Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([C:6]1[S:7][CH:8]=[C:9]2[C:14]=1[NH:13][C:12](=[O:15])[CH:11]=[C:10]2Cl)=O)C.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>>[CH2:17]([O:21][C:22]([C:11]1[C:12](=[O:15])[NH:13][C:14]2[C:9]([C:10]=1[N:27]1[CH2:28][CH2:29][N:24]([C:22]([O:21][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:23])[CH2:25][CH2:26]1)=[CH:8][S:7][CH:6]=2)=[O:23])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCOC(=O)c1scc2c(Cl)cc(=O)[nH]c12
Product: CCOC(=O)c1c(N2CCN(C(=O)OC(C)(C)C)CC2)c2cscc2[nH]c1=O

Procedure:
In another method, intermediate 7-chloro-5-oxo-4,5-dihydro-2-thia-4-aza-indene-3-carboxylic acid ethyl ester, depicted by formula (25), was reacted with tert-butyl-1-piperazine carboxylate to yield 7-(4-tert-butoxycarbonyl-piperazin-1-yl)-5-oxo-4,5-dihydro-2-thia-4-aza-indene-6-carboxylic acid ethyl ester, depicted by formula (28). This intermediate was either reacted with an appropriate halide (R1—X) or boronic acid (R1—B(OH)2) to yield an intermediate of structure (29), which was deprotected and reacted with an appropriate acid chloride (R3—COCl) or acid (R3—COOH) to yield target compounds of structure (II), with R2 as ethyl carboxylate, and R1 and R3 as defined above, as shown in Scheme 14.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[CH:15]=[CH2:16]>C(O)(=O)C>[C:14]([CH2:15][CH2:16][N:1]([CH2:5][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][CH:7]=1)([O:18][CH2:19][CH3:20])=[O:17]
Reactant: C=CC(=O)OCC
Reactant: CCOC(=O)Cc1ccc(N)cc1
Solvent: CC(=O)O
Product: CCOC(=O)CCN(CCC(=O)OCC)c1ccc(CC(=O)OCC)cc1

Procedure:
The 2-pentenyleneimino starting material is prepared as follows: The mixture of 89.6 g ethyl 4-aminophenylacetate, 400 g ethyl acrylate and 100 ml acetic acid is refluxed for 19 hours and concentrated in vacuo. The concentrate is poured onto 500 ml ice water, the mixture made basic with aqueous sodium hydroxide and extracted with diethyl ether. The extract is dried, filtered, evaported, the residue distilled and the fraction boiling at 211°-213°/0.6 mm Hg collected, to yield the ethyl 4-(bis-carbethoxyethylamino)-phenylacetate.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:7][C:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15]([NH2:18])(=[O:17])=[O:16])=[N:5][N:4]=1.C1([O:25][C:26](=O)[NH:27][C:28]2[N:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]([O:36][CH3:37])[N:29]=2)C=CC=CC=1.N12CCCN=C1CCCCC2>O1CCOCC1.O>[CH3:35][O:34][C:32]1[CH:31]=[C:30]([O:36][CH3:37])[N:29]=[C:28]([NH:27][C:26]([NH:18][S:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][C:6]2[S:7][C:3]([S:2][CH3:1])=[N:4][N:5]=2)(=[O:16])=[O:17])=[O:25])[N:33]=1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Reactant: CSc1nnc(Cc2ccccc2S(N)(=O)=O)s1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2Cc2nnc(SC)s2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.8 %

Procedure:
To a suspension containing 0.63 g of the sulfonamide prepared in Example 3 in 10 ml of p-dioxane was added 0.6 g phenyl(4,6-dimethoxypyrimidin-2-yl)carbamate followed by dropwise addition of 0.33 g of 1.8-diazabicyclo[5.4.0]undec-7-ene (DBU). The solution was stirred at room temperature for two hours then diluted with about 75 ml of water. After extracting the cloudy aqueous solution 1×30 ml of diethyl ether, the clear aqueous layer was acidified with concentrated hydrochloric acid (red to litmus paper), and the suspension was filtered. The residue was triturated with 5 ml of warm ethyl acetate to give 0.2 g of the subject compound; m.p. 171°-175° C. NMR (CDCl3, DMSO-d6): δ 2.7(s, SCH3); 4.0(s, OCH3); 4.95(s, CH2); 5.9(s, pyrimidine H); 7.6-8.4(m, ar); 9.8(s, NH) ppm.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:10]=[C:11]([C:17]#[N:18])[CH:12]=[C:13]([CH:16]=2)[C:14]#[N:15])=[C:6]([F:19])[C:5]([CH2:20][C:21]2[CH:26]=[C:25]([CH3:27])[C:24](=[O:28])[NH:23][N:22]=2)=[CH:4][CH:3]=1.ClC1C=C(C=[C:36]([O:38]C2C(Cl)=CC=C(CC3C=C(C)C(=O)NN=3)C=2F)C=1)C#N.ClC1C(OC2C=C(C=C(C(F)F)C=2)C#N)=C(F)C(CC2C=C(C)C(=O)NN=2)=CC=1>>[Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:10]=[C:11]([C:17]#[N:18])[CH:12]=[C:13]([CH:16]=2)[C:14]#[N:15])=[C:6]([F:19])[C:5]([CH2:20][C:21]2[CH:26]=[C:25]([CH3:27])[C:24](=[O:28])[N:23]([CH2:36][OH:38])[N:22]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(Cc2ccc(Cl)c(Oc3cc(Cl)cc(C#N)c3)c2F)n[nH]c1=O
Reactant: Cc1cc(Cc2ccc(Cl)c(Oc3cc(C#N)cc(C#N)c3)c2F)n[nH]c1=O
Agent: Cc1cc(Cc2ccc(Cl)c(Oc3cc(C#N)cc(C(F)F)c3)c2F)n[nH]c1=O
Product: Cc1cc(Cc2ccc(Cl)c(Oc3cc(C#N)cc(C#N)c3)c2F)nn(CO)c1=O

Procedure:
Compounds I-22, I-27 and I-29 can be prepared in similar manner except 5-[6-chloro-2-fluoro-3-(5-methyl-6-oxo-1,6-dihydro-pyridazin-3-ylmethyl)-phenoxy]-isophthalonitrile was replaced with 3-chloro-5-[6-chloro-2-fluoro-3-(5-methyl-6-oxo-1,6-dihydro-pyridazin-3-ylmethyl)-phenoxy]-benzonitrile, 3-[6-chloro-2-fluoro-3-(5-methyl-6-oxo-1,6-dihydro-pyridazin-3-ylmethyl)-phenoxy]-5-difluoromethyl-benzonitrile and 3-[6-chloro-2-fluoro-3-(5-methyl-6-oxo-1,6-dihydro-pyridazin-3-ylmethyl)-phenoxy]-5-difluoromethyl-benzonitrile respectively.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[C:6]([C:10]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)[C:13](=[O:25])[O:12][N:11]=2)=[N:7][O:8][N:9]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:26][S:27]([O:1][CH2:2][CH2:3][NH:4][C:5]1[C:6]([C:10]2[N:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:24])[F:23])[CH:16]=3)[C:13](=[O:25])[O:12][N:11]=2)=[N:7][O:8][N:9]=1)(=[O:29])=[O:28]
Reactant: O=c1onc(-c2nonc2NCCO)n1-c1cccc(C(F)(F)F)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)OCCNc1nonc1-c1noc(=O)n1-c1cccc(C(F)(F)F)c1
Reaction time: 0.08 h
Yield: 95.1 %

Procedure:
To a solution of 3-{4-[(2-hydroxyethyl)amino]-1,2,5-oxadiazol-3-yl}-4-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5(4H)-one (1.0 g, 2.9 mmol) in ethyl acetate (8.5 mL) was added methanesulfonyl chloride (0.29 mL, 3.7 mmol) in one portion. The reaction was stirred for 5 minutes and triethylamine (0.52 mL, 3.7 mmol) was added, also in one portion. After stirring for an additional 10 minutes, the reaction was quenched with the addition of water (5 mL). The product was extracted with ethyl acetate (2×5 mL), dried over sodium sulfate and concentrated in vacuo to give the desired product (1.2 g, 99%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[CH:19][CH:18]=[CH:17]2)(=[O:10])=[O:9].CCN(C(C)C)C(C)C.[C:31](OC(=O)C)(=[O:33])[CH3:32]>C1COCC1>[N:20]1[C:21]2[C:16](=[CH:15][CH:14]=[CH:13][C:12]=2[NH:11][S:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[NH:1][C:31](=[O:33])[CH3:32])(=[O:10])=[O:9])[CH:17]=[CH:18][CH:19]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccccc1S(=O)(=O)Nc1cccc2cccnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(=O)Nc1ccccc1S(=O)(=O)Nc1cccc2cccnc12
Yield: 17.8 %

Procedure:
In the similar fashion using route 15 general procedure 30, 2-amino-N-(quinolin-8-yl)benzenesulfonamide (Example Compound 8) (100 mg, 0.33 mmol), DIPEA (140 μl, 0.83 mmol), acetic anhydride (23 μl, 0.49 mmol), THF (3 ml) gave the title compound (20 mg, 18%) after purification by column chromatography with DCM/MeOH/NH3 (49:1:1) as the eluent.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH2:13]=O.[Cl:15][C:16]1[CH:17]=[C:18]([CH:33]=[CH:34][C:35]=1[Cl:36])[CH2:19][N:20]([CH3:32])[C:21](=[O:31])[CH:22]=[C:23]1[C:27](=[O:28])OC(C)(C)[O:24]1>CO>[CH2:11]([O:10][C:8]([N:5]1[CH2:4][CH2:3][CH:2]([N:1]2[CH2:13][C:22]([C:21](=[O:31])[N:20]([CH2:19][C:18]3[CH:33]=[CH:34][C:35]([Cl:36])=[C:16]([Cl:15])[CH:17]=3)[CH3:32])=[C:23]([OH:24])[C:27]2=[O:28])[CH2:7][CH2:6]1)=[O:9])[CH3:12]
Reactant: C=O
Reactant: CCOC(=O)N1CCC(N)CC1
Reactant: CN(Cc1ccc(Cl)c(Cl)c1)C(=O)C=C1OC(C)(C)OC1=O
Solvent: CO
Product: CCOC(=O)N1CCC(N2CC(C(=O)N(C)Cc3ccc(Cl)c(Cl)c3)=C(O)C2=O)CC1
Reaction time: 2 h
Yield: 27.2 %

Procedure:
To a stirred warm (60° C.) solution of ethyl 4-amino-1-piperidinecarboxylate (86.1 mg, 0.5 mmol) and paraformaldehyde (16 mg, 0.5 mmol) in methanol (2 mL) was added N-(3,4-dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-methyl-acetamide (175 mg, 0.5 mmol). After 2 h, the reaction mixture was cooled and purified using preparative HPLC on a C18 column using water/methanol-(0.1% TFA) as the eluent. The fractions containing the desired product were combined, concentrated and lyophilized to give the title compound as a white powder (64 mg, 27% yield). 1HNMR (500 MHz, CDCl3) δ: 10.16 (2H, br s), 7.40 (1H, d, J=8.2 Hz), 7.35 (1H, s), 7.10 (1H, d, J=8.0 Hz), 4.59 (2H, s), 4.34–4.18 (3H, m), 4.13 (2H, q, J=7.0 Hz), 4.09 (2H, s), 2.06 (2H, s), 2.87–2.80 (2H, br m), 1.82–1.76 (2H, br m), 1.63–1.55 (2H, m), 1.25 (3H, t, J=7.0 Hz). MS calcd for C21H26Cl2N3O5 (M+H): 470.36. found: 470.02.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]([NH:8][C:9]1[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][C:10]=1[C:11]([O:13]C)=O)=[O:7])[CH3:2].CCOCC.CC[O-].[Na+].[Na]>C(O)C>[OH:7][C:6]1[C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:23])=[C:11]([OH:13])[C:10]2[C:9](=[C:18]([C:19]([F:22])([F:21])[F:20])[CH:17]=[CH:16][CH:15]=2)[N:8]=1
Reactant: CCOC(=O)CC(=O)Nc1c(C(=O)OC)cccc1C(F)(F)F
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)c1c(O)nc2c(C(F)(F)F)cccc2c1O
Yield: 94.8 %

Procedure:
35.66 g of the product of Step B were added to 800 ml of anhydrous ether in the presence of sodium ethylate prepared from 2.69 g of sodium and 54 ml of ethanol and the mixture was vacuum filtered. The recovered precipitate was dissolved in water and the pH of the solution was adjusted to 1 by addition of 20% hydrochloric acid to obtain 30.56 g of ethyl 2,4-dihydroxy-8-trifluoromethyl-quinoline-3-carboxylate melting at 190° C which was used as is for the next step.
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([OH:15])[CH:10]=1.CC(C)([O-])C.[K+].Br[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=1>O>[CH3:6][O:7][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:15][C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][N:25]=2)[CH:10]=1
Reactant: FC(F)(F)c1ccc(Br)nc1
Reactant: COC(=O)c1cccc(O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Oc2ccc(C(F)(F)F)cn2)c1
Yield: 79.9 %

Procedure:
To a dimethylformamide (1.0 mL) solution of 3-hydroxy-benzoic acid methyl ester (183 mg, 1.2 mmol) was added potassium t-butoxide (147 mg, 1.2 mmol). Upon stirring the reaction at room temperature for 15 min, 2-bromo-5-trifluoromethyl-pyridine (300 mg, 1.32 mmol) was added. The reaction was stirred at room temperature for 15 h. Crude reaction mass was added to water, aqueous layer was acidified to pH 4.0 and product was extracted with ethyl acetate to give 3-(5-trifluoromethyl-pyridin-2-yloxy)-benzoic acid methyl ester (285 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([F:11])=[CH:4][C:3]=1[S:12][CH2:13][CH2:14][OH:15].O=[C:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[F:11][C:5]1[C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]([NH:1][CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)=[C:3]([S:12][CH2:13][CH2:14][OH:15])[CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1cc([N+](=O)[O-])c(F)cc1SCCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc([N+](=O)[O-])c(F)cc2SCCO)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.4 %

Procedure:
To a stirred solution of 2-(2-amino-5-fluoro-4-nitrophenylthio)ethanol (434 mg, 1.869 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (372 mg, 1.869 mmol) in dichloroethane (10 mL) and acetic acid (0.321 mL, 5.61 mmol) was added sodium triacetoxyborohydride (594 mg, 2.80 mmol). The resulting mixture was stirred at room temperature. After 1 hour, additional tert-butyl 4-oxopiperidine-1-carboxylate (372 mg, 1.869 mmol) was added, followed by additional sodium triacetoxyborohydride (594 mg, 2.80 mmol). After a further 3 hours, more tert-butyl 4-oxopiperidine-1-carboxylate (372 mg, 1.869 mmol) was added followed by more sodium triacetoxyborohydride (594 mg, 2.80 mmol). The reaction mixture was stirred overnight. The mixture was then quenched with 1 N NaOH (10 mL), water (20 mL), and saturated sodium carbonate (20 mL). The organic products were then extracted with dichloromethane (3×20 mL). The combined organics were dried, filtered, concentrated, and then chromatographed using 1:3 ethyl acetate:hexanes on silica gel to give the desired product (710 mg, 91%). 1H NMR (DMSO-d6) δ 7.45 (d, J=12.0 Hz, 1H), 7.23 (d, J=6.6 Hz, 1H), 5.08 (t, J=5.4 Hz, 1H), 5.02 (d, J=8.1 Hz, 1H), 3.96-3.84 (m, 2H), 3.69-3.55 (m, 5H), 2.99-2.83 (m, 2H), 1.92-1.83 (m, 2H), 1.45-1.18 (m, 11H); ESI-MS (m/z, %): 360 (100), 128 (30).
Reaction SMILES: [F:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11](I)=[CH:10][CH:9]=2)[O:6][C:5]([CH3:16])([CH3:15])[N:4]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[C:24]([Si:26]([CH3:29])([CH3:28])[CH3:27])#[CH:25].N1CCCCC1>[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.C1(C)C=CC=CC=1>[F:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([C:25]#[C:24][Si:26]([CH3:29])([CH3:28])[CH3:27])=[CH:10][CH:9]=2)[O:6][C:5]([CH3:16])([CH3:15])[N:4]1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]
Reactant: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(I)cc2)OC1(C)C
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(C#C[Si](C)(C)C)cc2)OC1(C)C
Temperature: 35 °C
Yield: 88.4 %

Procedure:
To a toluene (40 ml) solution of (4S,5R)-tert-butyl 4-(fluoromethyl)-5-(4-iodophenyl)-2,2-dimethyloxazolidine-3-carboxylate (2.0 g, 4.6 mmols) is added ethynyltrimethylsilane (451 mg, 4.6 mmols), copper (I)iodide (88 mg, 0.46 mmols, 0.1 equivs), Bis(triphenylphosphine)palladium(II)dichloride (165 mg, 0.23 mmols, 0.05 equivs) and piperidine (782 mg, 9.2 mmols, 2 equivs). The mixture is heated in an atmosphere of nitrogen at 35° C. for six hours. The mixture is filtered through a pad of Celite. The pad of Celite is washed with ethylacetate (2×15 ml). The combined organic filtrates were concentrated using rotary evaporation at reduced pressure to give a crude viscous oil. The oil is purified by flash column chromatography (grading from 100% hexanes to 15% EtOAc) to give the title compound (1.65 g): m/z (Cl) 306 ([M+H]+-Boc).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12](=O)[CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([OH:23])[CH:16]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[N+:25]([C:28]1[CH:33]=[CH:32][C:31]([NH:34][NH2:35])=[CH:30][CH:29]=1)([O-:27])=[O:26].Cl>C(O)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:10]2[N:34]([C:31]3[CH:30]=[CH:29][C:28]([N+:25]([O-:27])=[O:26])=[CH:33][CH:32]=3)[N:35]=[C:12]([CH:13]=[CH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([OH:23])[CH:16]=3)[CH2:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: NNc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(C=CC(=O)C=Cc2ccc(OC)c(O)c2)cc1O
Agent: Cl
Solvent: CCO
Product: COc1ccc(C=CC2=NN(c3ccc([N+](=O)[O-])cc3)C(c3ccc(OC)c(O)c3)C2)cc1O
Yield: 97.4 %

Procedure:
To a stirred mixture of 1,5-bis(3-hydroxy-4-methoxyphenyl)-1,4-pentadien-3-one (29.6 g, 90.8 mmol), absolute ethanol (220 mL), and 4-nitrophenylhydrazine (16.8 g, 100 mmol for 90 percent purity, 10 percent water) was added conc. HCl (20 mL), and the mixture was stirred and heated at reflux for 24 hours. The mixture was then stirred at room temperature for 16 hours, and the orange crystals that formed were removed by filtration. The product was washed with ethanol and hexane, and dried in a vacuum oven at 90°-100° C. for 12 hours. The product was obtained as orange-red microcrystals (37.2 g, 97.4 percent yield) mp 215°-217° C.; 1H NMR (DMSO-d6) δ9.09 (s, 2H), 8.05 (d, 2H, J=9.5 Hz), 7.06-6.61 (m, 10H), 5.52 (dd, 1H, J1=11.6 Hz, J2= 4.1 Hz,), 3.80 (s, 3H), 3.76 (m, 1H), 3.73 (s, 3H), and 3.07 (m, 1H).
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][O:9][C:10]([C:12]1[CH:13]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1)=[O:11])(=[O:5])[C:2]([CH3:4])=[CH2:3].[OH:22][N:23]=[C:24]([C:31]#[N:32])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C.O>C(Cl)Cl>[C:1]([O:6][CH2:7][CH2:8][O:9][C:10]([C:12]1[CH:13]=[C:14]([S:18]([O:22][N:23]=[C:24]([C:31]#[N:32])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1)=[O:11])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)OCCOC(=O)c1cccc(S(=O)(=O)Cl)c1
Reactant: N#CC(=NO)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: C=C(C)C(=O)OCCOC(=O)c1cccc(S(=O)(=O)ON=C(C#N)c2ccccc2)c1
Temperature: 0 °C
Yield: 65.5 %

Procedure:
With cooling to 0° C. and with stirring, a solution of 16.6 g (0.05 mole) of 3-[2-(methacryloxy)ethoxycarbonyl]benzenesulfonyl chloride (1b) in 50 ml of CH2Cl2 is added dropwise to a solution of 7.3 g (0.05 mole) of α-hydroxyiminobenzyl cyanide (1c) and 5.05 (0.05 mole) of triethylamine in 100 ml of methylene chloride. The reaction mixture is subsequently stirred for 18 hours at room temperature. Water is then added to the reaction mixture, and the organic phase is separated, washed with water and dried over MgSO4. The solution is concentrated by evaporation, and the oily residue is dried under high vacuum, affording 14.5 g of the title compound as a viscous colourless mass.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[C:12](N1C=CN=C1)(N1C=CN=C1)=[O:13].[NH2:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[N:30]([CH3:34])[CH:29]=[CH:28]2.Cl>CCOCC.C(O)C>[CH3:34][N:30]1[C:31]2[C:27](=[CH:26][C:25]([NH:24][C:12]([NH:1][C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[CH:5]=[N:4][CH:3]=3)=[O:13])=[CH:33][CH:32]=2)[CH:28]=[CH:29]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cncc2ccccc12
Reactant: Cn1ccc2cc(N)ccc21
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: Cn1ccc2cc(NC(=O)Nc3cncc4ccccc34)ccc21

Procedure:
The title compound was prepared from 4-aminoisoquinoline, 1,1'-carbonyl diimidazole and 5-amino-1-methyl-indole using a procedure similar to that described for Example 1, and then converted to the hydrochloride salt using hydrogen chloride in ether/ethanol, in 26% overall yield, m.p. 195°-197° C.
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.[CH2:20]([N:27]1[CH2:31][CH2:30][CH2:29][C:28]1=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])(O)=O.[Na+]>C1COCC1.C(O)(=O)C>[CH2:20]([N:27]1[CH2:31][CH2:30][CH:29]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:28]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C1CCNC1
Reactant: O=C1CCCN1Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: c1ccc(CN2CCC(N3CCCC3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3.82 g (18.0 mmol) NaBH(OAc)3 are added to a solution of 1.23 mL (15.0 mmol) pyrrolidine and 2.41 mL (15.0 mmol) N-benzylpyrrolidinone in 100 mL THF and acidified with 2 mL acetic acid. The reaction is stirred overnight at RT. The reaction solution is combined with 200 mL saturated NaHCO3 solution and extracted twice with 200 mL EtOAc. The organic phase is dried over MgSO4 and the solvent is eliminated i.vac. The purification is carried out by column chromatography on silica gel (EtOAc/MeOH/NH3 8:2:0.2).
Reaction SMILES: NOS(O)(=O)=O.CC(C)([O-])C.[K+].[CH2:13]([O:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH:25]=[CH:24]2)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CC(C)([O-])C.[K+].C[N:37]1CCCC1=O.NOS(O)(=O)=O.CN1CCCC1=O>CN1CCCC1=O>[CH2:13]([O:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[N:26]([NH2:37])[CH:25]=[CH:24]2)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CN1CCCC1=O
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Agent: CC(C)(C)[O-]
Agent: NOS(=O)(=O)O
Agent: [K+]
Product: Nn1ccc2cc(OCc3ccccc3)ccc21
Reaction time: 2.77 h
Yield: 953.5 %

Procedure:
A solution of 5.3 kg (5.2 kg corrected for 97% purity) of hydroxylamine-O-sulfonic acid (HOSA) in 19.1 kg of N-methylpyrrolidinone (NMP), is prepared and chilled to 0–5° C. A second solution is prepared from 10.6 kg (10.0 kg corrected for 95% purity) of potassium tert-butoxide and 19.3 kg of NMP. An amination vessel is charged with 5.0 kg (4.7 kg corrected for 94% purity) of 5-benzyloxyindole, 15.5 kg of NMP and an initial charge of 0.4 kg of the potassium tert-butoxide/NMP solution. The HOSA/NMP solution and the remaining potassium tert-butoxide/NMP solution are then simultaneously and proportionally metered into the amination vessel over a period of 166 minutes while maintaining a reaction temperature of 14–29° C. to yield a solution containing 4.3 kg (86.0% yield) of 5-benzyloxy-1H-indol-1-amine as determined by external standard HPLC assay. After adding 105 L water, and cooling to 0–5° C., the mixture is filtered. The filtered solid is partitioned with 63 L n-butyl acetate and 8.5 L water, then filtered. The organic phase is concentrated under reduced pressure to give a solid which contains 3.9 kg (77.4% yield) of 5-benzyloxy-1H-indol-1-amine as determined by external standard HPLC assay.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]([CH3:36])[CH:28]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([N+:15]([O-])=O)[C:12]([N:18]([CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])[CH3:19])=[CH:11][C:10]=2[O:25][CH3:26])=[N:6][CH:7]=1.[NH4+].[Cl-]>C(O)C.O.C(OCC)C.[Fe]>[Cl:1][C:2]1[C:3]([C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]([CH3:36])[CH:28]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([NH2:15])[C:12]([N:18]([CH2:20][CH2:21][N:22]([CH3:23])[CH3:24])[CH3:19])=[CH:11][C:10]=2[O:25][CH3:26])=[N:6][CH:7]=1
Reactant: COc1cc(N(C)CCN(C)C)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cn(C)c3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: COc1cc(N(C)CCN(C)C)c(N)cc1Nc1ncc(Cl)c(-c2cn(C)c3ccccc23)n1
Reaction time: 0.25 h
Yield: 78.9 %

Procedure:
A mixture of N-[5-chloro-4-(1-methylindol-3-yl)pyrimidin-2-yl]-N′-(2-dimethylamino-ethyl)-2-methoxy-N′-methyl-5-nitrobenzene-1,4-diamine (Intermediate 98, 553 mg, 1.08 mmol), iron (363 mg, 6.51 mmol) and NH4Cl (43.5 mg, 0.81 mmol) in ethanol (23 mL) and water (7.67 mL) were heated at reflux for 1.5 h. The mixture was then cooled and concentrated in vacuo. The resulting residue was dissolved in CH2Cl2 (100 mL) and CH3OH (10 mL) and this mixture was stirred for 0.25 h and then filtered. The filter cake was washed with further CH2Cl2 and CH3OH and the combined organics were dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-5% methanolic ammonia in CH2Cl2 provided a solid. This solid was dissolved in diethyl ether and a small amount of brown precipitate was removed by filtration. The filtrate was concentrated in vacuo to give the title compound (409 mg, 79%) as a brown glass; 1H NMR: (CDCl3) 2.26 (6H, s), 2.38-2.43 (2H, m), 2.68 (3H, s), 2.94-2.98 (2H, m), 3.84 (3H, s), 3.91 (3H, s), 6.71 (1H, s), 7.26-7.36 (2H, m), 7.40 (1H, d), 7.63 (1H, s), 8.09 (1H, s), 8.21 (1H, s), 8.33 (1H, s), 8.67 (1H, d); m/z: ES+ MH+ 480.32.