Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][S:8]([NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][N:29]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:30][C@H:31]([OH:38])[C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)=[CH:22][CH:21]=2)=[CH:16][C:15]=1[O:46][CH2:47][CH:48]([CH3:50])[CH3:49])=[O:13])(=[O:10])=[O:9])(=O)C.[OH-].[Na+]>CO.O1CCCC1>[OH:4][CH2:5][CH2:6][CH2:7][S:8]([NH:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][CH2:28][N:29]([CH2:30][C@H:31]([OH:38])[C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)[C:39](=[O:40])[O:41][C:42]([CH3:44])([CH3:45])[CH3:43])=[CH:24][CH:25]=2)=[CH:16][C:15]=1[O:46][CH2:47][CH:48]([CH3:50])[CH3:49])=[O:13])(=[O:10])=[O:9]
Reactant: CC(=O)OCCCS(=O)(=O)NC(=O)c1ccc(-c2ccc(CCCN(C[C@H](O)c3cccnc3)C(=O)OC(C)(C)C)cc2)cc1OCC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)COc1cc(-c2ccc(CCCN(C[C@H](O)c3cccnc3)C(=O)OC(C)(C)C)cc2)ccc1C(=O)NS(=O)(=O)CCCO
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 89.6 %

Procedure:
To a solution of 3-[[[[4′-[3-[(tert-butoxycarbonyl)-[(2R)-2-hydroxy-2-(3-pyridyl)ethyl]amino]propyl]-3-isobutoxy-4-biphenylyl]carbonyl]amino]sulfonyl]propyl acetate (108 mg) in methanol (1.08 ml) and tetrahydrofuran (0.324 ml) was added 1N aqueous sodium hydroxide solution (0.455 ml) and the mixture was stirred at room temperature for 45 minutes. The reaction mixture was concentrated under reduced pressure and the pH value was adjusted to 6.0 with 0.1N hydrochloric acid. The mixture was extracted with ethyl acetate (twice) and the extracts were washed with water and brine, and dried over magnesium sulfate. Filtration followed by evaporation under reduced pressure gave tert-butyl [3-[4′-[[[(3-hydroxypropyl)sulfonyl]amino]carbonyl]-3′-isobutoxy-4-biphenylyl]-propyl][(2R)-2-hydroxy-2-(3-pyridyl)ethyl]carbamate (91.1 mg) as a white solid (foam).
Reaction SMILES: [CH:1]1[C:5]2=[C:6]([NH2:10])[N:7]=[CH:8][N:9]=[C:4]2[N:3]([C@@H:11]2[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]2O)[CH:2]=1.[CH2:20]=O.[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>CN(C=O)C>[NH2:10][C:6]1[C:5]2[C:1]([CH2:20][N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:2][N:3]([C@@H:11]3[O:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[CH2:12]3)[C:4]=2[N:9]=[CH:8][N:7]=1
Reactant: Nc1ncnc2c1ccn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: C=O
Reactant: C1COCCN1
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(CN1CCOCC1)cn2[C@H]1C[C@H](O)[C@@H](CO)O1

Procedure:
can be prepared by using the Mannich reaction. The 5-morpholinomethyl derivative (Watanabe et al., Nucleosides & Nucleotides, 1(2), 191-203, 1982) is obtained by heating tubercidin together with paraformaldehyde and morpholine in DMF. The 5-morpholine derivative (33) is obtained in accordance with the silylation and deoxygenation described in Ex. 33.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[C:16]([F:29])=[CH:17][C:18]3[C:19]4[CH2:28][NH:27][CH2:26][CH2:25][C:20]=4[N:21]([CH3:24])[C:22]=3[CH:23]=2)[C:11](=[O:30])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:35](C)=O.[Na+]>ClCCl.C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[C:16]([F:29])=[CH:17][C:18]3[C:19]4[CH2:28][N:27]([CH3:35])[CH2:26][CH2:25][C:20]=4[N:21]([CH3:24])[C:22]=3[CH:23]=2)[C:11](=[O:30])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c2c(c3cc(F)c(-n4ccc(OCc5ccccc5)cc4=O)cc31)CNCC2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN1CCc2c(c3cc(F)c(-n4ccc(OCc5ccccc5)cc4=O)cc3n2C)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 71.9 %

Procedure:
To a solution of 4-(benzyloxy)-1-(8-fluoro-5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one (100 mg, 0.26 mmol) in dichloromethane/acetic acid (1% acetic acid, 10 mL) were sequentially added formaldehyde (37% aqueous solution, 22 μL, 0.74 mmol) and NaBH(OAc)3 (316 mg, 1.49 mmol). The reaction mixture was stirred at room temperature for 2.5 h. The mixture was concentrated under reduced pressure, and the residue was dissolved in CH2Cl2. The organic layer was washed with H2O and 5% aqueous LiCl, dried over Na2SO4, filtered and concentrated. Purification by flash chromatography (silica gel, CH2Cl2/(10:1:0.1 CH2Cl2/MeOH/NH4OH), 0:1 to 1:1) gave 4-(benzyloxy)-1-(8-fluoro-2,5-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one (78 mg, 38%) as a yellow solid. The free base was converted to the HCl salt using 1.25M HCl in methanol providing the title compound (75 mg, 95%) as a off-white solid: 1H NMR (300 MHz, CD3OD) δ 7.53-7.33 (m, 7H), 7.27 (d, J=10.5 Hz, 1H), 7.28 (dd, J=7.8, 2.4 Hz, 1H), 6.10 (d, J=2.7 Hz, 1H), 5.17 (s, 2H), 3.79 (br s, 2H), 3.67 (s, 3H), 3.03-3.00 (m, 4H), 2.64 (s, 3H); ESI MS m/z 418 [M+H]+; HPLC (Method A) 95.7% (AUC), tR=14.5 min.
Reaction SMILES: C[O:2][C:3]1[CH:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]2[C:10]([CH2:11][CH:12]=1)=[CH:9][CH:8]=[C:7]([O:13][CH3:14])[CH:6]=2.C(O)(=O)C(O)=O.CO>O>[OH:2][C:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][C:7]([O:13][CH3:14])=[CH:8][CH:9]=2)[C:4]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)C1C(OC)=CCc2ccc(OC)cc21
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: CO
Product: COC(=O)C1=C(O)CCc2ccc(OC)cc21
Temperature: 20 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
A mixture of II (0.124 mole), oxalic acid (0.124 mole), 400 ml. methanol and 120 ml. water was warmed until solution occurred. This solution was then stirred at 20° C. for 18 hours. The resultant mixture was warmed again to solution and then concentrated. The residue was treated with dilute potassium carbonate and extracted with methylene chloride. The extracts were dried (MgSO4), filtered and concentrated to give III (~100%). Two recrystallizations of a small sample from methanol gave an analytical sample; mp 48.0°-48.5° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7](=[O:25])[N:8]2[C@H:11]2[CH2:16][CH2:15][C@H:14](C3N(C([O-])=O)C=CN=3)[CH2:13][CH2:12]2)=[C:4]([Cl:26])[N:3]=1.[C:27](=[O:30])([O-:29])[O-:28].[K+].[K+].[CH3:33]O>>[C:27](=[O:29])([O:28][CH3:33])[O:30][C@H:14]1[CH2:13][CH2:12][C@H:11]([N:8]2[C:7](=[O:25])[NH:6][C:5]3[C:9]2=[N:10][C:2]([NH2:1])=[N:3][C:4]=3[Cl:26])[CH2:16][CH2:15]1
Reactant: CO
Reactant: O=C([O-])[O-]
Reactant: Nc1nc(Cl)c2[nH]c(=O)n([C@H]3CC[C@H](c4nccn4C(=O)[O-])CC3)c2n1
Agent: [K+]
Product: COC(=O)O[C@H]1CC[C@H](n2c(=O)[nH]c3c(Cl)nc(N)nc32)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a suspension of trans-4-(2-amino-6-chloro-8-oxo-7,8-dihydropurin-9-yl)cyclohexyl-1H-imidazole-1-carboxylate (10.6 g, 28.1 mmol) in anhydrous methanol (400 mL) was added potassium carbonate (1.1 g, 10% wt) with stirring at room temperature. After 15 h, the reaction was found to be complete by LC-MS. The solvent was removed in vacuo, and water (1 L) was added with stirring at room temperature. Filtration under vacuum gave the desired product as a pink solid (yield quantitative). MS (EI) m/z 342.1 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([Br:18])[C:3]=1[N:19]([CH3:40])[C:20]([C:22]1[C:23]([O:38][CH3:39])=[C:24]([N:28](C)[C:29]([C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)=[O:30])[CH:25]=[CH:26][CH:27]=1)=[O:21].ClC1C=CC=C(C(OO)=[O:49])C=1>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([Br:18])[C:3]=1[N:19]([CH3:40])[C:20]([C:22]1[C:23]([O:38][CH3:39])=[C:24]([NH:28][C:29]([C:31]2[CH:36]=[CH:35][N+:34]([O-:49])=[CH:33][CH:32]=2)=[O:30])[CH:25]=[CH:26][CH:27]=1)=[O:21]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1c(C(=O)N(C)c2c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc2Br)cccc1N(C)C(=O)c1ccncc1
Solvent: ClCCl
Product: COc1c(NC(=O)c2cc[n+]([O-])cc2)cccc1C(=O)N(C)c1c(Br)cc(C(F)(C(F)(F)F)C(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of N-[3-[[2,6-dibromo-4-[1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl]phenyl]-methyl-carbamoyl]-2-methoxy-phenyl]-N-methyl-pyridine-4-carboxamide (Example G-17) (0.0657 g, 0.178 mmole) in dichloromethane (1.08 ml) was added by small portions 3-chloroperbenzoic acid (purity 70%) (0.0657 g, 0.266 mmole). After 2.5 hours stirring at 25° C., the yellow solution was quenched with aqueous sodium sulfite, diluted with dichloromethane and washed twice with saturated aqueous sodium bicarbonate, then with brine. The organic solution was dried over sodium sulfate. The product was isolated after removal of the solvent, as a white powder (melting range: 134-230° C.) showing, by LC-MS analysis (method 6 described hereunder) a retention time of 1.03 min and a M+H+ peak of 702.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)[C:13](O)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[NH2:51][C:52]1[CH:57]=[CH:56][C:55]([Cl:58])=[CH:54][N:53]=1.N1C(C)=CC=CC=1C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:18][CH2:19][C:20](=[O:23])[CH2:21][CH2:22]2)[C:13]([NH:51][C:52]2[CH:57]=[CH:56][C:55]([Cl:58])=[CH:54][N:53]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: Nc1ccc(Cl)cn1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCC(=O)CC2)C(=O)O)cc1Cl
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCC(=O)CC2)C(=O)Nc2ccc(Cl)cn2)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.2 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-(4-oxo-cyclohexyl)-propionic acid (prepared as in Example 60, 300 mg, 0.84 mmol) and triphenylphosphine (288 mg, 1.09 mmol) in methylene chloride (6.0 mL) cooled to 0° C. was treated with N-bromosuccinimide (192 mg, 1.09 mmol) in small portions. After the complete addition of N-bromosuccinimide, the reaction mixture was allowed to warm to 25° C. over 30 min. The bright orange reaction mixture was then treated with 2-amino-5-chloropyridine (220 mg, 1.68 mmol) and 2,6-lutidine (0.42 mL, 3.36 mmol). The resulting reaction mixture was stirred at 25° C. for 4 h. The reaction mixture was then diluted with methylene chloride (25 mL) and was successively washed with a 10% aqueous hydrochloric acid solution 1×20 mL), a saturated aqueous sodium bicarbonate solution 1×20 mL) and water 1×20 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 65/35 hexanes/ethyl acetate to 1/1 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-(5-chloro-pyridin-2-yl)-3-(4-oxo-cyclohexyl)-propionamide (265mg, 67%) as a white foam: [α]23589=−35.71° (c=0.35, chloroform); EI-HRMS m/e calcd for C21H22Cl2N2O4S (M+H)+ 469.0750. found 469.0754.
Reaction SMILES: C(N(CC)CC)C.[C@@H:8]1([N:16]2[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]2=[O:18])[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[CH2:9]1.[CH3:25][O:26][C:27]1[CH:48]=[CH:47][C:30]([C:31](Cl)([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)=[CH:29][CH:28]=1.CO>C1COCC1>[CH3:39][O:38][C:35]1[CH:34]=[CH:33][C:32]([C:31]([O:14][CH2:13][C@H:12]2[O:15][C@@H:8]([N:16]3[CH:24]=[C:22]([CH3:23])[C:20](=[O:21])[NH:19][C:17]3=[O:18])[CH2:9][C@@H:10]2[OH:11])([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:30]2[CH:47]=[CH:48][C:27]([O:26][CH3:25])=[CH:28][CH:29]=2)=[CH:37][CH:36]=1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cc(C)c(=O)[nH]c3=O)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 85.3 %

Procedure:
Triethylamine (10 ml) in 200 ml THF was injected into a solid mixture of 6.8 g (28.0 mmol) thymidine and 10.2 g (28.6 mmol) 4,4'-dimethoxytrityl chloride under nitrogen with stirring. The solution was stirred at room temperature for 2 hours. After completion of the reaction, 10 ml methanol was added to consume the excess DMTrCl. The mixture was stirred for 5 minutes and the solvent removed by rotary evaporation. The residue was dissolved in 250 ml of ethyl acetate and the solution was washed with saturated NaHCO3 and dried over MgSO4. The solid was recrystallized from ethyl acetate/hexane to obtain 13.0 g 5'-protected thymidine 16 (85.6%).: m.p. 124°-126° C.; 1H NMR (200 MHz, CDCl3) δ8.97 (s, 1H, NH), 7.60 (m, 1H, H-6), 6.72-7.42 (m, 13H, Ph), 6.42 (m, 1H, H-1'), 4.56 (m, 1H, H-3'), 4.05 (m, 1H, H-4'), 3.78 (s, 6H, OMe2), 3.41 (m, 2H, H-5'), 2.62 (m, 1H, OH), 2.46 (m, 2H, H-2'), 1.46 (s, 3H, Me); 13C NMR (50 MHz, CDCl3) δ163.0 (C-4), 157.6, 149.8 (C-2), 143.5, 135.0 (C-6), 134.7, 134.6, 129.4, 127.4, 127.3, 126.5, 112.8, 110.9 (C-5), 86.7 (C-4'), 86.2, 84.7 (C-1'), 72.5 (C-3'), 63.8 (C-5'), 55.5 (OCH3), 41.3 (C-2'), 12.5 (CH3).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[C:8]([CH3:16])=[C:9]([C:14]#[N:15])[S:10][C:11]=1[S:12][CH3:13])=O.[C:18]1([NH:24][C:25]([NH2:27])=[NH:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(#N)C.CO>[CH3:16][C:8]1[C:7]([C:5]2[CH:4]=[CH:3][N:27]=[C:25]([NH:24][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:26]=2)=[C:11]([S:12][CH3:13])[S:10][C:9]=1[C:14]#[N:15]
Reactant: CSc1sc(C#N)c(C)c1C(=O)C=CN(C)C
Reactant: N=C(N)Nc1ccccc1
Solvent: CO
Solvent: CC#N
Product: CSc1sc(C#N)c(C)c1-c1ccnc(Nc2ccccc2)n1
Temperature: 25 °C

Procedure:
To a solution of 4-(3-dimethylamino-acryloyl)-3-methyl-5-methylsulfanyl-thiophene-2-carbonitrile (0.2 mmol) in acetonitrile (0.25 mL) was added N-phenyl guanidine (1 equivalent, 0.2 mmol) and the reaction heated at reflux for 24 hours. The resulting mixture was cooled to room temperature then diluted with methanol (3 mL). The resulting slurry was filterred washed with methanol to afford IIb-7.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].[C:13](#[N:15])C.[C-]#N.[K+].O>C(O)C>[C:13]([CH2:2][C:3]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:4]=1[C:5]#[N:6])#[N:15]
Reactant: CC#N
Reactant: COc1ccc(C#N)c(CBr)c1
Agent: [C-]#N
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COc1ccc(C#N)c(CC#N)c1
Reaction time: 4 h

Procedure:
2-(Bromomethyl)-4-methoxybenzonitrile (36 g, example 235, step 1) was suspended in 200 ml of ethanol, 200 ml of acetonitrile was added followed by KCN (8.3 g) and 150 ml of water. Mixture was stirred and the colorless solution turned to yellow. The reaction was complete after 4 hours of stirring. The volatiles were removed under vacuum, and the residual solid was redissolved in ethyl acetate (200 ml) and washed with water (100 ml) and brine (100 ml). The organics were then dried over sodium sulfate. Ethyl acetate was removed and the residue was recrystallized from ethyl acetate and dichloride methane to provide 17 g of 2-(cyanomethyl)-4-methoxybenzonitrile.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([O:18][C:19]3[CH:24]=[CH:23][N:22]=[C:21]([C:25](O)=[O:26])[CH:20]=3)[CH:15]=[CH:14][C:12]=2[N:13]=1.CN(C(ON1N=NC2[CH:39]=[CH:40][CH:41]=[N:42]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C1(N)CC1>CN1C(=O)CCC1>[CH:41]1([NH:42][C:25](=[O:26])[C:21]2[CH:20]=[C:19]([O:18][C:16]3[CH:15]=[CH:14][C:12]4[N:13]=[C:9]([NH:8][C@@H:3]5[CH2:4][CH2:5][CH2:6][CH2:7][C@H:2]5[OH:1])[S:10][C:11]=4[CH:17]=3)[CH:24]=[CH:23][N:22]=2)[CH2:39][CH2:40]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1cc(Oc2ccc3nc(N[C@@H]4CCCC[C@H]4O)sc3c2)ccn1
Agent: F[P-](F)(F)(F)(F)F
Agent: NC1CC1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC1CC1)c1cc(Oc2ccc3nc(N[C@@H]4CCCC[C@H]4O)sc3c2)ccn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 5.9 %

Procedure:
To the reaction solution of 4-(2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-yloxy)picolinic acid (5 mg, 39 μmol), HATU (15 mg, 39 μmol) and DIPEA (14 μL, 78 μmol) in 1 ml of NMP was added cyclopropylamine (7 ul mg, 30 μmol). The reaction solution was stirred at room temperature for 12 hours. The crude reaction solution was purified on prep HPLC and evaporated in vaccuo to give N-cyclopropyl-4-(2-((1R,2R)-2-hydroxycyclohexylamino)benzo[d]thiazol-6-yloxy)picolinamide (1 mg, 2.3 μmol) as white powder. ES/MS m/z 425.2 (MH+).
Reaction SMILES: C([O:4][CH:5]1[CH2:10][CH:9]2[N:11]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:13])[CH:6]1[CH2:7][C@H:8]2[C:22]([O:24][CH2:25][CH3:26])=[O:23])(=O)C.C1CCN2C(=NCCC2)CC1>CO>[OH:4][CH:5]1[CH2:10][CH:9]2[N:11]([C:12]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[O:13])[CH:6]1[CH2:7][C@H:8]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)[C@@H]1CC2C(OC(C)=O)CC1N2C(=O)OCc1ccccc1
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)[C@@H]1CC2C(O)CC1N2C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 45 %

Procedure:
A mixture of O7-benzyl O5-ethyl (5R)-2-acetoxy-7-azabicyclo[2.2.1]heptane-5,7-dicarboxylate (0.87 g, 2.4 mmol) and DBU (0.73 g, 4.8 mmol) in methanol (20 mL) was stirred for 12 hours at room temperature. After removal of solvent, the residue was purified by silica gel chromatography to give O7-benzyl O5-ethyl (5R)-2-hydroxy-7-azabicyclo[2.2.1]heptane-5,7-dicarboxylate 151d. Yield: 45%. MS: calc'd (MH +) 306, measured (MH+) 306.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[OH-].[K+].[C:9](=[S:11])=[S:10].[CH3:12]I>C(O)C.O>[C:4]([CH2:3][CH2:2][NH:1][C:9](=[S:11])[S:10][CH3:12])([OH:6])=[O:5]
Reactant: CI
Reactant: S=C=S
Reactant: NCCC(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CSC(=S)NCCC(=O)O
Reaction time: 0.5 h

Procedure:
β-Alanine (17.8 g., 0.2 mol.) was added to a solution of 22.4 g. (0.4 mol.) of potassium hydroxide in 500 ml. of water at 25°. Carbon disulfide (12.2 ml., 0.2 mol.) was added and the reaction mixture was refluxed for three hours. The mixture was cooled, 28.4 g. (0.2 mol.) of methyl iodide and 500 ml. of ethanol were added and the resulting mixture was stirred for 30 minutes. The precipitate was collected by filtration, the filtrate was concentrated and the aqueous residue was combined with the solid material and brought to pH 8.5-9 by addition of 10% aqueous sodium hydroxide. The resulting suspension was extracted with ethyl acetate. Ethyl acetate was added to the aqueous phase which was then acidified to pH 1.5 with 6N hydrochloric acid. The layers were separated and the aqueous phase was extracted with ethyl acetate. The ethyl acetate extracts were combined, dried (MgSO4) and evaporated to dryness to give methyl 2-carboxyethyldithiocarbamate.
Reaction SMILES: [CH2:1]([O:3][C:4](Cl)=[S:5])[CH3:2].[NH2:7][C:8]1[CH:9]=[C:10]([NH:18][C:19]2[N:28]=[CH:27][C:26]3[N:25]([CH3:29])[C:24](=[O:30])[CH2:23][N:22]([CH:31]([CH3:33])[CH3:32])[C:21]=3[N:20]=2)[CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1.O>N1C=CC=CC=1>[CH2:1]([O:3][C:4](=[S:5])[NH:7][C:8]1[CH:13]=[C:12]([C:14]([F:16])([F:17])[F:15])[CH:11]=[C:10]([NH:18][C:19]2[N:28]=[CH:27][C:26]3[N:25]([CH3:29])[C:24](=[O:30])[CH2:23][N:22]([CH:31]([CH3:33])[CH3:32])[C:21]=3[N:20]=2)[CH:9]=1)[CH3:2]
Reactant: CC(C)N1CC(=O)N(C)c2cnc(Nc3cc(N)cc(C(F)(F)F)c3)nc21
Reactant: CCOC(=S)Cl
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=S)Nc1cc(Nc2ncc3c(n2)N(C(C)C)CC(=O)N3C)cc(C(F)(F)F)c1
Yield: 68 %

Procedure:
Ethylchlorothioformate (0.754 ml; 7.230 mmol) was added dropwise to a cooled (0° C.) suspension of 2-(3-Amino-5-trifluoromethyl-phenylamino)-8-isopropyl-5-methyl-7,8-dihydro-5H-pteridin-6-one (2.5 g; 6.573 mmol) in 10 ml of dry Pyridine. The reaction mixture was allowed to reach room temperature and maintained at that temperature 2 h. Water was added to the reaction mixture and the precipitated formed was filtered washed with water and dried in vacuo. 2.1 g (4.48 mmol; 68% yield) of a yellow powder were obtained.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=O)[NH:8][C:6](=O)[C:5]2=[CH:11][CH:12]=1.[ClH:13]>O1CCCC1>[Cl:13][C:11]1[CH:12]=[CH:2][CH:3]=[C:4]2[C:5]=1[CH2:6][NH:8][CH2:9]2
Reactant: O=C1NC(=O)c2cc(Cl)ccc21
Reactant: Cl
Solvent: C1CCOC1
Product: Clc1cccc2c1CNC2

Procedure:
To a solution of 4-chlorophthalimide (60 g) in 1 liter of tetrahydrofuran was added borane-methyl sulfide complex (100 ml of 10M), and the mixture was refluxed overnight. After cooling, 100 ml of 6N hydrochloric acid was added slowly, the mixture refluxed for 2 hours, and then filtered. The filtrate was concentrated under reduced pressure, and the resulting aqueous solution washed with ethyl acetate. The aqueous layer was then basified with ammonium hydroxide and extracted with methylene chloride. Solvent was removed from the extract, and the residue distilled under vacuum to give 4-chloroisoindoline, a white solid, m.p. 48°-50° C.
Reaction SMILES: CC1([C:8](NC(=O)OC2C=CC=CC=2)=[O:9])C=CC=CN1.[CH3:20][C:21]1[N:26]=[C:25]([C:27]([NH2:29])=[O:28])[CH:24]=[CH:23][CH:22]=1.Cl.[NH:31]1[CH2:36][CH2:35][C:34](=[CH:37][C:38]2[CH:39]=[C:40]([CH:52]=[CH:53][CH:54]=2)[O:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]([F:51])([F:50])[F:49])=[CH:44][N:43]=2)[CH2:33][CH2:32]1.C(N(C(C)C)CC)(C)C>C(#N)C>[CH3:20][C:21]1[N:26]=[C:25]([C:27]([NH:29][C:8]([N:31]2[CH2:36][CH2:35][C:34](=[CH:37][C:38]3[CH:54]=[CH:53][CH:52]=[C:40]([O:41][C:42]4[CH:47]=[CH:46][C:45]([C:48]([F:51])([F:49])[F:50])=[CH:44][N:43]=4)[CH:39]=3)[CH2:33][CH2:32]2)=[O:9])=[O:28])[CH:24]=[CH:23][CH:22]=1
Reactant: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Reactant: CC1(C(=O)NC(=O)Oc2ccccc2)C=CC=CN1
Reactant: Cc1cccc(C(N)=O)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cccc(C(=O)NC(=O)N2CCC(=Cc3cccc(Oc4ccc(C(F)(F)F)cn4)c3)CC2)n1
Temperature: 50 °C

Procedure:
Phenyl 2-methylpicolinoylcarbamate (150 mg, 0.585 mmol, prepared according to the procedure in Example 15, Step 1 from 6-methyl-pyridine-2-carboxamide), 2-(3-piperidin-4-ylidenemethyl-phenoxy)-5-trifluoromethyl-pyridine hydrochloride (175 mg, 0.472 mmol) (from Example 1, Step 5), and diisopropylethyl amine (0.16 mL, 0.92 mmol) were combined in acetonitrile (5 mL) and warmed to 50° C. After 3 hours the mixture was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography (10-75% EtOAc in CH2Cl2) to provide the title compound (0.197 g). MS APCI M+ 497.2, 376.12, 335.12; 1H NMR (400 MHz, CD3OD) δ ppm 2.61 (s, 3H) 2.46-2.70 (m, 4H) 3.64 (m, 4H) 6.47 (s, 1H) 6.96-7.06 (m, 2H) 7.08-7.19 (m, 2H) 7.40 (td, J=7.69, 0.73 Hz, 1H) 7.50 (dd, J=7.80, 0.46 Hz, 1H) 7.88 (t, J=7.71 Hz, 1H) 7.98 (ddd, J=7.74, 0.99, 0.50 Hz, 1H) 8.08 (ddd, J=8.73, 2.48, 0.66 Hz, 1H) 8.42 (td, J=1.75, 0.87 Hz, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[C:11](O[C:14](=[O:25])[C:15]=2[C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)=[O:12])=[CH:2]1.O>CN(C=O)C>[NH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]([C:15]2[C:14]([N:1]([C:9]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:11](=[O:12])[C:10]=2[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)=[O:25])=[CH:17]1
Reactant: O=C1OC(=O)C(c2c[nH]c3ccccc23)=C1c1c[nH]c2ccccc12
Solvent: O
Solvent: CN(C)C=O
Product: O=C1C(c2c[nH]c3ccccc23)=C(c2c[nH]c3ccccc23)C(=O)N1c1ccccc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 191.7 %

Procedure:
To a solution of 2,3-bis(1H-indol-3-yl)maleic anhydride (100 mg, 0.3 mmol) synthesized according to a known method (Tetrahedron, Vol. 44, p. 2887, 1988) and dissolved in DMF (10 mL) and water (10 mL) was added anilne (0.12 mL, 1.2 mmol), and the whole was stirred at 100 ° C. for 2 hours. The reaction mixture was concentrated under reduced pressure to remove DMF, and the concentrate was extracted with ethyl acetate. The extract was washed with water, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was purified by column chromatography over silica gel (ethyl acetate:n-hexane=2:1) to obtain 2,3-bis(1H-indol-3-yl)N-phenylmaleimide (116 mg, 94.4%) as red solids.