Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]([CH:6]=O)=[CH:4][N:3]=[CH:2]1.[N:8]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N+:9]=[N-:10].[Na]>C(O)C>[N:8](/[C:11](=[CH:6]\[C:5]1[S:1][CH:2]=[N:3][CH:4]=1)/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N+:9]=[N-:10]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: O=Cc1cncs1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)/C(=C/c1cncs1)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 22.7 %

Procedure:
To a solution of thiazole-5-carbaldehyde (20 g, 176.77 mmol) and ethyl 2-azidoacetate (91.2 g, 707.1 mmol) in anhydrous ethanol (100 mL) was added sodium (16.26 g, 707.1 mmol) dissolved in anhydrous ethanol (1000 mL) dropwise between −10° C. and 0° C. After the addition, the mixture was stirred below 0° C. for 4 hours, and then warm to the ambient temperature and allowed to stir overnight. The reaction mixture was washed with saturated ammonium chloride, extracted with acetic ester (500 mL×3), the combined organic phase was dried by anhydrous sodium sulphate, and then filtered. The filtrate was concentrated and purified by column chromatograph on silica gel eluted with (petrol ether/acetic ester 20:1→10:1) to afford the title compound (9 g, 23%) as an yellow solid. LCMS (M+H+) m/z: calcd. 224.04. found 224.9.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][CH2:12]NC(C)C)=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH3:17][N:18]([CH3:35])[C:19]1[O:20][CH:21]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[C:22](=[O:24])[N:23]=1.C(P(CCCC)CCCC)CCC.C(OCC)(=O)C>C(#N)C.C(OCC)C>[CH3:17][N:18]([CH3:35])[C:19]1[O:20][C:21]([CH:11]([C:6]2[C:5]3[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=3)[NH:8][CH:7]=2)[CH3:12])([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[C:22](=[O:24])[N:23]=1
Reactant: CC(C)NCCc1c[nH]c2cc(F)ccc12
Reactant: CN(C)C1=NC(=O)C(C(=O)OCc2ccccc2)O1
Agent: CCCCP(CCCC)CCCC
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(c1c[nH]c2cc(F)ccc12)C1(C(=O)OCc2ccccc2)OC(N(C)C)=NC1=O
Yield: 60.9 %

Procedure:
To a mixture of 6-fluoro-3-(1-isopropylamino)ethylindole (435 mg), benzyl 2-dimethylamino-4-oxo-2-oxazolin-5-carboxylate (518 mg) in acetonitrile (15 ml) was added tri-n-butylphosphine (492 μl). The mixture was refluxed for 2.5 hours. Removal of the solvent gave a residue, to which a mixture of ethyl acetate and ethyl ether in a ration of 10:1 was added to provide benzyl 2-dimethylamino-5-[1-(6-fluoroindol-3-yl)ethyl]-4-oxo-2-oxazolin-5-carboxylate (509 mg) as a crystal.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:5]=[C:4]([Br:15])[CH:3]=1.[CH2:16]([O:18][C:19](=[O:30])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][C:23]=1[CH3:29])[CH3:17].CN1C(=O)CCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C(OCC)(=O)C>[CH2:16]([O:18][C:19](=[O:30])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28][C:2]2[CH:7]=[C:6]([O:8][CH2:9][CH:10]3[CH2:14][CH2:13][CH2:12][CH2:11]3)[CH:5]=[C:4]([Br:15])[CH:3]=2)=[CH:24][C:23]=1[CH3:29])[CH3:17]
Reactant: CCOC(=O)COc1ccc(S)cc1C
Reactant: Brc1cc(Br)cc(OCC2CCCC2)c1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCOC(=O)COc1ccc(Sc2cc(Br)cc(OCC3CCCC3)c2)cc1C

Procedure:
1,3-Dibromo-5-cyclopentylmethoxy-benzene (2.9 g; 8.6 mmol), (4-Mercapto-2-methyl-phenoxy)-acetic acid ethyl ester (1.5 g; 6.6 mmol), tris(dibenzylideneacetone)dipalladium(0) (0.18 g, 0.20 mmol) and 1,1′-bis(diphenylphosphino)-ferrocen (0.22 g; 0.40 mmol) was added to a dried microwave flask under an atmosphere of nitrogen. The reaction flask was sealed and dry NMP (10 mL) and TEA (3.7 mL; 26.5 mmol) was added through the septum. The reaction flask was reacted in a microwave oven at 140° C. for 1 h. Ethyl acetate (30 mL) and aqueous 5% citric acid (30 mL) was added to the reaction mixture and the phases were separated. The aqueous phase was extracted with ethyl acetate (30 mL×2) and the pooled organic phases were dried (MgSO4) and evaporated to dryness. The reaction mixture was purified by flash chromatography (heptane→heptane: ethyl acetate (9:1½). Yield: 1.45 g (46%). HPLC-MS: m/z: 479.8 (M)+; Rt: 3.18 min.
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=2)[CH2:7][CH2:8][CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1.Cl.[NH2:19][OH:20]>N1C=CC=CC=1>[OH:20][N:19]=[CH:14][C:13]1[CH:16]=[CH:17][C:10]([CH:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH2:7][CH2:8][CH3:9])=[CH:11][CH:12]=1
Reactant: CCCC(c1ccc(C=O)cc1)n1ccnc1
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: CCCC(c1ccc(C=NO)cc1)n1ccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.5 g of 4-[1-(1-imidazolyl)-butyl]-benzaldehyde (see example 6) is dissolved in 2 ml of pyridine and mixed with 0.215 g of hydroxylamine hydrochloride. It was stirred overnight at room temperature and precipitated in 30 ml of water and extracted with ether. After removal of the solvent under vacuum, 0.4 of 1-[1-(4-hydroxyiminomethylphenyl)-butyl]-imidazole is obtained as yellow oil.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]([OH:10])=O)[C:5]([CH3:11])=[N:4]1)[CH3:2].CN(C)C=O.C(Cl)(=O)C(Cl)=O.[NH2:23][C:24]1[CH:25]=[C:26]([CH:43]=[CH:44][C:45]=1[Cl:46])[O:27][C:28]1[CH:29]=[CH:30][C:31]2[N:32]([CH:34]=[C:35]([NH:37][C:38]([CH:40]3[CH2:42][CH2:41]3)=[O:39])[N:36]=2)[N:33]=1>CN(C)C(=O)C.O1CCCC1>[Cl:46][C:45]1[CH:44]=[CH:43][C:26]([O:27][C:28]2[CH:29]=[CH:30][C:31]3[N:32]([CH:34]=[C:35]([NH:37][C:38]([CH:40]4[CH2:42][CH2:41]4)=[O:39])[N:36]=3)[N:33]=2)=[CH:25][C:24]=1[NH:23][C:8]([C:6]1[C:5]([CH3:11])=[N:4][N:3]([CH2:1][CH3:2])[CH:7]=1)=[O:10]
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1Cl
Reactant: CCn1cc(C(=O)O)c(C)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2Cl)c(C)n1
Yield: 32.3 %

Procedure:
Using 1-ethyl-3-methyl-1H-pyrazole-4-carboxylic acid (188 mg, 1.22 mmol), tetrahydrofuran (4.5 mL), N,N-dimethylformamide (30 μL, 0.39 mmol), oxalyl chloride (107 μL, 1.22 mmol), N-[6-(3-amino-4-chlorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (300 mg, 0.87 mmol) and N,N-dimethylacetamide (6.0 mL), and in the same manner as in Example 249, the title compound (135 mg, 33%) was obtained as a white powder. melting point 200° C.
Reaction SMILES: [C-:1]#[N:2].Br[C:4]1[C:5]([Cl:16])=[CH:6][N:7]=[C:8]2[C:13]=1[N:12]=[C:11]([O:14][CH3:15])[CH:10]=[CH:9]2.[Cl-].[NH4+]>CN(C)C=O>[Cl:16][C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:4]=1[C:1]#[N:2])=[N:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2
Reactant: COc1ccc2ncc(Cl)c(Br)c2n1
Reactant: [C-]#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1ccc2ncc(Cl)c(C#N)c2n1
Temperature: 130 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
CoppeeI cyanide (39.3 g, 0.44 mol, 1.2 eq) is added at room temperature to a stirred solution of 8-bromo-7-chloro-2-methoxy-[1,5]naphthyridine (100 g, 0.37 mol, 1.0 eq) in N,N-dimethylformamide (1.5 L). After 8 hours stirring at 130° C., the reaction mixture is cooled down to room temperature and treated with a saturated ammonium chloride aqueous solution (1.5 L). The aqueous layer is separated and extracted with ethyl acetate (2×1.5 L). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is washed with ethanol (20 mL) to afford 3-chloro-6-methoxy-[1,5]naphthyridine-4-carbonitrile as an off-white solid (49.5 g, 62% yield).
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C@@H:9]([CH:11]1[CH2:13][CH:12]1[C:14]#[N:15])[CH3:10].ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[Cl:35][C:36]1[CH:44]=[C:43]2[C:39]([C:40]([C:46]3[N:47]=[C:48]4[C:54]([C:55](O)=[O:56])=[CH:53][N:52]([CH2:58][O:59][CH2:60][CH2:61][Si:62]([CH3:65])([CH3:64])[CH3:63])[C:49]4=[N:50][CH:51]=3)=[N:41][N:42]2[CH3:45])=[CH:38][CH:37]=1>C(OCC)(=O)C.O.CN(C=O)C>[C:14]([CH:12]1[CH2:13][CH:11]1[C@H:9]([NH:8][C:55]([C:54]1[C:48]2[C:49](=[N:50][CH:51]=[C:46]([C:40]3[C:39]4[C:43](=[CH:44][C:36]([Cl:35])=[CH:37][CH:38]=4)[N:42]([CH3:45])[N:41]=3)[N:47]=2)[N:52]([CH2:58][O:59][CH2:60][CH2:61][Si:62]([CH3:65])([CH3:64])[CH3:63])[CH:53]=1)=[O:56])[CH3:10])#[N:15]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Reactant: C[C@@H](N)C1CC1C#N
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C1CC1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
2-((R)-1-Amino-ethyl)-cyclopropanecarbonitrile trifluoroacetate, diastereomer A (crude from Step 2) was treated with 1-hydroxybenzotriazole (153 mg, 1.14 mmol), 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (662 mg, 1.75 mmol,), DIPEA (0.76 ml, 4.37 mmol), 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (400 mg, 0.87 mmol) and DMF (6.0 ml) to give a light yellow solution. After stirring at room temperature overnight, the reaction mixture was diluted with ethyl acetate and water. The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, EtOAc in heptane gradient) to provide 210 mg (44%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-1-(2-cyano-cyclopropyl)-ethyl]-amide (diastereomer A) as a colorless oil. MS: (M+H)+=551.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([O:10]C)=[O:9])[CH:5]=[C:4](Cl)[N:3]=1.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])(O)=O.[Na+]>C1COCC1>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:3]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1cc(Cl)nc(N)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Nc1nc(C(=O)O)cc(-c2ccccc2)n1
Temperature: 90 °C
Yield: 73.8 %

Procedure:
A solution of methyl 2-amino-6-chloropyrimidine-4-carboxylate (0.2 g, 1.07 mmol) and phenylboronic acid (0.16 g, 1.3 mmol) in THF (10 mL) was treated with saturated aqueous NaHCO3 (1.6 mL). Nitrogen was bubbled through the solution for 5 min then tetrakis(triphenylphosphine)palladium(0) (0.04 g) was added and the mixture refluxed under nitrogen overnight. The mixture was treated with aqueous LiOH (1-M, 1 mL), heated at 90° C. for 2 h, concentrated in vacuo and partitioned between ethyl acetate and water. The aqueous layer was acidified to pH 1 with 2-N HCl, the resulting suspension centrifuged, the liquors decanted and the resulting solid dried to give the title compound (0.17 g, 72%) as a white powder which was used directly in the next step without further purification; M/Z 216 (M+H)+; retention time 1.60 min (Method AM).
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[F:39][C:40]([F:50])([F:49])[C:41]1[CH:42]=[C:43]([CH:46]=[CH:47][CH:48]=1)[CH2:44][NH2:45]>C1COCC1.O>[C:1]([CH2:3][C:4]([NH:45][CH2:44][C:43]1[CH:46]=[CH:47][CH:48]=[C:41]([C:40]([F:39])([F:49])[F:50])[CH:42]=1)=[O:6])#[N:2]
Reactant: NCc1cccc(C(F)(F)F)c1
Reactant: N#CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: N#CCC(=O)NCc1cccc(C(F)(F)F)c1
Yield: 50.7 %

Procedure:
Cyanoacetic acid (297.0 mg, 3.5 mmol), N-(3-dimethylaminopropyl)-N′-ethyl-carbodiimide hydrochloride (1.34 g, 7.0 mmol), 1-hydroxybenzotriazole hydrate (641.0 mg, 4.2 mmol) and DIPEA (1.8 g, 14.0 mmol) and 3-(trifluoromethyl)benzylamine (611.0 mg, 3.5 mmol) were suspended in THF. The mixture was heated to 60° for 18 h. Water was added to the mixture and the product extracted with EtOAc, dried over MgSO4 and concentrated. The crude product was purified by flash chromatography, CH2Cl2/MeOH 98:2, yielding 430.0 mg (51%) of the title compound.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[CH:15][C:14]([O:17][CH:18]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][CH:30]([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)[CH2:19][CH3:20])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)=O>CO>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[CH:15][C:14]([O:17][C@@H:18]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][CH:30]([CH3:31])[CH3:32])=[O:28])[CH2:23][CH2:22]3)[CH2:19][CH3:20])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CCC(Oc1ccc(-c2ccc(S(C)(=O)=O)cc2)nc1)C1CCN(C(=O)OC(C)C)CC1
Agent: O=C=O
Solvent: CO
Product: CC[C@@H](Oc1ccc(-c2ccc(S(C)(=O)=O)cc2)nc1)C1CCN(C(=O)OC(C)C)CC1

Procedure:
The racemic 1-methylethyl 4-[1-({6-[4-(methylsulfonyl)phenyl]-3-pyridinyl}oxy)propyl]-1-piperidinecarboxylate (prepared as in Example 142) was subjected to Chiral HPLC [column: AS-H, column mobile phase: 80% CO2: 20% MeOH (2 mL/min), pressure 140 bar, temperature 40° C., 215 nm] analysis and then separated to give two (R and S) enantiomers. The title compound was isolated as a white foam with Tr of 10.65 min (first eluting peak). The (R) absolute stereochemistry was assigned by Ab initio VCD analysis.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]=[CH2:5].[P:6]([O:13]CC)([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9]>C(Cl)(Cl)Cl>[CH2:2]([P:6](=[O:13])([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9])[CH2:3][CH:4]=[CH2:5]
Reactant: C=CCCBr
Reactant: CCOP(OCC)OCC
Solvent: ClC(Cl)Cl
Product: C=CCCP(=O)(OCC)OCC
Temperature: 25 °C

Procedure:
1-bromo-3-butene (39.0 mmol) and triethyl phosphite (1 g, 6 mmol) were dissolved and reacted in CHCl3 (30 mL). Then, the reaction solution was refluxed for 12 hours, cooled to room temperature and filtered through a glass filter. Chloroform (CHCl3) was completely removed from the solution under vacuum to thereby give an oily compound as the title compound. The 1H NMR results of the compound thus obtained are given as follows.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N:9]2[N:13]=[N:12][CH:11]=[N:10]2)=[CH:4][C:3]=1/[CH:14]=[CH:15]/[C:16]([O:18]CC)=O.C(=O)([O-])[O-].[Na+].[Na+]>Cl>[CH3:8][C:7]1[CH:6]=[C:5]([N:9]2[N:13]=[N:12][CH:11]=[N:10]2)[CH:4]=[C:3]2[C:2]=1[NH:1][C:16](=[O:18])[CH:15]=[CH:14]2
Reactant: CCOC(=O)/C=C/c1cc(-n2ncnn2)cc(C)c1N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1cc(-n2ncnn2)cc2ccc(=O)[nH]c12

Procedure:
5M Hydrochloric acid (20 cm3) was added to trans-ethyl 3-(2-amino-3-methyl-5-[tetrazol-2-yl]phenyl)prop-2-enoate (0.45 g) and the mixture was heated on a steam bath for 1 hour. The mixture was then cooled, brought to pH 7 with aqueous sodium carbonate solution, and extracted with dichloromethane:methanol, 20:1 (3×50 cm3). The combined organic extracts were dried (MgSO4), filtered and evaporated to dryness. The residue was chromatographed on silica (Merck "MK 60.9385" [Trade Mark]) eluting with ethyl/acetate:methanol, 10:1. Combination and evaporation of the appropriate fractions afforded 8-methyl-6-(tetrazol-2-yl)-2-(1H)-quinolone, 0.25 H2O, m.p. 264°-266°, (0.08 g).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>O.C(O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc2ccn(Cc3ccccc3)c2c1
Reactant: OB(O)c1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: c1ccc(Cn2ccc3ccc(-c4ccccc4)cc32)cc1
Yield: 58.4 %

Procedure:
1-Benzyl-6-phenyl-1H-indole was prepared by coupling 1-benzyl-6-bromo-1H-indole (3.48 g, 12.2 mmol), and phenylboronic acid (1.63 g, 13.4 mmol), using tetrakis(triphenylphosphine) palladium (0.976 g, 0.846 mmol), and sodium carbonate (5.2 g, 49 mmol) in water (25 mL), ethanol (5 mL), and toluene (55 mL), according to the procedure described in Step 2 of Example 2. Purification by flash chromatography using 0-2.5% ethyl acetate in hexane as an eluant afforded the title compound as a light green solid (2.02 g, 58%), mp: 109-110° C. Mass spectrum (+ES, [M+H]+) m/z 284; 1HNMR (500 MHz, DMSO-d6): δ 7.75(s, 1H), 7.6-7.65 (m, 3H), 7.55 (d, 1H, J=3.1 Hz), 7.45 (t, 2H, J=7.5 Hz), 7.3-7.35 (m, 4H), 7.2-7.25 (m, 3H), 6.5 (d, 1H, J=3.0 Hz), and 5.5 ppm (s, 2H). Elemental Analysis for C21H17N: Calculated: C, 89.01; H, 6.05; N, 4.94. Found: C, 89.04; H, 5.87; N, 4.79.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:11]=[C:12]([C:16]([NH:18][CH3:19])=[O:17])[CH:13]=[CH:14][CH:15]=2)[C:5]([C:20]#[N:21])=[C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:3]=1[C:28]#[N:29].Cl.[NH:31]1[CH2:34][CH:33]([OH:35])[CH2:32]1.C(N(CC)CC)C.O>O1CCCC1>[C:20]([C:5]1[C:6]([S:8][CH2:9][C:10]2[CH:11]=[C:12]([C:16]([NH:18][CH3:19])=[O:17])[CH:13]=[CH:14][CH:15]=2)=[N:7][C:2]([N:31]2[CH2:34][CH:33]([OH:35])[CH2:32]2)=[C:3]([C:28]#[N:29])[C:4]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)#[N:21]
Reactant: CNC(=O)c1cccc(CSc2nc(Cl)c(C#N)c(-c3ccccc3)c2C#N)c1
Reactant: OC1CNC1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNC(=O)c1cccc(CSc2nc(N3CC(O)C3)c(C#N)c(-c3ccccc3)c2C#N)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
50 mg (0.12 mmol) of 3-{[(6-chloro-3,5-dicyano-4-phenylpyridin-2-yl)sulfanyl]methyl}-N-methylbenzenecarboxamide Example 85A were initially charged in 1 ml of tetrahydrofuran. After addition of 19.6 mg (0.18 mmol) of azetidin-3-ol hydrochloride and 24.2 mg (0.24 mmol) of triethylamine, the mixture was stirred at RT for 30 min. Water was added to the reaction mixture until a clear solution had formed. The solution was purified by preparative HPLC (Chromasil, water/acetonitrile+0.1% trifluoroacetic acid).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].[CH3:9][O:10][CH2:11]Cl.C(OCC)(=O)C>CN(C=O)C>[CH3:9][O:10][CH2:11][O:7][C:6]1[CH:1]=[C:2]([CH3:8])[CH:3]=[CH:4][CH:5]=1
Reactant: COCCl
Reactant: Cc1cccc(O)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCOc1cccc(C)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Part A. Sodium hydride dispersion in mineral oil (5.05 g, 50% w/w, 105 mmol) was washed with hexane and dried under vacuum. DMF (100 mL) was added, the slurry was cooled to 0° C., and treated with a solution of m-cresol (10 mL, 95.6 mmol) in DMF (20 mL). The resulting mixture was allowed to stir for 1 h, then was treated with chloromethyl methyl ether (8.00 mL, 105 mmol) by syringe. The mixture was stirred overnight, then poured into ethyl acetate (200 mL). This was washed with water (3×200 mL) and brine (100 mL), and the aqueous phases were back-extracted in sequence with ethyl acetate. The extracts were combined, dried over magnesium sulfate, filtered and evaporated. The oily product was purified by elution through a plug of silica gel with 10:90 ethyl acetate-hexane. Evaporation then afforded the pure product, 3-(methoxymethoxy)toluene, as an oil (13.93 g, 91.5 mmol, 96%). TLC RF 0.46 (10:90 ethyl acetate-hexane). 1H NMR (300 MHz, CDCl3): d 7.17 (1H, t, J=7.7 Hz), 6.86-6.81 (3H, m), 5.17 (2H, s), 3.48 (3H, s), 2.33 (3H, s). MS(H2O-GC/MS): m/e 153 (60), 121 (100).
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:45])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:26]5[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=5[OH:33])[CH:23]=[CH:24][CH:25]=4)[N:19]=[C:15]3[CH:14]=[C:13]([CH3:34])[C:12]=2[C@H:35]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[C:36]([O:38][CH3:39])=[O:37])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[CH3:46][C@@H:47](O)[CH2:48][CH:49]=[CH2:50].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.C1(C)C=CC=CC=1.CCOCC>[CH2:1]([O:4][C:5]1([CH3:45])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[CH:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:26]5[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=5[O:33][C@H:49]([CH2:48][CH:47]=[CH2:46])[CH3:50])[CH:23]=[CH:24][CH:25]=4)[N:19]=[C:15]3[CH:14]=[C:13]([CH3:34])[C:12]=2[C@H:35]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[C:36]([O:38][CH3:39])=[O:37])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CC[C@@H](C)O
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(-c5cc(C)ccc5O)c4)cn23)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(-c5cc(C)ccc5O[C@@H](C)CC=C)c4)cn23)CC1
Reaction time: 18 h
Yield: 93.9 %

Procedure:
To a solution of (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(2′-hydroxy-5′-methyl-[1,1′-biphenyl]-3-yl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate (51 mg, 0.083 mmol, 1 equiv), (R)-pent-4-en-2-ol (22 mg, 0.250 mmol, 3 equiv), and PPh3 (44 mg, 0.167 mmol, 2 equiv) in THF (0.8 mL) was added DEAD (0.066 mL of a 40% solution in toluene, 0.167 mmol, 2 equiv). After stirring 18 h, the yellow solution was diluted with ether, washed with water, dried (MgSO4), and concentrated in vacuo. The crude product was purified by flash column chromatography (0-100% EtOAc [2% TEA]/hexane) to provide the product (53 mg, 94%) as a colorless film. LCMS (ESI, M+1): 680.45.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH:12](=O)[CH2:13][CH2:14][CH3:15]>>[CH2:12]([NH:9][C:8]1[CH:10]=[CH:11][C:5]([O:4][CH:1]([CH3:3])[CH3:2])=[CH:6][CH:7]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CC(C)Oc1ccc(N)cc1
Reactant: CCCC=O
Product: CCCCNc1ccc(OC(C)C)cc1
Yield: 87.4 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 137, 4-isopropoxyaniline (500 mg, 3.31 mmol) and butyraldehyde (300 μL, 3.31 mmol) were converted to the title compound (600 mg, 83%). 1H NMR (CDCl3) δ 6.88-6.74 (m, 2H), 6.67-6.51 (m, 2H), 4.41-4.30 (m, 1H), 3.08 (t, J=7.0 Hz, 2H), 1.66-1.37 (m, 4H), 1.30 (s, 3H), 1.29 (s, 3H), 0.99-0.87 (m, 3H); MS(ESI+) m/z 208.2 (M+H)+.
Reaction SMILES: [OH:1][C:2]1(C(OC)=O)[CH:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH2:7][C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[NH:4][C:3]1=[O:21].[I-].[Li+]>N1C=CC=CC=1>[OH:1][C@H:2]1[C@@H:8]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH2:7][C:6]2[CH:17]=[CH:18][CH:19]=[CH:20][C:5]=2[NH:4][C:3]1=[O:21]
Reactant: COC(=O)C1(O)C(=O)Nc2ccccc2CC1c1ccc(OC)cc1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: COc1ccc([C@H]2Cc3ccccc3NC(=O)[C@H]2O)cc1

Procedure:
A solution containing 5.26 g (14.6 mmol) of 1,3,4,5-tetrahydro-3-hydroxy-3-(methoxycarbonyl)-4-(4-methoxyphenyl)-2H-1-benzazepin-2-one and 19. (147 mmol) of anhydrous lithium iodide in 150 ml of dry pyridine was refluxed for one hour. After concentration, the crude product was dissolved in ethyl acetate, washed with 6M hydrochloric acid followed by saturated bicarbonate and dried over sodium sulfate. Concentration followed by trituration with ether gave 2.81 g of essentially pure cis isomer, melting point 173.5°-175.5° C. (dec).