Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]1([S:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[F:23][B-:24]([F:27])([F:26])[F:25].[H+]>C(OCC)C.C1C=CC=CC=1>[F:23][B-:24]([F:27])([F:26])[F:25].[C:3]1([S+:15]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=S(c1ccccc1)c1ccccc1
Reactant: Brc1ccccc1
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Mg]
Solvent: CCOCC
Solvent: c1ccccc1
Product: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a suspension of magnesium turning (12 g) in ethyl ether (500 ml), bromobenzene (83.5 g, 0.54 mole) was added dropwise under reflux with stirring and continued to stir for 1 hour under reflux. to this Grignard reagent, benzene (500 ml) was added and concentrated until 500 ml. To this resultant mixture, a solution of diphenylsulfoxide (30 g, 0.15 mole) in benzene (200 ml) was added and reacted with stirring for 40 hours under reflux. After the reaction mixture was cooled to 0° C., 40% tetrafluoroboric acid (50 ml) was added dropwise at 0°-5° C. and reacted with stirring for 5 hours at the same temperature. After standing at room temperature overnight, the aqueous layer separated was extracted with methylene chloride (100 ml×3), the organic layer was washed with H2O, dried over anhydrous sodium sulfate and dried. The residual crude solid was recrystallized from chloroform/ethyl ether to give 28 g of triphenylsulfonium tetrafluoroborate as white crystals. m.p. 291°-292° C.
Reaction SMILES: [NH:1]([CH2:8][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:11](Br)[CH:12]=[CH2:13]>>[CH2:13]([N:1]([CH2:8][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:12]=[CH2:11]
Reactant: C=CCBr
Reactant: OCCNc1ccccc1
Product: C=CCN(CCO)c1ccccc1

Procedure:
2-anilinoethanol (13.7 g, 0.10 mol) is treated with allyl bromide (18.15 g, 0.15 mol), in the manner as set forth in Example 3, to provide N-allyl-N-(2-hydroxyethyl)benzenamine.
Reaction SMILES: Cl.[C:2]([C:5]1([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:4])[CH3:3].C(=O)(O)[O-].[Na+].[CH2:24](Cl)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(#N)C>[CH2:24]([N:8]1[CH2:7][CH2:6][C:5]([C:2](=[O:4])[CH3:3])([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)[CH2:10][CH2:9]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(=O)C1(Cc2ccc(Cl)cc2)CCNCC1
Reactant: ClCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CC(=O)C1(Cc2ccc(Cl)cc2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 98.8 %

Procedure:
A suspension of 4-Acetyl-4-(4-chlorobenzyl)-piperidine hydrochloride (0.600 g, 2.09 mmol) in acetonitrile (20 mL) was treated with solid sodium bicarbonate (200 mg, xs) and benzyl chloride (292 mg, 2.3 mol) and heated to reflux for 3 hours. The reaction was then cooled to room temperature, poured into saturated aqueous sodium bicarbonate (200 mL) and extracted with ethyl acetate (3×100 mL). The combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated at reduced pressure. The residue was chromatographed on silica gel eluting with 2% Methanol/chloroform to give 706 mg of the title compound. 1H NMR CDCl3 δ 7.25 (m, 5H), 7.22 (d, J=8.5 Hz, 2H), 6.96 (d, J=8.5 Hz, 2H), 3.45 (s, 2H), 2.78 (s 2H), 2.76 (m, 2H), 2.20-2.0 (m, 4H), 2.06 (s, 3H), 1.75-1.50 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14](/[CH:17]=[CH:18]/[CH2:19][CH2:20][C:21]3[N:26]=[CH:25][C:24]([F:27])=[CH:23][N:22]=3)(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.ClC1C=CC(N2CCN(S(/C=C\CCC3N=CC(F)=CN=3)(=O)=O)CC2)=NC=1.[NH2:55][OH:56]>O1CCCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH:18]([NH:55][OH:56])[CH2:19][CH2:20][C:21]3[N:26]=[CH:25][C:24]([F:27])=[CH:23][N:22]=3)(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[N:6][CH:7]=1
Reactant: O=S(=O)(/C=C/CCc1ncc(F)cn1)N1CCN(c2ccc(Cl)cn2)CC1
Reactant: NO
Agent: O=S(=O)(/C=C\CCc1ncc(F)cn1)N1CCN(c2ccc(Cl)cn2)CC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=S(=O)(CC(CCc1ncc(F)cn1)NO)N1CCN(c2ccc(Cl)cn2)CC1
Reaction time: 18 h

Procedure:
To a solution of 2-((E)-4-[4-(5-chloropyridin-2-yl)piperazino]sulfonylbut-3-enyl)-5-fluoropyrimidine and 2-((Z)-4-[4-(5-chloropyridin-2-yl)piperazino]sulfonylbut-3-enyl)-5-fluoropyrimidine (0.44 g), in tetrahydrofuran (5 ml), was added hydroxylamine (1.0 ml, 50% aqueous solution). The mixture was stirred for 18 hours and then diluted with EtOAc (10 ml) and washed with saturated ammonium chloride solution (10 ml). The organic layer was dried over Na2SO4 and evaporated in vacuo to give 2-[4-[4-(5-chloropyridin-2-yl)piperazino]sulfonyl-3-(hydroxyamino)butyl]-5-fluoropyrimidine (0.483 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[CH:6][C:5]([N:12]=[C:13]=[O:14])=[C:4]([F:15])[CH:3]=1.[NH2:16]/[C:17](/[CH3:26])=[C:18](/[CH2:24][CH3:25])\[C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C)C=O>[CH2:24](/[C:18](=[C:17](/[NH:16][C:13]([NH:12][C:5]1[CH:6]=[C:7]([O:8][CH:9]([CH3:10])[CH3:11])[C:2]([Cl:1])=[CH:3][C:4]=1[F:15])=[O:14])\[CH3:26])/[C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:25]
Reactant: CCOC(=O)/C(CC)=C(/C)N
Reactant: CC(C)Oc1cc(N=C=O)c(F)cc1Cl
Solvent: CN(C)C=O
Product: CCOC(=O)/C(CC)=C(/C)NC(=O)Nc1cc(OC(C)C)c(Cl)cc1F

Procedure:
using 4-chloro-2-fluoro-5-isopropoxyphenyl isocyanate in dimethylformamide with ethyl 3-amino-2-ethylcrotonate there is obtained ethyl 2-ethyl-3-[3-(4-chloro-2-fluoro-5-isopropoxyphenyl)ureido]-crotonate, m.p. 112°-114° C. and from this intermediate with sodium hydride in dimethylformamide there is obtained 5-ethyl-3-(4-chloro-2-fluoro-5-isopropoxyphenyl)-6-methyl-2,4(1H,3H)-pyrimidinedione, m.p. 128°-130° C.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:17]=[CH:16][C:6]([CH2:7][P:8](=[O:15])([O:12]CC)[O:9]CC)=[CH:5][CH:4]=1>Cl.CCO>[F:19][C:2]([F:1])([F:18])[C:3]1[CH:17]=[CH:16][C:6]([CH2:7][P:8](=[O:9])([OH:12])[OH:15])=[CH:5][CH:4]=1
Reactant: CCOP(=O)(Cc1ccc(C(F)(F)F)cc1)OCC
Agent: Cl
Solvent: CCO
Product: O=P(O)(O)Cc1ccc(C(F)(F)F)cc1

Procedure:
The diethyl 4-trifluoromethylbenzylphosphonate (3.0 g, 10 mmol) was dissolved in a mixture of 50 mL of conc hydrochloric acid and 5 mL of EtOH and heated at reflux for 17 hours. After cooling the mixture in an ice bath, white crystalline material was collected. Recrystallization of the solid from H2O gave 1.80 g, 75% of the analytically pure product: mp=163°-164° C.; D.C.I.M.S.[MH+,241].
Reaction SMILES: [CH2:1]([C:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][C:10]([C:16]([O:18]C)=[O:17])=[CH:11][CH:12]=2)[N:7]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([O:35]C)=[O:34])=[CH:23][CH:22]=2)[CH:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>>[CH2:1]([C:5]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][C:10]([C:16]([OH:18])=[O:17])=[CH:11][CH:12]=2)[N:7]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([OH:35])=[O:34])=[CH:25][CH:26]=2)[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cn(Cc2ccc(-c3ccccc3C(=O)OC)cc2)c2cc(C(=O)OC)ccc2c1=O
Agent: [Na+]
Agent: [OH-]
Product: CCCCc1cn(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2cc(C(=O)O)ccc2c1=O
Yield: 76.9 %

Procedure:
Using the procedure of Example 2, 290 mg of the product of Example 9 and 5 ml of a 5N sodium hydroxide solution were reacted to obtain 210 mg of the desired product melting at >260° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[NH:13][C:12](=[O:14])[C:11]3=[C:15]([CH2:28][CH3:29])[N:16]=[C:17]([C@H:18]4[CH2:23][CH2:22][C@@H:21]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19]4)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:30]([O:34][CH2:35][CH3:36])(=[O:33])[CH:31]=[CH2:32].C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:24]([C@@H:21]1[CH2:20][CH2:19][C@H:18]([C:17]2[N:10]3[C:11]([C:12](=[O:14])[NH:13][C:8]([C:4]4[CH:3]=[C:2](/[CH:32]=[CH:31]/[C:30]([O:34][CH2:35][CH3:36])=[O:33])[CH:7]=[CH:6][CH:5]=4)=[N:9]3)=[C:15]([CH2:28][CH3:29])[N:16]=2)[CH2:23][CH2:22]1)([CH3:25])([CH3:27])[CH3:26]
Reactant: CCc1nc([C@H]2CC[C@@H](C(C)(C)C)CC2)n2nc(-c3cccc(Br)c3)[nH]c(=O)c12
Reactant: C=CC(=O)OCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1cccc(-c2nn3c(c(CC)nc3[C@H]3CC[C@@H](C(C)(C)C)CC3)c(=O)[nH]2)c1
Temperature: 25 °C

Procedure:
740 mg (1.62 mmol) cis-2-(3-bromophenyl)-7-(4-tert-butylcyclohexyl)-5-ethylimidazo[5,1-f][1,2,4]triazin-4(3H)-one (Example 27A), 1.6 g (16.2 mmol) ethyl acrylate, 327 mg (3.24 mmol) triethylamine and 227 mg (0.32 mmol) dichlorobis(triphenylphosphine)palladium(II) are stirred at 120° C. in 20 ml DMF in an argon atmosphere for 18 hours. After cooling down to room temperature, the mixture is filtrated over Celite, and the product is isolated by column chromatography or preparative HPLC.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@H:14]([C:15]([O:17][CH3:18])=[O:16])[CH2:13][CH2:12][NH:11][CH2:10]2)=[CH:5][CH:4]=1.[C:19]1([CH2:25][CH:26]=O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])(=O)C.[Na+].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClCCCl>[F:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[C@H:14]([C:15]([O:17][CH3:18])=[O:16])[CH2:13][CH2:12][N:11]([CH2:26][CH2:25][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:10]2)=[CH:5][CH:4]=1
Reactant: COC(=O)[C@@H]1CCNC[C@H]1c1ccc(F)cc1
Reactant: O=CCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Solvent: ClCCCl
Product: COC(=O)[C@@H]1CCN(CCc2ccccc2)C[C@H]1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The product from step A (770 mg, 2.81 mmol) in 1,2-dichloroethane (10 mL) was treated at rt with phenylacetaldehyde (0.987 mL, 8.44 mmol), sodium acetate (231 mg, 2.81 mmol) and sodium triacetoxyborohydride (1.79 g, 8.44 mmol). The mixture was stirred at rt for approximately 18 h, then poured into 1 M sodium hydroxide (10 mL) and extracted with ethyl acetate. The combined organic portions were dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by column chromatography on SiO2 (10% MeOH/methylene chloride) to afford the title compound. HPLC/MS: 342.3 (M+1); Rt=1.00 min (2 minute method).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@@H:7]([NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH2:6]2.S(Cl)(Cl)=O.[F:23][C:24]([F:42])([F:41])[C:25]1[C:29]2[CH2:30][N:31](C(OC(C)(C)C)=O)[CH2:32][CH2:33][C:28]=2[NH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[F:42][C:24]([F:23])([F:41])[C:25]1[C:29]2[CH2:30][NH:31][CH2:32][CH2:33][C:28]=2[N:27]([CH2:2][C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][CH:11]=2)[CH2:8][C@@H:7]([NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])[CH2:6]3)[N:26]=1
Reactant: CC(C)S(=O)(=O)N[C@@H]1Cc2ccc(CO)cc2C1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(C(F)(F)F)c2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CC(C)S(=O)(=O)N[C@@H]1Cc2ccc(Cn3nc(C(F)(F)F)c4c3CCNC4)cc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 6 %

Procedure:
(R)—N-(5-(hydroxymethyl)-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide (23 mg, 0.086 mmol) was dissolved in DCM (5 mL) and thionyl chloride (51 mg, 0.43 mmol) was added. The reaction mixture was stirred at room temperature for 1 h before being concentrated to dryness. The whole was dissolved in DMF (2 mL) to this was added tert-butyl 3-(trifluoromethyl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (25 mg, 0.086 mmol) followed by potassium carbonate (24 mg, 0.172 mmol). The reaction mixture was heated to 65° C. for 3 h before being quenched with water (2 mL) and the organics extracted with EtOAc (3×5 mL). The combined organics were washed with brine, dried (MgSO4) and concentrated under reduced pressure. The residue was treated with 1:1 TFA/DCM (2 mL) for 2 h before being concentrated to dryness. Purification by preparative basic HPLC gave (R)—N-(5-((3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)-2,3-dihydro-1H-inden-2-yl)propane-2-sulfonamide (2.3 mg, 5.2 μmol, 6.1%). MS (ESI): m/z [M+H]+ 443.2
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.C(N(CC)CC)C.[C:30]([Si:36]([CH:41]([CH3:43])[CH3:42])([CH:38]([CH3:40])[CH3:39])Cl)([CH:33]([CH3:35])[CH3:34])([CH3:32])[CH3:31]>C1(C)C=CC=CC=1>[C:1]([O:6][Si:36]([C:30]([CH:33]([CH3:35])[CH3:34])([CH3:32])[CH3:31])([CH:41]([CH3:42])[CH3:43])[CH:38]([CH3:39])[CH3:40])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CC(C)C(C)(C)[Si](Cl)(C(C)C)C(C)C
Reactant: C=C(C)C(=O)O
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)O[Si](C(C)C)(C(C)C)C(C)(C)C(C)C
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A flask equipped with a stirrer, reflux condenser, dropping funnel and thermometer was charged with 17.2 g (0.2 mol) of methacrylic acid, 120 ml of toluene, and 0.06 g of 2,6-di-tert-butyl-4-methylphenol. At room temperature, 22.3 g (0.22 mol) of triethylamine was added dropwise over one hour. At the end of dropwise addition, the flask was heated at 80° C. After the internal temperature became constant, 47.0 g (0.20 mol) of thexyldiisopropylchlorosilane was added dropwise over two hours. After the completion of dropwise addition, the reaction solution was stirred for 5 hours at 80° C. The reaction solution was then cooled to room temperature, and the resulting hydrochloric acid salt removed by filtration. The filtrate was distilled, collecting 43.2 g of a fraction having a boiling point of 92-97° C./0.13 kPa.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:13])[CH:11]=1)[C:5]([O:7]C)=[O:6].[OH-].[Li+].CO>O>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[O:13])[CH:11]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(Br)cc(C(=O)N2CCCC2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(Br)cc(C(=O)N2CCCC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a round-bottom flask were charged methyl 3-bromo-5-(pyrrolidine-1-carbonyl)benzoate (0.86 g, 2.5 mmol), lithium hydroxide (0.071 g, 3.0 mmol), methanol (5 mL) and water (5 mL). The mixture was stirred at room temperature for 2 h. Methanol was removed under reduced pressure. The aqueous layer was acidfied to pH=1 with 1N aq. HCl, and then extracted with CH2Cl2. The separated organic phase was dried over Na2SO4, filtered, and concentrated to dryness to afford the desired product as a white solid. 1H NMR (400 MHz, DMSO-d6): 13.54 (br, 1H), 8.09 (t, J=1.6 Hz, 1H), 7.98 (t, J=1.5 Hz, 1H), 7.94 (t, J=1.8 Hz, 1H), 3.47 (t, J=6.7 Hz, 2H), 3.37 (t, J=6.5 Hz, 2H), 1.90-1.80 (m, 4H).
Reaction SMILES: [CH:1]1([N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH2:15][CH3:16])[CH:12]=3)[C:7]([C:17]#[N:18])=[C:6]2[C:19]2[CH:24]=[CH:23][C:22]([NH:25][CH2:26][CH3:27])=[CH:21][CH:20]=2)[CH2:4][CH2:3][CH2:2]1.Cl[C:29]([O:31][CH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:30].ClC([O-])=O>N1C=CC=CC=1>[CH:32]1([O:31][C:29](=[O:30])[N:25]([C:22]2[CH:21]=[CH:20][C:19]([C:6]3[N:5]([CH:1]4[CH2:2][CH2:3][CH2:4]4)[C:13]4[C:8]([C:7]=3[C:17]#[N:18])=[CH:9][CH:10]=[C:11]([O:14][CH2:15][CH3:16])[CH:12]=4)=[CH:24][CH:23]=2)[CH2:26][CH3:27])[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: O=C(Cl)OC1CCCC1
Reactant: CCNc1ccc(-c2c(C#N)c3ccc(OCC)cc3n2C2CCC2)cc1
Agent: O=C([O-])Cl
Solvent: c1ccncc1
Product: CCOc1ccc2c(C#N)c(-c3ccc(N(CC)C(=O)OC4CCCC4)cc3)n(C3CCC3)c2c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 86.9 %

Procedure:
1-Cyclobutyl-6-ethoxy-2-(4-ethylaminophenyl)-1H-indole-3-carbonitrile (35 mg, 0.10 mmol), prepared as in example 1CO, step C, is dissolved in pyridine (300 μL). Cyclopentyl chloroformate (25 μL, 0.17 mmol) is added. The reaction mixture is stirred at room temperature for 2.5 h. More chloroformate (10 μL, 0.07 mmol) is added to drive the reaction to completion. After an additional 90 min of stirring, the reaction mixture is partitioned between aqueous HCl and EtOAc. The organic layer is dried and concentrated. Purification by silica gel chromatography yields [4-(3-cyano-1-cyclobutyl-6-ethoxy-1H-indol-2-yl)-phenyl]-ethyl-carbamic acid cyclopentyl ester (41 mg, 87%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:49])([F:48])[C:3]1[CH:4]=[C:5]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[N:34]([CH2:39][CH3:40])[CH2:35][CH2:36][O:37][CH3:38])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]([OH:22])=[O:21])[CH2:16][CH2:15]2)=[CH:10][N:9]=1.[OH-].[Na+:51]>C(O)C>[Na+:51].[F:49][C:2]([F:1])([F:48])[C:3]1[CH:4]=[C:5]([CH:41]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:43]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[N:34]([CH2:39][CH3:40])[CH2:35][CH2:36][O:37][CH3:38])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:15][CH2:16][CH:17]([C:20]([O-:22])=[O:21])[CH2:18][CH2:19]2)=[CH:10][N:9]=1
Reactant: CCN(CCOC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCC(C(=O)O)CC2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCN(CCOC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCC(C(=O)[O-])CC2)cn1

Procedure:
Ethyl 1-[2-((3,5-bis-trifluoromethyl-benzyl)-{2-[ethyl-(2-methoxy-ethyl)-amino]-5-trifluoromethyl-benzyl}-amino)-pyrimidin-5-yl]-piperidine-4-carboxylate (205 mg) is dissolved in ethanol (2 ml) and thereto is added 2N-aqueous sodium hydroxide solution (418 μl) and the mixture is stirred at room temperature overnight. Thereto are added ethyl acetate and a saturated aqueous citric acid solution, and the mixture is separated and the organic layer is washed with a saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=1:1→0:1) to give 1-[2-((3,5-bis-trifluoromethyl-benzyl)-{2-[ethyl-(2-methoxy-ethyl)-amino]-5-trifluoromethyl-benzyl}-amino)-pyrimidin-5-yl]-piperidine-4-carboxylic acid (155 mg). The resulting carboxylic acid is dissolved in ethanol (1 ml) and thereto is added 2N-aqueous sodium hydroxide solution (110 μl) and the reaction solution is concentrated under reduced pressure to give 1-[2-((3,5-bis-trifluoromethyl-benzyl)-{2-[ethyl-(2-methoxy-ethyl)-amino]-5-trifluoromethyl-benzyl}-amino)-pyrimidin-5-yl]-piperidine-4-carboxylic acid sodium salt (159 mg). MS (m/z): 706 [M−Na]−
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[F:19])[N:15]=[C:14]([I:20])[C:13]([CH2:21]N1C=CC(C(O)(CC)CC(OC(C)(C)C)=O)=CC1=O)=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=[O:43])C.[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)CCCC.CO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[F:19])[N:15]=[C:14]([I:20])[C:13]([CH2:21][OH:43])=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCC(O)(CC(=O)OC(C)(C)C)c1ccn(Cc2cc3cc(OCc4ccccc4)c(F)cc3nc2I)c(=O)c1
Reactant: CC(=O)[O-]
Agent: [Pd+2]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CO
Solvent: CCCCCO
Product: OCc1cc2cc(OCc3ccccc3)c(F)cc2nc1I
Temperature: 80 °C
Reaction time: 16 h

Procedure:
A mixture of tert-butyl 3-[1-(6-benzyloxy-7-fluoro-2-iodo-3-quinolylmethyl)-2-oxo-1,2-dihydro-4-pyridinyl]-3-hydroxypentanoate (obtained according to 1.i, 1.6 g, 2.4 mmol), tetrabutylammonium bromide (0.77 g, 2.4 mmol), potassium acetate (0.24 ml, 2.4 mmol) and palladium acetate (0.55 g, 2.4 mmol) in anhydrous amyl alcohol (30 ml) is heated at 80° C. under an argon atmosphere for 3 hours, then concentrated under reduced pressure. The residue is taken up in methanol (50 ml) and dichloromethane (100 ml), filtered through celite then concentrated under reduced pressure in order to produce a pink solid which is taken up in methanol, then treated with hot activated carbon. The liquor obtained by filtration is concentrated to 5 ml, then placed at 4° C. for 16 hours. The resulting precipitate is collected by filtration and washed with diethyl ether in order to produce, after drying, 370 mg (29%) of a white solid, m.p. >275° C.
Reaction SMILES: COCN[C:5]([C:7]1[C:8]([NH2:16])=[N:9][C:10]([S:13][CH2:14][CH3:15])=[N:11][CH:12]=1)=[O:6].Br[C:18]1[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=1[O:26][CH3:27]>>[NH2:16][C:8]1[C:7]([C:5]([C:20]2[C:19]([O:26][CH3:27])=[CH:18][CH:23]=[C:22]([F:24])[C:21]=2[F:25])=[O:6])=[CH:12][N:11]=[C:10]([S:13][CH2:14][CH3:15])[N:9]=1
Reactant: CCSc1ncc(C(=O)NCOC)c(N)n1
Reactant: COc1cc(F)c(F)cc1Br
Product: CCSc1ncc(C(=O)c2c(OC)ccc(F)c2F)c(N)n1

Procedure:
The same procedure as described in Example 47 was used, starting from 4-amino-2-ethylsulfanylpyrimidine-5-carboxylic acid methoxymethylamide, Example 1, and 2-bromo-4,5-difluoro-anisole (Astatech), to give (4-amino-2-ethylsulfanyl-pyrimidin-5-yl)-(2,3-difluoro-6-methoxy-phenyl)-methanone as a white solid. MS (M+H)+, 326.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([NH:16]C(=O)C)[CH2:12][CH2:11]2)=[N:8][CH:9]=1)#[N:3].[OH-].[Na+]>>[NH2:16][CH:13]1[CH2:14][CH2:15][N:10]([C:7]2[CH:6]=[CH:5][C:4]([C:2]#[N:3])=[CH:9][N:8]=2)[CH2:11][CH2:12]1
Reactant: CC(=O)NC1CCN(c2ccc(C#N)cn2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: N#Cc1ccc(N2CCC(N)CC2)nc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 85.1 %

Procedure:
2N HCl (3 mL) was added to N-(1-(5-cyanopyridin-2-yl)piperidin-4-yl)acetamide (300 mg, 1.22 mmol) and the reaction mixture was stirred at 100° C. for 5 h. The reaction mixture was cooled to room temperature and the pH of the aqueous layer was adjusted to 8-9 using 10% NaOH solution. The product was extracted with CH2Cl2 and the combined extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford 6-(4-aminopiperidin-1-yl)nicotinonitrile (210 mg, crude), which was carried through without further purification. 1H NMR (300 MHz, DMSO-d6) δ 8.43 (d, J=2.3 Hz, 1H), 7.79-7.75 (dd, J=9.1 Hz, 2.3 Hz, 1H), 6.90 (d, J=9.2 Hz, 1H), 4.28-4.23 (m, 2H), 3.07-2.98 (m, 2H), 2.87-2.78 (m, 1H), 1.75-1.71 (m, 2H), 1.19-1.07 (m, 2H). MS (ESI) m/z: Calculated for C11H14N4: 202.12. found: 203.2 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.Cl.[NH2:18][CH2:19][C:20]1[CH:25]=[C:24]([OH:26])[CH:23]=[CH:22][C:21]=1[OH:27].C(N(CC)CC)C>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:18][CH2:19][C:20]1[CH:25]=[C:24]([OH:26])[CH:23]=[CH:22][C:21]=1[OH:27]
Reactant: NCc1cc(O)ccc1O
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1NC(=O)c2ccc(Br)cc2/C1=C/NCc1cc(O)ccc1O
Yield: 16.1 %

Procedure:
To a mixture of 6-bromo-4-methoxymethylene-4H-isoquinoline-1,3-dione (400 mg, 1.42 mmol) and 2-aminomethyl-benzene-1,4-diol hydrochloride salt (250 mg, 1.42 mmol) in N,N-dimethylformamide (DMF) (10 mL) is added triethylamine (Et3N) (0.3 mL, 2.13 mmol). The resulting precipitate is filtered to give 89 mg (16.1%) of the title compound as a beige solid. MS (ESI) m/z 387.0 (M−H)−1.