Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13].N12CCCN=C1CCCCC2.[Cl:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][C:43]=1[CH3:44])[C:38](O)=[O:39].Cl.CN(C)CCCN=C=NCC>CC#N>[Cl:34][C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][C:43]=1[CH3:44])[C:38]([NH:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[O:22])[N:7]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:8]2=[O:13])=[O:39]
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: Cc1ccc(C(=O)O)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc(C(=O)NCc2cccc3c2C(=O)N(C2CCC(=O)NC2=O)C3=O)cc1Cl
Reaction time: 0.17 h
Yield: 77.5 %

Procedure:
To a stirred suspension of 4-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.7 g, 2.2 mmol) in CH3CN (60 ml), was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.8 g, 5.4 mmol). After stirring for 10 minutes, 1-hydroxybenzenetriazole (0.35 g, 2.6 mmol) and 3-chloro-4-methyl-benzoic acid (0.4 g, 2.4 mmol) were added. To the reaction mixture, was then added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.62 g, 3.2 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was then concentrated in vacuo, and the residue was stirred in H2O (50 mL). A suspension formed and after filtration the solid was reslurried in acetone (20 mL). The suspension was filtered to afford 3-chloro-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-4-methyl-benzamide as a white solid (0.75 g, 79%): mp, 249-251° C.; HPLC: Waters Symmetry C-18, 3.9×150 mm, 5 micro, 1 mL/min, 240 nm, 40/60 (CH3CN/H2O): tR=6.8 min. (97%); 1H NMR (DMSO-d6): δ 2.06-2.11 (m, 1H), 2.39 (s, 3H), 2.53-2.64 (m, 2H), 2.85-2.96 (m, 1H), 4.94 (d, J=5.8 Hz, 2H), 5.15-5.20 (dd, J=5, 12 Hz, 1H), 7.47-7.97 (m, 6H), 7.82-7.89 (m, 3H), 9.22 (t, J=6 Hz, 1H), 11.15 (s, 1H). 13C NMR (DMSO-d6) δ: 19.55, 21.97, 30.92, 38.36, 48.86, 121.89, 126.07, 127.15, 127.60, 131.22, 131.52, 133.11, 133.33, 134.80, 139.06, 139.10, 165.13, 166.94, 167.50, 169.81, 172.74. Anal Calcd for C22H18ClN3O5: C, 60.08; H, 4.12; N, 9.55; Cl, 8.06. Found: C, 59.69; H, 4.15; N, 9.60; Cl, 8.08.
Reaction SMILES: [CH2:1]([C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:11])[CH2:2][CH3:3].BrC[CH2:14][CH2:15][CH2:16][C:17]#[N:18]>>[CH2:1]([C:4]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:5]=1[O:11][CH2:14][CH2:15][CH2:16][C:17]#[N:18])[CH2:2][CH3:3]
Reactant: CCCc1c(O)cccc1Cl
Reactant: N#CCCCCBr
Product: CCCc1c(Cl)cccc1OCCCC#N

Procedure:
Five and seven-tenths grams of 2-propyl3-chlorophenol were then reacted with 5.9 ml. of 5bromovaleronitrile following the procedure of Example 2A. The resulting 4-(2-propyl-3-chlorophenoxy)butane nitrile was provided by chromatography. This purified nitrile intermediate (3.3 g.) was dissolved in about 65 ml. of methylene chloride to which 3.0 g. of aluminum chloride and 1.7 ml. of acetyl chloride had been added and the reaction was heated to reflux overnight. The reaction was cooled, additional methylene chloride was added, and the mixture was poured into ice/hydrochloric acid. The layers were separated and the organic layer was washed first with an aqueous sodium bicarbonate solution and then with water. The organic solution was dried over sodium sulfate and evaporated to dryness. Purification by chromatography provided 2.67 g. of the desired 4-(2-propyl-3-chloro4-acetylphenoxy)butane nitrile. NMR.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.C(N(CC)CC)C.[CH2:13]([N:15]=[C:16]=[O:17])[CH3:14].Cl>C1COCC1.C(OCC)(=O)C>[CH2:13]([NH:15][C:16]([N:1]1[CH:5]=[CH:4][CH:3]=[N:2]1)=[O:17])[CH3:14]
Reactant: c1cn[nH]c1
Reactant: CCN=C=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCNC(=O)n1cccn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.9 %

Procedure:
To a solution of pyrazole (1.7 g, 25 mmol) and 4 mL triethylamine in 50 mL dry THF was added ethyl isocyanate (2 g, 28 mmol) at 0° C. and the resulting reaction solution was stirred at RT for 18 h. Ethyl acetate and 2N HCl were added. The aq layer was separated and extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine, dried and concentrated in vacuo to give an oil. The oil was triturated with cold hexane to give 2.5 g of N-ethyl-1H-pyrazole-1-carboxamide as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[S:10][CH:9]=[C:8]([C:11]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=3[CH3:23])[C:17](O)=[O:18])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:24][C:25]1[N:26]=[CH:27][N:28]([C:30]2[CH:31]=[C:32]([CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=2)[NH2:33])[CH:29]=1>>[NH2:1][C:2]1[C:3]2[S:10][CH:9]=[C:8]([C:11]([NH:13][C:14]3[CH:15]=[C:16]([C:17](=[O:18])[NH:33][C:32]4[CH:34]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:36]=[C:30]([N:28]5[CH:29]=[C:25]([CH3:24])[N:26]=[CH:27]5)[CH:31]=4)[CH:20]=[CH:21][C:22]=3[CH3:23])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1cn(-c2cc(N)cc(C(F)(F)F)c2)cn1
Reactant: Cc1ccc(C(=O)O)cc1NC(=O)c1csc2c(N)ncnc12
Product: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(NC(=O)c4csc5c(N)ncnc45)c3)cc(C(F)(F)F)c2)cn1

Procedure:
The procedure of Step 5 of Example 1 was repeated except for using 3-(4-aminothieno[3,2-d]pyrimidine-7-carboxamido)-4-methylbenzoic acid obtained in Step 4 of Example 8 and 3-(4-methyl-1H-imidazole-1-yl)-5-(trifluoromethyl)aniline to obtain the title compound (see Table 1).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:19]=[C:14]3[CH2:15][O:16][CH2:17][CH2:18][N:13]3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[C:20]([O:23][CH2:24][C:25]1[C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:28]=[CH:27][C:26]=1[N:40]1[CH2:52][CH2:51][N:43]2[C:44]3[CH2:45][CH2:46][CH2:47][CH2:48][C:49]=3[CH:50]=[C:42]2[C:41]1=[O:53])(=[O:22])[CH3:21].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CC([O-])=O.[Na+]>CC#N.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:20]([O:23][CH2:24][C:25]1[C:26]([N:40]2[CH2:52][CH2:51][N:43]3[C:44]4[CH2:45][CH2:46][CH2:47][CH2:48][C:49]=4[CH:50]=[C:42]3[C:41]2=[O:53])=[CH:27][CH:28]=[CH:29][C:30]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:19]=[C:14]3[CH2:15][O:16][CH2:17][CH2:18][N:13]3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1)(=[O:22])[CH3:21]
Reactant: Cn1nc(Cl)cc(Nc2cc3n(n2)CCOC3)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCOC4)c(=O)n(C)n2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 110 °C
Yield: 32.9 %

Procedure:
A mixture of 6-chloro-4-(6,7-dihydro-4H-pyrazolo[5,1-c][1,4]oxazin-2-ylamino)-2-methylpyridazin-3(2H)-one 147a (400 mg, 1.42 mmol), 2-(1-oxo-3,4,6,7,8,9-hexa-hydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-benzyl acetate 114a (660 mg, 1.42 mmol), PdCl2(dppf) (155 mg, 0.21 mmol), K3PO4 (150 mg), and NaOAc (50 mg) in MeCN (20 mL) and H2O (4 mL) was heated at 110° C. in sealed tube for 2 h. The solvent was evaporated in vacuo and the residue was purified on reverse phase Combi-flash to give 147b (273 mg, 33%). MS: [M+H]+ 584.
Reaction SMILES: [NH2-].[Na+].C1([C@@:9]2([OH:19])[CH2:14][C@@H:13]3[C:15]([CH3:17])([CH3:16])[C@@:10]2([CH3:18])[CH2:11][CH2:12]3)C=CC=CC=1.ClCCN(C)C>O1CCOCC1>[C:10]12([CH3:18])[C:15]([CH3:17])([CH3:16])[CH:13]([CH2:12][CH2:11]1)[CH2:14][C:9]2=[O:19]
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)[C@@](O)(c1ccccc1)C2
Agent: CN(C)CCCl
Agent: [NH2-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC12CCC(CC1=O)C2(C)C
Reaction time: 4 h

Procedure:
To a suspension of 45.5 g (1.05 mole) sodium amide (content: 90% by weight/weight) and 500 ml of anhydrous dioxane a mixture of 220 g of the colourless oil obtained by the hydrolysis containing (1R,2S,4R)-(−)-2-[phenyl]-1,7,7-tri-[methyl]-bicyclo[2.2.1]heptane-2-ol, and 100 ml of anhydrous dioxane is added at the boiling point within half an hour. The mixture is heated to boiling for 2 hours, whereupon 113.0 g (1.05 mole) of (2-{chloro}-ethyl)-dimethylamine are added and the reaction mixture is heated to boiling for a further period of 4 hours.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=[C:13](Cl)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]1=[O:21])(=O)C.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)[NH2:27].[OH-].[Na+]>C1COCC1>[CH3:22][O:23][C:24]1[CH:25]=[C:26]([NH:27]/[C:13](=[C:6]2\[C:5](=[O:21])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[CH:10][CH:11]=3)/[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: COc1cccc(N)c1
Reactant: CC(=O)N1C(=O)C(=C(Cl)c2ccccc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)c1

Procedure:
Prepared analogously to Example 2 from 1-acetyl-3-(1-chloro-1-phenyl-methylidene)-2-indolinone and 3-methoxyaniline in THF and subsequent treatment with sodium hydroxide solution.
Reaction SMILES: [H-].[Na+].[CH2:3]([SH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.F[C:12]1[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=[C:14]([O:22][CH3:23])[N:13]=1.O>CN(C)C=O>[CH3:23][O:22][C:14]1[N:13]=[C:12]([S:10][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(OC)nc1F
Reactant: SCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OC)nc1SCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.5 %

Procedure:
To a stirred mixture of 0.8 g (0.0161 mol) of 50% sodium hydride (in mineral oil), which had been washed with hexanes, in 20 mL dry dimethylformamide cooled to -5° under nitrogen was added dropwise 1.9 mL (0.0161 mol) benzyl mercaptan The suspension was stirred at room temperature for 1 hour, cooled to 0°, and a solution of 3.2 g (0.0147 mol) of the product of Example 13 in 20 mL dry dimethylformamide was added dropwise. After warming to room temperature, the solution was poured into water and extracted with ether. The combined organic layers were washed with water and with brine, dried over magnesium sulfate, and evaporated to an oil which was purified by flash chromatography to afford 3.0 g (64%) of a yellow solid: m.p. 67°-71°; NMR (CDCl3, 200 MHz) 3.88 (3H, s), 3.96 (3H, s), 4.46 (2H, s), 6.44 (1H, d, J=9Hz), 7.2-7.5 (5H, m), 8.1 (1H, d, J=9Hz); IR (nujol) 1700, 1580, 1305, 1255 cm-1.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([C:10]([CH3:13])([CH3:12])[CH3:11])[CH:3]=1.[H-].[Na+].[CH3:16][O:17][CH2:18][CH2:19][O:20][CH2:21]Cl.O>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:5]([O:9][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:6][C:7]=1[CH3:8]
Reactant: COCCOCCl
Reactant: Cc1cc(O)c(C(C)(C)C)cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COCCOCOc1cc(C)c(Br)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 4-bromo-2-t-butyl-5-methylphenol from Example YY (32.8 g, 135 mmol) in THF (150 mL) was treated portionwise with NaH (6.5 g of a 60% dispersion in oil, 162 mmol), and the mixture was stirred at room temperature for 1 hour. To the suspension was added 2-methoxyethoxymethyl chloride (18 mL, 158 mmol) all at once, and the resulting mixture was stirred at room temperature overnight. H2O (200 mL) was added slowly, followed by EtOAc (200 mL). The organic layer was separated, washed with H2O, and dried (MgSO4). Concentration gave the title compound. 1H NMR (CDCl3) δ 1.31 (s, 9 H), 2.29 (s, 3 H), 3.36 (s, 3 H), 3.55 (m, 2 H), 3.78 (m, 2 H), 5.25 (s, 2 H), 7.02 (s, 1 H), 7.33 (s, 1 H).
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[CH2:6][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[O:4][C:3]1=[O:25].[CH3:26][N:27]1[C:31]([CH3:32])=[N:30][N:29]=[C:28]1[SH:33].O.OC1N=CN=C2C=1NC(S)=N2>O>[Cl:24][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:25])[C:2]([S:33][C:28]3[N:27]([CH3:26])[C:31]([CH3:32])=[N:30][N:29]=3)=[C:7]([OH:8])[CH2:6]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: Cc1nnc(S)n1C
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cl)C(=O)O2)cc1Cl
Agent: Oc1ncnc2nc(S)[nH]c12
Solvent: O
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Sc3nnc(C)n3C)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared as described in Example C(70), where 3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione was used in place of 3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione and 4,5-dimethyl-4H-1,2,4-triazole-3-thiol, as shown in Example C(88), Step 1, was used in place of 6-hydroxy-8-mercaptopurine monohydrate. 1H NMR (500 MHz, DMSO-d6, WET suppression of DMSO-h6 (2.5 ppm) and H2O (3.35 ppm) peak areas) δ 1.49-1.64 (m, 8H) 1.92 (m, 2H) 2.33 (m, 1H) 2.37 (s, 3H) 2.50 (m, 2H, overlap with dmso) 2.62 (d, J=15 Hz, 1H) 2.80 (d, J=17.6 Hz, 1H) 3.55 (s, attenuation due to proximity to H2O peak) 3.80 (s, 3H) 7.02 (d, J=8.5 Hz, 1H) 7.12 (dd, J=8.5, 1.9 Hz, 1H) 7.24 (d, J=1.9 Hz, 1H). MS (APCI) calcd for C23H28ClN3O4S: 478.01; found M=478.1.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[N:6][CH:5]=[N:4]1.[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C@:16]1([O:36][CH2:35]1)[C@H:17]([N:19]1[CH:23]=[CH:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[C:20]1=[O:34])[CH3:18].O>CN(C)C=O.C(OCC)(=O)C>[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C@:16]([OH:36])([CH2:35][N:3]1[CH:7]=[N:6][CH:5]=[N:4]1)[C@H:17]([N:19]1[CH:23]=[CH:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:33])[F:32])=[CH:26][CH:25]=2)[C:20]1=[O:34])[CH3:18]
Reactant: c1nc[nH]n1
Reactant: C[C@@H](n1ccn(-c2ccc(C(F)(F)F)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](n1ccn(-c2ccc(C(F)(F)F)cc2)c1=O)[C@@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Yield: 82.8 %

Procedure:
60% Sodium hydride in oil (65 mg) was dispersed in 4 ml of dimethylformamide, and 118 mg of 1,2,4-triazole was added thereto with ice cooling. The resulting mixture was stirred at room temperature for ten minutes. The solution of 362 mg of 1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-3-(4-trifluoromethylphenyl)-2(1H,3H)-imidazolone prepared hereinabove in 2 ml of dimethylformamide was added thereto and the resulting mixture was heated at 50° C. for five hours. After cooling, to the reaction solution was added 8 ml of cold water and 40 ml of ethyl acetate to fractionate and the aqueous layer was extracted with ethyl acetate twice. The ethyl acetate layers were combined, washed with water and a saturated aqueous solution of sodium chloride successively, dried over anhydrous magnesium sulfate and distilled off under reduced pressure. The residue was purified by silica gel chromatography (eluent: ethyl acetate/hexane=1/1 to 2/1 to ethyl acetate) to give 350 mg of 1-[(1R,2S)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-(4-trifluoromethylphenyl)-2(1H,3H)-imidazolone as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[C:4]([Cl:10])[CH:3]=1.CN(C)C1C=CC=CC=1.[Br:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26](Cl)=[O:27]>>[Br:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([NH:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[C:4]([Cl:10])[CH:3]=1)=[O:27]
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Reactant: O=C(Cl)CCCCCBr
Solvent: CN(C)c1ccccc1
Product: O=C(CCCCCBr)Nc1cc(Cl)c(O)c(Cl)c1
Temperature: 25 °C
Yield: 89 %

Procedure:
was prepared in 89% yield from 24.4 g (0.14 mol) of 4-amino-2,6-dichlorophenol, 18.1 g (0.15 mol) of N,N-dimethylaniline and 28.8 g (0.14 mol) of 6-bromohexanoyl chloride according to the procedure of Example 6, part a, except that the reaction was cooled on ice during the addition and was stirred at room temperature rather than refluxed. The product was crystallized from ethanol-water, mp 113°-114° C.
Reaction SMILES: [CH2:1](S)C.[H-].[Na+].C[O:7][C:8]1[CH:32]=[CH:31][C:11]([C:12]([C:14]2[CH2:15][C:16]3[C:21]([C:22]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:20][CH:19]=[C:18]([O:29]C)[CH:17]=3)=[O:13])=[CH:10][CH:9]=1.Cl>CN(C=O)C>[OH:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([C:14]2[CH2:15][CH2:1][C:16]3[C:21]([C:22]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:20][CH:19]=[C:18]([OH:29])[CH:17]=3)=[O:13])=[CH:31][CH:32]=1
Reactant: COc1ccc(C(=O)C2=C(c3ccccc3)c3ccc(OC)cc3C2)cc1
Reactant: CCS
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(C1=C(c2ccccc2)c2ccc(O)cc2CC1)c1ccc(O)cc1
Temperature: 60 °C

Procedure:
To 300 ml. of DMF were added under nitrogen and with ice bath cooling, 9.3 gms. of ethyl mercaptan. To the mixture then were added 7.2 gms. of a 50 percent sodium hydride-oil mixture. The mixture represents 0.15 mole of sodium hydride. To the resulting mixture then were added 11.1 gms. (0.03 mole) of the product from Example 1. The mixture was heated at 60° C. for 1 hour. Analysis of the reaction mixture by TLC indicated the presence of starting material plus another component, probably the mono-hydroxy compound. The temperature of the reaction mixture was raised to 110° C., and this temperature was maintained for one hour. TLC showed no starting material; however, the presence of two components was noted. The reaction mixture therefore was heated for an additional one hour at 125° C. after which a single spot was noted by TLC analysis. The reaction mixture then was acidified by addition of cold 1N hydrochloric acid. The mixture was extracted with ethyl acetate. The ethyl acetate was washed with water and evaporated. The resulting residue was recrystallized from a mixture of methanol and acetone to give 8 g. of the title compound, m.p. 205°-207° C.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].CI.[CH:9]1([N:12]([CH2:28][C:29]2[CH:34]=[C:33]([O:35][CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:32]=[C:31]([OH:41])[CH:30]=2)[C:13]([C@@H:15]2[O:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]2)=[O:14])[CH2:11][CH2:10]1.O>CN(C)C=O>[CH:9]1([N:12]([CH2:28][C:29]2[CH:34]=[C:33]([O:35][CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:32]=[C:31]([O:41][CH3:1])[CH:30]=2)[C:13]([C@@H:15]2[O:20][CH2:19][CH2:18][N:17]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:16]2)=[O:14])[CH2:10][CH2:11]1
Reactant: O=C([O-])[O-]
Reactant: COCCCOc1cc(O)cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CCO2)C2CC2)c1
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COCCCOc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CCO2)C2CC2)cc(OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Potassium carbonate (54 mg) and methyl iodide (24 μL) were added to a solution of tert-butyl(2R)-2-({cyclopropyl[3-hydroxy-5-(3-methoxypropoxy)benzyl]amino}carbonyl)morpholin-4-carboxylate (a compound obtained in Reference Example 12, 120 mg) in N,N-dimethylformamide (6 ml) and the mixture was stirred at room temperature for 2 hours. Water was added to the mixture under ice-cooling and it was extracted with ethyl acetate. The organic layer was washed with water and saturated brine successively, dried over sodium sulfate and concentrated in vacuo. The resulted residue was purified with a silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=2/1) to give tert-butyl(2R)-2-({cyclopropyl[3-methoxy-5-(3-methoxypropoxy)benzyl]amino}carbonyl)morpholin-4-carboxylate (88 mg) as a colorless oil.
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li+].[Cl-].[CH:32]12[CH2:46][CH:36]([N:37]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:38]1)[CH2:35][NH:34][CH2:33]2>>[C:42]([O:41][C:39]([N:37]1[CH2:38][CH:32]2[CH2:46][CH:36]1[CH2:35][N:34]([C:20]([C:19]1[CH:18]=[N:17][C:16]([NH:15][C:12]3[N:13]=[CH:14][C:9]4[CH:8]=[C:7]([C:25](=[O:29])[N:26]([CH3:27])[CH3:28])[N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:10]=4[N:11]=3)=[CH:24][CH:23]=1)=[O:22])[CH2:33]2)=[O:40])([CH3:45])([CH3:43])[CH3:44]
Reactant: CC(C)(C)OC(=O)N1CC2CNCC1C2
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCC1
Agent: [Cl-]
Agent: [Li+]
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CC5CC(C4)N(C(=O)OC(C)(C)C)C5)cn3)nc2n1C1CCCC1
Yield: 80 %

Procedure:
Following general amide formation method 1, 6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-nicotinic acid (in a salt form with 5 eq. of LiCl) (571 mg, 0.942 mmol) was combined with tert-butyl 3,6-diazabicyclo[3.2.1]octane-6-carboxylate (200 mg, 0.942 mmol) to give 446 mg of 3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,6-diaza-bicyclo[3.2.1]octane-6-carboxylic acid tert-butyl ester in 80% yield. MS (ESI) m/e (M+H+): 588.9.
Reaction SMILES: [Cl:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13](I)=[CH:14][C:6]1=2.[CH3:22][CH:23]([CH3:34])[CH2:24][CH2:25][N:26]1[CH:30]=[C:29](B(O)O)[CH:28]=[N:27]1>>[Cl:1][C:2]1[C:19]([F:20])=[CH:18][CH:17]=[C:16]([F:21])[C:3]=1[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][C:7]2[N:11]=[CH:12][C:13]([C:29]3[CH:28]=[N:27][N:26]([CH2:25][CH2:24][CH:23]([CH3:34])[CH3:22])[CH:30]=3)=[CH:14][C:6]1=2
Reactant: CC(C)CCn1cc(B(O)O)cn1
Reactant: Fc1ccc(F)c(CN2CCNc3ncc(I)cc32)c1Cl
Product: CC(C)CCn1cc(-c2cnc3c(c2)N(Cc2c(F)ccc(F)c2Cl)CCN3)cn1
Yield: 21 %

Procedure:
1-(2-Chloro-3,6-difluorobenzyl)-7-iodo-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine (99 mg) was reacted with 1-(3-methylbutyl)-1H-pyrazole-4-boronic acid, pinacol ester as in General Procedure 4B to give the title compound as a brown solid (21% yield). M.p.=134° C., LCMS: m/z=431.92 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 0.96 (6H, d, J=6.6 Hz), 1.61 (1H, m), 1.80 (2H, m), 3.28 (2H, t, J=4.8 Hz), 3.51 (2H, m), 4.15 (2H, t, J=7.5 Hz), 4.50 (2H, s), 4.90 (1H, bs), 6.96 (1H, d, J=1.5 Hz), 7.02 (1H, m), 7.12 (1H, m), 7.51 (1H, s), 7.63 (2H, m).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][CH:10]2[O:12][CH2:11]2)=[CH:6][CH:5]=1)#[N:2].[CH2:15]([NH:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH3:18]>CO>[C:1]([CH2:3][C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][CH:10]([OH:12])[CH2:11][N:19]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:15][CH2:16][CH2:17][CH3:18])=[CH:6][CH:5]=1)#[N:2]
Reactant: CCCCNCCCC
Reactant: N#CCc1ccc(OCC2CO2)cc1
Solvent: CO
Product: CCCCN(CCCC)CC(O)COc1ccc(CC#N)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
30 g. of 3-(4-cyanomethylphenoxy)propylene oxide were mixed with 133.5 ml dibutylamine and 300 ml methanol and stirred at room temperature for 20 hours. The mixture was concentrated in a rotary evaporator and the residue was taken up in 225 ml of 1 N hydrochloric acid. The acidic solution was extracted with a total of 300 ml of dichloromethane. The dichloromethane phase was discarded. The aqueous phase was mixed with about 70 ml of 4 N caustic soda solution and extracted by shaking with 200 ml dichloromethane. The dichloromethane phase was dried over sodium sulfate. The desiccant was filtered off and the dichloromethane was drawn off with a rotary evaporator.