Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH2:5][C:6]([OH:8])=O)[CH3:2].N1C=CC=CC=1C1C=CC=CN=1.[CH3:22][O:23][C:24]([C:26]1[C:35]2[C:30](=[CH:31][C:32]([CH2:36]C(Cl)=O)=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1)=[O:25].Cl>C1COCC1.CCOCC>[CH3:22][O:23][C:24]([C:26]1[C:35]2[C:30](=[CH:31][C:32]([CH2:36][C:6](=[O:8])[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:9])=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1)=[O:25]
Reactant: COC(=O)c1cccc2cc(CC(=O)Cl)ccc12
Reactant: CCOC(=O)CC(=O)O
Agent: Cl
Agent: c1ccc(-c2ccccn2)nc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)CC(=O)Cc1ccc2c(C(=O)OC)cccc2c1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A solution of 8.56 g (64.8 mMol) of malonic acid monoethyl ester and 112 mg (0.72 mMol) 2,2′-bipyridine in 200 ml THF is cooled to −78° C. Then 60 ml of a 1.6 M solution of nbutyllithium in THF are added dropwise (color changes from yellow to red!). Warming the mixture up to −10° C., renders the mixture turn to yellow again. Addition of another 10 ml of a 1.6 M solution of nbutyllithium in THF results in a persistent red color of the mixture. After cooling to −78° C., a suspension of 36 mMol 6-chlorocarbonylmethyl-naphthalene-1-carboxylic acid methyl ester in 250 ml THF is added during 40 min and then stirring is continued for 1 h. The dark mixture is poured into 200 ml of 1 N HCl and 400 ml ether, the aq. phase separated off and extracted with 2 portions of EtOAc. The organic layers are washed with brine, dried (Na2SO4) and concentrated to the title compound which can be used in the Step 3.6 as such. Pure product can be obtained by chromatography (Combi Flash; hexane/EtOAc 85:15): MS: [M−1]=313; HPLC: tRet=15.5.
Reaction SMILES: [NH2:1][C:2]1[CH:33]=[CH:32][C:5]([O:6][CH2:7][CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([C:16]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[OH:17])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[CH3:34][N:35]=[C:36]=[O:37]>C1C=CC=CC=1>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:16]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)([OH:17])[CH:13]2[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][CH2:7][O:6][C:5]3[CH:32]=[CH:33][C:2]([NH:1][C:36]([NH:35][CH3:34])=[O:37])=[CH:3][CH:4]=3)[CH2:11][CH2:12]2)=[CH:19][CH:20]=1
Reactant: Nc1ccc(OCCCN2CCC(C(O)(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1
Reactant: CN=C=O
Solvent: c1ccccc1
Product: CNC(=O)Nc1ccc(OCCCN2CCC(C(O)(c3ccc(F)cc3)c3ccc(F)cc3)CC2)cc1
Reaction time: 1 h
Yield: 31.4 %

Procedure:
To a solution of 4.5 g (0.01 mole) of 1-[3-(4-aminophenoxy)propyl]-α,α-bis(4-fluorophenyl)-4-piperidinemethanol in 50 ml of benzene was added dropwise a solution of 0.6 g (0.01 mole) of methylisocyanate in 10 ml of benzene. The mixture was stirred for 1 hr during which time a solid precipitated. The mixture was diluted with 25 ml of cyclohexane, the solid was collected by filtration and recrystallized from 2-propanol to yield 1.6 g (31%) of title compound as a white solid, mp 177°-178° C.
Reaction SMILES: [C:1](ON=O)(C)([CH3:3])[CH3:2].C(Br)C=C.N[C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1.NC1C=CC=CC=1>CC#N>[CH2:3]([C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1)[CH:1]=[CH2:2]
Reactant: CC(C)(C)ON=O
Reactant: N#Cc1ccc(N)cc1
Solvent: Nc1ccccc1
Solvent: C=CCBr
Solvent: CC#N
Product: C=CCc1ccc(C#N)cc1
Temperature: 43 °C
Yield: 37.2 %

Procedure:
To a solution of t-butylnitrite (535 μl, 4.5 mmol) and allyl bromide (3.9 ml, 45.0 mmol) in CH3CN (3 ml), 4-aminobenzonitrile (354 mg, 3.0 mmol) was added during 20 minutes, while maintaining the temperature of the reaction mixture at 42-44° C. At the end of the addition of the aniline, extra t-butylnitrite (180 μl, 1.5 mmol) was added to the reaction mixture which then was stirred at 50° C. for three hours during which extra t-butylnitrite (180 μl, 1.5 mmol) was added. The volatile material in the reaction mixture was removed at reduced pressure. Heptane-ethyl acetate (10 ml, 1:1) was then added to the crude product and the mixture was filtered. Column chromatography (heptane-ethyl acetate 49:1) of the concentrated filtrate gave 160 mg (37%) 4-allyl-benzonitrile as a clear oil containing 16% of 4-bromo-benzonitrile. This corresponds to 30% yield of 4-allylbenzonitrile. 1H NMR (CDCl3, 400 MHz) δ 7.60, (m, 2H, J=8.3 Hz), 7.31, (m, 2H, J=8.3 Hz), 5.99-5.88, (m, 1H), 5.18-5.08, (m, 2H), 3.46, (d, 2H, J=6.7 Hz); Anal HRMS Calcd. for C10H9N (M): 143.0735. Found: 143.0734.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].O=S(Cl)[Cl:14]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[C:7]([Cl:14])=[O:8]
Reactant: O=C(O)c1cc(Cl)ccc1I
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)c1cc(Cl)ccc1I
Temperature: 100 °C

Procedure:
To a solution of 5-chloro-2-iodobenzoic acid (3.0 g, 10.6 mmol) in toluene (150 mL), SOCl2 (7.75 mL, 106 mmol) was added and the mixture was heated at 100° C. for 3 hours. The solvent was concentrated in vacuum and the residue was co-evaporated from toluene twice to give the title compound as a grey solid. Yield (3.2 g, 100%)
Reaction SMILES: [CH:1](=[C:8]1[CH2:12][N:11]([C:13]([O:15]C(C)(C)C)=O)[C@H:10]([C:20]([OH:22])=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:34]=[CH:33][C:27]([O:28][CH2:29]C(Cl)=O)=[CH:26][CH:25]=1.[CH3:35][O:36][C:37]1[CH:38]=[C:39]([CH:42]=[CH:43][C:44]=1[O:45][CH3:46])[CH2:40][NH2:41]>>[CH:1](=[C:8]1[CH2:12][N:11]([C:13](=[O:15])[CH2:29][O:28][C:27]2[CH:26]=[CH:25][C:24]([Cl:23])=[CH:34][CH:33]=2)[C@H:10]([C:20]([NH:41][CH2:40][C:39]2[CH:42]=[CH:43][C:44]([O:45][CH3:46])=[C:37]([O:36][CH3:35])[CH:38]=2)=[O:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(=Cc2ccccc2)C[C@H]1C(=O)O
Reactant: O=C(Cl)COc1ccc(Cl)cc1
Reactant: COc1ccc(CN)cc1OC
Product: COc1ccc(CNC(=O)[C@@H]2CC(=Cc3ccccc3)CN2C(=O)COc2ccc(Cl)cc2)cc1OC

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-benzylidene-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, (4-chlorophenoxy)acetyl chlo-ride, and 3,4-dimethoxybenzylamine the title compound was obtained in 49% purity by LC/MS. MS(ESI+): m/z=521.6.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([C:15]2[N:19]([CH3:20])[C:18]([O:21][CH:22]([C:24]3[CH:28]=[C:27]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=4)[O:26][N:25]=3)[CH3:23])=[N:17][N:16]=2)[CH:12]=[CH:11][N:10]=1)C1C=CC=CC=1>C(O)C.[Pd].ClCCl>[Cl:35][C:31]1[CH:30]=[C:29]([C:27]2[O:26][N:25]=[C:24]([CH:22]([O:21][C:18]3[N:19]([CH3:20])[C:15]([C:13]4[CH:12]=[CH:11][NH:10][C:9](=[O:8])[CH:14]=4)=[N:16][N:17]=3)[CH3:23])[CH:28]=2)[CH:34]=[CH:33][CH:32]=1
Reactant: CC(Oc1nnc(-c2ccnc(OCc3ccccc3)c2)n1C)c1cc(-c2cccc(Cl)c2)on1
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: CC(Oc1nnc(-c2cc[nH]c(=O)c2)n1C)c1cc(-c2cccc(Cl)c2)on1
Reaction time: 8 h
Yield: 37.8 %

Procedure:
The title compound of example 35.1 (125 mg, 0.256 mmol) was stirred in ethanol (2 mL). Palladium on carbon (10%, 50 mg) was added and the reaction was stirred under hydrogen (balloon pressure) overnight. The reaction mixture was then diluted with dichloromethane and filtered to remove the palladium catalyst. The filtrate was concentrated, then chromatographed in 10% methanol in ethyl acetate to yield the desired product (38.5 mg, 38%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([C:13]2[S:20][C:19]([CH3:21])=[C:18]3[C:14]=2[CH2:15][C@H:16]2[C:22]([CH3:24])([CH3:23])[C@H:17]23)=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].[CH2:25]([CH:27]1[O:29][CH2:28]1)Cl>C(O)(C)C.[OH-].[Na+].C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11]([C:13]2[S:20][C:19]([CH3:21])=[C:18]3[C:14]=2[CH2:15][C@H:16]2[C:22]([CH3:24])([CH3:23])[C@H:17]23)=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH2:25][CH:27]1[CH2:28][O:29]1
Reactant: Cc1sc(C(=O)CCc2ccc(O)c(Cl)c2)c2c1[C@H]1[C@@H](C2)C1(C)C
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: Cc1sc(C(=O)CCc2ccc(OCC3CO3)c(Cl)c2)c2c1[C@H]1[C@@H](C2)C1(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 24.3 %

Procedure:
A solution of 3-(3-chloro-4-hydroxy-phenyl)-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (139 mg, 0.385 mmol, Intermediate 6) in isopropanol (4 mL) and 3 N aq. NaOH (1.7 mL) is treated with epichlorohydrine (110 mg, 1.16 mmol). The reaction mixture is stirred at rt for 18 h. The mixture is diluted with acetic acid (0.3 mL) and the solvent is removed under reduced pressure. The residue is purified by prep. HPLC (Waters Xterra MS18, 75×30 mm ID, 10 μm, 10 to 95% acetonitrile in water containing 0.5% formic acid) to give 3-(3-chloro-4-oxiranylmethoxy-phenyl)-1-((1aS,5aR)1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (39 mg) as a pale yellow oil; LC-MS: tR=1.15 min, [M+1]+=417.21.
Reaction SMILES: [Cl:1]C(Cl)(Cl)COC([N:7]1[CH:12]2[CH2:13][CH2:14][CH2:15][CH:8]1[CH2:9][C:10](=[O:16])[CH2:11]2)=O.CCOCC>C(O)(=O)C.[Zn]>[ClH:1].[CH:8]12[NH:7][CH:12]([CH2:13][CH2:14][CH2:15]1)[CH2:11][C:10](=[O:16])[CH2:9]2
Reactant: O=C1CC2CCCC(C1)N2C(=O)OCC(Cl)(Cl)Cl
Agent: [Zn]
Solvent: CCOCC
Solvent: CC(=O)O
Product: Cl
Product: O=C1CC2CCCC(C1)N2
Temperature: 65 °C
Yield: 84.7 %

Procedure:
To suspension of zinc (67.2 g, 1.03 g-atom) in glacial acetic acid (40 mL) at 65° C. was slowly added a solution of 9-(2,2,2-trichlorocarbethoxy)-9-azabicyclo[3.3.1]nonan-3-one (80.9 g, 0.26 mol) in glacial acetic acid (120 mL) over 1 hour. An additional 40 mL of glacial acetic acid was used to rinse the addition funnel and the reaction was stirred at 65° C. until no further gas evolution was observed. The reaction was allowed to cool slightly and water (40 mL) was added to dissolve the organic acetate salts. The reaction was filtered and solvent was removed under vacuum. The resultant orange oil was slowly added to concentrated ammonium hydroxide (80 mL) using water (80 mL) to aid in the transfer. An additional 80 mL of concentrated ammonium hdroxide was added, followed by the addition of a solution of 31 g of sodium hydroxide in 155 mL of water. The solution was extracted with methylene chloride (6×300 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to an oil. The oil was dissolved in 200 mL of ether and the solution was slowly added to 1N hydrogen chloride in ether (310 mL) while vigorously stirring to give 38.7 g (86% yield) of a colorless hydrochloride, m.p. 216°-219° C. after trituration with ether and drying. Anal. (C8H14ClNO).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:12]=2[N:13]=1.CCN(C(C)C)C(C)C.[CH3:28][C:29]1[CH:34]=[C:33]([CH3:35])[CH:32]=[C:31]([CH3:36])[C:30]=1[S:37](Cl)(=[O:39])=[O:38]>O1CCOCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[NH:10][C:11]2[CH:17]=[C:16]([NH:18][S:37]([C:30]3[C:31]([CH3:36])=[CH:32][C:33]([CH3:35])=[CH:34][C:29]=3[CH3:28])(=[O:39])=[O:38])[CH:15]=[CH:14][C:12]=2[N:13]=1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: Nc1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1cc(C)c(S(=O)(=O)Nc2ccc3nc(-c4c(Cl)cccc4Cl)[nH]c3c2)c(C)c1
Reaction time: 8 h

Procedure:
To a vial containing a solution of 2-(2,6-dichloro-phenyl)-3H-benzoimidazol-5-ylamine, prepared as described in Example 1-6, in dioxane (0.2 M, 0.10 mL) was added DIPEA (0.5 M in toluene, 0.050 mL), followed by 2,4,6-trimethyl-benzenesulfonyl chloride (0.2 M in toluene, 0.12 mL). After overnight at ambient temperature, solid phase extraction (SPE) by strong cation exchange (SCX) was followed by silica gel column chromatography to give N-[2-(2,6-Dichloro-phenyl)-3H-benzoimidazol-5-yl]-2,4,6-trimethyl-benzenesulfonamide: MS (m/z) 460.06 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18]3[N:23]=[CH:22][C:21]4=[CH:24][CH:25]=[C:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[O:33][CH3:34])[N:20]4[N:19]=3)[CH:15]=2)[CH2:10][CH:9]1[OH:35])(C)(C)C.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>C(Cl)Cl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[NH2:7][CH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:18]3[N:23]=[CH:22][C:21]4=[CH:24][CH:25]=[C:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=5[O:33][CH3:34])[N:20]4[N:19]=3)[CH:15]=2)[CH2:10][CH:9]1[OH:35]
Reactant: COc1ccccc1-c1ccc2cnc(Nc3ccc4c(c3)C(NC(=O)OC(C)(C)C)C(O)C4)nn12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccccc1-c1ccc2cnc(Nc3ccc4c(c3)C(N)C(O)C4)nn12

Procedure:
The titled compound was prepared through an acid catalyzed deprotection using {2-hydroxy-6-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-indan-1-yl}-carbamic acid tert-butyl ester and trifluoroacetic acid in methylene chloride to provide 1-amino-6-[7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-indan-2-ol; compound with trifluoroacetic acid as a tan lyophilate. LCMS (E/I+) 371 (M+H). 1H NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 8.97 (s, 1H), 8.33 (m, 3H), 7.86 (d, 2H, J=7.6 Hz), 7.56 (s, 1H), 7.44 (t, 1H, J=8 Hz), 7.21 (d, 1H, J=8 Hz), 7.13 (m, 2H), 6.98 (d, 1H, J=4.5 Hz), 6.94 (d, 1H, J=4.5 Hz), 5.55 (broad s, 1H), 4.31 (d, 2H, J=23 Hz), 3.79 (s, 3H), 3.22 (dd, 1H, J=5.8, 15.4 Hz), 2.71 (dd, 1H, J=4.5, 15.7 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[O:5][CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.CS(O[CH2:21][CH:22]1[O:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23]1)(=O)=O>C(#N)C>[NH3:9].[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[Cl:15])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:21][CH:22]2[O:27][CH2:26][CH2:25][N:24]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:23]2)[CH2:8][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCOC(COS(C)(=O)=O)C1
Reactant: Clc1ccc(OC2CCNCC2)cc1Cl
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCOC(CN2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)C1
Product: N

Procedure:
To a solution of the product from Example 1, Step (b) dissolved in acetonitrile (12 ml) was added the product of Example 2, Step (a). The mixture was refluxed for 12 hrs and the solvents were evaporated. Purification by flash chromatography (silica) eluting with dichloromethane: methanol: NH3 (aq) (2:98:0.1) gave the sub-title compound as an oil (1.9 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[F:11][CH2:12][CH2:13][NH2:14].CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:14][CH2:13][CH2:12][F:11])=[O:9]
Reactant: NCCF
Reactant: O=C(O)c1cncc(Br)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCF)c1cncc(Br)c1

Procedure:
2.03 g (10 mmol) 5-bromonicotinic acid, 1 g (1 eq.) 2-fluoroethylamine, 2.31 g (1.2 eq.) EDC.HCl, 123 mg (0.1 eq.) DMAP and 5.6 mL (4 eq.) triethylamine are stirred in 60 mL dichloromethane for 20 hours at room temperature. The reaction mixture is extracted with dichloromethane and water, the combined organic phases are washed with brine, dried with sodium sulfate and evaporated. The residue is triturated in diethylether and hexane to yield after filtration the desired product as a white powder. MS(ES+): 347 and 349 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([O:10][C:11](=[O:34])[NH:12][C:13]1[C:14]([CH3:33])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][CH:19]=1)[CH3:9].[CH2:35]([O:37][C:38](=[O:49])[C:39]([C:42]1[CH:47]=[CH:46][C:45](Br)=[CH:44][CH:43]=1)([CH3:41])[CH3:40])[CH3:36]>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>[CH2:35]([O:37][C:38](=[O:49])[C:39]([C:42]1[CH:47]=[CH:46][C:45]([C:21]2[CH:22]=[CH:23][C:18]([C:17]3[O:16][N:15]=[C:14]([CH3:33])[C:13]=3[NH:12][C:11]([O:10][CH:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH3:9])=[O:34])=[CH:19][CH:20]=2)=[CH:44][CH:43]=1)([CH3:41])[CH3:40])[CH3:36]
Reactant: CCOC(=O)C(C)(C)c1ccc(Br)cc1
Reactant: Cc1noc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c1NC(=O)OC(C)c1ccccc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: CCOC(=O)C(C)(C)c1ccc(-c2ccc(-c3onc(C)c3NC(=O)OC(C)c3ccccc3Cl)cc2)cc1

Procedure:
Following the procedure described in Example 17, Step 2, {3-methyl-5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-isoxazol-4-yl}-carbamic acid 1-(2-chloro-phenyl)-ethyl ester, 2-(4-bromo-phenyl)-2-methyl-propionic acid ethyl ester, and bis(triphenylphosphine)palladium(II) dichloride were reacted to provide 2-(4′-{-4-[1-(2-chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-2-methyl-propionic acid ethyl ester; further purification by preparative HPLC was required. The ester was hydrolyzed to the acid as described in Example 17, Step 3; purification by preparative HPLC was utilized.
Reaction SMILES: C[NH:2]N.[Br:4][C:5]1[CH:6]=[C:7]([CH3:21])[C:8]2[S:13][CH2:12][C:11](=[CH:14][N:15](C)[CH3:16])[C:10](=O)[C:9]=2[C:19]=1[CH3:20]>C(O)C>[Br:4][C:5]1[CH:6]=[C:7]([CH3:21])[C:8]2[S:13][CH2:12][C:11]3[C:10](=[N:2][N:15]([CH3:16])[CH:14]=3)[C:9]=2[C:19]=1[CH3:20]
Reactant: Cc1cc(Br)c(C)c2c1SCC(=CN(C)C)C2=O
Reactant: CNN
Solvent: CCO
Product: Cc1cc(Br)c(C)c2c1SCc1cn(C)nc1-2
Yield: 72.1 %

Procedure:
4.53 mL (0.085 mol) of methyl hydrazine (purchased from Aldrich Chemical Company) was added dropwise to a mixture of 21.54 g (0.066 mol) of the title compound of Step D in 115 mL of ethanol. The mixture was stirred at reflux under nitrogen for 5 hr and was then evaporated to dryness. The crude product was chromatographed over silica gel eluting with a mixture of (1:9) ethyl acetate:hexane to yield two components. Concentration of the major fraction yielded 14.72 g of the title compound of Step E as an oil; 1H NMR (CDCl3): δ2.3 (s,3H), 2.82 (s,3H), 3.76 (s,2H), 3.9 (s,3H), 7.2 (s, 1H), 7.3 (s,1H). Concentration of the minor fraction yielded 3.87 g of the isomer 8-bromo-1,4-dihydro-1,6,9-trimethyl[1]benzothiopyrano[4,3-c]pyrazole as an oil; 1H NMR (CDCl3): δ2.3 (s,3H), 2.46 (s,3H), 3.75 (s,3H), 3.59 and 3.81 (2d,2H), 7.4 (s,1H), 7.45 (s,1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6](C(C#N)=[CH:9][N:10]=2)[CH:7]=1.[OH-:13].[Na+].[CH3:15][CH2:16][OH:17]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:15]([C:16]([OH:13])=[O:17])=[CH:9][N:10]=2)[CH:7]=1
Reactant: N#Cc1cnc2ccc(Br)cn12
Reactant: [OH-]
Reactant: CCO
Agent: [Na+]
Product: O=C(O)c1cnc2ccc(Br)cn12
Reaction time: 12 h

Procedure:
A stirring solution of 6-bromoimidazo[1,2-a]pyridine-3-carbonitrile [JMC 54(7). 2455-2466; 2011] (1.0 g), EtOH (10 mL) and aq. NaOH (1.0 g, 10 mL) was heated at 100° C. After 12 h, the reaction mixture was cooled and concentrated to dryness by rotary evaporator under reduced pressure. Subsequently, the crude solid was diluted with water, cooled in ice-bath and acidified with conc. HCl till pH 4 while stirring. The resulting suspension was suction filtered and the solid was dried overnight. Subsequently, the collected solid was further dried over P2O5 under high vacuum to obtain 6-bromoimidazo[1,2-a]pyridine-3-carboxylic acid (0.91 g) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 13.27 (s, 1H), 9.36 (s, 1H), 8.24 (s, 1H), 7.77 (d, J=9.5 Hz, 1H), 7.67 (d, J=9.5, 1.7 Hz, 1H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([OH:10])([CH3:9])[CH2:6][C:7]#[CH:8].CN(C)C=O.N1C=CN=C1.Cl[Si:22]([CH3:25])([CH3:24])[CH3:23]>O>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([CH3:9])([O:10][Si:22]([CH3:25])([CH3:24])[CH3:23])[CH2:6][C:7]#[CH:8]
Reactant: C#CCC(C)(O)CCCCl
Reactant: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: C#CCC(C)(CCCCl)O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of 7-chloro-4-hydroxy-4-methyl-1-heptyne in 80 ml. of dimethylformamide at 0° C., is added 43.8 g. (0.644 moles) of imidazole and 35.02 g. (0.322 moles) of chlorotrimethylsilane. The mixture is stirred at room temperature for 45 minutes, poured into water and extracted with hexane. The hexane solution is washed with dilute sodium bicarbonate solution, dried over magnesium sulfate and the solvent removed leaving an orange liquid. This liquid is distilled giving the desired product in the fraction boiling at 83°-88° C., 1.5 mm. as a colorless liquid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@:19]([CH2:28][CH2:29][C:30]([NH2:32])=O)([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:18][C:17]3=[O:33])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C@@H:14]([N:16]3[CH2:21][CH2:20][C@:19]([CH2:28][CH2:29][C:30]#[N:32])([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[O:18][C:17]3=[O:33])[CH3:15])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CC[C@](CCC(N)=O)(c2ccccc2)OC1=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](c1ccc(-c2ccc(F)cc2)cc1)N1CC[C@](CCC#N)(c2ccccc2)OC1=O
Reaction time: 2 h
Yield: 7.5 %

Procedure:
To a solution of 3-((R)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanamide (110 mg, 0.25 mmol) and DIEA (170 mg, 1.05 mmol) in anhydrous CH2Cl2 (5 mL) was added TFAA (158 mg, 0.75 mmol) at 0° C. The mixture was stirred for 2 h. The solvent was removed under reduced pressure, and the residue was purified by preparative HPLC to afford 3-((R)-3-((S)-1-(4′-fluorobiphenyl-4-yl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propanenitrile (8 mg, yield 10%). LC-MS Method 3 tR=1.458, min, m/z=429.2; 1H NMR (CDCl3): 1.52 (d, 3H), 2.01 (m, 1H), 2.14 (m, 2H), 2.29 (m, 3H), 2.53 (m, 2H), 2.90 (m, 1H), 5.62 (m, 1H), 6.93 (m, 2H), 7.04 (m, 2H), 7.16-7.25 (m, 2H), 7.30-7.47 (m, 5H).
Reaction SMILES: [NH2:1][C:2]1[C:34]([Cl:35])=[CH:33][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:36][CH3:37])[CH:3]=1.[CH:38](=O)[CH3:39].C([BH3-])#N.[Na+]>>[NH2:1][C:2]1[C:34]([Cl:35])=[CH:33][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]([CH2:38][CH3:39])[CH2:23][C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:36][CH3:37])[CH:3]=1
Reactant: CC=O
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCCNCc2ccc([N+](=O)[O-])cc2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCN(CCCCCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)CC1)Cc1ccc([N+](=O)[O-])cc1

Procedure:
4-Amino-5-chloro-2-methoxy-N-((1-(6-(4-nitrobenzylamino)hexyl)-piperidin-4-yl)methyl)benzamide (0.89 g) as starting compound, acetaldehyde (0.11 ml) and sodium cyanoborohydride (0.25 g) were reacted and treated in the same manner as in Example 136 to give 0.4 g of 4-amino-5-chloro-N-((1-(6-(N-ethyl-N-(4-nitrobenzyl)amino)hexyl)-piperidin-4-yl)methyl)-2-methoxybenzamide.