Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH:4]1[CH2:23][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19]CCC)=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N+:2]=[N-:3].[CH2:24]([O:27][C:28]1[C:33]([Cl:34])=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:35])[C:25]#[CH:26]>>[Cl:34][C:33]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:35])[C:28]=1[O:27][CH2:24][C:25]1[N:1]([CH:4]2[CH2:23][N:8]3[C:9]4[C:14]([C:15]([CH2:16][C:17]([OH:19])=[O:18])=[C:7]3[CH2:6][CH2:5]2)=[CH:13][CH:12]=[CH:11][CH:10]=4)[N:2]=[N:3][CH:26]=1
Reactant: C#CCOc1c(Cl)cccc1Cl
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)CC(N=[N+]=[N-])CC2
Product: O=C(O)Cc1c2n(c3ccccc13)CC(n1nncc1COc1c(Cl)cccc1Cl)CC2

Procedure:
The title compound was prepared using analogous procedures described in EXAMPLE 3 from propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-α]indol-10-yl)acetate and 2,6-dichlorophenyl prop-2-yn-1-yl ether. 1H NMR (400 MHz, DMSO-d6): δ 12.14 (s, 1 H), 7.91 (s, 1 H), 7.54 (d, 2 H), 7.49 (d, 1 H), 7.35 (d, 1 H), 7.25 (t, 1 H), 7.11-7.00 (m, 2 H), 5.48-5.32 (m, 3 H), 4.78 (dd, 1 H), 4.37 (t, 1 H), 3.62 (d, 2 H), 3.43-3.34 (m, 1 H), 3.24-3.09 (m, 1 H), 3.09-2.97 (m, 1 H). MS (+ESI) m/z: 471.1.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:24]5=[N:34][NH:35][C:36]([NH:37][CH3:38])=[C:23]5[CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C>C(O)(C(F)(F)F)=O>[NH2:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:27]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:26][C:25]4[C:24]5=[N:34][NH:35][C:36]([NH:37][CH3:38])=[C:23]5[CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: CNc1[nH]nc2c1CCc1nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc1-2
Solvent: O=C(O)C(F)(F)F
Product: CNc1[nH]nc2c1CCc1nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cc1-2
Reaction time: 0.01 h
Yield: 81.7 %

Procedure:
tert-butyl(1-(4-(3-(methylamino)-8-phenyl-4,5-dihydro-2H-pyrazolo[3,4-f]quinolin-7-yl)phenyl)cyclobutyl)carbamate (47 mg, 0.090 mmol) was dissolved in TFA (2 mL) and stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (˜2 mL) and concentrated to dryness under reduced pressure three times. The residue was then slurried in diethyl ether (2 mL) and after settling the supernatant solvent removed by pipette. This was repeated three times. The remaining solvent was removed under reduced pressure and freeze-dried to give the desired product as an off-white solid (31 mg, 53% yield). 1H-NMR (500 MHz, CD3OD) δ 8.08 (1H, s), 7.50 (2H, d), 7.44 (2H, d), 7.30-7.50 (3H, m), 7.23-7.27 (2H, m), 3.30 (2H, t), 2.98 (3H, s), 2.87 (2H, t), 2.73-2.81 (2H, m), 2.54-2.64 (2H, m), 2.19-2.31 (1H, m), 1.92-2.04 (1H, m). LCMS (Method A) RT=3.28 min, M+H+=422.18.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.[F:9][C:10]([F:21])([F:20])[O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH2:17])=[CH:14][CH:13]=1>>[F:9][C:10]([F:20])([F:21])[O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][NH:17][C:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)=[O:8])=[CH:14][CH:13]=1
Reactant: NCc1ccc(OC(F)(F)F)cc1
Reactant: O=C(O)c1ccsc1
Product: O=C(NCc1ccc(OC(F)(F)F)cc1)c1ccsc1

Procedure:
Prepared in a similar manner to example 4 using thiophene-3-carboxylic acid and 4-trifluoromethoxy-benzylamine. MS (M+H, 302.0).
Reaction SMILES: [C:1]([CH:3]([NH:13][C:14](=O)[CH2:15][CH3:16])[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)#[N:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:38]>C(#N)C>[Cl:38][C:1]1[N:2]=[C:14]([CH2:15][CH3:16])[NH:13][C:3]=1[CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: CCC(=O)NC(C#N)COCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CCc1nc(Cl)c(COCc2ccccc2)[nH]1
Reaction time: 0.25 h
Yield: 64.2 %

Procedure:
A solution of N-{1-cyano-2-[(phenylmethyl)oxy]ethyl}propanamide (3.62 g, 15.6 mmol), triphenylphosphine (10.2 g, 39.0 mmol), and carbon tetrachloride (3.8 mL, 39.0 mmol) in acetonitrile (150 mL) was heated at 45° C. for 4.5 h. The reaction was concentrated and the residue was stirred in CH2Cl2 (170 mL) and 0.5 N NaOH (150 mL) for 15 min. The organic layer was isolated, dried (Na2SO4), filtered, concentrated and the residue was purified by silica gel flash column chromatography (5-50% EtOAc:hexanes) to give the title compound (2.51 g, 64%) as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.29-7.38 (m, 5H), 4.52 (s, 2H), 4.50 (s, 2H), 2.65 (q, 2H), 1.26 (t, 3H). ES-LCMS: m/z 250.6, 252.9 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][N:9]([C:13]([N:15]([CH3:17])[CH3:16])=[O:14])[C:10](Cl)=[O:11].O>O1CCCC1>[CH3:16][N:15]([CH3:17])[C:13]([N:9]([CH3:8])[C:10]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:11])=[O:14]
Reactant: Nc1ccccc1
Reactant: CN(C)C(=O)N(C)C(=O)Cl
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)N(C)C(=O)Nc1ccccc1
Reaction time: 1 h
Yield: 146.9 %

Procedure:
Into 50 ml of anhydrous tetrahydrofuran, 7.4 g (0.08 mol) of aniline was added thereinto and dissolved and the mixture was cooled below 0° C. under stirring. Into this cooled mixture, a solution obtained by dissolving 6.4 g (0.04 mol) of 2,4,4-trimethylallophanoyl chloride in 10 ml of anhydrous tetrahydrofuran was added drop-wise under stirring. After the reaction was continued for 1 hour at room temperature, the solvent was remvoed by distillation under reduced pressure. To the residue thus obtained, water was added and insoluble material was separated by filtration and was recrystallized from ethanol to obtain 13.0 g (yield: 73%) of 1,1,3-trimethyl-5-phenylbiuret having a melting point of 89.5°-90.5° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[N:8]2[C:9](=[O:21])[C:10]3[NH:11][CH:12]=[N:13][C:14]=3[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:7]2=[N:6][N:5]=1.[Br:22]N1C(=O)CCC1=O>C1COCC1>[NH2:1][CH2:2][CH2:3][C:4]1[N:8]2[C:9](=[O:21])[C:10]3[NH:11][C:12]([Br:22])=[N:13][C:14]=3[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:7]2=[N:6][N:5]=1
Reactant: CCCCCn1c2nc[nH]c2c(=O)n2c(CCN)nnc12
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: CCCCCn1c2nc(Br)[nH]c2c(=O)n2c(CCN)nnc12
Temperature: 70 °C
Reaction time: 1 h
Yield: 74.1 %

Procedure:
To a mixture of 3-(2-aminoethyl)-9-pentyl-6,9-dihydro-5H-[1,2,4]triazolo[4,3-a]purin-5-one (310 mg, 1.1 mmol) in THF (50 mL), was added N-Bromosuccinimide (0.29 g, 1.6 mmol). The mixture was stirred at 70° C. for 1 hour. The reaction mixture was concentrated. The solid was filtered and washed with EtOAc to yield the desired product (300 mg, 76% yield). LCMS calculated for C13H19BrN7O (M+H): 368.1, 370.1. found: 368.0, 370.0.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[BH4-].[Na+].O>C(O)C>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OC1CCC2(CC1)OCCO2
Temperature: 5 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
A stirred, cooled (5° C.) solution of 1,4-dioxaspiro[4.5]decan-8-one (20 g, 0.128 mol) in ethanol (250 ml) was treated with sodium borohydride (7.3 g, 0.192 mol) in portions over 20 minutes. The reaction mixture was stirred at 5° C. for 1 hour then at room temperature for 1 hour. Water (20 ml) was added and the mixture was stirred vigorously for 10 minutes then concentrated in vacuo. The residue was partitioned between water (100 ml) and ethyl acetate (100 ml). The organic layer was separated and the aqueous re-extracted with ethyl acetate (100 ml). The combined organics were dried (sodium sulphate) then evaporated to give the title alcohol as a colourless oil (17.1 g, 84%). MS ES+, m/z=159 for (M+H)+; δ(360 MHz, CDCl3) 1.52-1.71 (4H, m), 1.78-1.92 (4H, m), 3.76-3.83 (1H, m), 3.91-3.94 (4H, m).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[N:8]=[C:9]([NH2:12])[CH:10]=[CH:11][C:5]2=[N:4][CH:3]=1.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:13]1([C:2]2[N:7]=[C:6]3[N:8]=[C:9]([NH2:12])[CH:10]=[CH:11][C:5]3=[N:4][CH:3]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1ccccc1
Reactant: Nc1ccc2ncc(Cl)nc2n1
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: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc2ncc(-c3ccccc3)nc2n1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
1.00 g of 3-chloropyrido[2,3-b]pyrazin-6-ylamine (5.54 mmol), 743 mg of phenylboronic acid (6.09 mmol), 640 mg of tetrakis(triphenylphosphine)palladium(0) (0.55 mmol) and 1.76 g of sodium carbonate (16.6 mmol) were initially charged in 100 ml of dimethylformamide/water (1:1) under nitrogen as a protective gas and stirred at 80° C. for 2 h. Once the reaction had ended, the mixture was filtered off with suction and the filtrate was poured onto 800 ml of distilled water. The aqueous phase was extracted repeatedly with ethyl acetate. The organic phase was freed of solvents under reduced pressure. The resulting solid was purified by means of column chromatography on silica gel (dichloromethane/methanol eluent). This gave a yellow solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[OH:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[CH2:22])=[CH:19][CH:18]=1.CC(C)=O>CCOCC.[I-].[K+]>[CH:21]([C:20]1[CH:23]=[CH:24][C:17]([O:16][CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:18][CH:19]=1)=[CH2:22]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: C=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: C=Cc1ccc(OCC(=O)OC(C)(C)C)cc1
Yield: 98.5 %

Procedure:
59.3 g (430 mmol) of potassium carbonate, 0.64 g of potassium iodide, 50.7 g (260 mmol) of tert-butyl bromoacetate and 31.2 g (260 mmol) of 4-hydroxystyrene are mixed with 145 ml of acetone in a 750 ml sulfonation flask. The resultant suspension is refluxed for 100 minutes, cooled, filtered and evaporated. The residue obtained is taken up in 750 ml of ether and washed twice with 100 ml of 1N NaOH solution in each case and then twice with 200 ml of water in each case. The organic phase is separated off, dried over magnesium sulfate and evaporated, leaving 60.02 g (256 mmol) of the desired product as a clear oil, which corresponds to a yield of 98.5% of theory. 1H-NMR (CDCl3, 300 MHz): δ ppm] 7.33/d/2H of the resultant product 6,84/d/2H 6,64/dd/1H 5,60/d/1H 5,12/d/1H 4,49/s/2H 1,47/s/9H
Reaction SMILES: [F:1][C:2]1([F:48])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18]CC4C=CC(OC)=CC=4)[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[C:9]=2[CH:36]([F:47])[C:37]2[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=2)[CH2:4][CH2:3]1.Cl[C:50]1[N:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][N:51]=1.Cl.C(=O)([O-])O.[Na+]>O1CCOCC1>[F:1][C:2]1([F:48])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([OH:18])[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][N:33]([C:50]4[N:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][N:51]=4)[CH2:32][CH2:31]3)[C:9]=2[CH:36]([F:47])[C:37]2[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCNCC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Reactant: COc1cnc(Cl)nc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3C(F)c3ccc(C(F)(F)F)cc3)C(O)CC(C)(C)C4)CC2)nc1
Temperature: 80 °C
Reaction time: 26.6 h
Yield: 44.3 %

Procedure:
To 100 mg (0.15 mmol) of (−)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(piperidin-4-yl)-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 10, 64 mg (0.44 mmol) of 2-chloro-5-methoxypyrimidine and 1 ml of 1,4-dioxane were added, and the reaction solution was stirred at 80° C. for 26.6 hours. After completion of the reaction, 0.5 ml of 6 N hydrochloric acid was added to the reaction solution and the mixture was stirred at 50° C. for 8 hours. After completion of the reaction, saturated sodium hydrogencarbonate aqueous solution was added to the reaction mixture and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=4/1 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure. n-Hexane was added to the obtained residue and the precipitate was obtained by filtration to provide 44 mg of the title compound as a white powder (yield: 45%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[CH3:25][N:26]1[CH2:31][CH2:30][O:29][C:28]2[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:27]1=2.O1CCOCC1>CO.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[OH:23][C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:4]2[CH:3]=[C:2]([C:33]3[CH:34]=[CH:35][C:27]4[N:26]([CH3:25])[CH2:31][CH2:30][O:29][C:28]=4[CH:32]=3)[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=2)=[O:24])=[CH:15][CH:16]=1)([CH3:22])[CH3:21]
Reactant: CN1CCOc2cc(B(O)O)ccc21
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(-c3ccc4c(c3)OCCN4C)n2n1
Temperature: 110 °C
Yield: 58.9 %

Procedure:
A suspension of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 60 mg, 0.174 mmol), 4-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazin-7-ylboronic acid (62 mg, 0.226 mmol), and 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (10 mg, 13.6 mmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (0.58 mL of 1,4-dioxane and 0.29 mL of saturated aqueous NaHCO3) was prepared in a 10 mL microwave reaction vessel and the sealed reaction vessel warmed to 110° C. for 10 minutes in a CEM microwave reactor. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC (50-50% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (46.9 mg, 59%). 1H NMR (DMSO-d6) δ: 10.99 (s, 1H), 7.95 (d, J=8.6 Hz, 2H), 7.89 (s, 1H), 7.57-7.62 (m, 2H), 7.54 (d, J=8.3 Hz, 2H), 6.81 (d, J=8.8 Hz, 1H), 6.25 (s, 1H), 4.20-4.24 (m, 2H), 3.32-3.35 (m, 2H), 2.91 (s, 3H), 2.35 (s, 3H), 1.39 (s, 6H); ESI-MS: m/z 458.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:26]=[CH:27][CH:28]=1)[CH2:7][C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH2:21][CH2:22][OH:23])=[C:15]([O:18][CH3:19])[CH:16]=2)[C:11]([CH:24]=[O:25])=[CH:10][N:9]=1)[CH3:2].[Se](=O)=[O:30]>C(OCC)(=O)C.CCCCCC>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:26]=[CH:27][CH:28]=1)[C:7]([C:8]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH2:21][CH2:22][OH:23])=[C:15]([O:18][CH3:19])[CH:16]=2)[C:11]([CH:24]=[O:25])=[CH:10][N:9]=1)=[O:30])[CH3:2]
Reactant: CCOc1cccc(Cc2ncc(C=O)c3cc(OCCO)c(OC)cc23)c1
Reactant: O=[Se]=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOc1cccc(C(=O)c2ncc(C=O)c3cc(OCCO)c(OC)cc23)c1
Temperature: 120 °C

Procedure:
To a stirred solution of 1-(3-ethoxy-benzyl)-6-(2-hydroxy-ethoxy)-7-methoxy-isoquinoline-4-carbaldehyde (50 mg, 0.13 mmol) was added selenium dioxide (146 mg, 1.30 mmol). The reaction mixture was heated at 120° C. for 1 hr. The solvent was evaporated and the residue was diluted with dichloromethane (30 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (20 mL), saturated aqueous sodium chloride solution (20 mL), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford a crude oil. Flash chromatography (Merck Silica gel 60, 70–230 mesh, 40% ethyl acetate/hexane) afforded 1-(3-ethoxy-benzoyl)-6-(2-hydroxy-ethoxy)-7-methoxy-isoquinoline-4-carbaldehyde as a major product (52 mg, 99% yield).
Reaction SMILES: BrC1C([C@H:8]2[C@H:13]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@@H:12]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@H:11]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@@H:10]([CH2:38][O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[O:9]2)=CC(CC2C=CC(CC)=CC=2)=C(Cl)C=1O.[CH2:58]([O:61][C:62]1[C:67]([O:68][CH2:69][CH:70]=[CH2:71])=[C:66]([Cl:72])[C:65]([CH2:73][C:74]2[CH:79]=[CH:78][C:77]([O:80][CH2:81][CH3:82])=[CH:76][CH:75]=2)=[CH:64][C:63]=1Br)[CH:59]=[CH2:60]>>[CH2:31]([O:30][C@H:11]1[C@H:12]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@@H:13]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C@H:8]([C:63]2[CH:64]=[C:65]([CH2:73][C:74]3[CH:79]=[CH:78][C:77]([O:80][CH2:81][CH3:82])=[CH:76][CH:75]=3)[C:66]([Cl:72])=[C:67]([O:68][CH2:69][CH:70]=[CH2:71])[C:62]=2[O:61][CH2:58][CH:59]=[CH2:60])[O:9][C@@H:10]1[CH2:38][O:39][CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CCc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(Br)c(O)c2Cl)cc1
Reactant: C=CCOc1c(Br)cc(Cc2ccc(OCC)cc2)c(Cl)c1OCC=C
Product: C=CCOc1c([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc(Cc2ccc(OCC)cc2)c(Cl)c1OCC=C

Procedure:
Similar procedure with preparation of 162 proceeded except for using compound 202 to obtain the compound 203.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[CH:13]([O:16][C:17]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][C:18]=1[C:19](O)=[O:20])([CH3:15])[CH3:14]>>[CH:13]([O:16][C:17]1[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][C:18]=1[C:19]([N:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:10]1)=[O:20])([CH3:15])[CH3:14]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: N#Cc1ccc2c(c1)CNCC2
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCc2ccc(C#N)cc2C1

Procedure:
Prepared in analogy to example 1.1 from 7-cyano-1,2,3,4-tetrahydro-isoquinoline (CA [149355-52-2]) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1).
Reaction SMILES: OO.S([O:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=1[Cl:15])(O)(=O)=O.Cl.Cl.[CH2:18]([O:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][C:24]=1[NH2:30])[CH2:19][CH2:20][CH3:21].N>O.C(O)C>[Cl:15][C:9]1[C:8](=[O:7])[CH:13]=[CH:12][C:11](=[N:14][C:27]2[CH:28]=[C:23]([O:22][CH2:18][CH2:19][CH2:20][CH3:21])[C:24]([NH2:30])=[CH:25][C:26]=2[NH2:29])[CH:10]=1
Reactant: CCCCOc1ccc(N)cc1N
Reactant: Nc1ccc(OS(=O)(=O)O)c(Cl)c1
Agent: Cl
Agent: N
Agent: OO
Solvent: CCO
Solvent: O
Product: CCCCOc1cc(N=C2C=CC(=O)C(Cl)=C2)c(N)cc1N
Temperature: 25 °C
Reaction time: 5 h

Procedure:
26 ml of 6% aqueous hydrogen peroxide solution are added to a solution of 180 mg (0.001 mol) of 4-amino-2-chlorophenol sulfate and 253 mg (0.001 mol) of 4-butoxybenzene-1,3-diamine dihydrochloride in 2 ml of water and 2 ml of ethanol, and the solution is adjusted to pH 9.5 with 20% aqueous ammonia. After stirring for 5 hours at room temperature, the precipitate formed is filtered off, washed with water and dried. A brown powder is obtained.
Reaction SMILES: [NH:1]([C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:6]=[C:5]([C:21]([F:24])([F:23])[F:22])[N:4]=1)[NH2:2].[C:25](Cl)(=[O:27])[CH3:26].Cl>N1C=CC=CC=1>[C:9]1([C:8]2[C:3]([NH:1][NH:2][C:25](=[O:27])[CH3:26])=[N:4][C:5]([C:21]([F:24])([F:23])[F:22])=[N:6][C:7]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: NNc1nc(C(F)(F)F)nc(-c2ccccc2)c1-c1ccccc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)NNc1nc(C(F)(F)F)nc(-c2ccccc2)c1-c1ccccc1
Reaction time: 0.17 h
Yield: 25.6 %

Procedure:
4-Hydrazino-5,6-diphenyl-2-(trifluoromethyl)pyrimidine (0.7 g, 2.1 mmol) (synthesized according to the procedure described in example 21) in pyridine (10 ml) was added acetylchloride (0.17 g, 2.2 mmol) dropwise at 20° C. under stirring for 10 minutes. After 30 minutes of stirring, the reaction mixture was poured onto ice-water mixture, acidified to pH 4 using hydrochloric acid and extracted with ethyl acetate. The organic extract was washed with water, dried over anhydrous sodium sulphate and concentrated under reduced pressure to afford the crude product, which was purified by column chromatography to furnish the title compound (0.2 g, 25.4%, HPLC purity 99.4%), mp: 113-116° C.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].Cl.[CH3:16][NH:17][O:18][CH3:19].CN1CCOCC1.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH3:19][O:18][N:17]([CH3:16])[C:4]([C:3]1[C:2]([CH3:1])=[N:10][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:8][CH:7]=1)=[O:5]
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)O
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CON(C)C(=O)c1ccc(C(F)(F)F)nc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-methyl-6-trifluoromethylnicotinic acid (500 mg, 2.44 mmol) and N,O-dimethylhydroxylamine hydrochloride (285 mg, 2.92 mmol) in dichloromethane (10 mL) were added N-methylmorpholine (0.32 mL, 2.92 mmol) and N-(3-dimethylaminopropyl-N′-ethylcarbodiimide hydrochloride (EDC, 560 mg, 2.92 mmol). The mixture was stirred at room temperature for 2 hours and washed with 1 N HCl and water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give N-methoxy-N-methyl-2-methyl-6-trifluoromethyl-3-pyridinecarboxamide quantitatively as oil. The crude product was used directly in the following reaction.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:15]([C:16]3[C:17](=O)[NH:18][C:19](=[O:22])[NH:20][CH:21]=3)[C:10]3[N:11]=[C:12]([CH3:14])[S:13][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:24]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:15]([C:16]3[C:17](=[S:34])[NH:18][C:19](=[O:22])[NH:20][CH:21]=3)[C:10]3[N:11]=[C:12]([CH3:14])[S:13][C:9]=3[CH:8]=[CH:7][C:6]=2[CH:24]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cc1nc2c(s1)C=Cc1cc(Cl)ccc1C2c1c[nH]c(=O)[nH]c1=O
Solvent: C1COCCO1
Product: Cc1nc2c(s1)C=Cc1cc(Cl)ccc1C2c1c[nH]c(=O)[nH]c1=S

Procedure:
The product from step (iv) (1.35 g) and Lawesson's reagent (1.85 g) were heated at reflux in dioxane (50 ml) under nitrogen for 16 h. The reaction mixture was partitioned between ethyl acetate and brine. The organic phase was collected, dried (MgSO4), and evaporated under reduced pressure to leave a brown solid. The solid was triturated with ethyl acetate and filtered to leave a yellow solid.