Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[Cl-].[CH2:11]([C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[O:19][CH2:18][CH2:17][CH:16]2[NH3+:23])[CH3:12].C(N(CC)CC)C>CN(C)C(=O)C>[CH2:11]([C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[O:19][CH2:18][CH2:17][CH:16]2[NH:23][C:2]1[CH:3]=[N:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1)[CH3:12]
Reactant: N#Cc1ncc(Br)cn1
Reactant: CCc1ccc2c(c1)C([NH3+])CCO2
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CCc1ccc2c(c1)C(Nc1cnc(C#N)nc1)CCO2
Yield: 9.8 %

Procedure:
0.20 g (1.09 mmol) of 5-bromo-2-cyanopyrimidine (ABCR 245244), 0.325 g (1.52 mmol) of 6-ethyl-3,4-dihydro-2H-chromen-4-aminium chloride and 0.35 g (3.3 mmol) of triethylamine in 1.5 ml of N,N-dimethylacetamide are heated in a closed cuvette in the microwave at 200° C. for 120 minutes (Biotage Initiator, http://www.biotage.com/DynPage.aspx?id=22001). The crude mixture obtained in this manner is applied to silica gel and purified by column chromatography using the mobile phase heptane/ethyl acetate. Concentration gives 0.03 g of 5-[(6-ethyl-3,4-dihydro-2H-chromen-4-yl)amino]pyrimidine-2-carbonitrile (wax-like) (yield 8% at a purity of 80%).
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1(OC(N(C)C)=[N+](C)C)[C:12]2N=CC=CC=2N=N1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C@:32]([N:38]2[C:46]3[C:41](=[C:42]([NH:47][S:48]([CH3:51])(=[O:50])=[O:49])[CH:43]=[CH:44][CH:45]=3)[CH:40]=[CH:39]2)([CH2:36][CH3:37])[C:33]([OH:35])=O)=[CH:28][CH:27]=1.CN1CCOCC1.CN>CN(C=O)C.CO>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([C@:32]([N:38]2[C:46]3[C:41](=[C:42]([NH:47][S:48]([CH3:51])(=[O:50])=[O:49])[CH:43]=[CH:44][CH:45]=3)[CH:40]=[CH:39]2)([CH2:36][CH3:37])[C:33]([NH:8][CH3:12])=[O:35])=[CH:30][CH:31]=1
Reactant: CC[C@](C(=O)O)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC[C@](C(=O)NC)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.34 g, 3.56 mmol) was added to a stirred solution of 4a (967 mg, 2.38 mmol) and 4-methylmorpholine (523 μL, 4.75 mmol) in DMF (12 mL). After 5 min, methylamine (3.56 mL of a 2.0 M solution in methanol, 7.13 mmol) was added, and the resulting mixture was allowed to stir at rt. After 3 h, the reaction mixture was partitioned between ethyl acetate and water. The layers were separated, and the organics were washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by flash chromatography on silica gel (gradient elution; 0%-85% EtOAc/hexanes as eluent) to afford the title compound 39. m/z (ES) 420 (MH)+; IP=B rating.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([C@@H:15]3[CH2:19][CH2:18][CH2:17][N:16]3[C:20](=[O:28])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[NH:13][CH:14]=2)=[CH:6][CH:5]=1)([O-])=O.CO.O1CCCC1.[Cl-].[NH4+]>O.[Fe]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([C@@H:15]3[CH2:19][CH2:18][CH2:17][N:16]3[C:20](=[O:28])[CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[NH:13][CH:14]=2)=[CH:6][CH:5]=1
Reactant: O=C(Cc1ccccc1)N1CCC[C@H]1c1nc(-c2ccc([N+](=O)[O-])cc2)c[nH]1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccc(-c2c[nH]c([C@@H]3CCCN3C(=O)Cc3ccccc3)n2)cc1
Temperature: 75 °C
Reaction time: 1 h

Procedure:
To a solution of the Product from Example 1I (0.137 g, 0.36 mmol) in a mixture of water (0.75 mL), methanol (1.5 mL) and tetrahydrofuran (1.5 mL) was added iron (0.102 g, 1.82 mmol) and ammonium chloride (0.030 g, 0.54 mmol) and the resulting mixture was heated with vigorous stirred at 75° C. for one hour. The warm reaction mixture was filtered through celite and rinsed well with methanol and tetrahydrofuran. The filtrate was concentrated and partitioned between 10% NaHCO3 solution and ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and concentrated to give a waxy solid that was used without purification (97%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:23]=[CH:22][C:17]([C:18](OC)=[O:19])=[CH:16][CH:15]=2)[CH:10]([OH:24])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Li+].O>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[CH:16][C:17]([CH2:18][OH:19])=[CH:22][CH:23]=2)[CH:10]([OH:24])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[NH3:8]
Reactant: COC(=O)c1ccc(C2CCN(Cc3ccccc3)CC2O)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: N
Product: OCc1ccc(C2CCN(Cc3ccccc3)CC2O)cc1
Temperature: 60 °C

Procedure:
A solution of 5.0 g (15.3 mmol) of methyl (3RS,4RS)-4-(1-benzyl-3-hydroxy-piperidin-4-yl)-benzoate in 50 ml of tetrahydrofuran was treated at room temperature with 720 mg (32.9 mmol) of lithium borohydride. Subsequently, the reaction mixture was heated to 60° C. for 15 hours. For the working-up, the reaction mixture was treated with 20 ml of water while cooling with ice and thereafter extracted twice with 50 ml of ethyl acetate each time. The organic phases were combined, dried over sodium sulphate and evaporated under reduced pressure. The crude (3RS,4RS)-1-benzyl-4-(4-hydroxymethyl-phenyl)-piperidine-3-ol obtained (Rf: 0.23, methylene chloride:methanol:ammonia=95:5:0.1) was used in the following step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([F:11])[C:3]=1[CH2:4][OH:5].[CH3:12][C:13]1[O:17][N:16]=[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14]=1[CH2:24]O.Cl[C:27]([N:29]1[C@H:34]([CH3:35])[CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][C@@H:30]1[CH3:43])=[O:28]>>[F:1][C:2]1[CH:9]=[C:8]([O:10][CH2:24][C:14]2[C:15]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[N:16][O:17][C:13]=2[CH3:12])[CH:7]=[C:6]([F:11])[C:3]=1[CH2:4][O:5][C:27]([N:29]1[C@H:34]([CH3:35])[CH2:33][NH:32][CH2:31][C@@H:30]1[CH3:43])=[O:28]
Reactant: Cc1onc(-c2ccccc2)c1CO
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1C(=O)Cl
Reactant: OCc1c(F)cc(O)cc1F
Product: Cc1onc(-c2ccccc2)c1COc1cc(F)c(COC(=O)N2[C@H](C)CNC[C@@H]2C)c(F)c1

Procedure:
cis-2,6-Dimethyl-piperazine-1-carboxylic acid 2,6-difluoro-4-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-benzyl ester was prepared from 2,6-difluoro-4-hydroxybenzyl alcohol, (5-methyl-3-phenyl-isoxazol-4-yl)-methanol and 1-chlorocarbonyl-cis-2,6-dimethyl-4-tert-butoxycarbonylpiperazine according to the procedures described for Example 54 and 121 to give the product as a yellow oil: δH (400 MHz; d6-DMSO) 1.15 (6H, d, J 7.0 Hz), 2.53 (3H, s), 2.62 (2H, dd, J 12.0, 4.5 Hz), 2.68 (2H, d, J 12.0 Hz), 3.80–3.88 (2H, m), 5.01–5.08 (4H, m), 6.84–6.91 (2H, m), 7.48–7.53 (3H, m) and 7.64–7.68 (2H, m).
Reaction SMILES: [CH2:1]([P:8]1(=[O:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:15]([O-])([OH:17])=[O:16].S(=O)(=O)(O)O.N>>[N+:15]([C:5]1[CH:6]=[CH:7][C:2]([CH2:1][P:8]2(=[O:14])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:3][CH:4]=1)([O-:17])=[O:16]
Reactant: O=P1(Cc2ccccc2)CCCCC1
Reactant: O=[N+]([O-])O
Agent: N
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc(CP2(=O)CCCCC2)cc1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
To 1-benzylphosphorinane-l-oxide (5.39 g) were added nitric acid (1.94 ml) and sulfuric acid (15 ml) at 0° C., and the mixture was stirred at 50-60° C. for 2 hours. The reaction mixture was added to crushed ice-water, neutralized with ammonia solution and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride solution, dried with magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified with column chromatography (ethanol/ethyl acetate=1:3→1:2) to give 1-(4-nitrobenzyl)phosphorinane-1-oxide (2.47 g)as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]([CH2:9]C(O)=O)[CH:5]=[C:6]([F:8])[CH:7]=1.CO>C(#N)C>[NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: Nc1cc(F)cc(CC(=O)O)c1[N+](=O)[O-]
Solvent: CO
Solvent: CC#N
Product: Cc1cc(F)cc(N)c1[N+](=O)[O-]
Yield: 103.2 %

Procedure:
To the crude 3-Amino-5-fluoro-2-nitro phenyl acetic acid (3.6 g, 16.8 mmol) was added Cu2O (10.1 g, 70.6 mmol) in 120 mL of acetonitrile along with 50 uL of methanol and the suspension was refluxed for 12 hours. The reaction mixture was filtered through Celite and the Celite pad washed with water and ethyl acetate. The filtrate was extracted with ethyl acetate, washed with water and brine, dried over Na2SO4 and concentrated to give 2.95 g of material which by 1H NMR was 80% pure. ESIMS [M+Na]—193; 1H NMR (500 MHz, DMSO) δ 6.67 (s, 2H), 6.56 (dd, J=11, 2.8 Hz, 1H), 6.39 (dd, J=11, 2.8 Hz, 1H), 2.50 (s, 3H).
Reaction SMILES: [BH4-].[Na+].Cl.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:12](=[O:19])[CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)[CH:9]=[CH:10][CH:11]=1>CO.O>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:12]([OH:19])[CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][NH:15]2)[CH:9]=[CH:10][CH:11]=1
Reactant: COc1cccc(C(=O)CC2CCCN2)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cccc(C(O)CC2CCCN2)c1
Yield: 80 %

Procedure:
4.8 g of sodium borohydride are added portionwise with stirring to a solution of 6.5 g of 1-(3-methoxyphenyl)-2-(2-pyrrolidinyl)-ethanone hydrochloride in 25 ml of methanol and 5 ml of water. After 1 hour the bulk of the methanol is distilled off under a vacuum. The residue is taken up with 20 ml of water and 10 ml of 6 N sodium hydroxide solution. The mixture is extracted 5 times with, in each case, 20 ml of diethylether. The organic phases are collected, dried over sodium sulphate and concentrated to an oil which is distilled. 4.5 g of the title compound are obtained as mixture of diastereoisomers of b.p. 136° at 0.005 mm Hg.
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[CH2:15][CH2:14][C:13]2[S:12][C:11]3[N:10]=[CH:9][N:8]=[C:7]([O:16][CH:17]4[CH2:22][CH2:21][C:20]([N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:23])[CH2:19][CH2:18]4)[C:6]=3[C:5]1=2)#[N:2].[OH:33][Li].O.OO>CO>[C:1]([CH2:3][C@H:4]1[CH2:15][CH2:14][C:13]2[S:12][C:11]3[N:10]=[CH:9][N:8]=[C:7]([O:16][CH:17]4[CH2:18][CH2:19][C:20]([N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:28])([CH3:30])[CH3:29])([CH3:23])[CH2:21][CH2:22]4)[C:6]=3[C:5]1=2)(=[O:33])[NH2:2]
Reactant: [Li]O
Reactant: CN(C(=O)OC(C)(C)C)C1(C)CCC(Oc2ncnc3sc4c(c23)[C@@H](CC#N)CC4)CC1
Agent: OO
Solvent: O
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)C1(C)CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(N)=O)CC4)CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 89.5 %

Procedure:
To a solution of tert-butyl N-(4-[[(3R)-3-(cyanomethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]-1-methylcyclohexyl)-N-methylcarbamate (100 mg, 0.2 mmol, 1.00 equiv) in 10 mL of methanol was added LiOH.H2O (30 mg, 0.7 mmol, 3.26 equiv) and H2O2 (30%, 0.8 mL) and stirred for 4 h at 0° C. The reaction was then quenched with saturated aqueous NaHSO3, extracted with 3×50 mL of ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified by column chromatography on silica gel with EtOAc/PE (1:2) to give the desired tert-butyl N-(4-[[(3R)-3-(carbamoylmethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]-1-methylcyclohexyl)-N-methylcarbamate (85 mg) as a light yellow oil.
Reaction SMILES: [CH2:1]([C:5]1([CH2:8][CH3:9])[CH2:7][NH:6]1)[CH2:2][CH2:3][CH3:4].[SH:10][C:11]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[CH:21][C:12]=1[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>N1C(C)=CC=CC=1C>[CH2:1]([C:5]1([CH2:8][CH3:9])[CH:7]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]2[CH:21]=[CH:22][C:23]([O:25][CH3:26])=[CH:24][C:11]=2[S:10][NH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC1(CC)CN1
Reactant: COc1ccc(C(=O)c2ccccc2)c(S)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1cccc(C)n1
Product: CCCCC1(CC)C=C(c2ccccc2)c2ccc(OC)cc2SN1
Reaction time: 1 h
Yield: 81 %

Procedure:
The product (55.2 g) from step (i), in 2,6-lutidine (100 ml), was added to a solution of the product (118.5 g) from step (c) in 2,6-lutidine (400 ml). The reaction mixture was stirred for 1 hour and p-toluenesulfonic acid (9.0 g) was added and then refluxed with a Dean Stark trap for 17 hours. The reaction mixture was concentrated in vacuo and the residue was partitioned between 5% NaHCO3 and EtOAc. The organic layer was separated, dried and concentrated to get an oil which was chromatographed on silica gel, using hexane: EtOAc (85:15) as the eluant, to afford the title product (124.3 g) as an orange oil. 1H NMR consistent with the desired structure.
Reaction SMILES: [CH3:1][C:2]1[C:13]([N+:14]([O-])=O)=[C:5]2[N:6]=[C:7]([CH3:12])[C:8]([CH3:11])=[C:9]([CH3:10])[N:4]2[N:3]=1.[Cl-:17].[NH4+]>[Zn].C(O)C>[ClH:17].[CH3:1][C:2]1[C:13]([NH2:14])=[C:5]2[N:6]=[C:7]([CH3:12])[C:8]([CH3:11])=[C:9]([CH3:10])[N:4]2[N:3]=1
Reactant: Cc1nc2c([N+](=O)[O-])c(C)nn2c(C)c1C
Reactant: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCO
Product: Cc1nc2c(N)c(C)nn2c(C)c1C
Product: Cl
Yield: 88.3 %

Procedure:
2.2 g of 2,5,6,7-tetramethyl-3-nitropyrazolo[1,5-a]pyrimidine, 40 cc of ethanol and 1 g of ammonium chloride were introduced into a 100 ml three-necked round-bottomed flask fitted with a magnetic stirrer, a condenser and a thermometer. The medium was brought to reflux, and 2.5 g of zinc powder were added in small portions in order to maintain the reflux. After 0.5 hour of refluxing, the zinciferous sludges were filtered. The filtrate was concentrated until it crystallized. The crystals were filtered off. Drying under vacuum and over phosphoric anhydride yielded 2 g of 2,5,6,7-tetramethylpyrazolo[1,5-a]pyrimidin-3-ylamine hydrochloride (yield=88.2%).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:10]=[C:11]=S)[CH3:9].[CH3:13][C:14]1[C:15]([NH:29][CH2:30][CH:31]([CH3:33])[CH3:32])=[C:16]([NH2:28])[C:17]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:18][C:19]=1[CH3:20]>N1C=CC=CC=1.C(OCC)(=O)C>[CH2:8]([NH:10][C:11]1[N:29]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:15]2[C:14]([CH3:13])=[C:19]([CH3:20])[N:18]=[C:17]([O:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:16]=2[N:28]=1)[CH3:9]
Reactant: CCN=C=S
Reactant: Cc1nc(Oc2ccccc2)c(N)c(NCC(C)C)c1C
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCNc1nc2c(Oc3ccccc3)nc(C)c(C)c2n1CC(C)C
Temperature: 80 °C
Yield: 58.1 %

Procedure:
Triethylamine (2.44 mL, 17.5 mmol) and ethyl isothiocyanate (0.92 g, 10.5 mmol) were sequentially added to a solution of 5,6-dimethyl-N4-(2-methylpropyl)-2-phenoxypyridine-3,4-diamine (2.5 g, 8.8 mmol) in pyridine (25 mL), and the reaction was heated for five minutes at 80° C. 1,(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.63 g, 10.5 mmol) was added, and the reaction was heated at 100° C. for two hours, allowed to cool to ambient temperature, and diluted with ethyl acetate. The resulting solution was washed sequentially with brine (2×) and saturated aqueous sodium bicarbonate (1×), dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide an oil. The crude product was purified by column chromatography on silica gel (eluting with 1-3% methanol in dichloromethane) to provide 1.73 g of N-ethyl-6,7-dimethyl-1-(2-methylpropyl)-4-phenoxy-1H-imidazo[4,5-c]pyridin-2-amine as an oil which solidified to white crystals upon standing overnight at ambient temperature.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].Cl[S:7][S:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][S:16]Cl)=[CH:11][CH:10]=1>ClCCCl>[CH2:1]([N:3]([S:7][S:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][S:16][N:3]([CH2:4][CH3:5])[CH2:1][CH3:2])=[CH:11][CH:10]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCNCC
Reactant: ClSSc1ccc(SSCl)cc1
Solvent: ClCCCl
Product: CCN(CC)SSc1ccc(SSN(CC)CC)cc1

Procedure:
25.0 ml (190 mmol) of diethylamine are used as initial charge in 150 ml of 1,2-dichloroethane in an inertized three-necked flask with dropping funnel, reflux condenser with hose coupling at its upper end, a tap with hose coupling and a Teflon stirrer bar, in a countercurrent of argon. 10.6 g (38.6 mmol) of 1,4-bis(chlorodisulphanyl)benzene in 50 ml of 1,2-dichloroethane are then slowly added dropwise, with stirring. The reaction mixture is stirred at room temperature for 4 hours. The resultant salt is filtered off, and the organic phase is washed three times with water and dried over sodium sulphate. After removal of the solvent on a rotary evaporator and drying in the vacuum generated by a rotary-vane pump, 1,4-bis(diethylaminodisulphanyl)benzene precipitates in the form of a yellow oil. The crude yield is 11.9 g (89%). Elemental analysis was carried out on the crude product.
Reaction SMILES: [C:1]([N:4]([CH2:37][C@@H:38]1[O:42][C:41](=[O:43])[N:40]([C:44]2[CH:49]=[CH:48][C:47]([N:50]3[CH2:57][C:56]4[C:52](=[N:53][N:54]([CH3:58])[CH:55]=4)[CH2:51]3)=[C:46]([F:59])[CH:45]=2)[CH2:39]1)[C:5]([O:7][CH2:8][O:9][C:10](=[O:36])[C:11]1[CH:16]=[CH:15][C:14]([O:17][P:18]([O:28]CC2C=CC=CC=2)([O:20]CC2C=CC=CC=2)=[O:19])=[CH:13][CH:12]=1)=[O:6])(=[O:3])[CH3:2]>C1CC=CCC=1.C1COCC1.[Pd]>[C:1]([N:4]([CH2:37][C@@H:38]1[O:42][C:41](=[O:43])[N:40]([C:44]2[CH:49]=[CH:48][C:47]([N:50]3[CH2:57][C:56]4[C:52](=[N:53][N:54]([CH3:58])[CH:55]=4)[CH2:51]3)=[C:46]([F:59])[CH:45]=2)[CH2:39]1)[C:5]([O:7][CH2:8][O:9][C:10](=[O:36])[C:11]1[CH:16]=[CH:15][C:14]([O:17][P:18]([OH:28])([OH:20])=[O:19])=[CH:13][CH:12]=1)=[O:6])(=[O:3])[CH3:2]
Reactant: CC(=O)N(C[C@H]1CN(c2ccc(N3Cc4cn(C)nc4C3)c(F)c2)C(=O)O1)C(=O)OCOC(=O)c1ccc(OP(=O)(OCc2ccccc2)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: C1=CCC=CC1
Solvent: C1CCOC1
Product: CC(=O)N(C[C@H]1CN(c2ccc(N3Cc4cn(C)nc4C3)c(F)c2)C(=O)O1)C(=O)OCOC(=O)c1ccc(OP(=O)(O)O)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A suspension of 15 (1 equiv) and 10% Pd/C (1 weight equiv of 15) in 1,4-cyclohexadiene and THF is stirred at rt for 6 h. The reaction mixture is filtered, concentrated in vacuo, purified directly by HPLC (C-18 column, 0-100% gradient elution, MeCN:H2O), and fractions containing product are lyophilized to give the title compound. Theoretical MS 646 (M+1)+
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:17]=[C:16]([NH2:18])[S:15][C:5]=2[C:6]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[N:7][CH:8]=1.Cl[CH2:20][C:21](Cl)=[O:22].C(N(C(C)C)C(C)C)C.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>ClCCCl.C1COCC1>[CH3:1][O:2][C:3]1[C:4]2[N:17]=[C:16]([NH:18][C:21](=[O:22])[CH2:20][N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[S:15][C:5]=2[C:6]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)=[N:7][CH:8]=1
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Reactant: C1COCCN1
Reactant: O=C(Cl)CCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: C1CCOC1
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)CN3CCOCC3)nc12

Procedure:
From 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine with chloroacetyl chloride and N-ethyldiisopropylamine in 1,2-dichloroethane and THF; then subsequent treatment with morpholine. ES-MS m/e (%): 394 (M+H+, 100).
Reaction SMILES: C=O.[C:3]1(S(O)=O)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:12]N(C)CCN(C)C.[C:20]([OH:23])(=O)[CH3:21]>C(Cl)(Cl)Cl>[CH:20]([O:23][CH:8]([CH3:7])[CH3:3])([CH3:21])[CH3:12].[CH3:7][CH2:8][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CN(C)CCN(C)C
Reactant: O=S(O)c1ccccc1
Reactant: CC(=O)O
Agent: C=O
Solvent: ClC(Cl)Cl
Product: CC(C)OC(C)C
Product: CCCCCC
Reaction time: 48 h

Procedure:
A mixture of 1,18 g of 1β-tert.-butoxy-8aβ-methyl-1,2,3,4,6,7,8,8a-octahydronaphthalene-6-one, 0,175 g of paraformaldehyde, 0.90 g of benzenesulfinic acid, 2,4 ml of N,N,N',N'-tetramethylethylendiamine and 1,6 ml of glacial acetic acid is stirred for 2 days at 70° under nitrogen atmosphere. The reaction mixture is taken up in chloroform, washed with a saturated solution of sodiumhydrogencarbonate and with 1 n HCl. The organic phase is dried with sodium sulfate and the solvent removed under vacuum. The yield of 2,33 g of the crude product is purified on silica gel by means of chromatography (benzine/ethyl acetate 95:5 → 50:50). After recristallisation from diisopropylether/hexane 0.452 g of rac. 1β-tert.-butoxy-8aβ-methyl-5-(phenylsulfonylmethyl)-1,2,3,4,6,7,8,8a-octahydronaphthalene-6-one is thus obtained, m.p. 96° - 98°. ε252 = 12700.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)CCC.Br[C:20]1[C:29]([CH3:30])=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:31][CH3:32])[CH:26]=2)[C:21]=1[O:33][CH2:34][O:35][CH3:36]>C1(C)C=CC=CC=1.CCOCC.O.C1(P([Pd-4](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)C=CC=CC=1>[CH3:32][O:31][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[C:21]([O:33][CH2:34][O:35][CH3:36])=[C:20]([C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)[C:29]([CH3:30])=[CH:28]2
Reactant: COCOc1c(Br)c(C)cc2cc(OC)ccc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: O
Solvent: Cc1ccccc1
Product: COCOc1c(-c2ccco2)c(C)cc2cc(OC)ccc12
Temperature: 105 °C
Yield: 76 %

Procedure:
2-(Tributylstannyl)-furan (0.4 mL, 1.29 mmol)) was added slowly to a solution of 2-bromo-6-methoxy-1-(methoxymethoxy)-3-methylnaphthalene (14 (0.4 g, 1.29 mmol) in toluene (10 mL). Reaction mixture was heated at 105° C. A portion (0.01 g) of tetrakis(triphenylphosphino)palladium (0) (0.061 g, 0.053 mmol) was added every 1 h until reaction was complete. Reaction mixture was cooled to RT then diluted with Et2O and water. The layers were separated and the organic layer was washed with brine, dried over MgSO4, filtered and concentrated. The crude oil was purified with a gradient of 20% EtOAc in hexanes to give 0.29 g (76%) of the title compound (213) as oil. 1H NMR (400 MHz, d-CDCl3): δ 2.36 (s, 3H), 3.37 (s, 3H), 3.93 (s, 3H), 4.85 (s, 2H), 6.49-6.50 (m, 1H), 6.53-6.55 (m, 1H), 7.05 (m, 1H), 7.11 (dd, J1=2.4 Hz, J2=9.2 Hz, 1H), 7.39 (s, 1H), 7.58-7.58 (m, 1H), 8.08 (d, J=9.2 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@@H:10]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:9]2)=[N:6][C:5](Br)=[CH:4][N:3]=1.[CH3:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([Sn](C)(C)C)[CH:37]=2)[NH:32][N:31]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@@H:10]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:9]2)=[N:6][C:5]([C:36]2[CH:37]=[C:38]3[C:33](=[CH:34][CH:35]=2)[NH:32][N:31]=[C:30]3[CH3:29])=[CH:4][N:3]=1
Reactant: Cc1n[nH]c2ccc([Sn](C)(C)C)cc12
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(Br)cnc2N)C[C@@H]1Cc1ccccc1
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1n[nH]c2ccc(-c3cnc(N)c(N4CCN(C(=O)OC(C)(C)C)[C@@H](Cc5ccccc5)C4)n3)cc12
Temperature: 120 °C
Yield: 70.9 %

Procedure:
To a solution of -amino-5-bromo-3-[(S)-4-Boc-3-benzylpiperazinyl]pyrazine 108 (100 mg, 0.223 mmol) and 3-methyl-5-trimethylstannanyl-1H-indazole 105 (66 mg, 0.223 mmol.) in DMF (3.5 mL) was added tris(dibenzylideneacetone)bipalladium (10 mg, 0.011 mmol), tri-o-tolylphosphine (7 mg, 0.023 mmol) and triethylamine (23 mg, 0.23 mmol). The reaction mixture was heated in a microwave reactor at 120° C. for 10 minutes. Ethyl acetate (100 mL) was added. The organic layer was washed with water and brine. The organic layer was dried over sodium sulfate and filtered through Celite. The organic solvent was evaporated under reduced pressure. The crude product was purified by RP-HPLC to yield the desired 2-amino-3-[(S)-4-Boc-3-benzylpiperazinyl]-5-(3-methyl-1H-indazol-5-yl)pyrazine 109 (79 mg, 0.158 mmol).