Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]3[C:11]([SH:14])=[N:12][N:13]=[C:6]3[C:5]=2[CH:4]=[N:3]1.[K].[CH3:16]I>CN(C)C=O>[CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]3[C:11]([S:14][CH3:16])=[N:12][N:13]=[C:6]3[C:5]=2[CH:4]=[N:3]1
Reactant: CI
Reactant: Cn1ncc2c1ncn1c(S)nnc21
Agent: [K]
Solvent: CN(C)C=O
Product: CSc1nnc2c3cnn(C)c3ncn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 3 g. of 7-methyl-3-mercapto-7H-pyrazolo[4,3-e][1,2,4]-triazolo[4,3-c]pyrimidine, potassium salt, in 25 ml. of dimethylformamide, 2.1 g. of methyl iodide are added and the mixture is stirred for 1 hour at room temperature. The reaction mixture is then poured into 200 ml. of water and the product, 7-methyl-3-methylthio-7H-pyrazolo[4,3-e][1,2,4]triazolo [4,3-c]-pyrimidine, is filtered under suction, crystallized from dimethylformamide and obtained as yellowish crystals, m.p. 204°-206°.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([OH:23])=O)=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].C1(N2CCN(C(C3C=C4C(=CC=3)NC(C(N3CCS(=O)(=O)CC3)=O)=C4)=O)CC2)CCCC1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[O:78]1[C:82]2([CH2:87][CH2:86][NH:85][CH2:84][CH2:83]2)[O:81][CH2:80][CH2:79]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[O:78]1[C:82]2([CH2:87][CH2:86][N:85]([C:21]([C:16]3[NH:17][C:18]4[C:14]([CH:15]=3)=[CH:13][C:12]([C:10]([N:7]3[CH2:8][CH2:9][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:5][CH2:6]3)=[O:11])=[CH:20][CH:19]=4)=[O:23])[CH2:84][CH2:83]2)[O:81][CH2:80][CH2:79]1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)O)cc3c2)CC1
Reactant: C1CC2(CCN1)OCCO2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCC5(CC4)OCCO5)cc3c2)CC1
Yield: 64 %

Procedure:
The title compound was synthesized in analogy to example 1, from 5-(4-isopropyl-piperazine-1-carbonyl)-1H-indole-2-carboxylic acid 1:1 hydrochlorid (example 1, intermediate b), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 1,4-dioxa-8-azaspiro[4.5]decane (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide, to give the desired product as a light brown solid (64%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([CH:9](O)[CH3:10])[C:3]=1[OH:12].[F:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Cl:1][C:2]1[C:3]([OH:12])=[C:4]([CH:9]([C:18]2[CH:19]=[C:14]([F:13])[CH:15]=[CH:16][C:17]=2[OH:20])[CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(O)c1cc(Cl)cc(Cl)c1O
Reactant: Oc1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(c1cc(F)ccc1O)c1cc(Cl)cc(Cl)c1O
Reaction time: 0.5 h

Procedure:
2,4-Dichloro-6-(1'-hydroxyethyl)phenol (10 g) was added in small portions to a melt of 4-fluoro phenol containing a trace of p-toluenesulphonic acid at 90° over a half hour period. The reaction mixture was stirred for a further 1/2 hr and cooled. The crystallization from benzene gave 1-(3,5-dichloro-2-hydroxyphenyl)-1-(5-fluoro-2-hydroxy phenyl) ethane (11 g, m.p. 150°).
Reaction SMILES: [Br:1][C:2]([Br:5])(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:25]([C:30]1[CH:35]=[CH:34][C:33]([C@H:36]2[CH2:41][CH2:40][C@H:39]([CH:42]=O)[CH2:38][CH2:37]2)=[CH:32][CH:31]=1)[CH2:26][CH2:27][CH2:28][CH3:29].CCCCCC>C(Cl)Cl>[Br:1][C:2]([Br:5])=[CH:42][C@H:39]1[CH2:38][CH2:37][C@H:36]([C:33]2[CH:32]=[CH:31][C:30]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:35][CH:34]=2)[CH2:41][CH2:40]1
Reactant: CCCCCc1ccc([C@H]2CC[C@H](C=O)CC2)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCCCCC
Product: CCCCCc1ccc([C@H]2CC[C@H](C=C(Br)Br)CC2)cc1
Temperature: -10 °C
Reaction time: 0.02 h

Procedure:
A solution of 5.0 g of tetrabromomethane in 60 ml of methylene chloride was placed a -10° C. in a sulphonation flask under argon gasification and treated within 5 minutes with a solution of 7.9 g of triphenylphosphine in 20 ml of methylene chloride. The resulting clear orange solution was stirred at -10° C. for a further 1 minute and then a solution of 1.95 g of trans-4-(p-pentylphenyl)cyclohexanecarboxaldehyde in 20 ml of methylene chloride was added dropwise within 3 minutes. The mixture was subsequently left to stand at -18° C. overnight, then poured into 600 ml of hexane and the separated precipitate was filtered off (rinsing with hexane). The concentrated filtrate was digested with 300 ml of hexane, left to stand at -18° C. for 30 minutes, filtered (rinsing with hexane) and the filtrate was concetrated. Low-pressure chromatography (0.5 bar) of the residue (1.87 g) on silica gel with hexane gave 503 mg of 1-[trans-4-(2,2-dibromovinyl)cyclohexyl)-4-pentylbenzene as colourless crystals (purity 95.8%); m.p. 35°-37.7° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.[C:13]([Si:17]([CH3:25])([CH3:24])[O:18][CH2:19][CH2:20][CH:21]1[CH2:23][O:22]1)([CH3:16])([CH3:15])[CH3:14]>CCO.O>[C:13]([Si:17]([CH3:25])([CH3:24])[O:18][CH2:19][CH2:20][CH:21]([OH:22])[CH2:23][NH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1)([CH3:14])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)OCCC1CO1
Reactant: Nc1ccc2c(c1)NC(=O)CS2
Solvent: CCO
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCC(O)CNc1ccc2c(c1)NC(=O)CS2
Yield: 29 %

Procedure:
A solution of 6-amino-4H-benzo[1,4]thiazin-3-one (3.56 g, 19.8 mmol; commercial) and (RS)-tert-butyl-dimethyl-(2-oxiranyl-ethoxy)-silane (prepared according to J. Org. Chem. (2008), 73, 1093; 4.0 g, 19.8 mmol) in EtOH/H2O (9:1; 140 mL) was heated at 80° C. for 2 days. The mixture was concentrated under reduced pressure and the residue was purified by CC (DCM/MeOH/NH4OH 1000:50:4) to afford the title intermediate as a brown oil (2.20 g, 29% yield).
Reaction SMILES: [F:1][C:2]([F:14])([O:6][C:7]1[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4].[Br:15]N1C(=O)CCC1=O.O>C(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[F:1][C:2]([F:14])([O:6][C:7]1[CH:8]=[C:9]([CH2:13][Br:15])[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:4])[F:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(OC(F)(F)C(F)F)c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: ClC(Cl)Cl
Product: FC(F)C(F)(F)Oc1cccc(CBr)c1
Yield: 93.7 %

Procedure:
To a solution of 3-(1,1,2,2-tetrafluoroethoxy)toluene (15 g, 72.1 mmol) in chloroform (200 ml) were added N-bromosuccinimide (14.11 g, 79.3 mmol) and 2,2′-azobis(isobutyronitrile) (590 mg, 3.60 mmol), and the mixture was heated under reflux for 30 min. The reaction solution was cooled and water (100 ml) was added. The mixture was extracted with chloroform. The extract was washed successively with water (100 ml) and saturated brine (100 ml), dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene (19.4 g, purity 56%, 53%). This compound was used for the next reaction without further purification.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].C(Cl)Cl.Cl.[OH:12][C:13]1[CH:37]=[C:36]([O:38][CH:39]2[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH:35]=[CH:34][C:14]=1[C:15]([NH:17][C:18]1[CH:27]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21])=[O:16]>N1C=CC=CC=1>[C:1]([N:42]1[CH2:41][CH2:40][CH:39]([O:38][C:36]2[CH:35]=[CH:34][C:14]([C:15]([NH:17][C:18]3[CH:27]=[C:26]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:25]=[CH:24][C:19]=3[C:20]([O:22][CH3:23])=[O:21])=[O:16])=[C:13]([OH:12])[CH:37]=2)[CH2:44][CH2:43]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(OC2CCNCC2)cc1O
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(OC2CCN(C(C)=O)CC2)cc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under ice-cooling, pyridine (0.010 mL) and acetic anhydride (4.0 μL) were sequentially added to a methylene chloride (1 mL) suspension of the obtained methyl 2-(2-hydroxy-4-(piperidin-4-yloxy)benzamido)-4-phenylbenzoate hydrochloride (0.017 g), followed by stirring at room temperature for 1 hour. Pyridine (0.49 mL) and acetic anhydride (4.0 μL) were sequentially added to the reaction mixture, followed by stirring at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and a 10% aqueous solution of citric acid and ethyl acetate were added to the residue. The organic layer was separated, washed with a 10% aqueous solution of citric acid, and a saturated aqueous solution of sodium chloride sequentially, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain 0.016 g of methyl 2-(4-((1-acetylpiperidin-4-yl)oxy)-2-hydroxybenzamido)-4-phenylbenzoate as a white solid.
Reaction SMILES: [CH2:1]([S:3]([CH2:6][CH2:7][C:8]12[CH2:15][CH2:14][C:11]([C:16]([O:18]C)=[O:17])([CH2:12][CH2:13]1)[CH2:10][CH2:9]2)(=[O:5])=[O:4])[CH3:2].[OH-].[K+]>O.CO>[CH2:1]([S:3]([CH2:6][CH2:7][C:8]12[CH2:13][CH2:12][C:11]([C:16]([OH:18])=[O:17])([CH2:14][CH2:15]1)[CH2:10][CH2:9]2)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)CCC12CCC(C(=O)OC)(CC1)CC2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCS(=O)(=O)CCC12CCC(C(=O)O)(CC1)CC2
Temperature: 60 °C

Procedure:
Ester 10-3 (880 mg, 3 mmol) was dissolved in 10% water/methanol solution (100 mL) and treated with 1 g of potassium hydroxide. The reaction was heated at 60° C. for 1 h then at 45° C. overnight. The mixture was concentrated in vacuo then acidified to pH 2 with 1M HCl and extracted with three portions of methylene chloride. The organic layers were combined, dried over anhydrous sodium sulfate and evaporated to give 4-[2-(ethylsulfonyl)ethyl]bicyclo[2.2.2]octane-1-carboxylic acid (10-4).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:10]=1[NH2:11].Cl[C:18]1[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:19]=1[C:20]([OH:22])=[O:21]>CN(C=O)C.[Cu]>[F:8][C:9]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:10]=1[NH:11][C:18]1[CH:26]=[C:25]([F:27])[C:24]([F:28])=[CH:23][C:19]=1[C:20]([OH:22])=[O:21]
Reactant: O=C(O)c1cc(F)c(F)cc1Cl
Reactant: Nc1ccc(F)cc1F
Agent: [Cu]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)c1cc(F)c(F)cc1Nc1ccc(F)cc1F
Temperature: 85 °C
Reaction time: 8 h
Yield: 63.1 %

Procedure:
A suspension of triethyl amine (15 ml, 0.11 mol), 2, 4-difluoroaniline (25 ml, 0.24 mol), copper bronze (2.7 g., 0.04 mol), in hot DMF (25 ml) was treated with a solution of 2-chloro-4,5-difluorobenzoic acid (23 g., 0.12 mol) in 25 ml of DMF and the temperature was maintained at 85° C. for 8 hours. The reaction mixture was allowed to cool to room temperature and was then stirred overnight. The reaction mixture was evaporated in vacuo and the residue was partitioned between ether and aqueous ammonium chloride. The organic phase was washed with 2N HCl and saturated aqueous lithium chloride solution. The ether was dried over sodium sulfate, treated with darco and then filtered and evaporated. The residue was crystallized from hexane-ether to afford 21.6 g (62%) of 2-(2,4-difluorophenylamino)-4,5-difluorobenzoic acid; m.p.: 215°-216° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([O:14][C:15]2[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[C:17]([F:24])[CH:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].FC1C=C([N+]([O-])=O)C=C(F)C=1>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([O:14][C:15]2[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[C:17]([F:24])[CH:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC(Oc2cc(F)cc([N+](=O)[O-])c2)C1
Agent: O=[N+]([O-])c1cc(F)cc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC[C@H](Oc2cc(F)cc([N+](=O)[O-])c2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-(3-Fluoro-5-nitro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester. A 3 L 3-neck round bottom flask was charged with sodium hydride (60% in oil, 54.24 g, 1.356 mol) and DMF (1 L). The flask was cooled in an ice bath, a solution of (S)-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester alcohol (210 g, 1.043 mol) in DMF (500 mL) was added dropwise over 30 minutes to the flask, maintaining an internal temperature below 5° C. The solution was stirred for 1 hour, then was added via a canula into a 5 L 3-neck round bottom flask charged with a solution of 3,5-difluoronitrobenzene (169.25 g, 1.064 mol) that was cooled in an ice bath. The addition lasted for 1 hour, maintaining an internal temperature below 5° C. The reaction mixture was warmed to room temperature and stirred for 4 hours and diluted with 6 L ethyl acetate. The organic layer was washed with saturated ammonium chloride (4 L), sodium bicarbonate (2 L) and brine (2 L), dried (Na2SO4) and concentrated to afford the desired product (S)-3-(3-fluoro-5-nitro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester as an syrup (360 g, purity ˜95%).
Reaction SMILES: [C:1]([O:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].CC[O-].[Na+].[Cl:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26]Cl)[N:21]=1>CN(C=O)C.C(OCC)C>[Cl:18][CH2:19][C:20]1[N:21]=[C:22]([CH3:26])[C:23]([O:8][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][C:1](=[O:3])[CH3:2])=[CH:24][CH:25]=1
Reactant: CC(=O)Oc1ccccc1C(=O)O
Reactant: ClCc1cccc(CCl)n1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(=O)Oc1ccccc1C(=O)Oc1ccc(CCl)nc1C
Reaction time: 168 h
Yield: 59.9 %

Procedure:
To a solution of acetylsalicylic acid (1.6 g, 8.88 mmoles) in N,N′-dimethylformamide (20 ml) and under stirring, sodium ethylate (0.64 g, 8.88 mmoles) is added. After 30 minutes the obtained solution is added to a solution of 2,6-bis-(chloromethyl)pyridine (4.72 g, 26.81 mmoles) in N,N′-dimethylformamide (20 ml). The solution is left at room temperature for 7 days, under stirring, then it is diluted with ethyl ether and washed with water. The separated organic phases are anhydrified with sodium sulphate and the solvent is evaporated at reduced pressure. The reaction crude product is purified by chromatography on silica gel eluting with n-hexane/ethyl acetate 7/3. 1.7 g of the product are obtained as a yellow oil.
Reaction SMILES: [CH2:1]([C:5](=[CH2:9])[C:6]([OH:8])=[O:7])[CH:2]([CH3:4])[CH3:3].[CH2:10]([O:17][NH2:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CO>[CH2:10]([O:17][NH:18][CH2:9][CH:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[C:6]([OH:8])=[O:7])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NOCc1ccccc1
Reactant: C=C(CC(C)C)C(=O)O
Solvent: CO
Product: CC(C)CC(CNOCc1ccccc1)C(=O)O
Yield: 34.4 %

Procedure:
2.85 g of isobutylacrylic acid and 10.9 g of O-benzylhydroxylamine were heated under reflux in 30 ml of methanol for 8 days. The solvent was removed by evaporation and the residue was dissolved in ethyl acetate and water. The organic layer was washed with 2N hydrochloric acid and water and then extracted six times with 30 ml of 5% sodium hydrogen carbonate solution each time. The aqueous solutions were combined, acidified with 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated to give an oil which soon crystallized. Trituration with petroleum yielded 1.92 g (35%) of N-benzyloxy 2(RS)-isobutyl-3-aminopropionic acid of melting point 73°-75° C. Rf (toluene/acetic acid 4:1) 0.52.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]3[N:21]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=4[O:34][CH3:35])[C:22](=[O:24])[NH:23][C:15]=23)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[C:43]([C:45]1[CH:52]=[CH:51][CH:50]=[CH:49][C:46]=1[CH2:47]Br)#[N:44].O>CN(C=O)C>[C:1]([O:5][C:6](=[O:36])[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]3[N:21]([CH2:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][C:27]=4[O:34][CH3:35])[C:22](=[O:24])[N:23]([CH2:47][C:46]4[CH:49]=[CH:50][CH:51]=[CH:52][C:45]=4[C:43]#[N:44])[C:15]=23)[CH2:9]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1ccc(Cn2c(=O)[nH]c3c(N4CCC[C@@H](NC(=O)OC(C)(C)C)C4)cc(C)nc32)c(OC)c1
Reactant: N#Cc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2c(=O)n(Cc3ccccc3C#N)c3c(N4CCC[C@@H](NC(=O)OC(C)(C)C)C4)cc(C)nc32)c(OC)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 97.8 %

Procedure:
1.03 g (R)-1-[3-(2,4-dimethoxybenzyl)-5-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl]piperidine-3-carbamic acid tert-butyl ester (2.07 mmol) was dissolved in 5 mL DMF. 0.57 g potassium carbonate (4.14 mmol) was added, and then 0.45 g 2-cyano-benzyl bromide (2.28 mmol) was added. The reaction solution was stirred for 5 h at room temperature, and slowly poured into 100 mL water to precipitate a solid, filtrated, and dried to afford 1.24 g crude product with a yield of 97.9%.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.C([C:10]1[C:15]([O:16][CH3:17])=[C:14]([O:18][CH3:19])[CH:13]=[CH:12][C:11]=1[S:20]([N:23]([CH2:40][CH2:41]Br)[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[CH2:31][C:32]1[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=1[F:39])(=[O:22])=[O:21])C>CN(C)C=O.C(OCC)(=O)C>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([N:23]([CH2:40][CH2:41][N:3]2[CH:7]=[CH:6][N:5]=[CH:4]2)[S:20]([C:11]2[CH:12]=[CH:13][C:14]([O:18][CH3:19])=[C:15]([O:16][CH3:17])[CH:10]=2)(=[O:22])=[O:21])=[C:25]([CH2:31][C:32]2[C:37]([F:38])=[CH:36][CH:35]=[CH:34][C:33]=2[F:39])[CH:26]=1
Reactant: c1c[nH]cn1
Reactant: CCc1c(S(=O)(=O)N(CCBr)c2ccc(Cl)cc2Cc2c(F)cccc2F)ccc(OC)c1OC
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N(CCn2ccnc2)c2ccc(Cl)cc2Cc2c(F)cccc2F)cc1OC
Reaction time: 18 h
Yield: 22 %

Procedure:
To 2 ml of dimethylformamide are added, at room temperature, 51 mg of sodium hydride at 50% in oil, followed by 72 mg of imidazole. After 30 minutes at this temperature, 0.4 g of ethyl N-(2-bromoethyl)-N-[2-(2,6-difluorobenzyl)-4-chlorophenyl]-3,4-dimethoxybenzenesulfonamide dissolved in 5 ml of dimethylformamide is introduced. The reaction medium is left for 18 hours at room temperature and then taken up in ethyl acetate and washed with water. The organic phase is dried over anhydrous sodium sulfate and concentrated. The residue is chromatographed on a column of silica gel, eluting with a 97/3 (v/v) toluene/ethyl acetate mixture to give 0.082 g of the expected product.
Reaction SMILES: [CH2:1]([N:3]([CH2:29][CH3:30])[C:4](=O)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]2[N:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)=[CH:16][N:15]=2)=[CH:9][CH:8]=1)[CH3:2].[Li].C1COCC1>CO>[CH2:29]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14]2[N:15]=[CH:16][C:17]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)=[CH:18][N:19]=2)=[CH:11][CH:12]=1)[CH3:30]
Reactant: CCN(CC)C(=O)CCc1ccc(Nc2ncc(-c3ccc(OC)cc3)cn2)cc1
Agent: [Li]
Solvent: C1CCOC1
Solvent: CO
Product: CCN(CC)CCCc1ccc(Nc2ncc(-c3ccc(OC)cc3)cn2)cc1

Procedure:
N,N-Diethyl-3-{4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-phenyl}-propionamide (0.1 mmol) is heated at reflux with lithium alluminium hydride in THF (1.0 M, 1.0 mmol) for 4 h. MeOH is added at rt to quench the reaction. Purification by preparative LCMS affords the title compound. 1H NMR (400 MHz, CDCl3) δ 12.4 (s, 1H), 8.62 (s, 2H), 8.59 (s, 1H), 7.61 (d, J=8.3 Hz, 2H), 7.43 (d, J=8.6 Hz, 2H), 7.17 (d, J=8.2 Hz, 2H), 7.02 (d, J=8.6 Hz, 2H), 3.86 (s, 3H), 3.1 (m, 4H), 3.96 (s, 1H), 3.0 (m, 2H), 2.71 (t, J=7.2, 2H), 2.06 (m, 2H), 1.27 (t, J=7.3 Hz, 6H). MS (m/z) (M+1)+ 391.2.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[Br:12][C:13]1[C:22]2[O:21][CH2:20][CH2:19][NH:18][C:17]=2[CH:16]=[C:15]([Cl:23])[CH:14]=1.[OH-].[Na+]>C(OCC)(=O)C>[CH2:5]([O:4][C:2]([N:18]1[C:17]2[CH:16]=[C:15]([Cl:23])[CH:14]=[C:13]([Br:12])[C:22]=2[O:21][CH2:20][CH2:19]1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Clc1cc(Br)c2c(c1)NCCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)N1CCOc2c(Br)cc(Cl)cc21
Reaction time: 3 h
Yield: 90.7 %

Procedure:
Benzyl chloroformate (1.877 g, 0.011 mol) was added dropwise to a solution of 8-bromo-6-chloro-3,4-dihydro-2H-benzo[1,4]oxazine (2.85 g, 0.01 mol) in a 1:1 mixture of ethyl acetate (30 mL) and 10% aqueous sodium hydroxide (30 mL). After 3 hours at ambient temperature, the layers were separated and the organic phase was washed with water (2×50 mL), saturated aqueous sodium bicarbonate (50 mL), dried (K2CO3) and concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluting with hexane-ethyl acetate; 7:3,V/V) to give 8-bromo-6-chloro-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid benzyl ester as an oil (3.47 g, 98%). A sample was recrystallized from ethanol-water. MS: MH+ 383. M.P. 95.0-97.7° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1I.[OH:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[C:33]1[CH:34]=[CH:35][C:30]([OH:29])=[CH:31][CH:32]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3I)n(-c3ccccc3)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3-c3ccc(O)cc3)n(-c3ccccc3)c(=O)c12
Yield: 7.4 %

Procedure:
(S)-2-(1-((6-Amino-5-iodopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (50 mg, 0.10 mol) was treated with (4-hydroxyphenyl)boronic acid (21 mg, 0.15 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (14 mg, 0.02 mol) and sodium carbonate (2M, 231 μl, 0.46 mol) according to the method described in Example 3 to give 5 mg (11% yield) of the title compound as a white solid. Purity 100%.
Reaction SMILES: [Br-].[NH2:2][C:3]1[CH:8]=[CH:7][N+:6]([CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[H][H]>[Pt](=O)=O.CO>[C:16]1([CH:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:6]2[CH2:7][CH2:8][CH:3]([NH2:2])[CH2:4][CH2:5]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: [H][H]
Reactant: Nc1cc[n+](C(c2ccccc2)c2ccccc2)cc1
Agent: O=[Pt]=O
Agent: [Br-]
Solvent: CO
Product: NC1CCN(C(c2ccccc2)c2ccccc2)CC1

Procedure:
To a solution of 15.5 parts of 4-amino-1-(diphenylmethyl)-pyridinium bromide in 600 parts by volume of methanol is added 1.6 part of platinum dioxide catalyst and the resulting mixture is shaken with hydrogen at 60 psi pressure and room temperature for forty-two hours. The catalyst is then removed by filtration and the filtrate evaporated to dryness in vacuo. The residue is suspended in 200 parts by volume of 10% sodium carbonate solution and extracted with three 200 parts by volume portions of methylene chloride. The methylene chloride extracts are combined, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The solid residue obtained is triturated with 250 parts by volume of anhydrous ethyl ether, filtered and the filtrate evaporated to yield 1-(diphenylmethyl)-4-piperidinamine, as a colorless solid melting at about 84°-95° C. This compound is represented by the following structural formula. ##STR20##