Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([NH:9][C@@H:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:8])[S:5][CH:6]=1.N[C@@H](CC1C=CC([Cl:48])=CC=1Cl)CN1C(=O)C2C(=CC=CC=2)C1=O.C1C(=O)N(Cl)C(=O)C1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([NH:9][C@@H:10]([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:8])[S:5][C:6]=1[Cl:48]
Reactant: N[C@@H](Cc1ccc(Cl)cc1Cl)CN1C(=O)c2ccccc2C1=O
Reactant: CC(C)(C)OC(=O)NC[C@H](Cc1ccccc1)NC(=O)c1cc(Br)cs1
Agent: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC[C@H](Cc1ccccc1)NC(=O)c1cc(Br)c(Cl)s1
Temperature: 50 °C
Yield: 65 %

Procedure:
A solution of 1,1-dimethylethyl ((2S)-2-{[(4-bromo-2-thienyl)carbonyl]amino}-3-phenylpropyl)carbamate (prepared according to Preparation 22), except substituting 2-[(2S)-2-amino-3-phenylpropyl]-1H-isoindole-1,3(2H)-dione for 2-[(2S)-2-amino-3-(2,4-dichlorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (200 mg, 0.455 mmol) and NCS (61 mg, 0.455 mmol) in DMF (3 ml) was heated at 50° C. in a sealed tube for 2 hours. The solvent was removed and the residue was purified by biotage (30% Hex/EtOAc) to give the title product (140 mg, 65%).
Reaction SMILES: [I:1]I.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])=[C:7]([F:18])[CH:6]=1>CO.S([O-])([O-])(=O)=O.[Ag+2]>[CH3:3][O:4][C:5]1[C:10]([I:1])=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])=[C:7]([F:18])[CH:6]=1
Reactant: COc1ccc(-c2ccccc2C)c(F)c1
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: COc1cc(F)c(-c2ccccc2C)cc1I
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of silver sulfate (0.34 g, 1.11 mmol), iodine (0.28 g, 1.11 mmol) in MeOH (10 ml) at room temperature, a solution of 2-fluoro-2′-methylbiphenyl-4-yl methyl ether from above (0.24 g, 1.11 mmol) in MeOH (5 ml) was added dropwise. The mixture was stirred at room temperature for 4 h until the color turned to light yellow. The solid was filtered off and the filtrate was concentrated. The residue was purified via flash column using hexane as the eluant to give the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11]/[C:12](=[CH:17]\[C:18]1[C:23]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])=[CH:22][CH:21]=[C:20]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:19]=1)/[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pt].C1COCC1.CO>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:17][C:18]1[C:23]([NH:24][C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])=[CH:22][CH:21]=[C:20]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[N:19]=1)[C:13]([O:15][CH3:16])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)/C(=C/c1nc(-c2ccccc2)ccc1NC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Agent: [Pt]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)C(Cc1nc(-c2ccccc2)ccc1NC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 16.9 %

Procedure:
A suspension of 1F (650 mg, 1.29 mmol) and 5 wt % platinum on activated carbon (500 mg) in THF (60 mL) and MeOH (60 mL) was stirred at RT under H2 at 80 psi for 5 days. The reaction mixture was filtered through a Celite pad and the filtrate was concentrated. The residue was purified by silica gel (40 g) column chromatography eluting with a gradient of EtOAc (0-60%) in hexane to give the title compound as a foam (110 mg, 17%). LC/MS (method A): retention time=3.82 min, (M+H)+=506.
Reaction SMILES: [CH3:1][N:2]([CH2:32][C:33]([NH:35][C@H:36]1[CH2:40][CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37]1)=[O:34])[C:3]([NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])=[N:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[O:6].[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51]>ClCCl>[F:48][C:49]([F:54])([F:53])[C:50]([OH:52])=[O:51].[CH3:1][N:2]([CH2:32][C:33]([NH:35][C@H:36]1[CH2:40][CH2:39][NH:38][CH2:37]1)=[O:34])[C:3]([NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[O:20])=[N:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=1)=[O:6]
Reactant: CN(CC(=O)N[C@H]1CCN(C(=O)OC(C)(C)C)C1)C(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(CC(=O)N[C@H]1CCNC1)C(=NC(=O)OCc1ccc([N+](=O)[O-])cc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
To a solution of the compound (1.48 g), which had been obtained in (1), in anhydrous dichloromethane (8 ml), trifluoroacetic acid (4 ml) was added dropwise under ice cooling. The reaction mixture was then treated in a similar manner to that described in Referential Example 16-(2), whereby the title compound was obtained. The product was provided for use in the subsequent reaction without isolation.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[C:4]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:3]=1.[CH3:14][NH2:15].CO>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:15][CH3:14])=[C:4]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:3]=1
Reactant: CS(=O)(=O)c1cc(Br)ccc1CBr
Reactant: CN
Solvent: CO
Product: CNCc1ccc(Br)cc1S(C)(=O)=O
Yield: 80 %

Procedure:
A solution of 4-bromo-1-bromomethyl-2-methanesulfonyl-benzene (300 mg, 0.9 mmol) in ˜40% MeNH2/MeOH (10 mL) was stirred at room temperature for 3 hours. TLC (petroleum ether:EtOAc 3:1) showed the reaction was complete. The reaction mixture was concentrated in vacuo to give crude title compound (200 mg, 80%) as a yellow oil, which was used for next step without further purification.
Reaction SMILES: C[O:2][C:3]1[C:16](=[O:17])[C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]([CH3:18])=[CH:7][C:6]=2[C:5](=[O:19])[CH:4]=1.[OH-].[Na+].Cl>CO>[OH:2][C:3]1[C:16](=[O:17])[C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]([CH3:18])=[CH:7][C:6]=2[C:5](=[O:19])[CH:4]=1
Reactant: COC1=CC(=O)c2cc(C)c3ccccc3c2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc2c(c3ccccc13)C(=O)C(O)=CC2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.8 %

Procedure:
3-Methoxy-9-methyl-1,4-phenanthrenequinone (1.17 g, 4.63 mM) was dissolved in 40 ml of methanol solution containing 5% NaOH, and the resulting solution was vigorously stirred at room temperature for 1 hour. The reaction solution was neutralized by 1N HCl and was then concentrated by distillation under reduced pressure. The resulting purified by chromatography to give 0.34 g (1.42 mM) of 3-Hydroxy-9-methyl-1,4-phenanthrenequinone.
Reaction SMILES: [CH:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]([OH:15])=O)=[CH:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O[N:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1.NC1C=CC=CC=1.C(O)C(N)(CO)CO>CN(C=O)C>[C:21]1([NH:17][C:13]([C:10]2[CH:11]=[N:12][C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[N:8][CH:9]=2)=[O:15])[CH:22]=[CH:23][CH:24]=[CH:25][CH:20]=1
Reactant: O=C(O)c1cnc(C2CCCCC2)nc1
Reactant: On1nnc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: NC(CO)(CO)CO
Solvent: Nc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)c1cnc(C2CCCCC2)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 33.8 %

Procedure:
A mixture of 2-cyclohexyl-pyrimidine-5-carboxylic acid (100 mg, 0.48 mmol), 1-hydroxybenzotriazole (74.2 mg, 0.55 mmol), and PS-DCC (505 mg, 1.28 mmol/g, 0.65 mmol) in DMF (8 mL) is shaken at room temperature for 15 minutes, and aniline (30 mg, 0.32 mmol) is added. The mixture is shaken at room temperature for 18 hours, PS-trisamine (388 mg, 3.75 mmol/g, 1.45 mmol) is added and the mixture is continually shaken at room temperature for 18 hours. The solid is filtered and washed with DCM. The filtrate is concentrated in vacuo to afford 2-cyclohexyl-pyrimidine-5-carboxylic acid phenylamide (45.6 mg, 51%) as a solid. MS: 282 (M+H); IC50=4960 nM.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:13][C:14]([CH3:16])=[CH2:15])=[C:4]([OH:12])[C:5]([CH2:9][CH:10]=[CH2:11])=[C:6]([CH3:8])[CH:7]=1.B(F)(F)F.CCOCC.C(=O)([O-])O.[Na+]>ClCCCl>[CH3:15][C:14]1([CH3:16])[O:12][C:4]2[C:5]([CH2:9][CH:10]=[CH2:11])=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[C:3]=2[CH2:13]1
Reactant: C=CCc1c(C)cc(C)c(CC(=C)C)c1O
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCCl
Product: C=CCc1c(C)cc(C)c2c1OC(C)(C)C2
Reaction time: 4 h
Yield: 97 %

Procedure:
2.44 g (11.3 mmol) of 3,5-dimethyl-2-(2-methyl-2-propen-1-yl)-6-(2-propen-1-yl)phenol (Compound No. 1) was dissolved in 20 ml of 1,2-dichloroethane, and 0.42 ml (3.39 mmol) of boron trifluoride etherate was added thereto at 0° C. The above mixture was then stirred in an atmosphere of argon gas for 4 hours, poured into an aqueous solution of sodium hydrogencarbonate, and extracted with ethyl acetate. The thus obtained extract layer was washed successively with water and a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, and then concentrated, whereby 2.37 g of a crude 2,3-dihydro-2,2,4,6-tetramethyl-7-(2-propen-1-yl)benzo[b]furan (Compound No. 2) was obtained as a yellow oily material.
Reaction SMILES: [CH2:1]=[C:2]1[C@H:9]([CH3:10])[O:8][C@@H:5]([O:6]C)[CH2:4][C@@H:3]1[NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14]>C(O)(=O)C.O>[CH2:1]=[C:2]1[C@H:9]([CH3:10])[O:8][CH:5]([OH:6])[CH2:4][C@@H:3]1[NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14]
Reactant: C=C1[C@@H](NC(=O)C(F)(F)F)C[C@H](OC)O[C@H]1C
Solvent: CC(=O)O
Solvent: O
Product: C=C1[C@@H](NC(=O)C(F)(F)F)CC(O)O[C@H]1C
Yield: 98.2 %

Procedure:
A solution of 0.51 g (2 mmol) of the intermediate VIII in 10 ml of acetic acid and 40 ml of water was heated at 100° C. for two hours, then evaporated to dryness to give 2,3,4,6-tetradeoxy-4-C-methylene-3-trifluoroacetamido-L-threo-hexopyranose (IX, 0.47 g, 99%) as a white solid: m.p. 168°-170° C., [α]D20° -160° (c=0.5, CHCl3). Treatment of IX (0.36 g, 1.5 mmol) in 25 ml of dry methylene dichloride with 4 ml of trifluoroacetic anhydride for 2 hours at 0° C. and 1 hour at 20° C. gave, after evaporation, the 1-0-trifluoroacetate (X), which was directly used for the preparation of the corresponding 1-chloro-derivative by treatment with dry hydrogen chloride in anhydrous diethyl ether at 0° C. After standing at 0° C. overnight, the reaction mixture was evaporated to dryness to give 2,3,4,6-tetradeoxy-4-C-methylene-3-trifluoroacetamido-L-threo-hexopyranosyl chloride (III-A, 0.35 g, 90%), suitable for the subsequent coupling reaction without further purification.
Reaction SMILES: [CH2:1]([CH:3]1[CH:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][NH:17][C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][CH:5]([CH2:20][CH2:21][CH2:22][C:23](OCC)=[O:24])[CH2:4]1)[CH3:2].[NH3:28]>>[CH2:1]([C@H:3]1[C@@H:7]([C:8]2[N:12]3[C:13]4[CH:19]=[CH:18][NH:17][C:14]=4[N:15]=[CH:16][C:11]3=[N:10][N:9]=2)[CH2:6][CH:5]([CH2:20][CH2:21][CH2:22][C:23]([NH2:28])=[O:24])[CH2:4]1)[CH3:2]
Reactant: CCOC(=O)CCCC1CC(CC)C(c2nnc3cnc4[nH]ccc4n23)C1
Reactant: N
Product: CC[C@@H]1CC(CCCC(N)=O)C[C@@H]1c1nnc2cnc3[nH]ccc3n12
Temperature: 85 °C
Yield: 100.2 %

Procedure:
Ethyl 4-(3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)butanoate (0.080 g, 0.217 mmol, prepared using III from Preparation #25 and (E)-ethyl 4-(diethoxyphosphoryl)but-2-enoate, W) and ammonia (7 N in MeOH, 6.2 mL, 43.3 mmol). The reaction vessel was sealed and heated to about 85° C. After about 2 days the tube was cooled to rt and the reaction mixture was concd in vacuo to provide 4-((3R,4S)-3-ethyl-4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentyl)butanamide (0.074 g, 100%) as a solid which was used without further purification: LC/MS (Table 1, Method c) Rt=0.50 min.; MS m/z: 341 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([CH3:11])[C:3]1=[O:12]>CO.C1COCC1.[Pd]>[NH2:8][C:6]1[CH:5]=[C:4]([CH3:11])[C:3](=[O:12])[N:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc([N+](=O)[O-])cn(C)c1=O
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(N)cn(C)c1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.7 %

Procedure:
A mixture of 1,3-dimethyl-5-nitropyridin-2(1H)-one (8.315 g, 49.4 mmol) and Pd/C 10% (1 g) in MeOH (100 mL) and THF (100 mL) was stirred under an atmospheric pressure of H2 at RT for 1.5 hr, filtered through celite, and concentrated. The residue was triturated in Et2O to afford the title compound (6.12 g, 90% yield) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.94 (s, 3 H) 3.31 (s, 3 H covered by water signal) 4.15 (br s, 2 H) 6.70 (s, 1 H) 6.95 (s, 1 H).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[F:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[C:17](O)=[O:18].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:17](=[O:18])[C:16]3[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:14]([F:13])[CH:15]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1ccc(C(=O)O)cc1F
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)Nc2c[nH]c3ncc(Br)c(F)c23)cc1F
Yield: 90.2 %

Procedure:
A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.87 mmol, Example 1, Step H), 3-fluoro-4-methoxybenzoic acid (311 mg, 1.83 mmol), BOP-Cl (0.465 g, 1.83 mmol), and triethylamine (0.606 mL, 4.35 mmol) in DCM (5 mL) was processed as described in Example 62, Step A, to provide N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-fluoro-4-methoxybenzamide (300 mg, 90% yield) as a solid. LCMS (APCI+) m/z 381.9, 383.9 (M+H)+, Retention time=3.23 minutes (Method 2).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[C:7]3[C:16](=[CH:17][CH:18]=[C:5]2[CH:4]=[N:3]1)[N:15]=[C:14]1[C:9]([C:10]([C:19](O)=[O:20])=[CH:11][CH:12]=[CH:13]1)=[N:8]3.[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH2:26]>>[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][NH:26][C:19]([C:10]1[C:9]2[C:14](=[N:15][C:16]3[C:7]([N:8]=2)=[C:6]2[N:2]([CH3:1])[N:3]=[CH:4][C:5]2=[CH:18][CH:17]=3)[CH:13]=[CH:12][CH:11]=1)=[O:20]
Reactant: CN(C)CCN
Reactant: Cn1ncc2ccc3nc4cccc(C(=O)O)c4nc3c21
Product: CN(C)CCNC(=O)c1cccc2nc3ccc4cnn(C)c4c3nc12

Procedure:
1-Methyl-1H-pyrazolo[3,4-α]phenazine-10-carboxylic acid (2-dimethylamino-ethyl)-amide was prepared from 1-methyl-1H-pyrazolo[3,4-α]phenazine-10-carboxylic acid (II.8) and N,N-dimethylethylenediamine
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:11][N:12]1[CH2:17][CH2:16][C:15]([CH2:24][NH2:25])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][CH2:13]1>>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:25][CH2:24][C:15]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:14][CH2:13][N:12]([CH3:11])[CH2:17][CH2:16]1)=[O:6]
Reactant: CN1CCC(CN)(c2ccccc2)CC1
Reactant: Cc1ccccc1C(=O)O
Product: Cc1ccccc1C(=O)NCC1(c2ccccc2)CCN(C)CC1

Procedure:
From 2-methylbenzoic acid and C-(1-methyl-4-phenyl-piperidin-4-yl)-methylamine. LCMS (MH+): m/z=323.1, tR (minutes, Method A)=0.56
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([OH:17])([C:13]([F:16])([F:15])[F:14])[C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[N:18]([CH2:29][CH3:30])[C:19](=O)[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.B.C1COCC1>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([OH:17])([C:9]([F:10])([F:11])[F:12])[C:13]([F:15])([F:16])[F:14])[CH:5]=[CH:4][C:3]=1[N:18]([CH2:29][CH3:30])[CH2:19][CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CCN(C(=O)CCc1ccccc1)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1Cl
Agent: B
Solvent: C1CCOC1
Product: CCN(CCCc1ccccc1)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1Cl
Temperature: 80 °C
Reaction time: 10 h
Yield: 90.9 %

Procedure:
A solution of 70 mg (0.15 mmol) of N-[2-chloro-4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-phenyl]-N-ethyl-3-phenyl-propionamide in 3 mL of THF was treated with 1 mL of 1M BH3.THF-complex in THF and stirred for 10 hours at 80° C. in a sealed tube. Evaporation of the solvent and column chromatography on silica gel with CH2Cl2/n-heptane 1:1 yielded 60 mg (91%) of 2-{3-chloro-4-[ethyl-(3-phenyl-propyl)-amino]-phenyl}-1,1,1,3,3,3-hexafluoro-propan-2-ol, colorless oil, MS: 440 (MH+, 1Cl).
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:6][C:5](=[O:15])[CH:4]=1)[CH3:2].[Cl:16]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:16][C:4]1[C:5](=[O:15])[NH:6][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][C:3]=1[CH2:1][CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCc1cc(=O)[nH]c(-c2ccccc2)n1
Solvent: CC(=O)O
Product: CCc1nc(-c2ccccc2)[nH]c(=O)c1Cl
Temperature: 0 °C
Yield: 87.1 %

Procedure:
A stirred solution of 7.81 g (39.1 mmol) of 6-ethyl-2-phenyl-4(3H)-pyrimidinone and 5.80 g (43.4 mmol) of N-chlorosuccinimide in 100 mL of glacial acetic acid was heated at 90° C. for 4 h. The mixture was cooled, poured onto crushed ice and allowed to stand until the ice had melted. The mixture was filtered and the solid collected was washed with water and a little ether. The solid was dried in a vacuum oven at 50 C. to afford 7.99 g of 5-chloro-6-ethyl-2-phenyl-4(3H)-pyrimidinone (an intermediate for compound 172) as a white solid. 1H-NMR (d6-DMSO) 1.30(3H,t), 2.8(2H,q), 7.6(3H,m), 8.2(2H.m).
Reaction SMILES: C([NH:11][S:12]([NH:15][CH:16]([CH2:20][CH2:21][CH3:22])[C:17]([OH:19])=[O:18])(=[O:14])=[O:13])(OCC1C=CC=CC=1)=O.[CH3:23]O>[Pd]>[CH3:23][O:19][C:17](=[O:18])[CH:16]([NH:15][S:12]([NH2:11])(=[O:14])=[O:13])[CH2:20][CH2:21][CH3:22]
Reactant: CO
Reactant: CCCC(NS(=O)(=O)NC(=O)OCc1ccccc1)C(=O)O
Agent: [Pd]
Product: CCCC(NS(N)(=O)=O)C(=O)OC
Reaction time: 2 h
Yield: 90 %

Procedure:
A mixture of 2-(N-carbobenzyloxyaminosulfonyl)aminopentanoic acid (46.7 g), methanol (350 mL) and 10% palladium on carbon (3.0 g) was hydrogenated at 55 psi for about 2 hours. The catalyst was removed by filtration through CELITE®, the solvent was removed in vacuo and the residue was purified by column chromatography on silica eluting with 50% ethyl acetate/hexane to afford 25.6 g (90%) of 2-(aminosulfonylamino)pentanoic acid methyl ester (Formula V: R=CH3 ; R1 =propyl; R2 =H; R3 =H), m.p. 63°-64° C.
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[N:12]1[C:20]2[CH:19]=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=2[C:14]2[CH2:22][N:23]([CH3:26])[CH2:24][CH2:25][C:13]1=2)(=O)=O.[OH-].[K+]>CN1C(=O)CCC1.O>[C:7]1([N:12]2[C:20]3[CH:19]=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[C:14]3[CH2:22][N:23]([CH3:26])[CH2:24][CH2:25][C:13]2=3)[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]=1
Reactant: Cc1ccc2c(c1)c1c(n2C2CCCCC2OS(C)(=O)=O)CCN(C)C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1ccc2c(c1)c1c(n2C2=CCCCC2)CCN(C)C1
Temperature: 120 °C
Yield: 82 %

Procedure:
To a solution of 2-(2,8-dimethyl-3,4-dihydro-1H-pyrido[4,3-b]indol-5(2H)yl)cyclohexyl methanesulfonate (0.33 g, 0.87 mmol) in NMP (3 mL), KOH (0.49 g, 8.7 mmol) was added at RT. The reaction mixture was heated overnight at 120° C. The reaction was monitored by LCMS. Upon completion, the reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure and purified by column chromatography (silica gel 3% MeOH in DCM) to afford 200 mg of the desired product. 1H NMR (CDCl3, HCl salt) δ (ppm): 7.50 (d, 2H), 7.40 (d, 2H), 7.23 (d, 1H), 7.1-7.0 (m, 2H), 6.9 (s, 1H), 3.8 (s, 2H), 3.0-2.8 (m, 4H), 2.6 (s, 3H), 2.45 (s, 3H), 2.0 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[CH3:13])([O-:3])=[O:2].[CH2:14]([O:16][C:17](=[O:23])[C:18](OCC)=[O:19])[CH3:15].CC[O-].[Na+].Cl>C(O)C>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:5]=1[CH2:13][C:18](=[O:19])[C:17]([O:16][CH2:14][CH3:15])=[O:23])([O-:3])=[O:2]
Reactant: CCOC(=O)C(=O)OCC
Reactant: Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=O)Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 2 h

Procedure:
2,6-Dinitrotoluene (10.0 g, 54.9 mmol) and oxalic acid diethylester (16.1 g, 110 mmol) are dissolved in ethanol (100 ml). Sodium ethylate (apx 2.5 N in ethanol, 54.9 mmol) is added, the mixture is stirred at 40° C. for 2 h. The solution is cooled to room temperature, adjusted to pH=3-4 with 2N hydrochloric acid, the solvent is evaporated in vacuo, the residue is partitioned between ethyl acetate and water, the organic layer is washed with water twice, dried over magnesium sulfate, filtered and evaporated. The crude product is purified with column chromatography on silica gel (eluent: cyclohexane/ethyl acetate, 2:1). Yield: 3.15 g (20%), mixture of keto/enol tautomers
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[N:8]=[C:9]=[S:10].[C:11]([NH:14][NH2:15])(=[O:13])[CH3:12]>O1CCOCC1.CCOCC>[C:11]([NH:14][NH:15][C:9](=[S:10])[NH:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[Br:1])(=[O:13])[CH3:12]
Reactant: CC(=O)NN
Reactant: S=C=Nc1ccncc1Br
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(=O)NNC(=S)Nc1ccncc1Br
Temperature: 80 °C
Reaction time: 0.75 h
Yield: 90.6 %

Procedure:
3-bromo-4-isothiocyanato-pyridine (1 g, 4.650 mmol) and acetylhydrazine (344.5 mg, 4.650 mmol) were dissolved in dry 1,4-dioxane (10 mL) and stirred at 80° C. for 0.75 hrs. The orange suspension was allowed to cool to RT. The viscous suspension was diluted with ether and the solid was collected by filtration and washed with ether (3×5 mL) to give 2-acetyl-N-(3-bromopyridin-4-yl)hydrazinecarbothioamide as a salmon-pink solid (1.2187 g, 91% Yield). MS (ES−) 288.9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:31])[CH:5]=[C:6]([Cl:30])[C:7]=1[CH2:8][C@@H:9]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH:22]([F:24])[F:23])=[C:17]([O:25][CH2:26][CH:27]2[CH2:29][CH2:28]2)[CH:16]=1)[O:10][C:11](=[O:14])[CH2:12][OH:13].[Cl:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][N:34]=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:30][C:6]1[CH:5]=[N+:4]([O-:31])[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C@H:9]([O:10][C:11](=[O:14])[CH2:12][O:13][C:37](=[O:38])[C:36]1[CH:40]=[CH:41][C:33]([Cl:32])=[N:34][CH:35]=1)[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH:22]([F:24])[F:23])=[C:17]([O:25][CH2:26][CH:27]2[CH2:29][CH2:28]2)[CH:16]=1
Reactant: O=C(CO)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Reactant: O=C(O)c1ccc(Cl)nc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(COC(=O)c1ccc(Cl)nc1)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Yield: 78 %

Procedure:
To a mixture of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-hydroxyacetoxy)ethyl)pyridine 1-oxide (See Scheme 21, step 6-9) (200 mg, 0.418 mmol), 6-chloronicotinic acid (72.5 mg, 0.460 mmol) and EDC (240 mg, 1.255 mmol) in dry DCM (10 ml), DMAP (51.1 mg, 0.418 mmol) was added, and stirring was continued for a week-end at room temperature. The solvent was evaporated; the residue was portioned between sat. sol. NaHCO3 and ethyl acetate, the organic phase was washed with brine, dried over sodium sulfate and evaporated, the residue was purified by flash chromatography on silica gel (eluent: DCM/MeOH/32% NH4OH 98/2/0.2) and (S)-3,5-dichloro-4-(2-(2-(6-chloronicotinoyloxy)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)pyridine 1-oxide was obtained as a white solid (202 mg, 0.327 mmol, 78% yield, MS/ESI+ 617.2 [MH]+).