Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH:3]1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:19]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH:26]=O)([O:21][CH3:22])=[O:20]>C(OCC)(=O)C.CCCCCC>[CH3:22][O:21][C:19](=[O:20])[C:23]1[CH:30]=[CH:29][CH:28]=[C:25]([CH2:26][NH:1][C@@H:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][CH2:4][C@H:3]2[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:24]=1
Reactant: NC1c2ccccc2CCC1Cc1ccccc1
Reactant: COC(=O)c1cccc(C=O)c1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)c1cccc(CN[C@@H]2c3ccccc3CC[C@H]2Cc2ccccc2)c1
Yield: 28 %

Procedure:
In a procedure similar to preparation C, the title compound was prepared from 1-amino-2-benzyltetralin and 3-carbomethoxybenzaldehyde. The trans isomer was isolated as an oil in 28% yield following chromatography on silica gel with ethyl acetate/hexane.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=[O:3])C.[C:8]([O:11][CH2:12][C@@H:13]1[C@@H:17]([CH2:18][O:19][C:20](=[O:22])[CH3:21])[O:16][CH2:15][O:14]1)(=[O:10])[CH3:9].[C:23](O)(=O)C>[Cl-].[Zn+2].[Cl-]>[C:5]([O:4][CH2:1][O:3][C@@H:13]([C@H:17]([O:16][C:15](=[O:14])[CH3:23])[CH2:18][O:19][C:20](=[O:22])[CH3:21])[CH2:12][O:11][C:8](=[O:10])[CH3:9])(=[O:7])[CH3:6]
Reactant: CC(=O)O
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)OC[C@H]1OCO[C@@H]1COC(C)=O
Agent: [Cl-]
Agent: [Zn+2]
Product: CC(=O)OCO[C@H](COC(C)=O)[C@@H](COC(C)=O)OC(C)=O
Reaction time: 8 h

Procedure:
100 ml of acetic anhydride was added to 70.12 g of (4R,5R)-4,5-bis(acetoxymethyl)-1,3-dioxolane obtained in Example 4 and mixed at room temperature to dissolve. After the addition of 3.05 g of anhydrous zinc chloride and 10 ml of glacial acetic acid, the mixture was stirred overnight. The resultant reaction mixture was extracted with 700 ml of ethyl acetate, neutralized with saturated aqueous solution of sodium hydrogen carbonate, washed with water and saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and filtered. The solvent was removed by evaporation to obtain 99.48 g of the title compound as a reddish brown oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[C:9]([NH:10][CH:11]([CH:14]=O)[CH2:12][CH3:13])=[CH:8][C:7]([CH3:16])=[N:6][C:5]=1[O:17][C:18]1[C:23]([CH3:24])=[CH:22][C:21]([Cl:25])=[CH:20][C:19]=1[CH3:26].[CH3:28][NH2:29].[O-]S([O-])(=O)=O.[Na+].[Na+].[Na]>ClC(Cl)C.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:27])[C:4]1[C:9]([NH:10][CH:11]([CH2:14][NH:29][CH3:28])[CH2:12][CH3:13])=[CH:8][C:7]([CH3:16])=[N:6][C:5]=1[O:17][C:18]1[C:23]([CH3:24])=[CH:22][C:21]([Cl:25])=[CH:20][C:19]=1[CH3:26]
Reactant: CCC(C=O)Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1C(=O)OC
Reactant: CN
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCC(CNC)Nc1cc(C)nc(Oc2c(C)cc(Cl)cc2C)c1C(=O)OC
Temperature: 25 °C

Procedure:
A mixture of 2-(4-chloro-2,6-dimethyl-phenoxy)-4-(1-formyl-propylamino)-6-methyl-nicotinic acid methyl ester (67 mg, 0.17 mmol) in dichloroethane (2 ml) was treated with methylamine, 1 drop of acetic acid, anhydrous Na2SO4 and sodium cyanoborohdride and stirred at rt. overnight. The mixture was quenched with water, extracted with methylene chloride. The organic layer was separated, dried, concentrated, and purified by silica gel Biotage using methylene chloride to 5% methanol in methylene chloride as eluent to give the title compound as an off-white solid. 1HNMR(CDCl3) 8.07(d, 1H), 7.02(s, 2H), 6.29(s, 1H), 3.87(s, 3H), 3.80(m, 1H), 2.88(m, 2H), 2.56(s, 3H), 2.11(s, 3H), 2.06(s, 6H), 1.63(m, 2H), 0.99(t, 3H)ppm
Reaction SMILES: C(N(C(C)C)CC)(C)C.Br[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13].Cl.[CH3:21][O:22][C:23](=[O:29])[CH:24]([CH:26]([CH3:28])[CH3:27])[NH2:25].C(OCC)C>C(Cl)Cl>[O:13]=[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:11][NH:25][CH:24]([CH:26]([CH3:28])[CH3:27])[C:23]([O:22][CH3:21])=[O:29]
Reactant: O=C(CBr)c1ccccc1
Reactant: COC(=O)C(N)C(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)C(NCC(=O)c1ccccc1)C(C)C

Procedure:
Diisopropylethylamine (7.66 ml) and 2-bromoacetophenone (4.2 g) are added to a suspension of DL-valine methyl ester hydrochloride (3.36 g, Reference compound No. 45-1) in methylene chloride (100 ml), and the mixture is refluxed for four days. The reaction mixture is allowed to stand at room temperature, diethyl ether is added to the mixture, and the whole is extracted with 0.1 N hydrochloric acid. Sodium hydrogencarbonate is added to the extract to basify the system, and the whole is extracted with ethyl acetate. The organic layer is washed with saturated brine and dried over magnesium sulfate. The organic layer is concentrated under reduced pressure to give the titled reference compound (4.92 g).
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21](OC)=[O:22])[N:4]=1)#[N:2].[NH2:25][C@@H:26]([CH2:31][OH:32])[CH2:27][C:28]([OH:30])=[O:29].C[O-].[Na+]>COCCO>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21]([NH:25][C@@H:26]([CH2:31][OH:32])[CH2:27][C:28]([OH:30])=[O:29])=[O:22])[N:4]=1)#[N:2]
Reactant: N[C@@H](CO)CC(=O)O
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: COCCO
Product: N#Cc1nc(C(=O)N[C@@H](CO)CC(=O)O)c(O)c2ccc(Oc3ccccc3)cc12
Temperature: 25 °C

Procedure:
Methyl 1-cyano-4-hydroxy-7-phenoxyisoquinoline-3-carboxylate (30 mg, 0.09 mmol), (R)-3-amino-4-hydroxybutanoic acid (67 mg, 0.56 mmol, PepTech) and sodium methoxide (28 mg, 0.53 mmol) were suspended in 2-methoxyethanol (3 mL). The resulting mixture was heated to reflux for 3 hours and then cooled to room temperature. The solvent was removed in vacuo and the residue was dissolved in H2O (15 mL) and EtOAc (15 mL). To the stirred mixture was added 1 N hydrochloric acid until pH was 1. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-50% EtOAc/CH2Cl2 with 0.5% formic acid) to give the title compound in 12 mg. MS: (−) m/z 405.97 (M−1).
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]1[CH2:12][CH:7]2[CH:6](O)[CH:5]1O.O.I([O-])(=O)(=O)=O.[Na+].[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>ClC(Cl)C.ClCCCl>[CH2:22]([N:29]1[CH2:5][CH:4]2[CH2:12][CH:7]([C:8]3[CH:9]=[CH:10][CH:11]=[C:2]([I:1])[C:3]=32)[CH2:6]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: OC1C2CC(c3c(I)cccc32)C1O
Reactant: NCc1ccccc1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: ClCCCl
Solvent: CC(Cl)Cl
Product: Ic1cccc2c1C1CC2CN(Cc2ccccc2)C1
Reaction time: 1.5 h
Yield: 60.8 %

Procedure:
5-Iodo-1,2,3,4-tetrahydro-1,4-methano-naphthalene-2,3-diol (8.33 g, 27.6 mmol) and Et3NBnCl (10 mg) were vigorously stirred in dichloroethane (25 mL) and H2O (75 mL) then treated with sodium periodate (6.17 g, 29.0 mmol). After 1.5 hours, the layers were separated and the aqueous layer extracted with DCE (2×40 mL). The combined organic layer was washed with H2O (4×30 mL) until no reaction to starch iodide paper was observed, then with saturated aqueous NaCl solution (30 mL). The organic layer was dried through a cotton plug and treated with benzyl amine (3.16 mL, 29.0 mmol) and stirred for 2 minutes then transferred to an addition funnel. This solution was added over ˜10 minutes to a vigorously stirred cooled (0° C.) mixture of NaHB(OAc)3 (18.72 g, 88.0 mmol) in DCE (150 mL). After addition was complete, the mixture was stirred without cooling for 2 hours. The mixture was quenched with saturated aqueous Na2CO3 solution (100 mL) and stirred for 1 hour, then the layers were separated and the aqueous layer was extracted with CH2Cl2 (3×50 mL). The combined organic layer was washed with saturated aqueous NaCl solution (50 mL), dried through a cotton plug and concentrated. Chromatography on Silica gel provided an oil (6.3 g, 61%). (TLC 5% EtOAc/hexanes Rf 0.10). 1H NMR (400 MHz, CDCl3) δ7.61 (d, J=8.0 Hz, 1H), 7.28-7.22 (m, 3H), 7.13 (d, J=8.0 Hz, 1H), 6.98-6.94 (m, 3H), 3.58 (AB dd, J=14.2 Hz, 2H), 3.26 (br s, 1H), 3.21 (br s, 1H), 3.04 (br d, J=10.2 Hz, 1H), 2.83 (br d, J=10.2 Hz, 1H), 2.47 (d, J=10.0 Hz, 1H), 2.39 (d, J=10.0 Hz, 1H), 2.34 (m, 1H), 1.72 (d, J=10.5 Hz, 1H). APCl MS m/e 376.0 [(M+1)+].
Reaction SMILES: [S:1]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=O)[NH:5][C:4]=2[CH:3]=[CH:2]1.B.CSC.CO>O1CCCC1>[S:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:4]=2[CH:3]=[CH:2]1
Reactant: O=C1CCCc2sccc2N1
Agent: B
Solvent: CO
Solvent: CSC
Solvent: C1CCOC1
Product: c1cc2c(s1)CCCCN2
Temperature: 0 °C
Reaction time: 16 h
Yield: 79.3 %

Procedure:
To a mixture of 21.2 g of 5,6,7,8-tetra-hydro-4H-thieno[3,2-b]azepin-5-one in 100 ml of tetrahydrofuran under argon, chilled to 0° C. is added 25.2 ml of a 10.0 molar solution of borane-dimethylsulfide in tetrahydrofuran. The solution is stirred at room temperature for 16 hours and is refluxed for 5 hours. The mixture is cooled to room temperature and 85 ml of methanol added dropwise (exotherm). The solvent is removed and 100 ml of methanol is added (2 times) and after each addition the solvent is removed. To the residual solid (dried under vacuum) is added 126 ml of 2N NaOH and the mixture refluxed 3 hours. The mixture is chilled (2 hours) and extracted with dichloromethane. The extract is dried (Na2SO4) and the solvent removed to give 15.4 g of brown solid, m.p. 55°-57° C. A sample (3 g) is sublimed to give 2.6 g of crystals, m.p. 64°-65° C.
Reaction SMILES: [Na].[CH2:2]([SH:5])[CH:3]=[CH2:4].[CH2:6]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](Cl)=[N:11][N:10]=1)[CH3:7]>CO>[CH2:6]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([S:5][CH2:2][CH:3]=[CH2:4])=[N:11][N:10]=1)[CH3:7]
Reactant: C=CCS
Reactant: CCOc1nnc(Cl)c2ccccc12
Agent: [Na]
Solvent: CO
Product: C=CCSc1nnc(OCC)c2ccccc12

Procedure:
0.23 g(0.01 mol) of metallic sodium was dissolved in 100 ml of absolute methanol and then mixed with 0.93 ml(0.01 mol) of allylmercaptan. To this mixture was added 2.09 g(0.01 mol) of 1-ethoxy-4-chlorophthalazine obtained from Preparation 10. The reaction solution was refluxed for 3 hours and then treated according to the same manner as Example 1 to obtain the title compound as a freezing white crystal.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[F:13][C:14]1[CH:15]=[C:16]([OH:21])[CH:17]=[C:18]([F:20])[CH:19]=1>>[N+:10]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[O:21][C:16]1[CH:15]=[C:14]([F:13])[CH:19]=[C:18]([F:20])[CH:17]=1)[C:6]#[N:7])([O-:12])=[O:11]
Reactant: Oc1cc(F)cc(F)c1
Reactant: N#Cc1ccc(Cl)c([N+](=O)[O-])c1
Product: N#Cc1ccc(Oc2cc(F)cc(F)c2)c([N+](=O)[O-])c1

Procedure:
In a similar manner, 4-chloro-3-nitrobenzonitrile (4.6 g, 25 mmol) and 3,5-difluorophenol were combined to produce 6.9 g of 3-nitro-4-(3,5-difluorophenoxy)benzonitrile (26.2), mp 132-136° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:14]#[CH:15])[C:11]=1[O:12][CH3:13])[C:6](O)=[O:7])#[N:2].C1(C)C=CC=CC=1.C(Cl)(=O)C([Cl:26])=O>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([C:14]#[CH:15])[C:11]=1[O:12][CH3:13])[C:6]([Cl:26])=[O:7])#[N:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C#Cc1cc(C(=O)O)cc(C#N)c1OC
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C#Cc1cc(C(=O)Cl)cc(C#N)c1OC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To 3-cyano-5-ethynyl-4-methoxybenzoic acid (610 mg), toluene (6 mL), N,N-dimethylformamide (1 droplet) and oxalyl chloride (0.32 mL) were added to the solution under ice cooling, and the mixture was stirred at room temperature for 1.5 hours. The solvent was distilled off under reduced pressure and the obtained residue was azeotroped with toluene and used for the synthesis of (c).
Reaction SMILES: [Li].[C:2]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)#[N:3].[Br-].[O:13]1CCO[CH:14]1[CH2:18][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>CO.CN(C)C=O>[C:2]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1/[CH:6]=[CH:18]/[CH:14]=[O:13])#[N:3]
Reactant: N#Cc1ccccc1C=O
Reactant: c1ccc([P+](CC2OCCO2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Li]
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: N#Cc1ccccc1/C=C/C=O
Temperature: 85 °C
Reaction time: 6 h
Yield: 45 %

Procedure:
A solution of lithium (77 mg) in methanol (30 ml) was added during 2 hours to a stirred suspension of 2-cyanobenzaldehyde and (1,3-dioxolan-2-yl-methyl)-triphenyl phosphonium bromide (4.71 g) in dimethylformamide (34 ml) at 85° C. The mixture was stirred at 85° C. for 6 hours, allowed to cool and poured into water (450 ml). The reaction mixture was extracted with diethyl ether (3×120 ml) and the combined ether extracts washed with saturated brine, dried (MgSO4) and evaporated. The residue was dissolved and stirred in tetrahydrofuran (30 ml) and 3M hydrochloric acid (30 ml) for 2 hours. The mixture was diluted with water (100 ml) and extracted with diethyl ether (300 ml). The ether was washed with saturated sodium hydrogen carbonate solution (2×50 ml) and saturated brine, dried (MgSO4) and evaporated. The residue was purified by flash column chromatography on silica, eluting with n-hexane-ethyl acetate (80:20:, by volume) to give as a pale yellow solid 2-cyano-(E)-cinnamaldehyde (504 mg, 45%) m.p. 107°-110° C.; NMR: 6.82 (1H,q), 7.69 (5H,m) and 9.81 (1H,d); m/e 157 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([CH2:12]O)[N:9]=[CH:8]2)=[CH:4][CH:3]=1.C([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])C.S(Cl)(Cl)=O.Cl.[C:28]1([CH3:34])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([CH2:12][N:18]3[CH2:19][CH2:20][C:34]([C:2]4[CH:15]=[CH:14][CH:5]=[CH:4][CH:3]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:22][CH2:21]3)[N:9]=[CH:8]2)=[CH:4][CH:3]=1
Reactant: Cc1ccccc1
Reactant: CCN(CC)CC
Reactant: OCc1cn(Cc2ccc(Cl)cc2)cn1
Agent: Cl
Solvent: O=S(Cl)Cl
Product: Clc1ccc(Cn2cnc(CN3CCC(c4ccccc4)(c4ccccc4)CC3)c2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
The product of step (a) (0.39 g) was dissolved in toluene (10 ml), triethylamine (0.26 ml) and thionyl chloride (0.13 ml) were added and the mixture stirred at room temperature for 20 hours. The solvent was removed by evaporation, a solution of 4,4-diphenylpiperidine hydrochloride (0.478 g) in dimethylsulphoxide (10 ml) and triethylamine (0.65 ml) added. After 2 hours water and ethyl acetate were added, the organic phase was separated, washed with brine, dried and the solvent removed to leave a gum. Purification by supercritical fluid chromatography gave a solid which was treated with 1.0M ethereal hydrogen chloride solution to give the product as a solid (0.02 g), m.p. 254-255° C.
Reaction SMILES: [Br:1][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].N1([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][C:14]2=C)CCCC1.[CH3:23][CH2:24]O>>[Br-:1].[CH2:6]([O:5][C:3]([CH2:2][N+:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:13](=[CH:16][N:15]2[CH2:24][CH2:23][CH2:13][CH2:14]2)[CH:14]=1)=[O:4])[CH3:7]
Reactant: C=C1Nc2ccccc2C1N1CCCC1
Reactant: CCOC(=O)CBr
Reactant: CCO
Product: CCOC(=O)C[N+]1=CC(=CN2CCCC2)c2ccccc21
Product: [Br-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
Ethyl bromoacetate (6.1 ml, 55.4 mmol) was added dropwise to a stirred solution of 3-pyrrolidin-1-yl-methylene-3H-indole (10 g, 50.4 mmol) in EtOH (40 ml) and the reaction mixture was kept stirring at rt overnight. The solid was filtered off, washed with small portions of EtOH and then dried in vacuo, affording title compound (17 g) as a beige solid in 93% yield. tR (LC-1): 1.45 min; ESI-MS(+): m/z 285.31 [M]+ (calcd 285.36 for C17H21BrN2O2+).
Reaction SMILES: [CH3:1][CH:2]([CH3:38])[C@@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=4)=[O:25])=[CH:19][CH:18]=3)[CH:14]=2)[C:9]1=[O:37])[C:4]([O:6]C)=[O:5].CO.[Li+].[OH-].Cl>C1COCC1.O>[CH3:1][CH:2]([CH3:38])[C@@H:3]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3[CH:18]=[CH:19][C:20]([NH:23][C:24]([NH:26][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=4)=[O:25])=[CH:21][CH:22]=3)[CH:14]=2)[C:9]1=[O:37])[C:4]([OH:6])=[O:5]
Reactant: COC(=O)[C@@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)ccc2C1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@H](C(=O)O)N1Cc2cc(-c3ccc(NC(=O)Nc4cccc(C(F)(F)F)c4)cc3)ccc2C1=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
The compound of example 360 (150 mg, 0.293 mmol) was taken in THF (4 mL) and MeOH (1 mL) and to this reaction mixture, 1 N LiOH (61.58 mg, 1.46 mmol) was added and stirred at room temperature for 2-3 h. After completion of the reaction, the solvent was evaporated and the residue obtained was dissolved in water and acidified with 1 N HCl to obtain the title compound, which was filtered and dried.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:53])[C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][C:24]([NH2:52])=[C:25]([O:27][CH:28]([C:30]4[C:35]([Cl:36])=[CH:34][CH:33]=[C:32]([O:37]CC5C(OC)=CC(OC)=CC=5OC)[C:31]=4[Cl:51])[CH3:29])[CH:26]=3)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>C1(C)C=CC=CC=1>[NH2:52][C:24]1[N:23]=[CH:22][C:21]([C:18]2[CH:17]=[CH:16][C:15]([C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[O:53])=[CH:20][CH:19]=2)=[CH:26][C:25]=1[O:27][CH:28]([C:30]1[C:35]([Cl:36])=[CH:34][CH:33]=[C:32]([OH:37])[C:31]=1[Cl:51])[CH3:29]
Reactant: COc1cc(OC)c(COc2ccc(Cl)c(C(C)Oc3cc(-c4ccc(C(=O)N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc3N)c2Cl)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(Oc1cc(-c2ccc(C(=O)N3CCNCC3)cc2)cnc1N)c1c(Cl)ccc(O)c1Cl

Procedure:
To 140 mg 4-[4-(6-Amino-5-{1-[2,6-dichloro-3-(2,4,6-trimethoxy-benzyloxy)-phenyl]-ethoxy}-pyridin-3-yl)-benzoyl]-piperazine-1-carboxylic acid tert-butyl ester (from general procedure 53) was added 1 mL TFA, the solution turned reddish immediately followed by addition of 100 μL triethyl silane 3 seconds later. The solution turned to yellow. After stirring for four hours 5 mL of toluene were added and the solvent was removed in vacuo. Chromatography with 10% MeOH/CH2Cl2 to 0.5% to 1% NH4OH/9.5 to 9% MeOH/90% CH2Cl2 led to 55 mg of a white solid, 62° A) yield.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11]S)=[CH:2]1.[N+](C([N+]([O-])=O)=O)([O-])=O.[N+:21]([CH2:24][C:25](=[O:27])[CH3:26])([O-:23])=[O:22]>C1C=CC=CC=1.B(F)(F)F.CCOCC.FC(F)(F)C(O)=O>[CH3:26][C:25]1([CH2:24][N+:21]([O-:23])=[O:22])[C:2]2[NH:1][C:9]3[C:4]([C:3]=2[CH2:10][CH2:11][O:27]1)=[CH:5][CH:6]=[CH:7][CH:8]=3
Reactant: CC(=O)C[N+](=O)[O-]
Reactant: SCCc1c[nH]c2ccccc12
Agent: FB(F)F
Agent: O=C([N+](=O)[O-])[N+](=O)[O-]
Solvent: c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CC1(C[N+](=O)[O-])OCCc2c1[nH]c1ccccc21

Procedure:
To a solution of 322 mg of tryptophol (II, R2, R3, R4, R5, R6 = H and X1 =OH) and 248 mg of the nitroketone, nitro-2-propanone, in 100 ml of benzene is added five drops of boron trifluoride etherate and three drops of trifluoroacetic acid. The reaction mixture is stirred and heated at reflux under water-separator for 18 hr. The benzene solution is cooled, washed with 10% sodium bicarbonate solution, water, saturated brine solution, and dried over magnesium sulfate. The solvent is removed and the residue is subjected to chromatography on silica gel. Elution with chloroform gives the title compound, νmaxCHCl3 3450, 1550cm-1, nmr (CHCl3) δ1.68 (s, 3H), 2.84 (t, 2H), 4.10 (t, 2H).
Reaction SMILES: NN.C(O)=O.[N:6]1([CH2:11][CH2:12][NH:13][C:14]2[N:19]=[C:18]([C:20]3[S:24][C:23]4[C:25]([C:29]5[C:34]([C@H:35]([N:37]=[N+]=[N-])[CH3:36])=[CH:33][N:32]=[C:31]([F:40])[CH:30]=5)=[CH:26][CH:27]=[CH:28][C:22]=4[CH:21]=3)[CH:17]=[CH:16][N:15]=2)[CH:10]=[CH:9][N:8]=[N:7]1>C(O)C.[Ni]>[N:6]1([CH2:11][CH2:12][NH:13][C:14]2[N:19]=[C:18]([C:20]3[S:24][C:23]4[C:25]([C:29]5[C:34]([C@H:35]([NH2:37])[CH3:36])=[CH:33][N:32]=[C:31]([F:40])[CH:30]=5)=[CH:26][CH:27]=[CH:28][C:22]=4[CH:21]=3)[CH:17]=[CH:16][N:15]=2)[CH:10]=[CH:9][N:8]=[N:7]1
Reactant: C[C@@H](N=[N+]=[N-])c1cnc(F)cc1-c1cccc2cc(-c3ccnc(NCCn4ccnn4)n3)sc12
Agent: [Ni]
Agent: NN
Solvent: O=CO
Solvent: CCO
Product: C[C@@H](N)c1cnc(F)cc1-c1cccc2cc(-c3ccnc(NCCn4ccnn4)n3)sc12
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 84.5 %

Procedure:
Add NH2NH2—HCOOH (Pre-prepared, 1 mL) to a solution of (R)—N-(2-(1H-1,2,3-triazol-1-yl)ethyl)-4-(7-(5-(1-azidoethyl)-2-fluoropyridin-4-yl)benzo[b]thiophen-2-yl)pyrimidin-2-amine (250 mg, 513.84 μmol) in ethanol (10 mL). Cool the mixture to 0° C. and add Raney Nickel (0.5 g, 8.52 mmol, wet with water as it packed). Stir the solution at RT for another 1.5 h, filter Raney Nickel out, and wash with methanol. Dilute filtrate with chloroform/IPA (3/1) and wash with saturated sodium carbonate. Dry the organic phase over sodium sulfate and concentrate in vacuo to give a brown tar. Purify the solid by passing through a FCC (10% methanol in DCM) to give the title compound as a pale brown solid (200 mg, 85%). MS (ES) m/z 461 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[CH2:10][C:9]2[NH:8][N:7]=[C:6]([C:11]3[NH:12][C:13]4[C:18]([CH:19]=3)=[CH:17][CH:16]=[C:15]([NH:20][CH3:21])[CH:14]=4)[C:5]=2[CH2:4][CH2:3]1.[O:23]=[C:24]1[CH2:29][O:28][CH2:27][CH2:26][N:25]1[CH2:30][C:31]([OH:33])=O.Cl.C(N=C=NCCCN(C)C)C>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:22])[CH2:10][C:9]2[NH:8][N:7]=[C:6]([C:11]3[NH:12][C:13]4[C:18]([CH:19]=3)=[CH:17][CH:16]=[C:15]([N:20]([CH3:21])[C:31](=[O:33])[CH2:30][N:25]3[CH2:26][CH2:27][O:28][CH2:29][C:24]3=[O:23])[CH:14]=4)[C:5]=2[CH2:4][CH2:3]1
Reactant: CNc1ccc2cc(-c3n[nH]c4c3CCC(C)(C)C4)[nH]c2c1
Reactant: O=C(O)CN1CCOCC1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Product: CN(C(=O)CN1CCOCC1=O)c1ccc2cc(-c3n[nH]c4c3CCC(C)(C)C4)[nH]c2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 67 %

Procedure:
Under an argon atmosphere, to a solution of N-[2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methylamine obtained in Example 4, Step 1 (40 mg, 0.14 mmol) and (3-oxomorpholin-4-yl)acetic acid obtained in Reference Example 4 (76 mg, 0.48 mmol) in pyridine (1.3 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (91 mg, 0.48 mmol) at room temperature, and the mixture was stirred at room temperature for 12 hr. Then, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in methanol (1.2 ml), 2 N aqueous sodium hydroxide solution (1.0 ml) was added, and the mixture was stirred at room temperature for 45 min. Then, to the reaction mixture were added water and ethyl acetate, and the organic layer was separated. The aqueous layer was extracted twice with ethyl acetate, and the combined organic layers were washed successively with water and saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (40 mg, yield 67%).