvents were evaporated and the residue was extracted with ethyl acetate and water, washed with sodium bicarbonate solution and dried. Solvents were evaporated. The residue was purified by ISCO flash column chromatography (0% to 100% ethyl acetate in hexanes) to give a white powder (160 mg, 79%). [MH]+=519.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13]([O:15][CH:16]([CH3:25])[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[O:14])[C@H:11]([C:26]([O:28]C)=[O:27])[O:10][C:9]1([CH3:31])[CH3:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>C(O)C.O>[C:1]([O:5][C:6]([N:8]1[C@H:12]([C:13]([O:15][CH:16]([CH3:25])[C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)=[O:14])[C@H:11]([C:26]([OH:28])=[O:27])[O:10][C:9]1([CH3:30])[CH3:31])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H]1OC(C)(C)N(C(=O)OC(C)(C)C)[C@@H]1C(=O)OC(C)c1ccc(OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(C(C)OC(=O)[C@@H]2[C@H](C(=O)O)OC(C)(C)N2C(=O)OC(C)(C)C)cc1
Reaction time: 2 h
Yield: 93.5 %

Procedure:
To a solution of 2.1 g of methyl (4S,5R)-3-tert-butoxycarbonyl-2,2-dimethyl-4-[α-methyl-(4-methoxy)benzyloxycarbonyl]-5-oxazolidinecarboxylate in 55 cm3 of ethanol is added, at a temperature in the region of 25° C., a solution of 0.172 g of lithium hydroxide hydrate in 10 cm3 of distilled water. The reaction medium is stirred for 2 hours at a temperature in the region of 20° and then concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40° C. The evaporation residue is dissolved in 20 cm3 of distilled water and the solution obtained is washed with twice 15 cm3 of diethyl ether, acidified to a pH in the region of 2 by addition of aqueous 0.5N hydrochloric acid solution and extracted with twice 100 cm3 of ethyl acetate. The organic phases are combined, washed with twice 15 cm3 of distilled water, dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at a temperature in the region of 40° C. 1.9 g of (4S,5R)-3-tert-butoxycarbonyl-2,2-dimethyl-4-[α-methyl-(4-methoxy)benzyloxycarbonyl]-5-oxazolidinecarboxylic acid are thus obtained in the form of a white foam.
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]([NH:13][C:14]([C:16]1[CH:24]=[C:23]2[C:19]([CH:20]=[N:21][N:22]2[CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:18][C:17]=1[O:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[F:37])=[O:15])[CH2:5][CH2:6][N:7]([CH2:9][CH2:10][O:11][CH3:12])[CH3:8].[BH4-].[Na+]>C1COCC1.CO>[OH:2][CH2:3][C@@H:4]([NH:13][C:14]([C:16]1[CH:24]=[C:23]2[C:19]([CH:20]=[N:21][N:22]2[CH2:25][CH:26]([CH3:28])[CH3:27])=[CH:18][C:17]=1[O:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:31]=1[F:37])=[O:15])[CH2:5][CH2:6][N:7]([CH2:9][CH2:10][O:11][CH3:12])[CH3:8]
Reactant: COCCN(C)CC[C@H](NC(=O)c1cc2c(cnn2CC(C)C)cc1Oc1ccc(F)cc1F)C(=O)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COCCN(C)CC[C@@H](CO)NC(=O)c1cc2c(cnn2CC(C)C)cc1Oc1ccc(F)cc1F
Temperature: 70 °C
Yield: 32.3 %

Procedure:
(S)-2-{[5-(2,4-Difluorophenoxy)-1-isobutyl-1H-indazole-6-carbonyl]-amino}-4-[(2-methoxyethyl)-methylamino]-butyric acid methyl ester (0.023 g, 0.043 mmol) and NaBH4 (0.016 g, 0.43 mmol) were dissolved in THF/MeOH (7 mL, 5:2) and heated to 70° C. in a sealed vial for 5 hours. The mixture was cooled to room temperature, concentrated under reduced pressure and chromatographed eluting with TEA/ethyl acetate (1:4) to provide 0.007 g of the product as viscous oil (31% yield). MS (APCI+) m/z 505 (M+1) detected.
Reaction SMILES: [F:1][C:2]([F:16])([C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1)[C:3]([F:6])([F:5])[F:4].[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][NH2:26])=[CH:20][CH:19]=1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][NH:26][C:11](=[O:13])[C:10]2[CH:9]=[CH:8][C:7]([C:2]([F:1])([F:16])[C:3]([F:4])([F:5])[F:6])=[CH:15][CH:14]=2)=[CH:20][CH:19]=1
Reactant: O=C(O)c1ccc(C(F)(F)C(F)(F)F)cc1
Reactant: NCCc1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(NCCc1ccc(F)cc1)c1ccc(C(F)(F)C(F)(F)F)cc1
Yield: 99.3 %

Procedure:
A solution of 4-pentafluoroethyl-benzoic acid (500 mg, 2.08 mmol), 2-(4-fluorophenyl)ethylamine (319 mg, 2.29 mmol), 4-methylmorpholine (632 mg, 6.24 mmol), and HBTU (1.19 g, 3.12 mmol) in DMF (38 mL) was stirred at RT for 16 h, then the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) afforded the title compound (746 mg, 99%). White solid, MS (ISP) 362.2 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].C(OC([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:34]=[N:35][C:36]([NH2:39])=[CH:37][CH:38]=2)[CH2:29][CH2:28]1)=O)(C)(C)C>>[CH3:1][NH:2][C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10]([NH:39][C:36]3[CH:37]=[CH:38][C:33]([N:30]4[CH2:29][CH2:28][NH:27][CH2:32][CH2:31]4)=[CH:34][N:35]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N)nc2)CC1
Reactant: CNC(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Product: CNC(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Yield: 76.6 %

Procedure:
Following Buchwald Method B, 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methylamide (500 mg, 1.80 mmol) and 4-(6-amino-pyridin-3-yl)-piperazine-1-carboxylic acid tert-butyl ester (550 mg, 1.98 mmol) gave 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid methylamide (580 mg, 77%). MS (ESI) m/z 421.2 (M+H)+
Reaction SMILES: Cl.[NH2:2][OH:3].C[O-].[Na+].C1COCC1.[Cl:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([C:22]([NH:24][CH:25]1[CH2:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[N:27]([CH2:35][C:36]#[N:37])[C:26]1=[O:38])=[O:23])=[CH:16]2>CO>[NH2:37]/[C:36](=[N:2]\[OH:3])/[CH2:35][N:27]1[C:28]2[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:34][CH:25]([NH:24][C:22]([C:17]2[NH:18][C:19]3[C:15]([CH:16]=2)=[CH:14][C:13]([Cl:12])=[CH:21][CH:20]=3)=[O:23])[C:26]1=[O:38]
Reactant: N#CCN1C(=O)C(NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: N/C(CN1C(=O)C(NC(=O)c2cc3cc(Cl)ccc3[nH]2)Cc2ccccc21)=N\O
Reaction time: 0.17 h
Yield: 43.8 %

Procedure:
A solution hydroxylamine hydrochloride (147 mg, 2.11 mmol) in MeOH (4 mL) was added to a solution of sodium methoxide in methanol (0.5 M, 4.2 mL, 2.1 mmol) that had been further diluted with methanol (4 mL). After stirring for 10 minutes, THF (4 mL) was added followed by portionwise addition of 5-chloro-N-[1-(cyanomethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-1H-indole-2-carboxamide (Method 11, 400 mg, 1.06 mmol). The reaction mixture was stirred at ambient temperature for 18 h, partitioned between EtOAc (80 mL) and diluted brine (80 mL), filtered and the layers of the filtrate separated. The organic phase was dried (Na2SO4) and the volatiles removed under reduced pressure to give the title material (191 mg, 44%) as a yellow solid.
Reaction SMILES: [OH:1][C@H:2]([CH2:26][OH:27])[CH2:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=3[F:25])=[CH:12][C:13](=[O:16])[N:14]([CH3:15])[C:7]=2[N:6]=[CH:5]1.[B-](F)(F)(F)[F:29].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>CN(C=O)C.C(#N)C>[OH:1][C@H:2]([CH2:26][OH:27])[CH2:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=3[F:25])=[C:12]([F:29])[C:13](=[O:16])[N:14]([CH3:15])[C:7]=2[N:6]=[CH:5]1
Reactant: F[B-](F)(F)F
Reactant: Cn1c(=O)cc(Nc2ccc(I)cc2F)c2c(=O)n(C[C@H](O)CO)cnc21
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cn1c(=O)c(F)c(Nc2ccc(I)cc2F)c2c(=O)n(C[C@H](O)CO)cnc21
Yield: 25.4 %

Procedure:
To a solution of (S)-3-(2,3-dihydroxypropyl)-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (example 5) (1.25 g, 2.58 mmol, 1 eq) in DMF (26 mL) was added a mixture of Selectfluor (1.187 g, 3.35 mmol, 1.3 eq) in acetonitrile (26 mL). The reaction mixture was irradiated with microwave at 82° C. for 10 minutes and filtered. The filtrate was purified by preparatory LC/MS (30-55% CH3CN in H2O) to give (S)-3-(2,3-dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (example 19) as an off-white solid (331 mg, 25% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.36-3.42 (m, 1 H) 3.42-3.51 (m, 1 H) 3.59 (s, 3 H) 3.63-3.72 (m, 1 H) 3.73-3.81 (m, 1 H) 4.32 (dd, J=13.14, 3.03 Hz, 1 H) 4.79 (br. s., 1 H) 5.10 (br. s., 1 H) 6.98 (td, J=8.46, 5.31 Hz, 1 H) 7.52 (dd, J=8.46, 1.14 Hz, 1 H) 7.68 (dd, J=10.36, 1.77 Hz, 1 H) 8.51 (s, 1 H) 10.24 (d, J=2.27 Hz, 1 H). [M+H] calc'd for C17H15F21N4O4, 505; found, 505.
Reaction SMILES: [N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=O.[NH2:16][C:17]([CH3:21])([CH3:20])[CH2:18][OH:19].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[N:1]1([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([NH:16][C:17]([CH2:18][OH:19])([CH3:21])[CH3:20])=[O:5]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Reactant: CC(C)(N)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(CO)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C

Procedure:
In a DMF solution containing 0.20 g of Boc-Pro-OH, 0.09 ml of 2-amino-2-methyl-1-propanol, 0.14 g of HOBt and 0.21 g of EDC hydrochloride were added and the resultant mixture was stirred for 14 hrs. The reaction mixture was treated similarly to that in Example 46 to give 80 mg of the title compound.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[OH:15][C:16]1([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:32][CH2:33][C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH:28]=3)[CH:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:19]3[CH2:20][CH2:21][C:16]([OH:15])([C:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][CH:26]=[C:27]([O:32][CH2:33][C:34]6[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=6)[CH:28]=5)[CH:23]=4)[CH2:17][CH2:18]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: OC1(c2ccc3cc(OCc4ccccc4)ccc3c2)CCNCC1
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CCC(O)(c2ccc3cc(OCc4ccccc4)ccc3c2)CC1
Yield: 82.5 %

Procedure:
Beginning with 0.170 gm (0.90 mmol) (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 0.300 gm (0.90 mMol) 4-hydroxy-4-(6-benzyloxynaphth-2-yl)piperidine, 0.388 gm (83%) of the title compound were recovered as a white solid by the procedure described in Example 9.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:33]=[CH:32][C:15]([C:16]([NH:18][C:19]2[CH:31]=[CH:30][CH:29]=[CH:28][C:20]=2[CH:21]=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:17])=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.C(OCC)(=O)C.[C].[Pd]>[O:1]([CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:33]=[CH:32][C:15]([C:16]([NH:18][C:19]2[CH:31]=[CH:30][CH:29]=[CH:28][C:20]=2[CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:17])=[CH:14][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C=Cc1ccccc1NC(=O)c1ccc(OCCCOc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)CCc1ccccc1NC(=O)c1ccc(OCCCOc2ccccc2)cc1
Yield: 79.6 %

Procedure:
To a solution of 250 mg of ethyl o-[p-(3-phenoxypropoxy)benzamido]cinnamate obtained in Example 34 in 10 ml of methanol and 20 ml of ethyl acetate was added 10% palladium-carbon. Catalytic reduction was performed until absorption of hydrogen was discontinued. The catalyst was filtered off and the residue was recrystallized from isopropyl alcohol to obtain 200 mg of ethyl 3-[o-[p-(3-phenoxypropoxy)benzamido]phenyl]propionate.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][Si:7]([O:14][CH2:15][CH3:16])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])=[C:2]=[O:3].[NH2:17][CH:18]1[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21][C:20]([CH3:27])([CH3:26])[CH2:19]1>ClCCl>[CH3:26][C:20]1([CH3:27])[CH2:19][CH:18]([NH:17][C:2]([NH:1][CH2:4][CH2:5][CH2:6][Si:7]([O:14][CH2:15][CH3:16])([O:8][CH2:9][CH3:10])[O:11][CH2:12][CH3:13])=[O:3])[CH2:23][C:22]([CH3:25])([CH3:24])[NH:21]1
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: CCO[Si](CCCN=C=O)(OCC)OCC
Solvent: ClCCl
Product: CCO[Si](CCCNC(=O)NC1CC(C)(C)NC(C)(C)C1)(OCC)OCC
Reaction time: 18 h

Procedure:
59.5 g (0.228 mol) of isocyanatopropyltriethoxysilane were initially charged in 50 ml of dichloromethane (abs.) and admixed with 35.63 g (0.228 mol) of 4-amino-2,2,6,6-tetramethylpiperidine in 30 ml of dichloromethane by dropwise addition at 20-40° C. and stirring for 18 h. Removal of the solvent in vacuo left 97.62 g of N-(2,2,6,6-tetramethyl-4-piperidinyl)-N′-[3-(triethoxysilyl)propyl]urea with residual traces of solvent as a colorless oil. The product was characterized using 1H NMR.
Reaction SMILES: S(=O)(=O)(O)O.[OH-:6].[Na+].[O:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1>O>[CH3:9][CH2:10][CH2:11][CH2:12][O:8][C@H:10]([CH2:9][OH:6])[CH2:11][CH3:12]
Reactant: C1CCOC1
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCCCO[C@@H](CC)CO
Temperature: 80 °C
Reaction time: 1 h

Procedure:
In the experiment in Example 17, the amount of 25% fuming sulfuric acid was changed to 180 g and the dropping thereof was conducted over one hour. The conversion after this treatment was 12%. Upon completion of said dropping, the internal temperature was elevated to 30° C. and the reaction was continued for one hour. Then, 130 g of water was added to terminate the polymerization and the conversion was measured. It was 52%. After replacing the dropping funnel by the distilling column, a solution prepared by dissolving 101 g of sodium hydroxide in 130 g of water was added continuously over one hour and heated in an oil bath at 80° C., and after said addition, the mixture was further heated and hydrolyzed at 80° C. for one hour. Unreacted tetrahydrofuran was simultaneously recovered by distillation during this operation. Then, a solution prepared by dissolving 23 g of sodium hydroxide in 25 g of water was added again continuously over one hour. At the same time, the oil bath temperature was raised to 100° C., and the mixture was heated and hydrolyzed while recovering unreacted tetrahydrofuran. After this treatment, the reaction mixture was allowed to stand to cause separation of layers, after which approximately 90% of the aqueous layer was taken out, and to the residue was added 150 g of a 20% by weight aqueous sodium sulfate solution and the resulting mixture was subjected to a heating and washing treatment at 100° C. for 2 hours. Then, in the same manner as in the preceding Examples, the aqueous layer was removed and the PTMG layer was again subjected to a heating and washing treatment at 80° C. for 30 minutes, after which the same operation was repeated once more. The resulting product was treated in the same way as in Example 17 to obtain PTMG. The results of its analyses are shown in Table 2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[CH3:19][S:20](Cl)(=[O:22])=[O:21].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:19][S:20]([NH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[CH:6][CH:7]=1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)Cc1cccc(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)Cc1cccc(NS(C)(=O)=O)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Methyl 3-aminophenylacetate (2.26 g, 13.7 mmol) was dissolved in dry methylene chloride (20 mL) and cooled to 0° C. Pyridine (2.2 mL, 27.2 mmol) was added followed by dropwise addition of methanesulfonyl chloride (1.3 mL, 16.8 mmol). The mixture was stirred at 0° C. for 1 hour and at room temperature for 3 hours, then poured into 100 mL of saturated sodium bicarbonate solution. The organic layer was washed with saturated sodium bicarbonate (100 mL), 1N HCl (2×100 mL) and brine. Dried over MgSO4. Solvent was evaporated to reveal methyl 3-(methanesulfonyl)phenylacetate. (3.36 g, 100%). 1H NMR (500 MHz, CDCl3) δ 7.32 (1H, dd), 7.2-7.1 (3H, m), 6.57 (1H, s), 3.72 (3H, s), 3.64 (2H, s), 3.02 (3H, s).
Reaction SMILES: [C:1]([OH:5])(=[O:4])[C:2]#[CH:3].C(N(CC)CC)C.[C:13]([OH:21])(=[S:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[C:13]([S:20]/[CH:3]=[CH:2]\[C:1]([OH:5])=[O:4])(=[O:21])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OC(=S)c1ccccc1
Reactant: C#CC(=O)O
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(O)/C=C\SC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 35 %

Procedure:
To a stirred, cooled (0° C.) solution of 15.4 ml (0.25 mol) of propiolic acid in 200 ml of absolute ethanol under nitrogen was added 3.48 ml (0.025 mol) of triethylamine. After 5 min, 33 ml (0.28 mol) of thiobenzoic acid was added very cautiously and dropwise. The exothermic reaction led to the ethanol reaching reflux despite the ice-water bath. After 15 min a solid precipitated from the orange solution. After 2 h at 0° C. the reaction mixture was filtered and the solid was washed twice with absolute ethanol and twice with chloroform to afford 18.3 g (35% yield of cis-3-(benzoylthio)propenoic acid as a white powder.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Cl:7][C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[C@H:17]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18]2)=[C:10](Cl)[N:9]=1>C(O)C>[Cl:7][C:8]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[C@H:17]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18]2)=[C:10]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[N:9]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](n2cnc3c(Cl)nc(Cl)nc32)C1
Reactant: C1COCCN1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CC[C@H](n2cnc3c(N4CCOCC4)nc(Cl)nc32)C1
Temperature: 80 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Morpholine (0.8 ml) and ethanol (10 ml) were added to tert-butyl(3S)-3-(2,6-dichloro-9H-purin-9-yl)pyrrolidine-1-carboxylate (1.55 g, 4.3 mmol) and the resulting mixture was stirred at 80° C. for 2 hours. The reaction mixture was cooled and then the solvent was evaporated under reduced pressure. The residue was partitioned with ethyl acetate and saturated aqueous sodium bicarbonate solution, the organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (1.76 g, 100%) as a white solid.
Reaction SMILES: I[C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:13]([C:15]1[CH:22]=[CH:21][C:18]([NH:19][CH3:20])=[C:17]([F:23])[CH:16]=1)#[CH:14]>C(#N)C.[Cu]I>[F:23][C:17]1[CH:16]=[C:15]([C:13]#[C:14][C:2]2[S:3][C:4]3[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=3[N:6]=2)[CH:22]=[CH:21][C:18]=1[NH:19][CH3:20]
Reactant: C#Cc1ccc(NC)c(F)c1
Reactant: COc1ccc2nc(I)sc2c1
Agent: [Cu]I
Solvent: CC#N
Product: CNc1ccc(C#Cc2nc3ccc(OC)cc3s2)cc1F
Temperature: 25 °C
Yield: 39.5 %

Procedure:
A 5 mL microwave tube was charged with 2 (0.2 g, 0.68 mmol), 7 (0.1 g, 0.68 mmol) [Pd(PPh3)4] (0.08 g, 0.034 mmol), CuI (0.02 g, 0.05 mmol) and TEA (0.28 mL, 2.04 mmol) in ACN (2.0 mL). The suspension was irradiated in a Biotage Emrys Optimizer microwave reactor (250 W) at 100° C. for 5 min. After cooling to room temperature the solvent was evaporated in vacuo. The residue was purified over silica gel using Hexanes:Dichloromethane (DCM) (0-100%) as the eluent to afford the coupling product 8 (0.084 g, 39%) as yellow solid. 1H NMR (400 MHz, CDCl3), δ: 2.92 (s, 3H), 3.87 (s, 3H), 6.64 (t, J=8.4 Hz, 1H), 7.11 (dd, J=12.0, 4.0 Hz, 1H), 7.22 (dd, J=10.4, 2 Hz, 1H), 7.27 (d, J=2.4, 1H), 7.33-7.35 (m, 1H), 7.96 (d, J=12 Hz, 1H); MS (ESI): 313.0 (M+H+).
Reaction SMILES: [CH2:1]1[CH2:8][C:7]2[CH:9]=[CH:10][C:11]([F:13])=[CH:12][C:6]=2[C:4](=[O:5])[CH2:3][CH2:2]1.[Br:14]Br.O>C(O)(=O)C>[Br:14][CH:3]1[CH2:2][CH2:1][CH2:8][C:7]2[CH:9]=[CH:10][C:11]([F:13])=[CH:12][C:6]=2[C:4]1=[O:5]
Reactant: O=C1CCCCc2ccc(F)cc21
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: O=C1c2cc(F)ccc2CCCC1Br
Yield: 100.2 %

Procedure:
To a stirred solution of 8-fluoro-1-benzosuberone (20.00 g, 112.2 mmol) in glacial acetic acid (125 ml) was added bromine (5.8 ml, 112.6 mmol) dropwise. Once the addition was complete, the solution was poured into water (400 ml) and extracted with EtOAc (500 ml). The extract was separated and washed with water (500 ml). The organic layer was dried over MgSO4, filtered and evaporated to yield 100% (28.9 g) of the desired product as a viscous oil: 1H-NMR (CDCl3) δ 2.00 (2H, m), 2.33 (2H, m), 2.84 (1H, m), 3.00 (1H, m), 4.83 (1H, m), 7.13 (2H, m), 7.29 (1H, dd).
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:26][CH3:27]>C(#N)C>[CH2:26]([N:16]1[CH2:15][CH2:14][CH:13]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([O:8][C:9]([F:10])([F:11])[F:12])[C:2]=2[F:1])[CH2:18][CH2:17]1)[CH3:27]
Reactant: CCI
Reactant: Fc1c(OC(F)(F)F)cccc1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN1CCC(c2cccc(OC(F)(F)F)c2F)CC1

Procedure:
Preparation according to Example 8: 4-[2-fluoro-3-(trifluoromethoxy)phenyl]piperidine (0.70 g, 2.66 mmol), acetonitrile (4 ml), potassium carbonate (0.92 g, 6.65 mmol), 1-iodoethane (0.275 ml, 2.93 mmol). Yield: 0.7 g. MS m/z (rel. intensity, 70 eV) 291 (M+, 14), 290 (10), 277 (15), 276 (bp), 193 (8).