Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[N:22][C:23]([CH3:27])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:3]=1.[CH:28]([S:31](Cl)(=[O:33])=[O:32])([CH3:30])[CH3:29].C(N(CC)C(C)C)(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([O:13][S:31]([CH:28]([CH3:30])[CH3:29])(=[O:33])=[O:32])=[CH:11][CH:12]=2)=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[N:22][C:23]([CH3:27])=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)[CH:3]=1
Reactant: Cc1ccc2c(Nc3cc(Cl)ccc3Oc3ccc(O)cc3)ccnc2n1
Reactant: CC(C)S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc2c(Nc3cc(Cl)ccc3Oc3ccc(OS(=O)(=O)C(C)C)cc3)ccnc2n1

Procedure:
The product from Example 165d (43 mg, 0.085 mmol) was reacted with isopropylsulfonyl chloride (14.5 mg, 0.102 mmol), N,N-diisopropylethylamine (33 mg, 0.255 mmol), and catalytic DMAP in CH2Cl2 for 18 h giving the crude title compound which was purified by HPLC with TFA providing the product as the trifluoroacetic acid (16 mg, 31%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.38 (d, J=6.99 Hz, 6H) 2.73 (s, 3H) 3.54-3.65 (m, 1H) 6.69 (d, J=6.99 Hz, 1H) 7.01 (d, J=9.19 Hz, 2H) 7.20 (d, J=9.19 Hz, 2H) 7.27 (d, J=8.82 Hz, 1H) 7.60 (dd, J=8.82, 2.57 Hz, 1H) 7.70-7.75 (m, 2H) 8.51 (d, J=6.99 Hz, 1H) 8.81 (d, J=8.82 Hz, 1H); MS (ESI+) m/z 484 (M+H)+.
Reaction SMILES: [CH2:1]([N:5]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=1[O:26][CH3:27])[C:6](=[O:16])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:29][C:30]1[CH:39]=[CH:38][CH:37]=[CH:36][C:31]=1[C:32]([O:34][CH3:35])=[O:33].C(=O)([O-])[O-].[K+].[K+].C(O)C(N)(CO)CO>C(#N)C>[CH2:1]([N:5]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[C:19]=1[O:26][CH3:27])[C:6](=[O:16])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:29][C:30]2[CH:39]=[CH:38][CH:37]=[CH:36][C:31]=2[C:32]([O:34][CH3:35])=[O:33])=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: COC(=O)c1ccccc1CBr
Reactant: CCCCN(Cc1cccc(OC)c1OC)C(=O)CCc1ccc(O)cc1
Agent: NC(CO)(CO)CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCCN(Cc1cccc(OC)c1OC)C(=O)CCc1ccc(OCc2ccccc2C(=O)OC)cc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 22.2 %

Procedure:
N-butyl-N-(2,3-dimethoxybenzyl)-3-(4-hydroxyphenyl)propanamide (50 mg, 0.13 mmol) and methyl 2-(bromomethyl)benzoate (0.034 g, 0.15 mmol) was dissolved in acetonitrile (10 ml) and potassium carbonate (37 mg, 0.27 mmol) was added. The mixture was stirred at 60° C. for three hours. Polymer supported trisamine (0.3 eqv) was added and stirred overnight. The polymer was filtered off and solvent was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with three portions of water. After drying the crude (MgSO4), the solvent had been removed by evaporation. The residue was purified by preparative HPLC (started with acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4). Removing the solvent by evaporation gave 15 mg of methyl 2-[(4-{3-[butyl(2,3-dimethoxybenzyl)amino]-3-oxopropyl}phenoxy)methyl]benzoate (21.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:16]2[CH2:15][CH2:14][NH:13][CH2:12][C:11]=2[CH:10]=[C:9]1[C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1.[Cl:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30]>ClCCl>[Cl:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([N:13]1[CH2:14][CH2:15][C:16]2[N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:9]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)=[CH:10][C:11]=2[CH2:12]1)=[O:30]
Reactant: COc1ccc(-c2cc3c(n2-c2ccccc2Cl)CCNC3)cc1
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: ClCCl
Product: COc1ccc(-c2cc3c(n2-c2ccccc2Cl)CCN(C(=O)c2cccc(Cl)c2)C3)cc1
Reaction time: 3 h
Yield: 73.8 %

Procedure:
To an 8-mL vial charged with piperidinomethyl polystyrene (3.57 mmol/g, 198.4 mg, 0.708 mmol) and a solution of 1-(2-chlorophenyl)-2-(4-methoxyphenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine (Example 2, 80.0 mg, 0.236 mmol) in 3 mL dichloromethane was added 3-chlorobenzoyl chloride (62.0 mg, 0.0.54 mmol). The reaction mixture was mixed by orbital shaking for 3 h. The solid was removed by filtration. The filtrate was evaporated, and the residue was purified on silica gel eluting with 1:5 EtOAc/hexanes to give a solid (83.2 mg, 74%): Rf=0.19 (1:2 EtOAc/hexanes).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH2:17][CH2:18][CH3:19])[C:13]([C:20]([NH:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:21])=[CH:12][N:11]=2)=[CH:5][CH:4]=1)#[N:2].[OH2:34]>C(O)C.CS(C)=O.[OH-].[Na+].OO>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:15]=[C:14]([NH:16][CH2:17][CH2:18][CH3:19])[C:13]([C:20]([NH:22][CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:21])=[CH:12][N:11]=2)=[CH:5][CH:4]=1)(=[O:34])[NH2:2]
Reactant: CCCNc1nc(Nc2ccc(C#N)cc2)ncc1C(=O)NCCCNC(=O)OC(C)(C)C
Reactant: O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: CCCNc1nc(Nc2ccc(C(N)=O)cc2)ncc1C(=O)NCCCNC(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl (3-(2-((4-cyanophenyl)amino)-4-(propylamino)pyrimidine-5-carboxamido)propyl)carbamate (D1, 220 mg) in ethanol (4 mL) and dimethyl sulfoxide (4 mL), 1.0 mol/L aqueous sodium hydroxide (2.4 mL) and 35% aqueous hydrogen peroxide (750 μL) were added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture, water was added. The solid matter was taken by filtration, washed with water, and then dried under reduced pressure to obtain tert-butyl (3-(2-((4-carbamoylphenyl)amino)-4-(propylamino)pyrimidine-5-carboxamido)propyl)carbamate (D2, 195 mg) as white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.[F:24][C:25]([F:36])([F:35])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1Br>>[F:1][C:2]1[CH:7]=[C:6]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[O:27][CH2:26][C:25]([F:24])([F:36])[F:35])[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1
Reactant: FC(F)(F)COc1ccccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Product: Nc1cnc(-c2ccc(-c3ccccc3OCC(F)(F)F)cc2F)cn1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 1 utilizing what 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazin-2-amine and 2-(2,2,2-trifluoroethoxy)bromobenzene. MS (ESI): mass calcd. for C18H13F4N3O, 363.10; m/z found, 363.9 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 8.03 (s, 1H), 7.91 (m, 1H), 7.56-7.34 (m, 4H), 7.25 (d, J=8.0, 1H), 7.16 (m, 1H), 6.71 (s, 2H), 4.82 (q, J=8.8, 2H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][NH:2]1.[CH2:10]([Cl:19])[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.Cl>C(O)C>[ClH:19].[CH2:10]([N:2]1[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1)[CH:11]=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ClCC=Cc1ccccc1
Reactant: c1ccc2c(c1)CNC2
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: C(=Cc1ccccc1)CN1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 34.1 %

Procedure:
The process for preparing this compound and its physical properties will be shown below. A mixture of 1.8 grams of isoindoline, 2.5 grams of cinnamyl chloride, 4 milliliters of triethylamine and 40 milliliters of ethanol is stirred for 4 hours at room temperature. After completion of the reaction, the solvent is distilled off, after which water is added to the residue and extracted with ether. The ether layer is collected and dried followed by distilling the ether off. The so obtained oily product is converted to a hydrochloride in a customary manner and then recrystallized from methyl ethyl ketone to obtain 1.4 grams (yield 34.6%) of N-cinnamylisoindoline hydrochloride as crystals having a melting point of 180°-182° C. (decomposition).
Reaction SMILES: [C:1]([C@@:4]1([OH:23])[C@@H:8]([CH:9]([C:11](=[O:13])[CH3:12])[OH:10])[O:7][C@@H:6]([N:14]2[CH:21]=[C:20]([I:22])[C:18](=O)[NH:17][C:15]2=[O:16])[CH2:5]1)(=[O:3])[CH3:2].C(N(CC)CC)C.C1(C)C=C(C)C=C(C)C=1S(Cl)(=O)=O.C1CCN2C(=NCCC2)CC1.[NH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[SH:62]>CN(C1C=CN=CC=1)C>[I:22][C:20]1[C:18]([NH:55][C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[SH:62])=[N:17][C:15](=[O:16])[N:14]([CH:21]=1)[C@@H:6]1[O:7][C@H:8]([CH:9]([C:11](=[O:13])[CH3:12])[OH:10])[C@@:4]([C:1](=[O:3])[CH3:2])([OH:23])[CH2:5]1
Reactant: CC(=O)C(O)[C@H]1O[C@@H](n2cc(I)c(=O)[nH]c2=O)C[C@@]1(O)C(C)=O
Reactant: Nc1ccccc1S
Agent: CN(C)c1ccncc1
Agent: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCN(CC)CC
Product: CC(=O)C(O)[C@H]1O[C@@H](n2cc(I)c(Nc3ccccc3S)nc2=O)C[C@@]1(O)C(C)=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3′,5′-diacetyl-5-iodo-2′-deoxyuridine (219 g, 5.00 mmol) acetonitrile (ACN, 75 ml), triethylamine (TEA, 6.96 ml, 50.0 mmol) and DMAP (0.15 g, 1.25 mmol) was added mesitylsulfonyl chloride (2.19 g, 10.0 mmol). After stirring at ambient temperature for 18 h, DBU (2.14 ml, 10.0 mmol) and 2-aminothiophenol was added (2.14 g, 20.0 mmol) and the solution was stirred for 1 h. The reaction mixture was concentrated and the crude product was partitioned between ethyl acetate (EA, 200 ml) and saturated aqueous sodium bicarbonate (SASB, 200 ml). The organic layer was dried (Na2SO4) and concentrated on the rotary evaporator. The crude product was purified by flash chromatography on silica gel [1-5% 2-propanol/dichloromethane (DCM)] to deliver the product 1H NMR (CDCl3) δ 2.10 (s, 3H), 2.15 (m; 1H, 2.17 (s, 3H, 2.77 (ddd, 1H, J=2.2, 5.2, 15.1 Hz), 4.14 (bs, 1H), 4.35 (m, 3H), 5.20 (m, 1H), 6.13 (t, 1H, J=65 Hz), 6.78 (m, 2H), 7.30 (m 2), 8.05 (s, 1H).
Reaction SMILES: [OH:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[H-].[Na+].[Br:10][C:11]1[CH:12]=[N:13][C:14](Cl)=[N:15][CH:16]=1>C1(C)C=CC=CC=1.CCOC(C)=O>[Br:10][C:11]1[CH:12]=[N:13][C:14]([O:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:15][CH:16]=1
Reactant: CCOC(=O)CO
Reactant: Clc1ncc(Br)cn1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1ncc(Br)cn1
Reaction time: 0.5 h
Yield: 60.8 %

Procedure:
To a solution of ethyl 2-hydroxyacetate (0.081 g, 0.775 mmol) in toluene (1.0 mL) was added NaH (60% in mineral oil, 0.037 g, 0.931 mmol) at room temperature. The mixture was stirred for 30 min and a solution of 5-bromo-2-chloropyrimidine (0.100 g, 0.517 mmol) in toluene (0.5 mL) was added. The reaction mixture was stirred at 60° C. for 16 h. The mixture was diluted with EtOAc and slowly quenched with water. The organic layer was separated, washed with water and brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo to provide the crude material. The crude material was purified by flash chromatography (0-50% ethyl acetate:hexanes) to afford the title compound (82 mg, 61% yield) as a clear colorless oil. LCMS, [M+H]+=260.9.
Reaction SMILES: CO[C:3](=[O:15])[CH2:4][NH:5][C:6]([C:8]1[CH:9]=[N:10][CH:11]=[C:12]([F:14])[CH:13]=1)=[O:7].[CH3:16][NH2:17]>C(O)C>[F:14][C:12]1[CH:11]=[N:10][CH:9]=[C:8]([CH:13]=1)[C:6]([NH:5][CH2:4][C:3](=[O:15])[NH:17][CH3:16])=[O:7]
Reactant: CN
Reactant: COC(=O)CNC(=O)c1cncc(F)c1
Solvent: CCO
Product: CNC(=O)CNC(=O)c1cncc(F)c1
Yield: 71.4 %

Procedure:
To a solution of [(5-fluoropyridine-3-carbonyl)-amino]-acetic acid methyl ester (2.96 g, 14.0 mmol) in ethanol (15 mL) was added methylamine (1.5 g, 33 wt % solution in ethanol, 70 mmol). This clear solution was then immediately put onto a 55° C. heating mantle for 10 min at which time the product had precipitated out of solution. The mixture was filtered in vacuo and the precipitate was washed with ethanol. The filtrate was concentrated and recrystallized from hot ethanol. This process was repeated again to give a white fluffy material (2.11 g, 72%): mp 201-202° C.; 1H NMR (300 MHz, DMSO-d6) δ 9.10 (m, 1H), 8.93 (s, 1H), 8.76 (d, J=2.5 Hz, 1H), 8.10 (m, 1H), 7.95 (br s, 1H), 3.86 (d, J=5.8 Hz, 2H), 2.61 (d, J=4.4 Hz, 3H); ESIMS m/z 212 (M+1), m/z 210 (M−1).
Reaction SMILES: [OH:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([O:23][CH2:24][CH3:25])[C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)=[CH:6][CH:5]=1.COC1C=C(C#C)C=CC=1OC.[NH2:38][C:39](N)=[O:40]>>[OH:1][N:2]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]([O:23][CH2:24][CH3:25])[C:11]#[C:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)=[CH:8][CH:9]=1)[C:39]([NH2:38])=[O:40]
Reactant: NC(N)=O
Reactant: CCOC(C#Cc1ccc(OC)c(OC)c1)c1ccc(CNO)cc1
Agent: C#Cc1ccc(OC)c(OC)c1
Product: CCOC(C#Cc1ccc(OC)c(OC)c1)c1ccc(CN(O)C(N)=O)cc1

Procedure:
1-[4-hydroxyaminomethylphenyl]-3-[3,4-dimethoxyphenyl]1-ethoxy-prop-2-yne, prepared from 3,4-dimethoxyphenylacetylene according to Example 5, was converted into the corresponding urea compound following the procedure of Example 8.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:6]=1.[CH3:11][C:12]1[CH:13]=[C:14]([CH:19]=[CH:20][C:21]=1B1OC(C)(C)C(C)(C)O1)[C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[C:7]([C:5]1[N:6]=[C:2]([C:21]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][C:12]=2[CH3:11])[S:3][CH:4]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: COC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: CC(C)(C)c1csc(Br)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(-c2nc(C(C)(C)C)cs2)c(C)c1
Yield: 92.4 %

Procedure:
To a suspension of 2-bromo-4-(1,1-dimethylethyl)thiazole (6 g, 27.3 mmol), methyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (9.78 g, 35.4 mmol), and potassium carbonate (11.30 g, 82 mmol) in 1,4-dioxane (20 mL) and water (5 mL), was added 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (1.113 g, 1.363 mmol). It was degassed and refilled with nitrogen, and was heated to reflux for 1 hour to see complete conversion of the 2-bromothiazole, by LCMS. It was distributed between water (50 mL) and ethyl acetate (200 mL). The organic layer was collected, dried over sodium sulfate, filtered and the filtrate concentrated. The crude isolate was purified on silica gel, eluting with 30% of ethyl acetate in hexanes, to get methyl 4-(4-tert-butylthiazol-2-yl)-3-methylbenzoate as a white solid (7.3 g, 93% yield). LCMS (M+H)+: 290.1. 1H NMR (CDCl3, 500 MHz): δ 8.00 (s, 1H), 7.93 (d, J=8.5 Hz, 1H), 7.83 (d, J=8.5 Hz, 1H), 7.02 (s, 1H), 3.97 (s, 3H), 2.70 (s, 3H), 1.43 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:8][C@H:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[N:6][CH:7]=1.[NH:17]1[C:25]2[C:20](=[CH:21][C:22](B(O)O)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1.N>>[N:11]12[CH2:16][CH2:15][CH:14]([CH2:13][CH2:12]1)[C@H:9]([O:8][C:5]1[N:4]=[CH:3][C:2]([C:22]3[CH:21]=[C:20]4[C:25](=[CH:24][CH:23]=3)[NH:17][CH:18]=[CH:19]4)=[CH:7][N:6]=1)[CH2:10]2
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: Brc1cnc(O[C@@H]2CN3CCC2CC3)nc1
Agent: N
Product: c1cc2cc(-c3cnc(O[C@@H]4CN5CCC4CC5)nc3)ccc2[nH]1

Procedure:
The product of Example 13E (283 mg, 1 mmol) was coupled with 5-indolylboronic acid (193 mg, 1.2 mmol) according to the procedure of Example 3A, The title product was purified by preparative HPLC (Gilson, column, Symmetry® C-8 7 μm, 40×100 mm. Eluting Solvent, MeCN/H2O (with 0.2% v. TFA) (v. 90/10 to 10/90 over 20 min.) Flow rate, 75 mL/min., uv, 250 nm) as solid (120 mg, yield, 38%). 1H NMR (300 MHz, CD3OD) δ 1.50-1.63 (m, 1H), 1.66-1.92 (m, 2H), 2.03-2.18 (m, 1H), 2.24-2.32 (m, 1H), 2.75-3.07 (m, 5H), 3.38-3.49 (m, 1H), 5.13-5.21 (m, 1H), 6.53 (dd, J=3.0, 0.7 Hz, 1H), 7.30 (d, J=3.4 Hz, 1H), 7.35 (dd, J=8.5, 1.7 Hz, 1H), 7.51 (dt, J=9.2, 0.7 Hz, 1H), 7.80 (dd, J=1.7, 0.7 Hz, 1H), 8.81 (s, 2H) ppm. MS (DCI/NH3): m/z 321 (M+H)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][O:7][C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH:10]=[C:11]([C:17]([OH:19])=O)[NH:12]3)=[CH:2]1.Cl.Cl.Cl.[NH2:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][C@@H:31]([N:33]2[CH2:38][CH2:37][CH:36]([OH:39])[CH2:35][CH2:34]2)[CH3:32])[CH2:26][CH2:25]1>>[OH:39][CH:36]1[CH2:35][CH2:34][N:33]([C@@H:31]([CH3:32])[CH2:30][N:27]2[CH2:26][CH2:25][CH:24]([NH:23][C:17]([C:11]3[NH:12][C:13]4[C:9]([CH:10]=3)=[C:8]([O:7][CH2:6][C:3]3[CH:4]=[CH:5][O:1][CH:2]=3)[CH:16]=[CH:15][CH:14]=4)=[O:19])[CH2:29][CH2:28]2)[CH2:38][CH2:37]1
Reactant: O=C(O)c1cc2c(OCc3ccoc3)cccc2[nH]1
Reactant: C[C@@H](CN1CCC(N)CC1)N1CCC(O)CC1
Agent: Cl
Product: C[C@@H](CN1CCC(NC(=O)c2cc3c(OCc4ccoc4)cccc3[nH]2)CC1)N1CCC(O)CC1

Procedure:
This compound is synthesized analogously to example 1 from 4-(furan-3-ylmethoxy)-1H-indole-2-carboxylic acid, 95 (see example 36) and amine 50.
Reaction SMILES: [Cl:1][C:2](=[CH2:5])[C:3]#[N:4].N.[C:7](Cl)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[Cl:1][CH:2]([CH2:5][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]#[N:4]
Reactant: O=C(Cl)c1ccccc1
Reactant: C=C(Cl)C#N
Agent: N
Product: N#CC(Cl)CC(=O)c1ccccc1

Procedure:
In the past, alpha-halogeno-betaaminopropionitriles have been isolated in the form of the hydrochloride or benzoyl compound of alpha-chloro-beta-aminopropionitrile. For example, the method described in Japanese Patent Publication No. 30152/64 comprises reacting alpha-chloroacrylonitrile with aqueous ammonia, and treating the product with benzoyl chloride to isolate alpha-chloro-beta-benzoylpropionitrile. L. Doub et al., J. Heterocyclic Chem., Vol. 7, pp. 527-535 (June 1970) disclose isolating alpha-chloro-beta-aminopropionitrile hydrochloride in a yield of about 55% by dissolving ammonia gas in methanol, reacting alpha-chloroacrylonitrile with the solution, distilling off the unreacted ammonia and methanol under reduced pressure, adding 25% methanolic hydrochloride to the residue at a temperature of as low as -45° C. to -35° C., and treating the product with ether. However, both of these methods are not entirely satisfactory for commercial practice because the reaction operation is complex and the yield of the final product is low.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].FC(F)(F)C(O)=O.[Cl:15][C:16]1[CH:17]=[N:18][C:19]2[NH:20][C:21]3[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=3)[CH2:26][CH2:27][C:28]3[CH:36]=[C:32]([NH:33][C:34]=1[N:35]=2)[CH:31]=[CH:30][C:29]=3[NH:37][C:38]([CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)=[O:39].[N:47]([C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)=[C:48]=[S:49]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH:47]([C:48]([N:43]1[CH2:44][CH2:45][CH:40]([C:38]([NH:37][C:29]2[CH:30]=[CH:31][C:32]3[NH:33][C:34]4[N:35]=[C:19]([NH:20][C:21]5[CH:22]=[CH:23][CH:24]=[C:25]([CH:46]=5)[CH2:26][CH2:27][C:28]=2[CH:36]=3)[N:18]=[CH:17][C:16]=4[Cl:15])=[O:39])[CH2:41][CH2:42]1)=[S:49])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCNCC1
Reactant: S=C=Nc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc2cc1CCc1cccc(c1)Nc1ncc(Cl)c(n1)N2)C1CCN(C(=S)Nc2ccccc2)CC1
Yield: 28 %

Procedure:
The desired compound was prepared according to the procedure of Example A9, step H using N-[6-chloro-2,4,8,22-tetraazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20), 3(22),4,6,9(21),10,12,16,18-nonaen-12-yl]piperidine-4-carboxamide bis(trifluoroacetate) and isothiocyanatobenzene as starting materials in 28% yield. LCMS for C31H30ClN7OS (M+H)+: m/z=584.2.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH3:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:13]([CH:15]1[O:17][CH2:16]1)Cl>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:13][CH:15]2[CH2:16][O:17]2)=[C:7]([CH3:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: ClCC1CO1
Reactant: Cc1cc(C(C)(C)C)ccc1O
Product: Cc1cc(C(C)(C)C)ccc1OCC1CO1

Procedure:
The title compound was prepared from 4-tert-butyl-2-methyl-phenol and epichlorohydrin employing the procedures as set forth in Step 1 of Example 2.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:10]([C:21]2[C:26]([F:27])=[CH:25][CH:24]=[C:23]([F:28])[C:22]=2[F:29])[C:11]2[C:12]([CH3:20])=[CH:13][C:14]([C:17]([NH2:19])=[O:18])=[N:15][CH:16]=2)=[O:9])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:38])C=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:10]([C:21]2[C:26]([F:27])=[CH:25][CH:24]=[C:23]([F:28])[C:22]=2[F:29])[C:11]2[C:12]([CH3:20])=[CH:13][C:14]([C:17]([NH2:19])=[O:18])=[N:15][CH:16]=2)(=[O:38])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1cc(C(N)=O)ncc1C(c1c(F)ccc(F)c1F)S(=O)c1ccc(F)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cc(C(N)=O)ncc1C(c1c(F)ccc(F)c1F)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 60 %

Procedure:
To a solution of 5-[[(4-fluorophenyl)sulfinyl](2,3,6-trifluorophenyl)methyl]-4-methylpyridine-2-carboxamide (106 mg, 0.25 mmol) in methylene chloride (5 ml), 3-chloroperbenzoic acid (66 mg, 0.25 mmol) was added at 0° C. After stirring for 5 days at room temperature, the reaction mixture was washed with 1 N aqueous sodium hydroxide. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the obtained residue was subjected to preparative thin-layer chromatography (developed with hexane:ethyl acetate=2:3, eluted with methylene chloride:methanol=4:1). The obtained fraction was concentrated under reduced pressure, and the resulting residue was washed with a mixed solvent of ethanol and diethyl ether, and was collected by filtration, to obtain the title compound (67 mg, 0.15 mmol, 61%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=O)=[CH:4][N:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:12].P(Cl)(Cl)(Cl)=O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][Cl:12])=[CH:4][N:3]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=C(O)c1ccc(Cl)nc1
Solvent: O=P(Cl)(Cl)Cl
Product: ClCc1ccc(Cl)nc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 108.6 %

Procedure:
6-Chloronicotinic acid (23.36 g, 0.18 mol), phosphorus pentachloride (41.65 g, 0.20 mol) and phosphorus oxychloride (20.50 ml, 0.22 mol) were stirred vigorously together at ambient temperature (20° C.). The resulting mixture was heated with stirring to 120° C. and kept at that temperature for a further 3 hours. The mixture was then allowed to cool to ambient temperature (20° C.) and excess phosphorus oxychloride was evaporated off under reduced pressure to yield 6-chloronicotinyl chloride as a brown oil 31.68 g, 100%), which was used directly in the following step.