Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C(=O)([O-])[O-].[K+].[K+].[CH3:15][O:16][C:17]([CH:19]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:18].[C:39]([O:43][C:44]([NH:46][C@H:47]([CH:51]=O)[CH:48]([CH3:50])[CH3:49])=[O:45])([CH3:42])([CH3:41])[CH3:40]>ClCCl>[Br:1]/[C:19](=[CH:51]\[CH:47]([NH:46][C:44]([O:43][C:39]([CH3:40])([CH3:41])[CH3:42])=[O:45])[CH:48]([CH3:49])[CH3:50])/[C:17]([O:16][CH3:15])=[O:18]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)[C@@H](C=O)NC(=O)OC(C)(C)C
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)/C(Br)=C/C(NC(=O)OC(C)(C)C)C(C)C
Temperature: -20 °C
Reaction time: 0.33 h
Yield: 8 %

Procedure:
N-Bromosuccinimide (4.60 g, 25.9 mmol) and anhydrous potassium carbonate (8.10 g, 58.8 mmol) are successively added, over a period of 20 minutes, to a solution of (methoxycarbonylmethylene)triphenylphosphorane (PH3P═CH—CO2Me, 7.90 g, 23.5 mmol) in dichloromethane (60 ml) cooled to −20.0° C. The mixture, yellow-brown, is left under stirring for 20 min and freshly prepared N-(Boc)Valinal 2 (4.74 g, 23.5 mmol) dissolved in CH2Cl2 (20 ml) is instilled. The addition completed, the mixture is left for 30 min at −20.0° C. and for 1 h at ambient temperature. A TLC check indicates the total disappearance of the aldehyde. The mixture is filtered on a fritted disc coated with celite, and the fritted disc is rinsed with ether. After evaporation of the filtrate under a vacuum, the yellow oil obtained is chromatographed on a silica gel (elution gradient Heptane/AcOEt 90/10→75/25). 2.10 g (27%, Rf=0.46 (AcOEt/Hept 1/3)) of pure isomer E, 0.63 g of mixture (7%, Z+E) and 3.2 g (41%, Rf=0.35 (AcOEt/Hept 1/3)) of pure isomer Z are obtained.
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[O:8][C:9]4[C:14]([C:15]=3[NH:16][C:17](=[O:18])[C:5]=2[CH:4]=[CH:3][CH:2]=1)=[CH:13][CH:12]=[CH:11][CH:10]=4.[C:19](OC(=O)C)(=[O:21])[CH3:20]>N1C=CC=CC=1>[CH:1]1[C:6]2=[C:7]3[C:15](=[N:16][C:17]([O:18][C:19](=[O:21])[CH3:20])=[C:5]2[CH:4]=[CH:3][CH:2]=1)[C:14]1[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=1)[O:8]3
Reactant: CC(=O)OC(C)=O
Reactant: O=c1[nH]c2c3ccccc3oc2c2ccccc12
Solvent: c1ccncc1
Product: CC(=O)Oc1nc2c3ccccc3oc2c2ccccc12
Temperature: 25 °C
Yield: 52 %

Procedure:
To a solution of compound 15c (500 mg, 2.13 mmol) in pyridine (10 mL) was added acetic anhydride (4 mL). The resultant mixture was heated at 100° C. for 9 h, then cooled slowly to room temperature overnight. The solvent was removed on the rotary evaporator and the residual oil was extracted into 50 mL ethyl acetate. The organic layer was washed with 50 mL of 1 N aqueous hydrochloric acid, dried (sodium sulfate), and the solvent removed in vacuo to provide 308 mg (52% yield) of compound 16g as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[O:22]1[C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=[N:23]1>>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:27]([C:26]4[O:22][N:23]=[CH:24][CH:25]=4)=[O:28])[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Reactant: O=C(O)c1ccno1
Product: Cc1ccc(NC(=O)c2ccno2)cc1-c1ccc(C(=O)NCC2CC2)cc1

Procedure:
N-(4′-{[(Cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)isoxazole-5-carboxamide was prepared from 5′-amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4- carboxamide and isoxazole-5-carboxylic acid using method D. NMR; δH [2H6] —DMSO 10.75, (1H, s), 8.81,(1H, d), 8.62,(1H, t), 7.93,(2H, d), 7.70,(1H, dd), 7.66,(1H, d), 7.44,(2H, d), 7.32,(1H, d), 7.24,(1H, d), 3.16,(2H, t), 2.21,(3H, s), 1.04,(1H, m), 0.43,(2H, m), 0.24,(2H, m). LCMS: retention time 3.17 min, MH+376.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[O:11][CH3:12])=O.[CH3:13][C:14]1[N:15]=[C:16]([CH2:19][C:20]([CH3:22])=[O:21])[S:17][CH:18]=1.N1CCCCC1.C(O)(=O)C>ClCCl>[CH3:12][O:11][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:3]=1[CH:1]=[C:19]([C:16]1[S:17][CH:18]=[C:14]([CH3:13])[N:15]=1)[C:20](=[O:21])[CH3:22])[C:7]#[N:8]
Reactant: COc1cc(C#N)ccc1C=O
Reactant: CC(=O)Cc1nc(C)cs1
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: C1CCNCC1
Product: COc1cc(C#N)ccc1C=C(C(C)=O)c1nc(C)cs1

Procedure:
400 mg (2.48 mmol) of the compound from example 3A and 424 mg (2.73 mmol) of the compound from example 4A are dissolved in 10 ml of dichloromethane, and 0.245 ml (2.48 mmol) of piperidine and 0.142 ml (2.48 mmol) of acetic acid are added. The reaction mixture is heated under reflux with an inverse water trap overnight. The volatile components are then removed in a rotary evaporator, and the crude product is purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). 390 mg (53% of theory) of the title compound are obtained as a mixture of the E/Z isomers.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11]1=[O:19])[CH2:7][CH2:8][CH3:9])[CH3:2].Br[CH2:22][C:23]1[C:27]2[C:28]([CH3:33])=[CH:29][C:30]([CH3:32])=[CH:31][C:26]=2[S:25][N:24]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:22][C:23]2[C:27]3[C:28]([CH3:33])=[CH:29][C:30]([CH3:32])=[CH:31][C:26]=3[S:25][N:24]=2)[C:11]1=[O:19])[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: CCCC(CC(=O)OCC)n1c(=O)[nH]c2ccccc21
Reactant: Cc1cc(C)c2c(CBr)nsc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(CC(=O)OCC)n1c(=O)n(Cc2nsc3cc(C)cc(C)c23)c2ccccc21
Yield: 55 %

Procedure:
To a solution of 3-(2-Oxo-2,3-dihydro-benzimidazol-1-yl)-hexanoic acid ethyl ester (50 mg, 0.18 mmol) in DMF (10 mL) were added 3-Bromomethyl-4,6-dimethyl-benzo[d]isothiazole, CAS: 3-Bromomethyl-4,6-dimethyl-1,2-benzisothiazole (69.5 mg, 0.27 mmol) and K2CO3 (50 mg, 0.36 mmol) at room temperature under nitrogen atmosphere. The solution was heated to 100 C for 2 hours. The solution was cooled down and water was added. The solution was extracted with EtOAc and the combined organic layer was dried with MgSO4. The solution was filtered and the filtrate was concentrated. The residue was purified by CombiFlash with 20% EtOAc in Hexane as the eluent to afford the desirable product 3-[3-(4,6-Dimethyl-1,2-benzisothiazol-3-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoic acid ethyl ester (45 mg, 55%) as colorless foam.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:14](Cl)=[O:15])[CH2:11][C:10]2([CH3:13])[CH3:12])=[CH:5][CH:4]=1.Cl.[NH2:18][C:19]1[N:24]=[C:23]([C:25]2[CH:30]=[CH:29][C:28]([S:31]([NH:34][CH3:35])(=[O:33])=[O:32])=[CH:27][CH:26]=2)[CH:22]=[CH:21][CH:20]=1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:14]([NH:18][C:19]3[CH:20]=[CH:21][CH:22]=[C:23]([C:25]4[CH:26]=[CH:27][C:28]([S:31](=[O:33])(=[O:32])[NH:34][CH3:35])=[CH:29][CH:30]=4)[N:24]=3)=[O:15])[CH2:11][C:10]2([CH3:13])[CH3:12])=[CH:5][CH:4]=1
Reactant: CNS(=O)(=O)c1ccc(-c2cccc(N)n2)cc1
Reactant: COc1ccc(C2(C(=O)Cl)CC2(C)C)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CNS(=O)(=O)c1ccc(-c2cccc(NC(=O)C3(c4ccc(OC)cc4)CC3(C)C)n2)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
1-(4-Methoxyphenyl)-2,2-dimethylcyclopropanecarbonyl chloride (0.20 mmol) was added to a solution of 4-(6-aminopyridin-2-yl)-N-methylbenzenesulfonamide HCl salt (60 mg, 0.20 mmol) in pyridine (1 mL) at room temperature. The reaction was stirred at 60° C. overnight and then was concentrated, dissolved in DMSO and purified by LC-MS to yield 1-(4-methoxyphenyl)-2,2-dimethyl-N-(6-(4-(N-methylsulfamoyl)-phenyl)pyridin-2-yl)cyclo-propanecarboxamide. ESI-MS m/z calc. 465.2. found 466.5 (M+1)+. Retention time 1.98 minutes.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[N:11]=1.Cl[C:18]([O:20][CH3:21])=[O:19].O>O1CCCC1>[F:9][C:10]1[C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:14][CH:13]=[C:12]([F:16])[N:11]=1
Reactant: COC(=O)Cl
Reactant: Fc1cccc(F)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(F)nc1F
Reaction time: 3 h
Yield: 43.2 %

Procedure:
To a stirred solution of 91 ml (0.182 mol) of 2.0 molar lithium diisopropylamide (in hexanes) in 200 mL dry tetrahydrofuran cooled to -70° under nitrogen was added dropwise a solution of 20.0 g of 2,6-difluoropyridine (0.174 mol) in 75 mL dry tetrahydrofuran such that the temperature was maintained below -60°. The solution was stirred at -70° for 3 hours and was then added via a cannula to a solution 21.7 g (0.230 mol) of methyl chloroformate in 100 mL dry tetrahydrofuran cooled to -70° under nitrogen. After stirring another hour at -70°, the mixture was poured into water and extracted with ether. The combined organic layers were washed with brine, dried over magnesium sulfate, and evaporated to a semisolid which was purified by flash chromatography to afford 13.0 g (43%) orange oil: NMR (CDCl3, 200 MHz) 3.95 (3H, s), 6.9 (1H, m), 8.5 (1H, m); IR (neat) 1745, 1730, 1610, 1415, 1290 cm-1.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][N:2]1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][C:21]3[C:27]([CH:28]([CH3:30])[CH3:29])=[CH:26][C:25]([C:31]#[N:32])=[CH:24][C:22]=3[N:23]=2)=[CH:15][CH:14]=1)=[O:12].C(=O)([O-])[O-].[K+].[K+].Cl[C:40]1[N:45]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:43]=[CH:42][N:41]=1>CO>[CH:28]([C:27]1[C:21]2[O:20][C:19]([C:16]3[CH:15]=[CH:14][C:13]([C:11]([N:2]4[CH2:3][CH2:4][C:5]5([CH2:10][CH2:9][N:8]([C:40]6[N:45]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:43]=[CH:42][N:41]=6)[CH2:7][CH2:6]5)[CH2:1]4)=[O:12])=[CH:18][CH:17]=3)=[N:23][C:22]=2[CH:24]=[C:25]([C:31]#[N:32])[CH:26]=1)([CH3:30])[CH3:29]
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)N4CCC5(CCNCC5)C4)cc3)oc12
Reactant: FC(F)(F)c1ccnc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)N4CCC5(CCN(c6nccc(C(F)(F)F)n6)CC5)C4)cc3)oc12
Temperature: 50 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
To a solution of 2-[4-(2,8-diazaspiro[4.5]dec-2-ylcarbonyl)phenyl]-7-isopropyl-1,3-benzoxazole-5-carbonitrile (25 mg, 0.046 mmol) in methanol (2 ml) were added potassium carbonate (13 mg, 0.094 mmol) and 2-chloro-4-(trifluoromethyl)pyrimidine (10 μl, 0.083 mmol). The mixture was heated to 50° C. and stirred at this temperature overnight, at which point LC/MS analysis showed a peak at the desired molecular weight. The reaction mixture was purified by flash chromatography on a Biotage Horizon, 25S column, eluting with 1 column volume of 100% dichloromethane followed by a gradient of 0 to 100% ethyl acetate in dichloromethane over 10 column volumes to provide the title compound (17.4 mg, 0.030 mmol, 65.7% yield). Mass spectrum (ESI) 575.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:27]3[CH2:31]CC[CH2:28]3)[N:9]=[C:10]([C:11]3[CH:12]=[C:13]4[C:17](=[CH:18][CH:19]=3)[N:16](C(OC(C)(C)C)=O)[CH:15]=[CH:14]4)[C:3]=12.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:16]1[C:17]2[C:13](=[CH:12][C:11]([C:10]3[C:3]4[C:4](=[N:5][CH:6]=[N:7][C:2]=4[NH2:1])[N:8]([CH:27]([CH3:31])[CH3:28])[N:9]=3)=[CH:19][CH:18]=2)[CH:14]=[CH:15]1
Reactant: CC(C)(C)OC(=O)n1ccc2cc(-c3nn(C4CCCC4)c4ncnc(N)c34)ccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)n1nc(-c2ccc3[nH]ccc3c2)c2c(N)ncnc21

Procedure:
Tert-butyl 5-(4-amino-1-cyclopentyl-1H-pyrazolo[3,4-d]pyrimidin-3-yl)-1H-indole-1-carboxylate (BA88) was dissolved in 50:50 CH2Cl2:TFA and stirred for one hour at room temperature. The reaction mixture was concentrated in vacuo and purified using by RP-HPLC (MeCN:H2O:0.1% TFA) to yield BA89 (6.3 mg). ESI-MS (M+H)+ m/z calcd 319.1, found 319.2.
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:16]([N:18]2[CH2:23][CH2:22][CH:21]([C:24]([O:26]CC)=[O:25])[CH2:20][CH2:19]2)=[O:17])=[CH:4][CH:3]=1.[OH-].[Li+]>C1COCC1.O.C(OCC)C>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[C:16]([N:18]2[CH2:19][CH2:20][CH:21]([C:24]([OH:26])=[O:25])[CH2:22][CH2:23]2)=[O:17])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CCN(C(=O)c2nc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1CCN(C(=O)c2nc3ccccc3n2Cc2ccc(Cl)cc2)CC1
Reaction time: 2 h

Procedure:
ethyl 1-(1-(4-chlorobenzyl)-1H-benzo[d]imidazole-2-carbonyl)piperidine-4-carboxylate (60 mg, 0.141 mmol) and lithium hydroxide, H2O (23.65 mg, 0.564 mmol) were dissolved in THF (Ratio: 1.000, Volume: 0.25 ml) and Water (Ratio: 2, Volume: 0.500 ml). The reaction was stirred for two hours before it was diluted with water and diethyl ether. The aqueous phase was washed with diethyl ether twice. It was then acidified to pH ˜2 and extracted with ethyl acetate. The organic phase was washed with saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated to obtain crude acid. No further purification was performed. (Yield: 54 mg, white solid). 1H-NMR (400 MHz, DMSO-d6) 12.28, 7.65, 7.36-7.18, 5.51, 4.36-4.27, 3.91-3.82, 3.12, 2.96, 1.92-1.83, 1.74-1.63, 1.50-1.17
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([N:26]2[CH2:25][CH2:24][N:23]([CH:22]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[C:19]3[CH:18]=[CH:17][C:16]([F:15])=[CH:21][CH:20]=3)[CH2:28][CH2:27]2)=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1
Reactant: Fc1ccc(C(c2ccc(F)cc2)N2CCNCC2)cc1
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c([N+](=O)[O-])c1
Temperature: 80 °C

Procedure:
Methyl 4-fluoro-3-nitrobenzoate Compound 3a (1.0 g, 5.02 mmol) (prepared as described in Nicolaou, et al., Bioorg. Med. Chem., 1998, 1185), 1-[bis(4-fluorophenyl)methyl]piperazine Compound 3b (1.59 g, 5.52 mmol) and potassium carbonate (0.76 g, 5.52 mmol) were dissolved in N,N-Dimethylformamide (15 mL) and heated to about 80° C. for about 5 h then cooled to rt. The reaction mixture was diluted with ethyl acetate (100 mL), washed with brine (2×50 mL) and water (2×50 mL), then dried over Na2SO4, filtered and concentrated in vacuo to give 4-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-3-nitro-benzoic acid methyl ester Compound 3c (2.4 g) as a yellow foam. MS m/z 468 (M+H). A mixture of the nitro substituted methyl ester Compound 3c (2.4 g, 5.13 mmol) and tin (II) chloride dihydrate (11.60 g, 51.34 mmol) was stirred in DMF (50 mL) for about 1 h. The reaction was diluted with ethyl acetate (100 mL), washed with brine (2×100 mL) and water (3×150 mL), then dried over Na2SO4, filtered and concentrated in vacuo to give 3-amino-4-{4-[bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-benzoic acid methyl ester Compound 3d (1.88 g) as a yellow foam. MS m/z 438 (M+H). A mixture of the amino substituted methyl ester Compound 3d (1.88 g, 4.30 mmol) and phenyl isocyanate Compound 3e (0.51 g, 4.30 mmol) was stirred in diethyl ether (50 mL) for about 18 h. The precipitate was collected by filtration, then washed with ether and hexane to provide Compound 11 (1.80 g) as an off-white solid. MS m/z 559 (M+H). A solution of Compound 11 (0.45 g, 0.81 mmol) and LiAlH4 in THF (1.0 M, 1 mL, 1.0 mmol) in THF (10 mL) was stirred for about 18 h. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with water (2×75 mL), dried over Na2SO4, filtered and concentrated in vacuo to give Compound 10 (0.31 g) as a white solid. MS m/z 529 (M+H).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22](O)=[O:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:25]([NH:27][NH2:28])=[O:26].ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH:25]([NH:27][NH:28][C:22]([C:16]1([C:13]2[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[CH:15][CH:14]=2)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=[O:23])=[O:26]
Reactant: O=C(O)C1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Reactant: NNC=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=CNNC(=O)C1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Yield: 171.6 %

Procedure:
4-[4-(3-Pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carboxylic acid (0.75 g, 0.225 mmol), formic hydrazide (0.162 g, 0.27 mmol), 1-hydroxybenzotriazole (0.304 g, 0.225 mmol), diisopropylethylamine (1.18 mL, 0.68 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.431 g, 0.225 mmol) in dichloromethane (10 mL) was stirred at room temperature for 18 hours. The reaction mixture was diluted with dichloromethane (100 mL) and washed with water (2×20 mL) The organics were dried over sodium sulphate, filtered and concentrated in vacuo to provide a cream solid. This was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (95:5:0.5 to 90:10:1) to provide the title compound (0.145 g, 17%) as a clear oil. LRMS ESI+ m/z 376 [MH]+, ESI− m/z 374 [M−H+]−.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([NH:21][C:22]2[CH:23]=[C:24]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:25]=[CH:26][C:27]=2[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:20])=[CH:15][CH:14]=1.O.NN>CCO>[NH2:3][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([NH:21][C:22]2[CH:23]=[C:24]([C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:25]=[CH:26][C:27]=2[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:20])=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1NC(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1NC(=O)c1ccc(CN)cc1

Procedure:
1,1-dimethylethyl {3-[({4-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}carbonyl)amino]biphenyl-4-yl}carbamate (17 g, 31 mmol) and hydrazine hydrate (3.01 mL, 62.1 mmol) were stirred in refluxing EtOH (135 mL) for 5 hours. Room temperature was attained and the white precipitate removed by filtration and washed with EtOH. The filtrate was concentrated in vacuo and purified by MPLC (10% [MeOH+1% NH4OH]-DCM) to give 1,1-dimethylethyl [3-({[4-(aminomethyl)phenyl]carbonyl}amino)biphenyl-4-yl]carbamate as a white solid. 1H NMR (d6-DMSO, 600 MHz) δ 9.86 (s, 1H), 8.77 (s, 1H), 7.90 (d, J=7.8 Hz, 2H), 7.85 (d, J=1.8 Hz, 1H), 7.62 (m, 3H), 7.49 (m, 3H), 7.44 (t, J=7.5 Hz, 2H), 7.33 (t, J=7.5 Hz, 1H), 3.79 (s, 2H), 1.45 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([O:8][CH3:9])=[C:4]([CH:10]([OH:13])[CH2:11][CH3:12])[CH:3]=1>O1CCCC1.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[N:7]=[N:6][C:5]([O:8][CH3:9])=[C:4]([C:10](=[O:13])[CH2:11][CH3:12])[CH:3]=1
Reactant: CCC(O)c1cc(Cl)nnc1OC
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: CCC(=O)c1cc(Cl)nnc1OC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
12.25 g 1-(6-Chloro-3-methoxy-pyridazin-4-yl)-propan-1-ol is dissolved in 410 ml tetrahydrofuran and 105 g of manganese dioxide is added. The reaction is stirred for 24 h at RT. Solids are removed by filtration, and the solution is treated with a further 105 g of manganese dioxide for 16 h at RT. Solids are removed by filtration, and the solvent is removed under reduced pressure. The product is purified by silica gel chromatography, eluting with a gradient of ethyl acetate in heptane. Yield 3.25 g. LC-MS (ES+) 201 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[N:11]([CH3:28])[C:10]=1[C:29]([OH:31])=[O:30])C1C=CC=CC=1.C1(S(C(N)C2N(C)C(C(O)=O)=C(O)C(=O)C=2)(=O)=O)C=CC=CC=1>>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([S:18]([NH:17][CH2:16][C:12]2[N:11]([CH3:28])[C:10]([C:29]([OH:31])=[O:30])=[C:9]([OH:8])[C:14](=[O:15])[CH:13]=2)(=[O:19])=[O:20])=[CH:22][CH:23]=1
Reactant: Cn1c(CNS(=O)(=O)c2ccc(Cl)cc2)cc(=O)c(OCc2ccccc2)c1C(=O)O
Agent: Cn1c(C(N)S(=O)(=O)c2ccccc2)cc(=O)c(O)c1C(=O)O
Product: Cn1c(CNS(=O)(=O)c2ccc(Cl)cc2)cc(=O)c(O)c1C(=O)O
Yield: 31.6 %

Procedure:
6-[(4-Chloro-benzenesulfonylamino)-methyl]-3-hydroxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (14-07) (140.0 mg, 31.55%) was synthesized as a brown solid from 3-benzyloxy-6-[(4-chloro-benzenesulfonylamino)-methyl]-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (13-07) (550.0 mg, 1.19 mmol) following the procedure described for 6-(benzenesulfonylamino-methyl)-3-hydroxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (14-01).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:5]([C:6](=[O:12])[NH:7][C:8](=O)[CH:9]=2)[CH2:4][CH2:3]1.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:8]1[CH:9]=[C:10]2[N:2]([CH3:1])[CH2:3][CH2:4][N:5]2[C:6](=[O:12])[N:7]=1
Reactant: CN1CCn2c1cc(=O)[nH]c2=O
Reactant: O=P(Cl)(Cl)Cl
Product: CN1CCn2c1cc(Cl)nc2=O
Temperature: 90 °C
Reaction time: 6 h
Yield: 92.4 %

Procedure:
A suspension of 1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidine-5,7(1H,6H)-dione (0.41 g, 2.45 mmol) in POCl3 (15 mL, 161 mmol) was stirred at 90° C. for 6 h. The suspension was concentrated in vacuo to remove all of POCl3. Cold water was added to the resultant residue, and then solid NaOH was added dropwise to adjust pH to ˜12. The solution was stirred at rt for 2 h. Aqueous HCl was added to adjust pH to ˜7. Purification via Mass Directed AutoPrep (MDAP) afforded the title compound as a white solid (0.42 g, 93% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@:8]2([CH3:18])[CH2:14][C:13]([CH3:16])([CH3:15])[O:12][CH2:11][C:10](=[S:17])[NH:9]2)[CH:7]=1.[Cl:20][C:21]1[C:22]([C:31](O)=[O:32])=[N:23][CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1>>[F:19][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:31]([C:22]2[C:21]([Cl:20])=[CH:26][C:25]([C:27]([F:29])([F:28])[F:30])=[CH:24][N:23]=2)=[O:32])=[CH:7][C:6]=1[C@:8]1([CH3:18])[CH2:14][C:13]([CH3:16])([CH3:15])[O:12][CH2:11][C:10](=[S:17])[NH:9]1
Reactant: O=C(O)c1ncc(C(F)(F)F)cc1Cl
Reactant: CC1(C)C[C@@](C)(c2cc(N)ccc2F)NC(=S)CO1
Product: CC1(C)C[C@@](C)(c2cc(NC(=O)c3ncc(C(F)(F)F)cc3Cl)ccc2F)NC(=S)CO1
Yield: 61 %

Procedure:
The compound was prepared in an analogous manner as described for intermediate B14A from (S)-5-(5-amino-2-fluoro-phenyl)-5,7,7-trimethyl-[1,4]oxazepane-3-thione (intermediate A17A) (106 mg, 0.38 mmol) and commercially available 3-chloro-5-(trifluoromethyl)pyridine-2-carboxylic acid [CAS No. 80194-68-9] (100 mg, 0.44 mmol). The compound was obtained as light yellow foam (133 mg, 61%). MS (ISP): m/z=490.2 [(M+H)+] and 492.3 [(M+2+H)+].