Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@H:4]([N:6]1[CH2:11][CH2:10][CH:9]([N:12]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:19]=2[CH3:20])[CH2:8][CH2:7]1)[CH3:5].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Br:50][C:51]1[N:59]=[CH:58][CH:57]=[C:56]([CH3:60])[C:52]=1[C:53](O)=[O:54].CCN(C(C)C)C(C)C>CN(C=O)C>[Br:50][C:51]1[N:59]=[CH:58][CH:57]=[C:56]([CH3:60])[C:52]=1[C:53]([NH:1][CH2:2][CH2:3][C@H:4]([N:6]1[CH2:7][CH2:8][CH:9]([N:12]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH2:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][C:19]=2[CH3:20])[CH2:10][CH2:11]1)[CH3:5])=[O:54]
Reactant: Cc1ccnc(Br)c1C(=O)O
Reactant: COc1ccc(N(Cc2cnccc2C)C2CCN([C@H](C)CCN)CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N(Cc2cnccc2C)C2CCN([C@H](C)CCNC(=O)c3c(C)ccnc3Br)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.3 %

Procedure:
(R)-[1-(3-Amino-1-methyl-propyl)-piperidin-4-yl]-(4-methoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amine (0.070 g, 0.18 mmol), EDCI (0.039 g, 0.20 mmol) and HOBT (0.027 g, 0.20 mmol) were combined in DMF (5 mL) to give a pale yellow solution. To this solution was added 2-bromo-4-methyl-nicotinic acid (0.043 g, 0.20 mmol) followed by DIPEA (38 μL, 0.22 mmol) and the resulting mixture was stirred at 25° C. for 16 h. Standard workup according to General Procedure C gave the crude product as a tan oil. Purification by column chromatography on silica gel (Et2O:MeOH:NH4OH, 89:10:1, v/v/v) afforded 2-bromo-N-((R)-3-{4-[(4-methoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-4-methyl-nicotinamide (0.040 g, 38%) as a white foam. 1H NMR (CDCl3) δ 0.98 (d+m, 4H,), 1.07 (m, 1H), 1.57 (m, 2H), 1.84 (m, 3H), 2.13 (br t, 1H), 2.36 (s, 6H), 2.53 (br t, 1H), 2.75-2.88 (m, 3H), 3.24-3.33 (m, 2H), 3.71 (s, 3H), 3.82 (m, 1H), 3.88 (m, 2H), 6.61 (d, 2H, J=9.0 Hz), 6.69 (d, 2H, J=9.0 Hz), 6.97 (d, 1H, J=6.0 Hz), 7.03 (d, 1H, J=6.0 Hz), 7.94 (d, 1H, J=6.0 Hz), 8.25 (s, 1H), 8.30 (d, 1H, J=6.0 Hz), 8.52 (br s, 1H). 13C NMR (CDCl3) δ. ES-MS m/z 582 (M+H), 604 (M+Na). Anal. Calcd. for C30H38N5O2Br.0.25 CH2Cl2: C, 60.37; H, 6.45; N, 11.64. Found: C, 60.34; H, 6.47; N, 11.52.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[S:13])[NH:11][N:10]=[N:9]2)=[C:4]([F:14])[CH:3]=1.Br[CH2:16][CH3:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)C>[CH2:16]([S:13][C:12]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[F:14])[N:9]=[N:10][N:11]=1)[CH3:17]
Reactant: CCBr
Reactant: Fc1cc(Cl)ccc1-n1nn[nH]c1=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)=O
Product: CCSc1nnnn1-c1ccc(Cl)cc1F
Yield: 81.4 %

Procedure:
A solution of 1.75 g (0.0076 mole) of 1-(4-chloro-2-fluorophenyl)-1,4-dihydro-5H-tetrazol-5-thione, 0.57 ml (0.0076 mole) of bromoethane, and 1.6 g (0.012 mole) of potassium carbonate in 8 ml of acetone was stirred at room temperature for seven hours. The solvent was evaporated from the reaction mixture under reduced pressure leaving a residue. This residue was dissolved in diethyl ether and the organic solution was washed with water. The washed organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to yield 1.6 g of (1-(4-chloro-2-fluorophenyl)-1H-tetrazol-5-yl) ethyl sulfide as a solid, m.p. 76°-79° C.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][N:7]([CH3:66])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:24]([O:60][CH3:61])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:58][CH3:59])[C@@H:34]([CH3:57])[C:35](=[O:56])[NH:36][C@H:37]([C:45]1[O:46][C:47]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[N:48][N:49]=1)[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:18])[CH3:17])=[O:13])[CH:9]([CH3:11])[CH3:10])(O)=[O:2].Cl.[O:68]=[C:69]1[CH:73]=[CH:72][C:71](=[O:74])[N:70]1[CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][C:80]([NH:82][NH2:83])=[O:81]>>[O:74]=[C:71]1[CH:72]=[CH:73][C:69](=[O:68])[N:70]1[CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][C:80]([NH:82][NH:83][C:1](=[O:2])[CH2:4][CH2:5][CH2:6][N:7]([CH3:66])[C@H:8]([C:12]([NH:14][C@H:15]([C:19]([N:21]([C@@H:23]([C@@H:62]([CH3:65])[CH2:63][CH3:64])[C@H:24]([O:60][CH3:61])[CH2:25][C:26]([N:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[C@H:33]([O:58][CH3:59])[C@@H:34]([CH3:57])[C:35](=[O:56])[NH:36][C@H:37]([C:45]1[O:46][C:47]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[N:48][N:49]=1)[CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)=[O:27])[CH3:22])=[O:20])[CH:16]([CH3:17])[CH3:18])=[O:13])[CH:9]([CH3:11])[CH3:10])=[O:81]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nnc(-c2ccccc2)o1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Reactant: NNC(=O)CCCCCN1C(=O)C=CC1=O
Agent: Cl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)c1nnc(-c2ccccc2)o1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)NNC(=O)CCCCCN1C(=O)C=CC1=O)C(C)C

Procedure:
7.4 mg (8.1 mmol) of N-(3-carboxypropyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1S)-2-phenyl-1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethyl]amino}propyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide and 6.3 mg (24.2 mmol) of 6-(2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)hexanehydrazide hydrochloride were coupled and worked up in analogy to Intermediate 157. 1.6 mg (13% of theory) of the title compound were obtained as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][C:24]=3[O:33][CH2:34][CH3:35])=[N:9]2)=[CH:4][CH:3]=1.[NH:36]1[CH2:42][CH2:41][C:40](=[O:43])[NH:39][CH2:38][CH2:37]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=3)[N:11]([C:20]([N:36]3[CH2:42][CH2:41][C:40](=[O:43])[NH:39][CH2:38][CH2:37]3)=[O:21])[C:10]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:25][C:24]=3[O:33][CH2:34][CH3:35])=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CCNCCN1
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Br)cc2)[C@@H](c2ccc(Br)cc2)N1C(=O)Cl
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@H](c2ccc(Br)cc2)[C@@H](c2ccc(Br)cc2)N1C(=O)N1CCNC(=O)CC1

Procedure:
1-[(4S,5R)-4,5-Bis-(4-bromo-phenyl)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl]-[1,4]diazepan-5-one was prepared from (4S,5R)-4,5-bis-(4-bromo-phenyl)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12b) and [1,4]diazepan-5-one (Oakwood Products) in an analogous manner as described in example 25. LR-MS: 695.3 [(M+H)+]
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[C:8]1=[O:26].[CH2:34]([O:36][CH2:37][CH2:38][N:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=[C:40]1[N:48]1[CH2:54][CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)[CH3:35]>>[CH3:33][O:32][C:28]1[CH:27]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:29]=1[O:30][CH3:31])[CH2:6][N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:51]2[CH2:52][CH2:53][CH2:54][N:48]([C:40]3[N:39]([CH2:38][CH2:37][O:36][CH2:34][CH3:35])[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=4[N:41]=3)[CH2:49][CH2:50]2)([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:8]1=[O:26]
Reactant: COc1cc(CN2CCC(CCOS(C)(=O)=O)(Cc3ccccc3)C2=O)cc(OC)c1OC
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Product: CCOCCn1c(N2CCCN(CCC3(Cc4ccccc4)CCN(Cc4cc(OC)c(OC)c(OC)c4)C3=O)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 1.6 using 1-(3,4,5-trimethoxybenzyl)-3-(phenylmethyl)-3-(2-methanesulfonyloxyethyl)-2-oxopyrrolidine and 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane to give the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH2:14]/[C:15](=[CH:23]/[C:24](/[CH3:39])=[CH:25]/[CH:26]([CH3:38])[CH2:27][CH:28]([CH3:37])[CH2:29][CH:30]([CH3:36])[CH2:31][CH:32]([CH3:35])[CH2:33][CH3:34])/[C:16]([O:18]C(C)(C)C)=[O:17])[C:3]([O:5][CH2:6][C:7]([O:9]C(C)(C)C)=[O:8])=[O:4].FC(F)(F)C(O)=O>ClCCl>[C:7]([CH2:6][O:5][C:3](=[O:4])[CH:2]([CH3:1])[CH2:14]/[C:15](=[CH:23]/[C:24](/[CH3:39])=[CH:25]/[CH:26]([CH3:38])[CH2:27][CH:28]([CH3:37])[CH2:29][CH:30]([CH3:36])[CH2:31][CH:32]([CH3:35])[CH2:33][CH3:34])/[C:16]([OH:18])=[O:17])([OH:9])=[O:8]
Reactant: CCC(C)CC(C)CC(C)CC(C)/C=C(C)/C=C(/CC(C)C(=O)OCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(C)CC(C)CC(C)CC(C)/C=C(C)/C=C(/CC(C)C(=O)OCC(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.6 %

Procedure:
(Step 2) To 1-(2-tert-butoxy-2-oxoethyl) 5-tert-butyl (Z)-2-methyl-4-{(E)-2,4,6,8,10-pentamethyldodec-2-enylidene}pentanedioate (14.7 mg, 0.027 mmol) obtained in Step 1, dichloromethane (2 mL) and trifluoroacetic acid (0.2 mL, 2.6 mmol) were added, and the resulting mixture was stirred at room temperature for 24 hours. The solvent was evaporated under reduced pressure, and the resulting residue was purified by thin-layer column chromatography (methanol/chloroform=1/9), whereby Compound 9 (8.6 mg, 74%) was obtained.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH:11]([OH:13])[CH2:10][CH:9]1[C:14](=[O:26])[NH:15][C:16]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18][CH:17]1[CH:19]=[CH2:20])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:24]([O:23][C:21]([C:16]1([NH:15][C:14]([CH:9]2[CH2:10][CH:11]([OH:13])[CH2:12][NH:8]2)=[O:26])[CH2:18][CH:17]1[CH:19]=[CH2:20])=[O:22])[CH3:25]
Reactant: C=CC1CC1(NC(=O)C1CC(O)CN1C(=O)OC(C)(C)C)C(=O)OCC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CC1CC1(NC(=O)C1CC(O)CN1)C(=O)OCC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Compound 122 (10.5 g, 28.4 mmol) was dissolved in DCM (70 ml) and cooled to 0° C., TFA (35 ml) was added. After appr 1 h the solution was evaporated and neutralized with aqueous sodium carbonate and evaporated on silica. Purification of the crude product by column chromatography on silica (MeOH/DCM: 15/85) gave 9.7 g of still unpure compound title compound. This material was used in the next step.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.S(Cl)([Cl:13])=O>>[CH3:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([Cl:13])=[O:10])[CH2:4][CH2:3]1
Reactant: O=S(Cl)Cl
Reactant: C[C@H]1CC[C@H](C(=O)O)CC1
Product: C[C@H]1CC[C@H](C(=O)Cl)CC1

Procedure:
Trans-4-methyl-cyclohexanecarbonyl chloride was prepared by heating to reflux trans-4-methyl-cyclohexanecarboxylic acid (5 g, 0.035 mmol) in thionylchloride (5.0 ml) for 2 h followed by purification of the corresponding acyl chloride under reduced pressure in a Kugel-Rhorr apparatus collecting the fraction distilling at 95° C. yielding 5.1 g of the desired material which was used in the next step without further purification. This acyl chloride (1.5 ml, aprox. 10 mmol) was dissolved along with 5-Bromo-3-isopropylamino-thiophene-2-carboxylic acid methyl ester (2 g, 7.12 mmol) in anhydrous dichloroethane (2 mL) and heated at 80° C. (closed vial) for 12 h. The solvents were evaporated, the resulting crude material was dissolved in methanol and left 30 min. at room temperature, concentrated and purified via flash chromatography on silica gel using a 5% EtOAc 95% hexanes mixture of eluents, in this manner 600 mg (21%) of 5-Bromo-3-[isopropyl-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester the was isolated. 1H NMR (CDCl3, 300 MHz): 6.78 (s, 1H), 4.93 (m, 1H), 3.69 (s, 3H), 2.00-1.20 (m, 8H), 1.14 (d, 3H), 0.93 (d, 3H), 0.81 (d, 3H), 0.72-0.70 (m, 2H).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[CH:18][CH3:19])[C:15](O)=[O:16].N1C=CC=CC=1>CCOCC>[CH3:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[CH:18][CH3:19])[C:15]([Cl:3])=[O:16]
Reactant: O=S(Cl)Cl
Reactant: CC=C(C(=O)O)c1ccccc1COC
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC=C(C(=O)Cl)c1ccccc1COC
Temperature: 20 °C
Reaction time: 3 h
Yield: 96.4 %

Procedure:
At 0° to 5° C., 3.7 g of thionyl chloride was dripped into 4.9 g (24 mmol) of α-(2-methoxymethylphenyl)-β-methylacrylic acid and 2.5 g of pyridine in 40 ml of ether. The mixture was stirred for 3 hours at about 20° C. After filtration, the residue was washed with diethyl ether. The filtrate was combined with the ether phase. After removal of the solvent, there was obtained 5.2 g (96.5%) of the title compound as a colorless oil. The crude product can be used for further reactions without any additional purification.
Reaction SMILES: [F:1][C:2]1[C:3]([C:27](O)=[O:28])=[CH:4][C:5]2[N:9]=[C:8]([NH:10][C:11]3[S:12][C:13]4[CH:19]=[C:18]([O:20][C:21]([F:24])([F:23])[F:22])[CH:17]=[CH:16][C:14]=4[N:15]=3)[N:7]([CH3:25])[C:6]=2[CH:26]=1.[CH2:30]([NH2:32])[CH3:31].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH2:30]([NH:32][C:27]([C:3]1[C:2]([F:1])=[CH:26][C:6]2[N:7]([CH3:25])[C:8]([NH:10][C:11]3[S:12][C:13]4[CH:19]=[C:18]([O:20][C:21]([F:23])([F:24])[F:22])[CH:17]=[CH:16][C:14]=4[N:15]=3)=[N:9][C:5]=2[CH:4]=1)=[O:28])[CH3:31]
Reactant: CCN
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)c(F)cc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1cc2nc(Nc3nc4ccc(OC(F)(F)F)cc4s3)n(C)c2cc1F

Procedure:
6-Fluoro-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzo-imidazole-5-carboxylic acid ethylamide (65 mg) was prepared by following General Procedure F starting from 6-fluoro-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100 mg), ethylamine (2 M in THF, 235 uL), HBTU (107 mg), and DIEA (62 uL). LC/MS: m/z 454.8. 1H NMR (DMSO-d6, 400 MHz): δ 12.34 (bs, 1H), 8.17 (s, 1H), 7.93 (s, 1H), 7.85 (s, 1H), 7.73 (s, 1H), 7.48 (s, 1H), 7.36 (d, 1H), 3.61 (bs, 3H), 3.33-3.21 (m, 2H), 1.14 (t, 3H).
Reaction SMILES: [CH3:1][O-:2].[Na+].C[O:5][C:6]([C:8]1[C:9]2[CH:10]=[CH:11][N:12]([CH:18]([CH3:20])[CH3:19])[C:13]=2[CH:14]=[C:15](Br)[CH:16]=1)=[O:7].Cl>CN1C(=O)CCC1.O.[Cu]I>[CH:18]([N:12]1[C:13]2[CH:14]=[C:15]([O:2][CH3:1])[CH:16]=[C:8]([C:6]([OH:5])=[O:7])[C:9]=2[CH:10]=[CH:11]1)([CH3:20])[CH3:19]
Reactant: COC(=O)c1cc(Br)cc2c1ccn2C(C)C
Reactant: C[O-]
Agent: [Cu]I
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1cc(C(=O)O)c2ccn(C(C)C)c2c1
Temperature: 120 °C
Yield: 178.6 %

Procedure:
Freshly prepared sodium methoxide (500 mg in 5 mL methanol) was added to a stirred suspension of 6-bromo-1-isopropyl-1H-indole-4-carboxylic acid methyl ester (500 mg, 1.68 mmol) and CuI (480 mg, 2.53 mmol) in NMP (8 mL) and then heated at 120° C. for 2 h. The reaction mixture was cooled to room temperature, diluted with water (5 mL) and acidified with 1N HCl. The reaction mixture was filtered through Celite and washed with EtOAc (5 mL). Separated the EtOAc layer from filtrate, dried over anhydrous Na2SO4 and concentrated under reduced pressure to furnish the crude 1-isopropyl-6-methoxy-1H-indole-4-carboxylic acid (700 mg), which was used in the next stage without further purification. 1H NMR (400 MHz, DMSO-d6): δ 1.44 (d, J=6.4 Hz, 6H), 3.84 (s, 3H), 4.80-4.76 (m, 1H), 6.87 (d, 1H), 7.33 (t, J=3.2 Hz, 2H), 7.49 (d, J=3.2 Hz, 1H), 12.65 (bs, 1H). LCMS (ES+): m/z=234.11 [M+H].
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[CH2:11][CH3:12].C([Sn](CCCC)(CCCC)[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)CCC.[Cl-].[Li+]>C1(C)C=CC=CC=1.[Pd]>[CH2:11]([C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[C:2]=1[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)[CH3:12]
Reactant: CCc1nc2ccccn2c1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Agent: [Pd]
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: CCc1nc2ccccn2c1-c1ccncc1
Yield: 38.7 %

Procedure:
To a solution of 3-bromo-2-ethyl-imidazo[1,2-a]pyridine (1.4 g, 6.28 mmol), 4-tributyistannylpyridine (2.31 g, 6.28 mmol) and Pd (II) (Ph3P)2Cl2 (442 mg, 0.63 mmol) in toluene (5 mL) was added lithium chloride (26.7 mg, 0.63). After refluxing for 18 h, the mixture was partitioned between ethyl acetate and aqueous sodium bicarbonate. The aqueous layer was extracted with ethyl acetate (3×). Combined organic phase was washed with brine and dried over anhydrous magnesium sulfate. Concentration followed by flash chromatography eluting with 100% ethyl acetate, then 10% methanol in methylene chloride afforded the title compound (543 mg) as a viscous oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][O:44][CH3:45])=[CH:37][CH:36]=1)[C:9]1[N:14]2[N:15]=[CH:16][CH:17]=[C:13]2[N:12]=[C:11]([NH:18][C@H:19]2[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]2)[C:10]=1[CH2:32][CH2:33][OH:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:53][S:54](Cl)(=[O:56])=[O:55].[Cl-].[NH4+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([C:35]1[CH:36]=[CH:37][C:38]([O:41][CH2:42][CH2:43][O:44][CH3:45])=[CH:39][CH:40]=1)[C:9]1[N:14]2[N:15]=[CH:16][CH:17]=[C:13]2[N:12]=[C:11]([NH:18][C@H:19]2[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[CH2:20]2)[C:10]=1[CH2:32][CH2:33][O:34][S:54]([CH3:53])(=[O:56])=[O:55])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: COCCOc1ccc(N(C(=O)OC(C)(C)C)c2c(CCO)c(N[C@H]3CCCN(C(=O)OC(C)(C)C)C3)nc3ccnn23)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCOc1ccc(N(C(=O)OC(C)(C)C)c2c(CCOS(C)(=O)=O)c(N[C@H]3CCCN(C(=O)OC(C)(C)C)C3)nc3ccnn23)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 106.1 %

Procedure:
To a methylene chloride (5 mL) solution containing tert-butyl (S)-3-[7-{tert-butoxycarbonyl-[4-(2-methoxyethoxy)phenyl]amino}-6-(2-hydroxyethyl)pyrazolo[1,5-a]pyrimidin-5-ylamino]piperidine-1-carboxylate (216 mg, 0.345 mmol), triethylamine (480 μL, 3.45 mmol) and methanesulfonyl chloride (80 μL, 1.04 mmol) were added, and this mixture was stirred at room temperature for 30 min. After the reaction, aqueous ammonium chloride was added to the reaction solution, and the mixture was extracted with methylene chloride. The combined methylene chloride layer was dried over sodium sulfate. After the sodium sulfate was filtered off, the filtrate was concentrated to obtain the title compound (258 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:9][O-:10].[Na+]>CO>[Br:1][C:2]1[CH:3]=[N:4][C:5]([O:10][CH3:9])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)cn1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Bromo-2-chloropyrimidine (10 g, 52 mmol) and sodium methoxide (8.42 g, 156 mmol) were taken in methanol (50 mL) and stirred at room temperature overnight. Reaction mixture was concentrated followed by the addition of water. The resulting mixture was extracted with ethyl acetate and dried over MgSO4. The titled compound was obtained after concentration (8.07 g, 82.5%).
Reaction SMILES: [C:1]1([O-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS(C)=O.[CH:12]1[C:15]2[CH:16]=[CH:17][C:18]([N:20]3[C:24](=[O:25])[C:23]4=[CH:26][C:27]([N+]([O-])=O)=[CH:28][CH:29]=[C:22]4[C:21]3=[O:33])=[CH:19][C:14]=2[CH:13]=1>O>[CH:12]1[C:15]2[CH:16]=[CH:17][C:18]([N:20]3[C:24](=[O:25])[C:23]4=[CH:26][C:27]([O:7][C:1]5[CH:6]=[CH:5][CH:4]=[C:3]([C:12]#[C:13][C:14]6[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=6)[CH:2]=5)=[CH:28][CH:29]=[C:22]4[C:21]3=[O:33])=[CH:19][C:14]=2[CH:13]=1
Reactant: O=C1c2ccc([N+](=O)[O-])cc2C(=O)N1c1ccc2c(c1)C=C2
Reactant: [O-]c1ccccc1
Solvent: CS(C)=O
Solvent: O
Product: O=C1c2ccc(Oc3cccc(C#Cc4ccccc4)c3)cc2C(=O)N1c1ccc2c(c1)C=C2
Temperature: 35 °C
Reaction time: 2 h

Procedure:
The dark phenolate/DMSO solution was allowed to cool to about 35° C. in an oil bath. N-4-benzocyclobutenyl 4-nitrophthalimide (1.00g, 3.40 mmol) was added next. The resultant reaction mixture was stirred under N2 at 30°-35° C. for another 21/2 hours. Then, the reaction mixture was poured into a separatory funnel containing about 300 ml of H2O and extracted with ethyl acetate (100 ml, 3×50 ml). The organic extract was then washed with saturated NaCl solution (2×150 ml) and dried over MgSO4. The volume of the dried extract was concentrated on a rotary evaporator to about 10 ml and passed through a chromatographic column containing about 100 g of silica gel saturated with petroleum ether. Elution was carried out with 100 ml petroleum ether, followed by 1:2 CH2Cl2 / petroleum ether. 4 bands were developed in the column. The desired product which was contained in the first band, was isolated as light yellow microcrystals. Yield: 0.45 g (30%). Calc. for C30H19NO3 : 81.62% C; 4.34% H; 3.17% N. Found: 81.05% C; 4.31% H; 3.09% N. Mass Spectroscopy: 441 (M+, 100%). Proton NMR (CDCl3): 3.20 (singlet, alicyclic protons); 7.00-7.93, (complex, aromatic protons). IR(KBr): 2700 m (alicyclic C--H stretches); 1706 m, 1778 vs (symmetric and asymmetric stretches of imide group): 1238 ms (Ar--O--Ar stretch).
Reaction SMILES: [Cl:1][C:2]1[C:3]([I:12])=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.OS(O)(=O)=O.[CH3:18][CH2:19]O>CCOC(C)=O>[Cl:1][C:2]1[C:3]([I:12])=[C:4]([CH2:8][C:9]([O:11][CH2:18][CH3:19])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1cccc(Cl)c1I
Reactant: CCO
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1cccc(Cl)c1I
Temperature: 25 °C

Procedure:
A mixture of 2-(3-chloro-2-iodophenyl)acetic acid (3.2 g, 11 mmol) in 50 mL EtOH was treated with 2 mL con. H2SO4, and refluxed for 2 hours. The mixture was cooled to room temperature, diluted with 200 mL EtOAc, washed with water (3×50 mL), saturated NaCl (20 mL), dried over anhydrous sodium sulfate and concentrated. The concentrate was purified by column chromatography (10-20% EtOAc/hexane) to give 3.62 g pale yellow oil. MS m/e: (M+H)+ 325.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([O:21]C)=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)(=O)=O.[F:23][C:24]([F:34])([F:33])[C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27][NH2:28]>>[F:23][C:24]([F:33])([F:34])[C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27][NH:28][CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([OH:21])=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1
Reactant: NCc1ccccc1C(F)(F)F
Reactant: COC(=O)c1ccnc(-c2cn(CCOS(C)(=O)=O)cn2)c1
Product: O=C(O)c1ccnc(-c2cn(CCNCc3ccccc3C(F)(F)F)cn2)c1
Yield: 6 %

Procedure:
The title compound was prepared in 6% yield from methyl 2-(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-imidazol-4-yl)pyridine-4-carboxylate (PREPARATION 6) and 2-(trifluoromethyl)benzylamine according to the procedure for the preparation of Example 58. 1HNMR (400 MHz, DMSO): δ 2.89 (2H, t, J=5.9 Hz), 3.88 (2H, s), 4.10 (2H, t, J=5.9 Hz), 7.42 (1H, t, J=7.7 Hz), 7.50 (1H, d, J=5.0 Hz), 7.59 (1H, d, J=7.6 Hz), 7.65 (2H, d, J=8.6 Hz), 7.74 (1H, s), 7.77 (1H, s), 8.25 (1H, s), 8.49 (1H, d, J=4.8 Hz). [M+H] Calc'd for C17H19F3N4O2, 391. Found, 391.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.N[C:17]1[CH:18]=[C:19]([CH2:23][C:24]#[N:25])[CH:20]=[CH:21][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:12][C:11]([C:13]([C:17]3[CH:18]=[C:19]([CH2:23][C:24]#[N:25])[CH:20]=[CH:21][CH:22]=3)=[O:15])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(-c2cccc(Cl)c2)o1
Reactant: N#CCc1cccc(N)c1
Product: N#CCc1cccc(C(=O)c2ccc(-c3cccc(Cl)c3)o2)c1

Procedure:
Carboxylic acid (65) (127 mg, 0.57 mmol) was coupled to aniline (80) (75 mg, 0.57 mmol) using Method C. The crude residue was purified by column chromatography eluting with 17% EtOAc in heptane to give the title compound.