Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=2[C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]3[C:22]([CH:23]=2)=[N:21][N:20]([CH3:24])[CH:19]=3)=[O:13])[CH:5]=[CH:4][N:3]=1.CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].[O:40]1[C:44]2([CH2:49][CH2:48][N:47]([C:50]([NH2:52])=[O:51])[CH2:46][CH2:45]2)[O:43][CH2:42][CH2:41]1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH3:24][N:20]1[CH:19]=[C:18]2[C:22]([CH:23]=[C:15]([NH:14][C:12]([C:11]3[CH:25]=[CH:26][CH:27]=[CH:28][C:10]=3[NH:9][CH2:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:52][C:50]([N:47]4[CH2:46][CH2:45][C:44]5([O:40][CH2:41][CH2:42][O:43]5)[CH2:49][CH2:48]4)=[O:51])[CH:7]=3)=[O:13])[CH:16]=[CH:17]2)=[N:21]1
Reactant: NC(=O)N1CCC2(CC1)OCCO2
Reactant: Cn1cc2ccc(NC(=O)c3ccccc3NCc3ccnc(Br)c3)cc2n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: Cn1cc2ccc(NC(=O)c3ccccc3NCc3ccnc(NC(=O)N4CCC5(CC4)OCCO5)c3)cc2n1
Temperature: 110 °C
Yield: 66.2 %

Procedure:
2-[(2-bromo-pyridin-4-ylmethyl)-amino]-N-(2-methyl-2H-indazol-6-yl)-benzamide (700 mg, 1.6 mmol) was suspended in dioxane (26 mL) and treated consecutively with DMF (7 mL), Pd2dba3 (32 mg, 0.03 mmol), Xantphos (61 mg, 0.1 mmol), cesium carbonate (632 mg, 1.9 mmol) and 1,4-dioxa-8-aza-spiro[4.5]decane-8-carboxylic acid amide (930 mg, 5 mmol). The reaction mixture was placed under a nitrogen atmosphere and heated for 4 hours at 110° C. (bath temperature). On cooling the reaction was partitioned between EtOAc and brine. The organic phase was dried, filtered and concentrated in vacuo. The residue was purified by chromatography on Isolute® Flash silica gel (Separtis) (Gradient elution: 100% CH2Cl2 to CH2Cl2/EtOH 10:1) to give 1,4-dioxa-8-aza-spiro[4.5]decan-8-carboxylic acid(4-{[2-(2-methyl-2H-indazol-6-ylcarbamoyl)-phenylamino]-methyl}-pyridin-2-yl)-amide (574 mg, 66%) as a solid; 1H-NMR (300 MHz, d6-DMSO) 10.20 (1H, s), 9.25 (1H, s), 8.32 (1H, s), 8.21 (1H, d), 8.17 (1H, s), 8.01 (1H, t), 7.87 (1H, s), 7.75-7.80 (1H, m), 7.70 (1H, d), 7.30-7.40 (2H, m), 6.99-7.01 (1H, m), 6.73 (1H, t), 6.60 (1H, d), 4.50 (2H, d), 4.20 (3H, s), 3.97 (4H, s), 3.54-3.59 (4H, m), 1.53-1.58 (4H, m); m/z (ES+) 542 [M+H]+.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([N:11]1[C:19]2[C:14](=[C:15]([CH:20]=[CH2:21])[CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12]1)(=[O:10])=[O:9].BrC1C=CC=C2C=1C=CN2S(C1C=CC=C([C:41]([F:44])([F:43])[F:42])C=1)(=O)=O.C([Sn](CCCC)(CCCC)C=C)CCC>>[F:42][C:41]([F:44])([F:43])[C:5]1[CH:4]=[C:3]([S:8]([N:11]2[C:19]3[C:14](=[C:15]([CH:20]=[CH2:21])[CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12]2)(=[O:10])=[O:9])[CH:2]=[CH:7][CH:6]=1
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)n1ccc2c(Br)cccc21
Reactant: C=Cc1cccc2c1ccn2S(=O)(=O)c1ccccc1C
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Product: C=Cc1cccc2c1ccn2S(=O)(=O)c1cccc(C(F)(F)F)c1
Yield: 80 %

Procedure:
The experimental for Intermediate 15 was followed using 4-bromo-1-{[3-(trifluoromethyl)phenyl]sulfonyl}-1H-indole (500 mg, 1.24 mmol; Intermediate 17), tributyl(vinyl)stannane (tot 0.723 mL, 2.86 mmol) and Pd(PPh3)2OAc2 (tot 46 mg, 0.062 mmol). The title compound (348 mg, 80%) was obtained as a yellow sticky oil. MS (ESI+) for C17H12F3NO2S m/z 352 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](N2C3C(=CC=CC=3)C=C2)=[CH:4][CH:3]=1.[NH:17]1[C:25]2[C:20](=[CH:21][C:22]([CH2:26][N:27]3[CH2:32][CH2:31][CH:30]([C:33]4[CH:34]=[C:35]([NH:39][C:40](=[O:44])[CH:41]([CH3:43])[CH3:42])[CH:36]=[CH:37][CH:38]=4)[CH2:29][CH2:28]3)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1.IC1C=CC=C(C)C=1>>[CH3:43][CH:41]([CH3:42])[C:40]([NH:39][C:35]1[CH:36]=[CH:37][CH:38]=[C:33]([CH:30]2[CH2:31][CH2:32][N:27]([CH2:26][C:22]3[CH:21]=[C:20]4[C:25](=[CH:24][CH:23]=3)[N:17]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=3)[CH:18]=[CH:19]4)[CH2:28][CH2:29]2)[CH:34]=1)=[O:44]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4[nH]ccc4c3)CC2)c1
Reactant: Cc1ccc(-n2ccc3ccccc32)cc1
Agent: Cc1cccc(I)c1
Product: Cc1cccc(-n2ccc3cc(CN4CCC(c5cccc(NC(=O)C(C)C)c5)CC4)ccc32)c1
Yield: 60 %

Procedure:
According to the procedure used for the synthesis of 1-(4-methylphenyl)1H-indole, N-{3-[1-(1H-indol-5-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide (37.5 mg, 0.100 mmol) and 1-iodo-3-methylbenzene (43.6 mg, 0.200 mmol) gave the desired product (28 mg, 60%). 1H NMR (400 MHz, CDCl3) δ 7.68–6.60 (m, 14H), 3.66 (s, 2H), 3.16–2.96 (m, 2H), 2.59–2.44 (m, 2H), 2.44 (s, 3H), 2.18–2.01 (m, 2H), 1.91–1.68 (m, 4H), 1.24 (d, 6H, J=6.8 Hz); ESMS m/e: 466.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:16][C:17]([CH3:26])([CH2:20][N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)[CH2:18]O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl.CO.C1COCC1>[CH3:16][C:17]([CH3:26])([CH2:20][N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)[CH2:18][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: N#CC1(c2ccc(O)cc2)CCOCC1
Reactant: CC(C)(CO)CN1CCCC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(COc1ccc(C2(C#N)CCOCC2)cc1)CN1CCCC1
Yield: 6.9 %

Procedure:
4-(4-Hydroxy-phenyl)-tetrahydro-pyran-4-carbonitrile (1.29 g, 6.4 mmol), 2,2-dimethyl-3-pyrrolidin-1-yl-propan-1-ol (0.8 g, 5.1 mmol), PPh3 (1.67 g, 6.4 mmol), THF (16 ml) and DIAD (1.25 ml, 6.4 mmol) were reacted together according to general procedure H. The crude material was subjected to chromatography on silica eluting with DCM:MeOH (98:2). The resulting solid was slurried in TBME:heptanes (1:2, 1 ml) to provide the title compound (120 mg, 5%) as a white solid. 1H NMR (400 MHz, CDCl3), δ 7.37 (d, 2H), 6.94 (d, 2H), 4.12-4.03 (m, 2H), 3.89 (td, 2H), 3.71 (s, 2H), 2.57 (br s, 4H), 2.47 (s, 2H), 2.15-1.99 (m, 4H), 1.70 (brs, 4H), 1.00 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:26][S:27][C:28]1[S:29][C:30]2[CH:36]=[C:35]([CH:37]=O)[CH:34]=[CH:33][C:31]=2[N:32]=1>C(O)(C(F)(F)F)=O>[CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH2:37][C:35]2[CH:34]=[CH:33][C:31]3[N:32]=[C:28]([S:27][CH3:26])[S:29][C:30]=3[CH:36]=2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: CSc1nc2ccc(C=O)cc2s1
Reactant: Cc1ccc(N)c([N+](=O)[O-])c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CSc1nc2ccc(CNc3ccc(C)cc3[N+](=O)[O-])cc2s1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 41.4 %

Procedure:
To a stirred mixture of 4-methyl-2-nitroaniline (1 g, 6.5 mmol) in TFA (15 mL) at 0 to 5° C. was added portionwise sodium triacetoxyborohydride (2.78 g, 13.2 mmol) and the mixture was stirred for 10 min. To the reaction mixture was added portionwise 2-(methylthio)benzo[d]thiazole-6-carbaldehyde (1.44 g, 6.9 mmol) from Step 1 of Example 100. After stirring at rt for 4 h, the mixture was poured into ice-water and extracted with EtOAc (100 mL×3). The combined organic layers were washed with saturated aq NaHCO3 (100 mL×2) and brine (100 mL). The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 3% EtOAc in petroleum ether to afford 4-methyl-N-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)-2-nitroaniline (0.93 g, 41%) as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.37 (br s, 1H), 8.01 (s, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.71 (s, 1H), 7.38 (dd, J=8.4, 2.4 Hz, 1H), 7.19 (dd, J=8.7, 2.1 Hz, 1H), 8.71 (d, J=8.7 Hz, 1H), 4.83 (d, J=6.0 Hz, 2H), 2.83 (s, 3H), 2.25 (s, 3H); LCMS (ESI) m/z 346 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:15]([C:19]([NH:21][C@@H:22]4[CH2:26][N:25]([CH3:27])[C@H:24]([C:28](OC)=[O:29])[CH2:23]4)=[O:20])=[C:16]([CH3:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[ClH:49]>ClCCl>[ClH:49].[ClH:49].[CH:1]1([CH2:7][O:8][C:9]2[C:10]3[N:11]([C:15]([C:19]([NH:21][C@H:22]4[CH2:23][C@@H:24]([CH2:28][OH:29])[N:25]([CH3:27])[CH2:26]4)=[O:20])=[C:16]([CH3:18])[N:17]=3)[CH:12]=[CH:13][CH:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)[C@@H]1C[C@H](NC(=O)c2c(C)nc3c(OCC4CCCCC4)cccn23)CN1C
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)N[C@H]1C[C@@H](CO)N(C)C1
Reaction time: 2 h

Procedure:
To a solution of 150 mg of methyl (2S,4S)-4-({[8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridin-3-yl]carbonyl}amino)-1-methylpyrrolidine-2-carboxylate and 4 ml of dichloromethane was added dropwise 1.5 ml of a 1 M diisobutylaluminum hydride/toluene solution under ice-cooling, followed by stirring for 2 hours under ice-cooling. Subsequently, 1 M hydrochloric acid was added thereto, the reaction mixture was filtered over Celite, and to the filtrate were added ethyl acetate to carry out a layer separation operation. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography. To a solution of the obtained purified product in ethyl acetate was added a hydrogen chloride/ethyl acetate solution, and the resulting solid was collected by filtration and dried to obtain 25 mg of 8-(cyclohexylmethoxy)-N-[(3S,5S)-5-(hydroxymethyl)-1-methylpyrrolidin-3-yl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide dihydrochloride.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Li])CCC.N1C=CC=CC=1[Li].[O:20]=[C:21]1[CH2:27][CH:26]2[CH2:28][CH:22]1[CH2:23][N:24]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25]2>C(OCC)C.C1COCC1>[OH:20][C:21]1([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[CH2:27][CH:26]2[CH2:28][CH:22]1[CH2:23][N:24]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25]2
Reactant: CCOC(=O)N1CC2CC(=O)C(C2)C1
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Agent: [Li]c1ccccn1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)N1CC2CC(C1)C(O)(c1cccnc1)C2
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
To a solution of 3-bromopyridine (1.04 g, 6.58 mmol) in dry diethyl ether (20 ml) at −78° C. was added 2.5 M n-butyllithium (2.63 ml, 6.6 mmol). The reaction was stirred for 30 min under nitrogen. The pyridinyllithium solution was then slowly transferred by cannula into a solution of ethyl 6-oxo-3-azabicyclo[3.2.1]octane-3-carboxylate (1.00 g, 5.07 mmol) in THF (10 ml) at −78° C. The reaction was stirred 4 h at −78° C. and then quenched with saturated aqueous ammonium chloride (10 ml). The reaction was then extracted with chloroform (3×25 ml), the combined extracts dried over sodium sulfate, filtered, and concentrated by rotary evaporation. Excess pyridine was removed by repeated azeotropic rotary evaporation with toluene to yield the desired product (1.20 g, 86%).
Reaction SMILES: N1C=CC=C2C(N)CCC=12.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[C:18](=[N:22]O)[CH2:17][CH2:16]2>>[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[CH:18]([NH2:22])[CH2:17][CH2:16]2
Reactant: COc1ccc2c(c1)CCC2=NO
Agent: NC1CCc2ncccc21
Product: COc1ccc2c(c1)CCC2N

Procedure:
Following the procedure for the preparation of 6,7-dihydro-5H-cyclopenta[b]pyridin-5-amine but substituting 5-methoxyindan-1-one oxime and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ 1.73, 2.75, 2.80, 2.94, 3.82, 4.34, 6.80, 7.25; HRMS (FAB) calcd for C10H11NO+H 162.0919, found 162.0922.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[C:40]([O:43][C:44]([CH3:76])([CH3:75])[CH2:45][NH:46][C:47](=[O:74])[C@H:48]([N:56]([CH3:73])[C:57](=[O:72])[C@H:58]([NH:70][CH3:71])[CH2:59][C:60]1[CH:69]=[CH:68][C:67]2[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=2)[CH:61]=1)[CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)(=[O:42])[CH3:41].C(N(C(C)C)C(C)C)C>CN(C)C=O.ClCCl.C(OCC)(=O)C>[C:40]([O:43][C:44]([CH3:76])([CH3:75])[CH2:45][NH:46][C:47](=[O:74])[C@H:48]([N:56]([C:57](=[O:72])[C@H:58]([N:70]([C:13](=[O:15])/[CH:12]=[CH:11]/[CH2:10][C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])([CH3:17])[CH3:16])[CH3:71])[CH2:59][C:60]1[CH:69]=[CH:68][C:67]2[C:62](=[CH:63][CH:64]=[CH:65][CH:66]=2)[CH:61]=1)[CH3:73])[CH2:49][C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)(=[O:42])[CH3:41]
Reactant: CN[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)NCC(C)(C)OC(C)=O
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OC(C)(C)CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](Cc1ccc2ccccc2c1)N(C)C(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 16 h
Yield: 101.1 %

Procedure:
(2E)-5-(tert-Butoxycarbonylamino)-5-methylhex-2-enoic acid (81 mg, 0.33 mmol) was dissolved in N,N-dimethylformamide (2 ml) and dichloromethane (2 ml). 1-Hydroxy-7-azabenzotriazole (45 mg, 0.33 mmol) was added. The solution was cooled to 0° C. N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (69 mg, 0.36 mmol) was added. A solution of 1,1-dimethyl-2-((2R)-2-(N-methyl-N-((2R)-2-methylamino-3-(2-naphthyl)propionyl)amino)-3-phenylpropionylamino)ethyl acetate (152 mg, 0.30 mmol) in dichloromethane (2 ml) and ethyldiisopropylamine (0.05 ml, 0.30 mmol) were added successively. The solution was stirred for 16 h, while warming up to room temperature. It was diluted with ethyl acetate (150 ml), washed with 1 N hydrochloric acid (100 ml) and saturated sodium hydrogen carbonate solution, and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (40 g), using ethyl acetate/heptane (first 1:1 (250 ml), then 2:1) to give 221 mg of 2-((2R)-2-(N-((2R)-2-(N-((2E)-5-(tert-butoxycarbonylamino)-5-methylhex-2-enoyl)-N-methylamino)-3-(2-naphthyl)propionyl)-N-methylamino)-3-phenylpropionylamino)-1,1-dimethylethyl acetate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[N:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21])[C:10]1[C:9](F)=[CH:8][CH:7]=[CH:6][C:5]2=1.[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:14]=[CH:13][C:12]2[N:11]3[C:10]4[C:5]([C:4]=2[CH:3]=1)=[CH:6][CH:7]=[CH:8][C:9]=4[NH:21][C:16]1[C:15]3=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccccc1-n1c2ccc(Br)cc2c2cccc(F)c21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1ccc2c(c1)c1cccc3c1n2-c1ccccc1N3
Temperature: 25 °C

Procedure:
25 g (72 mmol) of 2-(6-bromo-1-fluorocarbazol-9-yl)phenylamine are dissolved in 200 ml of DMF under a protective gas, 2.8 g (72 mmol) of NaH (60% in oil) are added at room temperature, and the mixture is boiled under reflux for 6 h. The mixture is subsequently warmed to room temperature over the course of 1 h, the solvent is removed, and the residue is purified by chromatography.
Reaction SMILES: C([N:8]([C@@H:10]([C:20]#[CH:21])[CH2:11][O:12][Si](C(C)(C)C)(C)C)[CH3:9])(OC(C)(C)C)=O.[F:22][C:23]1[C:24](I)=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])/[C:26]/2=[CH:33]\[C:34]1[NH:35][CH:36]=[CH:37][C:38]=1[O:39][CH3:40]>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.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.[Cu]I>[F:22][C:23]1[C:24]([C:21]#[C:20][C@H:10]([NH:8][CH3:9])[CH2:11][OH:12])=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27](=[O:32])/[C:26]/2=[CH:33]\[C:34]1[NH:35][CH:36]=[CH:37][C:38]=1[O:39][CH3:40]
Reactant: C#C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C)C(=O)OC(C)(C)C
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN[C@@H](C#Cc1c(F)ccc2c1/C(=C/c1[nH]ccc1OC)C(=O)N2)CO
Reaction time: 2 h

Procedure:
Using Method C above, (S)-2-(N-Boc-N-methylamino)-1-(tert-butyldimethylsilyloxy)-but-3-yne (190 mg, 0.61 mmol) (Example 115C above) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (80 mg, 0.21 mmol) (Starting Material 6) using (Ph3P)4Pd (24 mg, 0.02 mmol) and a catalylic amount of CuI in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80° C. for 5.5 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4, concentrated and the residue was chromatographed on a silica gel column with a 40-100% EtOAc in hexanes gradient. The resulting intermediate was dissolved directly in 6 mL of a 50% trifluoroacetic acid in CH2Cl2 solution that contained 0.5 mL of H2O at 0° C. and stirred for 2 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with ammonium hydroxide. The organic layer was dried over Na2SO4 and concentrated. (S)-(Z)-1,3-Dihydro-5-fluoro-4-[3-methylamino-4-hydroxy-1-butynyl]-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one was obtained after silica gel column chromatography with a 0-10% MeOH in CH2Cl2 gradient and precipitation out of THF with excess of pentane. (Yield 32 mg, 42%).
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:12][C:11]2[N:10]=[CH:9][C:8](/[CH:13]=[CH:14]/[C:15]([OH:17])=O)=[CH:7][C:6]=2[CH2:5][CH2:4]1.Cl.[CH2:19]([O:26][CH:27]1[CH2:30][NH:29][CH2:28]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH2:19]([O:26][CH:27]1[CH2:28][N:29]([C:15](=[O:17])/[CH:14]=[CH:13]/[C:8]2[CH:7]=[C:6]3[C:11](=[N:10][CH:9]=2)[NH:12][C:3](=[O:2])[CH2:4][CH2:5]3)[CH2:30]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: c1ccc(COC2CNC2)cc1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CCc2cc(/C=C/C(=O)N3CC(OCc4ccccc4)C3)cnc2N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.8 %

Procedure:
A 16 mL vial flask was successively charged with (2E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride (60 mg, 0.24 mmol), DMF (5.8 mL), 3-(benzyloxy)azetidine hydrochloride (58 mg, 0.29 mmol; which may be prepared as described in Step 2), DIPEA (96 μL, 0.58 mmol), DMAP (2.4 mg, 0.02 mmol) and EDAC (56 mg, 0.29 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. The residue was purified by precipitation in MeOH/H2O and then triturated in acetone/diethyl ether to give the title compound as a beige solid (33 mg, 38%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=1[NH:5][S:6]([C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=1)(=[O:8])=[O:7].C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+].Cl>C1COCC1.O>[OH:14][CH2:13][C:12]1[CH:11]=[CH:10][C:9]([S:6]([NH:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]=2[O:2][CH3:1])(=[O:7])=[O:8])=[CH:17][CH:16]=1
Reactant: COc1ccccc1NS(=O)(=O)c1ccc(C(=O)O)cc1
Agent: CCOC(=O)Cl
Agent: Cl
Agent: [BH4-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccccc1NS(=O)(=O)c1ccc(CO)cc1
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
In an atmosphere of argon and with cooling in an ice bath, 4-[(2-methoxyanilino)sulfonyl]benzoic acid (150 mg, 0.488 mmol) was dissolved in THF (5 ml), to which were subsequently added dropwise triethylamine (0.14 ml, 1.0 mmol) and ethyl chloroformate (50 μl, 0.509 mmol). After 30 minutes of stirring at the same temperature, the thus formed precipitate was removed by filtration, and the resulting filtrate was concentrated. The thus obtained residue was dissolved in 5 ml of THF, and, with cooling in an ice bath, sodium borohydride (46.5 mg, 1.22 mmol) and water (1 ml) were added to the resulting solution. After 40 minutes of stirring at the same temperature, the reaction mixture was adjusted to pH 4 to 5 with 2N hydrochloric acid and extracted with ether. The organic layer was washed with saturated brine and dried on anhydrous magnesium sulfate. After removing the solvent by evaporation, the resulting colorless oily material was purified by silica gel column chromatography (ether) to obtain 99.6 mg (69.6%) of the title compound in the form of colorless solid.
Reaction SMILES: [C:1]([C@@:18]1([N:26]2[C:36]3[N:35]=[C:33]([NH2:34])[NH:32][C:30](=[O:31])[C:29]=3[N:28]=[CH:27]2)[O:25][C@H:22]([CH2:23][OH:24])[C@@H:20]([OH:21])[CH2:19]1)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]CCCCCCCC.C(Cl)(=O)CCCCCCC.C(Cl)(=O)CCCCCCCCCCCCCCC>>[C:1]([C@@:18]1([N:26]2[C:36]3[N:35]=[C:33]([NH2:34])[NH:32][C:30](=[O:31])[C:29]=3[N:28]=[CH:27]2)[O:25][C@H:22]([CH2:23][OH:24])[C@@H:20]([OH:21])[CH2:19]1)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCCCCCCCCC(=O)[C@]1(n2cnc3c(=O)[nH]c(N)nc32)C[C@H](O)[C@@H](CO)O1
Agent: CCCCCCCC(=O)Cl
Agent: CCCCCCCCCCCCCCCC(=O)Cl
Product: CCCCCCCC(=O)[C@]1(n2cnc3c(=O)[nH]c(N)nc32)C[C@H](O)[C@@H](CO)O1

Procedure:
This compound was prepared using the procedure for palmitoyl-2'-deoxyguanosine, substituting the appropriate amount of octanoyl chloride for palmitoyl chloride.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH2:9]([O:11][C:12]([C:14]1([C:17]([CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[O:18])[CH2:16][CH2:15]1)=[O:13])[CH3:10].O>CS(C)=O>[Cl:27][C:24]1[CH:23]=[CH:22][C:21]([O:20][CH2:19][C:17]2([C:14]3([C:12]([O:11][CH2:9][CH3:10])=[O:13])[CH2:15][CH2:16]3)[CH2:4][O:18]2)=[CH:26][CH:25]=1
Reactant: C[S+](C)(C)=O
Reactant: CCOC(=O)C1(C(=O)COc2ccc(Cl)cc2)CC1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C1(C2(COc3ccc(Cl)cc3)CO2)CC1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
3.6 g (0.13 mol) of 80% strength sodium hydride are added under an argon atmosphere and with stirring at 10° to 20° C. to a suspension of 24 g (0.11 mol) of trimethylsulphoxonium iodide in 100 ml of dimethyl sulphoxide. After stirring for 30 minutes at 20° C., 17.1 g (0.061 mol) of 4-chlorophenoxymethyl 1-ethoxycarbonylcycloprop-1-yl ketone are added. The mixture is warmed to 60° C. for 1 hour. After this, the mixture is poured into 300 ml of water and extracted with methylene chloride. The combined organic extracts are washed with water, dried over magnesium sulphate and concentrated. 14 g (77.8% of theory) of 2-[(4-chlorophenoxy)-methyl]-2-(1-ethoxycarbonyl-cycloprop-1-yl)-oxirane are obtained as an oil which is further reacted without additional purification. ##STR18##
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[CH:27]=[C:28]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH:33]2[CH3:38])[CH:29]=[CH:30][CH:31]=1.[Cl:39][C:40]1[C:41]([C:50]([F:53])([F:52])[F:51])=[N:42][N:43]([CH2:46][C:47](O)=[O:48])[C:44]=1[CH3:45]>>[Cl:39][C:40]1[C:41]([C:50]([F:52])([F:51])[F:53])=[N:42][N:43]([CH2:46][C:47]([N:35]2[CH2:36][CH2:37][N:32]([C:28]3[CH:27]=[C:26]([CH3:25])[CH:31]=[CH:30][CH:29]=3)[CH:33]([CH3:38])[CH2:34]2)=[O:48])[C:44]=1[CH3:45]
Reactant: Cc1cccc(N2CCNCC2C)c1
Reactant: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1cccc(N2CCN(C(=O)Cn3nc(C(F)(F)F)c(Cl)c3C)CC2C)c1

Procedure:
Title compound was prepared following the HATU mediated coupling protocol P, wherein 1-(3-Methylphenyl)-2-methyl-piperazine and (4-Chloro-5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetic acid were used as the coupling components, to give the product as a solid: 1H NMR (DMSO-d6, 400 MHz) 7.68 (br, 1H), 7.17 (br, 1H), 6.71 (br, 2H), 5.41 (m, 2H), 4.08 (m, 4H), 3.70 (m, 2H), 3.50 (br m, 2H), 2.30 (s, 3H), 2.18 (s, 3H), 1.01 (m, 3H) ppm; MS (ES) M+H expected=415.1, found=415.1.