Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[C:5]([C:9]([O:11]CC)=[O:10])[S:6][C:7]=1[I:8])#[N:2].[OH-].[Na+]>O1CCCC1.O>[C:1]([C:3]1[C:4]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[C:5]([C:9]([OH:11])=[O:10])[S:6][C:7]=1[I:8])#[N:2]
Reactant: CCOC(=O)c1sc(I)c(C#N)c1-c1ccc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1c(I)sc(C(=O)O)c1-c1ccc(Cl)cc1Cl
Reaction time: 8 h
Yield: 111.2 %

Procedure:
To a solution of ethyl 4-cyano-3-(2,4-dichlorophenyl)-5-iodothiophene-2-carboxylate (1.44 g, 0.00318 mol) in tetrahydrofuran (20 mL) and water (10 mL) was added a solution of 1.00M sodium hydroxide in water (16 mL). The solution was allowed to stir overnight. The reaction was quenched with a solution of 1N hydrogen chloride in water (18 mL) and extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the crude title compound (1.50 g, 100%) used directly in the next reaction. LCMS: (FA) ES+, 378. 1H NMR (400 MHz, d6-DMSO) δ: 7.68 (d, 1H, J=2.0 Hz), 7.46-7.34 (m, 2H).
Reaction SMILES: Cl[CH2:2][C@H:3]1[O:7][C@@H:6]([N:8]2[C:17]3[N:16]=[CH:15][N:14]=[C:12]([NH2:13])[C:11]=3[N:10]=[C:9]2[CH3:18])[C@H:5]([OH:19])[C@@H:4]1[OH:20].[CH3:21][NH:22][CH3:23]>CO>[CH3:21][N:22]([CH2:2][C@H:3]1[O:7][C@@H:6]([N:8]2[C:17]3[N:16]=[CH:15][N:14]=[C:12]([NH2:13])[C:11]=3[N:10]=[C:9]2[CH3:18])[C@H:5]([OH:19])[C@@H:4]1[OH:20])[CH3:23]
Reactant: CNC
Reactant: Cc1nc2c(N)ncnc2n1[C@@H]1O[C@H](CCl)[C@@H](O)[C@H]1O
Solvent: CO
Product: Cc1nc2c(N)ncnc2n1[C@@H]1O[C@H](CN(C)C)[C@@H](O)[C@H]1O

Procedure:
A mixture of 3a (150 mg, 0.50 mmol) and a 2M solution of dimethylamine in methanol (10 mL) in a steel bomb was heated for 2 days at 90° C. The reaction mixture was concentrated to dryness and purified by column chromatography (elution with 4:1:0.15 chloroform:methanol:NH4OH). The desired fractions were combined, concentrated and dried in vacuo: yield 38 mg (25%); MS m/z 309 (M+H)+; 1HNMR (DMSO-d6) δ 8.08 (s, 1H, H-2), 7.11 (bs, 2H, 6-NH2), 5.74 (d, 1H, H-1′, J1′,2′=5.5 Hz), 5.31 (d, 1H, OH-2′, J2′-2′OH=5.9 Hz), 5.18 (d, 1H, OH-3′, J3′-3′OH=5.4 Hz), 5.03 (ddd, 1H, H-2′, J1′,2′=5.5 Hz, J2′,3′=4.6 Hz, J2′-2′OH=5.9 Hz), 4.15 (ddd, 1H, H-3′, J2′,3′=4.6 Hz, J3′,4′=5.5 Hz, J3′-3′OH=5.4 Hz), 3.91-3.96 (m, 1H, H-4′), 2.55-2.61 (m, 1H, 5′-CH2), 2.53 (s, 3H, 8-CH3), 2.42-2.48 (m, 1H, 5′-CH2), 2.14 (bs, 6H, N—(CH3)2); UV λmax, nm, pH 1, 258.5 (∈ 15,300), pH 7, 259.3 (∈ 15,300), pH 13, 260.1 (∈ 15,500). Anal. (C13H20N6O3.0.35CHCl3.0.5C2H5OH) C, H, N.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[C:16]3[C:11]([C:12]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)=[N:13][C:14]([C:18]4[CH:19]=[N:20][C:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[N:22][CH:23]=4)=[N:15]3)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[OH:38][C:39]([CH3:44])([CH3:43])[C:40](O)=[O:41].CN(C=O)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O>[OH:38][C:39]([CH3:44])([CH3:43])[C:40]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[C:16]3[C:11]([C:12]([N:32]4[CH2:33][CH2:34][O:35][CH2:36][CH2:37]4)=[N:13][C:14]([C:18]4[CH:19]=[N:20][C:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[N:22][CH:23]=4)=[N:15]3)=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1)=[O:41]
Reactant: CC(C)(C)OC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3ccc(-c4cccc(N)c4)cc3n2)cn1
Reactant: CC(C)(O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3ccc(-c4cccc(NC(=O)C(C)(C)O)c4)cc3n2)cn1
Temperature: 25 °C
Reaction time: 12 h
Yield: 51.2 %

Procedure:
In a 25 mL round bottom flask, tert-butyl (5-(7-(3-aminophenyl)-4-morpholinoquinazolin-2-yl)pyrimidin-2-yl)carbamate (0.1 g, 0.0002 mol), 2-hydroxy-2-methylpropanoic acid (0.052 g, 0.0005 mol) and DMF (10 mL) were added. To the flask, HATU (0.152 g, 0.0004 mol) and TEA (0.081 mL, 0.0006 mol) were added and then stirred at room temperature for 12 hours. To the reaction mixture was added water to provide a precipitate. The precipitate was collected by filtration to provide the crude product. The crude product was purified by flash column chromatography (2% methanol in chloroform) to obtain the title compound (0.06 g, 60%). LC-MS (ESI) Calculated mass. 585.2, Observed mass [M+H]+: 586.1 (RT=0.83 min).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:5]=[C:4]([NH:14][S:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[C:3]=1[O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:35][CH3:36].[Br:37][C:38]1[CH:47]=[CH:46][C:41]([O:42][CH2:43][CH2:44][OH:45])=[CH:40][CH:39]=1>>[Br:37][C:38]1[CH:47]=[CH:46][C:41]([O:42][CH2:43][CH2:44][O:45][C:2]2[N:7]=[C:6]([C:8]3[N:13]=[CH:12][CH:11]=[CH:10][N:9]=3)[N:5]=[C:4]([NH:14][S:15]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[C:3]=2[O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[O:35][CH3:36])=[CH:40][CH:39]=1
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Reactant: OCCOc1ccc(Br)cc1
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(-c2ncccn2)nc1OCCOc1ccc(Br)cc1

Procedure:
N-{6-Chloro-2-(2-pyrimidyl)-5-(2-methoxyphenoxy)pyrimidin-4-yl}-4-tert-butylbenzenesulfonamide and 2-(4-bromophenoxy)ethanol are treated in the same manner as in Example 192-(1) to give N-{6-{2-(4-bromophenoxy)ethoxy}-2-(2-pyrimidyl)-5-(2-methoxyphenoxy)pyrimidin-4-yl}-4-tert-butylbenzenesulfonamide.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:25])=[C:7]([C:9]2[NH:10][C:11](=[O:24])[N:12]([C:14]3[CH:15]=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=3)[N:13]=2)[CH:8]=1.[C:26](Cl)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].CCN(C(C)C)C(C)C>C1COCC1>[Cl:25][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:8][C:7]=1[C:9]1[NH:10][C:11](=[O:24])[N:12]([C:14]2[CH:15]=[N:16][C:17]([C:20]([F:21])([F:23])[F:22])=[CH:18][CH:19]=2)[N:13]=1
Reactant: NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)nc3)c(=O)[nH]2)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)nc3)c(=O)[nH]2)c1
Yield: 18.7 %

Procedure:
The title compound was prepared according to the procedure described in Example-108 by using 5-(5-(aminomethyl)-2-chlorophenyl)-2-(6-(trifluoromethyl)pyridin-3-yl)-2H-1,2,4-triazol-3(4H)-one (Intermediate-91, 0.350 g, 0.945 mmol), pivaloyl chloride (0120 g, 0.945 mmol), DIPEA (2.0 mL), dry THF (10 mL) to afford 0.080 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.11 (s, 9H), 4.30 (d, J=6.3 Hz, 2H), 7.43 (d, J=8.4 Hz, 1H), 7.61-7.64 (m, 2H), 8.06 (d, J=9.0 Hz, 1H), 8.19 (m, 1H), 8.58 (d, J=8.4 Hz, 1H), 9.32 (s, 1H), 12.82 (s, 1H); MS (m/z): 454.50 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[CH2:11][CH:12]=O)[C:6]#[N:7].[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:19][CH:18]=1)([O-:16])=[O:15].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[CH2:11][CH2:12][N:28]1[CH2:29][CH2:30][N:25]([CH2:24][CH2:23][C:20]2[CH:19]=[CH:18][C:17]([N+:14]([O-:16])=[O:15])=[CH:22][CH:21]=2)[CH2:26][CH2:27]1)[C:6]#[N:7]
Reactant: COc1cc(C#N)ccc1CC=O
Reactant: O=[N+]([O-])c1ccc(CCN2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(C#N)ccc1CCN1CCN(CCc2ccc([N+](=O)[O-])cc2)CC1

Procedure:
A solution of 3-methoxy-4-(2-oxoethyl)benzonitrile (91 mg, 0.56 mmol), 1-[2-(4-nitrophenyl)ethyl]piperazine (110 mg, 0.56 mmol) and NaBH(OAc)3 (393 mg, 1.87 mmol) in anhydrous DCM (15 mL) was stirred at ambient temperature overnight. The reaction was completed according to TLC. The reaction mixture was added 15 mL of DCM, washed with brine, separated the organic layer, dried over anhydrous sodium sulfate and concentrated. The residue was purified by preparative TLC to give the product. 1H-NMR (400 MHz, CDCl3) δ 8.15 (d, J=8.5 Hz, 3H), 7.37 (d, J=8.5 Hz, 3H), 7.05 (s, 1H), 3.85 (s, 3H), 2.85˜2.96 (m, 5H), 2.49˜2.75 (m, 11H). MS m/z: 395 (M+1)+. (0.30 μM)
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8](O)=[O:9])[N:3]=1.P(Cl)(Cl)([Cl:16])=O.CN(C)C=O>C(#N)C>[NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8]([Cl:16])=[O:9])[N:3]=1
Reactant: CO/N=C(\C(=O)O)c1nsc(N)n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)Cl)c1nsc(N)n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In 80.0 ml of acetonitrile, 10.0 g of 2-(5-amino-1,2,4-thiadiazol-3-yl)-2(Z)-methoxyiminoacetic acid were stirred at -20° C., followed by the dropwise addition of a chlorinating reagent, which had been prepared beforehand by gradually adding 8.4 g of phosphorus oxychloride at 5° C. to a mixture of 25 ml of acetonitrile and 4.0 g of N,N-dimethylformamide (DMF) and then reacting them for 30 minutes. After they were reacted for 5 minutes, 200 ml of ice water were poured into the reaction mixture to precipitate crystals. The crystals were collected by filtration, washed with 100 ml of ice water and then stirred for 30 minutes in 100 ml of n-hexane. After filtration, the resulting crystals were dried under reduced pressure, whereby the title compound was obtained. Yield: 8.90 g (81.6%). Purity: 97.9%.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH2:24][O:25][CH2:26][CH2:27][OH:28])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CS(O[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])(=O)=O>C1(C)C=CC=CC=1>[CH2:42]([O:41][C:39](=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][O:28][CH2:27][CH2:26][O:25][CH2:24][CH2:23][O:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:43]
Reactant: CCOC(=O)CCCCCOS(C)(=O)=O
Reactant: OCCOCCOCCOCCOCCOCCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCCCOCCOCCOCCOCCOCCOCCOCc1ccccc1
Temperature: 0 °C
Yield: 43.8 %

Procedure:
Sodium hydride (3.225 g or a 60% oil dispersion, 80.6 mmol) was suspended in 80 ml of anhydrous toluene, placed under a nitrogen atmosphere and cooled in an ice bath. A solution of the non-polydispersed alcohol XX (27.3 g, 73.3 mmol) in 80 ml dry toluene was added to the NaH suspension. The mixture was stirred at 0° C. for thirty minutes, allowed to come to room temperature and stirred for another five hours, during which time the mixture became a clear brown solution. The non-polydispersed mesylate XXI (19.21 g, 80.6 mmol) in 80 ml dry toluene was added to the NaH/alcohol mixture, and the combined solutions were stirred at room temperature for three days. The reaction mixture was quenched with 50 ml methanol and filtered through basic alumina. The filtrate was concentrated in vacuo and purified by flash chromatography (silica gel, gradient elution: 3/1 ethyl acetate/hexanes to ethyl acetate) to yield the non-polydispersed product as a pale yellow oil (16.52 g, 44%). FAB MS: m/e 515 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:19][C:20]([O:22]C)=[O:21])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])=[O:10].[OH-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:19][C:20]([OH:22])=[O:21])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])=[O:10]
Reactant: COC(=O)Cc1ccc(NC(=O)Nc2ccccc2C)c(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)O)cc1Br
Temperature: 25 °C
Reaction time: 14 h
Yield: 195.3 %

Procedure:
To a stirred solution of methyl 3-bromo-4-[N′-(2-methylphenyl)ureido]phenylacetate (650 mg, 1.72 mmol) in THF (10 ml) was added 0.25 N NaOH (10 ml). After stirring at room temperature for 14 h, the solvent was concentrated in vacuo. The residue was triturated by the addition of 1 N HCl and dried at 60° C. for 2 days under a reduced pressure to give 3-bromo-4-[N′-(2-methylphenyl)ureido]phenylacetic acid (1.22 g, 100%) as colorless powder. 1H-NMR (DMSO-d6) δ 2.26 (s, 3H), 3.32 (s, 2H), 6.93 (m, 2H), 7.10–7.17 (m, 4H), 7.76 (d, J=8.1 Hz, 2H), 8.52 (s, 1H); MS (ESI) m/z 385 (M++Na), 387 (M++2+Na).
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:27])[NH:6][C:7]1[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C@H:23]([CH3:26])[CH2:24][OH:25])[CH:17]=2)[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[CH3:30][C@H:31]1[CH2:36][CH2:35][CH2:34][CH2:33][N:32]1[C:37]1[N:41]2[CH:42]=[C:43]([O:46][C@H:47]3[C:56]4[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=4)[C@@H:50]([NH2:57])[CH2:49][CH2:48]3)[CH:44]=[CH:45][C:40]2=[N:39][N:38]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:57][C@@H:50]2[C:51]3[C:56](=[CH:55][CH:54]=[CH:53][CH:52]=3)[C@H:47]([O:46][C:43]3[CH:44]=[CH:45][C:40]4[N:41]([C:37]([N:32]5[CH2:33][CH2:34][CH2:35][CH2:36][C@@H:31]5[CH3:30])=[N:38][N:39]=4)[CH:42]=3)[CH2:48][CH2:49]2)=[O:27])[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C@H:23]([CH3:26])[CH2:24][OH:25])[CH:17]=2)[N:9]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: C[C@H](CO)Oc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)c1
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: C[C@H](CO)Oc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCC[C@@H]5C)n4c3)c3ccccc32)c1
Temperature: 70 °C
Reaction time: 7.5 h
Yield: 60.6 %

Procedure:
A solution of Intermediate 151c (102 mg, 0.22 mmol) in 1,4-dioxane (2.0 mL) was treated with Intermediate 81d (75 mg, 0.20 mmol) and DIPEA (0.043 mL, 0.25 mmol) and the mixture was stirred at 70° C. for 7.5 h then at 50° C. for 64 h. The cooled solution was concentrated in vacuo, and the residue was partitioned between DCM and water. The phases were separated and the aqueous layer was extracted with DCM (×2). The combined organic phase was washed with brine, dried (Na2SO4) and concentrated in vacuo to a brown gum. The gum was purified by FCC, using 0-10% MeOH in DCM to give the title compound as a yellow glass (84 mg, 61%). LCMS (Method 3): Rt 3.75 min, m/z 693.5 [MH+].
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]3[CH2:15][CH2:16][C:17]4[NH:18][C:19](=[O:22])[CH:20]=[CH:21][C:12]([C:13]=43)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.S(Cl)([Cl:25])=O>C(#N)C>[Cl:25][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]3[CH2:15][CH2:16][C:17]4[NH:18][C:19](=[O:22])[CH:20]=[CH:21][C:12]([C:13]=43)=[CH:11][N:10]=2)=[CH:5][CH:4]=1
Reactant: O=C1C=CC2=CN=C(c3ccc(CO)cc3)N3CCC(=C23)N1
Reactant: O=S(Cl)Cl
Solvent: CC#N
Product: O=C1C=CC2=CN=C(c3ccc(CCl)cc3)N3CCC(=C23)N1

Procedure:
This compound was prepared by reacting 500 mg (1.7 mmol) of alcohol 58a, suspended in 25 mL of acetonitrile with 4 equivalents of thionyl chloride. After complete conversion as determined by HPLC analysis the reaction was concentrated in vacuo and the crude benzylchloride was without further purification. HPLC Rt=3.060 min.
Reaction SMILES: [CH:1]1([CH2:10][CH2:11]O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C([Br:16])C=C>C(#N)C>[CH:1]1([CH2:10][CH2:11][Br:16])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: C=CCBr
Reactant: OCCC1CCc2ccccc21
Solvent: CC#N
Product: BrCCC1CCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
N,N-Carbonyl diimidazole (2.0 g, 12.3 mmol) was added to a solution of 2-indanylethanol (2.0 g, 12.3 mmol) in acetonitrile. The reaction mixture was stirred at room temperature for 1 h and allyl bromide (8.93 g, 73.8 mmol) was added. The reaction mixture was heated to 70° C. for 24 h and was poured onto water. The aqueous solution was extracted with Et2O and the organic solution was washed with water (1×) followed by brine (1×). The organic solution was dried over MgSO4, filtered, and concentrated to afford the title compound (2.54 g). 1H NMR (400 MHz, CDCl3) δ7.10-7.25 (m, 4H), 3.48 (t, 2H), 3.11 (m, 2H), 2.63 (m, 3H), 2.07 (m, 2H).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][C@@H:14]([CH3:19])[C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:20][C:21]([CH3:29])([CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])[C:22]#[N:23]>>[C:22]([C:21]([NH:20][C:10]([C:7]1[CH:6]=[C:5]([O:13][C@@H:14]([CH3:19])[C:15]([F:18])([F:17])[F:16])[C:4]([CH:1]2[CH2:2][CH2:3]2)=[CH:9][N:8]=1)=[O:12])([CH3:29])[CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])#[N:23]
Reactant: CC(N)(C#N)CS(C)(=O)=O
Reactant: C[C@H](Oc1cc(C(=O)O)ncc1C1CC1)C(F)(F)F
Product: C[C@H](Oc1cc(C(=O)NC(C)(C#N)CS(C)(=O)=O)ncc1C1CC1)C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 78e, using 5-Cyclopropyl-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-pyridine-2-carboxylic acid (Example 68a) and 2-Amino-3-methanesulfonyl-2-methyl-propionitrile (Example 80a) as starting materials and isolated (503 mg, 54%) as a white solid; MS (ESI, m/z): 420.4 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@@H:4]1[C@H:9]([OH:10])[CH2:8][CH2:7][CH2:6][N:5]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].CCN(C(C)C)C(C)C.[Si:28](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3](=[O:18])[C@@H:4]1[C@H:9]([O:10][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH2:8][CH2:7][CH2:6][N:5]1[C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12]
Reactant: COC(=O)[C@@H]1[C@H](O)CCCN1C(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)CCCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
To a solution of 77C (3.3 g, 12.7 mmol) in DCM (50 mL) was added DIPEA (6.63 mL, 38.1 mmol), tert-butyldimethylsilyl chloride (3.83 g, 25.4 mmol, 2.0 equiv) and DMAP (310 mg, 5.24 mmol, 0.2 equiv). The resulting mixture was stirred at rt overnight. TLC showed no completion and therefore another 2.2 mL of DIPEA and 1.91 g of tert-butyldimethylsilyl chloride were added and stirred at rt for 3 days. The mixture was concentrated and the residue was diluted with EtOAc (100 mL), washed with 0.5 N HCl (2×30 mL), brine (2×30 mL), dried (MgSO4) and evaporated to give the crude product as a light pink oil. Purification of the crude product by flash chromatography (5-10% EtOAc/hexane) gave the desired product 77D (3.8 g, 81%): Rf (10% EtOAc/hexane) 0.25; HPLC (Phenomenex Luna 5 u C18 4.6×50 mm, linear gradient over 4 min) retention time 4.3 min (100%); MS (ES) m/z 374 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[C:4]=1[CH:5]=[C:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8].CO>[C].[Pd].C(O)(=O)C>[CH3:22][O:21][C:17]1[CH:18]=[CH:19][CH:20]=[C:3]([O:2][CH3:1])[C:4]=1[CH2:5][CH:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(=Cc1c(OC)cccc1OC)C(=O)OCC
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)C(Cc1c(OC)cccc1OC)C(=O)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.5 %

Procedure:
A mixture of 2.8 g of diethyl (2,6-dimethoxybenzylidene)malonate, 0.6 g of palladium-carbon, 50 ml of methanol and 50 ml of glacial acetic acid was stirred at 25° C. overnight. The solution was filtered and concentrated, and the residue was taken up in ethyl acetate and extracted with 20% NaHCO3 and some ice. Thereafter, the mixture was extracted with 1N, HCl, back-washed with saturated NaCl solution, the organic phase was dried and evaporated under reduced pressure. The crude product was distilled in a high vacuum at 170° C./0.6 mbar. 2.1 g of diethyl (2,6-dimethoxybenzyl)malonate were obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[C:3]=1[NH:4][CH2:5][CH2:6][S:7][CH3:8].O.O.[Sn](Cl)Cl.Cl.C1N=CN([C:27](N2C=NC=C2)=[O:28])C=1>C(O)C>[CH3:1][C:2]1[C:3]2[N:4]([CH2:5][CH2:6][S:7][CH3:8])[C:27](=[O:28])[NH:13][C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: CSCCNc1c(C)cccc1[N+](=O)[O-]
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: CSCCn1c(=O)[nH]c2cccc(C)c21
Temperature: 25 °C
Reaction time: 12 h
Yield: 67.5 %

Procedure:
To a solution of 2-methyl-N-[2-(methylthio)ethyl]-6-nitroaniline (2.6 g, 12 mmol) in ethanol (6.0 mL) was added a solution of Tin(II) chloride dihydrate (7.9 g, 35 mmol) in concd. hydrochloric acid (8.0 mL) at 0° C. and warmed to rt. After 4h, the reaction was quenched by addition of 6N sodium hydroxide (100 mL) and extracted with ethyl acetate (100 mL×2), dried over sodium sulfate, filtered and concentrated. The crude material was dissolved in THF (50 mL) and to this solution was added CDI (2.3 g, 14 mmol) and the mixture was stirred at rt. After 12 h, to the mixture was added CDI (1.5 g, 6.7 mmol) and the reaction mixture was refluxed for 5 h. Then the mixture was cooled to rt and evaporated to dryness. To this was added water (100 mL) and extracted with ethyl acetate (100 mL×2). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over sodium sulfate, filtered and concentrated. The obtained material was dissolved in methanol (30 mL) and to this solution was added 2N sodium hydroxide (3 mL) and stirred at rt for 2 h. Then the mixture was quenched by addition of sat. aq. sodium bicarbonate (50 mL) and extracted with ethyl acetate (100 mL×2). The combined organic layers were washed with water (50 mL), brine (50 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with dichloromethane/methanol (20/1-10/1) to afford 1.8 g (69%) of the title compound.
Reaction SMILES: [C:1]1([N:7](C2C=CC=CC=2)[NH:8][C:9]([C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14](=[O:21])[N:13]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:12]=2[CH3:28])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:36]([O:38][CH3:39])=[O:37]>ClCCCl>[CH3:39][O:38][C:36]([N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[NH:8][C:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[N:13]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:12]=1[CH3:28])=[O:10])=[O:37]
Reactant: Cc1c(C(=O)NN(c2ccccc2)c2ccccc2)c2ccccc2c(=O)n1-c1ccccc1
Reactant: COC(=O)Cl
Solvent: ClCCCl
Product: COC(=O)N(NC(=O)c1c(C)n(-c2ccccc2)c(=O)c2ccccc12)c1ccccc1
Temperature: 100 °C
Yield: 34.2 %

Procedure:
A mixture of 3-methyl-1-oxo-2-phenyl-1,2-dihydro-isoquinoline-4-carboxylic acid N′-phenyl-hydrazide (5a, 490 mg, 1.3 mmol) and methyl chloroformate (0.6 ml, 8 mmol) in 1,2-dichloroethane (10 ml) was heated under microwave irradiation for 10 min at 100° C. Volatiles were removed in vacuo and the product was purified by flash chromatography (SiO2, gradient heptane-1:1 ethyl acetate/heptane) to give 190 mg of solid. LC-MS (m/z) 428.8 (MH+); tR=1.22.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([O:12][CH3:13])=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[NH:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([N+:25]([O-])=O)[CH:21]=2)[N:16]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[C:8]([O:12][CH3:13])=[C:7]2[C:3]=1[CH2:4][CH2:5][CH:6]2[NH:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([NH2:25])[CH:21]=2)[N:16]=1
Reactant: COc1c(Cl)cc(Cl)c2c1C(Nc1ccc3cc([N+](=O)[O-])ccc3n1)CC2
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1c(Cl)cc(Cl)c2c1C(Nc1ccc3cc(N)ccc3n1)CC2
Temperature: 25 °C

Procedure:
Rac-(4,6-dichloro-7-methoxy-indan-1-yl)-(6-nitro-quinolin-2-yl)-amine (250 mg, 0.62 mmol) were taken up in a mixture of ethanol (5 mL) and water (2.5 mL). After the addition of ammonium chloride (17 mg, 0.31 mmol) and iron powder (173 mg, 3.1 mmol) the reaction mixture was heated tom reflux for 6 h. After cooling to ambient temperature the reaction mixture was filtered through Dicalit®, the filtrate was concentrated and the residue was subjected to column chromatography (silica gel, heptane ethyl acetate gradient 9:1→1:1). Rac-N2-(4,6-dichloro-7-methoxy-indan-1-yl)-quinoline-2,6-diamine was obtained as a yellow oil (0.11 g, 45%); MS: m/e=375.4 (M+H+).