Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])=[C:4]([O:16][CH3:17])[CH:3]=1.[C:18]1(C)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(B(O)O)C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>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.O>[CH3:17][O:16][C:4]1[CH:3]=[C:2]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:7]=[N:6][C:5]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15]
Reactant: Cc1ccccc1
Reactant: COc1cc(Cl)nnc1Oc1ccccc1C
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: OB(O)c1ccccc1
Solvent: O
Product: COc1cc(-c2ccccc2)nnc1Oc1ccccc1C
Reaction time: 8 h
Yield: 59.7 %

Procedure:
210 mg (0.837 mmol) of 6-chloro-4-methoxy-3-(2-methylphenoxy)pyridazine obtained in Example 2 (1), toluene (4 mL) and water (0.5 mL) were mixed, 161 mg (1.32 mmol) of phenylboronic acid, 365 mg (2.64 mmol) of potassium carbonate and 102 mg (0.0879 mmol) of tetrakis(triphenylphosphine)palladium were successively added to the mixture at room temperature, and the resulting mixture was refluxed for 2 hours and 50 minutes. The reaction mixture was allowed to stand at room temperature overnight, the mixture was filtered through Celite, and ethyl acetate and water were added to the filtrate. The organic layer was separated, washed with brine. After drying over anhydrous sodium sulfate, the solvent was removed. The obtained residue was purified by silica gel column chromatography (eluted with hexane:ethyl acetate=3:1) to obtain 146 mg (0.500 mmol, Yield: 59.7%) of 4-methoxy-3-(2-methylphenoxy)-6-phenylpyridazine.
Reaction SMILES: Br[C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:11][C:12]1[C:17](B(O)O)=[CH:16][N:15]=[CH:14][N:13]=1.O1CCOCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O>[S:8]1[CH:9]=[CH:10][C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([C:17]3[C:12]([CH3:11])=[N:13][CH:14]=[N:15][CH:16]=3)[C:7]1=2
Reactant: Brc1cccc2ccsc12
Reactant: Cc1ncncc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: O
Product: Cc1ncncc1-c1cccc2ccsc12
Temperature: 100 °C
Yield: 30.3 %

Procedure:
A vessel capable of sealing was charged with a mixture of 7-bromobenzo[b]thiophene (100 mg, 0.467 mmol), 4-methylpyrimidin-5-ylboronic acid (97 mg, 0.70 mmol), PdCl2(dppf)-CH2Cl2 adduct (19.2 mg, 0.023 mmol), dioxane (3 mL), and a 2.0 M water solution of K3PO4 (0.7 mL, 1.41 mmol) and was purged with nitrogen for 10 min. The vessel was sealed and heated at 100° C. for 16 hours. Upon cooling, the reaction mixture was diluted with CH2Cl2 and filtered with CH2Cl2/MeOH washing. The filtrate was concentrated under reduced pressure. The residue was dissolved in CH2Cl2 and washed with water, brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude material was purified by BIOTAGE® eluting with 0%-15% EtOAc/CH2Cl2 at 30 mL/min. Concentration of appropriate fractions provided the title compound (32 mg, 30% yield). LC/MS: Example 108A @ 2.49 min (RT) (Condition G). MS (ES): m/z=227.07.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ ppm 9.19 (1 hr, s), 8.68 (1 hr, s), 7.92 (1 hr, d, J=8.06 Hz), 7.38-7.52 (3 hr, m), 7.23 (1 hr, d, J=7.05 Hz), 2.44 (3 hr, s).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]#[N:12])[CH:9]=2)[N:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[N:3]=1.C(N(C(C)C)CC)(C)C.[C:28]1([C:34]#[CH:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>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.[Cu]I.C(#N)C>[O:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH:13]1[N:4]1[C:5]2[C:10](=[CH:9][C:8]([C:11]#[N:12])=[CH:7][CH:6]=2)[C:2]([C:35]#[C:34][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:3]1
Reactant: C#Cc1ccccc1
Reactant: N#Cc1ccc2c(c1)c(Br)nn2C1CCCCO1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc2c(c1)c(C#Cc1ccccc1)nn2C1CCCCO1
Yield: 76.2 %

Procedure:
A mixture of 3-bromo-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (400 mg, 1.31 mmol), 10.0 mL of acetonitrile (CH3CN), diisopropylethylamine (172 mg, 1.33 mmol, 1.01 equiv.), dichlorobis(triphenylphosphine)palladium(II) [(Ph3)P2PdCl2, 0.0187 mmol, 0.0143 equiv.), copper (I) iodide (CuI, 13.1 mg, 0.0688 mmol, 0.0525 equiv.), and phenylacetylene (147 mg, 1.44 mmol, 1.10 equiv.) were refluxed for 3 h and concentrated. Purification by silica gel chromatography using 20–30% EtOAc in hexanes afforded the title compound (327 mg, 76.2% yield): ES-MS (m/z) 328 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[N:11]([CH3:15])[C:10]([CH3:16])=[C:9]2[C:17]([O:19]C)=[O:18])=[CH:4][CH:3]=1.[OH-].[Na+].O.CCOC(C)=O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[N:11]([CH3:15])[C:10]([CH3:16])=[C:9]2[C:17]([OH:19])=[O:18])=[CH:6][CH:7]=1
Reactant: COC(=O)C1=C(C)N(C)C(=O)CC1c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CC1=C(C(=O)O)C(c2ccc(Cl)cc2)CC(=O)N1C
Temperature: 60 °C
Yield: 74.9 %

Procedure:
The product from step 1 (470 mg, 1.6 mmol, 1.0 equiv) was dissolved in MeOH (10 mL) and 2.5 M NaOH (2.5 mL) was added. The mixture was heated to 60° C. for three hours. When the reaction had cooled to room temperature, water and EtOAc were added. The phases were separated, and the aqueous layer was adjusted to pH 7 with 6N HCl. The aqueous phase was extracted with ethyl acetate. The organic extracts were dried over Na2SO4 and concentrated to dryness. The residue was azeotroped with hexanes to provide 335 mg (75%) of the title compound as a foamy white solid. MS (ES+) m/e 280 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C@H:27]([CH2:28][OH:29])[CH2:26][O:25][C:24]4=[O:30])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[H-].[Na+].I[CH3:34].O>CN(C)C=O>[CH3:1][C:2]1[C:3]([N:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C@H:27]([CH2:28][O:29][CH3:34])[CH2:26][O:25][C:24]4=[O:30])=[CH:19][CH:18]=3)=[O:16])[CH2:13][CH2:14]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4CO)cc3)CC2)c(C)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C)cc3C)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9 %

Procedure:
(R)-3-{4-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]phenyl}-4-hydroxymethyloxazolidin-2-one (205 mg) described in Example 72 was dissolved in N,N-dimethylformamide (1 mL), sodium hydride (32 mg) was added, and the mixture was stirred at room temperature for 30 min. Iodomethane (142 mg) was added, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (chloroform:methanol) to give the title compound (19 mg).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][OH:7])(=[O:3])[CH3:2].[CH2:8](OS(=O)(=O)OCCC)[CH2:9][CH3:10].[OH-].[K+]>>[C:1]([CH2:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][CH3:10])(=[O:3])[CH3:2]
Reactant: CCCOS(=O)(=O)OCCC
Reactant: CC(=O)CCCO
Agent: [K+]
Agent: [OH-]
Product: CCCOCCCC(C)=O
Temperature: 75 °C
Yield: 50 %

Procedure:
50 Grams of 3-acetyl-1-propanol was placed in a round-bottom flask, and 98 g of di-n-propylsulfuric acid and 90 ml of a 40% potassium hydroxide aqueous solution were concurrently dropwise added. The reaction temperature was maintained at 70 to 80° C. by adjusting the dropping amount. After the completion of the reaction, the reaction mixture was extracted with ether, and an ether layer was washed with water and then dried over anhydrous sodium sulfate. The ether was distilled off, and the remainder was vacuum-distilled for isolation and purification, to give 34.8 g of an end product (85° C./20 mmHg; yield 50%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:18][OH:19])([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]2[C:10]([CH2:11][CH:12]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:20](OC(=O)C)(=[O:22])[CH3:21].N1C=CC=CC=1>O>[C:20]([O:19][CH2:18][C:4]1([CH2:13][CH2:14][CH:15]([CH3:16])[CH3:17])[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:11][CH:12]=[C:3]1[O:2][CH3:1])(=[O:22])[CH3:21]
Reactant: COC1=CCc2ccccc2C1(CO)CCC(C)C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: COC1=CCc2ccccc2C1(CCC(C)C)COC(C)=O
Yield: 81 %

Procedure:
A mixture of Example 179A (0.18 g, 0.7 mmol), acetic anhydride (0.2 mL), and pyridin (1 mL) was stirred at room temperature for 18 h. The solution was diluted with water (3 mL) and extracted with ethyl acetate (2× 1 mL). The combined organic extracts were dried (Na2SO4) and concentrated in vacuo. Column chromatography on silica (hexane to 5% ethyl acetate/hexane) afforded product as a colorless oil (0.17 g, 81%). 1H NMR (300 MHz, CDCl3) δ ppm 0.66 (m, 1H), 0.76 (dd, J=9.56, 6.62 Hz, 6H), 0.89 (m, 1H), 1.38 (m, 1H), 1.61 (m, 1H), 1.81 (s, 3H), 1.95 (m, 1H), 3.50 (s, 2H), 3.58 (s, 3H), 4.24 (d, J=10.66 Hz, 1H), 4.42 (d, J=10.66 Hz, 1H), 5.01 (t, J=3.49 Hz, 1H), 7.20 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:11])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.CN(C)CCN(C)C.C([Li])CCC.[Li].CON(C)[C:29](=[O:32])[CH2:30][Cl:31]>CCCCCC.C1COCC1.O>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH3:11])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[C:29](=[O:32])[CH2:30][Cl:31]
Reactant: COc1cc(C)cc(OC)c1
Reactant: CON(C)C(=O)CCl
Agent: CN(C)CCN(C)C
Agent: [Li]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C)cc(OC)c1C(=O)CCl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 15.7 %

Procedure:
7.61 g of 3,5-dimethoxytoluene and 6.10 g of tetramethylethylenediamine are dissolved under nitrogen in 150 ml of hexane. The solution is cooled to 0° C., 32.8 ml of 1.6 M butyllithium in hexane are added and the mixture is stirred at 10° C. for 20 minutes and then at 20° C. for 1 hour. To the lithium derivative cooled to -10° C., a solution, cooled to 0° C., of 6.13 g of N-methoxy-N-methylchloroacetamide in 50 ml of THF is added in the course of 20 minutes. The reaction mixture is left for one hour at a temperature of between 0° and 5° C. and for one hour at 20° C., and then poured into 100 ml of water. The resulting mixture is extracted with twice 300 ml of diethyl ether, the ether phases are washed with saturated sodium chloride solution, and the organic phases are dried over magnesium sulphate, filtered and concentrated under vacuum. The residue is chromatographed on silica, eluting with a DCM/hexane (50:50; v/v) mixture. Concentration of the pure fractions yields 1.6 g of the expected product; m.p. 82°-84° C.
Reaction SMILES: C(OC1C=CC([C@@H](O)CNCCC2C=CC(NC(C3C=C(S(C4C=C5C(=C(C)C=4)N=CC(C(N)=O)=C5NC4C=CC=C(OC)C=4)(=O)=O)C=CC=3)=O)=CC=2)=C2C=1NC(=O)C=C2)C1C=CC=CC=1.[CH2:67]([O:74][C:75]1[CH:76]=[CH:77][C:78]([C@@H:86]([O:141][Si](C(C)(C)C)(C)C)[CH2:87][NH:88][C:89]([CH3:140])([CH3:139])[CH2:90][C:91]2[CH:92]=[C:93]([CH:136]=[CH:137][CH:138]=2)[C:94]([N:96]2[CH2:101][CH2:100][N:99]([C:102]([C:104]3[CH:105]=[C:106]([S:110]([C:113]4[CH:114]=[C:115]5[C:120](=[C:121]([CH3:123])[CH:122]=4)[N:119]=[CH:118][C:117]([C:124]([NH2:126])=[O:125])=[C:116]5[NH:127][C:128]4[CH:133]=[CH:132][CH:131]=[C:130]([O:134][CH3:135])[CH:129]=4)(=[O:112])=[O:111])[CH:107]=[CH:108][CH:109]=3)=[O:103])[CH2:98][CH2:97]2)=[O:95])=[C:79]2[C:84]=1[NH:83][C:82](=[O:85])[CH:81]=[CH:80]2)[C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1>>[CH2:67]([O:74][C:75]1[CH:76]=[CH:77][C:78]([C@@H:86]([OH:141])[CH2:87][NH:88][C:89]([CH3:139])([CH3:140])[CH2:90][C:91]2[CH:92]=[C:93]([CH:136]=[CH:137][CH:138]=2)[C:94]([N:96]2[CH2:97][CH2:98][N:99]([C:102]([C:104]3[CH:105]=[C:106]([S:110]([C:113]4[CH:114]=[C:115]5[C:120](=[C:121]([CH3:123])[CH:122]=4)[N:119]=[CH:118][C:117]([C:124]([NH2:126])=[O:125])=[C:116]5[NH:127][C:128]4[CH:133]=[CH:132][CH:131]=[C:130]([O:134][CH3:135])[CH:129]=4)(=[O:111])=[O:112])[CH:107]=[CH:108][CH:109]=3)=[O:103])[CH2:100][CH2:101]2)=[O:95])=[C:79]2[C:84]=1[NH:83][C:82](=[O:85])[CH:81]=[CH:80]2)[C:68]1[CH:69]=[CH:70][CH:71]=[CH:72][CH:73]=1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N5CCN(C(=O)c6cccc(CC(C)(C)NC[C@H](O[Si](C)(C)C(C)(C)C)c7ccc(OCc8ccccc8)c8[nH]c(=O)ccc78)c6)CC5)c4)cc23)c1
Agent: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)Nc5ccc(CCNC[C@H](O)c6ccc(OCc7ccccc7)c7[nH]c(=O)ccc67)cc5)c4)cc23)c1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(C(=O)N5CCN(C(=O)c6cccc(CC(C)(C)NC[C@H](O)c7ccc(OCc8ccccc8)c8[nH]c(=O)ccc78)c6)CC5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 144, using Intermediate 142 as a substrate. ES/MS calcd. for C58H58N7O9S+ 1028.4. Found m/z=1028.3 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[S:7][C:6]([CH:8]([OH:10])[CH3:9])=[CH:5][CH:4]=1)#[N:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[NH2:2][CH2:1][C:3]1[S:7][C:6]([CH:8]([OH:10])[CH3:9])=[CH:5][CH:4]=1
Reactant: CC(O)c1ccc(C#N)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)c1ccc(CN)s1
Temperature: 0 °C
Yield: 75.5 %

Procedure:
To a stirred solution of 400 mg (2.61 mmol) (±)-1-[5-cyano-thiophen-2-yl]-ethanol in 20 ml tetrahydrofuran at 0° C. was added drop-wise 8 ml (8.10 mmol) 1.0M lithium aluminum hydride in tetrahydrofuran. The mixture was refluxed for 1 h., cooled to 0° C., then quenched with methanol added drop-wise. The mixture was diluted with chloroform and washed with water. The resulting emulsion was filtered through Celite and the filtrate layers separated. The organic extract was dried (MgSO4) then concentrated in vacuo to give 310 mg (76%) oil.
Reaction SMILES: [CH3:1][N:2]1[C:14]2[C:13]([C:15]3[S:16][C:17]([CH3:20])=[CH:18][CH:19]=3)=[CH:12][C:11]3[C:6](=[C:7]([NH2:22])[N:8]=[C:9]([NH2:21])[N:10]=3)[C:5]=2[CH:4]=[CH:3]1.[H-].[Na+].I[CH3:26].O>CN(C)C=O>[CH3:1][N:2]1[C:14]2[C:13]([C:15]3[S:16][C:17]([CH3:20])=[CH:18][CH:19]=3)=[CH:12][C:11]3[C:6](=[C:7]([NH:22][CH3:26])[N:8]=[C:9]([NH2:21])[N:10]=3)[C:5]=2[CH:4]=[CH:3]1
Reactant: Cc1ccc(-c2cc3nc(N)nc(N)c3c3ccn(C)c23)s1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CNc1nc(N)nc2cc(-c3ccc(C)s3)c3c(ccn3C)c12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 11.6 %

Procedure:
A solution of 7-methyl-6-(5-methyl-thiophen-2-yl)-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine (100 mg, 0.32 mmol) in N,N-dimethylformamide (5.0 mL) at 25° C. was treated with 60% sodium hydride (25 mg, 0.62 mmol) and iodomethane (0.62 mL, 0.35 mmol) and stirred at 25° C. for 15 min. The resulting mixture was poured into water and extracted with a 9/1 methylene chloride/methanol solution. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 9:1 methylene chloride/methanol) afforded 7,N1-dimethyl-6-(5-methyl-thiophen-2-yl)-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine (12 mg, 11.5%) as a light yellow solid; EI-HRMS m/e calcd for C17H17N5S (M+H)+ 324.1278, found 324.1280; and 7,N1,N1-trimethyl-6-(5-methyl-thiophen-2-yl)-7H-pyrrolo[3,2-f]quinazoline-1,3-diamine (18 mg, 16.5%) as a dark brown solid; EI-HRMS m/e calcd for C18H19N5S (M+H)+ 338.1434, found 338.1437.
Reaction SMILES: Cl[C:2]1[CH:23]=[CH:22][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[CH:10]=2)=[O:7])=[CH:4][N:3]=1.[OH:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>C(O)CCC>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:22]=[CH:23][C:2]([N:30]3[CH2:31][CH2:32][N:27]([CH2:26][CH2:25][OH:24])[CH2:28][CH2:29]3)=[N:3][CH:4]=2)=[CH:10][C:11]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=1
Reactant: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(Cl)nc1
Reactant: OCCN1CCNCC1
Solvent: CCCCO
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(N2CCN(CCO)CC2)nc1

Procedure:
Procedure F was performed using 50 mg of 6-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)nicotinamide and 90 μL of 1-(2-hydroxyethyl)piperazine in 0.5 mL of BuOH. Purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(4-(2-hydroxyethyl)piperazin-1-yl)nicotinamide. MS (Q1) 438.0 (M)+.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]=1[CH2:17][C:18]#[N:19].N.[H][H]>C(O)CC.[Ni]>[NH2:19][CH2:18][CH2:17][CH:3]1[CH:2]([CH3:1])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: [H][H]
Reactant: Cc1c(CC#N)n(-c2ccccc2)c2ccccc12
Agent: [Ni]
Agent: N
Solvent: CCCO
Product: CC1c2ccccc2N(c2ccccc2)C1CCN

Procedure:
To a solution of 83 g of 3-methyl-1-phenyl-2-indole acetonitrile in 340 ml of n-propanol there are added 100 ml of concentrated aqueous ammonia and two spoons of Raney nickel. The mixture is hydrogenated at 60° and normal pressure. After the hydrogen take-up is complete, filtration is effected and the filtrate is made slightly acid with glacial acetic acid under cooling. After the addition of water, washing with diethyl ether is effected and the aqueous phase is made alkaline with dilute ammonia. The latter is extracted with methylene chloride and the extract is concentrated by evaporation after washing with water and drying over sodium sulphate. The residue, 2-aminoethyl-3-methyl-1-phenylindole, is then converted into the hydrochloride. M.Pt. 202°-207° (from acetone/diethyl/ether).
Reaction SMILES: [C:1]1([N:7]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[S:8]([C:11]2[CH:30]=[CH:29][C:14]3[N:15]([CH3:28])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:38].C(O)C.C(=O)([O-])[O-].[NH4+:46].[NH4+]>ClCCl.C(O)C>[ClH:38].[C:1]1([N:7]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[S:8]([C:11]2[CH:30]=[CH:29][C:14]3[N:15]([CH3:28])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:46])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)(=[O:9])=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CCN(c1ccccc1)S(=O)(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CCN(c1ccccc1)S(=O)(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C
Yield: 87 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)aminomethyl]benzimidazol-5-yl-sulfonic acid-N-phenyl-N-(2-ethoxycarbonylethyl)amide, ethanolic hydrochloric acid, ethanol, and ammonium carbonate. Yield: 87% of theory, C27H30N6O4S (534.6); Rf value: 0.13 (silica gel; dichloromethane/ethanol=9:1); EKA mass spectrum: (M+H)+=535; (M+H+Na)++=279.
Reaction SMILES: FC1C=CC(S(CCC)(=O)=O)=CC=1C#C[Si](C)(C)C.[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[CH:36])([CH3:23])([CH3:22])[CH3:21].Br[C:39]1[C:44]([CH3:45])=[CH:43][C:42]([NH:46][C:47](=[O:49])[CH3:48])=[C:41]([S:50]([CH2:53][CH2:54][CH3:55])(=[O:52])=[O:51])[CH:40]=1>>[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[C:36][C:39]1[CH:40]=[C:41]([S:50]([CH2:53][CH2:54][CH3:55])(=[O:52])=[O:51])[C:42]([NH:46][C:47](=[O:49])[CH3:48])=[CH:43][C:44]=1[CH3:45])([CH3:23])([CH3:22])[CH3:21]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: CCCS(=O)(=O)c1cc(Br)c(C)cc1NC(C)=O
Agent: CCCS(=O)(=O)c1ccc(F)c(C#C[Si](C)(C)C)c1
Product: CCCS(=O)(=O)c1cc(C#Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)c(C)cc1NC(C)=O

Procedure:
Following the general method as outlined in Intermediate 107, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and N-[4-Bromo-5-methyl-2-(propane-1-sulfonyl)-phenyl]-acetamide (Intermediate 230), the title compound was obtained as a brown sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [CH:1]([C:3]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][C:9]([O:18][CH3:19])=[CH:8][C:4]=1[C:5](O)=[O:6])=O.O.[NH2:21][NH2:22]>>[CH3:19][O:18][C:9]1[CH:8]=[C:4]2[C:3]([CH:1]=[N:21][NH:22][C:5]2=[O:6])=[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1
Reactant: NN
Reactant: COc1cc(C(=O)O)c(C=O)c(-c2ccccc2)c1
Solvent: O
Product: COc1cc(-c2ccccc2)c2cn[nH]c(=O)c2c1

Procedure:
This compound is obtained according to the procedure described in 1.2. by reacting 2-formyl-5-methoxy-3-phenylbenzoic acid with hydrazine hydrate.
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:7]([CH3:15])=[C:6]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[S:23]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)(=[O:25])=[O:24])[CH:5]=2)[CH2:3][CH2:2]1.ClS([N:35]=[C:36]=O)(=O)=O.CN(C)C=O>>[C:36]([C:5]1[C:6]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S:23]([N:26]2[CH2:27][CH2:28][CH2:29][CH2:30]2)(=[O:24])=[O:25])=[C:7]([CH3:15])[N:8]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:4]=1[CH:1]1[CH2:3][CH2:2]1)#[N:35]
Reactant: CCOC(=O)Cn1c(C2CC2)cc(Cc2ccccc2S(=O)(=O)N2CCCC2)c1C
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)N2CCCC2)c(C#N)c1C1CC1
Yield: 5 %

Procedure:
General procedure II was followed using ethyl 2-(5-cyclopropyl-2-methyl-3-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetate (1.09 g, 2.53 mmol), chlorosulfonyl isocyanate (0.275 mL, 3.16 mmol) and N,N-dimethylformamide (0.196 mL, 2.53 mmol) to afford ethyl 2-(3-cyano-2-cyclopropyl-5-methyl-4-(2-(pyrrolidin-1-ylsulfonyl)benzyl)-1H-pyrrol-1-yl)acetate (58.0 mg, 0.127 mmol, 5% yield) as a viscous oil. 1D-NOESY experiment was performed to confirm the drawn regioisomer (irradiation of methyl group and 1-2% interaction with both methylene groups).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([CH:27]([CH3:34])[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:26])=[CH:21][CH:20]=1>C(Cl)(Cl)Cl>[O:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]([CH:27]([CH3:34])[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:26])=[CH:23][CH:24]=1
Reactant: C1=COCCC1
Reactant: CC(C(=O)c1ccc(O)cc1)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Product: CC(C(=O)c1ccc(OC2CCCCO2)cc1)c1ccccc1
Yield: 38.3 %

Procedure:
2,3-Dihydropyran (4.6 g.) and a few crystals of toluene-p-sulphonic acid were added to a solution of 4-hydroxy-α-methyldesoxybenzoin (11.3 g.) in chloroform (100 ml.). The resulting solution was heated under reflux for 5 mins., cooled and washed with 5% w/v aqueous sodium bicarbonate solution. The chloroform solution was then dried and evaporated, and the residue crystallised from acetone to give 4-(2-tetrahydropyranyloxy)-α-methyldesoxybenzoin (5.93 g.), m.p. 94°-96° C.