Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][C:12]([CH:15]([O:18][C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)[CH2:16][CH3:17])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:37]([O:41][C:42](=[O:46])[CH2:43][CH2:44][NH2:45])(C)(C)C.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:29][C:2]([F:1])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[CH:13][C:12]([CH:15]([O:18][C:19]3[CH:27]=[CH:26][C:22]([C:23]([NH:45][CH2:44][CH2:43][C:42]([O:41][CH3:37])=[O:46])=[O:24])=[CH:21][CH:20]=3)[CH2:16][CH3:17])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: CCC(Oc1ccc(C(=O)O)cc1)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Reactant: CC(C)(C)OC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(Oc1ccc(C(=O)NCCC(=O)OC)cc1)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.6 %

Procedure:
To a mixture of 4-{1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-propoxy}-benzoic acid (345 mg, 0.86 mmol) in methylene chloride (10 mL) are added triethyl amine (0.36 mL, 2.58 mmol), DMAP (5.0 mg), 3-amino-propionic acid tert-butyl ester (468.2 mg, 2.58 mmol) and EDCI (495.6 mg, 2.58 mmol) at room temperature. The reaction mixture is stirred at room temperature overnight, loaded on silica gel, eluted with eluted with hexanes with a gradient from 0% of ethyl acetate to 100% of ethyl acetate giving methyl 3-(4-{1-[6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-propoxy}-benzoylamino)-propionoate (400 mg).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:4]=1[CH2:10][C:11](=[NH:15])[O:12][CH2:13][CH3:14].[N:16]#[C:17]N>C(O)C.C(OCC)C>[C:17]([N:15]=[C:11]([O:12][CH2:13][CH3:14])[CH2:10][C:4]1[CH:5]=[CH:6][C:7]([F:9])=[CH:8][C:3]=1[F:2])#[N:16]
Reactant: CCOC(=N)Cc1ccc(F)cc1F
Reactant: N#CN
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: CCOC(Cc1ccc(F)cc1F)=NC#N
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of Example 4A (7.0 g, 29.7 mmol) in ethanol (100 mL) was added a solution of cyanamide (1.25 g, 29.7 mmol) in diethyl ether (25 mL). The reaction mixture was stirred at room temperature for 3 days. The reaction mixture was then filtered and the filtrate was concentrated to obtain the titled compound. MS (ESI+) m/z 225 (M+H)+.
Reaction SMILES: C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].Br[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.[F:23][C:24]([F:36])([F:35])[O:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1>O>[F:23][C:24]([F:35])([F:36])[O:25][C:26]1[CH:31]=[C:30]([C:15]2[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1ccc(-c2cccc(OC(F)(F)F)c2)cc1
Temperature: 25 °C
Yield: 80.8 %

Procedure:
A mixture of toluene (35 mL) and water (5 mL) was degassed with nitrogen for 30 minutes. A mixture of sodium carbonate (1.9 g, 18.09 mmol), 4-bromobenzaldehyde (0.7 g, 3.72 mmol), 3-trifluoromethoxyphenylboronic acid (2.86 g, 4.78 mmol) and tetrakis triphenyl phosphene palladium(0) (0.9 g, 0.75 mmol) was added to the above degassed water/toluene mixture. The reaction mixture was refluxed overnight. After the reaction is completed it was cooled to room temperature and extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate and concentrated. The resulting residue was purified by column chromatography using 5% ethyl acetate in hexane to obtain the title compound (0.8 g, 80%).
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][NH:7][S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:21](Cl)(=[O:24])[CH:22]=[CH2:23]>C(Cl)Cl>[C:21]([O:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][NH:7][S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1)(=[O:24])[CH:22]=[CH2:23]
Reactant: C=CC(=O)Cl
Reactant: CS(=O)(=O)NCc1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)Oc1ccc(CNS(C)(=O)=O)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 20.1 g (0.10 mol) of N-(4-hydroxybenzyl)methanesulfonamide, 10.1 g (0.10 mol) of triethylamine and 100 ml of methylene chloride cooled to approximately 0° C. was added a solution of 9.0 g (0.10 mol) of acryloyl chloride in 50 ml of methylene chloride over a 10-minute period. Stirring was continued for 30 minutes, and the mixture was filtered. The filtrate was washed twice with water, dried over magnesium sulfate and concentrated in a rotary evaporator. The residue was recrystallized from 100 ml of 1:1 hexane:1,2-dichloroethane. The yield of N-(4-acryloyloxybenzyl)methanesulfonamide was 8.2 g (32.1 percent of theory), m.p.=112° to 115° C.
Reaction SMILES: [CH:1](=[O:10])[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:11]([Mg]Br)=[CH2:12].[NH4+].[Cl-]>C1COCC1>[C:4]1([CH2:3][CH2:2][CH:1]([OH:10])[CH:11]=[CH2:12])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=CCCc1ccccc1
Reactant: C=C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=CC(O)CCc1ccccc1
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 62.6 %

Procedure:
A modified procedure of Molander was used (Molander, G. A. et al., The Journal of Organic Chemistry 2009, 74, 1297). A stirred solution of hydrocinnamaldehyde 65 (2.50 g, 2.45 ml, 18.6 mmol) in THF (25 ml) was cooled to −78° C. Vinyl magnesium bromide solution (1 M in THF) (22.4 ml, 22.4 mmol) was added dropwise over ˜5 min. The reaction mixture was stirred at −78° C. for 1.5 h, then 0° C. for 3 h. The reaction mixture was poured into saturated NH4Cl solution (50 ml) and extracted with Et2O (3×50 ml). The combined organic phases were washed with saturated NaCl solution (50 ml) before being dried (MgSO4), filtered and concentrated to give a pale yellow liquid. This material was purified by column chromatography, eluting with petrol/EtOAc (9:1), to give the vinyl alcohol 64 (1.89 g, 63%) as a clear colourless liquid. The 1H, 13C, and IR data were consistent with the literature (Molander, G. A. et al., The Journal of Organic Chemistry 2009, 74, 1297; Kim, J. W. et al., Chemistry—A European Journal 2008, 14, 4104).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([OH:14])=[O:13])(=[O:7])=[O:6].C(Cl)(=O)C(Cl)=O.[CH:31](O)([CH3:33])[CH3:32].N1C=CC=CC=1>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([O:14][CH:31]([CH3:33])[CH3:32])=[O:13])(=[O:6])=[O:7]
Reactant: CC(C)O
Reactant: CC(C)(COS(=O)(=O)CCCCl)[C@@H](OCc1ccccc1)C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)OC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCCl
Yield: 76.3 %

Procedure:
Following the general procedure for the preparation of carboxylic esters from carboxylic acids of Description 15, (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoic acid (11) (0.73 g, 1.9 mmol) dissolved in 20 mL of anhydrous dichloromethane (DCM) was reacted with 1.1 mL (2.2 mmol) of oxalyl chloride (2.0 M in DCM). After completion of the reaction, a solution of 2 mL (1.57 g, 26.1 mmol) of isopropanol (iPrOH) and 0.16 mL of pyridine (0.15 g, 1.9 mmol) in 10 mL of anhydrous dichloromethane (DCM) was added to the acid chloride. After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (EtOAc/Hxn=1:2) as eluent to provide 0.61 g (75% yield) of the title compound (25a) as a colorless oil. Rf=0.67 (EtOAc/Hxn=1:2). 1H NMR (400 MHz, CDCl3): δ=1.06 (s, 3H), 1.08 (s, 3H), 1.30-1.32 (m, 3H), 2.25-2.32 (m, 2H), 3.65 (t, J=5.6 Hz, 2H), 3.81 (s, 1H), 3.98 (d, J=9.2 Hz, 1H), 4.23 (d, J=9.2 Hz, 1H), 4.35 (d, J=11.2 Hz, 1H), 4.62 (d, J=11.2 Hz, 1H), 5.14 (m, 1H), 7.33-7.36 (m, 5H) ppm. MS (ESI) m/z 420.94 (M+H)+, 442.95 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: C([O:8][C:9]([C:11]1([N:17]([C:36](=[O:41])[CH2:37][CH2:38][CH2:39][CH3:40])[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:35][N:34]=[N:33][N:32]=3)=[CH:21][CH:20]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10])C1C=CC=CC=1.C(OCC)(=O)C>O1CCOCC1.[Pd]>[C:9]([C:11]1([N:17]([C:36](=[O:41])[CH2:37][CH2:38][CH2:39][CH3:40])[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[NH:32][N:33]=[N:34][N:35]=3)=[CH:21][CH:20]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([OH:10])=[O:8]
Reactant: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)C1(C(=O)OCc2ccccc2)CCCCC1
Agent: [Pd]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1)C1(C(=O)O)CCCCC1

Procedure:
A solution of 2.4 g (4.3 mmol) of N-(1-benzyloxycarbonylcyclohexyl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine in 40 ml of dioxan is hydrogenated with the addition of 0.5 g of Pd/C (10%) and worked up, in a manner analogous to that described in Example 73. The N-(1-carboxycyclohexyl)-N-pentanoyl-N-[2'-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-amine is thus obtained in the form of colourless crystals (from ethyl acetate) melting between 134° and 136°.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:3]=1[O:4][CH2:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[CH3:22])=[O:7].N1C=CC=CC=1.Cl[C:35]([O:37][C:38]1[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=1)=[O:36]>ClCCl>[N+:44]([C:41]1[CH:40]=[CH:39][C:38]([O:37][C:35](=[O:36])[NH:1][C:2]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:3]=2[O:4][CH2:5][C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH2:10][C@H:9]2[CH3:22])=[O:7])=[CH:43][CH:42]=1)([O-:46])=[O:45]
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ccc(Cl)cc1N
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@@H]1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ccc(Cl)cc1NC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a solution of 2-(2-amino-4-chloro-phenoxy)-1-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1-yl]-ethanone (0.14 g, 0.36 mmol) in dichloromethane (5 mL) was added pyridine (0.032 mL, 0.39 mmol) and 4-nitrophenyl chloroformate (0.079 g, 0.39 mmol). The reaction was stirred at ambient temperature for one hour and concentrated in vacuo to give the title compound (0.20 g).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]=[O:8].[Br:9]Br.O>C(Cl)(Cl)Cl>[Br:9][C:5]1[S:4][C:3]([CH:7]=[O:8])=[C:2]([CH3:1])[CH:6]=1
Reactant: BrBr
Reactant: Cc1ccsc1C=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1cc(Br)sc1C=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a solution of 3-methylthiophene-2-carbaldehyde (5.7 g) in chloroform (40 mL) was added dropwise bromine (2.5 mL) at 0° C. and, after the completion of the dropwise addition, the mixture was and stirred at 0° C. for 30 min, and then at room temperature for 1 hr, and then under reflux overnight. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was crystallized from ethyl acetate/hexane to give the title compound (8.1 g, 88%) as a brown solid.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=2.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].I[CH2:25][CH3:26].C(OCC)(=O)C>CN(C=O)C>[CH2:25]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=2)[CH:10]=[C:2]1[CH3:1])[CH3:26]
Reactant: Cc1cc2ccc([N+](=O)[O-])cc2[nH]1
Reactant: CCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCn1c(C)cc2ccc([N+](=O)[O-])cc21
Reaction time: 2 h
Yield: 100 %

Procedure:
Cool a solution of 2-methyl-6-nitro-1H-indole, 18 (0.31 g, 1.76 mmol) in anhydrous DMF (5 mL) under inert atmosphere at 0° C. Add sodium hexamethyldisilazide (1.0M in THF, 1.9 mL, 1.9 mmol) and stir 5 minutes. Add iodoethane (filtered through basic alumina) (0.43 mL, 5.28 mmol), warm to ambient temperature, and stir 2 hours. Quench the reaction with saturated aqueous sodium bicarbonate, add ethyl acetate, and wash with saturated aqueous sodium bicarbonate followed by saturated aqueous brine. Dry the organic layer over sodium sulfate, filter, and concentrate in vacuo. Chromatograph over silica gel using hexanes/ethyl acetate (9:1) to afford the title compound, (0.36 g, 100%). 1H NMR (CDCl3, 300 MHz) δ 2.47 (s, 31), 4.18 (q, J=7.1 Hz, 2), 6.23 (s, 3H), 7.48 (d, J=8.8 Hz, 1H), 7.95 (dd, J=1.9, 8.6 Hz, 1H), 8.23 (d, J=1.9 Hz, 1H).
Reaction SMILES: Br[C:2]1[C:3]([O:21][CH2:22][CH3:23])=[C:4]([CH:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12])[CH:5]=[C:6]([Cl:10])[C:7]=1[C:8]#[N:9].[CH3:24][S:25]([C:28]1[CH:29]=[N:30][CH:31]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:33]=1)(=[O:27])=[O:26].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([C:32]2[CH:31]=[N:30][CH:29]=[C:28]([S:25]([CH3:24])(=[O:27])=[O:26])[CH:33]=2)[C:3]([O:21][CH2:22][CH3:23])=[C:4]([CH:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12])[CH:5]=1
Reactant: CC1(C)OB(c2cncc(S(C)(=O)=O)c2)OC1(C)C
Reactant: CCOc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C#N)c1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCOc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C#N)c1-c1cncc(S(C)(=O)=O)c1
Temperature: 100 °C
Yield: 62.5 %

Procedure:
To tert-butyl [-1-(3-bromo-5-chloro-4-cyano-2-ethoxyphenyl)ethyl]carbamate (50 mg, 0.1 mmol, from Example 179, Step 3) and 3-(methylsulfonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (30. mg, 0.11 mmol, Peptech, catalog #BE358) in 1,4-dioxane (4 mL) was added potassium carbonate (30 mg, 0.2 mmol) in water (2 mL). The reaction was degassed with N2. Tetrakis(triphenylphosphine)palladium(0) (40 mg, 0.04 mmol) was added and degassed again with N2. The reaction was heated at 100° C. overnight. The reaction was allowed to cool to room temperature and was partitioned between EtOAc and water. The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated to give crude product. The product was purified by chromatography on silica gel eluting with a hexane:EtOAc gradient to give tert-butyl (1-{5-chloro-4-cyano-2-ethoxy-3-[5-(methylsulfonyl)pyridin-3-yl]phenyl}ethyl)carbamate as a yellow oil (0.030 g, 60%). LCMS calculated for C22H27ClN3O5S (M+H)+: m/z=480.1. found: 480.1.
Reaction SMILES: [OH:1][C@@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[F:29][C:30]([F:39])([F:38])[C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[CH3:20][CH:19]([CH3:21])[C:18]([NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH:8]2[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][C@@H:2]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[O:1][C:34]3[CH:35]=[CH:36][C:31]([C:30]([F:39])([F:38])[F:29])=[CH:32][CH:33]=3)[CH2:6][CH2:7]2)[CH:12]=1)=[O:22]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](O)c3ccccc3)CC2)c1
Reactant: Oc1ccc(C(F)(F)F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](Oc3ccc(C(F)(F)F)cc3)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 38.9 %

Procedure:
A mixture of N-(3-{1-[(3R)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (9.53 mg, 0.0250 mmol), 4-trifluoromethylphenol (8.100 mg, 0.050 mmol), triphenylphosphine (9.8 mg, 0.0375 mmol) and diethyl azodicarboxylate (5.22 mg, 0.0300 mmol) in THF (1.0 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (5.10 mg, 38.9% yield) as a thick oil: 1H NMR δ 8.06 (s, 1H), 7.49 (s, 1H), 7.44 (apparent d, 2H, J=0.6 Hz), 7.38-7.30 (m, 4H), 7.30-7.20 (m, 3H), 6.96 (apparent d, 1H, J=7.6 Hz), 6.91 (apparent d, 2H, J=8.6 Hz), 5.34 (m, 1H), 3.19 (m, 2H), 2.72 (m, 2H), 2.53 (m, 2H), 2.40-1.80 (m, 8H), 1.25 (d, 6H, J=6.8 Hz); ESMS m/e: 525.4 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=4[CH3:30])[C:24](O)=[O:25])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[N:31]1[CH:36]=[C:35]([C:37]2([NH2:40])[CH2:39][CH2:38]2)[CH:34]=[N:33][CH:32]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([C:24](=[O:25])[NH:40][C:37]5([C:35]6[CH:36]=[N:31][CH:32]=[N:33][CH:34]=6)[CH2:39][CH2:38]5)[CH:27]=[CH:28][C:29]=4[CH3:30])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:6][CH:7]=1
Reactant: NC1(c2cncnc2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5cncnc5)CC4)ccc3C)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.1 g, 0.25 mmol, 1 eq), 1-(pyrimidin-5-yl)cyclopropanamine (0.041 g, 0.3 mmol, 1.2 eq) (60% purity), HOBT (0.057 g, 0.42 mmol, 1.7 eq), EDC.HCl (0086 g, 0.44 mmol, 1.8 eq) in DCM at ambient temperature under nitrogen was added Diisopropylehtylamine (0.162 g, 1.2 mmol, 5.0 eq). The clear mixture was stirred at ambient temperature for overnight. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer is further washed with water, dried over sodium sulphate and concentrated. The product obtained was further purified by column chromatography (neutral alumina) using 0.5% Methanol/DCM and finally it was purified by preparative HPLC. Yield: 0.02 g (20%). 1H NMR (400 MHz, DMSO-d6): δ 1.34-1.35 (m, 2H), 1.41-1.42 (m, 2H), 2.29 (s, 3H), 2.81-2.82 (d, 3H), J=4.56 Hz), 738-7.45 (m, 4H), 7.58 (d, 1H, J=0.96 Hz), 7.75 (d, 1H, J=8.4 Hz), 7.81 (s, 1H), 7.83 (m, 1H), 7.98-8.01 (m, 2H), 8.46-8.47 (d, 1H, J=4.6 Hz), 8.64 (s, 2H), 9.01 (s, 1H), 9.31 (s, 1H). LCMS: (ES+) m/z=521.2 (M+H). LCMS Method: Column-Ascentis Express C18 (5×2.1 mm-2.7 μm) Mphase A: 2% ACN-98% H2O-10 mM NH4COOH Mphase B: 98% ACN-2% H2O-10 mM NH4COOH Flow: 1 ML/Min
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]2=[CH:9][CH:10]=[C:11]([CH:12]=O)[N:5]2[N:4]=1.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O)(=O)C.C(Cl)Cl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]2=[CH:9][CH:10]=[C:11]([CH2:12][NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:5]2[N:4]=1
Reactant: CSc1ncc2ccc(C=O)n2n1
Reactant: Nc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CSc1ncc2ccc(CNc3ccccc3)n2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
2-Methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine-7-carbaldehyde (0.200 g, 1.04 mmol) and Aniline (0.104 mL, 1.14 mmol) were dissolved in a solution of Acetic acid (0.100 mL, 1.76 mmol) and Methylene chloride (10 mL, 200 mmol) and the reaction was allowed to stir at room temperature for 1 hour. Sodium triacetoxyborohydride (0.439 g, 2.07 mmol) was then added and the reaction was allowed to continue stirring at room temperature until HPLC showed consumption of starting material. The reaction mixture was poured over saturated sodium bicarbonate and organics were extracted with dichloromethane. Combined extracts were then dried over sodium sulfate, filtered and reduced. The crude reaction mixture was then purified by Isco flash column chromatography (hexanes/ethyl acetate eluent) and combined fractions were reduced and dried under vacuum to afford 0.280 g of (2-Methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-7-ylmethyl)-phenyl-amine. 1H NMR (400 MHz, DMSO, d6) δ 8.92 (s, 1H), 7.06 (m, 2H), 6.90 (d, 1H, J=4.61 Hz), 6.83 (d, 1H, J=4.61 Hz), 6.65 (m, 2H), 6.54 (t, 1H, J=7.28 Hz), 6.13 (t, 1H, J=6.16 Hz), 4.61 (d, 2H, J=6.16 hz), 2.56 (s, 3H).
Reaction SMILES: [Na].[CH3:2][OH:3].[CH3:4][C:5]1[CH:10]=[C:9]([N+]([O-])=O)[C:8]([CH3:14])=[CH:7][N+:6]=1[O-:15].Cl>C(OCC)(=O)C>[CH3:2][O:3][C:9]1[C:8]([CH3:14])=[CH:7][N+:6]([O-:15])=[C:5]([CH3:4])[CH:10]=1
Reactant: Cc1c[n+]([O-])c(C)cc1[N+](=O)[O-]
Reactant: CO
Agent: Cl
Agent: [Na]
Solvent: CCOC(C)=O
Product: COc1cc(C)[n+]([O-])cc1C

Procedure:
12.2 g of sodium were dissolved 2 1 of methanol under argon, whereupon 60 g of 2,5-dimethyl-4-nitropyridine 1-oxide were added portionwise and the solution was left to boil under reflux overnight. The pH was adjusted to 7 with 5N hydrogen chloride in ethyl acetate while cooling and the mixture was evaporated in vacuo. The residue was taken up in 1 1 of methylene chloride, the solution was filtered through silica gel, which was rinsed with 0.4 1 of methylene chloride, and the combined filtrates were evaporated in vacuo The residue crystallized from methylene chloride/petroleum ether and there was obtained 4-methoxy-2,5-dimethylpyridine 1-oxide of melting point 99-101° .
Reaction SMILES: C([O:5][C:6](=[O:38])[CH:7]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][O:28][C:29]3[S:30][C:31]4[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=4[N:33]=3)=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[S:30]1[C:31]2[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=2[N:33]=[C:29]1[O:28][CH2:27][C:24]1[CH:25]=[CH:26][C:21]([C:18]2[CH:19]=[CH:20][C:15]([S:12]([NH:11][CH:7]([CH:8]([CH3:10])[CH3:9])[C:6]([OH:38])=[O:5])(=[O:14])=[O:13])=[CH:16][CH:17]=2)=[CH:22][CH:23]=1
Reactant: CC(C)C(NS(=O)(=O)c1ccc(-c2ccc(COc3nc4ccccc4s3)cc2)cc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(NS(=O)(=O)c1ccc(-c2ccc(COc3nc4ccccc4s3)cc2)cc1)C(=O)O
Reaction time: 6 h

Procedure:
Step 4B 2-[4′-(Benzothiazol-2-yloxymethyl)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid tert-butyl ester (140 mg, 0.25 mml) was dissolved in 6 mL of methylene chloride followed by the addition of TFA (3 mL) The reaction was complete in 6 hrs as determined by TLC. Solvent was removed and the residue was dissolved in EtOAc. n-Hexane was added into the solution and solid precipitated from the mixture. The precipitate was collected and dried to afford 86 mg of in 68% yield.