Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH3:21])[CH2:14][CH2:15][O:16][CH2:17][C:18]([OH:20])=O)(=[O:12])=[O:11])=[C:5]([CH3:22])[C:4]=1[CH3:23].[CH3:24][N:25]([CH:27]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH:28]1[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]1)[CH3:26]>C1COCC1>[CH3:26][N:25]([CH:27]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[CH:28]1[CH2:29][CH2:30][CH:31]([NH:34][C:18](=[O:20])[CH2:17][O:16][CH2:15][CH2:14][N:13]([S:10]([C:6]2[C:7]([CH3:9])=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:23])[C:5]=2[CH3:22])(=[O:11])=[O:12])[CH3:21])[CH2:32][CH2:33]1)[CH3:24]
Reactant: CN(C)C(c1ccccc1)C1CCC(N)CC1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)CCOCC(=O)O)c(C)c1C
Solvent: C1CCOC1
Product: COc1cc(C)c(S(=O)(=O)N(C)CCOCC(=O)NC2CCC(C(c3ccccc3)N(C)C)CC2)c(C)c1C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
N,N′-Carbonyldiimidazole (195 mg, 1.2 mmol) was added to a soln. of {2-[(4-methoxy-2,3,6-trimethylbenzenesulfonyl)-methylamino]-ethoxy}-acetic acid (Intermediate C) (346 mg, 1 mmol) in THF (5 ml) and the mixture was stirred at RT for 1 h. A soln. of 4-(dimethylaminophenylmethyl)-cyclohexylamine (Intermediate VII) (256 mg, 1.1 mmol) in THF (5 ml) was then added and the reaction mixture was stirred at RT for 3 d. Thereafter, the soln. was concentrated i. vac., the residue was taken up in NaHCO3 soln. and the mixture was extracted with MC (3×30 ml). The combined organic phases were dried with Na2SO4 and concentrated i. vac. Further purification was carried out by means of flash chromatography with CHCl3/MeOH (95:5).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15](Cl)=[N:16][OH:17])=[CH:10][CH:9]=2)=[CH:2]1.[C:19]([C:21]1[C:22]([NH2:28])=[N:23][C:24]([NH2:27])=[CH:25][CH:26]=1)#[CH:20].C(N(CC)CC)C>O1CCCC1>[S:1]1[CH:5]=[CH:4][C:3]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]3[CH:20]=[C:19]([C:21]4[C:22]([NH2:28])=[N:23][C:24]([NH2:27])=[CH:25][CH:26]=4)[O:17][N:16]=3)=[CH:10][CH:9]=2)=[CH:2]1
Reactant: C#Cc1ccc(N)nc1N
Reactant: ON=C(Cl)Cc1ccc(OCc2ccsc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ccc(-c2cc(Cc3ccc(OCc4ccsc4)cc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 56.9 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (4-(thiophen-3-ylmethoxy)-phenyl)-acetohydroximoyl chloride (150 mg, 0.532 mmol) described in Manufacturing Example 77-1-4 and 3-ethynyl-pyridin-2,6-diamine (45.2 mg, 0.339 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (185 μL, 1.33 mmol). This reaction mixture was stirred for 1.5 hours at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1˜ethyl acetate) to obtain the title compound (73 mg, 36%).
Reaction SMILES: Br[CH2:2][CH2:3][O:4]C1CCCCO1.[ClH:11].[CH3:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[NH:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:16]=[N:15][CH:14]=1>>[ClH:11].[OH:4][CH2:3][CH2:2][N:27]1[CH2:28][CH2:29][CH:24]([NH:23][C:21]2[CH:20]=[CH:19][CH:18]=[C:17]3[C:22]=2[C:13]([CH3:12])=[CH:14][N:15]=[CH:16]3)[CH2:25][CH2:26]1
Reactant: Cc1cncc2cccc(NC3CCNCC3)c12
Reactant: BrCCOC1CCCCO1
Agent: Cl
Product: Cc1cncc2cccc(NC3CCN(CCO)CC3)c12

Procedure:
According to the method of Example 144, an alkylation reaction with 2-(2-bromoethoxy)tetrahydro-2H-pyran and a deprotection reaction were performed by using the compound of Example 106 to obtain the title compound.
Reaction SMILES: COC1C=C(OC)C=CC=1[CH2:5][NH:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[NH:15][C:16]1[N:21]=[C:20]([NH:22][C@H:23]2[C:32]3[C:27](=[CH:28][CH:29]=[C:30]([F:33])[CH:31]=3)[O:26][CH2:25][CH2:24]2)[C:19]([NH2:34])=[CH:18][N:17]=1.O.[C:42]1(C)C=CC(S(O)(=O)=O)=CC=1.C(OC)(OC)OC>CO>[F:33][C:30]1[CH:31]=[C:32]2[C:27](=[CH:28][CH:29]=1)[O:26][CH2:25][CH2:24][C@H:23]2[N:22]1[CH:42]=[N:34][C:19]2[C:20]1=[N:21][C:16]([N:15]1[C:8]3[CH:9]=[C:10]([C:11]#[N:12])[CH:13]=[CH:14][C:7]=3[N:6]=[CH:5]1)=[N:17][CH:18]=2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: COc1ccc(CNc2ccc(C#N)cc2Nc2ncc(N)c(N[C@@H]3CCOc4ccc(F)cc43)n2)c(OC)c1
Solvent: CO
Solvent: O
Solvent: COC(OC)OC
Product: N#Cc1ccc2ncn(-c3ncc4ncn([C@@H]5CCOc6ccc(F)cc65)c4n3)c2c1
Reaction time: 0.08 h

Procedure:
To a microwave vial was added the above amine, a catalytic amount of para-toluene sulfonic acid monohydrate, trimethyl orthoformate (0.5 mL) and MeOH (1 mL). The vial was capped and heated in an Emrys™ Optimizer microwave at 150.degree C. for 5 minutes. The mixture was concentrated in vacuo, and purified by RP HPLC to yield 4.6 mg of the titled product as the TFA salt, NMR CDCl3 1H δ 9.5 (br s, 1H), 9.3 (s, 1H), 9.0 (s, 1H), 8.2 (br s, 1H), 8.0 (d, 1H), 7.7 (d, 1H), 7.1-7.0 (m, 2H), 6.6 (dd, 1H), 6.0 (t, 1H), 4.4 (m, 1H), 4.3 (m, 1H), 2.7 (m, 2H); 19F δ −121, −76 ppm; MH+=412.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].CN(C=O)C.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[S:30][C:29]([NH:31][C:32]2[CH:41]=[CH:40][C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=2)=[N:28][C:27]=1[C:42]([NH2:44])=[O:43]>C1COCC1.N1C=CC=CC=1>[C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:9]([NH:25][C:26]2[S:30][C:29]([NH:31][C:32]3[CH:41]=[CH:40][C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:33]=3)=[N:28][C:27]=2[C:42]([NH2:44])=[O:43])=[O:11])=[CH:12][CH:13]=1)(=[O:3])[CH3:2]
Reactant: NC(=O)c1nc(Nc2ccc3ccccc3c2)sc1N
Reactant: CC(=O)Nc1ccc(C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(C(=O)Nc2sc(Nc3ccc4ccccc4c3)nc2C(N)=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 3.8 %

Procedure:
To a mixture of 4-acetamidobenzoic acid (0.204 g, 1.14 mmol) and a catalytic amount of DMF in dry THF (15 mL) was added dropwise oxalyl chloride (0.2 mL, 2.30 mmol) at 0° C., and the mixture was stirred for 2 hrs at rt. The solvent was evaporated, and the residual oxalyl chloride was removed with azeotropic distillation using toluene under nitrogen atmosphere 4 times. The resulting acid chloride was then dissolved in pyridine (6 mL) and cooled to 0° C. To this solution, a solution of 5-amino-2-(naphthalene-2-ylamino)thiazole-4-carboxamide (0.27 g, 0.95 mmol) in pyridine (6 mL) was added at 0° C., and the mixture was stirred for 12 hrs at rt. The solvent was evaporated, and the residue was suspended into 1M HCl, and the resulting solids were collected and dried. The crude solids were purified by silica gel column chromatography eluted with 3% MeOH in DCM to give 16 mg (3.7% yield) of the titled compound.
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([CH2:35][CH2:36][CH3:37])[N:6]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[C:28]([C:33]#[N:34])=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:23][CH:22]=2)[C:7](=[O:19])[C:8]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH:16]([CH3:18])[CH3:17])=[CH:11][CH:10]=1)[CH3:2].Cl.[NH2:39]O.[C:41](=[O:44])([O-])[OH:42].[Na+]>CS(C)=O.C(OCC)(=O)C>[CH2:1]([C:3]1[N:4]=[C:5]([CH2:35][CH2:36][CH3:37])[N:6]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]3[NH:39][C:41](=[O:44])[O:42][N:34]=3)=[CH:25][CH:26]=2)[C:7](=[O:19])[C:8]=1[C:9]1[CH:10]=[CH:11][C:12]([O:15][CH:16]([CH3:17])[CH3:18])=[CH:13][CH:14]=1)[CH3:2]
Reactant: NO
Reactant: O=C([O-])O
Reactant: CCCc1nc(CC)c(-c2ccc(OC(C)C)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1nc(CC)c(-c2ccc(OC(C)C)cc2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 90 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
4′-{[4-Ethyl-5-(4-isopropoxyphenyl)-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.5 g) was dissolved in dimethyl sulfoxide (5 mL), and hydroxylamine hydrochloride (0.71 g) and sodium hydrogen carbonate (1 g) were added. The mixture was stirred overnight at 90° C. After cooling, the reaction mixture was diluted with ethyl acetate, washed with water, dried over sodium sulfate and concentrated. The residue was dissolved in tetrahydrofuran (5 mL), and N,N′-carbonyldiimidazole (0.25 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.23 mL) were added. After stirring for 30 min, the reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.44 g, 79%).
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C:3](=[O:5])[CH3:4].[C:7](#[N:10])[CH:8]=[CH2:9].Cl>>[CH3:1][C:2]([CH3:6])([C:3](=[O:5])[CH3:4])[CH2:9][CH2:8][C:7]#[N:10]
Reactant: C=CC#N
Reactant: CC(=O)C(C)C
Agent: Cl
Product: CC(=O)C(C)(C)CCC#N
Temperature: 350 °C
Reaction time: 18 h

Procedure:
A mixture of 40 g of 3-methyl-2-butanone and 2 g of Triton B was heated to 350° C., and 20 g of acrylonitrile was added to the mixture over a period of 1 hour. Then, the mixture was stirred for 18 hours, and hydrochloric acid was added to the mixture to make the mixture acidic and the mixture was extracted with ether.
Reaction SMILES: C(O)(=O)/C=C\C(O)=O.C1(CN2CCC(C[CH2:23][C:24]3[C:28]4[CH:29]=[C:30]5[CH2:35][C:34](=[O:36])[NH:33][C:31]5=[CH:32][C:27]=4[O:26][N:25]=3)CC2)C=CC=CC=1.N1C=CC=CC=1.O>CN(C)C=O>[CH3:23][C:24]1[C:28]2[CH:29]=[C:30]3[CH2:35][C:34](=[O:36])[NH:33][C:31]3=[CH:32][C:27]=2[O:26][N:25]=1
Reactant: O=C1Cc2cc3c(CCC4CCN(Cc5ccccc5)CC4)noc3cc2N1
Agent: O=C(O)/C=C\C(=O)O
Solvent: CN(C)C=O
Solvent: O
Solvent: c1ccncc1
Product: Cc1noc2cc3c(cc12)CC(=O)N3
Temperature: 127.5 °C
Yield: 64.9 %

Procedure:
A mixture of the oxime acetate formed in step c (4.48 g, 18.0 mmol) and pyridine (14.6 mL, 180 mmol) in dimethylformamide (DMF) (660 mL) was heated at 125-130° C. for 4 hours. The cooled reaction mixture was poured over water and extracted with EtOAc (4 times). The combined organic layer was washed with water and brine and dried (MgSO4), filtered, and concentrated. Purification by silica gel flash chromatography (50% EtOAc/hexanes→100% EtOAc) gave the title compound (2.20 g, 65%) as a pale yellow-orange solid.
Reaction SMILES: [CH:1]1[NH:2][C:3](=[O:12])[CH:4]=[C:5]2[C:10]=1[C:9](=[O:11])[CH2:8][CH2:7][CH2:6]2.[CH3:13]I>C1C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[CH3:13][N:2]1[C:3](=[O:12])[CH:4]=[C:5]2[C:10]([C:9](=[O:11])[CH2:8][CH2:7][CH2:6]2)=[CH:1]1
Reactant: CI
Reactant: O=C1CCCc2cc(=O)[nH]cc21
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: c1ccccc1
Product: Cn1cc2c(cc1=O)CCCC2=O

Procedure:
The novel intermediates of the present invention originate from a novel process which utilizes dihydro=resorcinol as the starting material. That substance thus is allowed to react with a chlorinating reagent such as phosphorus trichloride to afford 3-chloro-2-cyclohexen-1-one. Reaction with cyanoacetamide and sodium hydride results in α-cyano-3-oxo-1-cyclohexen-1-acetamide, which is contacted with a dialkylformamide acetal, for example dimethylformamide diethyl acetal or dimethylformamide dineopentyl acetal, to produce 2,3,5,6,7,8-hexahydro-3,8-dioxo-4-isoquinolinecarboni=trile. Elimination of the cyano group is effected by heating with hydrobromic acid, thus affording 2,3,5,6,7,8-hexahydro-3,8-isoquinolinedione. Heating with an alkyl, trialkylsilyl or cycloalkyl halide produces the corresponding 6-alkoxy, 6-trialkylsilyloxy and 6-cycloalkoxy 7-aza-1-tetralones together with the N-alkylated or N-cycloalkylated derivatives. Typically, 2,3,5,6,7,8-hexahydro-3,8-isoquinolinedione is heated in benzene at the reflux temperature with methyl iodide and silver carbonate to yield 7-aza-6-methoxy-1-tetra=lone together with 2-methyl-2,3,5,6,7,8-hexahydro-3,8-isoquinolinedione. The reaction of the keto group of the latter tetralone with vinyl magnesium chloride results in 7-aza-6-methoxy-1-vinyl-1-tetralol, which is contacted with a 2-(lower alkyl)cyclopentane-1,3-dione, such as 2-methylcyclopentane-1,3-dione, in the presence of a basic catalyst such as triethylamine to afford 5,6,7,8-tetrahydro-3-methoxy-8-[(2-methyl-1,3-dioxocylopent-2-yl)ethylidene]isoquinoline. Alternatively, the tetralol is converted to the iso-thiouronium salt, which is reacted with the dione to afford the latter product. Cyclization of the latter diketone, suitably in the presence of p-toluenesulfonic acid, results in dl-2-aza-3-methoxyestra-1,3,5(10), 8,14-pentaen-17-one. Catalytic hydrogenation, using a palladium-on-calcium carbonate catalyst effects saturation of the 14-double bond, thus producing dl-2-aza-3-methoxyestra-1,3,5(10),8-tetraen-17-one, while chemical reduction, for example with sodium borohydride, converts the 17-keto group, thus yielding dl-2-aza-3-methoxyestra-1,3,5(10),8,14-pentaen-17β-ol. The 14-double bond of the latter substance is catalytically reduced, using a palladium-on-calcium carbonate catalyst, to yield dl-2-aza-3-methoxy=estra-1,3,5(10),8-tetraen-17β-ol, which is allowed to react with sodium in liquid ammonia to afford dl-2 -aza-3-methoxyestra-1,3,5(10)-trien-17β-ol.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7][C@@H:6]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH:24][C:25](=[O:45])[C@H:26]([CH:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[NH:27][C:28]([O:30][CH3:31])=[O:29])[O:5][CH2:4]1.C1N=CN([C:51]([N:53]2C=N[CH:55]=[CH:54]2)=[O:52])C=1.[F:58][C:59]1C=[CH:65][CH:64]=[CH:63][C:60]=1CN>N1C=CC=CC=1.CCOC(C)=O>[F:58][C:59]1[CH:60]=[CH:63][CH:64]=[CH:65][C:55]=1[CH2:54][NH:53][C:51]([O:1][CH2:2][C@H:3]1[N:8]([C:9]([O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:10])[CH2:7][C@@H:6]([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH:24][C:25](=[O:45])[C@H:26]([CH:32]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[NH:27][C:28]([O:30][CH3:31])=[O:29])[O:5][CH2:4]1)=[O:52]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](CO)CO1)C(c1ccccc1)c1ccccc1
Reactant: NCc1ccccc1F
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COC(=O)N[C@H](C(=O)Nc1ccccc1CC[C@@H]1CN(C(=O)OC(C)(C)C)[C@H](COC(=O)NCc2ccccc2F)CO1)C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of tert-butyl (2R,5R)-5-(hydroxymethyl)-2-[2-(2-{[N-(methoxycarbonyl)-β-phenyl-L-phenylalanyl]amino}phenyl)ethyl]morpholine-4-carboxylate (Example 1, step 10) (1 eq) and CDI (2.05 eq.) was dissolved in dry Pyridine (0.04 M) and the resulting solution stirred under N2 at rt for 5 h and then at 49° C. for 0.5 h; then neat 2-fluorobenzylamine (6 eq.) was added and the resulting mixture further stirred at the same temperature for 12 h. The crude reaction mixture was diluted with EtOAc, washed with 5% aq. KHSO4 then sat. NaHCO3, dried over Na2SO4, filtered and concentrated. The residue was purified by automated silicagel flash chromatography system eluted with a gradient 0% to 5% MeOH in DCM, to afford title compound.
Reaction SMILES: [OH:1][CH:2]([N:15]1[C@H:18]([SH:19])[C@H:17]([NH:20][C:21](=[O:29])[CH2:22]C2C=CC=CC=2)[C:16]1=[O:30])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:4].Br[CH2:32][C:33]([CH:35]1[CH2:39][CH2:38][CH2:37][O:36]1)=[O:34].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)(=O)C>[OH:1][CH:2]([N:15]1[C@H:18]([S:19][CH2:32][C:33]([CH:35]2[CH2:39][CH2:38][CH2:37][O:36]2)=[O:34])[C@@:17]([NH:20][C:21](=[O:29])[CH3:22])([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:16]1=[O:30])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:4]
Reactant: COc1ccc(COC(=O)C(O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2S)cc1
Reactant: O=C(CBr)C1CCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COc1ccc(COC(=O)C(O)N2C(=O)[C@](NC(C)=O)(c3ccccc3)[C@H]2SCC(=O)C2CCCO2)cc1
Reaction time: 0.17 h

Procedure:
The crude thiol was dissolved in acetone (35 ml) and treated with a solution of (RS)-2-bromoacetyltetrahydrofuran (3.48 g, 18.0 mmol) in acetone (5 ml). After 10 min, potassium carbonate (1.24 g, 8.9 mmol) was added, and the mixture stirred for a further 30min. The reaction mixture was diluted with ethyl acetate, washed successively with water (x2) and brine, dried and concentrated. The residue was flash chromatographed on silica gel eluting with 50, 70 and 80% ethyl acetate in hexane yielding the title compound as a colourless foam (5.40 g, 55%); νmax (CH2Cl2) 3409, 1781, 1745, 1684, 1613, 1516 cm-1. [Mass spectrum +ve ion (3-nitrobenzyl alcohol, sodium acetate) MNa+ (565)].
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]=[C:5]=[O:6].[N:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH2:13])[CH:8]=1.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Cl:1][CH2:2][CH2:3][NH:4][C:5]([NH:13][C:9]1[CH:8]=[N:7][CH:12]=[CH:11][CH:10]=1)=[O:6]
Reactant: O=C=NCCCl
Reactant: Nc1cccnc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(NCCCl)Nc1cccnc1
Temperature: 25 °C
Yield: 94.3 %

Procedure:
1-Chloro-2-isocyanato-ethane (560 mg, 5.31 mmol) was added dropwise to a stirred solution of pyridin-3-ylamine (500 mg, 5.31 mmol) in toluene (10 mL) over a period of 30 minutes at 0° C. The reaction temperature was maintained at room temperature for 5 hours. The reaction was monitored by TLC (100% ethyl acetate). The reaction mixture was filtered, washed with toluene and dried under reduced pressure to afford 1.0 g (98% yield) of 1-(2-Chloro-ethyl)-3-pyridin-3-yl-urea.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([CH:10]=[CH:11][C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:25]([CH:27]1[O:29][CH2:28]1)Cl>CC(C)=O>[O:29]1[CH2:28][CH:27]1[CH2:25][O:18][C:15]1[CH:14]=[CH:13][C:12]([CH:11]=[CH:10][C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH:3]=[CH:2][NH:1]3)=[CH:17][CH:16]=1
Reactant: ClCC1CO1
Reactant: Oc1ccc(C=Cc2cccc3[nH]ccc23)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C(=Cc1cccc2[nH]ccc12)c1ccc(OCC2CO2)cc1
Reaction time: 5 h

Procedure:
A mixture of 5.8 g of the product of Step A, 120 ml of acetone, 3.6 g of potassium carbonate and 9.6 ml of epichlorhydrin was refluxed for 24 hours with stirring under an inert atmosphere. Then, 9.6 ml of epichlorhydrin were added and reflux was continued for 5 hours. After filtering, the solvent was evaporated under reduced pressure at 60° C., and the fractions with Rf=0.35 were recovered by chromatography on silica (eluent:methylene chloride) to obtain 5.25 g of 4-[2-[4-[(2-oxiranyl)-methoxy]-phenyl]-ethenyl]-1H-indole melting at ≃128° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[C:5]([C:15]2[N:16]=[C:17]3[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:18]3=[N:19][CH:20]=2)=[CH:4][CH:3]=1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>>[CH3:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:32](=[O:34])[CH3:33])[CH2:10]2)[C:5]([C:15]2[N:16]=[C:17]3[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[C:18]3=[N:19][CH:20]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2cnc3c(ccn3COCC[Si](C)(C)C)n2)c(NC2CCCNC2)n1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1CCCC(Nc2nc(C)ccc2-c2cnc3c(ccn3COCC[Si](C)(C)C)n2)C1

Procedure:
1-(3-{6-Methyl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-ylamino}-piperidin-1-yl)-ethanone was prepared from {6-methyl-3-[5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-pyridin-2-yl}-piperidin-3-yl-amine and acetic anhydride, following the general synthetic procedures described in the above Examples.
Reaction SMILES: [C:1]1(O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.P(OCCCC)(OCCCC)OCCCC>O>[C:13]1([NH:12][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1ccccc1
Reactant: Oc1cccc2ccccc12
Agent: CCCCOP(OCCCC)OCCCC
Solvent: O
Product: c1ccc(Nc2cccc3ccccc23)cc1
Temperature: 196 °C
Yield: 91 %

Procedure:
288 parts of α-naphthol, 205 parts of aniline and 10 parts of tributyl phosphite are mixed and first heated to 196° C. The reaction commences, with elimination of water. The water is removed by means of a water separator and the aniline which has escaped is returned. The internal temperature is raised to 235° C in the course of 8 hours. At this point, the elimination of water has ended (33 parts of water). The reaction mixture is cooled to 150° C and the excess aniline and α-naphthol are distilled off under reduced pressure. Thereafter, 400 parts of phenyl-α-naphthylamine are obtained at a boiling point of 202° - 203° C/5 mm Hg; the product has a melting point of 55° - 58° C and corresponds to a yield of 91% of theory.
Reaction SMILES: Br[C:2]1[O:6][CH:5]=[C:4]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH:11]=2)=[O:8])[CH:3]=1.[N:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+]>O.COCCOC.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>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7]([C:4]2[CH:3]=[C:2]([C:28]3[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=3)[O:6][CH:5]=2)=[O:8])=[CH:11][C:12]=1[N:18]1[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]1
Reactant: OB(O)c1ccncc1
Reactant: COc1ccc(NC(=O)c2coc(Br)c2)cc1N1CCN(C)CC1
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(NC(=O)c2coc(-c3ccncc3)c2)cc1N1CCN(C)CC1
Yield: 18 %

Procedure:
5-bromo-N-[4-methoxy-3-(4-methyl- 1-piperazinyl)phenyl]furan-3-carboxamide (0.16 g;0.41 mmol) was stirred with 4-pyridylboronic acid (0.050 g;0.41 mmol), tetrakis(triphenylphosphine)palladium(0) (0.024 g;5 mol %) and anhydrous sodium carbonate (0.047 g;0.45 mmol) in water (8 ml) and DME (8 ml) and the whole heated at reflux under Ar (18 hours). The reaction mixture was poured into 10% Na2CO3 (aq) (20 ml ) and extracted into CHCl3. The organic extracts were combined, dried over Na2 SO4, filtered and the filtrate evaporated in vacuo to a brown gum. The gum was purified by flash silica-gel chromatography and eluted with 4%MeOH/CHCl3 to yield a orange oil which was triturated with hexane/Et2O. The solid that formed was collected by filtration and dried in vacuo to yield the title compound as a tan solid (0.029 g;18%), mp=103°-105° C.