Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[Br:13][C:14]1[CH:19]=[C:18]([C:20]2[C:32]3[C:31]([CH3:33])=[C:30]([CH3:34])[S:29][C:28]=3[C:27]([Br:35])=[C:26]3[C:21]=2[CH:22]=[CH:23][CH:24]=[CH:25]3)[CH:17]=[C:16]([Br:36])[C:15]=1[OH:37].O[C@@H:39]([CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:40]([O:42][CH3:43])=[O:41].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CCOCC.C1C=CC=CC=1>[CH3:43][O:42][C:40](=[O:41])[C@H:39]([O:37][C:15]1[C:16]([Br:36])=[CH:17][C:18]([C:20]2[C:32]3[C:31]([CH3:33])=[C:30]([CH3:34])[S:29][C:28]=3[C:27]([Br:35])=[C:26]3[C:21]=2[CH:22]=[CH:23][CH:24]=[CH:25]3)=[CH:19][C:14]=1[Br:13])[CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: Cc1sc2c(Br)c3ccccc3c(-c3cc(Br)c(O)c(Br)c3)c2c1C
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCOCC
Product: COC(=O)[C@@H](Cc1ccccc1)Oc1c(Br)cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc1Br
Temperature: 80 °C
Yield: 97.4 %

Procedure:
Diethylazodicarboxylate (0.262 mL, 1.67 mmol) was added dropwise to a stirred, room temperature solution of 2,6-dibromo-4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-phenol (0.60 g, 1.11 mmol), and (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (0.300 g, 1.67 mmol), triphenylphosphine (0.437 g, 1.67 mmol) and benzene (5 mL) and the solution was heated in an 80° C. oil bath for 6 h. Upon cooling to room temperature, the reaction mixture was diluted with ether and silica gel (30 mL) was added. The reaction mixture was concentrated and the silica adsorbate was flash chromatographed (95:5 petroleum ether:ethyl acetate) to provide the title compound as a white solid (0.76 g, 97%): mp 174-175° C.: NMR (DMSO-d6); δ 8.21 (ddd, J=8,1,1 Hz, 1H), 7.74 (d, J=2 Hz, 1H), 7.73 (d, J=2 Hz, 1H),7.67 (ddd, J=8, 6, 1 Hz, 1H), 7.53 (ddd, J=8, 7, 1 Hz, 1H), 7,43 (d, J=8 Hz, 1H), 7.35-7.24 (m, 5H), 5.11 (dd, J=7, 6 Hz, 1H), 3.61 (s, 3H), 3.43 (dd, 13, 6 Hz, 1H), 3.40 (dd, 13, 7 Hz, 1H), 2.44 (d, J=1 Hz, 3H), 1.60 (d, J=1 Hz, 3H); MS (+FAB): 3 bromine isotope pattern 700(20%), 702 (70%), 704 (75%), 706 (25%); Anal. Calc. for C30H23Br3O3S: C, 51.23, H, 3.30, N, 0.00. Found: C, 51.52, H, 3.36, N, 0.12.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4](Cl)[N:3]=1.[CH3:17][C@H:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(N(CC)CC)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([NH:25][CH:18]([CH3:17])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:3]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: Clc1nc(Cl)c2ncn(C3CCCC3)c2n1
Solvent: CCN(CC)CC
Product: CC(Nc1nc(Cl)nc2c1ncn2C1CCCC1)c1ccccc1

Procedure:
2-Chloro-6-[(α-methylbenzyl)amino]-9-cyclopentylpurine is prepared from 2,6-dichloro-9-cyclopentylpurine, (S)-α-methylbenzylamine, and triethylamine essentially as described above in Example 1, Scheme A, step b.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](O)=[C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:18]4[N:22]([CH:23]5[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]5)[C:21]5[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=5[N:19]=4)[CH:14]=3)[N:9]=2)[CH:7]=1.[Cl:37][C:38]1[CH:39]=[C:40]2[C:48](=[CH:49][CH:50]=1)[N:47](C)[C:46]1C=CC(C(=O)C)=CC2=1.[OH-].[K+]>C(O)C>[Cl:37][C:38]1[CH:50]=[C:49]2[C:48](=[CH:40][CH:39]=1)[N:47]([CH3:46])[C:3]1[CH:4]=[CH:5][C:6]([C:8]3[CH:17]=[CH:16][C:15]4[C:10](=[CH:11][CH:12]=[C:13]([C:18]5[N:22]([CH:23]6[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]6)[C:21]6[CH:29]=[CH:30][C:31]([C:33]([OH:35])=[O:34])=[CH:32][C:20]=6[N:19]=5)[CH:14]=4)[N:9]=3)=[CH:7][C:2]2=1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(Br)ccc4O)ccc3c1)n2C1CCCCC1
Reactant: CC(=O)c1ccc2c(c1)c1cc(Cl)ccc1n2C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cn1c2ccc(Cl)cc2c2cc(-c3ccc4cc(-c5nc6cc(C(=O)O)ccc6n5C5CCCCC5)ccc4n3)ccc21
Yield: 12 %

Procedure:
Following the procedure and workup for Compound 354, Compound 354e (100 mg, 0.256 mmol) was reacted with 1-(6-chloro-9-methyl-9H-carbazol-3-yl)-ethanone (0.256 mmol) in ethanol (2 mL) using 10% w/v KOH in ethanol (506 μL, 0.64 mmol) to produce the title compound (18 mg, 12% yield). MS: 585.21 (M+H+); HPLC Procedure A, retention time=16.25 min.
Reaction SMILES: [S:1]([NH:11][C@H:12]([C:14]([OH:16])=O)[CH3:13])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].S(Cl)([Cl:19])=O>CCCCCC>[S:1]([NH:11][C@H:12]([C:14]([Cl:19])=[O:16])[CH3:13])([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](C)C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: CCCCCC
Product: Cc1ccc(S(=O)(=O)N[C@@H](C)C(=O)Cl)cc1
Temperature: 50 °C
Yield: 93 %

Procedure:
A mixture of N-tosyl-L-alanine (3.1 g; 13 mmol) and thionyl chloride (6 mL) was heated for 1.5 hours at 50° C. then diluted with dry hexane (50 mmL). The mixture was stirred rapidly, chilled and the solid was collected by filtration to obtain 3.15 g (93%) of N-tosyl-L-alaninyl chloride (35) having a melting point of 99°-100° C. The IR spectrum of this material was identical to that of the recrystallized material prepared according to method (i).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19]OS(C3C=CC(C)=CC=3)(=O)=O)=[CH:14][CH:15]=2)[C:10]([S:31]([C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:37]=[CH:36][CH:35]=2)(=[O:33])=[O:32])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1>C1COCC1>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][CH2:19][N:44]3[CH2:48][CH2:47][CH2:46][CH2:45]3)=[CH:14][CH:15]=2)[C:10]([S:31]([C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:37]=[CH:36][CH:35]=2)(=[O:33])=[O:32])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3c(c2)c(S(=O)(=O)c2cccc4ccccc24)nn3Cc2ccccc2)cc1
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc2ccccc12)c1nn(Cc2ccccc2)c2ccc(OCCN3CCCC3)cc12

Procedure:
A solution of toluene-4-sulfonic acid 2-[1-benzyl-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (0.379 g, 0.619 mmol) and pyrrolidine (1.0 mL, 12 mmol) in THF (80 mL) was stirred at 70° C. in a sealed tube for 3 hours. The reaction mixture was solvent evaporated and partitioned in ethyl acetate and aqueous sodium bicarbonate. The organic phase was then washed with water and brine. It was dried with anhydrous magnesium sulfate, filtered and concentrated. Drying at 80° C. in vacuo for 25 minutes gave 1-benzyl-3-(naphthalene-1-sulfonyl)-5-(2-pyrrolidin-1-yl-ethoxy) -1H-indazole as a yellow-orange solid (0.259 g, 82.0% mmol). This was dissolved in chloroform, and ethereal hydrochloride was added. The mixture was concentrated and dried for 13 hours in vacuo at 81° C. The result was the hydrochloride as a buff foam (0.267 g); Mass Spectrum (+EI, [M+H]+) m/z 512.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:20].[O:21]1[C:25]2[CH:26]=[CH:27][C:28]([C:30](O)=[O:31])=[CH:29][C:24]=2[O:23][CH2:22]1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][N:14]3[CH2:18][CH2:17][CH2:16][CH:15]3[CH3:19])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:20][C:30]([C:28]1[CH:27]=[CH:26][C:25]2[O:21][CH2:22][O:23][C:24]=2[CH:29]=1)=[O:31]
Reactant: Cc1cc(N2CCC(CN3CCCC3C)C2)ccc1N
Reactant: O=C(O)c1ccc2c(c1)OCO2
Product: Cc1cc(N2CCC(CN3CCCC3C)C2)ccc1NC(=O)c1ccc2c(c1)OCO2

Procedure:
The title compound was prepared in a manner substantially the same as Example 1 by coupling 2-methyl-4-[3-(2-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-phenylamine with benzo[1,3]dioxole-5-carboxylic acid. MS: 422.5 (M+H).
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3[N:29]([C:30]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:28]=[N:27][N:26]=3)=[CH:15][CH:14]=2)[CH:6]=[C:7]([CH2:9][CH2:10][NH2:11])[N:8]=1)[CH2:2][CH3:3].O.[C:50]([O:54][CH2:55][CH3:56])(=[O:53])[CH:51]=O>O1CCCC1>[CH2:1]([C:4]1[N:5]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3[N:29]([C:30]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[N:28]=[N:27][N:26]=3)=[CH:17][CH:18]=2)[C:6]2[CH:51]([C:50]([O:54][CH2:55][CH3:56])=[O:53])[NH:11][CH2:10][CH2:9][C:7]=2[N:8]=1)[CH2:2][CH3:3]
Reactant: CCOC(=O)C=O
Reactant: CCCc1nc(CCN)cn1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc1)C(C(=O)OCC)NCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
A mixture of 2-n-propyl-4-(2-aminoethyl)-1-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methylimidazole (6.92 g), ethyl glyoxylate hydrate (1.30 g) and tetrahydrofuran (70 ml) is stirred overnight at room temperature. The mixture is evaporated, and the residue is purified by silica gel column chromatography (solvent; chloroform/ethanol) to give ethyl 2-n-propyl-3-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (5.32 g) as a foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:9][CH3:10])[CH:3]=1.[CH:11]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1)([CH3:13])[CH3:12].O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:18][C:17]2[CH:20]=[CH:21][C:14]([CH:11]([CH3:13])[CH3:12])=[CH:15][CH:16]=2)[C:5]([OH:8])=[C:4]([CH2:9][CH3:10])[CH:3]=1
Reactant: CC(C)c1ccc(CCl)cc1
Reactant: CCc1cc(Cl)ccc1O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCc1cc(Cl)cc(Cc2ccc(C(C)C)cc2)c1O
Temperature: 60 °C
Reaction time: 5.5 h

Procedure:
117.5 g (0.75 mol) 4-chloro-2-ethylphenol are dissolved with 42.25 g (0.25 mol) 4-isopropylbenzylchloride in 200 ml chloroform. 22.5 g water-free zinc chloride are added thereto for the alkylation reaction. Already at 30° C. a powerful reaction takes place. The entire mixture is after-stirred 5-6 h at 60° C. for completion of the alkylation. After a cooling it is subsequently washed three times each with 200 ml water, and then dried across sodium sulfate, after which the solvent chloroform is driven off.
Reaction SMILES: N#N.Cl[CH2:4][C:5]1[S:9][C:8]([C:10]2([CH3:15])[O:14][CH2:13][CH2:12][O:11]2)=[CH:7][CH:6]=1.[C-:16]#[N:17].[Na+].O>CS(C)=O>[CH3:15][C:10]1([C:8]2[S:9][C:5]([CH2:4][C:16]#[N:17])=[CH:6][CH:7]=2)[O:14][CH2:13][CH2:12][O:11]1
Reactant: [C-]#N
Reactant: CC1(c2ccc(CCl)s2)OCCO1
Agent: N#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC1(c2ccc(CC#N)s2)OCCO1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-yl]-methanol (10.00 g, 49.94 mmol) in dry CH2Cl2 (100 mL) was treated at 0° C. with Et3N (9.04 mL, 64.92 mmol) followed by DMAP (610 mg, 4.99 mmol) and Ms-Cl (4.65 mL, 59.92 mmol). After stirring at rt for 2 h, the reaction was quenched with water (200 mL). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude 2-(5-chloromethyl-thiophen-2-yl)-2-methyl-[1,3]dioxolane as a yellow oil. In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of this crude 2-(5-chloromethyl-thiophen-2-yl)-2-methyl-[1,3]dioxolane in DMSO (400 mL) was treated with sodium cyanide (9.07 g, 185.09 mmol) and the reaction mixture was stirred at 80° C. for 1 h. Water (400 mL) was added to the cooled reaction mixture and the product was extracted with EA (2×500 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (60:40 hept-EA) gave the title compound: TLC: rf (60:40 hept-EA)=0.34. LC-MS-conditions 02: tR=0.89 min.
Reaction SMILES: [C:1]([O:8][CH2:9][CH3:10])(=[O:7])[C:2]([O:4]CC)=O.CO.[NH:13](CCO)[CH2:14][CH2:15][OH:16]>C(O)(C)C>[OH:16][CH2:15][CH2:14][N:13]1[CH2:10][CH2:9][O:8][C:1](=[O:7])[C:2]1=[O:4]
Reactant: OCCNCCO
Reactant: CCOC(=O)C(=O)OCC
Solvent: CC(C)O
Solvent: CO
Product: O=C1OCCN(CCO)C1=O
Temperature: 2.5 °C
Reaction time: 8 h

Procedure:
A 4(2-hydroxyethyl)morpholine-2,3-dione was prepared at low temperatures by the following procedure. Into a five-necked 22 liter round bottomed flask equipped with a reflux condenser, nitrogen bubbler, addition funnel, thermocouple well, and mechanical stirrer was charged 3000 g (20.53 mol) of diethyl oxalate and 2000 ml of isopropyl alcohol. The solution was cooled to 0 to 5° C. using a cold bath of ice and methanol. A solution of 2160 g (20.53 mol) of diethanolamine dissolved in 2000 ml of isopropyl alcohol was added through the addition funnel during a period of 5 to 6 hours. The reaction is exothermic. After addition was complete, the mixture was allowed to stand at room temperature overnight. The product is collected by filtration. After air drying, 2923 g (89.5% yield) of white crystals were obtained with identical spectral properties to the compound prepared in Example 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](Cl)=[N:9][OH:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:19]([N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33])[CH2:20][C:21]#[CH:22]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:22]=[C:21]([CH2:20][CH2:19][N:23]3[C:27](=[O:28])[C:26]4[C:25](=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:24]3=[O:33])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: ON=C(Cl)c1ccc(F)cc1
Reactant: C#CCCN1C(=O)c2ccccc2C1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1CCc1cc(-c2ccc(F)cc2)no1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.9 %

Procedure:
Under a nitrogen atmosphere, 4-fluoro-N-hydroxybenzenecarboximidoyl chloride (31 g, 180 mmol), prepared as described in Parts A through C of Example 11, was added dropwise to a solution of anhydrous triethylamine (19 mL, 210 mmol) and N-(3-butynyl)phthalimide (19.04 g, 95.58 mmol) in dichloromethane (1 L). The reaction was stirred at room temperature for 24 hours and then diluted with dichloromethane, washed sequentially with aqueous potassium carbonate, water, and brine; dried over potassium sulfate; filtered; and concentrated under reduced pressure. The resulting solid was triturated with ethanol, isolated by filtration, and washed with diethyl ether to provide 29.87 g of 2-{2-[3-(4-fluorophenyl)isoxazol-5-yl]ethyl}-1H-isoindole-1,3(2H)-dione. A portion of the product was recrystallized from isopropyl alcohol and dried to provide an analytically pure sample as white crystals, mp 155.0-156.0° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.F[C:7]1[CH:8]=[C:9]2[C:15]([C:16]3[N:17]=[N:18][C:19]([C:23]([CH3:29])([CH3:28])[C:24]([O:26]C)=O)=[C:20](O)[N:21]=3)=[N:14][N:13]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[F:37])[C:10]2=[N:11][CH:12]=1.[NH3:38].[Cl-].[Na+]>C(#N)C>[F:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[CH2:30][N:13]1[C:10]2=[N:11][CH:12]=[CH:7][CH:8]=[C:9]2[C:15]([C:16]2[N:17]=[N:18][C:19]3[C:23]([CH3:28])([CH3:29])[C:24](=[O:26])[NH:38][C:20]=3[N:21]=2)=[N:14]1
Reactant: N
Reactant: COC(=O)C(C)(C)c1nnc(-c2nn(Cc3ccccc3F)c3ncc(F)cc23)nc1O
Agent: [Cl-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC#N
Product: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nnc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 ml of phosphoryl chloride were added to 9.700 g (22.025 mmol) of the compound from Example 61A, and the mixture was stirred at RT overnight. The reaction mixture was dissolved in 150 ml of acetonitrile and, with ice cooling, stirred into a mixture of 1337 ml of concentrated aqueous ammonia solution (35% strength) and 1300 ml of acetonitrile. The mixture was stirred at room temperature for 2 days. 300 g of sodium chloride were then added. Two phases formed. The organic phase was separated off and concentrated to dryness. The residue was taken up in ethyl acetate (150 ml). A precipitate formed and was filtered off with suction through a frit. The filter cake was washed three times with water and then three times with ethyl acetate (5 ml). The residue was dried under high vacuum. This gave 4.58 g (51% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH3:23])[C:5]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1.[N:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH3:23])[C:5]2[C:10]([C:27]3[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=3)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1
Reactant: OB(O)c1ccncc1
Reactant: CNc1nc(Cl)nc2c1c(I)cn2S(=O)(=O)c1ccc(C)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CNc1nc(Cl)nc2c1c(-c1ccncc1)cn2S(=O)(=O)c1ccc(C)cc1
Temperature: 100 °C
Yield: 43.9 %

Procedure:
To a mixture of 2-chloro-N-methyl-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.05 g, 0.11 mmol), Pd(PPh3)2Cl2 (0.015 g, 0.022 mmol) and pyridine-4-ylboronic acid (0.03 g, 0.24 mmol) in p-dioxane (0.7 mL) was added a solution of Na2CO3 (0.035 g, 0.33 mmol) in water (0.3 mL). After degassing, the mixture was heated at 100° C. for 1.5 h. The mixture was purified by flash column chromatography (Hexane/EtOAc=1:1) to give 2-chloro-N-methyl-5-(pyridin-4-yl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (0.02 g).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][C:20]1[CH:21]=[C:22]([C:27]2[O:31][C:30]([CH3:32])=[N:29][C:28]=2[C:33](O)=[O:34])[CH:23]=[C:24]([CH3:26])[CH:25]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:33]([C:28]3[N:29]=[C:30]([CH3:32])[O:31][C:27]=3[C:22]3[CH:21]=[C:20]([CH3:19])[CH:25]=[C:24]([CH3:26])[CH:23]=3)=[O:34])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: Cc1cc(C)cc(-c2oc(C)nc2C(=O)O)c1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3nc(C)oc3-c3cc(C)cc(C)c3)n2)o1

Procedure:
Following general procedure B followed by either C or D, 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(3,5-dimethyl-phenyl)-2-methyl-oxazole-4-carboxylic acid. LC-MS-conditions 01: tR=1.02 min; [M+H]+=419.11.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[S:15]([OH:18])(=[O:17])=[O:16].O>ClCCl>[C:1]1([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([S:15]([OH:18])(=[O:17])=[O:16])=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(Cc2ccccc2)cc1
Reactant: O=S(=O)(O)Cl
Solvent: O
Solvent: ClCCl
Product: O=S(=O)(O)c1ccc(Cc2ccccc2)cc1

Procedure:
To 33.6 g (0.2 mol) of diphenylmethane in 100 g of dichloromethane at room temperature, 23.4 g (0.2 mol) of chlorosulfonic acid was added dropwise. The solution was ripened for 2 hours, whereupon 50 g of water was added. This reaction mixture was used in the subsequent reaction without isolation.
Reaction SMILES: Br[CH:2](Br)[C:3]1[CH:16]=[CH:15][C:6]([C:7]([NH:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])=[O:8])=[CH:5][C:4]=1[C:17]([F:20])([F:19])[F:18].CC[OH:24]>O.C(OC)(C)(C)C.[N+]([O-])([O-])=O.[Ag+]>[CH:2]([C:3]1[CH:16]=[CH:15][C:6]([C:7]([NH:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])=[O:8])=[CH:5][C:4]=1[C:17]([F:20])([F:19])[F:18])=[O:24]
Reactant: CCO
Reactant: C[Si](C)(C)CNC(=O)c1ccc(C(Br)Br)c(C(F)(F)F)c1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: COC(C)(C)C
Solvent: O
Product: C[Si](C)(C)CNC(=O)c1ccc(C=O)c(C(F)(F)F)c1
Yield: 100 %

Procedure:
4-(dibromomethyl)-3-(trifluoromethyl)-N-[(trimethylsilyl)methyl]benzamide (22.0 g, 49.1 mmol) and AgNO3 (16.7 g, 98.3 mmol) in EtOH and H2O were refluxed for 2 hours, then diluted with t-BuOMe and washed with brine. Dried over MgSO4 and evaporation yielded the product (15.0 g, 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.[O:9]1[C:13]2([CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]2)[O:12][CH2:11][CH2:10]1>>[C:4]1([CH3:8])[CH:5]=[CH:6][CH:7]=[C:2]([C:16]2([OH:19])[CH2:17][CH2:18][C:13]3([O:12][CH2:11][CH2:10][O:9]3)[CH2:14][CH2:15]2)[CH:3]=1
Reactant: Cc1cccc(Br)c1
Reactant: O=C1CCC2(CC1)OCCO2
Product: Cc1cccc(C2(O)CCC3(CC2)OCCO3)c1

Procedure:
The title compound was prepared as a white solid from 3-bromotoluene (Aldrich) and 1,4-dioxa-spiro[4.5]decan-8-one using the procedure described in Step A of Example 1.
Reaction SMILES: [CH2:1]([N:6]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH3:18])[CH:15]=2)[C:9](=O)[C:7]1=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].[C:19]1([CH2:25][C:26]([NH:28][NH2:29])=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:18][O:17][C:14]1[CH:15]=[C:16]2[C:11](/[C:9](=[N:29]/[NH:28][C:26](=[O:27])[CH2:25][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)/[C:7](=[O:8])[N:6]2[CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:12][CH:13]=1
Reactant: CCCCCN1C(=O)C(=O)c2ccc(OC)cc21
Reactant: NNC(=O)Cc1ccccc1
Product: CCCCCN1C(=O)/C(=N\NC(=O)Cc2ccccc2)c2ccc(OC)cc21

Procedure:
The title compound was prepared as a yellow solid, using 1-pentyl-6-methoxy-isatin obtained in Example 39(A) and Phenylacetic hydrazide according to the synthetic method E. NMR (CDCl3): δ 0.91 (t, 3H), 1.33 to 1.39 (m, 4H), 1.66-1.69 (m, 2H), 3.62-3.76 (m, 2H), 3.85-3.88 (m, 3H), 4.14 and 4.23 (s for isomers, 1H), 6.38-6.64 (m, 2H), 7.22-7.26 (m1H), 7.32 (m, 2H), 7.38-7.39 (m, 1H), 7.42 (d, 1H), 7.54 and 7.56 (d for isomers, 1H), 9.25 and 12.44 and 12.99 (br s for isomers, 1H).
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[NH2:7][C@H:8]([C:12]([OH:14])=[O:13])[CH:9]([CH3:11])[CH3:10].C(N(CC)CC)C.Cl>C(Cl)Cl>[Br:1][CH:2]([CH3:6])[C:3]([NH:7][C@H:8]([C:12]([OH:14])=[O:13])[CH:9]([CH3:11])[CH3:10])=[O:4]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: CC(Br)C(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(Br)C(=O)N[C@H](C(=O)O)C(C)C

Procedure:
70.2 g (409.7 mmol) of α-bromopropionic acid chloride is added in drops at 0° C. to 40 g (341.4 mmol) of valine and 103.7 g (1024 mmol) of triethylamine in 600 ml of methylene chloride. In this case, the temperature remains between 0° C.-5° C. 1000 ml of 5% aqueous hydrochloric acid is added, and the organic phase is separated. The organic phase is extracted once more with 500 ml of 5% aqueous hydrochloric acid, dried on magnesium sulfate and evaporated to dryness in a vacuum. The residue is recrystallized from acetone/diisopropyl ether.