Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[OH:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[CH2:12][CH2:13][C:14]2=[O:19]>CCOC(C)=O>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:9][C:10]2[C:11]3[CH2:12][CH2:13][C:14](=[O:19])[C:15]=3[CH:16]=[CH:17][CH:18]=2)[N:3]=1
Reactant: Clc1cncc(Cl)n1
Reactant: O=C1CCc2c(O)cccc21
Solvent: CCOC(C)=O
Product: O=C1CCc2c(Oc3cncc(Cl)n3)cccc21
Yield: 90 %

Procedure:
Using Method DD with 2,6-dichloropyrazine (200 mg, 1.34 mmol) and 4-hydroxyindanone (219 mg, 1.49 mmol), and crystallisation in AcOEt, the title compound was obtained (314 mg). Yield: 90%. 1H NMR (250 MHz, DMSO-d6) δ 2.70 (t, 2H, H3, J=5.7 Hz), 2.94 (t, 2H, H2, J=5.7 Hz), 7.55-7.64 (m, 3H, Harom), 8.57 (s, 1H, HPz 5), 8.66 (s, 1H, HPz 3). m/z: 261.0 [(M+H)+, calcd for C13H9ClN2O2 260.0].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]\[CH2:10][CH2:11][NH2:12])[CH:5]=[CH:6][CH:7]=1.[H][H]>CO.[Pt](=O)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])[CH:5]=[CH:6][CH:7]=1
Reactant: NCC/C=C\c1cccc(Cl)c1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CO
Product: NCCCCc1cccc(Cl)c1
Temperature: 25 °C
Yield: 97.8 %

Procedure:
To a solution of (Z)-4-(3-chlorophenyl)but-3-en-1-amine (1.80 g, 9.91 mmol) in methanol (30 mL) was added platinum(IV) oxide (0.18 g, 0.79 mmol), and to the resulting stirred mixture at ambient temperature was fitted a balloon of hydrogen. The flask was purged and refilled five times with hydrogen, and the resulting mixture was stirred at ambient temperature under a balloon of hydrogen for 1 hour. The catalyst was removed by filtration through a glass microfibre filter, and the filtrate was concentrated to afford 4-(3-chlorophenyl)butan-1-amine as a light yellow oil (1.78 g, 98% yield).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:9]=[C:8]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)[C:7]([Cl:19])=[CH:6][N:5]=1.[CH3:20]I>C1COCC1.O>[Cl:3][C:4]1[N:9]=[C:8]([C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH3:20])[CH:11]=2)[C:7]([Cl:19])=[CH:6][N:5]=1
Reactant: Clc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(-c2nc(Cl)ncc2Cl)c2ccccc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 69.8 %

Procedure:
NaH (0.795 g, 19.88 mmol) was added to 3-(2,5-dichloropyrimidin-4-yl)-1H-indole (Intermediate 11, 5.0 g, 18.9 mmol) in THF (200 mL) at 0° C. under N2 and the mixture was stirred at 0° C. for 0.25 h. CH3I (1.243 mL, 19.88 mmol) was then added and the mixture was allowed to warm to r.t. and was stirred for 1 h. The mixture was cooled again in an ice bath and further NaH (0.795 g, 19.88 mmol) was added. The suspension was stirred at 0° C. for 10 minutes then CH3I (1.243 mL, 19.88 mmol) was added and the mixture was stirred for 1 h. The mixture was then diluted with water (100 mL) which resulted in the formation of some solid. The solid was collected by filtration and was washed with water and EtOAc and then dried, to give the title compound (3.67 g, 70%) as a beige solid. The organic solution was further washed with water and sat. brine and then dried (MgSO4) and concentrated in vacuo. Trituration of the residue with diethyl ether gave a solid which was collected by filtration and dried in vacuo to give the title compound (477 mg, 9%) as a brown solid: This material was only 71% pure so it was kept separate from the earlier batch; 1H NMR: 3.97 (3H, s), 7.34 (2H, dtd), 7.59-7.65 (1H, m), 8.56 (1H, dd), 8.73 (1H, s), 8.79 (1H, s); m/z: ES+ MH+ 278.06.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[CH:18][CH:17]=2)[C:7]=1[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:5])[CH3:2].[F:32][C:33]([F:45])([F:44])[O:34][C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:38]3[CH:37]=[CH:36][C:35]([O:34][C:33]([F:32])([F:44])[F:45])=[CH:40][CH:39]=3)[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:24])[CH3:25])=[CH:18][CH:17]=2)[C:7]=1[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:5])[CH3:2]
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccc(OC(C)C)cc1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(OC(F)(F)F)cc3)ccc2n1-c1ccc(OC(C)C)cc1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 2-ethoxycarbonylmethyl-5-hydroxy-1-(4-isopropoxyphenyl)-indole-3-carboxylic acid ethyl ester (212 mg, 0.50 mmol, see step (b) Example 12) and 4-trifluoromethoxyphenylboronic acid (154 mg, 0.75 mmol). Yield 156 mg (53%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrCC(OC)=O.[Br-].[CH3:27][O:28][C:29]([CH2:31][P+:32]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30].[PH4+].[OH-].[Na+]>C1C=CC=CC=1.O>[CH3:27][O:28][C:29]([CH:31]=[P:32]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)=[O:30]
Reactant: COC(=O)C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: COC(=O)CBr
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 70 °C
Yield: 80 %

Procedure:
Triphenyl phosphine (13 g.) was dissolved in dry benzene (60 ml.) and methyl bromoacetate (8.3 g.) was added dropwise. The solution was heated at 70° C., for 2 days, and then cooled and filtered. The residue was washed with benzene and dried to give about 16 g. of (methoxycarbonyl methyl)triphenylphosphonium bromide. The phosphonium salt (10 g.) was dissolved in water (250 ml.) and 5% aqueous sodium hydroxide was added dropwise with stirring until the solution became alkaline to litmus. The resulting precipitate was filtered off, washed with water and dried. Crystallisation from ethyl acetate/petroleum spirit gave (methoxycarbonyl methylene) triphenyl phosphorane as a colourless solid in about 80% yield.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=1[N:19]1[N:23]=[C:22]([CH3:24])[CH:21]=[N:20]1)=[O:11].Br[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1>>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[N:19]2[N:23]=[C:22]([CH3:24])[CH:21]=[N:20]2)=[O:11])=[N:27][CH:28]=1
Reactant: Clc1ccc(Br)nc1
Reactant: Cc1ccc(-n2ncc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Product: Cc1ccc(-n2ncc(C)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(Cl)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A44 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(4-methyl-2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-bromo-5-chloropyridine. ESI-MS (m/z): 439 [M+1]+.
Reaction SMILES: [C:1]([CH:4]([CH2:10][C:11](=O)[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[Cl:19])[C:5]([O:7][CH2:8][CH3:9])=[O:6])(=O)[CH3:2].[Cl:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>C(O)C>[Cl:21][C:22]1[CH:28]=[CH:27][C:25]([N:26]2[C:11]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])=[CH:10][C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])=[C:1]2[CH3:2])=[CH:24][CH:23]=1
Reactant: CCOC(=O)C(CC(=O)c1ccc(Cl)cc1Cl)C(C)=O
Reactant: Nc1ccc(Cl)cc1
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccc(Cl)cc2Cl)n(-c2ccc(Cl)cc2)c1C
Yield: 97 %

Procedure:
10 g of the compound obtained in step A) are dissolved in 45 ml of anhydrous ethanol in the presence of 4.1 g of 4-chloroaniline. The mixture is heated at the reflux point of the ethanol for 3 days. After evaporating off the solvent, the expected product is crystallized from an isopropanol/ethanol mixture. 12.5 g of white crystals are obtained.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=[CH:10][C:4]=2[C:3]=1[C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1.[CH2:29]([OH:33])[CH2:30][C:31]#[CH:32]>>[CH3:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([C:32]#[C:31][CH2:30][CH2:29][OH:33])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:19]1[CH:20]=[CH:21][C:22]([C:25]([F:27])([F:28])[F:26])=[CH:23][CH:24]=1
Reactant: C#CCCO
Reactant: Cc1sc2cc(OS(=O)(=O)C(F)(F)F)ccc2c1-c1ccc(C(F)(F)F)cc1
Product: Cc1sc2cc(C#CCCO)ccc2c1-c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to example 13.1, the Trifluoro-methanesulfonic acid 2-methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl ester was reacted with 3-butyn-1-ol to yield the 4-[2-Methyl-3-(4-trifluoromethyl-phenyl)-benzo[b]thiophen-6-yl]-but-3-yn-1-ol as brown oil, MS: 360 (M+).
Reaction SMILES: [CH2:1]([N:4]1[C:8]2[CH:9]=[C:10]([NH2:13])[CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1)[CH2:2][CH3:3].[Br:14]Br.N>CO.C(Cl)Cl>[CH2:1]([N:4]1[C:8]2[C:9]([Br:14])=[C:10]([NH2:13])[CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1)[CH2:2][CH3:3]
Reactant: BrBr
Reactant: CCCn1cnc2ccc(N)cc21
Agent: N
Solvent: ClCCl
Solvent: CO
Product: CCCn1cnc2ccc(N)c(Br)c21
Yield: 37 %

Procedure:
To a solution of 3-propyl-5-aminobenzimidazole (0.71 g, 4.3 mmol) in 10 ml of ACOH was added solution of Br2 in ACOH until it produces a precipitation. The reaction mixture was concentrated in vacuo to provide a brown solid which was subjected to column chromatography (5% NH3 sat'd MeOH/CH2Cl2) to provide 0.40 g (1.6 mmol, 37%) of the product.
Reaction SMILES: [H-].[K+].[NH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2.[C:14]1(=O)[O:18][CH2:17][CH2:16][CH2:15]1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>O1CCCC1.CN(C)P(=O)(N(C)C)N(C)C>[N:12]1[C:13]2[C:8](=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]2[CH2:14][CH2:15][CH2:16][C:17]2=[O:18])[CH:9]=[CH:10][CH:11]=1
Reactant: Nc1cccc2cccnc12
Reactant: O=C1CCCO1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C1CCCN1c1cccc2cccnc12
Temperature: 25 °C
Yield: 5.4 %

Procedure:
Potassium hydride in oil was washed with dry pentane (in a dry nitrogen atmosphere) leaving 2.5 g (0.062 mole) of potassium hydride which was covered with dry tetrahydrofuran (25 ml). To the slurry of potassium hydride (at room temperature) was added dropwise a solution of 8-aminoquinoline (5 g, 0.035 mole) in dry tetrahydrofuran (25 ml), with stirring, followed by addition of dry hexamethylphosphoric triamide (25 ml). After stirring for 1 hour at room temperature, the reaction was cooled in an ice bath and a solution of γ-butyrolactone (2.8 ml, 0.036 mole) in dry tetrahydrofuran (10 ml) was added and the reaction stirred for 1 hour. The reaction was warmed to room temperature and a solution of p-toluenesulphonyl chloride (8 g, 0.042 mole) in dry tetrahydrofuran (10 ml) was added. The reaction was poured into ice water, filtered and the pH was adjusrted to pH 3.5. The product was extracted with methylene chloride and washed with cupric chloride to remove traces of 8-aminoquinoline. The product organics were dried, concentrated under reduced pressure and the residue was crystallized from ether/pentane affording 1-(8-quinolyl)-2-pyrrolidinone, yield 5.4%, which was identical by tlc and NMR in comparison with the product of Example 1.
Reaction SMILES: [CH:1]12[NH:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([NH:13][C:14]3[N:19]=[C:18]([NH:20][C@@H:21]4[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]4[NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:17]([Cl:32])=[CH:16][N:15]=3)=[CH:3][C:2]2=1.[CH:33]1([CH:36]=O)[CH2:35][CH2:34]1>>[CH:33]([N:12]1[CH:9]2[CH2:10][CH2:11][CH:1]1[C:2]1[CH:3]=[C:4]([NH:13][C:14]3[N:19]=[C:18]([NH:20][C@@H:21]4[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]4[NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[C:17]([Cl:32])=[CH:16][N:15]=3)[CH:5]=[CH:6][C:7]=1[CH2:8]2)([CH2:34][CH3:35])[CH3:36]
Reactant: O=CC1CC1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Nc2ccc3c(c2)C2CCC(C3)N2)ncc1Cl
Product: CCC(C)N1C2CCC1c1cc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)ccc1C2
Yield: 68.1 %

Procedure:
Following a procedure analogous to 80a, N-{(1R,2R)-2-[2-(12-aza-tricyclo[7.2.1.0*2,7*]dodeca-2(7),3,5-trien-4-ylamino)-5-chloro-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide (90 mg, 0.19 mmol) and cyclopropanecarbaldehyde (0.056 mL, 0.75 mmol), were converted to the title compound as an off-white solid (69 mg, 69%): 1:1 mixture of diastereomers. 1HNMR (400 MHz, DMSO-d6) δ 9.1 (s, 1H), 7.9 (s, 1H), 7.6 (s, 0.5H), 7.5 (s, 0.5H), 7.3 (m, 1H), 7.2 (d, 0.5H, J=8.6 Hz), 7.1 (d, 0.5H, J=8.3 Hz), 6.9 (d, 1H, J=8.3 Hz), 6.7 (d, 1H, J=8.3 Hz), 4.0 (m, 1H), 3.9-3.8 (m, 1H), 3.5 (m, 1H), 3.4-3.3 (m, 1H), 3.0-2.9 (m, 4H), 2.5-2.4 (m, 1H), 2.3 (d, 1H, J=16.9 Hz), 2.2-2.0 (m, 5H), 1.9 (m, 3H), 1.6-1.2 (m, 6H), 0.9-0.8 (m, 2H), 0.4 (m, 2H); MS (m/e) 531 (M+1); mp 120-124° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]2[C:8](N3CCOCC3)([C:9](=[O:21])[N:10]([C:14]3[CH:19]=[CH:18][C:17]([I:20])=[CH:16][CH:15]=3)[CH2:11][CH2:12]2)[N:7]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[N:6]=1)=[O:4].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:13]2[CH2:12][CH2:11][N:10]([C:14]3[CH:15]=[CH:16][C:17]([I:20])=[CH:18][CH:19]=3)[C:9](=[O:21])[C:8]=2[N:7]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)C1=NN(c2ccc(Cl)cc2)C2(N3CCOCC3)C(=O)N(c3ccc(I)cc3)CCC12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1nn(-c2ccc(Cl)cc2)c2c1CCN(c1ccc(I)cc1)C2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-(4-chloro-phenyl)-6-(4-iodo-phenyl)-7a-morpholin-4-yl-7-oxo-3a,4,5,6,7,7a-hexahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylic acid methyl ester (52, 595 mg, 1.0 mmol) in methylene chloride (CH2Cl2, 4 mL) was treated with trifluoroacetic acid (TFA, 1.0 mL) at 25° C., and the resulting reaction mixture was stirred at 25° C. for an additional 30 min. When HPLC and TLC showed the reaction was complete, the solvents were removed in vacuo. The residue was directly purified by flash column chromatography (SiO2, 5–20% EtOAc/hexane gradient elution) to afford the desired elimination product (53, 467 mg, 508 mg theoretical, 92%) as a pale-yellow oil, which solidified upon standing at room temperature in vacuo. For 53, CIMS m/z 508/510 (M++H, C20H15ClIN3O3).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[C:15]1([CH:21]2[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C>CCO>[C:15]1([CH:21]2[CH2:26][CH2:25][CH2:24][N:23]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=4)[N:7]=3)[CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: c1ccc(C2CCCNC2)cc1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1nnc2ccc(N3CCCC(c4ccccc4)C3)nn12
Temperature: 70 °C
Yield: 60.2 %

Procedure:
A solution of 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (49 mg, 0.22 mmol) in EtOH (1.0 mL) was added to a mixture of 3-phenylpiperidine (53 mg, 0.33 mmol) and DIPEA (57 μL, 0.33 mmol) in EtOH (1.0 mL). The reaction mixture was heated to 70° C. overnight and the crude product was purified by preparative LCMS (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 5% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to give 6-(3-phenylpiperidin-1-yl)-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (46 mg, 61%).
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:8][N:7]([CH2:9][CH2:10][N:11]2[C:16](=[O:17])[CH:15]=[N:14][C:13]3[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[N:21][C:12]2=3)[CH2:6][CH:5]([CH2:24][N:25]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:4]1.NN>CCO>[NH2:25][CH2:24][C@H:5]1[CH2:4][C@@H:3]([O:2][CH3:1])[CH2:8][N:7]([CH2:9][CH2:10][N:11]2[C:16](=[O:17])[CH:15]=[N:14][C:13]3[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[N:21][C:12]2=3)[CH2:6]1
Reactant: COc1ccc2ncc(=O)n(CCN3CC(CN4C(=O)c5ccccc5C4=O)CC(OC)C3)c2n1
Agent: NN
Solvent: CCO
Product: COc1ccc2ncc(=O)n(CCN3C[C@@H](CN)C[C@@H](OC)C3)c2n1
Temperature: 40 °C
Reaction time: 24 h
Yield: 77.6 %

Procedure:
To 2-[((3RS,5SR)-5-(methyloxy) 1-{2-[6-(methyloxy)-3-oxopyrido[2,3-b]pyrazin-4(3H)-yl]ethyl}-3-piperidinyl)methyl]-1H-isoindole-1,3(2H)-dione (110 mg, 0.23 mmol) in EtOH (5 mL) was added anhydrous hydrazine (0.5 mL, 15.0 mmol). The reaction was warmed to 40° C. and allowed to stir under nitrogen for 24 h. The reaction was filtered through a pad of Celite® and the filtrate was partitioned between EtOAc (50 mL) and water (10 mL). The aqueous layer was further extracted with EtOAc (2×25 mL), and the combined organic layers were dried over Na2SO4. The solvents were removed to provide the desired compound (62 mg; 77%) as a tan solid which was used without further purification.
Reaction SMILES: [CH3:1][CH:2]1[CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH:8]=[CH:7][CH2:6][CH:5]([CH:14]([CH:16]=[CH:17][CH3:18])[CH3:15])[N:4]=[CH:3]1.S(O)(O)(=O)=O.[NH2:24][OH:25].Cl>O>[CH3:1][CH:2]([CH2:13][CH:12]=[CH:11][CH2:10][CH2:9][CH:8]=[CH:7][CH2:6][CH:5]([CH:14]([CH:16]=[CH:17][CH3:18])[CH3:15])[NH2:4])[CH:3]=[N:24][OH:25]
Reactant: CC=CC(C)C1CC=CCCC=CCC(C)C=N1
Reactant: NO
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: O
Product: CC=CC(C)C(N)CC=CCCC=CCC(C)C=NO
Yield: 195.2 %

Procedure:
The procedure described in Example 1(b) is repeated, except that 122.7 g (0.5 mol) of 3-methyl-12-(3-penten-2-yl)-1-aza-1,5,9-cyclododecatriene, 41.1 g (0.25 mol) of hydroxylamine sulfate, 50 ml of concentrated hydrochloric acid and 250 ml of water are used. Working up yields 135.9 g (0.488 mol) of 2-methyl-11-(3-penten-2-yl)-11-amino-undeca-4,8-dienal oxime; yield 97.6% of theory. nD20 =1.5091.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([C:13]([F:16])([F:15])[F:14])=[CH:6][C:5]=1[NH2:17].[C:19](OC(=O)C)(=[O:21])[CH3:20]>>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7]([C:13]([F:16])([F:15])[F:14])=[CH:6][C:5]=1[NH:17][C:19](=[O:21])[CH3:20]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(C(F)(F)F)cc1N
Reactant: CC(=O)OC(C)=O
Product: COC(=O)c1cc([N+](=O)[O-])c(C(F)(F)F)cc1NC(C)=O
Temperature: 25 °C
Yield: 77 %

Procedure:
A solution of 2.0 g (7.57 mmol) of 2-amino-5-nitro-4-trifluoromethyl-benzoic acid methyl ester in 20 ml of acetic anhydride is heated to reflux for 4 hours. The mixture is allowed to cool to room temperature and concentrated in vacuo. The residue is taken up in ethyl acetate and washed with water, aqueous saturated NaHCO3-solution and brine. The organic phase is dried over Na2SO4, filtered and concentrated in vacuo. Purification by flash chromatography (SiO2, hexane/ethyl acetate 3:1) provided 1.79 g (77%) of 2-acetylamino-5-nitro-4-trifluoromethyl-benzoic acid methyl ester as yellow crystals, m.p. 75-80° C.
Reaction SMILES: [C:1]([C:3]1([C:6]2[CH:14]=[CH:13][C:9](C(O)=O)=[CH:8][CH:7]=2)[CH2:5][CH2:4]1)#[N:2].C1(P([N:29]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>C(O)(C)(C)C>[NH2:29][C:9]1[CH:13]=[CH:14][C:6]([C:3]2([C:1]#[N:2])[CH2:5][CH2:4]2)=[CH:7][CH:8]=1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: N#CC1(c2ccc(C(=O)O)cc2)CC1
Solvent: CC(C)(C)O
Solvent: CCN(CC)CC
Product: N#CC1(c2ccc(N)cc2)CC1
Temperature: 95 °C
Reaction time: 0.5 h

Procedure:
750 mg (4 mmol) of 4-(1-cyano-cyclopropyl)-benzoic acid (Example 110b) in 20 ml of tert-butanol are stirred in presence of 0.86 ml (4 mmol) diphenylphosphoryl azide (DPPA, Fluka, Buchs, Switzerland) and 0.59 ml (4 mmol) triethylamine at 95° C. for 3 h. Are added 0.43 ml (2 mmol) DPPA and 0.29 ml (2 mmol) triethylamine and the reaction mixture is stirred at 95° C. for 30 min. The reaction mixture is evaporated to dryness and then is taken in EtOAc and washed with H2O, dried over Na2SO4, filtered and evaporated. The solid is separated by flash chromatography (CH2Cl2-MeOH 99:1). The purified compound is treated in 5 ml 4 M HCl in dioxane at rt for 2 h. The crude deprotected product is purified by flash chromatography (CH2Cl2-MeOH 98:2). The product is triturated in MeOH to give the title compound. Analytical HPLC: tret=3.68 minutes (Grad 2).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[C:9]2[CH:10]=[CH:11][C:12]3[S:17][C:16]4[N:18]=[CH:19][CH:20]=[N:21][C:15]=4[N:14]([CH2:22][O:23][CH3:24])[C:13]=3[CH:25]=2)[CH:5]=[CH:4][CH:3]=1.[C:34]([O:38][CH2:39][CH3:40])(=[O:37])[CH:35]=[CH2:36].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O>[CH3:24][O:23][CH2:22][N:14]1[C:13]2[CH:25]=[C:9]([CH:8]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[C:6]3[N:7]=[C:2](/[CH:36]=[CH:35]/[C:34]([O:38][CH2:39][CH3:40])=[O:37])[CH:3]=[CH:4][CH:5]=3)[CH:10]=[CH:11][C:12]=2[S:17][C:16]2[N:18]=[CH:19][CH:20]=[N:21][C:15]1=2
Reactant: COCN1c2cc(C(O[Si](C)(C)C(C)(C)C)c3cccc(Br)n3)ccc2Sc2nccnc21
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)/C=C/c1cccc(C(O[Si](C)(C)C(C)(C)C)c2ccc3c(c2)N(COC)c2nccnc2S3)n1
Temperature: 90 °C

Procedure:
To a solution of 0.72 g of 8-[(6-bromopyridin-2-yl)-(tert-butyldimethylsiloxy)methyl]-10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazine in N,N-dimethylformamide (8 ml) were added 0.17 ml of ethyl acrylate, 0.22 ml of triethylamine, 12 mg of palladium (II) acetate and 33 mg of triphenylphosphine and the resulting mixture was heated to 90° C. for 30 hours. Then the reaction mixture was brought back to room temperature and distributed into water and ethyl acetate. The organic layer was extracted, washed successively with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (diluted with dichloromethane/ethyl acetate) to thereby give 540 mg of the title compound as a yellow oily substance.
Reaction SMILES: [H-].[Na+].CI.[Br:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[NH:13][CH:12]=[CH:11]2.[C:15]([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O>[CH3:15][N:13]1[C:14]2[C:10](=[CH:9][CH:8]=[CH:7][C:6]=2[Br:5])[CH:11]=[CH:12]1
Reactant: Brc1cccc2cc[nH]c12
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: C1CCOC1
Product: Cn1ccc2cccc(Br)c21
Reaction time: 1 h

Procedure:
A 60% dispersion of sodium hydride in mineral oil (1.40 g, 97 mmol) was washed with hexanes (3×10 mL, 1×5 mL), suspended in THF (50 mL) and CH3I added (1.64 mL, 26.3 mmol) followed by a solution of 7-bromoindole (4.06 g, 20.7 mmol) in THF (15 mL), with vigorous gas evolution. After 1 h at rt, the mixture was treated with additional CH3I (0.28 mL, 4.5 mmol) and stirred overnight. Saturated aq NaHCO3 was added and the mixture poured into EtOAc, which was separated, washed with saturated aq NaHCO3, dried (MgSO4) and concentrated to afford 1-methyl-7-bromoindole as an off-white semisolid which was used without further purification.