Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:11]1([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:15]=[CH:14][CH:13]=[CH:12]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(O)CCCCCCCCCO.[OH-].[K+].COCCOCCOCCOC>>[CH2:16]([C:11]1([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:12][CH2:13][CH2:14][CH2:15]1)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCC1(CCCCCCCCCC)C=CC=C1
Agent: OCCCCCCCCCCO
Agent: [K+]
Agent: [OH-]
Solvent: COCCOCCOCCOC
Product: CCCCCCCCCCC1(CCCCCCCCCC)CCCC1

Procedure:
In a one-liter three-necked flask fitted with a mechanical stirrer and a Soxhlet extractor packed with 3A molecular sieves (about 15 g) and topped with a condenser, 25.1 g of di-(n-decyl)cyclopentadiene (73 mmol), 12.6 g of 1,10-decanediol (73 mmol), 5 g of KOH, and 250 g of triglyme were stirred and deoxygenated with a stream of nitrogen. The mixture was then heated to reflux under nitrogen for two hours. The mixture was cooled and washed with water to remove base and triglyme. The product was dried and hydrogenated over palladium on carbon. The resulting product was characterized by gel permeation chromatography to determine the molecular weight. The number average molecular weight was 1250, indicating that on average about 3 di(n-decyl)cyclopentadienes had been crosslinked. The weight average molecular weight of 2250 indicates that molecules containing a higher number of crosslinked di(n-decyl)cyclopentadienes were formed. The measured viscosity at 100°, 40 cSt, is consistent with these high molecular weights.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:14][O:15][C:16]1[C:25]2[C:24]([NH2:26])=[N:23][S:22](=[O:28])(=[O:27])[NH:21][C:20]=2[CH:19]=[CH:18][CH:17]=1)=O)(C)(C)C.[ClH:29]>C(O)C>[ClH:29].[NH2:26][C:24]1[C:25]2[C:16]([O:15][CH2:14][C@H:9]3[CH2:10][CH2:11][CH2:12][CH2:13][NH2+:8]3)=[CH:17][CH:18]=[CH:19][C:20]=2[NH:21][S:22](=[O:27])(=[O:28])[N:23]=1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1COc1cccc2c1C(N)=NS(=O)(=O)N2
Agent: Cl
Solvent: CCO
Product: NC1=NS(=O)(=O)Nc2cccc(OC[C@H]3CCCC[NH2+]3)c21
Temperature: 60 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
To a solution of (R)-tert-butyl-2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidine-1-carboxylate (Example 15b, 10.7 g, 26.1 mmol) in ethanol (175 mL) was added HCl in ethanol (104 mL, 2.5M, 261 mmol). The reaction stirred at 60° C. under nitrogen for 4 hours. The compound was collected by filtration as an off white solid (7.70 g, 85% yield for three steps). 1H NMR (400 MHz, DMSO-d6) δ 1.03-1.90 (br m, 6H), 2.89 (br t, J=2.8 Hz, 1H), 3.27 (br m, 1H), 3.61 (br m, 1H), 4.27-4.40 (br m, 2H), 6.67 (d, J=7.6 Hz, 1H), 6.80 (d, J=8.8 Hz, 1H), 7.46 (t, J=8.0 Hz, 1H), 7.79 (br s, 1H), 8.35 (br s, 1H), 9.26 (br s, 2H), 10.97 (br s, 1H). MS 311 (MH+).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][N:8]=[C:9]([C:13]1([O:19][CH2:18][CH2:17][O:16]1)[CH2:14][Br:15])[C:10]([OH:12])=O.[NH2:20][CH:21]1[C:32](=[O:33])[N:23]2[CH:24]([C:29]([OH:31])=[O:30])[CH:25]([OH:28])[CH2:26][S:27][C@H:22]12.C[Si](CC(N)=O)(C)C>C(OCC)(=O)C.O.CN(C)C=O>[CH3:6][O:7][N:8]=[C:9]([C:13]1([O:19][CH2:18][CH2:17][O:16]1)[CH2:14][Br:15])[C:10]([NH:20][CH:21]1[C:32](=[O:33])[N:23]2[CH:24]([C:29]([OH:31])=[O:30])[CH:25]([OH:28])[CH2:26][S:27][C@H:22]12)=[O:12]
Reactant: CON=C(C(=O)O)C1(CBr)OCCO1
Reactant: NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12
Agent: C[Si](C)(C)CC(N)=O
Solvent: O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)C(O)CS[C@H]12)C1(CBr)OCCO1
Yield: 85.9 %

Procedure:
Phosphorus oxychloride (0.5 ml.) was added to a solution of N,N-dimethylformamide (0.42 ml) in dry ethyl acetate (1 ml.) under cooling, and 2-methoxyimino-3,3-ethylenedioxy-4-bromobutyric acid (syn isomer, 1.2 g.) was added thereto under cooling and stirred at the same temperature. The solution was added to a stirred solution of 7-amino-3-hydroxycepham-4-carboxylic acid (1.0 g.) and trimethylsilylacetamide (6.0 g.) in dry ethyl acetate (50 ml.), at -20° C. and stirred at the same temperature for an hour. Ethyl acetate (20 ml.) and water (10 ml) were added to the resultant solution and the ethyl acetate layer was separated. The aqueous layer was extracted with ethyl acetate (20 ml.). The ethyl acetate layer and the extract were combined, and extracted with a saturated aqueous solution of sodium bicarbonate (20 ml.), and water (20 ml.) successively. After ethyl acetate (50 ml) was added thereto, the aqueous solution was adjusted to pH 2.0 with 6N hydrochloric acid, and the ethyl acetate layer was separated. The aqueous layer was extracted with ethyl acetate (25 ml×2). The ethyl acetate layer and the extract were combined, washed with a saturated sodium chloride aqueous solution and dried over magnesium sulfate. After evaporating the solvent is vacuo, the residue was pulverized with diisopropyl ether. The precipitates were collected by filtration to give 7-(2-methoxyimino-3,3-ethylenedioxy-4-bromobutyramido)-3-hydroxycepham-4-carboxylic acid (syn isomer, 1.8 g.).
Reaction SMILES: [CH3:1][C:2]1([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]3[N:25]=[N:26][NH:27][C:28]=3[Si](C)(C)C)[CH:19]=2)[CH:7]2[CH:3]1[CH2:4][N:5]([CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]2=[O:8].[F-].[K+].S(=O)(=O)(O)O>C(O)C>[CH3:1][C:2]1([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]3[NH:25][N:26]=[N:27][CH:28]=3)[CH:19]=2)[CH:7]2[CH:3]1[CH2:4][N:5]([CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]2=[O:8]
Reactant: CC1(c2cccc(-c3nn[nH]c3[Si](C)(C)C)c2)C2CN(CCCc3ccccc3)C(=O)C21
Agent: O=S(=O)(O)O
Agent: [F-]
Agent: [K+]
Solvent: CCO
Product: CC1(c2cccc(-c3cnn[nH]3)c2)C2CN(CCCc3ccccc3)C(=O)C21
Temperature: 25 °C
Reaction time: 16 h
Yield: 66.1 %

Procedure:
To a solution of 6-methyl-3-(3-phenylpropyl)-6-{3-[5-(trimethylsilyl)-1H-1,2,3-triazol-4-yl]phenyl}-3-azabicyclo[3.1.0]hexan-2-one (Preparation 38, 58.0 mg, 0.13 mmol) in ethanol (2 ml) was added potassium fluoride (8.3 mg, 0.14 mmol) and a drop of concentrated sulphuric acid. The mixture was heated at reflux for 4 hours and then stirred at room temperature for 16 hours. The solvent was removed in vacuo and the crude residue was absorbed onto silica. This material was then purified by silica column chromatography eluting first with hexane:ethyl acetate (1:1) and then increasing gradually to neat ethyl acetate. The desired title compound (32 mg, 66%) was isolated as a colourless oil.
Reaction SMILES: [CH2:1]([C:6]1[CH:31]=[CH:30][C:9]([CH:10]=[CH:11][C:12]([NH:14][C:15]2[C:20]3[O:21][CH:22]([C:25]4[NH:29][N:28]=[N:27][N:26]=4)[CH2:23][O:24][C:19]=3[CH:18]=[CH:17][CH:16]=2)=[O:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].C(O)C.[H][H]>[C].[Pd].C(OCC)(=O)C>[CH2:1]([C:6]1[CH:31]=[CH:30][C:9]([CH2:10][CH2:11][C:12]([NH:14][C:15]2[C:20]3[O:21][CH:22]([C:25]4[NH:29][N:28]=[N:27][N:26]=4)[CH2:23][O:24][C:19]=3[CH:18]=[CH:17][CH:16]=2)=[O:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: [H][H]
Reactant: CCCCCc1ccc(C=CC(=O)Nc2cccc3c2OC(c2nnn[nH]2)CO3)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCCCCc1ccc(CCC(=O)Nc2cccc3c2OC(c2nnn[nH]2)CO3)cc1
Yield: 93.1 %

Procedure:
8-(p-pentylcinnamoyl)amino-2-(5-tetrazolyl)-1,4-benzodioxane (216 mg; synthesized in example 2(1)) and palladium-carbon (50 mg; content 5) were suspended in a mixed solvent (6 ml) of ethanol, ethanol and ethyl acetate (1:1:1). In an atmosphere of hydrogen, the suspension was stirred for 90 min at room temperature. After stirring, the suspension was filtered through celite. The filtrate was condenced under reduced pressure. Thre residue was purified by column chromatography on silica gel (methylene chloride:methanol=19:1) to give the title compound (202 mg) having the following physical data:
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:42])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14]([C:23]3[CH2:41][C:25]5([CH2:28][C:27]([C:35]([O:37]C(C)C)=[O:36])([C:29]([O:31]C(C)C)=[O:30])[CH2:26]5)[CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:43]([C:46]([CH3:48])=[CH2:47])[CH2:44][CH2:45][C@:5]1([NH:49][CH2:50][CH2:51][N:52]([C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)[S:53]([C:56]([F:59])([F:58])[F:57])(=[O:55])=[O:54])[CH2:4][CH2:3]2.[OH-].[Na+].Cl>O1CCOCC1.CO>[CH3:1][C@:2]12[C@@:19]3([CH3:20])[C@@H:10]([C@:11]4([CH3:42])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:21])([CH3:22])[C:14]([C:23]3[CH2:41][C:25]5([CH2:26][C:27]([C:35]([OH:37])=[O:36])([C:29]([OH:31])=[O:30])[CH2:28]5)[CH:24]=3)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:43]([C:46]([CH3:48])=[CH2:47])[CH2:44][CH2:45][C@:5]1([NH:49][CH2:50][CH2:51][N:52]([C:60]1[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1)[S:53]([C:56]([F:57])([F:58])[F:59])(=[O:55])=[O:54])[CH2:4][CH2:3]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCCN(c3ccccc3)S(=O)(=O)C(F)(F)F)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC7(C6)CC(C(=O)OC(C)C)(C(=O)OC(C)C)C7)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: C=C(C)[C@@H]1CC[C@]2(NCCN(c3ccccc3)S(=O)(=O)C(F)(F)F)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC7(C6)CC(C(=O)O)(C(=O)O)C7)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 50 °C
Reaction time: 3 h
Yield: 42 %

Procedure:
To a solution of diisopropyl 6-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-((2-(1,1,1-trifluoro-N-phenylmethylsulfonamido)ethyl)amino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)spiro[3.3]hept-5-ene-2,2-dicarboxylate (15 mg, 0.016 mmol) in dioxane (2 mL) and MeOH (1 mL) was added 1N NaOH (1 mL, 1 mmol). The mixture was stirred at 50° C. for 3 h. The mixture was neutralized by 1N HCl (1 mL) to pH ˜6 and solids formed were collected by filtration. The crude product was purified by preparative HPLC using method 14 to give 6-((1R,3 aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-3a-((2-(1,1,1-trifluoro-N-phenylmethylsulfonamido)ethyl)amino)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)spiro[3.3]hept-5-ene-2,2-dicarboxylic acid in 42% yield as a solid. MS: m/e 841.5 (M+H)+, 2.52 min (method 4). 1H NMR (400 MHz, METHANOL-d4) δ 7.52-7.43 (m, 5H), 5.93 (s, 1H), 5.56-5.52 (m, 1H), 4.72 (d, J=1.8 Hz, 1H), 4.60 (s, 1H), 3.99 (s., 2H), 2.77-2.65 (m, 4H), 2.63-2.51 (m, 5H), 2.15 (dd, J=17.8, 6.5 Hz, 1H), 1.92-1.83 (m, 2H), 1.78-0.94 (m, 19H), 1.69 (s, 3H), 1.16 (s, 3H), 1.11 (s, 3H), 1.09 (s, 3H), 0.98 (s, 3H), 0.87 (s, 3H). 19F NMR (376 MHz, METHANOL-d4) δ −75.37 (s., 3F).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([NH2:10])=[CH:8][N:7]([CH3:11])[N:6]=1)=[O:4].C(N(CC)CC)C.[C:19]1([C:25](Cl)([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[C:9]([NH:10][C:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:8][N:7]([CH3:11])[N:6]=1)=[O:4]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1nn(C)cc1N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1nn(C)cc1NC(c1ccccc1)(c1ccccc1)c1ccccc1
Yield: 91.1 %

Procedure:
A solution of 4-amino-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester (160 mg, 1.03 mmol) in N,N-dimethylformamide (1.0 mL) at 25° C. was treated with triethylamine (0.35 mL, 2.6 mmol) and triphenylmethylchloride (316 mg, 1.13 mmol). Additional N,N-dimethylformamide (2.0 mL) was added to the reaction to aid stirring. The reaction was stirred at 25° C. for 18 h. At this time, the reaction was concentrated in vacuo. The residue was dissolved in dichloromethane (50 mL) and then was washed with a IN aqueous hydrochloric acid solution (1×10 mL), a saturated aqueous sodium bicarbonate solution (1×10 mL), and a saturated aqueous sodium chloride solution (1×10 mL). The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 1-methyl-4-(trityl-amino)-1H-pyrazole-3-carboxylic acid methyl ester (373 mg, 91.1%) as an off-white solid: 1H NMR (DMSO-d6, 300 MHz) δ7.25 (m, 16H), 3.74 (s, 3H), 3.53 (s, 3H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1(OB(O)O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+]>O.C(O)C>[C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)Oc1ccccc1
Reactant: Ic1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: c1ccc(-c2ccccc2)cc1
Temperature: 60 °C
Yield: 90 %

Procedure:
After obtaining the supported metal nanoparticles, the catalytic activity was examined using a very popular cross coupling reaction—Suzuki reaction, which is commonly used in the pharmaceutical industry, as shown in FIG. 8. Still referring to FIG. 8, Iodobenzene (0.5 mmol), phenyl boric acid (0.8 mmol) and K2CO3 (1.0 mmol) were added to a 4 mL mixture of a water:ethanol (1:1) solution. Then, the supported nano-Pd on XAD-4 (100 mg) was added, and the reaction mixture was heated to 60° C. for 12 hours. The supported catalyst was recovered by filtration, and the filtrate was extracted by ether. The evaporation of ether furnished the crude product, which was purified by regular flash column chromatography, as known to those of ordinary skill in the art, to yield pure biphenyl in 90% yield. The supported metal nanoparticles could be reused three times without significant activity loss.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.[O:6]1[CH:11]=[CH:10][CH2:9][CH2:8][CH2:7]1>C(O)(C(F)(F)F)=O.[H-].[Na+]>[O:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[N:1]1[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: C1=COCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: c1cnn(C2CCCCO2)c1
Temperature: 95 °C
Reaction time: 5 h
Yield: 104.2 %

Procedure:
1H-Pyrazole (14.3 g, 0.21 mol) is dissolved in 3,4-dihydro-2H-pyran (26.74 g, 0.32 mol) in the presence of a catalytic amount of TFA (0.1 mL, 1.3 mmol). The reaction mixture is stirred at 95° C. for 5 hours, cooled and then quenched using NaH (0.2 g, 5 mmol). The solvent is removed to give the title compound as a brown oil (33.3 g, 99%), which is used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:14](=O)[CH3:15])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[CH3:17][C:18]([S@:21]([NH2:23])=[O:22])([CH3:20])[CH3:19]>>[CH3:17][C:18]([S@:21]([NH:23][CH:14]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[C:2]([CH3:1])[CH:3]=1)[CH3:15])=[O:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1ccc(OCC(F)(F)F)c(C)c1
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)ccc1OCC(F)(F)F
Yield: 64 %

Procedure:
The title compound is prepared in 64% yield (6.05 g, colorless oil) from 1-(3-methyl-4-(2,2,2-trifluoroethoxy)phenyl)ethanone (6.55 g, 28.2 mmol, Step-2) and (R)-2-methylpropane-2-sulfinamide (5.13 g, 42.3 mmol) in a similar manner to Step-4 of Amine-1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:27][CH:28]=O)[C:5]([O:25][CH3:26])=[C:6]([C:8]2[S:12][C:11]([C:13]3[CH:14]=[CH:15][C:16]([CH2:21][CH:22]([CH3:24])[CH3:23])=[C:17]([CH:20]=3)[C:18]#[N:19])=[N:10][N:9]=2)[CH:7]=1.[NH:30]1[CH2:33][CH:32]([C:34]([OH:36])=[O:35])[CH2:31]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O>[C:18]([C:17]1[CH:20]=[C:13]([C:11]2[S:12][C:8]([C:6]3[C:5]([O:25][CH3:26])=[C:4]([CH2:27][CH2:28][N:30]4[CH2:33][CH:32]([C:34]([OH:36])=[O:35])[CH2:31]4)[CH:3]=[C:2]([F:1])[CH:7]=3)=[N:9][N:10]=2)[CH:14]=[CH:15][C:16]=1[CH2:21][CH:22]([CH3:23])[CH3:24])#[N:19]
Reactant: COc1c(CC=O)cc(F)cc1-c1nnc(-c2ccc(CC(C)C)c(C#N)c2)s1
Reactant: O=C(O)C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: ClCCl
Product: COc1c(CCN2CC(C(=O)O)C2)cc(F)cc1-c1nnc(-c2ccc(CC(C)C)c(C#N)c2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 21 %

Procedure:
To a solution of 5-{5-[5-fluoro-2-(methyloxy)-3-(2-oxoethyl)phenyl]-1,3,4-thiadiazol-2-yl}-2-(2-methylpropyl)benzonitrile (D37) (75 mg) and 3-azetidinecarboxylic acid (37 mg) in dichloromethane (DCM) (15 mL) stirred at room temperature was added AcOH (0.15 mL). The reaction mixture was stirred at room temperature for 10 min. Then sodium triacetoxyborohydride (58.2 mg) was added. Stirring continued for overnight. Water was added to quench the reaction, and DCM was removed by evaporation. The mixture was extracted by EA/THF/MeCN for 3 times. The combined organic solution was washed by brine, dried over anhydrous Na2SO4. The dried solution was filtered and concentrated. The residue was purified by Mass Directed AutoPrep to give 1-{2-[3-{5-[3-cyano-4-(2-methylpropyl)phenyl]-1,3,4-thiadiazol-2-yl}-5-fluoro-2-(methyloxy)phenyl]ethyl}-3-azetidinecarboxylic acid (E15) (19 mg) as an off-white solid. δH (DMSO-d6, 400 MHz): 0.94 (6H, d), 1.99 (1H, m), 2.33 (1H, m), 2.67 (4H, m), 2.77 (2H, d), 3.17 (4H, m), 3.80 (3H, s), 7.47 (1H, dd), 7.68 (1H, d), 7.90 (1H, dd), 8.34 (1H, dd), 8.50 (1H, d). δF (DMSO-d6, 376 MHz): −117.2. MS (ES): C26H27FN4O3S requires 494. found 495.2 (M+H+).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][NH2:10])(C)(C)C.CCN(C(C)C)C(C)C.[Br:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[NH2:10][CH2:9][CH2:8][NH:7][S:28]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[Br:21])(=[O:30])=[O:29]
Reactant: O=S(=O)(Cl)c1ccccc1Br
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: NCCNS(=O)(=O)c1ccccc1Br
Temperature: 0 °C
Reaction time: 16 h
Yield: 86.2 %

Procedure:
To solution of (2-amino-ethyl)-carbamic acid tert-butyl ester (208 mg, 1.3 mmol) in CH2Cl2 (20 mL) was added DIEA (300 μL, 1.72 mmol) at 0° C., followed by the addition of 2-bromo-benzenesulfonyl chloride (383 mg, 1.5 mmol). After it was stirred at 0° C. for 1 h and at the room temperature for another 16 h, the reaction mixture was evaporated thoroughly. The residue was diluted with 20% TFA in CH2Cl2 (10 mL), stirred for 3 h at the room temperature, and evaporated. Chromatography of the residual crude with CH2Cl2/MeOH/28% aqueous NH4OH (90:10:1) afforded the title compound (313 mg, 86%). 1H NMR (DMSO-d6) δ 2.86 (t, J=8 Hz, 2H), 3.04 (t, J=8 Hz, 2H), 7.55-7.65 (2H), 7.89 (d, J=8 Hz, 1H), 8.01 (d, J=8 Hz, 1H); ESI-MS m/z 279.1 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)(Cl)=O.[OH-].[NH4+:19].O>C(COC)OC>[NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:19])=[O:5]
Reactant: Nc1c(C(=O)O)cccc1[N+](=O)[O-]
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: COCCOC
Product: NC(=O)c1cccc([N+](=O)[O-])c1N
Temperature: 50 °C
Reaction time: 12 h
Yield: 89 %

Procedure:
To a solution of 2-amino-3-nitrobenzoic acid (prepared using the procedure as described in U.S. Pat. No. 6,737,421, EXAMPLE 2, part b) in dimethoxyethane (DME, 7.1 mL/g), was added thionyl chloride (1.33 equivalents). The mixture was stirred at 50° C. for 12 hours, cooled and slowly added to concentrated ammonium hydroxide (22 equivalents). The mixture was stirred at 50° C. for 2 hours, water was added, and the mixture was cooled and filtered. The solid was washed with water and isopropanol, and dried under vacuum to give the title compound (89% yield).
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.[C:66]1([NH:72][CH2:73][CH2:74][NH2:75])[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1>O.C(=O)(O)[O-].[Na+].CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:75][CH2:74][CH2:73][NH:72][C:66]5[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: NCCNc1ccccc1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NCCNc2ccccc2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.08 h
Yield: 65.4 %

Procedure:
A mixture of 0.045 g (0.1 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid (I-22), 0.042 g (0.110 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate, 0.052 ml (0.300 mmole) of ethyldiisopropyl amine and 1.0 mL of dimethylformamide was stirred for 5 minutes and then 0.016 g (0.12 mmole) N-phenyl-ethane-1,2-diamine was added. The mixture was stirred for 3 hours, then diluted with 10 mL of water plus 2 mL of saturated aqueous sodium bicarbonate and then extracted 3 times with 10 mL of ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by reverse phase silica gel chromatography, eluting with water-acetonitrile (gradient, 0:100-80:20) to give 0.037 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(2-phenylamino-ethyl)-benzamide (I-119) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[C:10]1[O:14][CH:13]=[N:12][CH:11]=1)[NH2:6].[C:15]([NH:19][C:20](=[O:24])[C:21](O)=[O:22])([CH3:18])([CH3:17])[CH3:16].Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1>ClCCl>[C:15]([NH:19][C:20](=[O:24])[C:21]([NH:6][C:5]1[CH:7]=[CH:8][C:9]([C:10]2[O:14][CH:13]=[N:12][CH:11]=2)=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:22])([CH3:18])([CH3:17])[CH3:16]
Reactant: COc1cc(N)ccc1-c1cnco1
Reactant: CC(C)(C)NC(=O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: COc1cc(NC(=O)C(=O)NC(C)(C)C)ccc1-c1cnco1
Yield: 80.7 %

Procedure:
A solution of 95 mg (0.5 mmol) of 3-methoxy-4-(5-oxazolyl)aniline, 73 mg (0.5 mmol) of N-tert-butyloxalamic acid, 134 mg (0.7 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 75 mg (0.55 mmol) of 1-hydroxy-7-azabenzotriazole in 4 ml of dichloromethane was stirred a room temperature for 18 hours. The resulting mixture was washed with 2M hydrochloric acid and saturated sodium bicarbonate, dried over magnesium sulphate and evaporated to dryness. The residue was triturated with petrol and collected by filtration to give 128 mg of N-tert-butyl-N′-[3-methoxy-4-(5-oxazolyl)phenyl]oxalamide as a pale yellow solid. MS: 318 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([OH:24])([CH3:23])[C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=1)(=[O:11])=[O:10].[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[CH:7]=[C:6]([N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:5]=[CH:4][C:3]=1[S:9]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([OH:24])([CH3:23])[C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=1)(=[O:11])=[O:10]
Reactant: C1CCNC1
Reactant: CC(O)(c1ccc(S(=O)(=O)c2ccc(F)cc2Cl)cc1)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(O)(c1ccc(S(=O)(=O)c2ccc(N3CCCC3)cc2Cl)cc1)C(F)(F)F
Reaction time: 12 h
Yield: 61.5 %

Procedure:
50 mg 2-[4-(2-Chloro-4-fluoro-benzenesulfonyl)-phenyl]-1,1,1-trifluoro-propan-2-ol (0.13 mmol, prepared as in the previous examples) was combined in a pressure tube with 50 mg pyrrolidine. The resulting mixture was then placed into a preheated 100° C. bath. After stirring for 12 h, the mixture was diluted with 10 mL CH2Cl2 and sat. NaHCO3, then extracted (3×10% MeOH/CH2Cl2). The organics were dried (MgSO4) and concentrated under reduced pressure. Purification by flash chromatography (SiO2, 25% EtOAc/Hexanes) gave 35 mg of the product as a white solid (0.08 mmol). 1H NMR (CDCl3, 400 MHz) δ 8.09 (d, J=8.4 Hz, 1H), 7.92 (d, J=7.6 Hz, 2H), 7.70 (d, J=7.8 Hz, 2H), 6.49 (m, 2H), 3.32 (s, 4H), 2.04 (s, 4H), 1.78 (m, 3H).