Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.[C:19](Cl)(=[O:23])[CH:20]([CH3:22])[CH3:21]>>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:19](=[O:23])[CH:20]([CH3:22])[CH3:21])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Reactant: CC(C)C(=O)Cl
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)C(C)C)nc12

Procedure:
Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and isobutyryl chloride the title compound was obtained as a light yellow solid (8%), MS: m/e=336 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=O)[CH2:8][CH:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:6][C:5]=2[NH:4][CH:3]=1.[C:18]([NH:21][NH2:22])([NH2:20])=[NH:19].[ClH:23].Cl.O>C(O)C>[ClH:23].[NH:21]([N:22]=[C:9]1[CH2:8][CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][C:5]2[NH:4][CH:3]=[C:2]([CH3:1])[C:10]1=2)[C:18]([NH2:20])=[NH:19]
Reactant: N=C(N)NN
Reactant: Cc1c[nH]c2c1C(=O)CC(c1ccccc1)C2
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1c[nH]c2c1C(=NNC(=N)N)CC(c1ccccc1)C2
Yield: 8.9 %

Procedure:
A mixture of 3-methyl-6-phenyl-4,5,6,7-tetrahydroindol-4-one (0.8 g), aminoguanidine hydrochloride (0.41 g), concentrated hydrochloric acid (0.18 ml), water (0.18 ml) and ethanol (50 ml) was refluxed for 30 minutes. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in water. The solution was washed with diethylether. To the mixture was added sodium hydroxide solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with magnesium sulfate. Under reduced pressure, the solvent was evaporated, and to the residue was 1N hydrochloric acid (2 ml). The solvent was evaporated, and the residue was recrystallized from ethanol-ethyl acetate to give 4-guanidinoimino-3-methyl-6-phenyl-4,5,6,7-tetrahydroindole hydrochloride (Compound 2) (0.1 g) as colorless crystals.
Reaction SMILES: CO[C:3](=[N:12][N+:13]([O-:15])=[O:14])[NH:4][CH2:5][C:6]1[S:10][C:9]([Cl:11])=[N:8][CH:7]=1.[CH3:16][NH2:17]>O>[Cl:11][C:9]1[S:10][C:6]([CH2:5][NH:4][C:3]([NH:17][CH3:16])=[N:12][N+:13]([O-:15])=[O:14])=[CH:7][N:8]=1
Reactant: COC(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Reactant: CN
Solvent: O
Product: CNC(=N[N+](=O)[O-])NCc1cnc(Cl)s1
Temperature: 25 °C
Reaction time: 14 h
Yield: 92.1 %

Procedure:
To a suspension of O-methyl-N-(2-chloro-5-thiazolylmethyl)-N'-nitroisourea (1.00 g, 4.00 mmol) in water (10 ml) was added 40% aqueous solution of methylamine (0.77 g; 9.92 mmol) dropwise. The mixture was stirred at room temperature for 14 hours and the resulting crystals were collected by filtration, washed with water (10 ml), and dried. As a result, 0.92 g (92.0% yield) of 1-(2-chloro-5-thiazolylmethyl)-3-methyl-2-nitroguanidine was obtained.
Reaction SMILES: [O:1]=[C:2]1[C:10](=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12](O)=[O:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[NH2:26]>>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([NH:26][C:12](=[O:13])[C:11](=[C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[NH:3][C:2]2=[O:1])[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]
Reactant: COc1ccc(N)cc1OC
Reactant: O=C(O)C(=C1C(=O)Nc2ccccc21)c1ccccc1
Product: COc1ccc(NC(=O)C(=C2C(=O)Nc3ccccc32)c2ccccc2)cc1OC
Yield: 7.8 %

Procedure:
(2-Oxo-1,2-dihydro-indol-3-ylidene)-phenyl-acetic acid (85 mg) was reacted with 3,4-dimethoxyaniline (110 mg) using method B to give 10 mg (8%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1.Cl[C:15]1[N:20]=[C:19]([NH:21][C:22]2[C:33]([F:34])=[CH:32][C:31]([F:35])=[CH:30][C:23]=2[C:24]([NH:26][CH2:27][C:28]#[CH:29])=[O:25])[C:18]([Cl:36])=[CH:17][N:16]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(=O)(O)[O-].[Na+]>C(O)(C)C>[Cl:36][C:18]1[C:19]([NH:21][C:22]2[C:33]([F:34])=[CH:32][C:31]([F:35])=[CH:30][C:23]=2[C:24]([NH:26][CH2:27][C:28]#[CH:29])=[O:25])=[N:20][C:15]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[CH2:11][CH2:10][CH2:9][C:8](=[O:12])[NH:7][C:6]=3[CH:13]=2)=[N:16][CH:17]=1
Reactant: Nc1ccc2c(c1)NC(=O)CCC2
Reactant: C#CCNC(=O)c1cc(F)cc(F)c1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: C#CCNC(=O)c1cc(F)cc(F)c1Nc1nc(Nc2ccc3c(c2)NC(=O)CCC3)ncc1Cl

Procedure:
8-Amino-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (0.037 g, 0.00021 mol), 2-(2,5-Dichloro-pyrimidin-4-ylamino)-3,5-difluoro-N-prop-2-ynyl-benzamide (0.069 g, 0.00019 mol), and 10-Camphorsulfonic acid (0.0045 g, 0.000019 mol), in Isopropyl alcohol (1 mL) was microwaved at 120° C. for 30 minutes. Sodium bicarbonate was added to the reaction mixture, which was then filtered and the resulting ppt was washed first with water then three times with 1 mL of Isopropyl alcohol. 2-[5-Chloro-2-(2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-8-ylamino)-pyrimidin-4-ylamino]-3,5-difluoro-N-prop-2-ynyl-benzamide was isolated as tan solids (49 mg, 51%). MP: 194° C.; LCMS: 497 (M+H); HNMR (DMSO): 9.33 (s, 1H), 9.27 (s, 1H), 8.93 (d, J=5.64 Hz, 1H), 8.87 (s, 1H), 8.14 (s, 1H), 7.57 (t, J=8.84 Hz, 1H), 7.34 (d, J=8.60 Hz, 1H), 7.19 (d, J=9.36 Hz, 1H), 7.09 (s, 1H), 6.93 (d, J=7.56 Hz, 1H), 3.99 (s, 2H), 3.11 (s, 1H), 2.57 (t, J=5.52 Hz, 2H), 2.08 (d, J=5.56 Hz, 2H), 2.03 (t, J=6.80 Hz, 2H);
Reaction SMILES: [F:1][C:2]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])=[CH:7][C:6]=1[C:17]1[C:22]([O:23][CH2:24][CH3:25])=[CH:21][C:20](=[O:26])[N:19]([CH3:27])[CH:18]=1.[H-].[Na+].Br[CH2:36][CH:37]1[CH2:39][CH2:38]1.O>CN(C=O)C>[CH:37]1([CH2:36][N:11]([C:8]2[CH:9]=[CH:10][C:5]([O:4][C:3]3[CH:28]=[CH:29][C:30]([F:32])=[CH:31][C:2]=3[F:1])=[C:6]([C:17]3[C:22]([O:23][CH2:24][CH3:25])=[CH:21][C:20](=[O:26])[N:19]([CH3:27])[CH:18]=3)[CH:7]=2)[S:12]([CH2:15][CH3:16])(=[O:13])=[O:14])[CH2:39][CH2:38]1
Reactant: BrCC1CC1
Reactant: CCOc1cc(=O)n(C)cc1-c1cc(NS(=O)(=O)CC)ccc1Oc1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(=O)n(C)cc1-c1cc(N(CC2CC2)S(=O)(=O)CC)ccc1Oc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8.9 %

Procedure:
To a solution of Example 72A (50 mg, 0.108 mmol) in DMF (1 mL) was added NaH (7.7 mg, 0.32 mmol) and the mixture was stirred at room temperature for 30 minutes. Then (bromomethyl)cyclopropane (43.6 mg, 0.323 mmol) was added and the mixture was stirred at 50° C. for 18 hours. Water (10 mL) was added and the mixture extracted with ethyl acetate (3×15 mL). The combined organics were washed with brine, dried (MgSO4), filtered, and concentrated. The residue was purified by HPLC (C18, CH3CN/water (0.1% NH4HCO3), 40-60%) to provide the title compound (5 mg, 8.96% yield). 1H NMR (400 MHz, CD3OD) δ 7.46 (s, 1H), 7.28 (dd, J=6.9, 2.6 Hz, 2H), 6.92 (dd, J=12.2, 8.4 Hz, 2H), 6.80 (d, J=9.6 Hz, 2H), 5.81 (s, 1H), 3.87 (q, J=7.0 Hz, 2H), 3.43 (d, J=7.1 Hz, 2H), 3.38 (s, 3H), 3.00 (q, J=7.4 Hz, 2H), 1.22 (t, J=7.4 Hz, 3H), 1.14 (t, J=7.0 Hz, 3H), 0.81 (d, J=7.8 Hz, 1H), 0.33 (dd, J=8.0, 1.2 Hz, 2H), 0.01 (d, J=5.9 Hz, 2H). MS (ESI+) m/z 519.2 (M+H)+.
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1.C(N(CC)CC)C>CC(C)=O>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:21][S:2]([C:5]2[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=2)(=[O:4])=[O:3])=[CH:18][CH:17]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(CNS(=O)(=O)c2ccc(C(=O)O)cc2)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 69.9 %

Procedure:
4-(Chlorosulfonyl)benzoic acid (5 g, 22.7 mmol) was added, in three portions as a solid, to a stirring solution of 4-methoxy benzylamine (6.1 g, 45 mmol) and triethylamine (2.3 g, 22.7 mmol) in acetone (100 mL) cooled to 0° C. via an ice water bath over a 10 minute period. The ice bath was removed and the reaction was stirred for an additional 4 hours. The reaction mixture was diluted with a solution of 5% acetic acid in H2O (150 mL) and extracted with ethyl acetate (3×, 100 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated on the rotovap. The resulting white solid was triturated with hexanes/ethyl acetate (9/1) to afford 4-(N-(4-methoxybenzyl)sulfamoyl)benzoic acid (5.1 g, 70%) as a white solid. 1H NMR (400 MHz, DMSO d6) δ 3.68 (s, 3H), 3.91 (s, 2H), 6.79 (d, J=8.4 Hz, 2H), 7.10 (d, J=8.8 Hz, 2H), 7.80 (d, J=8.8 Hz, 2H), 8.02 (d, J=8.4 Hz, 2H).
Reaction SMILES: [BH4-].[Na+].[O:3]=[C:4]1[CH2:8][CH2:7][CH:6]([CH:9]=[CH:10][C:11](=[O:19])[CH:12]([CH2:17][CH3:18])[CH2:13][CH2:14][CH2:15][CH3:16])[CH:5]1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27]>[OH-].[Na+].C(O)C>[OH:3][CH:4]1[CH2:8][CH2:7][CH:6]([CH:9]=[CH:10][CH:11]([OH:19])[CH:12]([CH2:17][CH3:18])[CH2:13][CH2:14][CH2:15][CH3:16])[CH:5]1[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27]
Reactant: CCCCC(CC)C(=O)C=CC1CCC(=O)C1CCCCCCC(=O)O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCC(CC)C(O)C=CC1CCC(O)C1CCCCCCC(=O)O
Temperature: 10 °C
Reaction time: 24 h
Yield: 14.8 %

Procedure:
A solution of sodium borohydride (0.095 g.) in 0.2N aqueous sodium hydroxide (0.95 ml.) was added dropwise to a solution of 7-[2-oxo-5-(4-ethyl-3-oxo-1-octenyl)cyclopentyl]heptanoic acid (0.4 g.) in ethanol (9 ml.) and N aqueous sodium hydroxide (1.2 ml.). The resulting solution was stirred for 1 day, and then the ethanol was removed in vacuo. A small quantity of water was added, and the solution was extracted twice with diethyl ether (to remove non-acidic material). The aqueous solution was covered with a layer of diethyl ether and acidified to pH 1 by the dropwise addition of concentrated hydrochloric acid, cooling the solution to about 10°C. The ether layer was separated and the aqueous layer extracted twice more with diethyl ether. The combined ether extracts were dried over magnesium sulphate, evaporated and purified by preparative thin-layer chromatography to give 7[2-hydroxy-5-(4-ethyl-3-hydroxy-1-octenyl)cyclopentyl]heptanoic acid (60 mg.), νmax 1700cm-1, 980 cm- 1. (Found: C, 71.0; H, 10.4. C22H40O4 requires C, 71.7; H, 10.9%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[C:17]([CH3:24])([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(OCC)(=O)C>CN(C)C=O>[CH:5]([C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=1)[O:1][C:17]([CH3:24])([CH3:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:6]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)Oc1cccc(C=O)c1

Procedure:
3-Hydroxybenzaldehyde (30.0 g, 0.246 mol) was dissolved in dimethylformamide (20 mL). Subsequently, potassium carbonate (51.00 g, 0.369 mol), and then ethyl 2-bromoisobutyrate (144.00 g, 0.737 mol) were added thereto, and the resultant mixture was stirred overnight at 80° C. The temperature of the reaction mixture was returned to room temperature. Ethyl acetate was added. Washing was performed sequentially with water and saturated brine, followed by drying over sodium sulfate. The reaction mixture was subjected to filtration, concentration under reduced pressure, and purification by silica gel column chromatography (n-hexane/ethyl acetate=5/1), whereby a colorless oil was obtained (57.70 g, 0.244 mol, 99.3%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:42])[CH2:15][S:16][C:17]2[S:21][C:20]([NH:22][C:23](=[O:41])[C@@H:24]([C:31]3[CH:36]=[CH:35][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:33][CH:32]=3)[CH2:25][CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[N:19][CH:18]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(Cl)(Cl)Cl.C(O)(C(F)(F)F)=O>[CH:26]1([CH2:25][C@H:24]([C:31]2[CH:32]=[CH:33][C:34]([S:37]([CH3:40])(=[O:39])=[O:38])=[CH:35][CH:36]=2)[C:23]([NH:22][C:20]2[S:21][C:17]([S:16][CH2:15][C:14](=[O:42])[N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:18][N:19]=2)=[O:41])[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)CSc2cnc(NC(=O)[C@H](CC3CCCC3)c3ccc(S(C)(=O)=O)cc3)s2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ncc(SCC(=O)N3CCNCC3)s2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(R)-4-(2-{2-[3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)propionylamino]-thiazol-5-ylsulfanyl}-acetyl)-piperazine-1-carboxylic acid tert-butyl ester (50 mg, 78.6 mml) was dissolved in a mixture of chloroform (2 mL) and TFA (1 mL). The mixture was stirred at room temperature for 2 h and evaporated to dryness in vacuo to give white crystals of (R)-3-cyclopentyl-2-(4-methanesulfonylphenyl)-N-[5-(2-oxo-2-piperazin-1-yl-ethylsulfanyl)-thiazol-2-yl]-propionamide. 1H-NMR (CD3OD): δ 7.92 (d, 2H), 7.67 (d, 2H), 7.48 (s, 1H), 3.97 (t, 1H), 3.81 (m, 4H), 3.73 (s, 3H), 3.29-3.23 (m, 4H), 3.10 (s, 3H), 2.24-2.16 (m, 1H), 1.90-1.75 (m, 3H), 1.69-1.59 (m, 3H), 1.50 (m, 2H), 1.17 (m, 2H); HPLC-MS: m/z: 537 (M+1).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:23][CH2:24][CH3:25])[NH:13][C:14](=[O:15])[C:8]2=[CH:7][N:6]=1)(=O)=O.[C:26](O)(=[O:28])[CH3:27]>[O-]CC.[Na+]>[CH2:26]([O:28][C:5]1[N:10]=[C:9]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:23][CH2:24][CH3:25])[NH:13][C:14](=[O:15])[C:8]2=[CH:7][N:6]=1)[CH3:27]
Reactant: CC(=O)O
Reactant: CCCOc1ccccc1-c1nc2nc(S(C)(=O)=O)ncc2c(=O)[nH]1
Agent: CC[O-]
Agent: [Na+]
Product: CCCOc1ccccc1-c1nc2nc(OCC)ncc2c(=O)[nH]1

Procedure:
A solution of 7-methylsulphonyl-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (0.50 g) in sodium ethoxide solution (from sodium, 0.16 g, and ethanol, 25 ml) was stirred at ambient temperature for 1.5 hours. Cooling and acidification of the reaction mixture with glacial acetic acid (0.42 g) yielded a precipitate which was twice recrystallized from ethanol to yield the title compound, 0.29 g, m.p. 196-197.5° C.
Reaction SMILES: C(OC(=O)[N:10]([CH2:20][C@H:21]([NH:27][C:28](=[O:44])[CH2:29][C:30](=[O:43])[NH:31][C:32]1[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[C:34]([NH2:42])[CH:33]=1)[C@@H:22]([OH:26])[CH2:23][CH2:24][CH3:25])[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=1[CH3:19])C1C=CC=CC=1.[CH:46](=O)[CH2:47][CH3:48].C([BH3-])#N.[Na+]>CO>[CH3:19][C:13]1[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:12]=1[CH2:11][NH:10][CH2:20][C@H:21]([NH:27][C:28](=[O:44])[CH2:29][C:30]([NH:31][C:32]1[CH:37]=[C:36]([C:38]([F:41])([F:39])[F:40])[CH:35]=[C:34]([NH:42][CH2:46][CH2:47][CH3:48])[CH:33]=1)=[O:43])[C@@H:22]([OH:26])[CH2:23][CH2:24][CH3:25]
Reactant: CCC[C@H](O)[C@H](CN(Cc1ccc(C)cc1C)C(=O)OCc1ccccc1)NC(=O)CC(=O)Nc1cc(N)cc(C(F)(F)F)c1
Reactant: CCC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCCNc1cc(NC(=O)CC(=O)N[C@@H](CNCc2ccc(C)cc2C)[C@@H](O)CCC)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of {(2S,3S)-2-[2-(3-amino-5-trifluoromethyl-phenylcarbamoyl)-acetylamino]-3-hydroxyhexyl}-(2,4-dimethyl-benzyl)-carbamic acid benzyl ester (97 mg, 0.15 mmol) in MeOH (3 mL) was charged with propionaldehyde (0.01 mL, 0.15 mmol), stirred for 15 min at RT, and then charged with sodium cyanoborohydride (12 mg, 0.19 mmol). The reaction was stirred at RT for 12 h, concentrated in vacuo, and dissolved in EtOAc. The resultant solution was washed successively with water, sat. NaHCO3, water, and brine. The organic phase was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was dissolved in MeOH (3 mL). This solution was charged with 5% Pd/C, Degussa style (11 mg), stirred under H2 (1 atm) for 12 h at RT, filtered, and concentrated in vacuo. Purification of the residue by reverse-phase HPLC provided the title compound as a white powder after lyopholization. MS found: (M+H)+=537.4.
Reaction SMILES: [H-].[Na+].[OH:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:6][CH2:5]1.[Si:18]([O:25][CH2:26][CH2:27][C@H:28]1[CH2:40][C:39]2[C:38]3[C:37](Cl)=[N:36][CH:35]=[N:34][C:33]=3[S:32][C:31]=2[CH2:30][CH2:29]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]>C1COCC1>[Si:18]([O:25][CH2:26][CH2:27][C@H:28]1[CH2:40][C:39]2[C:38]3[C:37]([O:3][CH:4]4[CH2:9][CH2:8][CH:7]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:14])([CH3:16])[CH3:15])[CH2:6][CH2:5]4)=[N:36][CH:35]=[N:34][C:33]=3[S:32][C:31]=2[CH2:30][CH2:29]1)([C:21]([CH3:24])([CH3:22])[CH3:23])([CH3:19])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)OCC[C@@H]1CCc2sc3ncnc(Cl)c3c2C1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCC(Oc2ncnc3sc4c(c23)C[C@H](CCO[Si](C)(C)C(C)(C)C)CC4)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.5 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 62 mg, 1.55 mmol, 30.00 equiv) was treated with tert-butyl trans-N-(4-hydroxycyclohexyl)carbamate (157 mg, 0.73 mmol, 1.40 equiv) in 8 mL of freshly distilled THF for 30 min in a water/ice bath under nitrogen. Then a solution of (12R)-12-[2-[(tert-butyldimethylsilyl)oxy]ethyl]-3-chloro-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraene (200 mg, 0.52 mmol, 1.00 equiv) in 5 mL of THF was added via syringe and the mixture was stirred at room temperature overnight. The reaction was quenched with saturated aqueous NH4Cl and extracted with 3×50 mL of ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:4) to give tert-butyl N-(4-[[(12R)-12-[2-[(tert-butyldimethylsilyl)oxy]ethyl]-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-3-yl]oxy]cyclohexyl)carbamate (200 mg, 68%) as a yellow oil.
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[CH2:5][O:4]1.[C:6]1([CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH2:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CO>[CH:12]([NH:13][CH2:5][CH:3]([OH:4])[CH2:2][Cl:1])([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: ClCC1CO1
Solvent: CO
Product: OC(CCl)CNC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
2-(Chloromethyl)oxirane (92 g, 1 mol) was added dropwise to a solution of diphenyl-methanamine (183 g, 1 mol) in CH3OH (1 L) at 0° C. then the mixture was stirred at r.t. overnight. The mixture was then concentrated in vacuo to give the title compound (201 g, 73%) which was used in next step without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:21][CH:20]2[CH2:22][CH:10]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][C:19]=32)[N:16]=[C:15]([CH3:23])[NH:14]4)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CS(C)=O.I[CH2:29][CH2:30][CH3:31].O>[OH-].[Na+]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]2[CH2:22][CH:20]([C:19]3[CH:18]=[C:17]4[C:13](=[CH:12][C:11]=32)[N:14]=[C:15]([CH3:23])[N:16]4[CH2:29][CH2:30][CH3:31])[CH2:21]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCI
Reactant: Cc1nc2cc3c(cc2[nH]1)C1CC3CN(C(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCn1c(C)nc2cc3c(cc21)C1CC3CN(C(=O)OC(C)(C)C)C1
Temperature: 40 °C

Procedure:
6-Methyl-5,7,13-triazatetracyclo[9.3.1.02,10.04,8]pentadeca-2(10),3,5,8-tetraene-13-carboxylic acid tert-butyl ester (80 mg, 0.267 mmol) was stirred in 50% aqueous NaOH solution (3 mL) and DMSO (1 mL) then treated with 1-iodopropane (0.03 mL, 0.321 mmol). This mixture was warmed to 40° C. for 2 hours then cooled, treated with H2O and extracted with EtOAc. The organic layer was washed with H2O (3×) then dried (Na2SO4), filtered and concentrated to an oil (90 mg,.0.253 mmol). (TLC 5% MeOH/CH2Cl2 (NH3) Rf 0.15).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]([NH2:12])[CH:9]=[CH:10][CH:11]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([NH:23][CH2:24][C:25]2[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([NH:23][CH2:24][C:25]2[CH:26]=[CH:27][C:28]([C:29]([NH:12][C:8]3[CH:9]=[CH:10][CH:11]=[C:6]([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)[CH:7]=3)=[O:30])=[CH:32][CH:33]=2)[CH:18]=[CH:19][C:20]=1[O:21][CH3:22]
Reactant: COc1ccc(NCc2ccc(C(=O)O)cc2)cc1OC
Reactant: Nc1cccc(-c2cccs2)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc(NCc2ccc(C(=O)Nc3cccc(-c4cccs4)c3)cc2)cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 24.9 %

Procedure:
To a stirred solution of 31 (122 mg, 0.696 mmol), acid 4 (182 mg, 0.633 mmol) and BOP (308 mg, 0.696 mmol) in DMF (4 ml) was added B3N (265 μl, 1.90 mmol). The reaction was stirred 3 h at room temperature under nitrogen, quenched with H2O and evaporated. The residue was extracted with ethyl acetate, washed with saturated solutions of NH4Cl, NaHCO3 and brine. The organic layer was dried over anhydrous MgSO4 and concentrated in vacuum to form a material which was purified by flash chromatography (eluent 40% EtOAc in hexane) to give the title compound 32 (70 mg, 25%) as a yellow solid. 1H NMR: (DMSO) δ (ppm): 10.25 (s, 1H), 8.09-8.08 (m, 1H), 7.73 (ddd, J=7.6, 3.7, 3.7 Hz, 1H), 7.54 (dd, J=5.1, 1.0 Hz, 1H), 7.49 (d, J=8.2 Hz, 2H), 7.45 (dd, J=3.7, 1.2 Hz, 1H), 7.42-7.32 (m, 2H), 7.13 (dd, J=5.1, 3.7 Hz, 1H), 6.64 (d, J=8.6 Hz, 1H), 6.31 (d, J=2.5 Hz, 1H), 6.00-5.97 (m, 2H), 4.31 (d, J=6.1 Hz, 2H), 3.65 (s, 3H), 3.59 (s, 3H). MS: (calc), 444.2; (obt.) 445.5 (MH)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH3:9])[N+:3]=1[O-].[NH2:11][C@H:12]1[C@H:16]([OH:17])[CH2:15][N:14]([C:18](=[O:31])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=2)[CH2:13]1>C(O)CCC>[Cl:8][C:6]1[CH:5]=[C:4]([CH3:9])[N:3]=[C:2]([NH:11][C@H:12]2[C@H:16]([OH:17])[CH2:15][N:14]([C:18](=[O:31])[CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][C:27]([F:28])([F:29])[F:30])=[CH:24][CH:25]=3)[CH2:13]2)[CH:7]=1
Reactant: N[C@@H]1CN(C(=O)Cc2ccc(OC(F)(F)F)cc2)C[C@H]1O
Reactant: Cc1cc(Cl)cc(Cl)[n+]1[O-]
Solvent: CCCCO
Product: Cc1cc(Cl)cc(N[C@@H]2CN(C(=O)Cc3ccc(OC(F)(F)F)cc3)C[C@H]2O)n1
Temperature: 130 °C
Reaction time: 10 h
Yield: 15.6 %

Procedure:
A mixture of 2,4-dichloro-6-methylpyridine 1-oxide (200 mg), 1-((3R,4R)-3-amino-4-hydroxypyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (340 mg), and n-butanol (0.6 mL) was stirred at 130° C. for 10 h. The reaction mixture was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (NH silica gel, ethyl acetate−ethyl acetate/methanol=20:1), and then the resulting solids were washed with hexane and diethyl ether to obtain 1-((3R,4R)-3-(4-chloro-6-methylpyridin-2-ylamino)-4-hydroxypyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (75 mg). (2) A mixture of 1-((3R,4R)-3-(4-chloro-6-methylpyridin-2-ylamino)-4-hydroxypyrrolidin-1-yl)-2-(4-trifluoromethoxyphenyl)ethanone (68 mg), morpholine (0.02 mL), sodium t-butoxide (42 mg), Pd(OAc)2 (1 mg), 2-(di-t-butylphosphino)biphenyl (3 mg), and toluene (1 mL) was heated at 100° C. for 10 h. The mixture was cooled to room temperature, then the reaction mixture was diluted with chloroform, insoluble matters were removed by Celite filtration, and then the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (NH silica gel, ethyl acetate, and silica gel, hexane/acetone=1:1) to obtain the title compound (8 mg).