Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Ba+2:2].[OH-].[CH3:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].CCCCCCCCCC1C=CC([OH:29])=CC=1.[C:30](=[O:32])=[O:31]>COCCO>[CH3:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O-:13])=[O:12].[CH3:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O-:13])=[O:12].[Ba+2:2].[C:30](=[O:29])([O-:32])[O-:31]
Reactant: CCCCCCCCCc1ccc(O)cc1
Reactant: CCCCCCCC(=O)O
Reactant: O=C=O
Agent: [Ba+2]
Agent: [OH-]
Solvent: COCCO
Product: CCCCCCCC(=O)[O-]
Product: O=C([O-])[O-]
Reaction time: 0.5 h
Yield: 28 %

Procedure:
34 g of anhydrous barium hydroxide was slowly added to 480 g of methyl cellosolve and dissolved therein. Next, 6 g of octylic acid and a mixture of 20 g of nonylphenol with 34 g of an alkylbenzene solvent were added thereto followed by stirring for approximately 30 minutes. Then the mixture was allowed to react while blowing carbon dioxide into the reaction system and the temperature was slowly elevated to 150° C. while removing the water thus formed. After dehydrating and removing the methyl cellosolve under reduced pressure, overbased barium octoate/carbonate (Ba=28%, metal ratio=10) was obtained as a brown viscous product.
Reaction SMILES: [NH2:1][C:2]([CH:6]1[CH2:15][CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][CH3:17])[CH:12]=2)[CH2:7]1)([CH3:5])[CH2:3][OH:4].C(N(CC)CC)C.Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[CH3:17][O:16][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]([C:2]1([CH3:5])[CH2:3][O:4][C:26](=[O:28])[NH:1]1)[CH2:15][CH2:14]2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1ccc2c(c1)CCC(C(C)(N)CO)C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2c(c1)CCC(C1(C)COC(=O)N1)C2
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 54.1 %

Procedure:
To 25 grams of 2-amino-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)propan-1-ol in 575 mL of dichloromethane was added 45 g of triethylamine. The mixture was cooled to 0° C., and kept below 5° C. while 21 g of triphosgene in dichloromethane was added dropwise. The mixture was stirred at 20-25° C. for 1.5 hrs. The reaction was followed by HPLC until the starting material disappeared. The mixture was concentrated under reduced pressure, 375 mL ethyl acetate was added to the residue. It was washed with water (50 mL×2), dried, decolorized with carbon, and concentrated and dried to afford 10 g of 4-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)-4-methyloxazolidin-2-one, M=261, purity 97%.
Reaction SMILES: [CH3:1][C@H:2]1[C@@:41]2([OH:43])[O:42][C@H:5]([CH2:6][C@H:7]([O:64][CH3:65])[C:8]([CH3:63])=[CH:9][CH:10]=[CH:11][CH:12]=[CH:13][C@@H:14]([CH3:62])[CH2:15][C@@H:16]([CH3:61])[C:17]([C@H:19]([O:59][CH3:60])[C@H:20]([OH:58])[C:21]([CH3:57])=[CH:22][C@@H:23]([CH3:56])[C:24]([CH2:26][C@@H:27]([C@@H:44]([CH2:46][C@H:47]3[CH2:52][C@@H:51]([O:53][CH3:54])[C@H:50]([OH:55])[CH2:49][CH2:48]3)[CH3:45])[O:28][C:29]([C@H:31]3[N:36]([C:37]([C:39]2=[O:40])=[O:38])[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])=[O:25])=[O:18])[CH2:4][CH2:3]1.C(N(C(C)C)C(C)C)C.O([CH2:83][CH2:84][O:85][CH2:86][CH3:87])S(C(F)(F)F)(=O)=O.Cl>C(OCC)(=O)C.C(Cl)Cl>[CH3:83][CH2:84][O:85][CH2:86][CH2:87][O:55][C@H:50]1[C@H:51]([O:53][CH3:54])[CH2:52][CH:47]([CH2:46][C@H:44]([CH:27]2[O:28][C:29](=[O:30])[C@H:31]3[N:36]([CH2:35][CH2:34][CH2:33][CH2:32]3)[C:37](=[O:38])[C:39](=[O:40])[C@:41]3([OH:43])[O:42][C@@H:5]([CH2:4][CH2:3][C@H:2]3[CH3:1])[CH2:6][C@H:7]([O:64][CH3:65])[C:8]([CH3:63])=[CH:9][CH:10]=[CH:11][CH:12]=[CH:13][CH:14]([CH3:62])[CH2:15][C@@H:16]([CH3:61])[C:17](=[O:18])[C@H:19]([O:59][CH3:60])[C@H:20]([OH:58])[C:21]([CH3:57])=[CH:22][C@@H:23]([CH3:56])[C:24](=[O:25])[CH2:26]2)[CH3:45])[CH2:48][CH2:49]1
Reactant: CCOCCOS(=O)(=O)C(F)(F)F
Reactant: CO[C@H]1C[C@@H]2CC[C@@H](C)[C@@](O)(O2)C(=O)C(=O)N2CCCC[C@H]2C(=O)O[C@H]([C@H](C)C[C@@H]2CC[C@@H](O)[C@H](OC)C2)CC(=O)[C@H](C)C=C(C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)C=CC=CC=C1C
Agent: CCOCCO[C@@H]1CCC(C[C@@H](C)C2CC(=O)[C@H](C)/C=C(\C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)CC(C)/C=C/C=C/C=C(\C)[C@@H](OC)C[C@@H]3CC[C@@H](C)[C@@](O)(O3)C(=O)C(=O)N3CCCC[C@H]3C(=O)O2)C[C@H]1OC
Agent: CO[C@H]1C[C@@H]2CC[C@@H](C)[C@@](O)(O2)C(=O)C(=O)N2CCCC[C@H]2C(=O)O[C@H]([C@H](C)C[C@@H]2CC[C@@H](O)[C@H](OC)C2)CC(=O)[C@H](C)/C=C(\C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)/C=C/C=C/C=C/1C
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOCCO[C@@H]1CCC(C[C@@H](C)C2CC(=O)[C@H](C)C=C(C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)CC(C)C=CC=CC=C(C)[C@@H](OC)C[C@@H]3CC[C@@H](C)[C@@](O)(O3)C(=O)C(=O)N3CCCC[C@H]3C(=O)O2)C[C@H]1OC
Temperature: 60 °C
Reaction time: 1 h

Procedure:
In a reaction flask, sirolimus (10 g, 10.9 mmol), ethyl di-isopropyl amine (78 g, 603.5 mmol), methylene chloride (35 ml) and 2-ethoxyethyl triflate (20 g, 88 mmol), each having a quantity about 10 times of that used in Example 3B, were added into the flask, which is filled with nitrogen gas. The reaction mixture is heated to 60° C. and is agitated for one hour and twenty minutes. Then, it is cooled, added with ethyl acetate (500 ml) and aqueous solution of hydrochloric acid (1N, 500 ml) and is further agitated. After agitation, it is settled for separating the layers. The organic layer is collected and respectively washed with pure water (500 ml), saturated saline (400 ml). The washed organic layer is dried and concentrated. The residue is then separated and purified by silica gel column chromatography to obtain white product of Biolimus A9 (2.9 g, 2.9 mmol), having a yield of 26.8% only.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.[CH:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(N(CC)CC)C>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.[Pd](Cl)Cl.O1CCCC1>[C:11]([C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[CH:7][C:6]=2[CH:10]=1)#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: Brc1ccc2sccc2c1
Reactant: C#CCCCCCCCC
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCC#Cc1ccc2sccc2c1
Temperature: 25 °C
Yield: 88.7 %

Procedure:
To a solution of 5-bromobenzothiophene (50.0 g), 1-decyne (35.7 g), triethylamine (71.2 g) and dry tetrahydrofuran (150 ml), under nitrogen, was added bis(triphenylphosphine)palladium (II) chloride (1.65 g) followed by copper (I) iodide (0.233 g) with stirring, at room temperature. The reaction mixture was covered with foil and stirred at reflux, under nitrogen, over the weekend. Additional bis-triphenylphosphine)palladium (II) chloride (0.5%) and 0.25% copper (I) iodide were added, and the reaction mixture was stirred at reflux for three days, cooled, filtered through a bed of celite and the filter cake was washed with ether. The residue was flash chromatographed (silica, 1% ethyl acetate-heptane). The appropriate fractions were collected and evaporated to give 56.3 g (89%) of product.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([NH:15][CH:16]([C:29]2[CH:34]=[C:33]([CH2:35][CH3:36])[CH:32]=[C:31]([O:37][CH2:38][CH2:39][OH:40])[C:30]=2[F:41])[C:17]2[NH:21][C:20](=[O:22])[N:19]([C:23]3[N:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:18]=2)[CH:12]=[CH:11][C:10]=1[C:42]#[N:43])(C)(C)C.ClCCl.C(OCC)(=O)C.Cl>C1(C)C=CC=CC=1>[CH2:35]([C:33]1[CH:32]=[C:31]([O:37][CH2:38][CH2:39][OH:40])[C:30]([F:41])=[C:29]([CH:16]([NH:15][C:13]2[CH:14]=[C:9]3[C:10](=[CH:11][CH:12]=2)[C:42](=[NH:43])[NH:7][CH2:8]3)[C:17]2[NH:21][C:20](=[O:22])[N:19]([C:23]3[N:24]=[CH:25][CH:26]=[CH:27][N:28]=3)[N:18]=2)[CH:34]=1)[CH3:36]
Reactant: CCc1cc(OCCO)c(F)c(C(Nc2ccc(C#N)c(CNC(=O)OC(C)(C)C)c2)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CCc1cc(OCCO)c(F)c(C(Nc2ccc3c(c2)CNC3=N)c2nn(-c3ncccn3)c(=O)[nH]2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 42.1 %

Procedure:
To a mixture of [2-cyano-5-({[5-ethyl-2-fluoro-3-(2-hydroxyethoxy)phenyl]-(5-oxo-1-pyrimidin-2-yl-4,5-dihydro-1H-[1,2,4]triazol-3-yl)methyl}amino)benzyl]carbamic acid t-butyl ester (34.2 mg) and dichloromethane (1.5 mL) there was added a 4N hydrogen chloride-ethyl acetate solution, and the mixture was stirred at room temperature for 4 hours. Toluene (10 mL) was added to the mixture, and the solvent in the mixture was distilled off. The residue was purified by reverse-phase high performance liquid chromatography (acetonitrile/water mixed solvent, 0.1% acetic acid) to obtain the target compound (12.0 mg).
Reaction SMILES: C([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][CH:13]=[C:14]2[O:17][CH2:18][CH:19]2[O:21][CH2:20]2)=[N:9]1)C1C=CC=CC=1.[CH3:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:24]=1[NH:30][CH2:31][CH2:32][NH2:33]>C(Cl)Cl>[NH:9]1[C:10]2[C:15](=[C:14]([O:17][CH2:18][CH:19]([OH:21])[CH2:20][NH:33][CH2:32][CH2:31][NH:30][C:24]3[C:25]([CH3:29])=[CH:26][CH:27]=[CH:28][C:23]=3[CH3:22])[CH:13]=[CH:12][CH:11]=2)[CH:16]=[N:8]1
Reactant: Cc1cccc(C)c1NCCN
Reactant: c1ccc(Cn2cc3c(OCC4CO4)cccc3n2)cc1
Solvent: ClCCl
Product: Cc1cccc(C)c1NCCNCC(O)COc1cccc2[nH]ncc12

Procedure:
6.2 g. 2-Benzyl-4-(2,3-epoxypropoxy)-indazole and 7.2 g. 2-(2,6-dimethylphenylamino)-ethylamine are stirred for 20 hours at 70° C. The reaction mixture is then dissolved in methylene chloride and purified chromatographically over a silica gel column using methylene chloride/methanol (saturated with ammonia) (20:1 v/v) as elution agent. After evaporation, the desired compound is obtained in the form of a viscous oil in a yield of 6.8 g. (69% of theory).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1.[Br:12][CH2:13][C:14]([C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1)=[O:15]>C1(C)C=CC=CC=1>[BrH:12].[C:20]([C:19]1[CH:22]=[CH:23][C:16]([C:14](=[O:15])[CH2:13][N:1]2[CH2:6][CH2:5][CH2:4][C@H:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]2)=[CH:17][CH:18]=1)#[N:21]
Reactant: CCOC(=O)[C@H]1CCCNC1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Solvent: Cc1ccccc1
Product: Br
Product: CCOC(=O)[C@H]1CCCN(CC(=O)c2ccc(C#N)cc2)C1
Reaction time: 8 h
Yield: 62.7 %

Procedure:
To a solution of commercially available (S)-ethyl piperidine-3-carboxylate (10 g, 63.6 mmol) in 200 mL toluene was added 4-(2-bromoacetyl)benzonitrile (17 g, 76 mmol). The reaction mixture was stirred overnight. The next day, the precipitated solid was collected by filtration and washed with ethyl acetate (×3) and dried under vacuum to give 15.2 g of (S)-ethyl 1-(2-(4-cyanophenyl)-2-oxoethyl)piperidine-3-carboxylate hydrobromide. MS (M+1)=301. HPLC Peak RT=1.51 minutes.
Reaction SMILES: [C:1]([C:5]1[N:9]([CH3:10])[N:8]([CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)/[C:7](=[N:17]/[C:18](=[O:36])[C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=2[O:29][CH2:30][CH2:31][C:32](O)([CH3:34])[CH3:33])/[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(S(F)(F)[F:43])CC>C(Cl)Cl>[C:1]([C:5]1[N:9]([CH3:10])[N:8]([CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)/[C:7](=[N:17]/[C:18](=[O:36])[C:19]2[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=[CH:21][C:20]=2[O:29][CH2:30][CH2:31][C:32]([F:43])([CH3:33])[CH3:34])/[CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCN(CC)S(F)(F)F
Reactant: Cn1c(C(C)(C)C)c/c(=N\C(=O)c2cc(C(F)(F)F)ccc2OCCC(C)(C)O)n1C[C@H]1CCCO1
Solvent: ClCCl
Product: Cn1c(C(C)(C)C)c/c(=N\C(=O)c2cc(C(F)(F)F)ccc2OCCC(C)(C)F)n1C[C@H]1CCCO1
Temperature: 25 °C
Yield: 22.3 %

Procedure:
The product from Example 43A (215 mg, 0.42 mmol) in CH2Cl2 (10 mL) was treated dropwise with DAST (66 μL, 0.504 mmol) at −78° C. The reaction mixture was allowed to warm up to room temperature for 4 hrs. The mixture was quenched with saturated NaHCO3 and extracted with EtOAc (2×). The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 50% hexanes/EtOAc to 100% EtOAc to 9:1:0.1 EtOAc:MeOH:Et3N) to afford 48 mg (22%) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 1.45 (d, J=21.48 Hz, 6H) 1.50 (s, 9H) 1.82-1.99 (m, 3H) 2.19-2.37 (m, 3 H) 3.67-3.83 (m, 2H) 4.14-4.23 (m, 1H) 4.24 (s, 3H) 4.48 (t, J=7.36 Hz, 2 H) 4.80-4.97 (m, 1H) 5.48 (d, J=17.18 Hz, 1H) 6.97 (s, 1H) 7.13 (d, J=8.59 Hz, 1H) 7.74 (dd, J=7.98, 1.84 Hz, 1H) 8.08 (d, J=2.15 Hz, 1H); MS (DCI/NH3) m/z 514 (M+H)+.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[C:15]([NH:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[CH:14]=[C:13]([CH3:33])[N:12]=1.O>COCCOCCOC>[CH3:33][C:13]1[N:12]=[C:11]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:16]([N+:17]([O-:19])=[O:18])=[C:15]([NH:20][CH2:21][CH2:22][O:23][CH2:24][CH2:25][CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)[CH:14]=1
Reactant: Oc1ccccc1
Reactant: Cc1cc(NCCOCCCc2cccnc2)c([N+](=O)[O-])c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOCCOC
Product: Cc1cc(NCCOCCCc2cccnc2)c([N+](=O)[O-])c(Oc2ccccc2)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 129.4 %

Procedure:
The general method described in Part E of Example 80 was used with the following modifications. A solution of phenol (1.45 g, 15.4 mmol) in diglyme (10 mL) was added to a cooled mixture of the sodium hydride dispersion (0.59 g, 14.7 mmol) in diglyme (15 mL), and the addition flask was rinsed twice with diglyme (5 mL), which was added to the reaction. A solution of (2-chloro-6-methyl-3-nitropyridin-4-yl)-{2-[3-(pyridin-3-yl)propoxy]ethyl}amine (4.9 g, 14 mmol) was added, and the reaction was heated at 60° C. for 20 hours. Additional reagent prepared from phenol (0.50 g, 5.3 mmol) and 60% sodium hydride (0.21 g, 5.3 mmol) in diglyme was added, and the reaction was heated at 60° C. for 2.5 hours. The reaction was allowed to cool to room temperature and slowly added to 800 mL of water and stirred for one hour to form a bright yellow solid. The solid was isolated by filtration and washed with hexane (50 mL) to provide 7.4 g of (6-methyl-3-nitro-2-phenoxypyridin-4-yl)-{2-[3-(pyridin-3-yl)propoxy]ethyl}amine as a yellow solid contaminated with water.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[CH:31][C:32]([C:34](=[O:36])[CH3:35])=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[CH:31][C:32]([C:34](=[O:36])[CH3:35])=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cc(C(C)=O)ccc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2cc(C(C)=O)ccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-5-acetyl-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][N:9]([C@H:12]([CH2:21][C:22]#[N:23])[C:13]([NH:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:14])[C:8](=[O:24])[C:7]3=[CH:25][N:26]([S:27]([C:30]4[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=4)(=[O:29])=[O:28])[C:5]([C:6]=23)=[N:4][CH:3]=1.[OH-:37].[Na+]>CO>[Cl:1][C:2]1[C:11]([CH2:10][NH:9][C@H:12]([CH2:21][C:22]#[N:23])[C:13]([NH:15][CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20]2)=[O:14])=[C:6]2[C:7]([C:8]([OH:24])=[O:37])=[CH:25][N:26]([S:27]([C:30]3[CH:36]=[CH:35][C:33]([CH3:34])=[CH:32][CH:31]=3)(=[O:29])=[O:28])[C:5]2=[N:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc3c4c(c(Cl)cnc42)CN([C@H](CC#N)C(=O)NC2CCCC2)C3=O)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2cc(C(=O)O)c3c(CN[C@H](CC#N)C(=O)NC4CCCC4)c(Cl)cnc32)cc1
Reaction time: 0.33 h
Yield: 2.1 %

Procedure:
To a solution of (R)-2-(6-chloro-3-oxo-1-tosylpyrrolo[4,3,2-de][2,6]naphthyridin-4(1H,3H,5H)-yl)-3-cyano-N-cyclopentylpropanamide in MeOH (2 mL) was added aqueous NaOH (1N, 0.5 mL). The reaction mixture was stirred for 20 min and the product was purified via preparative mass trigger LC-MS (AcCN/H2O, 5-50%). The fractions were collected, concentrated, and dried in vacuo to afford the title compound as a yellow oil (0.5 mg, 2.1% from Step A starting material). 1H NMR (400 MHz, CD3OD) δ 1.37-1.72 (m, 4H) 1.83-1.95 (m, 4 H) 3.22-3.26 (m, 2 H) 3.69-3.76 (m, 1 H) 5.11 (s, 1 H) 5.14-5.17 (m, 1 H) 5.18 (s, 1 H) 7.88 (s, 1 H) 8.27 (s, 1 H). [M+H] calc'd for C18H18ClN5O2, 372; found, 372.4.
Reaction SMILES: [C:1]12([C:11]3[N:15]([CH3:16])[C:14]([C:17]4[CH:22]=[CH:21][C:20]([S:23][CH3:24])=[CH:19][CH:18]=4)=[N:13][N:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.ClC1C=CC=C(C(OO)=[O:33])C=1>C(Cl)Cl>[C:1]12([C:11]3[N:15]([CH3:16])[C:14]([C:17]4[CH:22]=[CH:21][C:20]([S:23]([CH3:24])=[O:33])=[CH:19][CH:18]=4)=[N:13][N:12]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ccc(-c2nnc(C34CC5CC(CC(C5)C3)C4)n2C)cc1
Solvent: ClCCl
Product: Cn1c(-c2ccc(S(C)=O)cc2)nnc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
A mixture of 3-(1-adamantyl)-4-methyl-5-[4-(methylthio)phenyl]-4H-1,2,4-triazole (4-23) (50 mg, 0.15 mmol) and m-chloroperbenzoic acid (85%, MCPBA) (45 mg, 0.22 mmol) in methylene chloride (0.75 mL) was stirred at room temperature for 25 min. The mixture was diluted with methylene chloride, washed with 10% aqueous K2CO3, water, and saturated brine and dried (MgSO4). The residue after evaporation in vacuo was purified by reverse-phase chromatography on a C-18 silica gel column with an acetonitrile-0.1% trifluoroacetic acid gradient to give 3-(1-adamantyl)-4-methyl-5-[4-(methylsulfinyl)phenyl]-4H-1,2,4-triazole (4-24).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[N:13][C:5]2[NH:6][C:7]3[CH2:12][CH2:11][NH:10][CH2:9][C:8]=3[C:4]=2[CH:3]=1.CCN(C(C)C)C(C)C.[Cl:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29].Cl.CCOCC>C1COCC1>[ClH:1].[Cl:24][C:25]1[CH:26]=[C:27]([C:28]([N:10]2[CH2:11][CH2:12][C:7]3[NH:6][C:5]4[N:13]=[CH:14][C:2]([Cl:1])=[CH:3][C:4]=4[C:8]=3[CH2:9]2)=[O:29])[CH:31]=[CH:32][CH:33]=1
Reactant: Clc1cnc2[nH]c3c(c2c1)CNCC3
Reactant: O=C(Cl)c1cccc(Cl)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(c1cccc(Cl)c1)N1CCc2[nH]c3ncc(Cl)cc3c2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 121.9 %

Procedure:
3-Chloro-6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrole (50 mg, 0.24 mmol) and DIEA (0.05 mL, 0.29 mmol) were dissolved in THF (2 mL). 3-Chlorobenzoyl chloride (0.04 mL, 0.29 mmol) was added dropwise, and the reaction solution was stirred at room temperature for 1 h. The crude reaction mixture was concentrated, and converted to the HCl salt by dissolving the crude material in MeOH (2 mL) and adding 1 M HCl/ether (2 equiv). The resulting solution was refrigerated overnight. The resulting precipitate was filtered and dried under vacuum to provide 21 (56 mg, 61% yield) as a pale yellow solid. LC-MS (M+H=347, obsd.=347).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([N:8]([CH:10]([CH3:12])[CH3:11])[CH3:9])[CH2:4][C@H:3]1[CH2:13][CH:14]([OH:18])[CH:15]([CH3:17])[CH3:16].C(N(C(C)C)CC)(C)C.[F:28][C:29]([F:44])([F:43])[C:30]1[CH:31]=[C:32]([CH:40]=[CH:41][CH:42]=1)[C:33]([NH:35][CH2:36][C:37]([OH:39])=[O:38])=[O:34].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(#N)C.CO>[OH:18][C@@H:14]([CH:15]([CH3:17])[CH3:16])[CH2:13][C@@H:3]1[CH2:4][C@H:5]([N:8]([CH:10]([CH3:12])[CH3:11])[CH3:9])[CH2:6][CH2:7][C@@H:2]1[NH:1][C:37](=[O:38])[CH2:36][NH:35][C:33](=[O:34])[C:32]1[CH:40]=[CH:41][CH:42]=[C:30]([C:29]([F:28])([F:44])[F:43])[CH:31]=1.[OH:18][C@H:14]([CH:15]([CH3:17])[CH3:16])[CH2:13][C@@H:3]1[CH2:4][C@H:5]([N:8]([CH:10]([CH3:11])[CH3:12])[CH3:9])[CH2:6][CH2:7][C@@H:2]1[NH:1][C:37](=[O:39])[CH2:36][NH:35][C:33](=[O:34])[C:32]1[CH:40]=[CH:41][CH:42]=[C:30]([C:29]([F:28])([F:44])[F:43])[CH:31]=1
Reactant: CC(C)C(O)C[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1N
Reactant: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC(C)[C@@H](O)C[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Product: CC(C)[C@H](O)C[C@@H]1C[C@H](N(C)C(C)C)CC[C@@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12.5 h

Procedure:
Examples 11p and 11q, Step 10: To a solution of 1-((1S,2S,5R)-2-amino-5-(isopropyl(methyl)amino)cyclohexyl)-3-methylbutan-2-ol (0.38 mmoles) in 3 ml of anhydrous acetonitrile were added diisopropylethylamine (0.27 ml, 1.52 mmoles), 2-(3-(trifluoromethyl)benzamido)acetic acid (141 mg, 0.57 mmoles) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (183 mg, 0.57 mmoles, Bachem), and the mixture was stirred for 12.5 hours at room temperature. Then several drops of methanol was added, and it was stirred for additional two hours. The solvent was evaporated off and the residue was purified by chromatography (silica gel, 1:9:90 cNH4OH-MeOH—CH2Cl2) to give N-(2-((1S,2S,4R)-2-((2R)-2-hydroxy-3-methylbutyl)-4-(isopropyl(methyl)amino)cyclohexylamino)-2-oxoethyl)-3-(trifluoromethyl)benzamide (Example 11p) and N-(2-((1S,2S,4R)-2-((2S)-2-hydroxy-3-methylbutyl)-4-(isopropyl(methyl)amino)cyclohexylamino)-2-oxoethyl)-3-(trifluoromethyl)benzamide (Example 11q). For both, MS found: (M+H)+=486.4.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]=[S:13].[CH2:14]([NH2:18])[CH:15]([CH3:17])[CH3:16].CCCCCC.[CH3:25][CH2:26][O:27]C(C)=O.CN1CCOCC1>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[N:18]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:26](=[O:27])[CH2:25][S:13]1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: CCOC(C)=O
Reactant: CC(C)CN
Solvent: CN1CCOCC1
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCC(=O)N1CC(C)C
Temperature: 80 °C
Reaction time: 18 h
Yield: 85 %

Procedure:
To a solution of 2-methyl-4-nitrophenyl isothiocyanate (0.190 g, 1.0 mmol) in DMF (5.3 mL) was added isobutylamine (0.4 M solution in DMF, 5.3 mL) and the reaction mixture was allowed to stir for 4 h at which time TLC analysis (hexane:EtOAc 3:1) indicated consumption of the isothiocyanate. To the resulting mixture was added chloroacetic acid (0.8 M solution in DMF, 4.0 mL) followed by N-methylmorpholine (0.7 mL, 6.4 mmol). The reaction mixture was stirred at 80° C. for 18 h, then was partitioned between water (10 mL) and EtOAc (25 mL). The aqueous phase was back-extracted with EtOAc (2×10 mL). The combined organic layers were washed with a saturated NaCl solution (25 mL), dried (Na2SO4) and concentrated under reduced pressure. The resulting residue was purified by MPLC (Biotage 40 S silica gel column, gradient from 5% EtOAc/hex to 33% EtOAc/hex) to afford 2-(2-methyl-4-nitrophenylimino)-3-isobutyl-1,3-thiazolidin-4-one as a pale yellow oil (0.52 g, 85%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[NH:17][C:16]([CH3:18])=[C:15]([C:19]([OH:21])=O)[C:14]=1[CH3:22].[NH2:23][CH2:24][CH:25]([OH:33])[CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[OH:33][CH:25]([CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)[CH2:24][NH:23][C:19]([C:15]1[C:14]([CH3:22])=[C:13](/[CH:12]=[C:5]2\[C:6](=[O:11])[NH:7][C:8]3[C:4]\2=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=3)[NH:17][C:16]=1[CH3:18])=[O:21]
Reactant: Cc1[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c(C)c1C(=O)O
Reactant: NCC(O)CN1CCOCC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(Br)cc32)c(C)c1C(=O)NCC(O)CN1CCOCC1

Procedure:
5-(5-Bromo-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (72.2 mg, 0.2 mmol) was condensed with 1-amino-3-morpholin-4-yl-propan-2-ol (38 mg, 0.24 mmol) to precipitate 5-[5-Bromo-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-hydroxy-3-morpholin-4-yl-propyl)-amide (55 mg, 55%). 1H NMR (DMSO-d6) δ 2.27 (m, 1H), 2.32 (m, 1H), 2.39(m, 4H), 2.41, 2.42 (2×s, 6H, 2×CH3), 3.13 (s, 1H), 3.35 (m, 1H), 3.55 (m, 4H), 3.77 (m, 1H), 4.74 (d, J=4.4 Hz, 1H, OH), 6.80 (d, J=8.4 Hz, 1H), 7.24 (dd, J=2.0, 8.0 Hz, 1H), 7.51 (t, J=5.6 Hz, 1H), 7.76 (s, 1H), 8.09 (d, J=2.0 Hz, 1H) (aromatic and vinyl), 10.99 (s, 1H, CONH), 13.62 (s, 1H, NH). LC-MS (m/z) 503.4 (M−1).