Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C@@H:18]1[C:24](=[O:25])[N:23]2[C@@H:19]1[CH2:20][C:21]([S:39][C:40]1[CH:41]=[CH:42][C:43]3[N:44]([N:46]=[N:47][N:48]=3)[N:45]=1)=[C:22]2[C:26]([O:28]CC1C=CC([N+]([O-])=O)=CC=1)=[O:27])([O:4]C(OCC1C=CC([N+]([O-])=O)=CC=1)=O)[CH3:3].P([O-])([O-])(O)=O.[K+:54].[K+]>O1CCCC1.C(O)C.[H][H].O.[Pt](=O)=O>[OH:4][C:2]([C@@H:18]1[C:24](=[O:25])[N:23]2[C@@H:19]1[CH2:20][C:21]([S:39][C:40]1[CH:41]=[CH:42][C:43]3[N:44]([N:46]=[N:47][N:48]=3)[N:45]=1)=[C:22]2[C:26]([O-:28])=[O:27])([CH3:3])[CH3:1].[K+:54]
Reactant: [H][H]
Reactant: CC(C)(OC(=O)OCc1ccc([N+](=O)[O-])cc1)[C@@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Sc3ccc4nnnn4n3)C[C@H]12
Agent: O=[Pt]=O
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(O)[C@@H]1C(=O)N2C(C(=O)[O-])=C(Sc3ccc4nnnn4n3)C[C@H]12

Procedure:
A mixture of 4-nitrobenzyl (5R, 6R)-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)ethyl]-7-oxo-3-(tetrazolo[1,5-b]pyridazin-6-ylthio)-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylate (0.4357 g), platinum (IV) oxide monohydrate (0.2179 g) in 0.047M aqueous dipotassium hydrogen phosphate (41.1 ml), tetrahydrofuran (52.3 ml) and ethanol (4.40 ml) was stirred for 3.7 hours in hydrogen gas under atmospheric pressure at ambient temperature. After the catalyst was filtered off, the filtrate was concentrated to half of the original volume. The aqueous concentrate was washed with diethyl ether (x3) and evaporated in vacuo. The residue was chromatographed on nonionic adsorption resin "Diaion CHP-20P" (Trademark, manufactured by Mitsubishi Chemical Industries) (220 ml) eluting with water (1.50 l), 5% aqueous isopropyl alcohol (400 ml) and 10% aqueous isopropyl alcohol (400 ml). The fractions, whose IV spectra showed λ max 233.0 nm and 282.5 nm, were combined and lyophilized to give crude product (0.1459 g), which was chromatographed again on "Diaion CHP-20P" (130 ml) eluting with water (340 ml), 5% aqueous isopropyl alcohol (360 ml) and 10 aqueous isopropyl alcohol (200 ml). The fractions containing the desired compound were collected and lyophilized to give potassium (5R, 6R)-6-(1-hydroxy-1-methylethyl)-3-(tetrazolo[1,5-b]pyridazin-6-ylthio)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (0.1299 g) as a yellow powder.
Reaction SMILES: [NH2:1][C:2]1[C:11]([OH:12])=[C:10]2[C:5]([C:6](=[O:20])[C:7]([I:19])=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:9]2)=[CH:4][CH:3]=1.[C:21]1(C)C=CC(S(O)(=O)=O)=CC=1>COC(OC)OC>[I:19][C:7]1[C:6](=[O:20])[C:5]2[CH:4]=[CH:3][C:2]3[N:1]=[CH:21][O:12][C:11]=3[C:10]=2[O:9][C:8]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccc2c(=O)c(I)c(-c3ccccc3)oc2c1O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(OC)OC
Product: O=c1c(I)c(-c2ccccc2)oc2c1ccc1ncoc12
Temperature: 100 °C
Reaction time: 2 h
Yield: 3494.8 %

Procedure:
To a solution of 7-amino-8-hydroxy-3-iodo-2-phenyl-chromen-4-one (151 mg, 0.4 mmol) in trimethylorthoformate (3 mL) was added p-toluenesulfonic acid (2 mg, 0.01 mmol). The reaction mixture was stirred at 100° C. for 2 hours, allowed to RT and the solvent removed. The resulting residue was subjected to flash chromatography (SiO2, gradient 20-100% ethyl acetate in cyclohexane) to give the title compound as a beige solid (136 mg, 87%). LCMS (Method G): RT=3.52 min, [M+H]+=389.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[N:6][CH:5]=1.[C:12]1(=O)[O:17][C:15](=[O:16])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12.O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15](=[O:16])[C:14]3[C:13](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:12]2=[O:17])=[N:6][CH:5]=1
Reactant: COC(=O)c1ccc(N)nc1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(N2C(=O)c3ccccc3C2=O)nc1
Yield: 59 %

Procedure:
A solution of 6-aminonicotinic acid methyl ester (1.1 g, 7.2 mmol) and phthalic anhydride (1.2 g, 7.9 mmol) in anhydrous toluene was heated at reflux overnight in a Dean-Stark apparatus until no more water was collected. The reaction mixture was concentrated under vacuum. The residue was dissolved in ethyl acetate (50 mL) and was washed with brine and water. The organic layer was dried over anhydrous Na2SO4 and concentrated under vacuum to give 6-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-nicotinic acid methyl ester (1.2 g, 60%), which was directly used in the next step without further purification. 1H NMR (300 MHz, d-DMSO) δ 9.12 (d, J=1.5 Hz, 1H), 8.52 (dd, J=2.1, 8.4 Hz, 1H), 8.03-7.92 (m, 4H), 7.72 (d, J=7.8 Hz, 1H), 3.91 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].CN1CCCC1.Cl[C:19]1[C:20]2[CH:27]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[NH:25][C:21]=2[N:22]=[CH:23][N:24]=1>O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[O:11][C:19]1[C:20]2[CH:27]=[C:26]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[NH:25][C:21]=2[N:22]=[CH:23][N:24]=1
Reactant: Clc1ncnc2[nH]c(-c3ccccc3)cc12
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: CN1CCCC1
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ncnc3[nH]c(-c4ccccc4)cc23)cc1F
Temperature: 130 °C
Reaction time: 8 h
Yield: 20.4 %

Procedure:
After adding 328 mg of 3-fluoro-4-nitrophenol, 0.22 ml of 2, 6-lutidine and 0.9 ml of N-methylpyrrolidine to 360 mg of the 4-chloro-6-phenyl-7H-pyrrolo[2,3-d]pyrimidine described in WO97/02266 and PCT/EP96/02728 and stirring the mixture overnight at 130° C., it was returned to room temperature, water was added, the precipitated solid was filtered out and washed with water and diethyl ether, and the collected solid was dried to obtain 112 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[S:17][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[C:4]=2[CH:3]=1.[N:18]1[CH:23]=[C:22]([CH:24]=O)[CH:21]=[N:20][CH:19]=1>>[Cl:1][C:2]1[S:17][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][CH:11]3[CH2:12][CH2:13][N:14]([CH2:24][C:22]4[CH:23]=[N:18][CH:19]=[N:20][CH:21]=4)[CH2:15][CH2:16]3)[C:4]=2[CH:3]=1
Reactant: O=Cc1cncnc1
Reactant: Clc1cc2c(NC3CCNCC3)ncnc2s1
Product: Clc1cc2c(NC3CCN(Cc4cncnc4)CC3)ncnc2s1

Procedure:
The title compound was prepared (119 mg, 45%) from 6-chloro-N-(piperidin-4-yl)thieno[2,3-d]pyrimidin-4-amine (200 mg, 0.74 mmol) and pyrimidine-5-carbaldehyde (80 mg, 0.74 mmol) by following the general procedure described for Preparation 11. 1H NMR (400 MHz, CDCl3): δ 9.05 (s, 1H), 8.65 (s, 2H), 8.35 (s, 1H), 7.00 (s, 1H), 5.50 (bs, 1H), 4.10 (m, 1H), 3.45 (s, 2H), 2.80 (m, 2H), 2.20 (m, 2H), 2.00 (m, 2H), 1.50 (m, 2H). MS (ESI) m/z: Calculated: 360.09; Observed: 361.1 (M++1).
Reaction SMILES: [OH-].[Na+].[C:3]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.CC(C)=O.[F:22][BH-](F)F.F[BH-](F)F.ClC[N+]12CC[N+](F)(CC1)CC2>CO.C(S([O-])(=O)=O)(F)(F)F.[Ag+]>[F:22][C:6]1[CH:7]=[CH:8][C:3]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:5]=1
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Reactant: F[BH-](F)F
Agent: [Ag+]
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CC(C)=O
Solvent: CO
Product: Fc1ccc(-c2ccccc2)cc1
Temperature: 23 °C
Reaction time: 0.25 h
Yield: 94.1 %

Procedure:
To NaOH (480 mg, 12.0 mmol, 1.20 equiv) in MeOH (20 mL) at 23° C. was added 4-biphenylboronic acid (1.98 g, 10.0 mmol, 1.00 equiv). After stirring for 15 min at 23° C., the reaction mixture was cooled to 0° C. and was added to AgOTf (7.71 g, 30.0 mmol, 3.00 equiv). After stirring for 30 min at 0° C., the solvent was removed under reduced pressure at 0° C. and the residual MeOH was completely removed by co-evaporation with acetone (20 mL×2). To the residue was added acetone (50 mL), MS3 Å (5.0 g), and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(trifluoroborate) (1) (3.72 g, 10.5 mmol, 1.05 equiv) and the reaction mixture was stirred for 30 min and concentrated in vacuo. The residue was dissolved in CH2Cl2 and filtered through a plug of Celite. After the removal of CH2Cl2, to the residue was added H2O (30 mL) and Et2O (30 mL) and the phases were separated. The aqueous phase was extracted with Et2O (2×20 mL). The combined organic phases are washed with brine (30 mL) and dried (Na2SO4). The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica gel eluting with hexanes to afford 1.62 g of 4-fluorobiphenyl as a colorless solid (94% yield).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[C:7]([O:11][C:12]([N:14]([CH2:22][CH2:23][C:24]#[N:25])[CH2:15][CH2:16][CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])=[O:13])([CH3:10])([CH3:9])[CH3:8]>CCOCC>[NH2:25][CH2:24][CH2:23][CH2:22][N:14]([C:12]([O:11][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:13])[CH2:15][CH2:16][CH2:17][CH2:18][N:19]([CH3:20])[CH3:21]
Reactant: CN(C)CCCCN(CCC#N)C(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CN(C)CCCCN(CCCN)C(=O)OC(C)(C)C
Temperature: 0 °C
Yield: 58.7 %

Procedure:
To a solution of LAH (0.62 mg, 16.30 mmol) in anhydrous ether (100 ml) was added N-(tert-butoxycarbonyl)-N-(2-cyanoethyl)-N',N'-dimethyl-1,4-diaminobutane 324 (2.22 g, 8.10 mmol) in anhydrous ether (50 ml) at 0° C. The mixture was stirred at 0° C. for thirty minutes. The excess LAH was quenched with 1N NaOH at 0° C., and the resulting suspension was filtered through Celite and washed with ether. The combined ether layers were washed with brine, dried over MgSO4, and concentrated in vacuo to yield a crude product. The crude product was purified on a flash silica gel column and eluted with chloroform:methanol:isopropylamine (15:1:1) to give N-(3-aminopropyl)-N-(tert-butoxycarbonyl)-N',N'-dimethyl-1,4-diaminobutane 325 (1.30 g, 59% yield). 1H NMR (400 MHz, CDCl3) δ: 1.40 (9H, s, t-Bu), 2.15 (6H, s, --N(CH3)2), 2.22 (2H, m), 2.65 (2H, t), 3.20 (4H, m).
Reaction SMILES: [CH2:1]([CH:9]([CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH2:10][O:11][C:12]1[C:13]2[C:21]([CH:22]=[C:23]3[CH:27]=[CH:26][S:25][C:24]=13)=[C:20]([O:28][CH2:29][CH:30]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:16]1[S:17][CH:18]=[CH:19][C:15]=1[CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C([Li])CCC.[CH3:64][Sn:65](Cl)([CH3:67])[CH3:66].O>C1COCC1>[CH3:64][Sn:65]([CH3:67])([CH3:66])[C:26]1[S:25][C:24]2[C:12]([O:11][CH2:10][CH:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])=[C:13]3[C:21](=[CH:22][C:23]=2[CH:27]=1)[C:20]([O:28][CH2:29][CH:30]([CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[C:16]1[S:17][C:18]([Sn:65]([CH3:67])([CH3:66])[CH3:64])=[CH:19][C:15]1=[CH:14]3
Reactant: C[Sn](C)(C)Cl
Reactant: CCCCCCCCCCC(CCCCCCCC)COc1c2cc3ccsc3c(OCC(CCCCCCCC)CCCCCCCCCC)c2cc2ccsc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCC(CCCCCCCC)COc1c2cc3cc([Sn](C)(C)C)sc3c(OCC(CCCCCCCC)CCCCCCCCCC)c2cc2cc([Sn](C)(C)C)sc12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
Compound (4a) (0.350 g, 0.420 mmol) was solubilized in anhydrous THF (17 mL) and cooled at −78° C. under N2. n-Butyllithium (0.42 mL, 2.5M) was then added and the stirring was continued for 30 minutes at this temperature and then 30 minutes at room temperature. The reaction mixture was cooled to −78° C. again before adding trimethylstannyl chloride (1.1 mL, 1.0M). The reaction was warmed up to room temperature and stirred overnight. The reaction was stopped by adding water, and the mixture was extracted with diethyl ether, dried over MgSO4, filtered, and concentrated in vacuo. The crude monomer was solubilized in 5 mL of THF and then dropped in methanol (200 mL). The product was allowed to precipitate in the freezer overnight before filtering and washing with cold methanol to afford a yellow fluffy powder as the title compound (0.420 g, 86%). 1H NMR (500 MHz, CDCl3, 298 K): 8.43 (s, 2H); 7.51 (s, 2H); 4.29 (d, J=5.4 Hz, 4H); 2.00 (quintet, J=6.0 Hz, 2H); 1.74 (m, 4H); 1.45 (m, 60H); 0.88 (m, 12H); 0.47 (s, 18H) ppm. 13C NMR (125 MHz, CDCl3, 298 K): 149.22; 142.73; 141.25; 132.62; 130.19; 124.51; 109.71; 75.50; 39.37; 31.99; 31.97; 31.42; 30.23; 29.83; 29.82; 29.78; 29.75; 29.47; 29.42; 27.08; 22.74; 14.19; 14.18; 8.40 ppm. HRMS (ESI-TOF-MS): m/z calcd for C60H104O2S2Sn2 1158.5516, found 1158.5543.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)=[CH:3][CH:2]=1.ClC1C=CC2[S:26]C3C(=CC=CC=3)NC=2C=1>>[Cl:14][C:10]1[C:9]2[S:26][C:3]3[C:4](=[CH:5][CH:6]=[CH:1][CH:2]=3)[NH:7][C:8]=2[CH:13]=[CH:12][CH:11]=1
Reactant: Clc1cccc(Nc2ccccc2)c1
Reactant: Clc1ccc2c(c1)Nc1ccccc1S2
Product: Clc1cccc2c1Sc1ccccc1N2

Procedure:
The conversion rate of the 3-chlorodiphenylamine is 80%, and the yield of 2-chlorophenothiazine is 63% with respect to the 3-chlorodiphenylamine converted.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]#[N:17])[CH:11]=2)[CH:4]=1.[CH3:18]I>C1COCC1.CCOC(C)=O>[CH3:18][N:9]([C:5]1[CH:4]=[N:3][CH:8]=[CH:7][CH:6]=1)[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]#[N:17])[CH:11]=1
Reactant: CI
Reactant: N#Cc1cc(Nc2cccnc2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(c1cccnc1)c1ccnc(C#N)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 32.1 %

Procedure:
NaH (185 mg, 7.71 mmol, 1.10 eq) was added to a flame-dried round-bottom flask and anhydrous THF (17.5 mL) was added. The slurry was cooled to 0° C. and compound 10 (1.374 g, 7.003 mmol, 1.000 eq) was added as a solution in THF (17.5 mL). After stirring at 0° C. for 30 minutes methyl iodide (481 μL, 7.71 mmol, 1.10 eq) was added and the reaction was allowed to warm to room temperature while stirring overnight. The reaction was diluted with EtOAc and washed with water (1×). The aqueous layer was back extracted (1×) with EtOAc and the combined organics were washed with brine, dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 473 mg (32%) of the title compound as a white solid: 1H NMR (400 MHz, CDCl3) δ1H NMR (400 MHz, DMSO-d6) δ 8.58 (d, J=2.5 Hz, 1H), 8.56 (dd, J=1.2, 4.7 Hz, 1H), 8.24 (d, J=6.0 Hz, 1H), 7.81 (dq, J=1.4, 8.2 Hz, 1H), 7.56-7.53 (m, 1H), 7.25 (d, J=2.6 Hz, 1H), 6.80 (dd, J=2.7, 6.0 Hz, 1H), 3.36 (s, 3H); ES-MS [M+1]+:211.1.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH:17]([CH3:19])[CH3:18])=[CH:5][CH:4]=1.[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[C:25]=1[N:33]=[C:34]=[O:35])([CH3:23])[CH3:22]>>[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:31])[CH3:32])[C:25]=1[NH:33][C:34](=[O:35])[N:10]([CH2:9][C:6]1[CH:5]=[CH:4][C:3]([N:2]([CH3:20])[CH3:1])=[CH:8][CH:7]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]([CH3:18])[CH3:19])([CH3:22])[CH3:23]
Reactant: CC(C)c1ccccc1NCc1ccc(N(C)C)cc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Product: CC(C)c1ccccc1N(Cc1ccc(N(C)C)cc1)C(=O)Nc1c(C(C)C)cccc1C(C)C
Yield: 8.5 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using [(4-dimethylaminophenyl)methyl](2-isopropylphenyl)amine (1.6 g) and 2,6-diisopropylphenyl isocyanate (1.7 g) as starting materials, N′-(2,6-diisopropylphenyl)-N-[(4-dimethylaminophenyl)methyl]-N-(2-isopropylphenyl)urea (0.24 g) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:34]=[CH:33][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[N:13]([CH2:24][C:25]4[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)[N:14]=[C:15]([NH:16][CH:17]4[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]4)[C:8]=23)=[C:4]([F:35])[CH:3]=1.CCN(C(C)C)C(C)C.[C:45]1([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[CH:50]=[CH:49][CH:48]=[C:47]([C:51](Cl)=[O:52])[CH:46]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[F:35][C:4]1[CH:3]=[C:2]([NH:1][C:51]([C:47]2[CH:46]=[C:45]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[CH:50]=[CH:49][CH:48]=2)=[O:52])[CH:34]=[CH:33][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[N:13]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)[N:14]=[C:15]([NH:16][CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)[C:8]=12
Reactant: O=C(Cl)c1cccc(-c2ccccc2)c1
Reactant: COc1ccc(Cn2nc(NC3CCN(C)CC3)c3c(Oc4ccc(N)cc4F)ccnc32)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(Cn2nc(NC3CCN(C)CC3)c3c(Oc4ccc(NC(=O)c5cccc(-c6ccccc6)c5)cc4F)ccnc32)cc1
Temperature: 25 °C
Yield: 58.6 %

Procedure:
To a stirred solution of 1-(4-methoxybenzyl)-4-(4-amino-2-fluorophenoxy)-N-(1-methylpiperidin-4-yl)-1H-pyrazolo[3,4-b]pyridin-3-amine (12 mg, 0.026 mmol) (prepared in Example 101, step A) in 260 μL dichloromethane at 0° C. under nitrogen was added DIEA (14 μL, 0.078 mmol) followed by biphenyl-3-carbonyl chloride (7 mg, 0.031 mmol). The reaction was allowed to warm to room temperature overnight. The reaction was diluted to 10 mL with dichloromethane and stirred rapidly with 10% sodium carbonate solution for 5 minutes. The organics were isolated and dried (MgSO4). The organics were filtered and concentrated to a residue that was loaded onto a Biotage 12S column with dichloromethane and eluted with 4/1 EtOAc/hexanes. The product containing fractions were pooled and concentrated to a yellow oil (10 mg, 59% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2([OH:17])[CH2:16][CH2:15][C:10]3([O:14][CH2:13][CH2:12][O:11]3)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.C1C=C(Cl)C=C(C(OO)=[O:26])C=1>C(Cl)Cl>[O-:26][N+:1]1[CH:2]=[CH:3][C:4]([C:7]2([OH:17])[CH2:8][CH2:9][C:10]3([O:14][CH2:13][CH2:12][O:11]3)[CH2:15][CH2:16]2)=[CH:5][CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: OC1(c2ccncc2)CCC2(CC1)OCCO2
Solvent: ClCCl
Product: [O-][n+]1ccc(C2(O)CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.5 %

Procedure:
To a solution of 2.35 g (10 mmol) of 8-pyridin-4-yl-1,4-dioxaspiro[4.5]decan-8-ol (prepared following the procedure described in Example 7) in 20 mL of methylene chloride was added 2.6 g (15 mmol) of mCPBA. The reaction mixture was stirred at room temperature for 1.5 h. Direct chromatography on silica gel afforded the title compound (2.45 g, 98%).
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7]1)=[O:5])C.[OH-].[Na+]>CO>[CH2:11]([N:8]1[CH2:9][CH2:10][C:6]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:4]([OH:5])=[O:3])[CH2:7]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CCOC(=O)C1(Cc2ccccc2)CCN(Cc2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1(Cc2ccccc2)CCN(Cc2ccccc2)C1
Yield: 76.8 %

Procedure:
To a solution of 1,3-dibenzylpyrrolidine-3-carboxylic acid ethyl ester (Example A18e, 13.1 g, 41 mmol) in 250 mL of methanol is added 2N NaOH (46 mL, 92 mmol) and the reaction is heated to reflux for 24 hours. The solution is cooled, concentrated, redissolved in water and extracted with ether. The pH of the aqueous layer is adjusted to 7 and the precipitated solid is collected, to give 9.3 g of the title compound, MS EI+: m/z 296 (MH+), mp 209–210° C.
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][C:3]=1[CH2:4][O:5][CH2:6][CH:7]1[CH2:34][CH2:33][C:10]2[N:11](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:12]=[N:13][C:9]=2[CH2:8]1.ClC1C=CC(C(F)(F)F)=CC=1COCC1CCC2N=CN(C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)C=2C1>C(O)(=O)C.O>[Cl:1][C:2]1[CH:38]=[CH:37][C:36]([C:39]([F:41])([F:40])[F:42])=[CH:35][C:3]=1[CH2:4][O:5][CH2:6][CH:7]1[CH2:34][CH2:33][C:10]2[NH:11][CH:12]=[N:13][C:9]=2[CH2:8]1
Reactant: FC(F)(F)c1ccc(Cl)c(COCC2CCc3c(ncn3C(c3ccccc3)(c3ccccc3)c3ccccc3)C2)c1
Agent: FC(F)(F)c1ccc(Cl)c(COCC2CCc3ncn(C(c4ccccc4)(c4ccccc4)c4ccccc4)c3C2)c1
Solvent: CC(=O)O
Solvent: O
Product: FC(F)(F)c1ccc(Cl)c(COCC2CCc3[nH]cnc3C2)c1
Temperature: 90 °C

Procedure:
A solution of a mixture of 5-(2-chloro-5-trifluoromethylbenzyloxymethyl)-1-triphenylmethyl-4,5,6,7-tetrahydro-1H-benzimidazole and 5-(2-chloro-5-trifluoromethylbenzyloxymethyl)-3-triphenylmethyl-4,5,6,7-tetrahydro-3H-benzimidazole in a mixture of acetic acid (5 ml) and water (0.6 ml) was heated to 90° C. for 2 hours. The reaction mixture was cooled to room temperature. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (40 g), using a mixture of DCM/methanol/25% aqueous ammonia (100:10:1) as eluent, to give 310 mg of the title compound.
Reaction SMILES: [S:1]1[C:5]([N:6]([CH2:20][CH2:21][C:22]([F:25])([F:24])[F:23])[S:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][CH:11]=2)(=[O:9])=[O:8])=[CH:4][C:3]2[CH:26]=[CH:27][CH:28]=[CH:29][C:2]1=2.OP(O)(O)=O.[C:35](OC(=O)C)(=[O:37])[CH3:36]>>[C:35]([C:4]1[C:3]2[CH:26]=[CH:27][CH:28]=[CH:29][C:2]=2[S:1][C:5]=1[N:6]([CH2:20][CH2:21][C:22]([F:25])([F:23])[F:24])[S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][CH:11]=1)(=[O:8])=[O:9])(=[O:37])[CH3:36]
Reactant: COC(=O)c1ccc(S(=O)(=O)N(CCC(F)(F)F)c2cc3ccccc3s2)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=P(O)(O)O
Product: COC(=O)c1ccc(S(=O)(=O)N(CCC(F)(F)F)c2sc3ccccc3c2C(C)=O)cc1
Temperature: 100 °C

Procedure:
To compound 385-A (0.388 g, 0.87 mmol) was added acetic anhydride (10 mL) and 85% H3PO4 (0.10 mL), and the reaction was heated at 100° C. for three days. Additional acetic anhydride (10 mL) was added, the reaction mixture heated for an additional 4 more days. The reaction mixture was cooled, concentrated under vacuum, partitioned between EtOAc (100 mL) and saturated NaHCO3 (50 mL), filtered, the organic layer washed with brine (50 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography (SiO2) eluting with an EtOAc-heptane gradient to afford 0.197 g of compound 385-B as a colorless oil. 1H-NMR (DMSO-d6): δ 2.64 (s, 3H), 2.91-2.72 (m, 2H), 4.01-3.87 (m, 5H), 7.54-7.43 (m, 2H), 7.87 (d, 2H), 7.99-7.92 (m, 1H), 8.19-8.08 (m, 3H); MS: m/z 486.1 (MH+).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([N:24]2[C:29](=[O:30])[CH:28]=[C:27]([O:31][C:32]3[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=3[F:39])[CH:26]=[N:25]2)[C:8]([NH:10][C:11]2[CH:16]=[N:15][C:14]([C@@H:17]3[CH2:21][O:20]C(C)(C)[O:18]3)=[CH:13][N:12]=2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO.C(Cl)Cl.C(OCC)(=O)C>[CH:1]1([CH2:6][CH:7]([N:24]2[C:29](=[O:30])[CH:28]=[C:27]([O:31][C:32]3[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=3[F:39])[CH:26]=[N:25]2)[C:8]([NH:10][C:11]2[CH:16]=[N:15][C:14]([C@@H:17]([OH:18])[CH2:21][OH:20])=[CH:13][N:12]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC1(C)OC[C@@H](c2cnc(NC(=O)C(CC3CCCC3)n3ncc(Oc4c(F)cccc4F)cc3=O)cn2)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(Nc1cnc([C@@H](O)CO)cn1)C(CC1CCCC1)n1ncc(Oc2c(F)cccc2F)cc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.1 %

Procedure:
A solution of 3-cyclopentyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[5-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl)-pyrazin-2-yl]-propionamide (685 mg, 1.26 mmol) in methanol (12.6 mL, 0.1 M) and methylene chloride (5 mL) was treated with para-toluenesulfonic acid (36 mg, 0.18 mmol). The reaction stirred at 25° C. overnight. At this time, the reaction was diluted with ethyl acetate (100 mL) and washed with a saturated aqueous sodium bicarbonate solution (150 mL), water (150 mL), and a saturated aqueous sodium chloride solution (150 mL). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo to afford 3-cyclopentyl-2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[5-((R)-1,2-dihydroxy-ethyl)-pyrazin-2-yl]-propionamide as an off-white solid (0.50 g, 81%); ES+-HRMS m/e calcd for C24H25N5O5F2 [M+H+] 502.1897 found 502.1894. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.04-1.21 (m, 1H), 1.27-1.85 (m, 8H), 1.91-2.08 (m, 1H), 2.22-2.41 (m, 1H), 3.50-3.62 (m, 1H), 3.62-3.73 (m, 1H), 4.62 (q, J=5.1 Hz, 1H), 4.72 (t, J=5.7 Hz, 1H), 5.52-5.64 (m, 2H), 6.07 (d, J=2.5 Hz, 1H), 7.33-7.56 (m, 3H), 8.31 (d, J=2.5 Hz, 1H), 8.45 (s, 1H), 9.13 (s, 1H), 11.25 (br. s., 1H).