Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[O:9]=[C:10](Cl)OC(Cl)(Cl)Cl.C(N(CC)CC)C>C1COCC1>[C:3]1(=[O:5])[O:4][C:10](=[O:9])[N:1]2[CH2:8][CH2:7][CH2:6][C@@H:2]12
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1OC(=O)N2CCC[C@@H]12
Temperature: 15 °C
Reaction time: 0.5 h
Yield: 165.3 %

Procedure:
L-Proline (11.5 g, 0.10 mol) was added to a 500 ml three neck flask fitted with a 125 ml addition funnel, thermometer and a nitrogen inlet tube. To the flask was added dry tetrahydrofuran (115 ml) and the mixture cooled to 15° C. using an ice/water bath. The addition funnel was charged with diphosgene (7.2 ml, 0.06 mol) and dry THF(50 ml). The diphosgene solution was added dropwise to the proline mixture over 45 minutes while maintaining a reaction mixture temperature in the range of 15° to 20° C. Once the addition was complete the mixture was warmed to 35° C. for 1 hour. At the end of this time a clear and colorless solution was obtained. The reaction mixture was then cooled to room temperature and concentrated under vacuum to a volume of approximately 50 ml. The residue was redissolved in 115 ml of THF and cooled to 0°-5° C. using an ice bath. Triethylamine (12 ml, 0.086 mol) was added dropwise to the cooled solution over 30 minutes. The solution was stirred a further 30 minutes after which time the solids were filtered and washed with THF(100 ml). The organics were concentrated under reduced pressure to give the desired compound (4) (14 g, 99%) as a light beige solid. The material was stored under nitrogen at -78° C. in order to avoid decomposition, and used without further purification in subsequent reactions.
Reaction SMILES: O.[C:2]1([CH3:12])[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.[NH2:14][C@H:15]([C:20]([OH:22])=[O:21])[CH2:16][CH:17]([CH3:19])[CH3:18].[CH2:23](O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:2]1([CH3:12])[CH:3]=[CH:4][C:5]([S:8]([OH:11])(=[O:9])=[O:10])=[CH:6][CH:7]=1.[CH2:23]([O:21][C:20](=[O:22])[C@H:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[NH2:14])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: OCc1ccccc1
Reactant: CC(C)C[C@H](N)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CC(C)C[C@H](N)C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 93.9 %

Procedure:
In a 200 ml 3 neck flask equipped with a Dean and Stark trap, reflux condenser (with drying tube attached), and mechanical stirrer, 15 grams (0.0789 mole) of p-toluenesulfonic acid monohydrate is refluxed until one equivalent of water is released. At this point 10 grams (0.07634 mole) leucine and 17.0 grams (0.15 mole) benzyl alcohol are added. The mixture is refluxed for 4 hours and allowed to cool to room temperature. The solvents are removed in vacuo and a white, solid residue is produced. The white solid is washed with anhydrous ether and recrystallized from ethanol/ether to yield in three crops 28.2 grams of leucine benzyl ester p-toluene sulfonate (94% yield) having a melting point of 157°-158° C. (with decomposition).
Reaction SMILES: [CH3:1][N:2]([C@H:9]1[CH2:14][CH2:13][CH2:12][C@@H:11]([O:15][C:16]2[C:17]([CH3:31])=[C:18]3[C:22](=[CH:23][CH:24]=2)[N:21](C2CCCCO2)[N:20]=[CH:19]3)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.O1CCOCC1>C(O)(C)C>[CH3:1][N:2]([C@H:9]1[CH2:14][CH2:13][CH2:12][C@@H:11]([O:15][C:16]2[C:17]([CH3:31])=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][N:20]=[CH:19]3)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1c(O[C@@H]2CCC[C@H](N(C)c3ccccc3)C2)ccc2c1cnn2C1CCCCO1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Product: Cc1c(O[C@@H]2CCC[C@H](N(C)c3ccccc3)C2)ccc2[nH]ncc12
Yield: 87.2 %

Procedure:
Under nitrogen, N-methyl-N-[cis-3-[(4-methyl-1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-yl)oxy]cyclohexyl]-N-phenylamine (89 mg, 0.212 mmol) was dissolved in isopropyl alcohol (4 ml), followed by adding thereto a 4N-hydrochloric acid/1,4-dioxane solution (4 ml), and the resulting mixture was stirred at room temperature for 22 hours. The solvent was distilled off under reduced pressure, and the residue was neutralized with aqueous ammonia and concentrated to dryness under reduced pressure. The resulting concentration residue was purified by a silica gel column chromatography (eluent: n-hexane/ethyl acetate=3/1) to obtain N-methyl-N-[cis-3-[(4-methyl-1H-indazol-5-yl)oxy]cyclohexyl]-N-phenylamine (62 mg, yield 87.1%) as a white amorphous substance.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]2[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[NH:18][C:19]4[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=4[N:21]=3)[CH2:14][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(OCC)(=O)C.O.[Pt](=O)=O>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][C:17]3[NH:21][C:20]4[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=4[N:18]=3)[CH2:14][CH2:15]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C1=C(CCCc2ccccc2)CCN(Cc2nc3ccccc3[nH]2)C1
Agent: O=[Pt]=O
Solvent: O
Solvent: CCOC(C)=O
Product: c1ccc(CCCC2CCN(Cc3nc4ccccc4[nH]3)CC2)cc1
Reaction time: 1.17 h
Yield: 51.1 %

Procedure:
A mixture of 2-(4-[3-phenylpropyl]-1,2,3,6-tetrahydropyridin-1-ylmethyl)benzimidazole (1.01 g, 3.05 mmol) and platinum (IV) oxide hydrate (56 mg) in ethyl acetate (75 ml) was hydrogenated on a Parr apparatus (30 psi maximum) for 70 minutes. Fresh catalyst was added (40 mg) and the mixture hydrogenated for a further 2.5 h. The mixture was filtered and evaporated to dryness. Flash chromatography eluting with 7.5% methanol in dichloromethane followed by recrystallisation from ethyl acetate/petrol (60°-80° C.) gave the title compound (0.52 g, 52%) as a white solid, m.p. 140°-141° C.; (Found: C, 79.25; H, 8.07; N, 12.39. C22H27N3 requires C, 79.24; H, 8.16; N, 12.60%); δH (DMSO-d6) 1.19 (SH, m, 2×CH2 +piperidinyl CH), 1.57 (4H, m, 2×CH2), 2.02 (2H, m, CH2), 2.55 (2H, m, piperidinyl CH2), 2.81 (2H, m, piperidinyl CH2), 3.66 (2H, s, CH2N), 7.15 (SH, m, ArH), 7.26 (2H, m, ArH), 7.43 (1H, br d, ArH), 7.51 (1H, br d, ArH), and 12.16 (1H, br s, N3H); m/z (CI+, NH3) 334 (M+1)+.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-])=O)[CH:9]=2)[CH:4]=[CH:3]1>C(O)C.O1CCCC1.[Pd]>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH2:11])[CH:9]=2)[CH:4]=[CH:3]1
Reactant: Cn1ccc2ccc([N+](=O)[O-])cc21
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Cn1ccc2ccc(N)cc21
Reaction time: 14 h

Procedure:
A mixture of 1-methyl-6-nitro-1H-indole (5.0 g, 28.4 mmol) and 10% Pd/C(1.0 g) in ethanol (200 ml) and tetrahydrofuran (100 ml) was hydrogenated at atmospheric pressure for 14 hours. The reaction mixture was filtered and concentrated to give 1-methyl-6-amino-1H-indole after crystallization from ether/hexane (3.8 g, 80%).
Reaction SMILES: [H-].[Na+].C1COCC1.[CH2:8]([O:15][CH2:16][CH2:17][OH:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl[C:20]1[C:25]2[CH2:26][CH2:27][CH2:28][C:24]=2[N:23]=[C:22]([NH2:29])[N:21]=1>C1COCC1>[CH2:8]([O:15][CH2:16][CH2:17][O:18][C:20]1[C:25]2[CH2:26][CH2:27][CH2:28][C:24]=2[N:23]=[C:22]([NH2:29])[N:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1nc(Cl)c2c(n1)CCC2
Reactant: OCCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1nc2c(c(OCCOCc3ccccc3)n1)CCC2

Procedure:
To stirred suspension of NaH (60% 552 mg) in THF 2-benzyloxyethanol (3.38 g, 20 mmol) was slowly added at room temperature. After the addition, 3.28 grams (19.4 mmol) of 4-chloro-6,7-dihydro-5H-cyclopentapyrimidin-2-ylamine was dissolved in 200 ml THF and added to it and the mixture was refluxed for 3 hours. Then the solvent was removed in vacuo and 100 ml water was added to the residue. The product was extracted with chloroform; washed well with water and dried over anhydrous MgSO4. It was filtered and concentrated. Low melting solid; Yield: 4.2 gram (73%); (M+H) 286.1
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:24]=[CH:23][C:12]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])=[CH:11][C:10]=1[O:25][CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.S(=O)(=O)(O)O.[N+:36]([O-])([OH:38])=[O:37]>ClCCl>[CH2:1]([O:8][C:9]1[C:10]([O:25][CH3:26])=[CH:11][C:12]([C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:14])=[C:23]([N+:36]([O-:38])=[O:37])[CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: COc1cc(C(=O)OCc2ccccc2)ccc1OCc1ccccc1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc(C(=O)OCc2ccccc2)c([N+](=O)[O-])cc1OCc1ccccc1
Temperature: 110 °C
Reaction time: 3 h

Procedure:
Benzyl 4-(benzyloxy)-3-methoxybenzoate (135 g) was dissolved in dichloromethane (339 ml). Glacial acetic acid (175.5 g) was added and the mixture cooled to 110° C. Concentrated sulfuric acid (151.6 g) was added in a controlled manner maintaining the temperature of the reaction mixture below 25° C. Concentrated nitric acid (61.6 g) was then added in 15 minutes keeping the temperature of the reaction mixture below 25° C. The reaction mixture was then heated to 40° C. and stirred for 3 hours. The lower aqueous layer was removed and the organic layer was washed twice with water (2×168 ml). The organic layer was distilled to at atmospheric pressure to remove dichloromethane (186 ml). Isopropanol (339 ml) was added to the reaction mixture at 40° C. The reaction mixture was held at 40° C. for 15 minutes. The resulting suspension was then cooled to 20° C. within 30 minutes, then to 5° C. and held at this temperature for one hour. The product (benzyl 4-(benzyloxy)-5-methoxy-2-nitrobenzoate) was isolated by filtration, washed with isopropanol (336 ml) and dried at less than 25° C. Yield: 135.7 g, 89.6%; NMR Spectrum (CDCl3) 3.9 (s, 3H), 5.2 (s, 2H), 5.3 (s, 2H), 7.1 (s, 1H), 7.3-7.4 (m, 100H), 7.5 (s, 1H); Mass Spectrum (M+H)+=394.1.
Reaction SMILES: [CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][C:9]([C:17]([O-])=[O:18])=[C:10]([C:14]([O-:16])=O)[CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[CH3:23][O:24][C:25]1[CH:33]=[CH:32][C:28]([CH2:29][CH2:30][NH2:31])=[CH:27][CH:26]=1.Cl>>[CH2:1]([N:4]([CH2:20][CH2:21][CH3:22])[CH:5]1[CH2:13][C:12]2=[CH:11][C:10]3[C:14](=[O:16])[N:31]([CH2:30][CH2:29][C:28]4[CH:32]=[CH:33][C:25]([O:24][CH3:23])=[CH:26][CH:27]=4)[C:17](=[O:18])[C:9]=3[CH:8]=[C:7]2[CH2:6]1)[CH2:2][CH3:3]
Reactant: COc1ccc(CCN)cc1
Reactant: CCCN(CCC)C1Cc2cc(C(=O)[O-])c(C(=O)[O-])cc2C1
Agent: Cl
Product: CCCN(CCC)C1Cc2cc3c(cc2C1)C(=O)N(CCc1ccc(OC)cc1)C3=O

Procedure:
Using procedure 49, 2-(dipropylamino)-2,3-dihydro-1H-indene-5,6-dicarboxylate (92, 0.35 g, 1.0 mmol) was treated with 4-methoxyphenethylamine (0.19 mL, 1.3 mmol). Purification using silica gel, eluting with 3:1 hexane/acetone, afforded an oil that was converted to an HCl salt and recrystallized from hot MeOH/EtOAc to give 113 as a white solid (m.p. 211-215° C.).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([CH:10]=O)=[CH:6][C:3]=1[C:4]#[N:5].[NH2:12]OS(O)(=O)=O>O>[F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]#[N:12])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: NOS(=O)(=O)O
Solvent: O
Product: N#Cc1ccc(F)c(C#N)c1
Temperature: 50 °C
Yield: 86.8 %

Procedure:
To a solution of 2-fluoro-5-formylbenzonitrile (5.1 g, 33.9 mmol) in water (75 ml) was added hydroxylamine-O-sulphonic acid (4.6 g, 40.7 mmol) and the reaction mixture was heated at 50° C. for 5 h. The mixture was filtered and the solid material was washed with water and dried in vacuo for 18 h to give the title compound (4.3 g)
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C@H:5]1[O:9][C:8]([CH3:11])([CH3:10])[O:7][C@@H:6]1[CH2:12][OH:13].[CH3:14][C:15]([Si:18](Cl)([CH3:20])[CH3:19])([CH3:17])[CH3:16].C(=O)([O-])O.[Na+]>C1COCC1>[Si:18]([O:13][CH2:12][CH:6]1[O:7][C:8]([CH3:10])([CH3:11])[O:9][CH:5]1[CH2:4][OH:3])([C:15]([CH3:17])([CH3:16])[CH3:14])([CH3:20])[CH3:19]
Reactant: CC1(C)O[C@H](CO)[C@@H](CO)O1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)OC(CO)C(CO[Si](C)(C)C(C)(C)C)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95801.8 %

Procedure:
To THF (50 mL), NaH (1.41 g, 0.032 mmol) was added at room temperature, followed by addition of ((4R,5R)-5-hydroxymethyl-2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (5.0 g, 0.031 mmol) at room temperature. The mixture was stirred at room temperature for 1 hr. After that, TBSCl (5.11 g, 0.034 mmol) was added at room temperature and stirred at room temperature overnight. The reaction solution was added with saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate. The residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (8.21 g, 96%).
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:8])[CH2:5][CH2:6][OH:7].[NH2:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12](Cl)[CH:11]=1>C1(C)C=CC=CC=1>[CH3:3][N:4]([CH3:8])[CH2:5][CH2:6][O:7][C:12]1[CH:11]=[C:10]([NH2:9])[CH:15]=[CH:14][N:13]=1
Reactant: CN(C)CCO
Reactant: Nc1ccnc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN(C)CCOc1cc(N)ccn1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 62.5 %

Procedure:
Sodium hydride (159 mg, 60% mineral oil dispersion, 3.98 mmol) was placed in a dried flask under a nitrogen atmosphere, followed by sequential addition of anhydrous toluene (10 ml) and 2-dimethylaminoethanol (177 mg, 2.0 mmol) with a syringe. After the resulting mixture was stirred at room temperature for 40 minutes, 4-amino-2-chloropyridine (203 mg, 1.59 mmol) was added, followed by heating to reflux for 16 hours. The reaction mixture was cooled, which was subsequently added dropwise slowly onto ice water, followed by extraction twice with ethyl acetate (10 ml). The organic layer was washed with brine (10 ml), and dried over sodium sulfate, followed by distilling off under reduced pressure, to obtain a crude product as a pale brown solid (180 mg).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[NH:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]([NH2:15])=[CH:8][C:7]=1[CH3:16])[CH3:2].[F:18][C:19]([F:29])([F:28])[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1.O>C(O)C>[CH2:1]([O:3][C:4](=[O:17])[NH:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]([NH:15][CH2:24][C:23]2[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:28])[F:29])=[CH:27][CH:26]=2)=[CH:8][C:7]=1[CH3:16])[CH3:2]
Reactant: CCOC(=O)Nc1c(C)cc(N)cc1[N+](=O)[O-]
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Solvent: O
Solvent: CCO
Product: CCOC(=O)Nc1c(C)cc(NCc2ccc(C(F)(F)F)cc2)cc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 75 %

Procedure:
(4-Amino-2-methyl-6-nitro-phenyl)-carbamic acid ethyl ester (0.50 g) and 4-trifluoromethyl-benzaldehyde (0.29 mL) were dissolved in ethanol (10 mL) and refluxed for 16 h. The reaction mixture was poured into water (75 mL) and the precipitate collected by filtration. Sodium cyanoborohydride (0.3 g) and acetic acid (0.5 mL) were added to the precipitate dispersed in methanol (10 mL) and stirred for 60 minutes. The reaction mixture was filtered, water (50 mL) was added and the organic solvent was removed in vacuo. The product was allowed to precipitate at 25° C. and collected by filtration and washed with water (100 mL) to furnish 0.47 g (75% yield) of the title compound as a yellow solid. LC-MS (m/z) 398 (MH+); tR=3.18, (UV, ELSD) 86%, 94%. 1H NMR (500 MHz, DMSO-d6): 1.20 (1,3H), 2.10 (s, 3H), 4.05 (m, 2H), 4.45 (m, 2H), 6.75 (m, 1H), 6.90 (m, 1H), 7.55 (m, 2H), 7.73 (m, 2H), 8.75 (s, 1H).
Reaction SMILES: [O:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:15][C:16]#[N:17]>>[O:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH2:15][C:16]#[N:17])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(OC2CCNCC2)cc1
Reactant: N#CCBr
Product: N#CCN1CCC(Oc2ccccc2)CC1

Procedure:
The title compound is synthesized by coupling of 4-Phenoxy-piperidine (commercially available from Alfa Aesar) and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+H=217.2: CtRet=4.80.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][CH2:9][C@H:10]2[CH2:15][CH2:14][C@H:13]([CH3:16])[CH2:12][CH2:11]2)=[C:6]([NH2:17])[CH:5]=[C:4]([Cl:18])[N:3]=1.[CH2:19](OC(OCC)OCC)C>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[C:7]2[N:8]([CH2:9][C@H:10]3[CH2:11][CH2:12][C@H:13]([CH3:16])[CH2:14][CH2:15]3)[CH:19]=[N:17][C:6]=2[CH:5]=[C:4]([Cl:18])[N:3]=1
Reactant: C[C@H]1CC[C@H](CNc2c(N)cc(Cl)nc2Cl)CC1
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: C[C@H]1CC[C@H](Cn2cnc3cc(Cl)nc(Cl)c32)CC1

Procedure:
A solution of 2,6-dichloro-N3-((trans-4-methylcyclohexyl)methyl)pyridine-3,4-diamine (126 g, 0.386 mol) in triethylorthoformate (1.0 L) and acetic anhydride (1.0 L) was stirred at 90° C. for 3 h. The solution was concentrated in vacuo, and the residue was dissolved in DCM/10% NaOH (2.0 L/1.0 L). The organic layer was separated and concentrated. The crude product was purified by a silica gel column, eluting with DCM/petroleum ether (1:1), to give 4,6-dichloro-3-((trans-4-methylcyclohexyl)methyl)-3H-imidazo[4,5-c]pyridine. MS ESI calc'd. for C14H17Cl2N3 [M+H]+ 298. found 298. 1H NMR (400 MHz, CDCl3): 7.96 (s, 1H); 7.66 (m, 1H); 4.28-4.26 (d, 2H); 1.85-1.79 (m, 1H); 1.73-1.71 (d, 2H), 1.70-1.61 (d, 2H), 1.34-1.33 (m, 1H) 1.12-1.02 (m, 2H), 0.94-0.84 (m, 5H).
Reaction SMILES: C(OC(=O)[NH:10][C@@H:11]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]2[N:19]([CH3:49])[N:20]=[CH:21][C:22]=2[NH:23][C:24]([C:26]2[N:27]=[C:28]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[C:45]([F:48])([F:47])[F:46])[S:29][C:30]=2[NH:31]C(OC(C)(C)C)=O)=[O:25])[CH2:13][CH2:12]1)C1C=CC=CC=1>O1CCOCC1.Cl>[NH2:31][C:30]1[S:29][C:28]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[C:45]([F:47])([F:48])[F:46])=[N:27][C:26]=1[C:24]([NH:23][C:22]1[CH:21]=[N:20][N:19]([CH3:49])[C:18]=1[N:14]1[CH2:15][CH2:16][CH2:17][C@@H:11]([NH2:10])[CH2:12][CH2:13]1)=[O:25]
Reactant: Cn1ncc(NC(=O)c2nc(-c3ccccc3C(F)(F)F)sc2NC(=O)OC(C)(C)C)c1N1CCC[C@@H](NC(=O)OCc2ccccc2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Cn1ncc(NC(=O)c2nc(-c3ccccc3C(F)(F)F)sc2N)c1N1CCC[C@@H](N)CC1
Temperature: 120 °C
Reaction time: 16 h
Yield: 59.5 %

Procedure:
A heterogeneous mixture of [(R)-1-(4-{[5-tert-butoxycarbonylamino-2-(2-trifluoromethyl-phenyl)-thiazole-4-carbonyl]-amino}-2-methyl-2H-pyrazol-3-yl)-perhydro-azepin-4-yl]-carbamic acid benzyl ester (83.9 mg, 0.117 mmol) in 1,4-dioxane (1.0 mL) and 2M aq. HCl (10 mL) was stirred at 120° C. under N2 for 16 h. The resultant homogeneous reaction was then slowly quenched with saturated aq. NaHCO3 solution and then extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified via reverse phase HPLC to afford 210 (33.4 mg, 59.2%) as a white solid. 1H NMR (400 MHz, DMSO) δ 8.51 (s, 1H), 7.90 (d, J=8.0 Hz, 1H), 7.78 (d, J=4.1 Hz, 2H), 7.68 (dd, J=8.1 Hz, 3.9 Hz, 1H), 7.58 (s, 1H), 7.46 (broad s, 2H), 3.64 (s, 3H), 3.10 (t, J=5.3 Hz, 4H), 3.02-2.90 (m, 1H), 1.89-1.73 (m, 3H), 1.64-1.44 (m, 3H); 2 protons buried in water peak; MS (ESI) m/z: 480.1 [M+H]+
Reaction SMILES: [ClH:1].[C:2]([C:5]1[CH:27]=[CH:26][C:8]([CH2:9][NH:10][C:11](=[O:25])[CH:12]([O:22][CH2:23][CH3:24])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[F:21])=[C:7]([O:28][C:29]2[CH:34]=[CH:33][C:32]([N+:35]([O-])=O)=[CH:31][N:30]=2)[CH:6]=1)(=[NH:4])[NH2:3]>CCO.C1COCC1.[Pd]>[ClH:1].[NH2:35][C:32]1[CH:33]=[CH:34][C:29]([O:28][C:7]2[CH:6]=[C:5]([C:2](=[NH:3])[NH2:4])[CH:27]=[CH:26][C:8]=2[CH2:9][NH:10][C:11](=[O:25])[CH:12]([O:22][CH2:23][CH3:24])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][C:14]=2[F:21])=[N:30][CH:31]=1
Reactant: CCOC(C(=O)NCc1ccc(C(=N)N)cc1Oc1ccc([N+](=O)[O-])cn1)c1ccc(OC)cc1F
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(C(=O)NCc1ccc(C(=N)N)cc1Oc1ccc(N)cn1)c1ccc(OC)cc1F

Procedure:
(RS)-N-[4-Carbamimidoyl-2-(5-nitro-pyridin-2-yloxy)-benzyl]-2-ethoxy-2-(2-fluoro-4-methoxy-phenyl)-acetamide hydrochloride was hydrogenated at rt and normal pressure in EtOH/THF using Pd (10% on charcoal) as a catalyst to give (RS)-N-[2-(5-amino-pyridin-2-yloxy)-4-carbamimidoyl-benzyl]-2-ethoxy-2-(2-fluoro-4-methoxy-phenyl)-acetamide hydrochloride. Light yellow solid. MS 468.1 ([M+H]+)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][NH:17][CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:5][CH:4]=1.[C:23]1([N:29]=[C:30]=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][C:15]4[CH2:16][N:17]([C:30]([NH:29][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=5)=[O:31])[CH2:18][CH2:19][C:20]=4[C:11]=3[CH:10]=[N:9]2)=[CH:21][CH:22]=1
Reactant: O=C=Nc1ccccc1
Reactant: COc1ccc(Cn2ncc3c4c(cnc32)CNCC4)cc1
Solvent: ClCCl
Product: COc1ccc(Cn2ncc3c4c(cnc32)CN(C(=O)Nc2ccccc2)CC4)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(4-methoxy-benzyl)-6,7,8,9-tetrahydro-3H-pyrazolo[3,4-c][2,7]naphthyridine (0.075 g, 0.256 mmol) in dichloromethane (3 mL) was added phenyl isocyanate (31 μL, 0.281 mmol). The reaction mixture was shaken at room temperature for 1 hour. The solvent was then removed under reduced pressure to give 3-(4-methoxybenzyl)-N-phenyl-8,9-dihydro-3H-pyrazolo[3,4-c][2,7]naphthyridine-7(6H)-carboxamide as a tan solid (LCMS [M+H]:414), which was used for next step without further purification. White solid; M.p.=>65° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.72 (s, 1H), 8.41 (s, 1H), 8.20 (s, 1H), 7.51-7.45 (m, 2H), 7.28-7.15 (m, 4H), 6.98-6.91 (m, 1H), 6.88-6.82 (m, 2H), 5.59 (s, 2H), 4.79 (s, 2H), 3.82 (t, 6.4 hz, 2H), 3.67 (s, 3H), 3.14 (t, J=J=6.4 Hz, 2H); LCMS [M+H]: 414.6.
Reaction SMILES: C([O:4][CH2:5][CH:6]([CH2:19][O:20][Si:21]([C:34]([CH3:37])([CH3:36])[CH3:35])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)/[CH:7]=[CH:8]/[P:9](=[O:18])([O:14][CH:15]([CH3:17])[CH3:16])[O:10][CH:11]([CH3:13])[CH3:12])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[Si:21]([O:20][CH2:19][CH:6]([CH2:5][OH:4])/[CH:7]=[CH:8]/[P:9](=[O:18])([O:14][CH:15]([CH3:16])[CH3:17])[O:10][CH:11]([CH3:12])[CH3:13])([C:34]([CH3:36])([CH3:35])[CH3:37])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(=O)OCC(/C=C/P(=O)(OC(C)C)OC(C)C)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CC(C)OP(=O)(/C=C/C(CO)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)OC(C)C
Yield: 73.2 %

Procedure:
A solution of diisopropyl (E)-3-acetoxymethyl-4-t-butyldiphenylsilyloxybut-1-enylphosphonate (5 g, 9.2 mmol) in methanol (50 ml) was stirred with potassium carbonate (63 g, 0.45 mmol) for 5 h at room temperature. The solvent was removed in vacuo and the residue was chromatographed on silica gel eluting with chloroform-methanol (100:1) of increasing polarity to (30:1) to give diisopropyl (E)-3-t-butyldiphenylsilyloxymethyl-4-hydroxybut-1-enylphosphonate as an oil (3.4 g, 73%): υmax (film) 3381, 3071, 3025, 2940, 2931, 2858, 2360, 2332, 1631, 1585, 1471 and 1428 cm-1 ; δH (CDCl3) 1.05 [9H, s, C(CH3)3 ], 1.25 (3H, d, J 6 Hz, CHCH3), 1.27 (3H, d, J 6.1 Hz, CHCH3), 1.31 [6H, d, J 6 Hz, CH(CH3)2 ], 2.15 (1H, t, J 5.9 Hz, D2O exchangeable OH), 2.65 (1H, m, CH), 3.80 (4H, m, 2×CH2), 4.65 [2H, m, 2×CH(CH3)2 ], 5.76 (1H, ddd, J 1, 17 and 19 Hz, PCH=CH), 6.64 (1H, ddd, J 8, 17 and 23 Hz, PCH=CH), 7.4-7.7 (10H, m, 2×C6H5) (Found: C, 63.65; H, 8.16%. M+ 504.2444. C27H41O5PSi.0.25 H2O requires C, 63.69; H, 8.22%. M+ 504.2461).