Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C(C2[C:14]([CH2:15][O:16][CH2:17][C:18]3[C:23](C4C(=CC=C(O)C=4)O)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=[CH:11][CH:10]=2)=CC(=CC=1)O)O.Br[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44].C(=O)([O-])[O-:49].[K+].[K+].[I-].[K+]>CN(C)C=O>[CH2:17]([O:16][C:15]1[CH:10]=[CH:11][C:12]([O:49][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][C:43]([O:45][CH2:46][CH3:47])=[O:44])=[CH:13][CH:14]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C([O-])[O-]
Reactant: Oc1ccc(O)c(-c2ccccc2COCc2ccccc2-c2cc(O)ccc2O)c1
Reactant: CCOC(=O)CCCCCCCCCCBr
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCCCCCCOc1ccc(OCc2ccccc2)cc1
Temperature: 0 °C
Yield: 134.4 %

Procedure:
In a 5000 ml flask equipped with a stirrer and a condenser were charged 400.2 g of hydroquinone monobenzyl ether, 586.5 g of ethyl 11-bromoundecanoate, 331.7 g of anhydrous potassium carbonate, 33.2 g of potassium iodide and 1500 ml of N,N-dimethylformamide (DMF), and the mixture was refluxed for 6 hours. This solution was poured into 2000 ml of ice-water to precipitate white crystals. The precipitated crystals were collected by filtration, washed with distilled water and recrystallized from ethanol to obtain 535.5 g of the title compound.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:18]2[C:17]([O:19][CH3:20])=[N:16][CH:15]=[N:14][C:13]=2[C:12]([CH2:21][NH:22][C@H:23]([C@H:29]([OH:35])[C:30](OCC)=[O:31])[C:24](OCC)=[O:25])=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Li+]>C(OCC)C.CO>[CH2:1]([O:8][CH2:9][N:10]1[C:18]2[C:17]([O:19][CH3:20])=[N:16][CH:15]=[N:14][C:13]=2[C:12]([CH2:21][NH:22][C@@H:23]([CH2:24][OH:25])[C@H:29]([OH:35])[CH2:30][OH:31])=[CH:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)[C@@H](O)[C@@H](NCc1cn(COCc2ccccc2)c2c(OC)ncnc12)C(=O)OCC
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: CCOCC
Product: COc1ncnc2c(CN[C@@H](CO)[C@H](O)CO)cn(COCc3ccccc3)c12

Procedure:
To a stirred solution of the product from Example 15.1 (0.166 g, 0.34 mmol) in diethyl ether (10 ml) was added methanol (0.14 ml, 3.41 mmol) and then lithium borohydride (0.85 ml, 1.71 mmol, 2.0M in THF). After 30 mins the reaction mixture was diluted with methanol and then concentrated. The residue was dissolved in methanol, diluted with concentrated aqueous ammonia (1 ml) and evaporated on to silica gel. The material was chromatographed on silica gel (DCM-methanol-conc. ammonia, 85:15:2, then 70:30:2, then 50:50:4). This gave three distinct compounds; firstly the title compound and then two different salt forms of the title compound. The three compounds were combined to give a colourless oil (0.103 g, 75%). 1H NMR (CD3OD) δ 8.42 (s, 1H), 7.64 (s, 1H), 7.28-7.16 (m, 5H), 5.75 (s, 2H), 4.50 (s, 2H), 4.10 (s, 3H), 3.83-3.68 (m, 3H), 3.63 (d, J=5.5 Hz, 2H), 3.31 (pentet, J=1.6 Hz, 1H).
Reaction SMILES: [CH:1](=[O:13])[C:2]1[CH:12]=[C:9]([O:10][CH3:11])[C:7]([OH:8])=[C:4]([O:5][CH3:6])[CH:3]=1.[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].[Si](Cl)(C(C)(C)C)(C)C.C(N(CC)C(C)C)(C)C>CN(C=O)C.CC(C)=O>[CH2:14]([O:8][C:7]1[C:9]([O:10][CH3:11])=[CH:12][C:2]([CH:1]=[O:13])=[CH:3][C:4]=1[O:5][CH3:6])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1cc(C=O)cc(OC)c1O
Reactant: ClCc1ccccc1
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: COc1cc(C=O)cc(OC)c1OCc1ccccc1

Procedure:
4-Benzyloxy-3,5-dimethoxybenzaldehyde (13j) was prepared by the reaction of syringaldehyde with benzyl chloride in the presence of K2CO3 in boiling acetone. Similarly, reaction of t-butyldimethylsilyl chloride with syringaldehyde in DMF in the presence of N,N-diisopropylethylamine gave 4-(t-butyldimethylsilyl)-oxy-3,5-dimethoxybenzaldehyde (13k) (Scheme VII). Wittig reaction of phosphonium bromides 14a-b with benzaldehydes 13a-k in THF in the presence of sodium hydride followed by preparative thin-layer chromatographic separation of the crude products afforded the cis stilbenes 15a-k and trans stilbenex 16a-k (Scheme VIII). Reaction of compounds 15k and 16k with tetra-n-butylammonium fluoride and in situ acetylation of the phenols with acetic anhydride gave the acetoxy compounds 15l and 16l (Scheme IX). The cis and trans geometries of the stilbenes were assigned by the characteristic 1H NMR coupling constants of the olefinic protons. Catalytic hydrogenation of stilbenes 15 and 16 at about 40 psi in the presence of 10% palladium on charcoal gave the dihydrostilbenes 17a-e (Scheme XIII). The amino ethers 17f-g were prepared by the reaction of 1-(4-hydroxyphenyl)-2-(3,4,5-trimethoxyphenyl)ethane (18) with dialkylaminoethyl chlorides 19a-b in refluxing acetone in the presence of K2CO 3 (Scheme X). Compounds 17h and 17i were prepared by the alkylation of 3,4,5-trimethoxyphenyl-acetonitrile (20a) and 4-methoxyphenylacetonitrile (20b) with 4-methoxybenzyl bromide (21a) and 3,4,5-trimethoxybenzyl bromide (21b), respectively, using LDA as the base (Scheme XI). Similarly, alkylation of methyl 4-methoxyphenylacetate (20b) with 3,4,5-trimethoxybenzyl bromide 21b gave product 17j.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:46][O:47][C:48]1[C:49]2[N:62]=[C:61]([NH2:63])[S:60][C:50]=2[C:51]([N:54]2[CH2:59][CH2:58][O:57][CH2:56][CH2:55]2)=[N:52][CH:53]=1>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:63][C:61]2[S:60][C:50]3[C:51]([N:54]4[CH2:59][CH2:58][O:57][CH2:56][CH2:55]4)=[N:52][CH:53]=[C:48]([O:47][CH3:46])[C:49]=3[N:62]=2)=[O:12])=[CH:13][CH:14]=1
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Reactant: COCCOc1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COCCOc1ccc(C(=O)Nc2nc3c(OC)cnc(N4CCOCC4)c3s2)cc1

Procedure:
From 4-(2-methoxy-ethoxy)-benzoic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 445 (M+H+, 100).
Reaction SMILES: C([O:4][C:5]([CH3:27])([C:7]1[O:8][C:9]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([S:25][CH3:26])=[CH:21][CH:20]=3)[CH:13]=2)=[N:10][N:11]=1)[CH3:6])(=O)C.[OH-].[Na+].O1CCCC1.CO>C(OCC)(=O)C>[CH3:26][S:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:14]2[CH:13]=[C:12]([C:9]3[O:8][C:7]([C:5]([OH:4])([CH3:6])[CH3:27])=[N:11][N:10]=3)[CH:17]=[CH:16][N:15]=2)=[CH:20][CH:21]=1
Reactant: CSc1ccc(Nc2cc(-c3nnc(C(C)(C)OC(C)=O)o3)ccn2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: CSc1ccc(Nc2cc(-c3nnc(C(C)(C)O)o3)ccn2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 3.6 %

Procedure:
A mixture of 1-methyl-1-[5-[2-[[4-(methylthio)phenyl]amino]-4-pyridyl]-1,3,4-oxadiazol-2-yl]ethyl acetate (192 mg, 4.99 mmol), 1 M aqueous sodium hydroxide solution (5 mL), tetrahydrofuran (5 mL) and methanol (5 mL) was stirred at room temperature for 1.5 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=10/1-0/1) and recrystallized from hexane/ethyl acetate to give the title compound (61.2 mg, yield 36%) as yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:32][O:33][CH3:34])[C:4]([CH3:31])=[C:5]([C:20]([O:22][CH2:23][O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[O:21])[C@@H:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([OH:10])=[O:9].[N+](=[CH2:37])=[N-].C(O)(=O)C>ClCCl.C(OCC)C>[CH3:1][C:2]1[N:3]([CH2:32][O:33][CH3:34])[C:4]([CH3:31])=[C:5]([C:20]([O:22][CH2:23][O:24][C:25](=[O:30])[C:26]([CH3:27])([CH3:28])[CH3:29])=[O:21])[C@@H:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([O:10][CH3:37])=[O:9]
Reactant: C=[N+]=[N-]
Reactant: COCN1C(C)=C(C(=O)O)[C@H](c2cccc([N+](=O)[O-])c2)C(C(=O)OCOC(=O)C(C)(C)C)=C1C
Solvent: CCOCC
Solvent: ClCCl
Solvent: CC(=O)O
Product: COCN1C(C)=C(C(=O)OC)[C@H](c2cccc([N+](=O)[O-])c2)C(C(=O)OCOC(=O)C(C)(C)C)=C1C
Reaction time: 1 h
Yield: 94 %

Procedure:
In 2 ml of dichloromethane was dissolved 476 mg of (S)-1,4-dihydro-2,6-dimethyl -1-methoxymethyl-4-(3-nitrophenyl) -5-pivaloyloxymethoxycarbonyl-3-pyridinecarboxylic acid obtained in Example 3 ro 4, and 6 ml of a 0.5M solution of diazomethane in diethyl ether was added to the solution under cooling with ice, followed by stirring for 1 hour. Acetic acid was added to the reaction mixture until the yellow color disappeared, and the reaction mixture was concentrated. The residue was purified by short silica gel column chromatogrpahy (ether acetate/hexane=1/3) to give 460 mg (yield: 94%) of (S)-methyl pivaloyloxymethyl 1,4-dihydro -2,6-dimethyl-1-methoxymethyl-4-(3-nitrophenyl) -3,5-pyridinedicarboxylate as a pale yellow crystal.
Reaction SMILES: [OH-].[Na+:2].[C:3]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:13]=[C:14]3[C:48](=[CH:49][CH:50]=2)[O:47][C:17]2([CH2:22][CH2:21][N:20]([C:23]([C:25]4[CH:30]=[C:29]([O:31][CH2:32][CH3:33])[C:28]([C:34]5[CH:39]=[CH:38][C:37]([C:40]([O:42]C)=[O:41])=[CH:36][CH:35]=5)=[C:27]([O:44][CH2:45][CH3:46])[CH:26]=4)=[O:24])[CH2:19][CH2:18]2)[CH2:16][C:15]3=[O:51])=[N:10][CH:11]=1)(=[O:5])[NH2:4].CO>C1COCC1.O>[C:3]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:13]=[C:14]3[C:48](=[CH:49][CH:50]=2)[O:47][C:17]2([CH2:22][CH2:21][N:20]([C:23]([C:25]4[CH:26]=[C:27]([O:44][CH2:45][CH3:46])[C:28]([C:34]5[CH:39]=[CH:38][C:37]([C:40]([O-:42])=[O:41])=[CH:36][CH:35]=5)=[C:29]([O:31][CH2:32][CH3:33])[CH:30]=4)=[O:24])[CH2:19][CH2:18]2)[CH2:16][C:15]3=[O:51])=[N:10][CH:11]=1)(=[O:5])[NH2:4].[Na+:2]
Reactant: CCOc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4ccc(C(N)=O)cn4)ccc2O3)cc(OCC)c1-c1ccc(C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCOc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4ccc(C(N)=O)cn4)ccc2O3)cc(OCC)c1-c1ccc(C(=O)[O-])cc1
Temperature: 25 °C
Reaction time: 288 h
Yield: 52.4 %

Procedure:
Aqueous 1N NaOH (11.6 ml, 11.6 mmol) was added to a stirred solution of methyl 4′-({6-(5-carbamoylpyridin-2-yl)-4-oxospiro[chroman-2,4′-piperidin]-1′-yl}carbonyl)-2′,6′-diethoxybiphenyl-4-carboxylate (3.85 g, 5.80 mmol) in THF (40 ml)-MeOH (40 ml) and the mixture was stirred at room temperature for 12 days. After water was added to the mixture, the organic solvents were evaporated under reduced pressure. The aqueous residue was purified by ODS column chromatography eluting with H2O/MeOH and the residue was crystallized from MeOH to give intended compound as a pale red solid. The solid was diluted in H2O and aqueous 1N NaOH, and was purified by ODS column chromatography eluting with H2O/MeOH, and the residue was crystallized from MeOH to give intended compound (2.04 g, 3.04 mmol, 52.4% yield) as a pale red crystal.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[C:9]([O:13][C:14]([N:16]1[C@H:21]([CH2:22][NH2:23])[C@@H:20]2[CH2:24][C@H:17]1[CH2:18][CH2:19]2)=[O:15])([CH3:12])([CH3:11])[CH3:10].C([O-])([O-])=O.[K+].[K+].CCN(C(C)C)C(C)C>CC1C=CC=CC=1C>[C:9]([O:13][C:14]([N:16]1[C@H:21]([CH2:22][NH:23][C:5]2[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)[C@@H:20]2[CH2:24][C@H:17]1[CH2:18][CH2:19]2)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Clc1ncc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1C
Product: CC(C)(C)OC(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1CNc1ncc(Br)cn1
Temperature: 138 °C

Procedure:
5-Bromo-2-chloro-pyrimidine (8.62 mmol) is added to a solution of (1R,3S,4S)-3-aminomethyl-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (6.63 mmol) in o-xylene (25 mL). K2CO3 (20.0 mmol) and DIPEA (19.9 mmol) are added successively and the mixture is heated to 138° C. for 16 h. The mixture is cooled to rt and filtered. The residue is washed with DCM and the combined filtrates are concentrated in vacuo to give the desired product which is used without further purification. LC-MS: tR=1.09 min; [M+H]+=383.3.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([NH2:16])=[N:13][C:14]=2[CH3:15])[CH:5]=[CH:4][N:3]=1.[CH3:17][C:18]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][N:19]=1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.CCOC(C)=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>[CH3:15][C:14]1[N:13]=[C:12]([NH2:16])[CH:11]=[CH:10][C:9]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:21]2[CH:20]=[N:19][C:18]([CH3:17])=[CH:23][CH:22]=2)[CH:7]=1
Reactant: Cc1nc(N)ccc1Oc1ccnc(Cl)c1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
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: CCOC(C)=O
Solvent: C1COCCO1
Product: Cc1ccc(-c2cc(Oc3ccc(N)nc3C)ccn2)cn1
Temperature: 85 °C
Yield: 88.7 %

Procedure:
A mixture of Example A7 (2.8 g, 11.88 mmol), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (3.38 g, 15.45 mmol) and K2CO3 (3.28 g, 23.76 mmol) in dioxane 48 mL) and water (12 mL) was sparged with Ar, treated with Pd(PPh3)4 (1.373 g, 1.188 mmol) and heated at 85° C. overnight. The mixture was cooled to RT, diluted with EtOAc, the solids removed via filtration through diatomaceous earth and the filtrate concentrated to dryness and purified via silica gel chromatography (MeOH/DCM). The material was treated with MeCN, the solid collected via filtration and re-purified via silica gel chromatography (MeOH/DCM) to afford 6-methyl-5-((6′-methyl-[2,3′-bipyridin]-4-yl)oxy)pyridin-2-amine (3.08 g, 89%). 1H NMR (400 MHz, DMSO-d6): δ 9.56 (d, J=2.4 Hz, 1 H), 8.96 (d, J=5.7 Hz, 1 H), 8.71 (dd, J=8.1, 2.4 Hz, 1 H), 7.86 (d, J=2.4 Hz, 1 H), 7.76 (d, J=8.1 Hz, 1 H), 7.66 (d, J=8.7 Hz, 1 H), 7.18 (dd, J=5.7, 2.4 Hz, 1 H), 6.94 (dd, J=8.6, 0.7 Hz, 1 H), 5.86 (s, 2 H), 2.97 (s, 3 H), 2.59 (s, 3 H); MS (ESI) m/z: 293.1 (M+H+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH:11]=[C:12]([C:14]([OH:16])=O)[N:13]=2)=[CH:5][CH:4]=1.C(Cl)CCl.[CH:21]1[CH:22]=CC2N(O)N=[N:27][C:25]=2[CH:26]=1.N1CCCC1>CN(C=O)C>[N:27]1([C:14]([C:12]2[N:13]=[C:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:2][OH:1])=[CH:8][CH:7]=3)[O:10][CH:11]=2)=[O:16])[CH2:22][CH2:21][CH2:26][CH2:25]1
Reactant: O=C(O)c1coc(-c2ccc(CO)cc2)n1
Reactant: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: C1CCNC1
Solvent: CN(C)C=O
Product: O=C(c1coc(-c2ccc(CO)cc2)n1)N1CCCC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
A stirred solution of 2-[4-(hydroxymethyl)phenyl]-1,3-oxazole-4-carboxylic acid (0.99 g, 4.5 mmol) in DMF was treated sequentially with EDC (1.04 g, 5.4 mmol), HOBt (0.67 g, 5.0 mmol and pyrrolidine (0.35 g, 5.0 mmol), stirred at 80° C. for 4 hours and evaporated to dryness. The resultant residue was dissolved in EtOAc and water. The layers were separated and the organic layer was washed successively with 1M HCl, water, saturated NaHCO3 and brine, dried over Na2SO4 and concentrated under reduced pressure The resultant residue was purified by flash chromatography (silica, EtOAc:hexanes 25%) to give the title product in 84% yield, identified by NMR and mass spectral analyses. LCMS (ESI+) 273 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]2[C:18]([C:19]#[N:20])=[CH:17][N:16]=[CH:15][C:14]=2[C:21]2[O:22][C:23]3[CH:29]=[CH:28][C:27]([CH:30]=O)=[CH:26][C:24]=3[CH:25]=2)[C:5]([CH3:11])=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[N:32]1([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.CCO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]2[C:18]([C:19]#[N:20])=[CH:17][N:16]=[CH:15][C:14]=2[C:21]2[O:22][C:23]3[CH:29]=[CH:28][C:27]([CH2:30][N:35]4[CH2:36][CH2:37][N:32]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:33][CH2:34]4)=[CH:26][C:24]=3[CH:25]=2)[C:5]([CH3:11])=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2
Reactant: Cc1c(Nc2c(C#N)cncc2-c2cc3cc(C=O)ccc3o2)cc(Cl)c2[nH]ccc12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(Nc2c(C#N)cncc2-c2cc3cc(CN4CCN(C(=O)OC(C)(C)C)CC4)ccc3o2)cc(Cl)c2[nH]ccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
To a stirred solution of 4-[(7-chloro-4-methyl-1H-indol-5-yl)amino]-5-(5-formyl-1-benzofuran-2-yl)nicotinonitrile (200 mg, 0.47 mmol) in THF (5 mL) and EtOH (2 mL) was added tert-butyl 1-piperazinecarboxylate (262 mg, 1.41 mmol) and acetic acid (54 mg, 0.9 mmol) and the reaction mixture was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (398 mg, 1.88 mmol) was added to the reaction mixture and the resulting solution was stirred at room temperature overnight. After the reaction was concentrated, ethyl acetate was added; and the organic phase was washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated. The residue was purified by flash column chromatography (ethyl acetate/hexane) to give tert-butyl 4-[(2-{4-[(7-chloro-4-methyl-1H-indol-5-yl)amino]-5-cyanopyridin-3-yl}-1-benzofuran-5-yl)methyl]piperazine-1-carboxylate as a yellow solid (203 mg, 73%). HPLC retention time: 9.5 min.(g); MS: 597.4 (M+H); and HRMS: 597.2378.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][CH:15]=[C:14]([F:22])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])(CC)C.CN(C)[CH:30]=[O:31].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.C1CCCCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH:30]=[O:31])=[C:14]([F:22])[CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc(F)cnc3N21
Reactant: CN(C)C=O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]C(C)CC
Solvent: O
Solvent: C1CCCCC1
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc(F)c(C=O)nc3N21
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2.885 g (4R,9aR)-7-fluoro-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 60 mL toluene at −78° C. was added 8.72 mL of a ca. 1.3 M solution of sec. butyl lithium in cyclohexane over 10 min. The orange mixture was stirred at −78° C. for 30 min. To the resulting viscous solution was added 1.00 mL dimethylformamide and the mixture was stirred at −78° C. for 1.5 h. To the reaction mixture was added 100 mL of a 10% citric acid solution in water. The phases were separated and the organic phase was evaporated to dryness and purified by chromatography on silica gel with heptane:ethyl acetate=2:1 to yield 0.585 g (4R,9aR)7-fluoro-6-formyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester as yellow-orange crystals; m.p.: 139–140° C. and 0.800 g (4R,9aR)-7-Fluoro-8-formyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[C:8]([Br:11])[NH:7][C:6]=2[C:5](=[O:12])[NH:4][C:3]1=[O:13].CN(C)C=O.C(N(C(C)C)CC)(C)C.Br[CH2:29][C:30]#[C:31][CH3:32]>O>[CH3:1][N:2]1[C:10]2[N:9]=[C:8]([Br:11])[N:7]([CH2:29][C:30]#[C:31][CH3:32])[C:6]=2[C:5](=[O:12])[NH:4][C:3]1=[O:13]
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]c(Br)nc21
Reactant: CC#CCBr
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC#CCn1c(Br)nc2c1c(=O)[nH]c(=O)n2C
Temperature: 85 °C
Yield: 85.4 %

Procedure:
3-Methyl-8-bromo-xanthine (30 gm) and N,N-dimethylformamide (170 mL) were charged into a 1000 mL round bottomed flask equipped with a mechanical stirrer. Diisopropylethylamine (DIPEA, 15.9 gm) and 1-bromo-2-butyne (16.2 gm) were added at 30° C. The reaction mixture was heated to 85° C. and maintained the temperature for 4 hours. The reaction mixture was cooled to 30° C. and pre cooled water (300 mL) was added. The solid formed was collected by filtration and washed with pre cooled water (150 mL) and diethyl ether (30 mL). The solid was dried in oven under vacuum at 50° C. to get 30.9 gm of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH2:5][C@H:6]([NH:20][C:21](=[O:31])[CH2:22][CH2:23][C:24](=O)[NH:25][CH2:26][CH2:27][C:28]#[N:29])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C[Si]([N:70]=[N+:71]=[N-:72])(C)C>C1COCC1>[CH2:1]([O:3][C:4](=[O:32])[CH2:5][C@H:6]([NH:20][C:21](=[O:31])[CH2:22][CH2:23][C:24]1[N:25]([CH2:26][CH2:27][C:28]#[N:29])[N:72]=[N:71][N:70]=1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:10][CH:9]=1)[CH3:2]
Reactant: CCOC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)CCC(=O)NCCC#N
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)CCc1nnnn1CCC#N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63.6 %

Procedure:
Next, to a solution of (R)-4-biphenyl-4-yl-3-[3-(2-cyano-ethylcarbamoyl)-propionylamino]-butyric acid ethyl ester (204 mg, 0.468 mmol) in THF (10 mL) at room temperature is added Ph3P (307 mg, 1.17 mmol) and the mixture is stirred at room temperature for 10 minutes. Then to the mixture at ice bath temperature is added DIAD (0.228 ml, 1.171 mmol) and trimethylsilyl azide (0.155 ml, 1.171 mmol). The resulting mixture is slowly warmed up to room temperature and stirred for 16 hours. The reaction mixture is concentrated under reduced pressure. The obtained residue is purified by flash chromatography (silica gel, 1% to 3% EtOH/DCM) to give (R)-4-biphenyl-4-yl-3-{3-[1-(2-cyano-ethyl)-1H-tetrazol-5-yl]-propionylamino}-butyric acid ethyl ester (137 mg, 64% yield). HPLC retention time=1.61 minutes (condition C); MS=461 (m+1).
Reaction SMILES: [Br:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH2:3]1.[C:7]1([P:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C1(C)C=CC=CC=1>[Br-:1].[CH:2]1([P+:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: BrC1CCCC1
Solvent: Cc1ccccc1
Product: [Br-]
Product: c1ccc([P+](c2ccccc2)(c2ccccc2)C2CCCC2)cc1

Procedure:
Bromocyclopentane and triphenylphosphine are directly heated to 110° C. for 6 hrs in the absence of a solvent, and part of the unreacted raw material is dissolved in toluene, to obtain cyclopentyl triphenylphosphonium bromide. The resulting cyclopentyl triphenylphosphonium bromide is reacted with potassium tert-butoxide in the solvent tetrahydrofuran at 0° C. to generate the corresponding Ylide reagent, which undergoes Witting reaction with