Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C=O)C.CO[C:8](=[O:43])[N:9]=[C:10](SC)[C:11]([C:28]1[C:29]([F:40])=[C:30]2[C:35](=[C:36]([O:38][CH3:39])[CH:37]=1)[O:34][CH2:33][CH2:32][CH2:31]2)=[N:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[O:21][N:20]=2)=[CH:15][CH:14]=1.Cl.Cl.[CH2:46]([O:48][C:49]([C:51]1[C:52]([NH:56][NH2:57])=[N:53][NH:54][CH:55]=1)=[O:50])[CH3:47]>C(N(CC)CC)C>[CH2:46]([O:48][C:49]([C:51]1[CH:55]=[N:54][NH:53][C:52]=1[N:56]1[C:8](=[O:43])[NH:9][C:10]([CH:11]([C:28]2[C:29]([F:40])=[C:30]3[C:35](=[C:36]([O:38][CH3:39])[CH:37]=2)[O:34][CH2:33][CH2:32][CH2:31]3)[NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[N:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[O:21][N:20]=3)=[CH:15][CH:14]=2)=[N:57]1)=[O:50])[CH3:47]
Reactant: CCOC(=O)c1c[nH]nc1NN
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C(F)(F)F)n2)cc1)c1cc(OC)c2c(c1F)CCCO2
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cn[nH]c1-n1nc(C(Nc2ccc(-c3noc(C(F)(F)F)n3)cc2)c2cc(OC)c3c(c2F)CCCO3)[nH]c1=O
Temperature: 85 °C
Reaction time: 16 h
Yield: 20.9 %

Procedure:
To 5 ml of a DMF solution containing 160 mg of [2-(5-fluoro-8-methoxychroman-6-yl)-2-[4-(5-trifluoromethyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester, 87 mg of 3-hydrazino-1H-pyrazole-4-carboxylic acid ethyl ester bishydrochloride (Example (157b)) and 0.124 ml of triethylamine were added. The resulting mixture was stirred at 85° C. for 16 hours under a nitrogen atmosphere. The reaction mixture was concentrated. The residue was dissolved in 8 ml of methanol and 0.068 ml of acetic acid, and then 187 mg of sodium cyanotrihydroborate was added thereto. The mixture was stirred at room temperature for 15 hours, and then 100 ml of ethyl acetate and 50 ml of water were added thereto. The organic layer was washed with 50 ml of water and then with 50 ml of saturated brine and was dried over anhydrous magnesium sulfate. The desiccating agent was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by NAM silica gel column chromatography (methanol-ethyl acetate) to give the title compound (39 mg).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:31]=[CH:30][C:16]([CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([O:26][CH3:27])=[O:25])=[CH:15][CH:14]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH:32](=O)[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.O>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]#[C:12][C:13]2[CH:14]=[CH:15][C:16]([CH2:17][N:18]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:19]3[CH:20]=[CH:21][C:22]([F:29])=[C:23]([CH:28]=3)[C:24]([O:26][CH3:27])=[O:25])=[CH:30][CH:31]=2)=[CH:9][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(C#Cc2ccc(CNc3ccc(F)c(C(=O)OC)c3)cc2)cc1
Reactant: CCCCCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CCCCCCN(Cc1ccc(C#Cc2ccc(CCCC)cc2)cc1)c1ccc(F)c(C(=O)OC)c1
Temperature: 70 °C
Reaction time: 3.5 h
Yield: 76.7 %

Procedure:
To a suspension of methyl 5-({4-[(4-butylphenyl)ethynyl]benzyl}amino)-2-fluorobenzoate (500 mg, 1.20 mmol) in anhydrous DCE (8 mL) were added hexanal (0.25 mL, 2.07 mmol) and sodium triacetoxyborohydride (825 mg, 3.89 mmol). The reaction mixture was stirred at 70° C. for 3.5 hrs. Then the reaction mixture was diluted with water (10 mL) and extracted with DCM (2×10 mL). The combined organic layers were dried over MgSO4 and the solvents were removed under reduced pressure. Purification by flash chromatography on silicagel (cHex/EtOAc) gave 460 mg (77%) of the title compound as a pale yellow oil. HPLC, Rt: 6.3 min (purity: 99.9%). 1H NMR (CDCl3) δ: 7.47 (d, J=8.3 Hz, 2H), 7.44 (d, J=8.3 Hz, 2H), 7.18 (m, 5H), 6.95 (dd, J=10.1, 9.0 Hz, 1H), 6.74 (m, 1H), 4.52 (s, 2H), 3.91 (s, 3H), 3.38 (t, J=7.7 Hz, 2H), 2.63 (t, J=7.7 Hz, 2H), 1.60 (m, 4H), 1.42-1.25 (m, 8H), 0.92 (m, 6H).
Reaction SMILES: [NH3:1].F[C:3]1[N:8]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[C:6](Cl)=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=1>C(OCC)C>[NH2:1][C:3]1[N:8]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:6]=[C:5]([C:15]([F:18])([F:17])[F:16])[N:4]=1
Reactant: Fc1nc(OC(F)(F)F)c(Cl)c(C(F)(F)F)n1
Reactant: N
Solvent: CCOCC
Product: Nc1nc(OC(F)(F)F)cc(C(F)(F)F)n1
Reaction time: 2 h

Procedure:
4.7 g (0.278 mol) of gaseous ammonia were passed over the course of 1 hour into a stirred mixture of 38.0 g (0.147 mol) of 2-fluoro(chloro)-4-trifluoromethoxy-6-trifluoromethylpyrimidine and 150 ml of diethyl ether at -75° to -70° C. The mixture was stirred for 2 hours each at -75° and at 25° C. The precipitate was filtered off with suction, and the organic phase was extracted with water, dried and evaporated. Chromatography on silica gel with methyl tert.-butyl ether yielded 20.4 g (56.1% of theory) of the title compound of melting point 47°-49° C.
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][CH2:6][CH2:7][N:8]1[C:12](=[O:13])/[C:11](=[CH:14]/[C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][C:16]=2[B:22]([F:24])[F:23])/[N:10]=[C:9]1[CH3:25])C.C(O)C.[OH-].[Na+]>O>[F:24][B:22]([F:23])[C:16]1[CH:17]=[C:18]([OH:21])[CH:19]=[CH:20][C:15]=1/[CH:14]=[C:11]1\[N:10]=[C:9]([CH3:25])[N:8]([CH2:7][CH2:6][CH2:5][C:4]([OH:26])=[O:3])[C:12]\1=[O:13]
Reactant: CCOC(=O)CCCN1C(=O)/C(=C/c2ccc(O)cc2B(F)F)N=C1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1=N/C(=C\c2ccc(O)cc2B(F)F)C(=O)N1CCCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
(Z)-ethyl-4-(4-(2-(difluoroboryl)-4-hydroxybenzylidene)-2-methyl-5-oxo-4,5-dihydro-1H-imidazole-1-yl)butyrate (1.82 g, 5.0 mmol) was dissolved in water (200 mL), then ethanol (50 mL) and sodium hydroxide (400 mg, 10.0 mmol) were added. The mixture was stirred for 2 hours at r.t., then acidified with aqueous HF solution and extracted with ethyl acetate (3×100 mL), washed with water (1×50 mL) and dried over anhydrous sodium sulfate. The mixture was evaporated and purified by column chromatography (chloroform:ethanol—5:1): 1.29 g. (Yield 77%)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:19]([NH2:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([C:10](=[O:12])[NH:26][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)c1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H](C(=O)NCc1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 62 %

Procedure:
(S)-tert-Butoxycarbonylamino-phenyl-acetic acid (1.00 g, 4 mmol) was dissolved in DCM (15 mL). Benzylamine (0.428 g, 4 mmol) and DIEA (0.65 g, 5 mmol) were added to the above mixture. The mixture which resulted was stirred at room temperature for a few minutes. PyBroP (2.10 g, 4.5 mmol) was added to the above solution in one portion and the reaction mixture was stirred overnight. The reaction mixture was diluted with DCM (150 mL) and washed with NaHCO3 (50 mL×2, sat.). The organic layer was collected and dried (Na2SO4) and the solvent was removed under reduced pressure. The crude product was purified by chromatography to provide the desired product (0.859, 62%).
Reaction SMILES: N=[N+]=[N-].[N-:4]=[N+]=[N-].[Na+].O.[C@H:9]1(C(O)=O)[CH2:14][CH2:13][CH2:12][C@@H:11]([C:15]([OH:17])=[O:16])[CH2:10]1>C(Cl)(Cl)Cl.S(=O)(=O)(O)O>[NH2:4][C@@H:9]1[CH2:14][CH2:13][CH2:12][C@H:11]([C:15]([OH:17])=[O:16])[CH2:10]1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)[C@@H]1CCC[C@H](C(=O)O)C1
Agent: O=S(=O)(O)O
Agent: [N-]=[N+]=N
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: N[C@@H]1CCC[C@H](C(=O)O)C1
Temperature: 0 °C
Yield: 93.9 %

Procedure:
A 7% (w/v) stock solution of hydrazoic acid in CHCl3 (196 ml, 0.32 mol, the stock solution was prepared by adding 400 g of NaN3 into 400 ml of water to CHCl3 (2 l)). Sulfuric acid (167 ml) was added under stirring at 0° C. slowly. The upper CHCl3 layer was decanted, dried over anhydrous sodium sulfate, filtrated and kept in the refrigerator. Titration analysis was done before usage. The solution was added dropwise over a period of 8 h to a solution of cis-cyclohexane-1,3-dicarboxylic acid (50.0 g, 0.29 mol) in a mixture of sulfuric acid (150 ml) and CHCl3 (500 ml) at 35° C. After the completion of addition, the reaction mixture was stirred at 40° C. for 10 h and further stirred at 50° C. for 3 h. The reaction mixture was cooled to room temperature and the acid layer was separated. The acid layer was basified with barium hydroxide to pH˜9 and the suspension was filtered. The filtrate was neutralized with diluted sulfuric acid and the suspension was filtered again. The filtrate was concentrated under vacuo to get the crude compound which was washed with MeOH (30 ml) to get 39.0 g (93.8%) of cis-3-aminocyclohexanecarboxylic acid as solid. [TLC system: 15% MeOH in CHCl3, Rf 0.1].
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:10]([O:12][C:13](=[O:23])[CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][C:18](=O)[CH2:17]1)[CH3:11].N1CCC[C@H]1C(O)=O>C(O)C>[CH2:10]([O:12][C:13](=[O:23])[CH2:14][CH2:15][CH:16]1[CH2:17][C:18]2=[N:1][C:2]3[N:3]=[CH:4][CH:5]=[CH:6][C:7]=3[CH:8]=[C:19]2[CH2:20][CH2:21]1)[CH3:11]
Reactant: CCOC(=O)CCC1CCCC(=O)C1
Reactant: Nc1ncccc1C=O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CCOC(=O)CCC1CCc2cc3cccnc3nc2C1
Temperature: 25 °C

Procedure:
A solution of 2-amino-pyridine-3-carbaldehyde (1-3) (0.244 g, 2.0 mmol) and 3-(3-oxo-cyclohexyl)-propionic acid ethyl ester (14-1) (0.245 g, 2.00 mmol; for prep., see J. R. Wiseman et. al., J. Am. Chem. Soc., 1970, 92, 956-962) in ethanol (10 mL) was treated with L-proline (0.230 g, 2.00 mmol) and heated at reflux for 12 h. The solution was cooled to ambient temperature and concentrated. The residue was purified by flash chromatography (10% acetone in CH2Cl2) to give 14-2.
Reaction SMILES: [C-:1]#[N:2].[K+].C1(C)C=CC(S(O[CH2:14][C@H:15]2[CH2:23][C@@H:22]3[C@@H:18]([CH2:19][N:20]([C:24](=[O:35])[C@H:25]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[O:33][CH3:34])[CH3:26])[CH2:21]3)[C@@:17]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[F:43])([OH:36])[CH2:16]2)(=O)=O)=CC=1>CS(C)=O.ClCCl>[C:1]([CH2:14][C@@H:15]1[CH2:23][C@@H:22]2[C@@H:18]([CH2:19][N:20]([C:24](=[O:35])[C@H:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[O:33][CH3:34])[CH3:26])[CH2:21]2)[C@@:17]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[F:43])([OH:36])[CH2:16]1)#[N:2]
Reactant: COc1ccccc1[C@H](C)C(=O)N1C[C@@H]2C[C@H](COS(=O)(=O)c3ccc(C)cc3)C[C@@](O)(c3ccccc3F)[C@@H]2C1
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: COc1ccccc1[C@H](C)C(=O)N1C[C@@H]2C[C@@H](CC#N)C[C@@](O)(c3ccccc3F)[C@@H]2C1
Temperature: 50 °C
Reaction time: 18 h
Yield: 149.6 %

Procedure:
0.35 g of potassium cyanide is added at room temperature to a solution of 1.55 g of (3aS,4S,6S,7aR)-6-p-toluenesulphonyloxymethyl-4-(2-fluorophenyl)-2-[(S)-2-(2-methoxyphenyl)propionyl]perhydroisoindol-4-ol in 15 cm3 of dimethyl sulphoxide. The reaction mixture is stirred at 50° C. for 18 hours and then diluted with 100 cm3 of dichloromethane, and the organic phase is washed with twice 50 cm3 of water then with 50 cm3 of saturated aqueous sodium chloride solution, dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). Recrystallization from diisopropyl ether gives 1.74 g of (3aS,4S,6S,7aR)-6-cyanomethyl-4-(2-fluorophenyl)-2-[(S)-2-(2-methoxyphenyl)propionyl]perhydroisoindol-4-ol in the form of white crystals melting at 182° C.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].BrCC1OC(C(F)(F)F)=CC=1.[Br:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[C:21]1([C:40]3[C:31](=[CH:32][C:33]4[O:38][CH2:37][CH2:36][O:35][C:34]=4[CH:39]=3)[O:30][CH2:29]1)[C:22](=[O:28])[NH:23]2.CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1>>[Br:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[C:21]1([C:40]3[C:31](=[CH:32][C:33]4[O:38][CH2:37][CH2:36][O:35][C:34]=4[CH:39]=3)[O:30][CH2:29]1)[C:22](=[O:28])[N:23]2[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C1Nc2cccc(Br)c2C12COc1cc3c(cc12)OCCO3
Reactant: CCCCCI
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: CCCCCN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(Br)cccc21

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using 1-iodopentane to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, and 4′-bromo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, 4′-bromo-1′-pentyl-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (54%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.20-7.15 (m, 2H), 6.87-6.83 (m, 1H), 6.45 (s, 1H), 6.16 (s, 1H), 4.89 (ABq, 2H), 4.20-4.11 (m, 4H), 3.85-3.59 (m, 2H), 1.72-1.67 (m, 2H), 1.38-1.25 (m, 4H), 0.92-0.85 (m, 3H); 13C NMR (75 MHz, CDCl3). δ 117.0, 156.4, 144.7, 144.5, 137.9, 130.13, 130.10, 126.9, 119.9, 118.1, 111.0, 107.5, 98.9, 76.8, 64.4, 63.8, 59.3, 40.5, 28.9, 27.0, 22.3, 13.9; MS (ES+) m/z 443.9 (M+1), 445.9 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[C:8]([CH:22]=1)[C:9]([NH:11][CH2:12][C:13]1[CH:21]=[CH:20][C:16]2[O:17][CH2:18][O:19][C:15]=2[CH:14]=1)=[O:10])([O-:3])=[O:2].C=O.[C:32]([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH3:32][N:27]1[CH2:28][CH2:29][CH:24]([NH:23][C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:22][C:8]=2[C:9]([NH:11][CH2:12][C:13]2[CH:21]=[CH:20][C:16]3[O:17][CH2:18][O:19][C:15]=3[CH:14]=2)=[O:10])[CH2:25][CH2:26]1
Reactant: [BH3-]C#N
Reactant: O=C(NCc1ccc2c(c1)OCO2)c1cc([N+](=O)[O-])ccc1NC1CCNCC1
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN1CCC(Nc2ccc([N+](=O)[O-])cc2C(=O)NCc2ccc3c(c2)OCO3)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.5 %

Procedure:
To a mixture of 5-nitro-2-(4-piperidinylamino)-N-(1,3-benzodioxol-5-ylmethyl)benzamide (80.0 mg) and 37% formaldehyde solution (192 mg) in methanol (4 mL) were added sodium cyanoborohydride (37.9 mg) and acetic acid (4 drops). After stirring for 2 hours at ambient temperature, the mixture was partitioned between an aqueous saturated sodium bicarbonate solution and chloroform. The organic layer was separated and washed with water and brine. Then, the resultant was dried over magnesium sulfate and evaporated in vacuo. The residue was triturated with diisopropyl ether to give 2-(1-methyl-4-piperidinylamino)-5-nitro-N-(1,3-benzodioxol-5-ylmethyl)benzamide as yellow powders (65.0 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[CH2:11]([N:13]([CH2:17][CH3:18])[CH2:14][CH2:15][NH2:16])[CH3:12].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C1COCC1>[CH2:11]([N:13]([CH2:17][CH3:18])[CH2:14][CH2:15][NH:16][C:8]([C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[CH:7][N:6]=1)=[O:10])[CH3:12]
Reactant: Nc1ccc(C(=O)O)nc1
Reactant: CCN(CC)CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCN(CC)CCNC(=O)c1ccc(N)cn1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The 5-amino-pyridine-2-carboxylic acid is coupled to N,N-diethyl-ethane-1,2-diamine (0.47 mL, 3.32 mmol), in the presence of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.26 g, 3.33 mmol), and DIPEA (0.59 mL, 3.33 mmol) in THF (10 mL). The mixture is stirred at room temperature for 48 hours. The solvent is removed in vacuo and the residue partitioned between water-EtOAc. The organic layer is dried over MgSO4, filtered and concentrated to give a residue purified by silica gel column chromatography. 5-Amino-pyridine-2-carboxylic acid (2-diethylamino-ethyl)-amide is isolated (394 mg, 100%) eluting with 96:4 DCM:NH3 (7M in MeOH).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C1(C)C=CC=CC=1>[CH3:21][S:22]([O:13][CH:10]1[CH2:11][CH2:12][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9]1)(=[O:24])=[O:23]
Reactant: OC1CCN(Cc2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CCN(Cc2ccccc2)C1
Temperature: 25 °C

Procedure:
1-Benzyl-3-pyrrolidinol (1.1 g) in toluene (10 mL) at 0° C. was treated with triethylamine (1 mL) and methanesulfonyl chloride (0.53 mL), warmed to room temperature, washed with saturated aqueous sodium bicarbonate, water, and brine, dried over anhydrous sodium sulfate, and concentrated. 1H NMR (300 MHz, DMSO-d6) δ 7.31 (s, 5H), 5.21 (m, 1H), 3.65 (q, 2H), 2.82 (m, 2H), 2.5 (m, 2H), 2.36 (m, 2H), 2.1 (m, 1H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]([N+:11]([O-])=O)=[N:3]1.[H][H]>C(OCC)(=O)C.C(O)C.[Pd]>[NH2:11][C:4]1[CH:5]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[N:2]([CH3:1])[N:3]=1
Reactant: [H][H]
Reactant: COC(=O)c1cc([N+](=O)[O-])nn1C
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(N)nn1C
Reaction time: 2.5 h
Yield: 100 %

Procedure:
In a 250 mL Parr hydrogenation flask was placed methyl 1-methyl-3-nitro-1H-pyrazole-5-carboxylate, (530 mg, 2.9 mmol) dissolved in ethyl acetate (15 mL) and ethanol (15 mL), to which was added 10% Pd/C (Degussa type) (100 mg). The mixture was placed on the Parr apparatus and pressurized with hydrogen to 50 PSI and shaken for 2.5 hrs. The reaction was filtered through a pad of celite which was washed with ethyl acetate. The solvent was removed under vacuum to give 119a as a white solid (450 mg, 2.9 mmol, quantitative yield).
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]2[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH2:22][OH:23])[C:6](=[O:24])[N:5]([CH3:25])[C:4]=2[N:3]=1.B(O)(O)[C:27]1[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pt]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:10]2[C:9]3[C:8](=[O:19])[N:7]([CH2:20][CH2:21][CH2:22][OH:23])[C:6](=[O:24])[N:5]([CH3:25])[C:4]=3[N:3]=[C:2]2[C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)=[CH:13][CH:14]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: Cn1c(=O)n(CCCO)c(=O)c2c1nc(Br)n2Cc1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pt]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2nc3c(c(=O)n(CCCO)c(=O)n3C)n2Cc2ccc(F)cc2)cc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 40.9 %

Procedure:
To a solution of 8-bromo-7-(4-fluorobenzyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (50 mg, 0.121 mmol, intermediate 62) in toluene (2 mL) and ethanol (0.5 mL) was added p-tolylboronic acid (19.7 mg, 0.145 mmol) followed by aqueous sodium carbonate solution (0.5 mL), and the mixture was degassed under nitrogen atmosphere three times. Tetrakis(triphenylphosphine)platinum (7.5 mg, 0.006 mmol) was added to the reaction under nitrogen and the resulting mixture was stirred at 100° C. for 16 h. The mixture was partitioned between ethyl acetate and brine. The organic phase was dried and concentrated to give crude product, which was purified via preparative HPLC to give 7-(4-fluorobenzyl)-1-(3-hydroxypropyl)-3-methyl-8-p-tolyl-1H-purine-2,6(3H,7H)-dione (20.9 mg, 40.9% yield) as white solid. 1H-NMR (CD3OD) δ 7.51-7.53 (d, 2H), 7.34-7.36 (d, 2H), 6.97-7.07 (m, 4H), 5.66 (s, 2H), 4.09-4.12 (t, 2H), 3.59-3.62 (t, 2H), 3.59 (s, 3H), 2.44 (s, 3H), 1.85-1.89 (m, 2H). LCMS retention time 2.306; LCMS MH+ 423.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[N:20]3[C:14]([CH2:15][NH:16][C:17]4[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=4[CH2:19]3)=[CH:13][CH:12]=2)=[O:10])[CH:2]=1.C(N(CC)C(C)C)(C)C.[C:34](Cl)(=[O:43])/[CH:35]=[CH:36]/[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>O1CCCC1>[C:37]1(/[CH:36]=[CH:35]/[C:34]([N:16]2[C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[CH2:19][N:20]3[C:11]([C:9]([NH:8][CH2:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:10])=[CH:12][CH:13]=[C:14]3[CH2:15]2)=[O:43])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1NC2
Reactant: O=C(Cl)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1N(C(=O)/C=C/c1ccccc1)C2
Temperature: 25 °C
Reaction time: 21 h
Yield: 85.2 %

Procedure:
To a suspension of N-(pyridin-3-ylmethyl)-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-3-carboxamide of Example 76, Step C (0.300 g, 0.942 mmol) and N,N-diisopropylethylamine (0.26 mL, 1.508 mmol) in dry tetrahydrofuran (10 mL) was added trans-cinnamoyl chloride (0.235 g, 1.41 mmol) and the reaction mixture was stirred at room temperature under nitrogen for 21 hours. The reaction was then quenched by the addition of 2 M sodium hydroxide (5 mL) and the mixture partitioned between ethyl acetate (50 mL) and 2 M sodium hydroxide (50 mL). The organic phase was separated, washed with 2 M sodium hydroxide (50 mL), water (50 mL) and brine (50 mL), dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford a yellow foam. Purification by flash chromatography using a solvent gradient of 1 to 4% methanol in dichloromethane gave a yellow syrup that was crystallized from diethyl ether/ethyl acetate/hexane to afford the title compound (0.360 g, 85%) as an off-white solid, m.p. 175° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]2[CH:12]=[C:13](I)[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH2:19][F:20])([CH2:17][F:18])[CH:7]=1)=[O:5])[CH3:2].[F:21][C:22]([F:33])([F:32])[C:23]([F:31])([F:30])[C:24]([F:29])([F:28])C([O-])=O.[K+].C1(C)C=CC=CC=1>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:11]2[CH:12]=[C:13]([C:24]([F:29])([F:28])[C:23]([F:31])([F:30])[C:22]([F:33])([F:32])[F:21])[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH2:19][F:20])([CH2:17][F:18])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=CC(CF)(CF)Oc2ccc(I)cc21
Reactant: O=C([O-])C(F)(F)C(F)(F)C(F)(F)F
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=CC(CF)(CF)Oc2ccc(C(F)(F)C(F)(F)C(F)(F)F)cc21

Procedure:
The procedure of Preparation Example 1 (6) was repeated using 2,2-bisfluoromethyl-6-iodo-2H-1-benzopyran-4-carboxylic acid ethyl ester, potassium heptafluorobutyrate, cuprous iodide, toluene and N,N-dimethylformamide to give 2,2-bisfluoromethyl-6-heptafluoropropyl-2H-1-benzopyran-4-carboxylic acid ethyl ester as an oil;
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:34][O:35][CH2:36][CH2:37][NH2:38]>>[CH3:34][O:35][CH2:36][CH2:37][NH:38][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6]
Reactant: COc1ccc(C2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: COCCN
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COCCNc1cc(C(=O)Nc2nc3c(OC)ccc(C4CCOCC4)c3s2)ccn1

Procedure:
From 2-bromo-N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-isonicotinamide with cesium carbonate and 2-methoxyethylamine. ES-MS m/e (%): 443 (M+H+, 100).