Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH2:4][CH2:5][C@@H:6]([O:12][C:13]1[CH:20]=[C:19]([CH3:21])[C:18]([F:22])=[CH:17][C:14]=1[C:15]#[N:16])[C:7]1[CH:11]=[CH:10][O:9][N:8]=1)=[N+]=[N-].[O:23]1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:47](=[O:50])([OH:49])[O-].[Na+]>O>[C:10]([OH:23])(=[O:9])/[CH:11]=[CH:7]/[C:47]([OH:49])=[O:50].[NH2:1][CH2:4][CH2:5][C@@H:6]([O:12][C:13]1[CH:20]=[C:19]([CH3:21])[C:18]([F:22])=[CH:17][C:14]=1[C:15]#[N:16])[C:7]1[CH:11]=[CH:10][O:9][N:8]=1
Reactant: C1CCOC1
Reactant: Cc1cc(O[C@H](CCN=[N+]=[N-])c2ccon2)c(C#N)cc1F
Reactant: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: Cc1cc(O[C@H](CCN)c2ccon2)c(C#N)cc1F
Product: O=C(O)/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 36 h

Procedure:
The solution produced in step (a) was treated with tetrahydrofuran (10 ml), water (1 ml) and triphenylphosphine (0.3 g) and stirred at ambient temperature for 36 h. The mixture was poured into saturated sodium bicarbonate (20 ml) and extracted into ethyl acetate. The extract was evaporated to dryness and the residue loaded onto an ion exchange resin (SCX isolute) and washed with acetonitrile and methanol. The product was eluted off the column with 7M ammonia in methanol to give an oil which was converted into the fumarate salt (0.104 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:32]2[CH:33]=[N:34][N:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=23)=[N:4][C:5]([NH:8][C:9]2[C:14]([O:15][CH3:16])=[CH:13][C:12]([N:17]3[CH2:22][CH2:21][N:20]([CH2:23][C:24]([N:26]([CH3:28])[CH3:27])=[O:25])[CH2:19][CH2:18]3)=[C:11]([N+:29]([O-])=O)[CH:10]=2)=[N:6][CH:7]=1.[NH4+].[Cl-]>C(O)C.O.[Fe]>[NH2:29][C:11]1[CH:10]=[C:9]([NH:8][C:5]2[N:4]=[C:3]([C:32]3[CH:33]=[N:34][N:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=34)[C:2]([Cl:1])=[CH:7][N:6]=2)[C:14]([O:15][CH3:16])=[CH:13][C:12]=1[N:17]1[CH2:18][CH2:19][N:20]([CH2:23][C:24]([N:26]([CH3:27])[CH3:28])=[O:25])[CH2:21][CH2:22]1
Reactant: COc1cc(N2CCN(CC(=O)N(C)C)CC2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1cc(N2CCN(CC(=O)N(C)C)CC2)c(N)cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Temperature: 25 °C
Yield: 86.5 %

Procedure:
A mixture of 2-(4-{4-[(5-chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)amino]-5-methoxy-2-nitrophenyl}piperazin-1-yl)-N,N-dimethylacetamide (Intermediate 58, 0.234 g, 0.41 mmol), iron (0.139 g, 2.48 mmol) and NH4Cl (0.015 g, 0.29 mmol) in ethanol (10 mL) and water (3.33 mL) was heated at reflux for 4 h. The mixture was then allowed to cool to r.t., was filtered and the filtrate concentrated in vacuo. Purification by ion exchange chromatography, using an SCX column and eluting with 1M methanolic ammonia, gave a brown gum after concentration of appropriate fractions. Further purification by FCC, eluting with 0-5% CH3OH in CH2Cl2 gave the title compound (0.19 g, 86%) as a yellow foam; 1H NMR: (CDCl3) 2.72 (4H, s), 2.93-3.01 (7H, m), 3.13 (3H, s), 3.27 (2H, s), 3.65-3.83 (2H, m), 3.84 (3H, s), 6.71 (1H, s), 6.96 (1H, td), 7.38 (1H, ddd), 7.55 (1H, s), 7.92 (1H, s), 8.36 (1H, s), 8.57 (1H, dt), 8.61-8.68 (1H, m), 8.94 (1H, s); m/z: ES+ MH+ 536.53.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](Br)[CH:16]=2)[CH:11]=[CH:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:21](B(O)O)=[CH:20]1>>[S:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:21]([C:15]2[CH:16]=[C:17]3[N:9]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH:10]=[CH:11][C:12]3=[N:13][CH:14]=2)=[CH:20]1
Reactant: Brc1cnc2ccn(OCc3ccccc3)c2c1
Reactant: OB(O)c1csc2ccccc12
Product: c1ccc(COn2ccc3ncc(-c4csc5ccccc45)cc32)cc1

Procedure:
The entitled compound was prepared from 1-(benzyloxy)-6-bromo-1H-pyrrolo[3,2-b]pyridine and 1-benzothiophen-3-ylboronic acid according to the procedure described in Example 1.
Reaction SMILES: [CH2:1]([CH:4]1[NH:9][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]([NH2:16])[CH2:6][CH2:5]1)[CH2:2][CH3:3].C([C@@H]1N[C@@H](C2C=CC=CC=2)[C@@H](N)CC1)CC.C([C@H]1N[C@H](C2C=CC=CC=2)[C@H](N)CC1)CC.[CH3:49][O:50][C:51]1[CH:52]=[C:53]2[C:58](=[CH:59][C:60]=1[CH:61]=O)[N:57]([CH3:63])[C:56](=[O:64])[CH2:55][CH2:54]2>>[CH3:49][O:50][C:51]1[CH:52]=[C:53]2[C:58](=[CH:59][C:60]=1[CH2:61][NH:16][CH:7]1[CH2:6][CH2:5][CH:4]([CH2:1][CH2:2][CH3:3])[NH:9][CH:8]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[N:57]([CH3:63])[C:56](=[O:64])[CH2:55][CH2:54]2
Reactant: COc1cc2c(cc1C=O)N(C)C(=O)CC2
Reactant: CCCC1CCC(N)C(c2ccccc2)N1
Agent: CCC[C@@H]1CC[C@@H](N)[C@@H](c2ccccc2)N1
Agent: CCC[C@H]1CC[C@H](N)[C@H](c2ccccc2)N1
Product: CCCC1CCC(NCc2cc3c(cc2OC)CCC(=O)N3C)C(c2ccccc2)N1

Procedure:
By a procedure similar to the previous examples 9 and 9A: prepared through the reaction of 6-propyl-2-phenyl-piperidin-3-ylamine [or (2S,3S,6S)-6-propyl-2-phenyl-piperidin-3-ylamine or (2R,3R,6R)-6-propyl-2-phenyl-piperidin-3-ylamine] with 6-Methoxy-1-methyl-2-oxo-1,2,3,4-tetrahydro-quinoline-7-carbaldehyde.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH3:14])[N:11]([NH2:13])[CH:12]=1.C(O)(=O)C.[CH:19](N)=[NH:20].C1(C)C=CC=CC=1>CC(O)CC>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH3:14])[N:11]([NH:13][CH:19]=[NH:20])[CH:12]=1
Reactant: N=CN
Reactant: Cc1nc(-c2ccccc2F)cn1N
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: CCC(C)O
Product: Cc1nc(-c2ccccc2F)cn1NC=N

Procedure:
Compound C3 (9.95 g, 52.0 mmol) and formamidine acetate (previously azeotroped with toluene, 13.5 g, 130 mmol) were combined in 2-butanol (160 mL) and heated at reflux for 3 hours. The reaction mixture was cooled and concentrated in vacuo. The residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was suspended in a mixture of heptane and ethyl acetate; filtration provided the product as a pale brown powder. Yield: 8.20 g, 37.6 mmol, 72%. LCMS m/z 219.3 [M+H]+. 1H NMR (500 MHz, DMSO-d6), presumed to be a mixture of rotamers and/or tautomers; characteristic peaks: δ 7.99-8.07 (m, 1.6H), 7.51 and 7.52 (2 s [1:1 ratio], 0.6H), 7.30 (dd, J=9.8, 9.8 Hz, 0.4H), 7.16-7.21 (m, 3.4H), 2.26 and 2.18 (2 s [1.6:1 ratio], 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([CH3:26])[NH:24][CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH:27]([C:29]([CH3:31])=[O:30])=[CH2:28]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([CH3:26])[N:24]([CH2:28][CH2:27][C:29](=[O:30])[CH3:31])[CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: Cc1nc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)c[nH]1
Reactant: C=CC(C)=O
Product: CC(=O)CCn1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)nc1C

Procedure:
(S)—N-{1-[3-(3-Chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-2-methyl-1-(3-oxobutyl)-1H-imidazole-4-carboxamide was prepared using the method of the previous Example starting from (S)—N-{1-[3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl]propan-2-yl}-2-methyl-1H-imidazole-4-carboxamide and methyl vinyl ketone. 1H NMR (400 MHz, CDCl3): 1.21 (3H, d), 2.17 (3H, s), 2.44 (3H, s), 2.89 (2H, t), 4.13 (2H, t), 4.29 (1H, distorted dd), 4.38 (1H, distorted dd), 4.55 (1H, m), 6.60 (1H, d), 7.44 (1H, s), 7.48 (1H, d), 7.58 (1H, d), 7.66 (1H, distorted d), 7.85 (1H, distorted dd), 8.00 (1H, d).
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][OH:9])(=[O:5])[C:2]([CH3:4])=[CH2:3].C(N(CC)CC)C.[C:17]([Cl:20])(Cl)=[O:18]>C(Cl)(Cl)Cl>[C:1]([O:6][CH2:7][CH2:8][OH:9])(=[O:5])[C:2]([CH3:4])=[CH2:3].[Cl:20][C:17]([O-:18])=[O:5]
Reactant: O=C(Cl)Cl
Agent: C=C(C)C(=O)OCCO
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C([O-])Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of hydroxyethyl methacrylate (HEMA, 1.3 g, 10 mmol) and triethyl amine (1.1 g, 11 mmol) in 10 mL of chloroform was added dropwise to a stirred solution of phosgene (20% solution in toluene, 15.6 ml, 30 mmol) in 15 mL of chloroform at 0° C. The mixture was stirred for 1 hour at 0° C. and subsequently put under 50 mbar pressure to remove the excess of phosgene. After 30 min, the mixture was further concentrated under reduced pressure using a rotavap. The product was dissolved in 25 mL of THF and filtered to remove solid Et3N.HCl. The THF was evaporated under reduced pressure and the residue was purified by Kugelrohr-distillation (90° C., 0.6 mmHg) affording the HEMA-chloroformate as a colourless oil (1.3 g, 67%).
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)[C:4]([O:6][CH2:7][C:8]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[CH:9]=1)=[O:5].C(N(CC)CC)C.[CH3:33][N:34]=[C:35]=[O:36]>O1CCCC1>[CH3:33][NH:34][C:35](=[O:36])[NH:2][CH:3]([CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)[C:4]([O:6][CH2:7][C:8]1[CH:9]=[C:10]([CH3:15])[CH:11]=[C:12]([CH3:14])[CH:13]=1)=[O:5]
Reactant: Cc1cc(C)cc(COC(=O)C(N)Cc2c[nH]c3ccccc23)c1
Reactant: CN=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNC(=O)NC(Cc1c[nH]c2ccccc12)C(=O)OCc1cc(C)cc(C)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
3,5-Dimethylbenzyl 2-amino-3-(3-indolyl)propionate hydrochloride (1.0 g) was suspended in tetrahydrofuran (10 ml). Triethylamine (0.38 ml) was added and the solution was stirred at room temperature for 15 minutes. Methyl isocyanate (0.19 ml) was added and the solution was stirred for 1 hour. The tetrahydrofuran was removed in vacuo and the residue was taken up in ethyl acetate. The organic phase was washed with dilute hydrochloric acid, water and sodium bicarbonate solution. The organic extract was dried (Na2SO4) and evaporated. The residual solid was recrystallised from ethyl acetate/petroleum ether to yield the title compound, (1.17 g), m.p. 66°-68° C. 1H NMR (360 MHz, CDCl3) δ7.99 (1H, s), 7.52 (1H, d, J=8 Hz), 7.30 (1H, d, J=8 Hz), 7.16 (1H, t, J=8 Hz), 7.08 (1H, t, J=8 Hz), 6.96 (1H, s), 6.88 (2H, s), 6.76 (1H, s), 5.01 (2H, s), 4.83 (1H, m), 3.26 (2H, d, J=5 Hz), 2.65 (3H, s), 2.30 (6H, s). Found: C, 68.64; H, 6.36; N, 10.86. C22H25O3N3. 0.3(H2O) requires C, 68.57; H, 6.66; N, 10.90.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8](=[O:16])[CH2:7]2)[CH2:3][CH2:2]1.Cl[C:18]1[N:23]=[C:22]([CH3:24])[N:21]=[C:20]([O:25][C:26]2[CH:35]=[C:34]([CH3:36])[C:29]3[NH:30][C:31](=[O:33])[O:32][C:28]=3[CH:27]=2)[CH:19]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:36][C:34]1[C:29]2[NH:30][C:31](=[O:33])[O:32][C:28]=2[CH:27]=[C:26]([O:25][C:20]2[CH:19]=[C:18]([N:1]3[CH2:2][CH2:3][C:4]4([C:15]5[C:10](=[N:11][CH:12]=[CH:13][CH:14]=5)[NH:9][C:8](=[O:16])[CH2:7]4)[CH2:5][CH2:6]3)[N:23]=[C:22]([CH3:24])[N:21]=2)[CH:35]=1
Reactant: Cc1nc(Cl)cc(Oc2cc(C)c3[nH]c(=O)oc3c2)n1
Reactant: O=C1CC2(CCNCC2)c2cccnc2N1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1nc(Oc2cc(C)c3[nH]c(=O)oc3c2)cc(N2CCC3(CC2)CC(=O)Nc2ncccc23)n1

Procedure:
26 mg (0.12 mmol) 1H-spiro[[1,8]naphthyridin-4,4′-piperidin]-2(3H)-one, 35 mg (0.12 mmol) 6-(6-chloro-2-methylpyrimidin-4-yloxy)-4-methylbenzo[d]oxazol-2(3H)-one and 42 μL (0.24 mmol) DIPEA in 2.0 mL DMF were stirred for 4 days at 60° C. The reaction mixture was purified by preparative HPLC-MS. The fractions containing product were combined and lyophilised.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[N:6]=[CH:5][N:4]=1.[F:16][C:17]1[CH:23]=[C:22]([CH3:24])[C:21]([O:25][C:26]([O:28][CH3:29])=[O:27])=[CH:20][C:18]=1[NH2:19]>C(O)(C)C>[ClH:2].[F:16][C:17]1[CH:23]=[C:22]([CH3:24])[C:21]([O:25][C:26]([O:28][CH3:29])=[O:27])=[CH:20][C:18]=1[NH:19][C:3]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[N:6]=[CH:5][N:4]=1
Reactant: O=[N+]([O-])c1ccc2c(Cl)ncnc2c1
Reactant: COC(=O)Oc1cc(N)c(F)cc1C
Agent: Cl
Solvent: CC(C)O
Product: COC(=O)Oc1cc(Nc2ncnc3cc([N+](=O)[O-])ccc23)c(F)cc1C
Temperature: 50 °C
Yield: 44 %

Procedure:
A solution of 4-chloro-7-nitroquinazoline hydrochloride (2.46 g, 10 mmol) and 2-fluoro-5-methoxycarbonyloxy-4-methylaniline (2.2 g, 11 mmol), (prepared as described for the starting material in Example 12), in isopropanol (25 ml) was heated at 50° C. for 1 hour. The mixture was allowed to cool, the precipitated solid was collected by filtration recrystallised from methylene chloride/methanol/isopropanol to give 4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-7-nitroquinazoline hydrochloride (1.8 g, 45%) as a yellow solid.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][C:6]1([OH:16])[CH2:15][CH2:14][C:9]2([O:13][CH2:12][CH2:11][O:10]2)[CH2:8][CH2:7]1.I[CH3:18].O>O1CCCC1>[CH3:18][O:16][C:6]1([CH2:5][O:4][CH3:3])[CH2:15][CH2:14][C:9]2([O:10][CH2:11][CH2:12][O:13]2)[CH2:8][CH2:7]1
Reactant: COCC1(O)CCC2(CC1)OCCO2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCC1(OC)CCC2(CC1)OCCO2
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 82.27 g sodium hydride (80%) in 2.1 L tetrahydrofuran was slowly added the solution of 208 g (1.03 mol) 8-(methoxymethyl)-1,4-dioxaspiro[4.5]decan-8-ol (prepared according to intermediate example 16f) in 1 L tetrahydrofuran under cooling. After 0.5 hours at 23° C. 143 mL iodomethane were added and the mixture was stirred at 23° C. overnight. Water was added and the mixture was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate. After filtration and removal of the solvent 227.5 g (max. 100%) of the title compound were obtained that was used without further purification.
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:8]=1)=O.Cl.[F:26][C:27]1[CH:28]=[C:29]([NH:33]N)[CH:30]=[CH:31][CH:32]=1.CCN(CC)CC>C(O)C>[F:26][C:27]1[CH:28]=[C:29]([N:33]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:30]=[CH:31][CH:32]=1
Reactant: CN(C)C=CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Reactant: NNc1cccc(F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1ccnn1-c1cccc(F)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 25.1 %

Procedure:
To a solution of 3-[3-(dimethylamino)prop-2-enoyl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (674 mg, 2.0 mmol) in ethanol (200 mL) were added 3-fluorophenylhydrazine hydrochloride (488 mg, 3.0 mmol) and Et3N (0.56 mL, 4.0 mmol). The mixture was stirred at 100° C. for 3 h and the solvent was removed under reduced pressure. Preparative HPLC chromatography provided 3-[1-(3-fluorophenyl)-1H-pyrazol-5-yl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one as a pale yellow solid (201 mg, 25%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[N:12]([C:19]([CH3:30])([CH3:29])[CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[CH:31]1([C:34]2[CH:35]=[N:36][N:37]([CH2:39][C:40](O)=[O:41])[CH:38]=2)[CH2:33][CH2:32]1>>[C:25]([Si:22]([CH3:23])([CH3:24])[O:21][CH2:20][C:19]([N:12]1[C:13]2[N:14]=[CH:15][N:16]=[CH:17][C:18]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:40](=[O:41])[CH2:39][N:37]3[CH:38]=[C:34]([CH:31]4[CH2:32][CH2:33]4)[CH:35]=[N:36]3)[CH:7]=[N:6][CH:5]=2)=[O:9])=[CH:11]1)([CH3:30])[CH3:29])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(N)c2)c2cncnc21
Reactant: O=C(O)Cn1cc(C2CC2)cn1
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(NC(=O)Cn3cc(C4CC4)cn3)c2)c2cncnc21

Procedure:
The title compound was prepared according to the method described for Example 1 using (5-Amino-pyridin-3-yl)-{7-[2-(tert-butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-methanone (Preparation 38) and (4-Cyclopropyl-1H-pyrazol-1-yl)acetic acid (Preparation 88) to afford the title compound as an an off-white solid in 41% yield, 55 mg.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([NH2:19])[C:5]2[N:6]=[CH:7][N:8]([C:17]=2[N:18]=1)[C@@H:9]1[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([OH:12])[CH2:10]1.[CH3:20][N:21]([CH:23]=O)[CH3:22].C(OC(OCC)N(C)C)C.C(Cl)Cl.CO>CO>[Br:1][C:2]1[N:18]=[C:17]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:9]2[O:16][C@H:13]([CH2:14][OH:15])[C@@H:11]([OH:12])[CH2:10]2)=[C:4]([N:19]=[CH:20][N:21]([CH3:23])[CH3:22])[N:3]=1
Reactant: Nc1nc(Br)nc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1
Reactant: CN(C)C=O
Agent: CCOC(OCC)N(C)C
Solvent: CO
Solvent: ClCCl
Product: CN(C)C=Nc1nc(Br)nc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1

Procedure:
The compound was produced analogously to example 8 except that the following amounts were used: 2-bromo-2′-deoxyadenosine (330 mg, 1.0 mmol), DMF (3 ml), dimethylformamide-diethylacetal (0.85 ml, 5 mmol). Colourless amorphous solid (306 mg, 80%). TLC (CH2Cl2/MeOH, 9:1): Rf 0.33. UV (MeOH): 318 (28600), 238 (13000). 1H-NMR ((D6(DMSO): 2.32, 2.67 (2m, H—C(2′)); 3.14, 3.23 (2s, CH3—N); 3.56 (m, H—C(5′)); 3.86 (m, H—C(4′)); 4.39 (m, H—C(3′)); 4.95 (t, J=5.5 Hz, HO—C(5′)); 5.33 (d, J=4.3 Hz, HO—C(3′)); 6.31 (“t”, J=6.3 Hz, H—C(1′)); 8.44 (s, H—C(8)); 8.85 (s, H—C(N═)). Anal. calc. for C13H17BrN6O3 (385.22): C, 40.53; H, 4.45; N, 21.82; found: C, 40.66; H, 4.50; N, 21.79.
Reaction SMILES: [CH2:1]([O:8][CH2:9][O:10][C@H:11]1[CH2:15][NH:14][C@@H:13]([CH2:16][O:17][C:18]2[C:19]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N:20][CH:21]=[CH:22][CH:23]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]([F:41])([F:40])[C@H:31]1[CH2:36][CH2:35][C@H:34]([C:37](O)=[O:38])[CH2:33][CH2:32]1.N1C2C(=CC=CC=2)C=C1C(O)=O>>[CH2:1]([O:8][CH2:9][O:10][C@H:11]1[CH2:15][N:14]([C:37]([C@H:34]2[CH2:33][CH2:32][C@H:31]([C:30]([F:29])([F:40])[F:41])[CH2:36][CH2:35]2)=[O:38])[C@@H:13]([CH2:16][O:17][C:18]2[C:19]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N:20][CH:21]=[CH:22][CH:23]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@H]1CC[C@H](C(F)(F)F)CC1
Reactant: CCOC(=O)c1ncccc1OC[C@H]1C[C@@H](OCOCc2ccccc2)CN1
Agent: O=C(O)c1cc2ccccc2[nH]1
Product: CCOC(=O)c1ncccc1OC[C@H]1C[C@@H](OCOCc2ccccc2)CN1C(=O)[C@H]1CC[C@H](C(F)(F)F)CC1

Procedure:
The title compound was prepared according to the procedure described in Step 1 of EXAMPLE 3 using ethyl 3-(((2R,4R)-4-(benzyloxymethoxy)pyrrolidin-2-yl)methoxy)picolinate (EXAMPLE 79 Step 4) and trans-4-(trifluoromethyl)cyclohexanecarboxylic acid instead of (R)-3-(pyrrolidin-2-ylmethoxy)picolinamide dihydrochloride and indole-2-carboxylic acid.
Reaction SMILES: C1(C)C=C[C:4]([S:7](O)(=O)=O)=[CH:3][CH:2]=1.[C:12]1([CH2:18][CH:19]=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[C:12]1([CH2:18][CH:19]2[S:7][CH2:4][CH2:3][CH2:2][O:20]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=CCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: c1ccc(CC2OCCCS2)cc1

Procedure:
To a solution of the thiol (14.67 g) from step a) in toluene (200 ml) was added p-toluenesulphonic acid (1 g) and phenylacetaldehyde (18.3 ml). The reaction was refluxed using a Dean and Stark apparatus. After the appropriate amount of water had been collected the reaction mixture was cooled, washed with saturated sodium bicarbonate, saturated brine and dried (K2CO3). The crude product was distilled (bp 100°-110°/0.3 mbars) to give a yellow liquid (19.65 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].CO[CH2:28][CH2:29]OC>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>[CH:28]([C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=[CH:4][CH:3]=1)=[CH2:29]
Reactant: O=C1c2ccccc2C(=O)N1Nc1ccc(Br)cc1
Reactant: COCCOC
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: [K+]
Solvent: O
Product: C=Cc1ccc(NN2C(=O)c3ccccc3C2=O)cc1
Temperature: 150 °C
Yield: 13 %

Procedure:
To a solution of 2-(4-bromophenylamino)isoindoline-1,3-dione (2 g, 6 mmol) in 1,2-dimethoxyethane (20 mL) and water (4 mL) were added vinyl boronic anhydride pyridine complex (4.57 g, 18.98 mmol) and K2CO3 (1.3 g, 9.5 mmol) followed by Pd(PPh3)4 (0.219 g, 0.189 mmol). The resultant reaction mixture was heated at 150° C. in a microwave for 30 min and then was concentrated under reduced pressure. Purification by column chromatography (SiO2, 15% EtOAc in petroleum ether) afforded the title compound as a solid (200 mg, 13%): mp 174-176° C.; 1H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 7.94 (m, 4H), 7.29 (d, J=8.4 Hz, 2H), 6.72 (d, J=8.4 Hz, 2H), 6.61 (m, 1H), 5.61 (d, J=17.6 Hz, 1H), 5.05 (d, J=11.2 Hz, 1H); ESIMS m/z 263.18 ([M−H]−).
Reaction SMILES: Br[C:2]1[CH:15]=[C:14]2[C:5]([NH:6][CH:7]=[C:8]2[CH2:9][CH2:10][N:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[Cu][C:17]#[N:18].CN1CCCC1=O>N>[CH3:12][N:11]([CH2:10][CH2:9][C:8]1[C:14]2[C:5](=[CH:4][CH:3]=[C:2]([C:17]#[N:18])[CH:15]=2)[NH:6][CH:7]=1)[CH3:13]
Reactant: N#C[Cu]
Reactant: CN(C)CCc1c[nH]c2ccc(Br)cc12
Agent: N
Solvent: CN1CCCC1=O
Product: CN(C)CCc1c[nH]c2ccc(C#N)cc12
Temperature: 200 °C

Procedure:
A flask is charged with 5-bromo-dimethyltryptamin (5.34 g, 20 mmol), copper (I)cyanide (2.69 g, 30 mmol), and N-Methylpyrrolidone (20 ml). The mixture is heated at 200° C. for 9 hours under a nitrogen atmosphere and then left stirring over night. The brown mixture is poured on water to give a brown precipitate. This is suspended in ammonia (100 ml 25% solution in water), and the mixture is stirred over night. Extraction with TBME (3*100 ml), and removal of the solvent from the dried (sodium sulfate) organic layer gives the title product as a yellow solid (properties as in Reference Example 3).
Reaction SMILES: [CH3:1][O-:2].[Na+].[NH2:4][CH:5]1[N:10]=[C:9]([Cl:11])[N:8]=[C:7](F)[N:6]1[O:13][CH:14]([F:16])[F:15]>CO>[NH2:4][CH:5]1[N:10]=[C:9]([Cl:11])[N:8]=[C:7]([O:2][CH3:1])[N:6]1[O:13][CH:14]([F:16])[F:15]
Reactant: NC1N=C(Cl)N=C(F)N1OC(F)F
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC1=NC(Cl)=NC(N)N1OC(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
8.4 g (0.047 mol) of 30% strength sodium methylate were added over the course of 15 minutes to a stirred mixture of 10 g (0.047 mol) of 2-amino-4-chlorodifluoromethoxy-6-fluoro-1,3,5-triazine and 100 ml of methanol at 0° C. The mixture was stirred at 0° C. for one hour and then concentrated under reduced pressure, taken up in methylene chloride and extracted with water. Drying and concentration yielded 10.4 g (98.5% of theory) of the title compound of melting point 109°-110° C.