Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]([NH:12][C:13]1[CH:42]=[CH:41][C:16]([O:17][C:18]2[CH:23]=[CH:22][N:21]=[C:20]3[CH:24]=[C:25]([C:27]([NH:29][CH2:30][CH2:31][CH2:32][NH:33]C(=O)OC(C)(C)C)=[O:28])[S:26][C:19]=23)=[CH:15][CH:14]=1)=[O:11].FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:33][CH2:32][CH2:31][CH2:30][NH:29][C:27]([C:25]1[S:26][C:19]2[C:20](=[N:21][CH:22]=[CH:23][C:18]=2[O:17][C:16]2[CH:15]=[CH:14][C:13]([NH:12][C:10]([NH:9][C:3]3[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=3[F:1])=[O:11])=[CH:42][CH:41]=2)[CH:24]=1)=[O:28]
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)NCCCNC(=O)OC(C)(C)C)sc34)cc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Oc3ccnc4cc(C(=O)NCCCN)sc34)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of tert-butyl {3-[({7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridin-2-yl}carbonyl)amino]propyl}carbamate (380 mg, 0.64 mmol) in 10 ml of methylene chloride was added 5 ml of trifluoroacetic acid. The mixture was stirred at room temperature for 30 minutes and evaporated to dryness under reduced pressure. The residue was re-dissolved in MeOH (5 ml) and poured into 100 ml of water with vigorous stirring. Saturated NaHCO3 solution was added until pH=8˜9. The precipitates were filtered, washed with water and dried in vacuo to give N-(3-aminopropyl)-7-[4-({[(2-fluoro-5-methylphenyl)amino]carbonyl}amino)phenoxy]thieno[3,2-b]pyridine-2-carboxamide as yellow solid. Yield: 270 mg, 85%.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8](=[O:19])[C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=2[OH:18])[CH2:3][CH2:2]1.[H][H]>C(O)C.[Pd]>[O:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8](=[O:19])[C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][C:10]=2[OH:18])[CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: O=C(OC1CCOCC1)c1ccc([N+](=O)[O-])cc1O
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(C(=O)OC2CCOCC2)c(O)c1
Yield: 35.1 %

Procedure:
2-Hydroxy-4-nitro-benzoic acid tetrahydro-pyran-4-yl ester (0.32 g, 1.20 mmol) was hydrogenated in ethanol (25 mL) with 10% palladium on charcoal catalyst (70 mg) until hydrogen uptake ceased. The mixture was filtered through Celite and concentrated to give a residue which was purified by flash column chromatography on silica, eluting with ethyl acetate/petroleum ether (5-35% gradient) to give 4-amino-2-hydroxy-benzoic acid tetrahydro-pyran-4-yl ester (100 mg, 35%).
Reaction SMILES: [C:1]1([CH:7]2[CH2:10][CH:9]([OH:11])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]([O:16][C:17]([N:19]1[CH2:22][CH:21]([O:23][C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=2O)[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(C=P(CCCC)(CCCC)CCCC)#N>C1(C)C=CC=CC=1>[C:12]([O:16][C:17]([N:19]1[CH2:22][CH:21]([O:23][C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=2[O:11][CH:9]2[CH2:8][CH:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:10]2)[CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: OC1CC(c2ccccc2)C1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(Cl)ccc2O)C1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC(Oc2cc(Cl)ccc2OC2CC(c3ccccc3)C2)C1
Temperature: 120 °C
Yield: 51.7 %

Procedure:
The mixture of the title compound of Step A (80 mg), 3-(5-chloro-2-hydroxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (200 mg) and cyanomethylenetri-n-butylphosphorane (1.0 mmol) in toluene (2 mL) was heated at 120° C. in a microwave reactor for 1 h. The mixture was cooled to rt and purified via PTLC providing 3-[5-chloro-2-(3-phenyl-cyclobutoxy)-phenoxy]-azetidine-1-carboxylic acid tert-butyl ester (120 mg). The ester was re-dissolved into CH2Cl2 (10 mL), and TFA (2 mL) was added. The mixture was stirred at rt for 4 h then concentrated to give the title compound (168 mg). MS (ESI): mass calcd. for C19H20ClNO2, 329.1; m/z found, 330.1 [M+H]+. 1H NMR (MeOD): 7.26-6.64 (m, 8H), 5.30-5.15 (m, 2H), 4.95-4.83 (m, 2H), 4.60-4.52 (m, 1H), 3.78-3.65 (m, 1H), 2.68-2.58 (m, 4H).
Reaction SMILES: [CH:1]1([N:4]([CH2:29][C:30]2[CH:35]=[C:34]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:33]=[C:32]([O:41][CH2:42][CH2:43][O:44][CH3:45])[CH:31]=2)[C:5]([C@H:7]2[C@H:12]([C:13]3[CH:18]=[CH:17][N:16]([CH2:19][CH3:20])[C:15](=[O:21])[CH:14]=3)[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]2)=[O:6])[CH2:3][CH2:2]1.Cl>C(Cl)Cl>[CH:1]1([N:4]([CH2:29][C:30]2[CH:35]=[C:34]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[CH:33]=[C:32]([O:41][CH2:42][CH2:43][O:44][CH3:45])[CH:31]=2)[C:5]([C@H:7]2[C@H:12]([C:13]3[CH:18]=[CH:17][N:16]([CH2:19][CH3:20])[C:15](=[O:21])[CH:14]=3)[CH2:11][CH2:10][NH:9][CH2:8]2)=[O:6])[CH2:3][CH2:2]1
Reactant: CCn1ccc([C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2C(=O)N(Cc2cc(CCCOC)cc(OCCOC)c2)C2CC2)cc1=O
Agent: Cl
Solvent: ClCCl
Product: CCn1ccc([C@@H]2CCNC[C@H]2C(=O)N(Cc2cc(CCCOC)cc(OCCOC)c2)C2CC2)cc1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a CH2Cl2 solution (0.07 M) of trans-1,1-dimethylethyl 3-{[cyclopropyl({3-{[2-(methyloxy)ethyl]oxy}-5-[3-(methyloxy)propyl]phenyl}methyl)amino]carbonyl}-4-(1-ethyl-2-oxo-1,2-dihydro-4-pyridinyl)-1-piperidinecarboxylate (1 eq.) from the previous step was added HCl (4.0 M dioxane solution, 30 eq.). The resulting solution was stirred at RT for 3 h. Following the removal of the volatiles in vacuo, the resulting residue was directly loaded onto a SiO2 column packed with 93:7 (v/v) CH2Cl2:2.0 M NH3 in MeOH. Elution with the same solvent system furnished the title compound as a white froth. MS (ESI+, M+H): 526. Human Renin IC50 (buffer): 200 nM. Human Renin IC50 (plasma): 460 nM.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C@:9]([CH2:14][CH2:15][C:16]#[N:17])([C:11]([OH:13])=[O:12])[CH3:10])=O)=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C>C1C=CC=CC=1>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]2[O:12][C:11](=[O:13])[C:9]([CH2:14][CH2:15][C:16]#[N:17])([CH3:10])[N:8]=2)=[CH:4][CH:3]=1
Reactant: C[C@](CCC#N)(NC(=O)c1ccc(Cl)cc1)C(=O)O
Solvent: c1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CC1(CCC#N)N=C(c2ccc(Cl)cc2)OC1=O
Yield: 80.1 %

Procedure:
2.8 g of N-(p-chlorobenzoyl)-2-(2-cyanoethyl)alanine and 2.0 g of acetic anhydride were dissolved in 30 ml of benzene and the solution was refluxed for one hour. The solvent was then distilled off and the resulting residue was recrystallized from di-isopropyl ether, to afford 2.1 g of the desired product as a colourless powder melting at 97°-98° C.
Reaction SMILES: [NH2:1][CH:2]([C:4]1[CH:5]=[C:6]([C:21]([N:23]([CH3:25])[CH3:24])=[O:22])[CH:7]=[C:8]2[C:13]=1[O:12][C:11]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[CH:10][C:9]2=[O:20])[CH3:3].Br[C:27]1[CH:28]=[C:29]([CH:32]=[C:33]([F:35])[CH:34]=1)[C:30]#[N:31]>>[C:30]([C:29]1[CH:28]=[C:27]([NH:1][CH:2]([C:4]2[CH:5]=[C:6]([C:21]([N:23]([CH3:24])[CH3:25])=[O:22])[CH:7]=[C:8]3[C:13]=2[O:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][C:9]3=[O:20])[CH3:3])[CH:34]=[C:33]([F:35])[CH:32]=1)#[N:31]
Reactant: N#Cc1cc(F)cc(Br)c1
Reactant: CC(N)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Product: CC(Nc1cc(F)cc(C#N)c1)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Yield: 81.7 %

Procedure:
8-(1-aminoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (300 mg, 0.87 mmol, [α]D20°: +35° in acetonitrile) was reacted with 3-bromo-5-fluorobenzonitrile (382 mg, 1.91 mmol) using a procedure similar to the one described in Example 8.00. Purification was done by flash chromatography on silica gel eluting with 0 to 5% MeOH in DCM followed by preparative HPLC on a Waters X-Bridge system. The fractions containing the desired compound were evaporated to dryness to afford 8-(1-(3-cyano-5-fluorophenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (330 mg, 82%) as a clear white solid. Mass Spectrum: M+H+ 465.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]1[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)=[C:17]2[C:12]([N:13]([CH3:29])[C:14](=[O:28])[N:15]([CH3:27])[C:16]2=[O:26])=[CH:11]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][CH2:9][N:10]1[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=2)=[C:17]2[C:12]([N:13]([CH3:29])[C:14](=[O:28])[N:15]([CH3:27])[C:16]2=[O:26])=[CH:11]1
Reactant: Cn1c(=O)c2c(-c3cccc(Cl)c3)n(CCNC(=O)OC(C)(C)C)cc2n(C)c1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(=O)c2c(-c3cccc(Cl)c3)n(CCN)cc2n(C)c1=O
Reaction time: 2 h

Procedure:
{2-[5-(3-Chloro-phenyl)-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrrolo[3,4-d]pyrimidin-6-yl]-ethyl}-carbamic acid tert-butyl ester (step 5) (429 mg, 0.991 mmol) was dissolved in DCM (10 ml). TFA (1.374 ml, 17.84 mmol) was charged in 2 portions and the reaction stirred under nitrogen. After 2 hrs, the pH of the mixture was adjusted to pH 11 with saturated K3CO3 solution (20 mL). The layers were separated and the aqueous extracted with DCM (4×20 mL). The combined organics were passed through a hydrophobic frit and evaporated under reduced pressure to afford a tan solid, which was dried under vacuum at 50° C. for 5 h to afford the title compound as a tan solid.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:14]2[O:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=1.[CH3:19][CH:20]1[NH:24][C:23](=O)[CH2:22][CH2:21]1.P(Cl)(Cl)(Cl)=O>>[CH3:19][CH:20]1[N:24]=[C:23]([N:6]2[C:5]3[CH:4]=[C:3]([C:2]([F:1])([F:17])[F:18])[CH:16]=[CH:15][C:14]=3[O:13][C:12]3[C:7]2=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:22][CH2:21]1
Reactant: CC1CCC(=O)N1
Reactant: FC(F)(F)c1ccc2c(c1)Nc1ccccc1O2
Solvent: O=P(Cl)(Cl)Cl
Product: CC1CCC(N2c3ccccc3Oc3ccc(C(F)(F)F)cc32)=N1

Procedure:
Reaction of 2-(trifluoromethyl)phenoxazine, 5-methyl-2-pyrrolidinone and phosphorus oxychloride according to the procedure of Example 1 provides the free base 10-(5-METHYL-1-PYRROLIN-2-YL)-2-(TRIFLUOROMETHYL)PHENOXAZINE as a distillable oil, b.p. 145°-152° C. at 0.03 mm Hg. Conversion of the free base to the hydrochloride salt affords 10-(5-METHYL-1-PYRROLIN-2-YL)-2-(TRIFLUOROMETHYL)PHENOXAZINE HYDROCHLORIDE, m.p. 192.5°-195.5° C. (dec.) (corr.)., in a 45% overall yield.
Reaction SMILES: Br[C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[C:14]=3[Cl:23])=[O:12])[CH2:10][C:5]2=[N:4][N:3]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:30]1(B(O)O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>COCCOC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:23][C:14]1[C:15]([C:19]([F:22])([F:21])[F:20])=[CH:16][CH:17]=[CH:18][C:13]=1[C:11]([N:9]1[CH2:8][CH2:7][N:6]2[C:2]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:3][N:4]=[C:5]2[CH2:10]1)=[O:12]
Reactant: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2c(Br)nnc2C1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2c(nnc2-c2ccccc2)C1

Procedure:
To 3-bromo-7-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine (0.150 g, 0.366 mmol, e.g. see Example 1 for methods of preparation) in 1,2-dimethoxyethane (DME) (3 mL) was added aqueous sodium carbonate solution (1.9 mL, 1 M) followed by phenylboronic acid (0.067 g, 0.549 mmol, commercially available e.g. from Sigma-Aldrich or Strem Chemicals) and dichlorobis(triphenylphosphine)palladium(II) (0.013 g, 0.018 mmol). The reaction mixture was heated at reflux for 7 hours. The mixture was diluted with water (10 mL) and extracted with ethyl acetate (twice). The combined organic fractions were dried, filtered and evaporated. An attempt to purify the crude material on silica gel chromatography using methanol in Dichloromethane (0-20%) as eluent was unsuccessful. The residue was then purified using mass-directed automated (preparative) HPLC (MDAP) to give 7-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-3-phenyl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine (0.076 g) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([OH:13])=[C:8]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:7]([CH3:20])=[CH:6]2.F[C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[O:27])=[CH:24][CH:23]=1)=[C:8]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:7]([CH3:20])=[CH:6]2
Reactant: O=Cc1ccc(F)cc1
Reactant: COc1ccc2c(O)c(-c3ccccc3)c(C)cc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc2c(Oc3ccc(C=O)cc3)c(-c3ccccc3)c(C)cc2c1
Temperature: 25 °C
Yield: 97.4 %

Procedure:
A round-bottomed flask was charged with 3-methyl-6-(methyloxy)-2-phenyl-1-naphthalenol (7) (2.5 g, 9.5 mmol), 4-fluorobenzaldehyde (1.22 mL, 11.4 mmol), Cs2CO3 (4.04 g, 12.4 mmol), and anhydrous DMF (25 mL) under N2. The reaction mixture was refluxed for 3 h. Reaction mixture was cooled at room temperature and purified by SiO2 column chromatography using hexanes:EtOAc (19:1 to 4:1) as an eluent to afford 3.41 g (98%) of the title compound as a white foam. 1H NMR (400 MHz, CDCl3): δ 9.80 (s, 1H), 7.68 (d, J=9.2 Hz, 1H), 7.62 (d, J=8.4 Hz, 2H), 7.61 (d, J=5.2 Hz, 1H), 7.25 (d, J=7.6 Hz, 2H), 7.22 (d, J=5.2 Hz, 1H), 7.15 (d, J=2.4 Hz, 1H), 7.14 (d, J=1.6 Hz, 1H), 7.11 (s, 1H), 7.07 and 7.04 (dd, J1=9.2 Hz, J2=2.4 Hz, 1H), 6.71 (d, J=8.8 Hz, 2H), 3.94 (s, 3H), 2.26 (s, 3H). LCMS (ESI) m/z, 368.92 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[S:13][C:12]([C@:14]3([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[S:20](=[O:22])(=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)[CH3:2].N1C=CC=CC=1.[CH2:37]([S:40](Cl)(=[O:42])=[O:41])[CH2:38][CH3:39]>C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[S:13][C:12]([C@:14]3([CH2:23][C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[S:20](=[O:22])(=[O:21])[CH2:19][CH2:18][N:17]([S:40]([CH2:37][CH2:38][CH3:39])(=[O:42])=[O:41])[CH2:16][CH2:15]3)=[CH:11][CH:10]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(-c2ccc([C@@]3(CC(=O)OC(C)(C)C)CCNCCS3(=O)=O)s2)cc1
Reactant: CCCS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CCCS(=O)(=O)N1CC[C@](CC(=O)OC(C)(C)C)(c2ccc(-c3ccc(CC)cc3)s2)S(=O)(=O)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 39919.5 %

Procedure:
To a solution of tert-butyl 2-[(S)-7-[5-(4-ethylphenyl)-2-thienyl]-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetate (7.91 g) and pyridine (30 ml) in chloroform (15 ml) was added a solution of propanesulfonyl chloride (5.02 mg) in chloroform (15 ml) at 0° C. The resulting mixture was stirred for 3 hours at 0° C. Ethyl acetate (200 ml) was added and the solution was washed with 1N hydrochloric acid (150 ml) for two times, saturated sodium bicarbonate, and brine, dried over magnesium sulfate and evaporated to give a brown gum. The gum was dissolved in ethyl acetate (75 ml) and silica gel (12 ml) was added to the solution. The silica gel was removed by filtration, and the resulting filtrate was evaporated. Silica gel column chromatography (eluent: ethyl acetate/hexane from 13/27 to 9/11) afforded tert-butyl 2-[(S)-7-[5-(4-ethylphenyl)-2-thienyl]-1,1-dioxoperhydro-4-propanesulfonyl-1,4-thiazepin-7-yl]acetate (7.81 g) as an yellowish solid.
Reaction SMILES: [C:1]([C:4]1[N:9]=[N:8][C:7]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[NH:17]C(=O)OC(C)(C)C)=[CH:6][C:5]=1[NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([OH:35])([CH3:34])[CH3:33])[N:27]=1)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:17][C@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]1[NH:10][C:7]1[N:8]=[N:9][C:4]([C:1]([NH2:2])=[O:3])=[C:5]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([OH:35])([CH3:33])[CH3:34])[N:27]=2)[CH:6]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cc(Nc2cccc(C(C)(C)O)n2)c(C(N)=O)nn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O)c1cccc(Nc2cc(N[C@@H]3CCCC[C@@H]3N)nnc2C(N)=O)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.2 %

Procedure:
To a solution of tert-butyl (1S,2R)-2-(6-carbamoyl-5-(6-(2-hydroxypropan-2-yl)pyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate (179 mg, 369 μmol) in CH2Cl2 (3.00 mL) was added TFA (1.48 g, 1.00 mL, 13.0 mmol) and mixture stirred to room temperature for 18 h. The solvent was evaporated and the residue purified by flash chromatography (spherical silica 20-45 μM, 23 g, Versaflash Supelco) eluting with 0 to 5% over 20 min (MeOH containing 10% NH4OH)/CH2Cl2 to give 6-((1R,2S)-2-aminocyclohexylamino)-4-(6-(2-hydroxypropan-2-yl)pyridin-2-ylamino)pyridazine-3-carboxamide (80 mg, 56.3% yield) as an off-white foam. 1H NMR (DMSO-d6) δ: 11.76 (s, 1H), 8.38 (br. s., 1H), 7.90 (s, 1H), 7.60-7.78 (m, 2H), 7.23 (d, J=7.6 Hz, 1H), 6.70-6.83 (m, 2H), 5.18 (s, 1H), 3.70 (br. s., 1H), 3.09 (br. s., 1H), 1.21-1.77 (m, 16H); LC-MS 386.1 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:7][C:8]1[C:13]([CH2:14][OH:15])=[CH:12][C:11]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[C:10]([C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[N:9]=1)[CH2:4][CH2:5][CH3:6].[CH3:33]I>O>[CH2:3]([O:7][C:8]1[C:13]([CH2:14][O:15][CH3:33])=[CH:12][C:11]([C:16]2[CH:17]=[CH:18][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:20][CH:21]=2)=[C:10]([C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[N:9]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CI
Reactant: CCCCOc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)cc1CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCCCOc1nc(-c2ccc(F)cc2)c(-c2ccc(S(C)(=O)=O)cc2)cc1COC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (11 mg 4.5 mMol) is added to a stirring solution of 2-butoxy-6-(4-fluorophenyl)-3-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]pyridine (50 mL). After 1 hour, methyl iodide (85 mg, 0.6 mMol) is added and the reaction mixture is stirred for 20 hours at room temperature. Water (1 mL) is added dropwise and the mixture is concentrated to an oily solid. The titled material is purified by silica gel chromatography.
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2]O.[Cl:6][C:7]1[CH:8]=[C:9]([NH2:22])[C:10]([NH:13][CH2:14][CH2:15][CH2:16][N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)=[CH:11][CH:12]=1.C([O-])(O)=O.[Na+].C(Cl)Cl>Cl.O>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]2[N:13]([CH2:14][CH2:15][CH2:16][N:17]3[CH:21]=[CH:20][N:19]=[CH:18]3)[C:2]([CH2:1][OH:5])=[N:22][C:9]=2[CH:8]=1
Reactant: O=C(O)CO
Reactant: Nc1cc(Cl)ccc1NCCCn1ccnc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: OCc1nc2cc(Cl)ccc2n1CCCn1ccnc1
Temperature: 90 °C
Yield: 29.3 %

Procedure:
Glycolic acid (1.98 g, 26 mmol, 3 eq.) was added to a solution of 4-chloro-N1-[3-(1H-imidazol-1-yl)propyl]benzene-1,2-diamine (12, 2.18 g, 8.7 mmol) in HCl (6N, 20 mL) at room temperature. The reaction mixture was heated up until 90° C. during 16 hours. After cooling to ambient temperature the reaction mixture was diluted with 100 mL water followed by addition of NaHCO3 until the pH was approximately 7. CH2Cl2 (30 ml) was added and the organic layer was separated and the aqueous layer was further extracted with additional CH2Cl2 (20 mL). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo and purified by flash chromatography (0 to 10% MeOH in CH2Cl2) to give {5-chloro-1-[3-(1H-imidazol-1-yl)propyl]-1H-benzimidazol-2-yl}methanol (13, 740 mg, 30%) as a white solid; LCMS m/z=291 (M+H)+
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:7]=[C:6]([Cl:8])[S:5][C:4]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH3:13][CH:14]([N:21]=[C:22]=S)[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19]>C(OCC)(=O)C>[Cl:8][C:6]1[S:5][C:4]2[S:9](=[O:10])(=[O:11])[N:12]=[C:22]([NH:21][CH:14]([CH3:13])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[NH:2][C:3]=2[CH:7]=1
Reactant: Nc1cc(Cl)sc1S(N)(=O)=O
Reactant: CC(C)CCCC(C)N=C=S
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)CCCC(C)NC1=NS(=O)(=O)c2sc(Cl)cc2N1

Procedure:
The title compound was prepared from 3-amino-5-chlorothiophene-2-sulfonamide hydrochloride and 1,5-dimethylhexyl isothiocyanate by a procedure analogous to the procedure described in example 3Bc-d; mp 197°-199° C. (ethyl acetate); 1H-NMR (DMSO-d6): δ 0.85 (d, 6H), 1.12 (d, 3H), 1.1-1.6 (m, 7H), 3.77 (m, 1H), 7.07 (s, 1H), 7.12 (br. s, 1H), 10.72 (br. s, 1H).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[C:6]([OH:12])[CH:5]=[CH:4][C:3]=1[C:13](=[O:17])[CH:14]([CH3:16])[CH3:15].C(OC(=O)[NH:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32]O)=[CH:28][CH:27]=1)(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[ClH:68].O1CCOCC1>C1(C)C=CC=CC=1>[ClH:68].[NH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][O:12][C:6]2[CH:5]=[CH:4][C:3]([C:13](=[O:17])[CH:14]([CH3:15])[CH3:16])=[C:2]([OH:1])[C:7]=2[C:8]([F:9])([F:10])[F:11])=[CH:28][CH:27]=1
Reactant: CC(C)C(=O)c1ccc(O)c(C(F)(F)F)c1O
Reactant: CC(C)(C)OC(=O)NCc1ccc(CO)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: CC(C)C(=O)c1ccc(OCc2ccc(CN)cc2)c(C(F)(F)F)c1O
Temperature: 25 °C
Yield: 78 %

Procedure:
Mechanically stir solutions of 1-(2,4-dihydroxy-3-trifluoromethyl-phenyl)-2-methyl-propan-1-one (211 g, 850.1 mmol), (4-hydroxymethyl-benzyl)-carbamic acid tert-butyl ester (195 g, 821.8 mmol), and triphenylphosphine (212 g; 808.3 mmol) in toluene (9 L) in two separate 22-L Morton flasks. Treat solutions with diisopropyl azodicarboxylate (183 mL, 923 mmol) over a 60 min period, then stir over the weekend at room temperature. Combine the solutions and evaporate to a brown oil. Dissolve the oil in 1,4-dioxane (8 L), treat with 4N hydrogen chloride solution in 1,4-dioxane (3 L, 12 mole), and heat to 92° C. for 6 hrs (out-gassing and precipitation is observed at 52° C. during the warm up period). Cool to room temperature, filter the resulting solid and wash with dioxane, 30% dioxane in hexanes, and hexanes to provide the title compound (510 g, 78% yield) as a tan solid. HPLC Rt=4.71 min; 1H NMR (DMSO-d6) δ 14.00 (s, 1H), 8.4 (bs, 3H), 7.50 (ABq, J=12.0, 8.0 Hz, 4H), 6.92 (d, J=8.0 Hz, 1H), 5.37 (s, 2H), 4.0 (m, 2H), 3.73 (hept, J=4.0 Hz, 1H), 1.12 (d, J=4.0 Hz, 6H); 19F NMR (DMSO-d6) δ-54.10; MS (m/z): 368.0 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([C:11]([OH:13])=O)=[CH:9][N:8]=[CH:7][CH:6]=1)=[O:4].S(Cl)([Cl:16])=O>>[CH3:1][O:2][C:3]([C:5]1[C:10]([C:11]([Cl:16])=[O:13])=[CH:9][N:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1ccncc1C(=O)O
Product: COC(=O)c1ccncc1C(=O)Cl

Procedure:
Following the procedure of Example 30, 4-methoxycarbonylnicotinic acid is reacted with thionyl chloride to give 4-methoxycarbonylnicotinoyl chloride. A slurry of the above chloride (22.7 mmol) in 100 ml of monoglyme (ethylene glycol dimethyl ether) is added to a chilled mixture of the sodium salt of diethyl malonate (2.2 eq.) in monoglyme. The mixture is allowed to warm to RT and is stirred at RT for 4 hours. Aq. sodium bicarbonate is added and the mixture is extracted with ether. It is then acidified to pH 2-3 and again extracted with ether. The combined organic phases of the acid layer are dried, filtered and concentrated to give methyl 3-(diethylmalonyl-carbonyl)-isonicotinate, which is then reacted with lithium hydroxide mono-hydrate and then hydrochloric acid to give 3-acetylisonicotinic acid.