Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[O:11][C:10]([CH3:12])=[C:9]([CH:13]([NH:18][C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=3)[CH2:14][CH:15]([CH3:17])[CH3:16])[CH:8]=2)=[C:5]([CH3:28])[O:4][N:3]=1.[CH3:29][NH:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34].Cl.C(N=C=NCCCN(C)C)C.O.OC1C2N=NNC=2C=CC=1>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[CH3:1][C:2]1[C:6]([C:7]2[O:11][C:10]([CH3:12])=[C:9]([CH:13]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([C:23]([N:30]([CH3:29])[CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:25])=[CH:26][CH:27]=3)[CH2:14][CH:15]([CH3:17])[CH3:16])[CH:8]=2)=[C:5]([CH3:28])[O:4][N:3]=1
Reactant: CCOC(=O)CCNC
Reactant: Cc1noc(C)c1-c1cc(C(CC(C)C)Nc2ccc(C(=O)O)cc2)c(C)o1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1noc(C)c1-c1cc(C(CC(C)C)Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)c(C)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.8 %

Procedure:
A solution of 4-({1-[5-(3,5-dimethylisoxazol-4-yl)-2-methylfuran-3-yl]-3-methylbutyl}amino)benzoic acid (191 mg), ethyl 3-(methylamino)propanoate (79 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (115 mg), hydroxybenzotriazole monohydrate (92 mg) and triethylamine (84 μL) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 4 hr. Ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and water, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure. To the residue were added ethanol (2 mL), tetrahydrofuran (2 mL) and 1N lithium hydroxide (1.0 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (191 mg, 89%).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]2[C:11]([CH2:12][CH2:13][CH2:14]O)=[CH:10][N:9]=[CH:8]2)=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O>>[Br:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][N:7]2[C:11]([CH2:12][CH2:13][CH2:14][Cl:20])=[CH:10][N:9]=[CH:8]2)=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCCCc1cncn1Cc1ccc(Br)cc1
Product: ClCCCc1cncn1Cc1ccc(Br)cc1

Procedure:
1-p-Bromobenzyl-5-(3-hydroxypropyl)-1H-imidazole is treated with thionyl chloride analogous to the method described in example (1c) to give the title compound (b).
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])[C:6]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=2[F:22])=[CH:5][CH:4]=1.[OH:23][C:24]1[CH:25]=[CH:26][C:27]([O:37][CH3:38])=[C:28]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>C(#N)C>[CH3:11][C:10]([CH3:13])([CH3:12])[CH2:9][C:7]1[N:8]=[C:3]([CH2:2][O:23][C:24]2[CH:25]=[CH:26][C:27]([O:37][CH3:38])=[C:28]([CH2:30][CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:29]=2)[CH:4]=[CH:5][C:6]=1[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:15]=1[F:22]
Reactant: CCOC(=O)CCc1cc(O)ccc1OC
Reactant: COc1ccc(F)c(-c2ccc(CCl)nc2CC(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)CCc1cc(OCc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)ccc1OC
Yield: 59.1 %

Procedure:
To a solution of 6-(chloromethyl)-2-(2,2-dimethylpropyl)-3-(2-fluoro-5-methoxyphenyl)pyridine (330 mg) in acetonitrile (8.0 mL) were added ethyl 3-(5-hydroxy-2-methoxyphenyl)propanoate (216 mg) and cesium carbonate (647 mg), and the mixture was heated under reflux for 15 hr. Ethyl acetate was added to the reaction mixture, and the insoluble material was filtered off. The solvent in the filtrate was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (290 mg) as a white solid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:30]=[C:29]([C:31](OCC)=[O:32])[CH:28]=[CH:27][C:21]=2[C:22](OCC)=[O:23])=[CH:16][CH:15]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].S(=O)(=O)(O)O>C1COCC1>[OH:23][CH2:22][C:21]1[CH:27]=[CH:28][C:29]([CH2:31][OH:32])=[CH:30][C:20]=1[C:17]1[CH:18]=[CH:19][C:14]([O:13][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[CH:15][CH:16]=1
Reactant: CCCCCCOc1ccc(-c2cc(C(=O)OCC)ccc2C(=O)OCC)cc1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CCCCCCOc1ccc(-c2cc(CO)ccc2CO)cc1
Temperature: 0 °C

Procedure:
LiAlH4 (5.3 g, 140 mmol) and about 200 ml of THF were blanketed with argon in a reaction vessel and diethyl 2-(4′-hexyloxyphenyl)terephthalate (40 g, 100 mmol) (cf. C1) together with a further 50 ml of THF were slowly added dropwise from a dropping funnel. The reaction mixture was stirred vigorously during this addition. The mixture was subsequently refluxed for about one hour. The reaction mixture was brought to RT and, while cooling in a water bath and blanketing with argon, ice water was carefully added dropwise until gas evolution had ceased. Dilute (10% strength) sulfuric acid was subsequently added dropwise until the turbid gray mixture was clear. The phases were separated by addition of chloroform and the aqueous phase was shaken twice with chloroform. The organic phases were washed once with H2O and subsequently evaporated. The crude product obtained was recrystallized from hexane/ethyl acetate (5:1).
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH:11]=O)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[N:29]1([C:34]([CH:36]2[CH2:40][CH2:39][NH:38][CH2:37]2)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][N:2]1[C:10]([CH2:11][N:38]2[CH2:39][CH2:40][CH:36]([C:34]([N:29]3[CH2:30][CH2:31][CH2:32][CH2:33]3)=[O:35])[CH2:37]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: O=C(C1CCNC1)N1CCCC1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(=O)N4CCCC4)C3)n(C)c2n1
Reaction time: 18 h
Yield: 74.2 %

Procedure:
A solution of 9-methyl-2-(2-methylbenzoimidazol-1-yl)-6-morpholin-4-yl-9H-purine-8-carbaldehyde (105 mg, 0.28 mmol) and pyrrolidin-1-yl-1-pyrrolidin-3-ylmethanone (60 mg, 0.36 mmol) in DCE (6 mL) was stirred at ambient temperature for 2 h. Sodium triacetoxyborohydride (96 mg, 0.45 mmol) was added and the mixture stirred for 18 h, then loaded onto an Isolute® SCX-2 cartridge (10 g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2 M NH3 in MeOH. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH; gradient from 100:0 to 70:30) to afford 364 as a white solid (110 mg, 74%). LCMS (Method G): RT=6.10 min, M+H+=530. 1H NMR (CDCl3, 400 MHz) δ 8.08 (m, 1 H); 7.70 (m, 1 H); 7.27 (m, 2 H); 4.35 (m, 4 H); 3.93 (s, 2 H); 3.92-3.81 (m, 7 H); 3.50-3.38 (m, 4 H); 3.19-3.08 (m, 1 H); 2.99 (m, 1 H); 2.94 (s, 3 H); 2.86 (m, 2 H); 2.70 (m, 1 H); 2.12 (m, 2 H); 2.02-1.90 (m, 2 H) and 1.91-1.81 (m, 2 H)
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:11](=[O:12])[C@H:10]2[CH2:13][CH2:14][CH2:15][C@H:9]2[NH:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2.[Br:24][CH2:25][C:26](Br)=[O:27]>C(OCC)(=O)C.CCCCCC>[Br:24][CH2:25][C:26]([N:8]1[C@@H:9]2[CH2:15][CH2:14][CH2:13][C@@H:10]2[C:11](=[O:12])[N:5]([CH2:4][C:3]2[CH:20]=[CH:21][CH:22]=[CH:23][C:2]=2[F:1])[C:6]2[CH:19]=[CH:18][CH:17]=[CH:16][C:7]1=2)=[O:27]
Reactant: O=C1[C@H]2CCC[C@H]2Nc2ccccc2N1Cc1ccccc1F
Reactant: O=C(Br)CBr
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1[C@H]2CCC[C@H]2N(C(=O)CBr)c2ccccc2N1Cc1ccccc1F
Yield: 62 %

Procedure:
Using (3aR*,10aS*)-9-(2-fluorobenzyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]-diazepin-10(1H)-one and bromoacetyl bromide, the titled compound was synthesized in substantially the same manner as in Working Example 122 in a yield of 62%, m.p. 198.5°-199.6° C. (ethyl acetate-hexane).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5](I)=[CH:4][C:3]=1[O:10][CH:11]([CH3:13])[CH3:12].[CH:14]([O-])=[O:15].[Na+].Cl>CN(C)C=O.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>[Cl:1][C:2]1[C:3]([O:10][CH:11]([CH3:13])[CH3:12])=[CH:4][C:5]([CH:14]=[O:15])=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)Oc1cc(I)c(F)cc1Cl
Reactant: O=C[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1cc(C=O)c(F)cc1Cl
Reaction time: 12 h
Yield: 34.6 %

Procedure:
Then, 62.9 g of 2-chloro-4-fluoro-5-iodo-1-isopropoxybenzene, 20.4 g of sodium formate, and 2.81 g of dichlorobis(triphenylphosphine)palladium were dissolved in 120 ml of N,N-dimethylformamide, which was stirred at 90° to 100° C. for 12 hours, while bubbling carbon monoxide thereinto. After completion of the reaction, the reaction mixture was cooled to room temperature, to which diluted hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 15 g of 4-chloro-2-fluoro-5-isopropoxybenzaldehyde.
Reaction SMILES: Br.[Br:2][CH2:3][C:4]([C:6]([C:8]1[N:9]=[CH:10][NH:11][CH:12]=1)=[O:7])=O.[C:13]([NH:16][C:17]([NH2:19])=[S:18])(=[NH:15])[NH2:14]>CC(C)=O>[BrH:2].[NH:16]([C:17]1[S:18][CH:3]=[C:4]([C:6]([C:8]2[N:9]=[CH:10][NH:11][CH:12]=2)=[O:7])[N:19]=1)[C:13]([NH2:15])=[NH:14]
Reactant: N=C(N)NC(N)=S
Reactant: O=C(CBr)C(=O)c1c[nH]cn1
Agent: Br
Solvent: CC(C)=O
Product: N=C(N)Nc1nc(C(=O)c2c[nH]cn2)cs1
Yield: 54.1 %

Procedure:
A mixture of 0.38 g (1.4 mmol) of 2-bromo-1-(4-imidazoyl)ethanone hydrobromide in 10 ml of acetone was warmed until homogeneous, then 0.17 g (1.4 mmol) of amidinothiourea was added and the mixture was heated at reflux for 0.5 hour. The mixture was cooled and the white precipitate was collected, washed with ether, and dried, thereby affording 0.24 g (60%) of 2-guanidino-4-(4-imidazoyl)thiazole hydrobromide, mp 225° (dec). nmr (DMSO-d6) (δ): 8.20 (s, 1H); 8.0 (b, 4H); 7.77 (s, 1H); 7.36 (s, 1H); high resolution mass spectrum: calcd. C7H8N6S: for 208.0531; found: 208.0517; calcd. for C7H8N6S.HBr.H2O: C, 27.37; H, 3.60; N, 27.36; found: C, 27.23; H, 3.57; N, 27.64.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.O>[C:11]1([NH:10][CH2:5][C:4]2[CH:3]=[C:2]([OH:1])[CH:9]=[CH:8][CH:7]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1cccc(O)c1
Reactant: Nc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: O
Product: Oc1cccc(CNc2ccccc2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.2 %

Procedure:
To a solution of 3-hydroxybenzaldehyde (1.05 g, 8.6 mmol) and aniline (821 μL, 9.0 mmol) in dichloromethane (35 mL) was added acetic acid (516 μL, 9.0 mmol). The reaction mixture was stirred at room temperature for 24 hours. Sodium triacetoxyborohydride (4.55 g, 21.5 mmol) was added, and the reaction was stirred at room temperature for 24 hours. Water was added to quench the reaction and the mixture was diluted with dichloromethane. The organic layer was washed with brine, passed through a hydrophobic frit and the solvent was removed in vacuo to afford the title compound as a brown oil (1.7 g, quantitative yield).
Reaction SMILES: [C:1]([CH:9]=[CH:10][C:11]([O:13]CC)=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:16][C@H:17]1[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]([CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:18]1=[O:36]>C1(C)C=CC=CC=1.[Pd]>[C:32]([O:31][C:29](=[O:30])[CH2:28][N:19]1[C:18](=[O:36])[CH:17]([NH:16][CH:10]2[CH2:9][CH:1]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[O:13][C:11]2=[O:12])[CH2:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]1=2)([CH3:35])([CH3:33])[CH3:34]
Reactant: CCOC(=O)C=CC(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N)CCc2ccccc21
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)CN1C(=O)C(NC2CC(c3ccccc3)OC2=O)CCc2ccccc21
Reaction time: 18 h

Procedure:
Ethyl 3-benzoylacrylate (13a) (55.6 g, 250 mmoles) is dropped into a solution of (3S)-3-amino-1-t-butoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-benzazepin-2-one (11) (66.2 g, 227 mmoles) in 200 ml of toluene, at room temperature in 1 h. The resulting mixture is left under stirring for 18 h, then added with 10% Pd—C (26 g, 22 mmoles) and hydrogenated at 3 atm for 18 h at room temperature. After completion of the reaction, the catalyst is filtered off, 50 ml of acetic acid are added and volatiles are distilled off at 110–120° C. inner temperature.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6]([I:35])=[C:7]([C:24]([NH:26][CH2:27][CH:28]([CH2:30][CH:31]([OH:34])[CH2:32][OH:33])[OH:29])=[O:25])[C:8]([I:23])=[C:9]([C:21]=1[I:22])[C:10]([NH:12][CH2:13][CH:14]([CH2:16][CH:17]([OH:20])[CH2:18][OH:19])[OH:15])=[O:11])(=[O:3])[CH3:2].Cl[CH2:37][CH2:38][OH:39].OS(O)(=O)=O>[OH-].[Na+]>[OH:34][CH:31]([CH2:32][OH:33])[CH2:30][CH:28]([OH:29])[CH2:27][NH:26][C:24](=[O:25])[C:7]1[C:6]([I:35])=[C:5]([N:4]([CH2:37][CH2:38][OH:39])[C:1](=[O:3])[CH3:2])[C:21]([I:22])=[C:9]([C:10]([NH:12][CH2:13][CH:14]([CH2:16][CH:17]([OH:20])[CH2:18][OH:19])[OH:15])=[O:11])[C:8]=1[I:23]
Reactant: OCCCl
Reactant: CC(=O)Nc1c(I)c(C(=O)NCC(O)CC(O)CO)c(I)c(C(=O)NCC(O)CC(O)CO)c1I
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)N(CCO)c1c(I)c(C(=O)NCC(O)CC(O)CO)c(I)c(C(=O)NCC(O)CC(O)CO)c1I
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Acetamido-N,N'-bis[(2,3-dihydroxypropyl)-2-hydroxyethyl]-2,4,6-triiodoisophthalamide, prepared as in Example 2, Step B, (83.5 g, 0.1 g-mole) is dissolved in 1 N NaOH (140 ml, 0.14 g-mole) and the solution is stirred at room temperature for 1 hour and 2-chloroethanol (13.7 g, 0.17 g-mole) is added. The solution is stirred at 50° C. for 5 hours to complete the reaction. The solution is acidified with H2SO4 and evaporated to dryness under reduced pressure. The residue is triturated with MeOH and the precipitated solid is filtered. The mother liquor is concentrated under vacuum and the crude product is purified by reverse-phase (C18) HPLC to give the purified final product. The yield of this reaction and purification is 80%.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25]4[CH:30]=[CH:29][C:28]([S:31](=[O:36])(=[O:35])[N:32]([CH3:34])[CH3:33])=[CH:27][CH:26]=4)[CH2:23][CH2:22][C:21]([C:37]([O:39]C)=[O:38])=[CH:20][C:19]=3[CH:41]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+]>CO.C1COCC1>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25]4[CH:26]=[CH:27][C:28]([S:31](=[O:35])(=[O:36])[N:32]([CH3:33])[CH3:34])=[CH:29][CH:30]=4)[CH2:23][CH2:22][C:21]([C:37]([OH:39])=[O:38])=[CH:20][C:19]=3[CH:41]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3c2ccc(S(=O)(=O)N(C)C)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3c2ccc(S(=O)(=O)N(C)C)cc2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
In methanol (50 ml) and THF (50 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-1-(N,N-dimethyl-4-sulfamoylphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylate (0.34 g). To the solution was added 1N sodium hydroxide solution (10 ml), and the mixture was stirred at room temperature at 60° C. for 1 hour, concentrated, neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried with anhydrous magnesium sulfate. The solvent was evaporated to give 7-[4-(2-butoxyethoxy)phenyl]-1-(N,N-dimethyl-4-sulfamoylphenyl)-2,3-dihydro-1H-1-benzazepine-4-carboxylic acid (0.33 g) as yellow crystals.
Reaction SMILES: [OH-].[Na+].CO.[CH3:5][C:6]1[N:11]=[C:10]([C:12]2[CH:13]=[N:14][N:15]([CH3:21])[C:16]=2[C:17]([O:19]C)=[O:18])[C:9]([CH3:22])=[CH:8][N:7]=1>O>[CH3:5][C:6]1[N:11]=[C:10]([C:12]2[CH:13]=[N:14][N:15]([CH3:21])[C:16]=2[C:17]([OH:19])=[O:18])[C:9]([CH3:22])=[CH:8][N:7]=1
Reactant: COC(=O)c1c(-c2nc(C)ncc2C)cnn1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ncc(C)c(-c2cnn(C)c2C(=O)O)n1
Temperature: 50 °C
Reaction time: 1 h
Yield: 52.5 %

Procedure:
Sodium hydroxide (0.31 g) was added to a mixed solution of methanol (15 ml) and water (15 ml) containing the methyl 4-(2,5-dimethylpyrimidin-4-yl)-1-methyl-1H-pyrazole-5-carboxylate (1.9 g) obtained in (Example 3.22) <Step 1>, and the obtained mixture was then stirred at 50° C. for 1 hour. Thereafter, methanol was distilled away from the reaction solution under reduced pressure, and the residue was then adjusted to pH 5-6 by addition of 1 N hydrochloric acid. Thereafter, water was distilled away under reduced pressure. The obtained residue was washed with methylene chloride, and the filtrate was then concentrated under reduced pressure, so as to obtain the title compound (0.94 g) in the form of a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]2[C:9]([C:10](O)([C:19]3[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([Br:29])[CH:20]=3)[C:11]=1[C:12]([NH:14][C:15](=[O:18])[CH2:16][Cl:17])=[NH:13])=[CH:8][CH:7]=[C:6]1[CH:31]=[CH:32][CH:33]=[CH:34][C:5]=21>C1(C)C(C)=CC=CC=1.O>[Br:29][C:21]1[CH:20]=[C:19]([CH:10]2[C:9]3[C:4](=[C:5]4[CH:34]=[CH:33][CH:32]=[CH:31][C:6]4=[CH:7][CH:8]=3)[O:3][C:2]([NH2:1])=[C:11]2[C:12]2[N:14]=[C:15]([CH2:16][Cl:17])[O:18][N:13]=2)[CH:24]=[C:23]([O:25][CH3:26])[C:22]=1[O:27][CH3:28]
Reactant: COc1cc(C2(O)C(C(=N)NC(=O)CCl)=C(N)Oc3c2ccc2ccccc32)cc(Br)c1OC
Solvent: O
Solvent: Cc1ccccc1C
Product: COc1cc(C2C(c3noc(CCl)n3)=C(N)Oc3c2ccc2ccccc32)cc(Br)c1OC
Temperature: 25 °C

Procedure:
2-Amino-4-(3-bromo-4,5-dimethoxy-phenyl)-N-chloroacetylhydroxy-4H-benzo[h]chromene-3-carboxamidine (23) (137 mg, 0.25 mmol) is taken in 10 ml xylene and refluxed under LC-MS control and is stirred further at room temperature till the reaction is complete. The reaction mixture is diluted with water to about 50 ml and stirred for 2 h at room temperature. Thus resulting precipitates are separated by filtration, washed well with water and is dried under high vacuum to get solids of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:15]=[C:16]([NH:20][C:21](=[O:32])OC2C=CC([N+]([O-])=O)=CC=2)[CH:17]=[CH:18][CH:19]=1.[N:33]([CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][NH2:47])=[N+:34]=[N-:35]>CN(C=O)C>[N:33]([CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][NH:47][C:21]([NH:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH:5]2[C:4]3[C:9](=[C:10]([Cl:12])[CH:11]=[C:2]([Cl:1])[CH:3]=3)[CH2:8][N:7]([CH3:13])[CH2:6]2)[CH:15]=1)=[O:32])=[N+:34]=[N-:35]
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(NC(=O)Oc3ccc([N+](=O)[O-])cc3)c2)C1
Reactant: [N-]=[N+]=NCCOCCOCCOCCN
Solvent: CN(C)C=O
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(NC(=O)NCCOCCOCCOCCN=[N+]=[N-])c2)C1
Reaction time: 2 h

Procedure:
To 4-nitrophenyl 3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylcarbamate (prepared by the procedure described in example 38) (200 mg, 0.40 mmol, 1.00 equiv, 95%) in DMF (5 mL) was added TEA (170 mg, 1.60 mmol, 4.00 equiv, 95%) and 2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethanamine (90 mg, 0.39 mmol, 1.00 equiv, 95%) and the resulting solution was stirred for 2 h. The mixture was then concentrated under vacuum, diluted with 10 mL of water and then extracted with 3×30 mL of ethyl acetate. The organic layers were combined, washed with 3×30 mL of brine, dried over anhydrous sodium sulfate and then evaporated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5˜1:1). This resulted in 160 mg (72%) of 1-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl)-3-(3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl)urea as pale-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:12])[CH:8]=2)[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CN(C=O)C>[CH2:19]([O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([Cl:1])[CH:11]=[CH:10]2)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: Oc1ccc2nc(Cl)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Clc1ccc2cc(OCc3ccccc3)ccc2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94 %

Procedure:
To a solution of 2-chloro-6-quinolinol 11 (5.45 g) in DMF (100 ml) is added, at 0° C., cesium carbonate (11.9 g). After 15 minutes at 0° C., benzyl bromide (4 ml) is added and the reaction is stirred for 12 h at room temperature. Water (100 ml) is then added and the solid obtained is filtered and washed with pentane. No further purification is needed. 6-(benzyloxy)-2-chloroquinoline 12 is obtained as a powder.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6]O)[C@@H:3]([OH:4])[CH2:2]1.[N-:18]=[N+:19]=[N-:20].[Li+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)Br>>[N:18]([CH2:6][C@H:5]1[O:8][C@@H:1]([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:2][C@@H:3]1[OH:4])=[N+:19]=[N-:20]
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: [N-]=[N+]=[N-]
Agent: BrC(Br)(Br)Br
Agent: [Li+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](CN=[N+]=[N-])O2)c(=O)[nH]c1=O
Reaction time: 0.17 h

Procedure:
Thymidine (2.42 g, 10.0 mmol) was dried under reduced pressure for 1 hour. Thereto was added 2.20 g (4.5 eq) of lithium azide, and the mixture was further dried for 1 hour. Distilled DMF (50 ml) was added to the reaction vessel, and the pressure was reduced for about 10 minutes with stirring. Further, 3.41 g (1.3 eq) of triphenylphosphine was added and, after confirmation of the dissolution of triphenylphosphine, 4.97 g (1.5 eq) of carbon tetrabromide was added to initiate the reaction. On that occasion, the solution turned yellow. After 40 minutes, the completion of the reaction was confirmed by TLC, and the reaction was quenched with methanol. The solution was distilled under reduced pressure, and the residue was purified by silica gel column chromatography (mobile phase MeOH:CHCl3=1:9) to give 5′-azido-5′-deoxythymidine.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([NH:6][C:7]2[C:11]([C:12]#[N:13])=[CH:10][S:9][CH:8]=2)=[C:4]([N+:16]([O-])=O)[CH:3]=1.C(OCC)(=O)C>C(O)C.[Pd]>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([NH:6][C:7]2[C:11]([C:12]#[N:13])=[CH:10][S:9][CH:8]=2)=[C:4]([NH2:16])[CH:3]=1
Reactant: N#Cc1cscc1Nc1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: N#Cc1cscc1Nc1ccc(Cl)cc1N

Procedure:
3-(4-Chloro-2-nitroanilino)-thiophene-4-nitrile (17.18 g, 0.06 mol) was hydrogenated in ethanol (300 ml) and ethyl acetate (100 ml) using a palladium/charcoal catalyst (3.5 g, 10%) in a Parr hydrogenator to give 3-(4-Chloro-2-aminoanilino)-thiophene-4-nitrile. After two hours, the reaction was complete, the catalyst was filtered off and the solution was evaporated to dryness under vacuum.