Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: OC1C=CC(C(NN(C(=O)/C=C/C2C3C(=CC=CC=3)N(C(OC(C)(C)C)=O)C=2)C(C)C)=O)=CC=1.C([O-])([O-])=O.[K+].[K+].BrCCBr.Br[CH2:46][CH2:47][O:48][C:49]1[CH:81]=[CH:80][C:52]([C:53]([NH:55][N:56]([C:60](=[O:79])/[CH:61]=[CH:62]/[C:63]2[C:71]3[C:66](=[CH:67][CH:68]=[CH:69][CH:70]=3)[N:65]([C:72]([O:74][C:75]([CH3:78])([CH3:77])[CH3:76])=[O:73])[CH:64]=2)[CH:57]([CH3:59])[CH3:58])=[O:54])=[CH:51][CH:50]=1.[NH:82]1[CH2:87][CH2:86][O:85][CH2:84][CH2:83]1>C(#N)C>[CH:57]([N:56]([C:60](=[O:79])/[CH:61]=[CH:62]/[C:63]1[C:71]2[C:66](=[CH:67][CH:68]=[CH:69][CH:70]=2)[N:65]([C:72]([O:74][C:75]([CH3:78])([CH3:77])[CH3:76])=[O:73])[CH:64]=1)[NH:55][C:53](=[O:54])[C:52]1[CH:80]=[CH:81][C:49]([O:48][CH2:47][CH2:46][N:82]2[CH2:87][CH2:86][O:85][CH2:84][CH2:83]2)=[CH:50][CH:51]=1)([CH3:59])[CH3:58]
Reactant: C1COCCN1
Reactant: CC(C)N(NC(=O)c1ccc(OCCBr)cc1)C(=O)/C=C/c1cn(C(=O)OC(C)(C)C)c2ccccc12
Agent: CC(C)N(NC(=O)c1ccc(O)cc1)C(=O)/C=C/c1cn(C(=O)OC(C)(C)C)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: BrCCBr
Product: CC(C)N(NC(=O)c1ccc(OCCN2CCOCC2)cc1)C(=O)/C=C/c1cn(C(=O)OC(C)(C)C)c2ccccc12
Temperature: 85 °C

Procedure:
(E)-tert-butyl 3-(3-(2-(4-hydroxybenzoyl)-1-isopropylhydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate (50.0 mg, 0.11 mmol) and K2CO3 (59.63 mg, 0.43 mmol) dissolved in anhydrous acetonitrile (10.0 ml), 1,2-dibromoethane (0.0465 ml, 0.54 mmol) was added drop-by-drop. The reaction mixture was refluxed at 85° C. for 48 hr. After concentration under reduced pressure, the solution was separated through silica gel chromatography (n-hexane:EtOAc:methanol=14:3:1) so that ivory solid form of (E)-tert-butyl 3-(3-(2-(4-(2-bromoethoxy)benzoyl)-1-isopropylhydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate was obtained.(34 mg, 55.3%). The resultant (E)-tert-butyl 3-(3-(2-(4-(2-bromoethoxy)benzoyl)-1-isopropylhydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate (34.0 mg, 0.06 mmol) and K2CO3 (16.5 mg, 0.12 mmol) were dissolved in anhydrous acetonitrile (10.0 ml), and the solution was drop-wise added with morpholine (0.01031 ml, 0.053 mmol). The reaction mixture was refluxed at 85° C. for 12 hr. After concentration under reduced pressure, the solution was separated through silica gel chromatography (MC:methanol=30:1) so that ivory solid form of (E)-tert-butyl3-(3-(1-isopropyl-2-(4-(2-morpholinoethoxy)benzoyl)hydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate was obtained (8.2 mg, 23.9%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([S:14][CH3:15])[NH:5][C:6](=O)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].P(Cl)(Cl)([Cl:18])=O>>[Cl:18][C:6]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:2]([CH3:1])[N:3]=[C:4]([S:14][CH3:15])[N:5]=1
Reactant: CCOC(=O)c1c(C)nc(SC)[nH]c1=O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1c(C)nc(SC)nc1Cl
Yield: 87 %

Procedure:
A round bottom flask was charged with ethyl 4-methyl-2-(methylthio)-6-oxo-1,6-dihydro-5-pyrimidinecarboxylate (6 g) and phosphorus oxychloride (30 mL) and heated to reflux for 3 h. The phosphorus oxychloride was removed under vacuum. The residue was chromatographed (silica gel, eluting with methylene chloride) to afford the product (5.73 g, 87% yield).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][C:22](C(Cl)=O)=[CH:21][CH:20]=1.[NH2:34]/[C:35](=[N:45]\O)/[CH2:36][NH:37]C(=O)OC(C)(C)C.NC(=NO)C1CCN(C(OC(C)(C)C)=O)CC1>>[CH3:15][O:14][N:13]=[C:11]1[CH2:10][C@@H:9]([C:16]2[O:18][N:45]=[C:35]([CH2:36][NH2:37])[N:34]=2)[N:8]([C:6]([C:31]2[CH:30]=[CH:29][C:28]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:33][CH:32]=2)=[O:7])[CH2:12]1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CC(C)(C)OC(=O)NC/C(N)=N/O
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Agent: CC(C)(C)OC(=O)N1CCC(C(N)=NO)CC1
Product: CON=C1C[C@@H](c2nc(CN)no2)N(C(=O)c2ccc(-c3ccccc3)cc2)C1

Procedure:
Following the general method as outlined in Example 59, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidine-carboxylic acid (Intermediate 2), [1,1′-biphenyl]-4-carbonyl chloride, and tert-butyl (2Z)-2-amino-2-(hydroxyimino)ethylcarbamate (an Intermediate 7), the title compound was obtained in 85% purity by HPLC. MS(ESI+): m/z=392.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[C:23](CO)[CH:22]=[CH:21][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17]O)=[CH:13][C:12]=1[O:19][CH3:20].O=S(Cl)[Cl:29].CCCCCCC.[CH:38]([Cl:41])(Cl)Cl>>[CH3:1][O:2][C:3]1[CH:24]=[C:23]([CH2:38][Cl:41])[CH:22]=[CH:21][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][Cl:29])=[CH:13][C:12]=1[O:19][CH3:20]
Reactant: COc1cc(CO)ccc1OCCCCOc1ccc(CO)cc1OC
Reactant: O=S(Cl)Cl
Reactant: ClC(Cl)Cl
Solvent: CCCCCCC
Product: COc1cc(CCl)ccc1OCCCCOc1ccc(CCl)cc1OC

Procedure:
A solution of 22 g 1,4-bis(2-methoxy-4-hydroxymethylphenoxy) butane in 200 ml warm CHCl3 was added dropwise to a solution of 60 ml SOCl2 in 100 ml CHCl3. After the addition was completed, the chloroform was boiled off while replacing with heptane. When the temperature reached the boiling point of heptane (97° C.), the solution was decanted from a small amount of yellow oil and allowed to cool. Decantation from oily impurities was continued until the white crystalline product began to form. The solution was cooled, and, after crystallization was completed, the product was filtered, washed with hexane, and air dried. One more recrystallization from heptane gave a pure-white crystalline product which was one spot on TLC. The yield was 23 grams, m.p. 116°-118° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:23]([NH2:24])=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:13][CH:12]=1.C(N(CC)CC)C.Cl[C:33](Cl)([O:35]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]1[CH:12]=[CH:13][C:14]([N:17]2[C:18]3=[N:19][CH:20]=[CH:21][CH:22]=[C:23]3[NH:24][C:33]2=[O:35])=[CH:15][CH:16]=1
Reactant: Nc1cccnc1Nc1ccc(Nc2nc3ccccc3o2)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=c1[nH]c2cccnc2n1-c1ccc(Nc2nc3ccccc3o2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 109.5 %

Procedure:
To a mixture of N2-[4-(1,3-benzoxazol-2-ylamino)phenyl]pyridine-2,3-diamine (0.080 g) and triethylamine (0.0638 g) in THF (1.5 mL) at 0° C., was added dropwise a solution of triphosgene (0.030 g) in THF (0.6 mL). The reaction mixture was stirred at 0° C. for 0.5 h. The cold bath was removed and the stirring continued at ambient temperature for another 0.5 h. After this time, a saturated aqueous solution of sodium bicarbonate was added. The organic layer was extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine (50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue obtained was purified by chromatography (silica, methylene chloride to 0.3:5:95 ammonium hydroxide/methanol/methylene chloride) to afford 3-[4-(1,3-benzoxazol-2-ylamino)phenyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (0.038 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[Br:13].[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N:21]=[C:22]=[O:23].CCN(CC)CC>C1COCC1>[Br:13][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:7][C:2]=1[NH:1][C:22]([NH:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH3:14])=[O:23]
Reactant: COC(=O)Cc1ccc(N)c(Br)c1
Reactant: Cc1ccccc1N=C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(NC(=O)Nc2ccccc2C)c(Br)c1
Reaction time: 21 h
Yield: 71.8 %

Procedure:
To a mixture of methyl 4-amino-3-bromophenylacetate (587 mg, 2.40 mmol) and 2-methylphenyl isocyanate (0.287 ml, 2.40 mmol) in THF (2 ml) was added Et3N (33 ml, 0.24 mmol) at room temperature. After 21 h stirring, the reaction mixture was concentrated in vacuo. The residue was triturated by the addition of n-hexane to give methyl 3-bromo-4-[N′-(2-methylphenyl)ureido]phenylacetate (650 mg, 72%) as a pale brown powder. 1H-NMR (CDCl3) δ2.34 (s, 3H), 3.53 (s, 2H), 3.68 (s, 3H), 6.18 (br, 1H), 6.96 br, 1H), 7.18-7.33 (m, 4H), 7.29 (d, J=4.4 Hz, 1H), 7.30 (d, J=7.3 Hz, 1H), 8.19 (d, J=8.3 Hz, 1H); MS (ESI) m/z 377 (M+), 379 (M++2).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([OH:12])=[CH:9]2)=[CH:4][CH:3]=1.[CH3:13]OS(OC)(=O)=O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2)[CH:11]=1
Reactant: Oc1ccc2ccc(Br)cc2c1
Reactant: COS(=O)(=O)OC
Product: COc1ccc2ccc(Br)cc2c1

Procedure:
The title compound, MS: m/e=236(M+), was prepared from 7-bromo-naphth-2-ol and dimethylsulfate following the procedure described in example 162.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[N:13]([CH3:14])[C:12]([CH3:16])([CH3:15])[CH2:11][C:4]2([NH:8][C:7](=[O:9])[NH:6][C:5]2=[O:10])[CH2:3]1.[O:18]1[CH2:29][CH:19]1[CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH:26]1[O:28][CH2:27]1.[OH-:30].[K+]>CO>[OH:18][CH:19]([CH2:29][N:6]1[C:5](=[O:30])[C:4]2([CH2:3][C:2]([CH3:1])([CH3:17])[N:13]([CH3:14])[C:12]([CH3:16])([CH3:15])[CH2:11]2)[NH:8][C:7]1=[O:9])[CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH:26]([OH:28])[CH2:27][N:6]1[C:5](=[O:10])[C:4]2([CH2:3][C:2]([CH3:17])([CH3:1])[N:13]([CH3:14])[C:12]([CH3:16])([CH3:15])[CH2:11]2)[NH:8][C:7]1=[O:9]
Reactant: [OH-]
Reactant: CN1C(C)(C)CC2(CC1(C)C)NC(=O)NC2=O
Reactant: C(COCC1CO1)OCC1CO1
Agent: [K+]
Solvent: CO
Product: CN1C(C)(C)CC2(CC1(C)C)NC(=O)N(CC(O)COCCOCC(O)CN1C(=O)NC3(CC(C)(C)N(C)C(C)(C)C3)C1=O)C2=O

Procedure:
10.0 g of 7,7,8,9,9-pentamethyl-1,3,8-triazaspiro[4.5]decane-2,4-dione, 3.0 g of ethylene glycol bis(2,3-epoxypropyl)ether and 0.1 g of potassium hydroxide were reacted in 60 ml of methanol, following substantially the same procedure as in Example 1. The desired Compound No. 166 was obtained in the form of white crystals, melting at 213°-215° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:24]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([C:38]([C@:41]5([CH2:47][O:48][Si](C(C)C)(C(C)C)C(C)C)[CH2:45][CH2:44][CH2:43][N:42]5[CH3:46])=[N:39][N:40]=4)[CH:37]=3)[CH2:23][CH2:22]2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].N>C1COCC1.CO.C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:17][C:18]([NH:20][C@@H:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@H:24]([O:31][C:32]3[CH:33]=[CH:34][C:35]4[N:36]([C:38]([C@:41]5([CH2:47][OH:48])[CH2:45][CH2:44][CH2:43][N:42]5[CH3:46])=[N:39][N:40]=4)[CH:37]=3)[CH2:23][CH2:22]2)=[O:19])[N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc([C@]5(CO[Si](C(C)C)(C(C)C)C(C)C)CCCN5C)n4c3)c3ccccc32)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N
Agent: [F-]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc([C@]5(CO)CCCN5C)n4c3)c3ccccc32)cc1
Temperature: 25 °C
Yield: 56.2 %

Procedure:
To a solution of Intermediate 85k (250 mg, 0.310 mmol) in THF (10 mL) at −30° C. was added TBAF (1M in THF, 620 μL, 0.620 mmol) and the mixture was allowed to warm to RT over 2 h. The reaction mixture was applied to an SCX-2 cartridge (10 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 0-10% [2M NH3 in MeOH] in DCM, gave a crude product. Recrystallisation from hot diethyl ether (50 mL), EtOAc (10 mL) and cyclohexane (20 mL) gave the title compound as a white powder (113 mg, 56%). LCMS (Method 5): Rt 3.68 min, m/z 649.1 [MH+]. 1H NMR (400 MHz, d4-MeOD): 1.29 (9H, s), 1.86-2.34 (11H, m), 2.38 (3H, s), 3.02 (1H, m), 3.09 (1H, dt, J 8.8, 3.5), 4.07 (1H, d, J 11.0), 4.25 (1H, d, J 4.3), 4.52 (1H, br s), 4.90 (1H, m), 5.25 (1H, t, J 4.3), 6.33 (1H, s), 7.18-7.36 (9H, m), 7.62 (1H, d J 7.6), 8.44 (1H, s).
Reaction SMILES: [NH2:1][C@H:2]([CH3:22])[CH2:3][C:4]1[C:12]2[C:7](=[C:8]([O:13][CH2:14][C:15]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[O:16])[CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.FC(F)(F)C([O-])=O.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C@@H:36]2[CH2:38][O:37]2)[CH:31]=1.CCN(C(C)C)C(C)C>C(#N)C>[OH:37][C@H:36]([C:32]1[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=1)[CH2:38][NH:1][C@H:2]([CH3:22])[CH2:3][C:4]1[C:12]2[C:7](=[C:8]([O:13][CH2:14][C:15]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[O:16])[CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1
Reactant: c1cncc([C@@H]2CO2)c1
Reactant: C[C@@H](N)Cc1c[nH]c2c(OCC(=O)NS(C)(=O)=O)cccc12
Agent: O=C([O-])C(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Cc1c[nH]c2c(OCC(=O)NS(C)(=O)=O)cccc12)NC[C@H](O)c1cccnc1

Procedure:
A mixture of (R)—N-{2-[3-(2-aminopropyl)-1H-indol-7-yloxy]-acetyl}methanesulfonamide.trifluoroacetate (40 mg, 0.091 mmol), (R)-(pyridin-3-yl)oxirane (48 mg, 0.36 mmol) and iPr2NEt (24 μL, 0.137 mmol) in acetonitrile (1 mL) is refluxed for 3 hours. After cooling, the mixture is concentrated and purified by preparative reversed phase HPLC (trifluoroacetic acid/water/acetonitrile) to give the desired N-(2-{3-[(2R)-2-((2R)-2-hydroxy-2-pyridin-3-ylethylamino)propyl]-1H-indol-7-yloxy}acetyl)methanesulfonamide.2 trifluoroacetate (3 mg, yield: 3%).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:17][CH2:16][CH2:15][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:7]=1.[NH2:18][C:19](=[O:35])[CH:20]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=1)[C:21]([O:23][CH:24]([CH3:26])[CH3:25])=[O:22]>>[NH2:18][C:19](=[O:35])[CH:20]([CH2:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][C:2]2[C:3]3[CH2:17][CH2:16][CH2:15][C:4]=3[N:5]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=3)[N:7]=2)=[CH:30][CH:29]=1)[C:21]([O:23][CH:24]([CH3:25])[CH3:26])=[O:22]
Reactant: CC(C)OC(=O)C(Cc1ccc(N)cc1)C(N)=O
Reactant: Clc1cccc(-c2nc(Cl)c3c(n2)CCC3)c1
Product: CC(C)OC(=O)C(Cc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2CCC3)cc1)C(N)=O
Yield: 78.3 %

Procedure:
Following general procedure A1, 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (0.063 g, 0.24 mmol) was reacted with isopropyl 3-amino-2-(4-aminobenzyl)-3-oxopropanoate (0.060 g, 0.24 mmol) to afford the title compound (0.090 g, 78%) as a light brown foam. MW=478.97. APCI MS m/z 479 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH3:11].[CH2:12]([C:16]1([N:44]([CH3:46])[CH3:45])[CH2:21][CH2:20][C:19]([C:22]2[NH:23][C:24]3[C:29]([C:30]=2[CH2:31]CN2C(=O)C4C(=CC=CC=4)C2=O)=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:18][CH2:17]1)[CH2:13][CH2:14][CH3:15].[F:47]C(F)(F)S(O)(=O)=O>ClCCl>[CH2:12]([C:16]1([N:44]([CH3:46])[CH3:45])[CH2:21][CH2:20][C:19]([C:22]2[NH:23][C:24]3[C:29]([C:30]=2[CH3:31])=[CH:28][C:27]([F:47])=[CH:26][CH:25]=3)([C:6]2[NH:7][C:8]3[C:4]([C:5]=2[CH3:11])=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)[CH2:18][CH2:17]1)[CH2:13][CH2:14][CH3:15]
Reactant: Cc1c[nH]c2ccc(F)cc12
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: CCCCC1(N(C)C)CC=C(c2[nH]c3ccccc3c2CCN2C(=O)c3ccccc3C2=O)CC1
Solvent: ClCCl
Product: CCCCC1(N(C)C)CCC(c2[nH]c3ccc(F)cc3c2C)(c2[nH]c3ccc(F)cc3c2C)CC1
Temperature: 24 °C
Reaction time: 240 h

Procedure:
5-fluoroskatole (670 mg, 4.49 mmol) together with 2-(2-(2-(4-butyl-4-dimethylaminocyclohex-1-enyl)-1H-indol-3-yl)-ethyl)isoindol-1,3-dione (700 mg, 1.49 mmol) was dissolved in abs. dichloromethane (5 ml) and mixed with trifluoromethane sulphonic acid (0.175 ml, 1.974 mmol). The batch was stirred for 10 d at 24° C. The precipitated light beige-coloured solid was separated by filtration and washed with dichloromethane (3×0.5 ml). The solid (1031 mg) was stirred for 10 min with 1N sodium hydroxide solution (20 ml) and dichloromethane (20 ml). The phases were separated. The aqueous phase was extracted with dichloromethane (2×20 ml). The combined organic extracts were dried over Na2SO4 and then concentrated to low volume. The product was purified by column chromatography.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[C@@H:23]([NH:25]C(OCC2C=CC=CC=2)=O)[CH3:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(O)=O>CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[C@@H:23]([NH2:25])[CH3:24])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H](NC(=O)OCc1ccccc1)c1nc2ccccc2n1[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: C[C@H](N)c1nc2ccccc2n1[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 83.3 %

Procedure:
A mixture of (R)-3-[2-((S)-1-benzyloxycarbonylaminoethyl)benzoimidazol-1-yl]piperidine-1-carboxylic acid tertbutyl ester (2.75 g, 5.75 mmol) 10% Pd/C (275 mg) and AcOH (4 mL) in EtOAc (40 mL) was purged with a stream of nitrogen and then was stirred at RT for 20 h under an hydrogen atmosphere. The suspension was then filtered through a PTFE frit and the filtrate was concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% 2M NH3/MeOH in DCM) affording (R)-3-[2-((S)-1-Aminoethyl)benzoimidazol-1-yl]piperidine-1-carboxylic acid tertbutyl ester as a white foam (1.65 g, 83%). LCMS: RT 2.30 min [M+H-tBu]+ 289.2.
Reaction SMILES: [OH:1][CH:2]([CH3:14])[CH:3]([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11]([OH:13])=O)[N:10]=1)[CH3:4].[NH2:15][C@H:16]([CH3:32])[CH2:17][N:18]1[CH:22]=[CH:21][C:20]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([Cl:31])[CH:24]=2)=[N:19]1>>[Cl:31][C:25]1[CH:24]=[C:23]([C:20]2[CH:21]=[CH:22][N:18]([CH2:17][C@H:16]([NH:15][C:11]([C:9]3[N:10]=[C:6]([NH:5][CH:3]([CH:2]([OH:1])[CH3:14])[CH3:4])[S:7][CH:8]=3)=[O:13])[CH3:32])[N:19]=2)[CH:30]=[CH:29][C:26]=1[C:27]#[N:28]
Reactant: C[C@@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: CC(O)C(C)Nc1nc(C(=O)O)cs1
Product: CC(O)C(C)Nc1nc(C(=O)N[C@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)cs1
Yield: 14.45 %

Procedure:
N—((R)-1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(3-hydroxybutan-2-ylamino)thiazole-4-carboxamide was prepared using the method of Example 34(d) starting from 2-(3-hydroxybutan-2-ylamino)thiazole-4-carboxylic acid (1.35 g, 6.24 mmol) and (R)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (1.356 g, 5.20 mmol). The product was purified by Flash-chromatography. Yield 14.45%. 1H-NMR (400 MHz; DMSO-d6): δ 0.98-1.19 (m, 9H), 3.57-3.72 (m, 2H), 4.23-4.47 (m, 3H), 4.67 (d, 1H), 6.94-6.97 (m, 1H), 7.11-7.14 (m, 1H), 7.37-7.53 (m, 1H), 7.69-7.80 (m, 1H), 7.80-7.85 (m, 1H), 7.90-8.00 (m, 2H), 8.06-8.09 (m, 1H).
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[CH:2]([CH3:4])[CH3:3].C([N-]C(C)C)(C)C.[Li+].CCCCCCC.C1COCC1.C(C1C=CC=CC=1)C.[CH3:36][Bi:37](Br)[CH3:38]>C1COCC1>[CH3:36][Bi:37]([CH3:38])[C:2]([CH3:4])([CH3:3])[C:1]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(C)C
Reactant: C[Bi](C)Br
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: COC(=O)C(C)(C)[Bi](C)C
Temperature: -78 °C
Yield: 46.9 %

Procedure:
Under argon gas atmosphere, 2.86 g (28 mmol) of methyl isobutyrate was dissolved in 25 ml of THF, and the solution was cooled to −78° C. To the solution was slowly added dropwise (for 10 minutes) 14.0 ml (28 mmol) of lithium diisopropylamide (Aldrich, a 2.0M heptane/THF/ethylbenzene solution thereof). While the mixture was gradually warmed (for 1 hour), the solution of 8.9 g of dimethylbismuthanyl bromide synthesized in Synthesis Example 6 in 25 ml of THF was added dropwise within the range of −40° C. to −30° C. to the mixture. Thereafter, the reaction solution was stirred until the solution temperature reached 0° C. (for 1 hour). The solids precipitated in the reaction solution were filtered off with quartz wool, THF was removed under reduced pressure, and the product was distilled under reduced pressure, giving 4.45 g of yellow oily material (46.7% yield, bp 59° C./2.0 mmHg). It was confirmed that the product was the desired one by MS (GCMS), 1H-NMR and 13C-NMR.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH3:12])[C:6](=[O:13])[C:5]2([CH3:15])[CH3:14].[CH3:16][N:17]1[C:21]([C:22]#[N:23])=[CH:20][CH:19]=[C:18]1B(O)O.[F-].[K+]>O1CCOCC1.CCOC(C)=O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[F:11][C:9]1[CH:10]=[C:2]([C:18]2[N:17]([CH3:16])[C:21]([C:22]#[N:23])=[CH:20][CH:19]=2)[CH:3]=[C:4]2[C:8]=1[N:7]([CH3:12])[C:6](=[O:13])[C:5]2([CH3:15])[CH3:14]
Reactant: Cn1c(C#N)ccc1B(O)O
Reactant: CN1C(=O)C(C)(C)c2cc(Br)cc(F)c21
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CN1C(=O)C(C)(C)c2cc(-c3ccc(C#N)n3C)cc(F)c21
Temperature: 45 °C
Reaction time: 6 h
Yield: 28 %

Procedure:
5-Bromo-7-fluoro-1,3,3-trimethyl-1,3-dihydro-2H-indol-2-one (0.10 g, 0.36 mmol), 1-methyl-5-cyano-2-pyrroleboronic acid (95 mg, 0.63 mmol), KF (69 mg, 1.19 mmol) were suspended in 1 mL of dioxane. Pd2(dba)3 monochloroform adduct (3.1 mg, 0.003 mmol) and Pd(P(t-Bu)3)2 (4.6 mg, 0.009 mmol) were added and the mixture was stirred vigorously at 45° C. for 6 h. The mixture was diluted with 100 mL of EtOAc and filtered through a plug of silica gel and concentrated. Purification by flash chromatography (2% acetone/hexane) afforded the title compound (30 mg, 28%) as a tan solid.
Reaction SMILES: BrC1C=CC(O)=C(C2C=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)C=1.[OH:37][C:38]1[C:43]([N+:44]([O-:46])=[O:45])=[CH:42][C:41]([CH3:47])=[CH:40][C:39]=1[C:48](=O)[CH3:49].[OH-].[K+]>C(O)C>[CH:23]1([N:22]2[C:21]3[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=3[N:19]=[C:18]2[C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:48]([C:39]2[CH:40]=[C:41]([CH3:47])[CH:42]=[C:43]([N+:44]([O-:46])=[O:45])[C:38]=2[OH:37])[CH:49]=[CH:16]3)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Reactant: CC(=O)c1cc(C)cc([N+](=O)[O-])c1O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)c(O)c([N+](=O)[O-])c1
Yield: 31 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-(2-hydroxy-5-methyl-3-nitro-phenyl)-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (40 mg, 31% yield).
Reaction SMILES: C1([NH2+]C2CCCCC2)CCCCC1.C([NH:24][C@H:25]([C:30]([O-:32])=O)[C:26]([CH3:29])([CH3:28])[CH3:27])(OCC1C=CC=CC=1)=O.CCN(C(C)C)C(C)C.ClC(OCC(C)C)=O.[CH2:50]([CH2:52][NH2:53])[OH:51]>C(Cl)Cl>[NH2:24][C@@H:25]([C:26]([CH3:27])([CH3:28])[CH3:29])[C:30]([NH:53][CH2:52][CH2:50][OH:51])=[O:32]
Reactant: CC(C)(C)[C@H](NC(=O)OCc1ccccc1)C(=O)[O-]
Reactant: NCCO
Agent: C1CCC([NH2+]C2CCCCC2)CC1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)[C@H](N)C(=O)NCCO
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of Cbz-tert-leucine dicyclohexylammonium salt (1.34 g, 3.0 mmol) and DIEA (0.7 ml) in DCM (25 mL) cooled in an ice-water bath was added isobutyl chloroformate (0.47 mL, 3.6 mmol). After stirring at 0° C. for 1 hour, ethanolamine was added (0.52 mL, 9.0 mmol) and stirred overnight. The reaction was quenched with saturated aqueous sodium bicarbonate. The organic phase was separated and dried over sodium sulfate. After evaporation under reduced pressure, the residue was dissolved in MeOH and passed through a SCX (Phenomenex®, Torrance, Calif.) cationic ion-exchange column to remove dicyclohexylamine and DIEA. The filtrate was evaporated and hydrogenated with Pd/C (0.5 g) under hydrogen at 45 psi in MeOH for 4 hours. Palladium catalyst was removed by filtration through celite. The filtrate was concentrated and dried under vacuum overnight to give intermediate 23 (0.35 g), which was used without further purification. LCMS (+ESI) m/z=175 [M+H]+.