Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([S:19][C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:30][CH3:31])=[CH:27][N:28]=4)[N:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)=[N:4][N:3]=1.CC1(C)C(C)(C)OB([C:40]2[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][CH:41]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>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].O1CCOCC1>[CH3:31][O:30][C:26]1[CH:25]=[C:24]2[C:29]([C:20]([S:19][C:16]3[CH:17]=[CH:18][C:13]([NH:12][C:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C:2]([C:40]5[CH2:45][CH2:44][N:43]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][CH:41]=5)=[N:3][N:4]=4)=[CH:14][CH:15]=3)=[CH:21][CH:22]=[N:23]2)=[N:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COc1cnc2c(Sc3ccc(Nc4nnc(Cl)c5ccccc45)cc3)ccnc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1cnc2c(Sc3ccc(Nc4nnc(C5=CCN(C(=O)OC(C)(C)C)CC5)c5ccccc45)cc3)ccnc2c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
In a 20 mL sealed tube, was added 1,4-dioxane (1.08 mL), purged the solvent with nitrogen for 5 minutes, and sealed the tube. To the tube was added 4-chloro-N-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenyl)phthalazin-1-amine (0.150 g, 0.336 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (0.125 g, 0.404 mmol) and sodium carbonate (2.0 M aqueous) (0.336 mL, 0.673 mmol). The mixture was purged with nitrogen, sealed, and then to it was added PdCl2(dppf) (0.012 g, 0.017 mmol). The mixture was again purged with nitrogen, sealed, and heated to 100° C., while stirring for 3 hours. The reaction was cooled to RT and concentrated. The crude material was purified by Isco silica gel chromatography using 0-100% CH2Cl2:MeOH(90:110)/CH2Cl2. The product containing fractions were concentrated to yield tert-butyl 4-(4-(4-(7-methoxy-1,5-naphthyridin-4-ylthio)phenylamino)phthalazin-1-yl)-5,6-dihydropyridine-1(2H)-carboxylate as light yellow solid. MS: [M+H]=593.0; Calc'd 592.7 for C33H32N6O3S.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[C:4]([C:13]([O:15]CC)=O)[N:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([Mg]Br)=[CH:21][CH:20]=1.C1COCC1>C1COCC1>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[C:4]([C:13]([C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)=[O:15])[N:3]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CCOC(=O)c1nc(Cl)c2cc(F)ccc2n1
Solvent: C1CCOC1
Product: O=C(c1ccc(F)cc1)c1nc(Cl)c2cc(F)ccc2n1
Temperature: -40 °C
Reaction time: 2 h
Yield: 69.3 %

Procedure:
To a stirred solution of ethyl 4-chloro-6-fluoroquinazoline-2-carboxylate (1.06 g, 4.5 mmol) in THF (15 mL) at −40° C., was added dropwise 1 M 4-fluorophenylmagnesium bromide/THF (5.85 mL, 5.85 mmol). The mixture was stirred at −40° C. for 2 h. The reaction was quenched by adding 0.5 N HCl at 0° C. and then the mixture was extracted with EtOAc (2×20 mL). The solid that precipitated from the combined organic layers was removed by filtration and the filtrate was washed with brine. The organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to afford (4-chloro-6-fluoroquinazolin-2-yl)(4-fluorophenyl)methanone as a solid (950 mg, 69%). 1H NMR (300 MHz, DMSO-d6) δ 8.32-8.36 (m, 1H), 8.13-8.21 (m, 4H), 7.43 (t, J=8.2 Hz, 2H); LC-MS (ESI) m/z 305 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.O=[C:12]1[CH2:16][S:15][CH2:14][CH:13]1[C:17](OC)=[O:18].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[O:18]=[C:17]1[N:3]2[CH:4]=[C:5]([C:6]([OH:8])=[O:7])[CH:9]=[CH:10][C:2]2=[N:1][C:12]2[CH2:16][S:15][CH2:14][C:13]1=2
Reactant: COC(=O)C1CSCC1=O
Reactant: Nc1ccc(C(=O)O)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: O=C(O)c1ccc2nc3c(c(=O)n2c1)CSC3
Temperature: 170 °C
Yield: 63.2 %

Procedure:
6-Aminonicotinic acid (10 g., 0.072 mol) [Berichte, 26, 2187,(1893)], methyl 4-oxotetrahydro-thiophene-3-carboxylate (28 g., 0.175 mol) [Monats, Chem., 104, 1520(1973)] and p-toluenesulfonic acid monohydrate (1.0 g) are thoroughly mixed and heated at 170° C. under nitrogen for 75 minutes. The distillate is collected in a Dean-Stark trap. The residue is cooled, tritrated with boiling chloroform and filtered to give the product as a yellow powder (11.3 g.). Recrystallization from dimethylformamide gives an analytical sample mp 314°-315° C. (dec).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:28][N:29]([CH:38]=[O:39])[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:8]([N:10]2[C@H:14]([C:15](O)=[O:16])[CH2:13][CH2:12][N:11]2[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.F[B-](F)(F)F.COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[NH2:69][C:70]1[CH:85]=[CH:84][C:73]([C:74]([O:76][CH2:77][C:78]2[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=2)=[O:75])=[CH:72][CH:71]=1>C(#N)C>[CH:1]1([CH2:6][C@H:7]([CH2:28][N:29]([CH:38]=[O:39])[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:8]([N:10]2[C@H:14]([C:15]([NH:69][C:70]3[CH:85]=[CH:84][C:73]([C:74]([O:76][CH2:77][C:78]4[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=4)=[O:75])=[CH:72][CH:71]=3)=[O:16])[CH2:13][CH2:12][N:11]2[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)O)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Reactant: Nc1ccc(C(=O)OCc2ccccc2)cc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CN1CCOCC1
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)Nc2ccc(C(=O)OCc3ccccc3)cc2)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Reaction time: 1 h
Yield: 79.2 %

Procedure:
To a solution of (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acid (300 mg, 0.558 mmol) in acetonitrile (10 mL) under N2 at 0° C. was added 4-methylmorpholine (123 mg, 2.2 mmol), followed by 4-[4,6-bis(methyloxy)-1,3,5-triazin-2-yl]-4-methylmorpholin-4-ium tetrafluoroborate (366 mg, 1.116 mmol). The mixture was stirred for 1 h and to this mixture was added phenylmethyl 4-aminobenzoate (191 mg, 0.837 mmol). The mixture was stirred at rt overnight. The mixture was concentrated, and the residue was purified by flash column chromatography eluting with petroleum ether/ethyl acetate (5:1 to 3:1) to provide the title compound (330 mg).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][OH:14])=[C:8]([N+:15]([O-:17])=[O:16])[CH:7]=1>C1COCC1>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][O:14][C:1]([Cl:4])=[O:2])=[C:8]([N+:15]([O-:17])=[O:16])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1CCO
Reactant: O=C(Cl)Cl
Solvent: C1CCOC1
Product: O=C(Cl)OCCc1ccc(Cl)cc1[N+](=O)[O-]
Reaction time: 2.5 h
Yield: 95 %

Procedure:
Phosgene was introduced in a solution of 2-(4-chloro-2-nitrophenyl)ethanol (6.8 g, 34 mmol) in THF (50 ml, dist. over CaH2) at room temperature. After 2.5 h, the excess phosgene and the solvent were removed by distillation in a high vacuum. 2-(4-chloro-2-nitrophenyl)ethoxycarbonyl chloride (8.53 g, 95%) was obtained as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[C:10]([N+:14]([O-])=O)=[CH:11][CH:12]=[CH:13][C:7]=2[CH:6]=1)=[O:4].[H][H]>CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3]([C:5]1[S:9][C:8]2[C:10]([NH2:14])=[CH:11][CH:12]=[CH:13][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc2cccc([N+](=O)[O-])c2s1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc2cccc(N)c2s1
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.3 %

Procedure:
7-Nitro-benzo[b]thiophene-2-carboxylic acid methyl ester (1 g, 4.22 mmol) was suspended in EtOAc (40 mL) and a suspension of 10% Pd/C (400 mg) in 20 mL EtOAc was added. Hydrogen gas was introduced into the flask from an H2-filled balloon attached to a needle inserted through a septum. The black suspension was stirred 12 h at room temperature. After stirring 12 h, the black suspension was filtered through diatomaceous earth and the filter cake was washed several times with EtOAc. The combined filtrates were dried (MgSO4), filtered and the solvent was removed to afford 7-amino-benzo[b]thiophene-2-carboxylic acid methyl ester as a yellow solid (860 mg, 100%).
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[SH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][O:22][C:23]([C@@H:25]1[CH2:29][C@H:28](Cl)[CH2:27][N:26]1[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:24]>CN(C=O)C>[CH3:21][O:22][C:23]([C@@H:25]1[CH2:29][C@@H:28]([S:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:27][N:26]1[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:24]
Reactant: SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@@H]1C[C@H](Cl)CN1C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)CN1C(=O)OC(C)(C)C
Temperature: 2 °C
Reaction time: 2.5 h
Yield: 87.2 %

Procedure:
A solution of 76 g (0.68 mol) potassium-tert.-butylate in 1.5 l DMF was cooled (−3° C.) and treated slowly (1.5 h) with 202 g (0.73 mol) triphenylmethanethiol in 0.8 l DMF (at max 1° C.). After 2.5 h at 0° C., a solution of 161 g (0.61 mol) of (2S,4S)-4-Chloro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester in 0.35 l DMF was added. The reaction was stirred over night at 2° C., evaporated, dissolved in 1.5 l EtOAc, poured into 2.7 l aqueous saturated NH4Cl solution and extracted with EtOAc (2×). The organic phase was washed with aqueous saturated NaHCO3, dried over Na2SO4 and evaporated. Chromatography on silicagel with hexane/EtOAc (95:5 to 7:3) gave 268 g (87%) (2S,4R)-4-Tritylsulfanyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester, MS: 504 (MH+).
Reaction SMILES: C(O[C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:9]2[CH:24]=[CH:25][CH:26]=[C:8]2[C:7]=1[OH:27])=[O:5])C.[NH2:28][CH2:29][C:30]([O-:32])=[O:31].[Na+]>>[F:23][C:20]([F:22])([F:21])[C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[CH2:13][N:10]1[C:11](=[O:12])[C:6]([C:4]([NH:28][CH2:29][C:30]([OH:32])=[O:31])=[O:5])=[C:7]([OH:27])[C:8]2=[CH:26][CH:25]=[CH:24][N:9]12
Reactant: CCOC(=O)c1c(O)c2cccn2n(Cc2cccc(C(F)(F)F)c2)c1=O
Reactant: NCC(=O)[O-]
Agent: [Na+]
Product: O=C(O)CNC(=O)c1c(O)c2cccn2n(Cc2cccc(C(F)(F)F)c2)c1=O

Procedure:
Prepared according to the glycinolysis condition used in Example 1 step d) from 1-(3-trifluoromethyl-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid ethyl ester (1.0 eq.) and sodium glycinate (15 eq.). ESI (m/z): 410 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][C:10]1[CH:14]=[N:13][N:12]([CH2:15][C@@H:16]2[C@H:19]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18](=[O:31])[NH:17]2)[N:11]=1.CCN(C(C)C)C(C)C.[C:41]([O:45][C:46]([N:48]([CH2:63][CH:64]1[CH2:67][N:66]([C:68]([O:70][C:71]([CH3:74])([CH3:73])[CH3:72])=[O:69])[CH2:65]1)[C:49](N1C=CC=N1)=[N:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])=[O:47])([CH3:44])([CH3:43])[CH3:42]>O1CCOCC1>[CH2:23]([O:22][C:21]([NH:20][C@@H:19]1[C:18](=[O:31])[NH:17][C@@H:16]1[CH2:15][N:12]1[N:11]=[C:10]([CH2:9][NH:8][C:49](=[N:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[N:48]([CH2:63][CH:64]2[CH2:65][N:66]([C:68]([O:70][C:71]([CH3:72])([CH3:74])[CH3:73])=[O:69])[CH2:67]2)[C:46]([O:45][C:41]([CH3:44])([CH3:42])[CH3:43])=[O:47])[CH:14]=[N:13]1)=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCc1cnn(C[C@H]2NC(=O)[C@H]2NC(=O)OCc2ccccc2)n1
Reactant: CC(C)(C)OC(=O)N=C(N(CC1CN(C(=O)OC(C)(C)C)C1)C(=O)OC(C)(C)C)n1cccn1
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N=C(NCc1cnn(C[C@H]2NC(=O)[C@H]2NC(=O)OCc2ccccc2)n1)N(CC1CN(C(=O)OC(C)(C)C)C1)C(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 68.7 %

Procedure:
To a solution of benzyl ((2R,3S)-2-((4-(aminomethyl)-2H-1,2,3-triazol-2-yl)methyl)-4-oxoazetidin-3-yl)carbamate 2,2,2-trifluoroacetate (340 mg, 0.77 mmol) in dioxane (6 mL) was added DIPEA (0.147 mL, 0.842 mmol) and a solution of tert-butyl 3-((N,N′-bis(tert-butoxycarbonyl)-1H-pyrazole-1-carboximidamido)methyl)azetidine-1-carboxylate (367 mg, 0.765 mmol) in dioxane (1 mL). After heating to 60° C. for 12 h, the reaction mixture was concentrated in vacuo and purified via silica gel chromatography (EtOAc-heptane, 0-95%) to afford the title compound (390 mg, 69%). LCMS: Rt=0.94 min, m/z=742.5 (M+1) Method 2m_acidic.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19](=O)[CH2:20][CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1.O.[NH2:30][NH2:31]>C(O)C>[C:12]1([N:5]2[C:6]3[N:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]3[NH:30][N:31]=[C:19]([CH2:20][CH2:21][C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)[C:3]=3[C:4]2=[O:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(CCc1cccnc1)c1c(O)c2cccnc2n(-c2ccccc2)c1=O
Reactant: NN
Solvent: CCO
Solvent: O
Product: O=c1c2c(CCc3cccnc3)n[nH]c2c2cccnc2n1-c1ccccc1
Yield: 78 %

Procedure:
The procedure of Example 1 was repeated using a suspension of 4-hydroxy-3-[1-oxo-3-(pyridin-3-yl)propyl]-1-phenyl-1,8-naphthyridin-2 (1H)-one (50 mg, 0.14 mmol, prepared in Synthetic Example 2) in ethanol (10 ml), and hydrazine monohydrate (80%, 20 μl, 0.50 mmol, 3.7 eq.), to obtain 5-phenyl-3-[2-(pyridin-3-yl)ethyl]-1H-pyrazolo[4,3-c][1,8]-naphthyridin-4 (5H)-one (yield: 78%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][C:6](=O)[CH2:7]Cl)[CH3:2].[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][N:13]=1>C(O)C>[CH2:1]([O:3][C:4](=[O:10])[CH2:5][C:6]1[N:11]=[C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][N:13]2[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)CC(=O)CCl
Reactant: Nc1ccc(Br)cn1
Solvent: CCO
Product: CCOC(=O)Cc1cn2cc(Br)ccc2n1
Temperature: 25 °C

Procedure:
4.90 ml of ethyl4-chloro-3-oxobutanoate was dissolved in 50 ml of ethanol, 5.19 g of 2-amino-5-bromopyridine was added, and the mixture was stirred all night by heating under reflux. After cooling down to room temperature, the solvents were distilled outunder reduced pressure, and then, ethyl acetate followed by saturated sodium bicarbonate aqueous solution were added. Organic layer was dried with anhydrous sodium sulfate, and the solvents were distilled outunder reduced pressure. The obtained residues were purified by preparative thin-layer chromatography (hexane:ethyl acetate=60:40) to obtain 9.49 mg of the above compound as a white solid.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.C([N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH:14]1[CH3:22])(=O)C>O>[CH3:22][CH:14]1[CH2:15][C:16]2[C:21](=[CH:20][CH:19]=[C:18]([N+:1]([O-:4])=[O:2])[CH:17]=2)[NH:13]1
Reactant: O=[N+]([O-])O
Reactant: CC(=O)N1c2ccccc2CC1C
Agent: O=S(=O)(O)O
Solvent: O
Product: CC1Cc2cc([N+](=O)[O-])ccc2N1
Temperature: 7.5 °C
Reaction time: 8 h
Yield: 26 %

Procedure:
To a cooled (0-10 C.) mixture of concentrated nitric acid (12 mL) and concentrated sulfuric acid (40 mL) was added 1-acetyl-2-methyl-indoline XII (12.5 g, 0.0713 moles), prepared by an analgous method to that described in Chem.Ber.; 14; 1881; 890, in small portions so that the internal temperature of the reaction remained between 10-20° C. The resulting mixture was allowed to stir at 5-10° C. overnight. The mixture was poured slowly into 300 mL of cold water and the precipitate that formed was collected by filtration, washed with water and redissolved in an ethanol-6N HCl solution and warmed to reflux for 30 minutes. The resulting solution was concentrated, EtOAc was added and the Ph of the solution adjusted to 10. The organic phase was separated and dried over MgSO4. The mixture was filtered, and evaporated and the crude material purified by column chromatography (50% EtOAc-Hexane) to give 3.31 g, 26% of 2-methyl-5-nitro-2,3-dihydro-1H-indole XIII: LRMS for C9H10N2O2 (M+H)+at m/z=179.
Reaction SMILES: [Cl:1][C:2]([CH:4]([Cl:8])[CH:5]([CH3:7])[CH3:6])=[CH2:3].Cl[C:10]1[CH:19]=C[C:13](NC(=S)[S-])=[C:12]([CH3:20])[CH:11]=1.C([NH+](CC)CC)C.C(=[O:32])C(C)C.[Br-]>>[Cl:1][C:2]([CH:4]([Cl:8])[CH:5]([CH3:7])[CH3:6])=[CH2:3].[CH3:13][CH:12]([CH3:20])[CH:11]([OH:32])[C:10]#[CH:19]
Reactant: CC(C)C=O
Reactant: Cc1cc(Cl)ccc1NC(=S)[S-]
Agent: C=C(Cl)C(Cl)C(C)C
Agent: CC[NH+](CC)CC
Agent: [Br-]
Product: C#CC(O)C(C)C

Procedure:
By the procedure of Example 2, the reactant 2-chloro-1-isopropylallyl 4-chloro-2-methyl dithiocarbanilate is prepared by the reaction of 2,3-dichloro-4-methyl-1-pentene and triethylammonium 4-chloro-2-methyldithiocarbanilate. The 2,3-dichloro-4-methyl-1-pentene is prepared by the reaction of isobutyraldehyde with acetylenemagnesium bromide to yield 4-methyl-1-pentyn-3-ol, which is converted to 2-chloro-4-methyl-1-pentene-3-ol by treatment with hydrogen chloride in the presence of mercuric chloride. The required 2,3-dichloro-4-methyl-1-pentene is then obtained by treating 2-chloro-4-methyl-1-pentene-3-ol with phosphorus trichloride.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[CH3:18][C:19]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:20]=1[NH2:21]>>[CH3:18][C:19]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:20]=1[NH:21][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)[N:3]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cnccn2)n1
Reactant: Cc1ccc(C)c(N)c1
Product: Cc1ccc(C)c(Nc2cc(C(F)(F)F)nc(-c3cnccn3)n2)c1

Procedure:
The title compound was prepared similar to 4-chloro-2-(2-pyrazinyl)-6-trifluoromethylpyrimidine (30 mg, 0.115 mmol) and 2,5-dimethylaniline (21 mg, 0.172 mmol) similar to Example 180 and was isolated as an off white solid (35 mg, 80% yield). 1H NMR (CDCl3): 9.74 (d, J=1.5 Hz, 1H), 8.76 (dd, J=1.5, 2.4 Hz, 1H), 8.71 (d, J=2.4 Hz, 1H), 7.48 (brs, 1H), 7.22 (d, J=8.1 Hz, 1H), 7.12 (m, 2H), 6.65 (s, 1H), 2.36 (s, 3H), 2.23 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:36]=[N:37][N:38]([CH:40]([CH3:44])[CH2:41][C:42]#[N:43])[CH:39]=2)O1.C(=O)(O)[O-].[Na+].O1CCOCC1>CO.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>[NH2:25][C:14]1[N:13]=[C:12]([N:8]2[CH:7]([CH3:26])[CH2:6][C:5]3[C:10](=[CH:11][C:2]([C:35]4[CH:36]=[N:37][N:38]([CH:40]([CH3:44])[CH2:41][C:42]#[N:43])[CH:39]=4)=[CH:3][CH:4]=3)[CH2:9]2)[CH:17]=[C:16]([N:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]2)[N:15]=1
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: CC(CC#N)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: C1COCCO1
Solvent: O
Solvent: CO
Product: CC1Cc2ccc(-c3cnn(C(C)CC#N)c3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Temperature: 90 °C
Reaction time: 8 h
Yield: 41.3 %

Procedure:
A mixture of 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (10 mg, 0.02 mmol; Peak 1, Example 49, Step 7), 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]butanenitrile (7.5 mg, 0.029 mmol), tetrakis(triphenylphosphine)palladium(0) (1.4 mg, 0.0012 mmol), and sodium bicarbonate (6.0 mg, 0.072 mmol) in a solution of 1,4-dioxane (0.2 mL) and water (0.1 mL) in a reaction vial was stirred at 90° C. overnight. After cooling it was diluted with methanol. After filtration the filtrate was purified with RP-HPLC (pH=10) to afford the desired product (3.9 mg). LCMS (M+H)+: m/z=472.3.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH:12]2[S:24][C:16]3=[N:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[N:15]3[CH2:14][CH2:13]2)(=O)=O)=CC=1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=1.[H-].[Na+]>C(Cl)(Cl)Cl>[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][CH2:11][CH:12]2[S:24][C:16]3=[N:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[N:15]3[CH2:14][CH2:13]2)=[CH:30][CH:29]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCn3c(nc4ccccc43)S2)cc1
Reactant: COc1ccc(N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1ccc(NCC2CCn3c(nc4ccccc43)S2)cc1
Yield: 31 %

Procedure:
3,4-Dihydro-2-p-toluenesulfonyloxymethyl-2H-(1,3)-thiazino[3,2-a]benzimidazole in the amount of 1.12 g (3 m mole) was dissolved in 30 ml of chloroform. Then, 0.44 g of p-anisidine (3.6 m mole) and a catalytic amount of sodium hydride were added under ice-cooled stirring conditions. The temperature of the mixture was allowed to rise to room temperature, and then refluxed for 12 hours. The reaction mixture was cooled and washed with water. After drying the chloroform layer over anhydrous magnesium sulfate, chloroform was evaporated under reduced pressure. The residue was chromatographed on silica gel and eluted with chloroform to obtain 0.28 g (yield: 31%) of the intended product, m.p. 155°-157° C.; IR νmaxKBr cm-1 : 3360, 3100-2800, 1430; Anal. Calcd. for C18H19N3OS: C, 66.44; H, 5.88; N, 12.91; S, 9.85; Found: C, 66.91; H, 5.90; N, 12.88; S, 9.70.
Reaction SMILES: [C:1]1(=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]3=2)[CH2:4][CH2:3][NH:2]1.I[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][C:22]=1[CH3:23].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:23][C:22]1[CH:21]=[CH:20][N:19]=[CH:18][C:17]=1[N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]3=[CH:7][CH:6]=2)[C:1]1=[O:15]
Reactant: O=C1NCCc2ccc3ccccc3c21
Reactant: Cc1ccncc1I
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCc2ccc3ccccc3c2C1=O
Yield: 55.4 %

Procedure:
Using analogous reaction conditions as described in Example 1, 3,4-dihydro-2H-benzo[h]isoquinolin-1-one (I-10d: 200 mg, 1.015 mmol) was reacted with 3-iodo-4-methyl-pyridine (266 mg, 1.214 mmol), 1,4-dioxane (15 mL), copper iodide (19 mg, 0.10 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (43 mg, 0.302 mmol) and potassium phosphate (538 mg, 2.53 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% methanol in CHCl3) afforded 162 mg of the product (55.47% yield).
Reaction SMILES: [CH:1]([O:4][C:5]1[C:8]([F:10])([F:9])[C:7]([F:12])([F:11])[C:6]=1F)([CH3:3])[CH3:2]>CCOCC>[CH:1]([O:4][CH:5]1[CH2:6][C:7]([F:11])([F:12])[C:8]1([F:9])[F:10])([CH3:3])[CH3:2]
Reactant: CC(C)OC1=C(F)C(F)(F)C1(F)F
Solvent: CCOCC
Product: CC(C)OC1CC(F)(F)C1(F)F
Yield: 66 %

Procedure:
280 g (1.39 mol) of 2,3,3,4,4-pentafluorocyclobutenyl isopropyl ether are hydrogenated in 1200 ml of ether as described in Example 5 and the mixture is worked up. 2,2,3,3-Tetrafluorocyclobutyl isopropyl ether is obtained in this way in a yield of 66% of theory.