Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([NH2:23])[CH:21]=4)[CH2:16][CH2:15]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>>[F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][CH2:7][N:8]2[CH2:9][CH2:10][CH:11]([N:14]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([NH:23][C:26](=[O:28])[CH3:27])[CH:21]=4)[CH2:16][CH2:15]3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Product: CC(=O)Nc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2
Yield: 41 %

Procedure:
1-[1-(4-Fluorophenethyl)piperidin-4-yl]-6-aminoindoline (1.0 g) and acetic anhydride (1 ml) were treated as in Example 133 to give the title compound (450 mg) as a pale yellow powder (yield: 41%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH:24]1[C:33]2[N:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH2:27][CH2:26][CH2:25]1)[CH2:12][CH2:13][CH2:14][NH:15][C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20]N=1)=[O:17].[C:34](O)(=O)C>>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH:24]1[C:33]2[N:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH2:27][CH2:26][CH2:25]1)[CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:17])[C:18]1[CH:34]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(=O)O
Reactant: O=C(NCCCN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21)c1ccccn1
Product: O=C(NCCCN(Cc1nc2ccccc2[nH]1)C1CCCc2cccnc21)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of the amine (80 mg, 0.18 mmol) in acetic acid (2 mL) was added hydrobromide saturated acetic acid (2 mL). The reaction mixture was stirred for 30 minutes. Then it was triturated with diethyl ether four times to afford the title compound as a yellow solid (99 mg), which was dried in vacuo. 1H NMR (D2O) δ 1.73-1.86 (m, 2H), 1.93-2.01 (m, 1H), 2.13-2.17 (m, 1H), 2.34-2.38 (m, 1H), 2.43-2.53 (m, 1H), 2.80-2.87 (m, 1H), 2.95-2.97 (br m, 2H), 3.17-3.23 (m, 1H), 3.28-3.35 (m, 1H), 3.53 (q, 1H, J=6.9 Hz), 4.28-4.54 (m, 3H), 7.31-7.38 (m, 4H), 7.49-7.51 (m, 3H), 7.63-7.72 (m, 3H), 8.24 (d, 1H, J=7.8 Hz), 8.55 (d, 1H, J=5.7 Hz). 13C NMR (D2O) δ 20.36, 20.49, 27.63, 28.08, 37.37, 48.27, 49.01, 60.18, 114.12, 125.86, 126.98, 129.20, 130.75, 132.67, 132.99, 139.30, 140.59, 147.99, 151.17, 172.84. ES-MS m/z 440 [M+H]+. Anal. Calcd. for C27H29N5O.2.1HBr.2.2H2O: C, 49.96; H, 5.51; N, 10.79; Br, 25.85. Found: C, 49.96; H, 5.45; N, 10.65; Br, 25.95.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]3[CH2:22][CH2:21][CH2:20][N:19]([CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])[C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]1([C:7]2[N:8]=[C:9]3[CH2:22][CH2:21][CH2:20][N:19]([CH2:23][CH2:24][CH2:25][CH2:26][O:27][CH2:28][C:29]([OH:31])=[O:30])[C:10]3=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)COCCCCN1CCCc2nc(-c3ccccc3)c(-c3ccccc3)nc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)COCCCCN1CCCc2nc(-c3ccccc3)c(-c3ccccc3)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 2-(4-(2,3-diphenyl-7,8-dihydropyrido[2,3-b]pyrazin-5(6H)-yl)butoxy)acetate (step 4)(20 mg, 0.042 mmol) in DCM (0.5 ml) was treated with TFA (0.5 ml, 6.49 mmol) and stirred at RT for 1 h. The solvent was removed in vacuo and the crude product was dissolved in DCM (with <10% MeOH) and basified with saturated sodium bicarbonate solution. The organic portion was separated and the aqueous was extracted with 10% MeOH/DCM. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:13]=[C:12]([S:14]([NH2:17])(=[O:16])=[O:15])[S:11][N:10]=2)=[CH:5][CH:4]=1.[C:18](OCC)(OCC)([O:20][CH2:21][CH3:22])[CH3:19]>CCCCCC>[CH2:18]([O:20][C:21](=[N:17][S:14]([C:12]1[S:11][N:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:13]=1)(=[O:16])=[O:15])[CH3:22])[CH3:19]
Reactant: COc1ccc(-c2nsc(S(N)(=O)=O)n2)cc1
Reactant: CCOC(C)(OCC)OCC
Solvent: CCCCCC
Product: CCOC(C)=NS(=O)(=O)c1nc(-c2ccc(OC)cc2)ns1

Procedure:
A mixture of 1.5 g of 3-(4-methoxyphenyl)-1,2,4-thiadiazole-5-sulfonamide and 5 ml of triethyl orthoacetate was refluxed for 4 hours. The mixture was cooled and diluted with hexane (15 ml), and the solids were collected and washed with hexane to give 1.7 g of solid. Recrystallization from 3:1 cyclohexane/benzne (100 ml) gave 1.16 g of needles, m.p. 156°-158°.
Reaction SMILES: C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.[OH:25][C@@H:26]([C@H:28]1[C:49](=[O:50])[N:30]2[CH:31]([C:36]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=3)=[O:37])[C:32](=O)[C@H:33]([CH3:34])[C@H:29]12)[CH3:27].FC(F)(F)S(O)(=O)=O.[SH:59][C@@H:60]1[CH2:64][N:63]([C:65]([O:67][CH2:68][C:69]2[CH:74]=[CH:73][C:72]([N+:75]([O-:77])=[O:76])=[CH:71][CH:70]=2)=[O:66])[C@H:62]([C:78]([N:80]2[CH2:85][CH2:84][N:83]([CH2:86][CH2:87][O:88][C:89](=[O:91])[NH2:90])[CH2:82][CH2:81]2)=[O:79])[CH2:61]1>C(#N)C>[C:89]([O:88][CH2:87][CH2:86][N:83]1[CH2:82][CH2:81][N:80]([C:78]([C@@H:62]2[CH2:61][C@H:60]([S:59][C:32]3[C@H:33]([CH3:34])[C@@H:29]4[C@@H:28]([C@H:26]([OH:25])[CH3:27])[C:49](=[O:50])[N:30]4[C:31]=3[C:36]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=3)=[O:37])[CH2:64][N:63]2[C:65]([O:67][CH2:68][C:69]2[CH:70]=[CH:71][C:72]([N+:75]([O-:77])=[O:76])=[CH:73][CH:74]=2)=[O:66])=[O:79])[CH2:85][CH2:84]1)(=[O:91])[NH2:90]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Reactant: NC(=O)OCCN1CCN(C(=O)[C@@H]2C[C@H](S)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CCN(CCOC(N)=O)CC4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Reaction time: 1 h
Yield: 28.6 %

Procedure:
91 μl of diphenylphosphoryl chloride and 77 μl of diisopropylethylamine were added dropwise, whilst ice-cooling, to a solution of 152 mg of 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-oxo-1-carbapenam-3-carboxylate in 2.0 ml of dry acetonitrile, and the resulting mixture was stirred at the same temperature for 1 hour. 176 μl of diisopropylethyl-amine and a solution of 318 mg of (2S,4S)-4-mercapto-2-[4-(2-carbamoyloxyethyl)-1-piperazinylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine trifluoromethane-sulfonate (prepared as described in Preparation 53) in 2.0 ml of dry acetonitrile were then simultaneously added dropwise to the mixture, whilst ice-cooling, and the resulting mixture was stirred at the same temperature for 2 hours, after which it was allowed to stand overnight in a refrigerator. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was mixed with an aqueous solution of sodium hydrogencarbonate. The mixture was then extracted with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate. The solvent was then removed from the extract by distillation under reduced pressure, and the resulting residue was purified by chromatography through a Lobar column (Merck, LiChroprep Si60, size B), using a 5:1 by volume mixture of ethyl acetate and methanol as the eluent to give 99 mg of the title compound, as a powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[C:26](I)=[N:25][C:24]4[C:19]3=[N:20][CH:21]=[N:22][C:23]=4[NH:28][CH3:29])=[CH:14][CH:13]=2)=[O:10])=[CH:4][C:3]=1[C:30]([F:33])([F:32])[F:31].[CH2:34]([OH:36])[CH3:35]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[C:26]([O:36][CH2:34][CH3:35])=[N:25][C:24]4[C:19]3=[N:20][CH:21]=[N:22][C:23]=4[NH:28][CH3:29])=[CH:14][CH:13]=2)=[O:10])=[CH:4][C:3]=1[C:30]([F:33])([F:32])[F:31]
Reactant: CNc1ncnc2c1nc(I)n2-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1
Reactant: CCO
Product: CCOc1nc2c(NC)ncnc2n1-c1ccc(NC(=O)Nc2ccc(Cl)c(C(F)(F)F)c2)cc1

Procedure:
The title compound can be prepared from 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-[4-(8-iodo-6-(methylamino)purin-9-yl)phenyl]urea and ethanol by using the same techniques as in Example 136.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:24])[S:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:25]1[S:26][CH:27]([CH2:30][C:31]([O:33]CC)=[O:32])[CH2:28][N:29]=1)=[CH:9]2.[OH-].[Na+].O1CCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(O)C>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[C:13]([N:15]([CH3:24])[S:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)(=[O:18])=[O:17])[CH:14]=1)[NH:11][C:10]([C:25]1[S:26][CH:27]([CH2:30][C:31]([OH:33])=[O:32])[CH2:28][N:29]=1)=[CH:9]2
Reactant: CCOC(=O)CC1CN=C(c2cc3cc(OCCOC)cc(N(C)S(=O)(=O)c4cccs4)c3[nH]2)S1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COCCOc1cc(N(C)S(=O)(=O)c2cccs2)c2[nH]c(C3=NCC(CC(=O)O)S3)cc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 98.5 %

Procedure:
A mixture of ethyl (2-{5-(2-methoxyethoxy)-7-[methyl(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetate (300 mg), 1N aqueous sodium hydroxide solution (2 mL), tetrahydrofuran (2 mL) and ethanol (2 mL) was stirred at room temperature for 15 hr. The reaction mixture was acidified with aqueous citric acid solution, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated to give the title compound (280 mg, yield 97%) as yellow crystals. The crystals were recrystallized from ethyl acetate-hexane to give yellow prism crystals. melting point 113-114° C.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[CH2:21][CH2:20][N:19]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[C:18]4=[O:28])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH2:31]([O:33]C1C=CC=CC=1N=C=O)[CH3:32].Cl>>[F:1][C:2]1[CH:30]=[CH:29][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]4[CH2:21][CH2:20][N:19]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=5[O:33][CH2:31][CH3:32])[C:18]4=[O:28])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C1N(CCN2CCC(c3noc4cc(F)ccc34)CC2)CCN1c1ccccc1
Reactant: CCOc1ccccc1N=C=O
Agent: Cl
Product: CCOc1ccccc1N1CCN(CCN2CCC(c3noc4cc(F)ccc34)CC2)C1=O

Procedure:
This product is obtained in the same manner as the compound of Example 5, but with replacement of the phenyl isocyanate by 2-ethoxyphenyl isocyanate in Step 1 of the synthesis. The hydrochloride of the title compound melts at 214°-218° C.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[Br:13])[NH:4][C:3]1=O.[CH:15]1([C:18]2[O:22][N:21]=[C:20]([CH2:23][N+:24]#[C-:25])[N:19]=2)[CH2:17][CH2:16]1>>[CH:15]1([C:18]2[O:22][N:21]=[C:20]([C:23]3[N:24]=[CH:25][N:4]4[C:5]5[C:10](=[C:9]([Br:13])[CH:8]=[CH:7][CH:6]=5)[C:11](=[O:12])[N:2]([CH3:1])[C:3]=34)[N:19]=2)[CH2:17][CH2:16]1
Reactant: [C-]#[N+]Cc1noc(C2CC2)n1
Reactant: Cn1c(=O)[nH]c2cccc(Br)c2c1=O
Product: Cn1c(=O)c2c(Br)cccc2n2cnc(-c3noc(C4CC4)n3)c12

Procedure:
M.p. 206,6° C. by reaction between 3-methyl-5-bromo-1,2,3,4-tetrahydro-2,4-dioxo-quinazoline an 5-cyclopropyl-3-isocyanomethyl-1,2,4oxadiazole.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[CH:14][CH:13]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 70 °C
Yield: 702.3 %

Procedure:
Under a dry nitrogen atmosphere a stirred mixture of 10.9 g (0.077 mole) 4-fluoronitrobenzene, 9.95 g (0.0077 mole) 4-chlorophenol, and 11.8 g (0.085 mole) potassium carbonate in 175 mL of dimethylsulfoxide was heated at 70° C. for two days. The reaction mixture was cooled and filtered. The filtrate was diluted with water until a volume of one liter was obtained. This mixture was extracted with three 200 mL portions of diethyl ether. The combined ether extract was washed with water followed by an aqueous saturated sodium chloride solution. The washed extract was dried over anhydrous sodium sulfate and filtered. Evaporation of the filtrate under reduced pressure yielded 13.5 g 4-(4-chlorophenoxy)nitrobenzene (mp 67°-70° C.).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:11][CH:10]([N:12]([CH2:18][CH2:19][CH3:20])[S:13]([CH2:16][CH3:17])(=[O:15])=[O:14])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:21])[CH:8]=2)[O:3]1.[H-].[Na+].[CH3:25][O:26][CH2:27][CH2:28]Br>CC(N(C)C)=O>[CH3:25][O:26][CH2:27][CH2:28][O:21][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[O:3][C:2]([CH3:1])([CH3:22])[CH2:11][CH:10]2[N:12]([CH2:18][CH2:19][CH3:20])[S:13]([CH2:16][CH3:17])(=[O:15])=[O:14]
Reactant: COCCBr
Reactant: CCCN(C1CC(C)(C)Oc2ccc(O)cc21)S(=O)(=O)CC
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCCN(C1CC(C)(C)Oc2ccc(OCCOC)cc21)S(=O)(=O)CC

Procedure:
0.491 g (1.5 mmol) of N-[2,2-dimethyl-6-hydroxychroman-4-yl]-N-(1-propyl)ethanesulfonamide (Example 22b) was reacted with NaH and 2-methoxyethyl bromide in DMA. 0.27 g of the title compound was obtained from petroleum ether, m.p. 78-80° C.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[CH:12]=[C:11]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[NH:10][N:9]=1)=[O:7])C>CO>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][CH2:13][C:11]2[NH:10][N:9]=[C:8]([C:6]([OH:7])=[O:5])[CH:12]=2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1cc(CCc2ccc(Cl)cc2)[nH]n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1cc(CCc2ccc(Cl)cc2)[nH]n1
Yield: 92.3 %

Procedure:
Freshly prepared aq. NaOH (10 M in H2O, 16.31 mmol) was added to a stirring, room temperature solution of 68 (0.9092 g, 3.26 mmol) in MeOH (8.2 mL, 0.4 M) under N2. The reaction was then heated to reflux until the reaction was judged complete by HPLC (7 min). The reaction was concentrated, redissolved in H2O (5 mL), and extracted with EtOAc (2 mL). 10% aq. HCl was added dropwise to the aqueous layer until the pH=2. The white solid that precipitated was filtered off and washed with cold H2O. The solid was dried under vacuum overnight to obtain 0.7543 g (92.2%) of 69. Since 69 still contained a very small amount of an impurity, it was dissolved in 38 mL of toluene with 10 mL of EtOAc and 14 mL of EtOH while heating to reflux. Pure white solid precipitated from the reaction after sitting overnight (0.4052 g). solid (Note: An undesired impurity has a retention time of 9.904 min by HPLC). 1H (CD3OD, 400 MHz): δ 7.24 (2H, d, J=8.3 Hz), 7.15 (2H, d, J=8.3 Hz), 6.54 (1H, s), 2.95 (4H, s) ppm. 13C (CD3OD, 100 MHz): δ 164.68, 148.23, 142.84, 140.91, 133.00, 131.08, 129.46, 107.59, 35.83, 28.78 ppm. DEPT (CD3OD, 100 MHz): CH2 carbons: 35.83, 28.78; CH carbons: 131.08, 129.46, 107.59 ppm. HPLC: 9.026 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[F:14][C:15]1[N:20]=[CH:19][C:18]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[CH:27]([CH3:31])[NH:26][CH2:25][CH2:24]3)=[CH:17][CH:16]=1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:26]3[CH2:25][CH2:24][C:23]4[C:28](=[CH:29][CH:30]=[C:21]([C:18]5[CH:19]=[N:20][C:15]([F:14])=[CH:16][CH:17]=5)[CH:22]=4)[CH:27]3[CH3:31])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: CC1NCCc2cc(-c3ccc(F)nc3)ccc21
Product: CC1c2ccc(-c3ccc(F)nc3)cc2CCN1C(=O)c1cc2ncc(Cl)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-(6-Fluoro-pyridin-3-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: I[C:2]1[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=1.[C:15]1([C:21]#[CH:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([C:21]#[C:22][C:2]2[CH:14]=[CH:13][C:5]([O:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:4][CH:3]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)COc1ccc(I)cc1
Reactant: C#Cc1ccccc1
Product: CCOC(=O)COc1ccc(C#Cc2ccccc2)cc1

Procedure:
The title compound was prepared from ethyl 2-(4-iodophenoxy)acetate (550 mg, 1.80 mmol) and phenylacetylene (0.17 mL, 1.80 mmol) according to the general procedure IE to give 390 mg (78%) of an orange solid after purification by flash chromatography (SiO2, EtOAc/hexanes, 1:5). Rf: 0.26 (EtOAc:hexanes, 1:5); 1HNMR (CDCl3) δ 7.53-7.45 (m, 4H), 7.36-7.25 (m, 3H), 6.90-6.87 (m, 2H), 4.63 (s, 2H), 4.32-4.23 (dq, 2H, J=7.2 Hz, 2.1 Hz), 1.35-1.24 (tt, 3H, J=7.2 Hz, 1.5 Hz); 13CNMR (CDCl3) δ 168.6, 157.8, 133.1, 131.5, 128.3, 128.0, 123.4, 116.6, 114.7, 89.0, 88.4, 65.4, 61.5, 14.1; EI-MS m/z 280 (M+).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[OH:12][C:13]1[CH:18]=[C:17](O)[CH:16]=[C:15]([OH:20])[CH:14]=1>CC(C)=O>[Cl:11][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:2]=1[NH:1][C:17]1[CH:16]=[C:15]([OH:20])[CH:14]=[C:13]([OH:12])[C:18]=1[C:4]2=[O:6]
Reactant: Nc1c(Cl)cccc1C(=O)O
Reactant: Oc1cc(O)cc(O)c1
Solvent: CC(C)=O
Product: O=c1c2cccc(Cl)c2[nH]c2cc(O)cc(O)c12
Temperature: 230 °C
Reaction time: 0.17 h
Yield: 37 %

Procedure:
A 250-mL sealed reactor was charged with 2-amino-3-chlorobenzoic acid (8.58 g, 50 mmol, and 1,3,5-trihydroxybenzene (110 mg, 1.0 mmol). The mixture was then heated to 230° C. for 40 min. The solids melted after ˜10 minutes and stayed as liquid for ˜1 minute before solidifying again. The mixture was cooled to room temperature and acetone (600 mL) was used to break the solids and transferred to a 1-L Erlenmeyer flask. The slurry was stirred for 30 minutes with periodic breaking of the solid with a spatula2. The solid was filtered and washed with acetone (200 mL), affording a dark yellow to brown powder. The powder was then triturated in hot methanol (1.5 L) at 60° C. for 30 minutes and filtered after the slurry cooled to ˜30° C. and washed with methanol (200 mL) to afford the product 3 (4.87 g, 37%) as yellow solid. 1H NMR (DMSO-d6): 6.06 (1H, d, J=2.3), 6.81 (1H, d, J=2.0), 7.23 (1H, t, J=8.1), 7.87 (1H, d, J=7.3), 8.11 (1H, d, J=7.3), 10.64 (1H, s), 10.97 (1H, s): LC-MS: m/z+1=262.1.
Reaction SMILES: [CH:1]1([NH:4][CH2:5][C:6]2[S:10][C:9](B(O)O)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.Br[C:15]1[CH:16]=[C:17]2[C:21](=[C:22]([C:24]([NH2:26])=[O:25])[CH:23]=1)[NH:20][CH:19]=[C:18]2[CH:27]1[CH2:32][CH2:31][N:30]([S:33]([CH2:36][CH3:37])(=[O:35])=[O:34])[CH2:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:1]1([NH:4][CH2:5][C:6]2[S:10][C:9]([C:15]3[CH:16]=[C:17]4[C:21](=[C:22]([C:24]([NH2:26])=[O:25])[CH:23]=3)[NH:20][CH:19]=[C:18]4[CH:27]3[CH2:28][CH2:29][N:30]([S:33]([CH2:36][CH3:37])(=[O:34])=[O:35])[CH2:31][CH2:32]3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1
Reactant: OB(O)c1ccc(CNC2CC2)s1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CNC5CC5)s4)cc23)CC1

Procedure:
Following the general procedure of 5-{5-[(ethylamino)methyl]-2-thienyl}-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), cyclopropylamine (0.022 mL, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 63 mg of crude {5-[(cyclopropylamino)methyl]-2-thienyl}boronic acid. The crude {5-[(cyclopropylamino)methyl]-2-thienyl}boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (80 mg, 0.193 mmol), potassium carbonate (160 mg, 1.16 mmol), and tetrakis(triphenylphosphine)palladium(0) (5 mg, 0.004 mmol) to give impure title compound. The impure title compound was purified again with the Agilent MDAP and isolated as the free base according to the procedure shown in Example 5 to give 6.8 mg of the title compound (7.2%).
Reaction SMILES: [NH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]1=[O:7].Br[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][N:10]=1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.[Cu]>[CH3:15][C:12]1[CH:13]=[CH:14][C:9]([N:1]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]2=[O:7])=[N:10][CH:11]=1
Reactant: O=c1cccc[nH]1
Reactant: Cc1ccc(Br)nc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: Cc1ccc(-n2ccccc2=O)nc1

Procedure:
2-Pyridinone (1.00 g, 10.5 mmol), 2-bromo-5-methyl-pyridine (1.81 g, 10.5 mmol), Copper (0.013 g, 0.20 mmol) and K2CO3 (1.60 g, 11.6 mmol) were heated at 180° C. for 16 hrs. The brown reaction mixture was cooled, diluted with EtOAc and washed with saturated NaHCO3. The aqueous layer was extracted with EtOAc (2×) and the combined organic extracts were washed with brine, dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed (silica gel, EtOAc as eluent) to afford the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[C:3]=1[CH2:4][CH:5]([C:8]#[N:9])[C:6]#[N:7].[H-].[Na+].Br[CH2:19][CH2:20][C:21]([F:24])([F:23])[F:22]>CN(C)C=O>[F:1][C:2]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[C:3]=1[CH2:4][C:5]([CH2:19][CH2:20][C:21]([F:24])([F:23])[F:22])([C:8]#[N:9])[C:6]#[N:7]
Reactant: FC(F)(F)CCBr
Reactant: N#CC(C#N)Cc1c(F)cc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)F)Cc1c(F)cc(F)cc1F
Yield: 9.6 %

Procedure:
Using 0.50 g of (2,4,6-trifluorobenzyl)malononitrile, 10 ml of N,N-dimethylformamide, 0.11 g of sodium hydride (60% in oil), and 0.46 g of 1-bromo-3,3,3-trifluoropropane, and according to the process described in the Production Example 1, there was obtained 0.07 g of 2-(2,4,6-trifluorobenzyl)-2-(3,3,3-trifluoropropyl)malononitrile (the present compound (17)).
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:16]3[N:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:20](=[O:28])[C:19]4=[C:29]([CH3:32])[CH:30]=[CH:31][N:18]4[N:17]=3)[CH2:13][CH2:14][OH:15])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[CH:3]=1.[OH:41][C:42]1[CH:43]=[C:44]([NH:57][S:58]([CH3:61])(=[O:60])=[O:59])[CH:45]=[C:46](B2OC(C)(C)C(C)(C)O2)[CH:47]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[OH:41][C:42]1[CH:43]=[C:44]([NH:57][S:58]([CH3:61])(=[O:60])=[O:59])[CH:45]=[C:46]([C:2]2[C:10]3[C:9]([NH:11][C@H:12]([C:16]4[N:21]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[C:20](=[O:28])[C:19]5=[C:29]([CH3:32])[CH:30]=[CH:31][N:18]5[N:17]=4)[CH2:13][CH2:14][OH:15])=[N:8][CH:7]=[N:6][C:5]=3[N:4]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[CH:3]=2)[CH:47]=1
Reactant: Cc1ccn2nc([C@H](CCO)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: CC1(C)OB(c2cc(O)cc(NS(C)(=O)=O)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccn2nc([C@H](CCO)Nc3ncnc4c3c(-c3cc(O)cc(NS(C)(=O)=O)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 39 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-3-hydroxypropyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.08 mmol) was treated with N-(3-hydroxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)methanesulfonamide (85 mg, 0.21 mmol), sodium carbonate (23 mg, 0.22 mmols) and 1,11-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (21 mg, 0.03 mmol) in 1,2-dimethoxyethane (1.6 ml) and water (0.40 ml) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 100%, hexane-ethyl acetate) to give 35 mg (39% yield, 65% purity) of the title compound.