Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[CH:2]1([CH2:7][NH2+:8][CH2:9][CH2:10]Cl)[CH2:6][CH2:5][CH2:4][CH2:3]1.[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[N:20]=[C:21]=[S:22]>>[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[N:20]=[C:21]1[N:8]([CH2:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:9][CH2:10][S:22]1
Reactant: S=C=Nc1cccc(Cl)c1Cl
Reactant: ClCC[NH2+]CC1CCCC1
Agent: [Cl-]
Product: Clc1cccc(N=C2SCCN2CC2CCCC2)c1Cl

Procedure:
2-Hydroxyethylamine was reacted with cyclopentylmethyl bromide according to Method B2a to give N-cyclopentylmethyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cyclopentylmethyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2,3-dichlorophenyl isothiocyanate to give 2-(2,3-dichlorophenylimino)-3-(cyclopentylmethyl)-1,3-thiazolidine.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([CH:15]1[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]1)#[N:14].N1([CH2:35][OH:36])C2C=CC=CC=2N=N1.[NH4+].[Cl-]>C1COCC1.CCCCCC>[C:13]([C:15]1([CH2:35][OH:36])[CH2:18][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:16]1)#[N:14]
Reactant: CC(C)(C)OC(=O)N1CC(C#N)C1
Reactant: OCn1nnc2ccccc21
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)N1CC(C#N)(CO)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.5 %

Procedure:
To a solution of N-isopropylpropan-2-amine (11.54 mL) in THF (50 mL) was added dropwise a solution of n-butyllithium in hexane (1.6 M, 51.45 mL) at −78° C. The reaction mixture was warmed to 0° C. and then stirred for 30 minutes. The reaction mixture was cooled to −78° C. again, and then a solution of tert-butyl 3-cyanoazetidine-1-carboxylate (5.0 g) in THF (30 mL) was added dropwise, followed by stirring at −78° C. for 1 hour. To the reaction mixture was added dropwise a solution of 1H-benzotriazol-1-yl-methanol (8.19 g) in THF (20 mL) at −78° C., followed by stirring at −78° C. for 3 hours. To the reaction mixture was added a saturated aqueous NH4Cl solution (100 mL), followed by extraction with EtOAc (50 mL) three times. The organic layer was washed with brine, dried over MgSO4, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (automatic purification device, hexane:EtOAc=100:0 to 50:50) to obtain tert-butyl 3-cyano-3-(hydroxymethyl)azetidine-1-carboxylate (5.68 g) as a white solid.
Reaction SMILES: S([O:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])(C(F)(F)F)(=O)=O.C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C.O[CH2:31][CH2:32][CH2:33][S:34][CH:35]1[CH2:39][CH2:38][O:37][C:36]1=[O:40]>C(Cl)Cl>[F:15][C:12]([F:13])([F:14])[S:9]([O:8][CH2:31][CH2:32][CH2:33][S:34][CH:35]1[CH2:39][CH2:38][O:37][C:36]1=[O:40])(=[O:10])=[O:11]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C1OCCC1SCCCO
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Solvent: ClCCl
Product: O=C1OCCC1SCCCOS(=O)(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Triflic anhydride (0.544 ml, 3.23 mmol) was added to a pre-cooled (0° C.) solution of 2,6-di-tert-butylpyridine (1.61 ml, 7.15 mmol) in methylene chloride (16 mL). A solution of 3-(3-hydroxypropylthio)-dihydrofuran-2(3H)-one (0.600 g, 3.41 mmol) dissolved in methylene chloride (2.5 mL) was added dropwise. The reaction was stirred at 0° C. for 15 minutes. The product was utilized in the subsequent step without isolation.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH:9][C:10](=[O:29])[C@@H:11]([NH:19][C:20]2([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH2:22][CH2:21]2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][C:6](C2C=CN=CC=2)=[CH:5][N:4]=1.COC1C(N)=CC([C:45]2[N:49]([CH:50]3[CH2:55][CH2:54][CH2:53][CH2:52][O:51]3)[N:48]=[CH:47][CH:46]=2)=CN=1>>[CH3:1][O:2][C:3]1[C:8]([NH:9][C:10](=[O:29])[C@@H:11]([NH:19][C:20]2([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH2:22][CH2:21]2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][C:6]([C:45]2[N:49]([CH:50]3[CH2:55][CH2:54][CH2:53][CH2:52][O:51]3)[N:48]=[CH:47][CH:46]=2)=[CH:5][N:4]=1
Reactant: COc1ncc(-c2ccnn2C2CCCCO2)cc1N
Reactant: COc1ncc(-c2ccncc2)cc1NC(=O)[C@H](Cc1ccccc1)NC1(c2ccccn2)CC1
Product: COc1ncc(-c2ccnn2C2CCCCO2)cc1NC(=O)[C@H](Cc1ccccc1)NC1(c2ccccn2)CC1

Procedure:
This example was made using the same general procedure as the synthesis of 11.1 starting with 2-methoxy-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-3-amine 14.1.C instead of 2-Methoxy-5-(pyridine-4-yl)pyridine-3-amine 11.1.B to give (2S)—N-(2-methoxy-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-3-yl)-3-phenyl-2-(1-(pyridin-2-yl)cyclopropylamino)propanamide 14.1.D.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Mg].CCOCC.[CH3:16][N:17]([CH3:25])[CH2:18][CH2:19][C:20]([CH:22]1[CH2:24][CH2:23]1)=[O:21]>O>[CH:22]1([C:20]([C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=2)([OH:21])[CH2:19][CH2:18][N:17]([CH3:25])[CH3:16])[CH2:24][CH2:23]1
Reactant: COc1ccc(Br)cc1
Reactant: CN(C)CCC(=O)C1CC1
Agent: [Mg]
Solvent: CCOCC
Solvent: O
Product: COc1ccc(C(O)(CCN(C)C)C2CC2)cc1
Temperature: 25 °C

Procedure:
The Grignard reagent prepared from 86 g. (0.46 mole) of 4-bromoanisole and 11.2 g. (0.46 mole) of magnesium metal in 200 ml. of dry ether was cooled to -20°C. and treated dropwise with 30 g. (0.23 mole) of cyclopropyl 2-dimethylaminoethyl ketone in 100 ml. of dry ether. After addition the mixture was allowed to warm to room temperature, then hydrolyzed with water and worked up as described in Preparation I. The oily product was distilled at 110°-115°C./0.1 mm.; the yield of free base was 16 g. (28%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([OH:12])[CH:3]=1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([O:12][CH2:19][C:18]2[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[CH:3]=1
Reactant: COc1ccc(CCl)cc1
Reactant: COC(=O)c1ccc(F)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(F)cc1OCc1ccc(OC)cc1
Yield: 95 %

Procedure:
Methyl 4-fluoro-2-hydroxybenzoate (0.88 mol) was dissolved in CH3CN (1.5 l). Para methoxy benzylchloride (1.3 mol) and K2CO3 (2.2 mol) were added. The mixture was refluxed for 12 h. The mixture was filtered to remove the solid. The solvent was removed under vacuum. The resulting residue was purified by flash column chromatography (eluent: CH2Cl2). Yield 270 g (90% purity, 95% yield).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:8][CH:9]=1.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Br)=[C:17]([CH2:23]Br)[CH:16]=1>CN(C)C=O>[Br:14][C:15]1[CH:16]=[C:17]2[C:18](=[CH:19][CH:20]=1)[CH2:21][N:13]([S:10]([C:7]1[CH:6]=[CH:5][C:4]([CH3:3])=[CH:9][CH:8]=1)(=[O:12])=[O:11])[CH2:23]2
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Reactant: BrCc1ccc(Br)cc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2Cc3ccc(Br)cc3C2)cc1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
In 70 ml of N,N-dimethylformamide was suspended 3.97 g of sodium hydride (purity: 60%), followed by adding thereto 50 ml of a N,N-dimethylformamide solution containing 8.49 g of p-toluenesulfonamide, and the resulting mixture was stirred at 60° C. for 30 minutes. A solution of 17.0 g of 1-bromo-3,4-di(bromomethyl)benzene in 50 ml of N,N-dimethylformamide was added to the reaction mixture at 60° C. and the resulting mixture was stirred at the same temperature for 1 hour. The reaction mixture obtained was added to 500 ml of ice water and the precipitate was collected by filtration and purified by a column chromatography (eluent: chloroform) to obtain 15.2 g of 5-bromo-2-(p-toluenesulfonyl)isoindoline as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([C:8]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[CH3:25])=[C:15]([CH2:26][OH:27])[CH:14]=3)[O:10][N:9]=2)[CH:7]=1>C(Cl)Cl.[O-2].[Mn+4].[O-2]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([C:8]2[N:12]=[C:11]([C:13]3[CH:14]=[C:15]([CH:26]=[O:27])[C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[CH3:25])=[CH:17][CH:18]=3)[O:10][N:9]=2)[CH:7]=1
Reactant: COc1ccc(F)cc1-c1noc(-c2ccc(-c3ccccc3C)c(CO)c2)n1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1ccc(F)cc1-c1noc(-c2ccc(-c3ccccc3C)c(C=O)c2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.1 %

Procedure:
Manganese(IV) oxide (111 mg; 1.28 mmol; 10 eq.) was added to a solution of Example 77 (50 mg; 0.13 mmol; 1 eq.) in DCM (5 mL) and the reaction mixture was stirred at room temperature for 4 hours. The suspension was filtered through a pad of CELITE and the solution concentrated in vacuo to afford title compound (46 mg; 93%) as a white solid.
Reaction SMILES: [C:1]([C:3]([CH3:30])([CH3:29])[C:4]1[CH:27]=[CH:26][C:7]([CH2:8][NH:9][C:10](=[O:25])[C:11]2[CH:16]=[CH:15][CH:14]=[N:13][C:12]=2[O:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)=[C:6]([F:28])[CH:5]=1)#[N:2].[N:31]([Si](C)(C)C)=[N+:32]=[N-:33].C[Sn](=O)C>C1(C)C=CC=CC=1>[F:28][C:6]1[CH:5]=[C:4]([C:3]([CH3:30])([C:1]2[NH:33][N:32]=[N:31][N:2]=2)[CH3:29])[CH:27]=[CH:26][C:7]=1[CH2:8][NH:9][C:10](=[O:25])[C:11]1[CH:16]=[CH:15][CH:14]=[N:13][C:12]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=1
Reactant: CC(C)(C#N)c1ccc(CNC(=O)c2cccnc2Oc2ccc(F)cc2)c(F)c1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: C[Sn](C)=O
Solvent: Cc1ccccc1
Product: CC(C)(c1ccc(CNC(=O)c2cccnc2Oc2ccc(F)cc2)c(F)c1)c1nnn[nH]1
Temperature: 100 °C
Reaction time: 168 h

Procedure:
To N-[4-(cyano-dimethyl-methyl)-2-fluoro-benzyl]-2-(4-fluoro-phenoxy)-nicotinamide (2.36 g) in a 50 mL sealable tube were added anhydrous toluene (2 mL), azidotrimethylsilane (1.42 mL), and dimethyl tin oxide (0.19 g). The reaction was stirred at 100° C. for seven days. The solvent was removed in vacuo. The residue was then taken up in acetone, and the precipitate was filtered and rinsed with water, giving a brown solid (1.13 g). The filtrate was concentrated, then taken up in satd. aq. sodium bicarbonate, (50 mL) and washed with ethyl acetate (50 mL). The aqueous was acidified to pH 3, and extracted with ethyl acetate (3×100 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The combined recovered solids were recrystallized with ethanol, yielding the title compound (1.26 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][C:31]=2[O:40][CH3:41])[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([S:12]([N:15](CC1C=CC(OC)=CC=1)[C:16]1[S:17][CH:18]=[CH:19][N:20]=1)(=[O:14])=[O:13])=[CH:7][CH:6]=2.C(Cl)Cl.C(O)(C(F)(F)F)=O>CO>[Cl:1][C:2]1[N:3]=[C:4]([C:30]2[CH:35]=[CH:34][C:33]([C:36]([F:37])([F:38])[F:39])=[CH:32][C:31]=2[O:40][CH3:41])[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([S:12]([NH:15][C:16]1[S:17][CH:18]=[CH:19][N:20]=1)(=[O:14])=[O:13])=[CH:7][CH:6]=2
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4OC)nc(Cl)cc3c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: COc1cc(C(F)(F)F)ccc1-c1nc(Cl)cc2cc(S(=O)(=O)Nc3nccs3)ccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A flask was charged with 3-chloro-1-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate RRR) (58.43 mg, 0.094 mmol), DCM (1 mL), and TFA (0.5 mL) to give a yellow solution (8:45 am). After 30 min of stirring at RT, the mixture was diluted with MeOH and concentrated. The residue was purified by chromatography on silica gel (0-10% MeOH/DCM) to give 47 mg of a light yellow solid. The solid was concentrated from DCM (2×), then taken up in DCM and filtered. The collected solid was washed with DCM (2×), then dried under vacuum for 10 min to give 3-chloro-1-(2-methoxy-4-(trifluoromethyl)phenyl)-n-(thiazol-2-yl)isoquinoline-6-sulfonamide as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm=12.95 (s, 1H), 8.57 (d, J=1.8 Hz, 1H), 8.39 (s, 1H), 7.87 (dd, J=1.8, 8.9 Hz, 1H), 7.72 (d, J=8.9 Hz, 1H), 7.61 (d, J=7.7 Hz, 1H), 7.56-7.48 (m, 2H), 7.30 (d, J=4.7 Hz, 1H), 6.90 (d, J=4.6 Hz, 1H), 3.76 (s, 3H). m/z (ESI) 500.2 (M+H)+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11](Cl)(=[O:13])=[O:12].C([N:17](CC)CC)C.[CH3:22][N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:32]#[N:33])[CH:30]=2)[CH:25]=[C:24]1[CH2:34][CH2:35][C@@H:36]1[CH2:40][CH2:39][CH2:38][NH:37]1>ClCCl.O>[CH3:22][N:23]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([C:32]([NH2:17])=[NH:33])[CH:30]=2)[CH:25]=[C:24]1[CH2:34][CH2:35][C@@H:36]1[CH2:40][CH2:39][CH2:38][N:37]1[S:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)(=[O:13])=[O:12]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: CCN(CC)CC
Reactant: Cn1c(CC[C@@H]2CCCN2)cc2ccc(C#N)cc21
Solvent: O
Solvent: ClCCl
Product: Cn1c(CC[C@@H]2CCCN2S(=O)(=O)c2ccc3ccccc3c2)cc2ccc(C(=N)N)cc21
Reaction time: 2 h

Procedure:
In a 25 ml flask, 30 mg of 1-methyl-2-((S)-2-pyrrolidin-2-ylethyl)indole-6-carbonitrile and 36 mg of 2-naphthalenesulfonyl chloride were dissolved in 3 ml of dichloromethane, and 0.055 ml of triethylamine was added at room temperature. The reaction mixture was stirred for 2 hours, diluted with water and then extracted three times with dichloromethane. The extracts were combined, dried over MgSO4 and then evaporated. The residue was purified with silica gel column chromatography [eluent: ethyl acetate/n-hexane (1:3)]. The fractions containing the pure desired product were combined and then evaporated to obtain 26.9 mg of the title compound as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:11][OH:12])[CH2:9][OH:10])=[C:4]([CH3:13])[CH:3]=1.[S:14](Cl)(Cl)=[O:15].ClCCl.[O:21]1CCOCC1>>[S:14]([O:10][CH2:9][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][C:4]=1[CH3:13])[CH2:11][OH:12])([OH:15])=[O:21]
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(N)ccc1C(CO)CO
Reactant: C1COCCO1
Solvent: ClCCl
Product: Cc1cc(N)ccc1C(CO)COS(=O)O
Yield: 90 %

Procedure:
(c') 2-(4-Amino-2-methylphenyl)-1,3-propanediol (0.8 g; 4.4 mmol) was taken up in dichloromethane/dioxane (1/1; 20 ml), and thionylchloride (1.6 g; 13.2 mmol) was added over 30 minutes, at room temperature. The solution was heated under reflux with stirring for an additional hour. The solvent was evaporated, the residue was neutralized with a NaHCO3 solution in water and the aqueous solution was thoroughly extracted with dichloromethane. The organic layers were dried over MgSO4 and evaporated to dryness. The remaining oil (0.9 g) consisted of 2-(4-amino-2-methylphenyl)-1,3-propanediol sulphite (yield 90%, purity >90%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([O:14]C)[C:8]([O:12]C)=[N:9]2)=[C:4]([CH2:16][NH:17][C:18]([C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)=[O:19])[CH:3]=1>Br.C(O)(=O)C.C(OCC)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:14])[C:8](=[O:12])[NH:9]2)=[C:4]([CH2:16][NH:17][C:18]([C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)=[O:19])[CH:3]=1
Reactant: COc1nc2cc(Br)cc(CNC(=O)c3ccco3)c2nc1OC
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: O=C(NCc1cc(Br)cc2[nH]c(=O)c(=O)[nH]c12)c1ccco1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
310 mg (0.79 mmol) of furan-2-carboxylic acid (7-bromo-2,3-dimethoxy-quinoxalin-5-ylmethyl)-amide are dissolved in 6 ml of an approximately 25% solution of hydrogen bromide in acetic acid, and the solution is stirred at room temperature for 16 hours. The mixture is diluted with diethyl ether, and the solid is filtered off and washed with diethyl ether. After drying under a high vacuum, the title compound is obtained in the form of a beige solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([NH2:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:13][Si](C=[N+]=[N-])(C)C>CC(C)=O.CCCCCC>[Cl:1][C:2]1[C:10]([NH2:11])=[CH:9][C:8]([Cl:12])=[CH:7][C:3]=1[C:4]([O:6][CH3:13])=[O:5]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Nc1cc(Cl)cc(C(=O)O)c1Cl
Solvent: CC(C)=O
Solvent: CCCCCC
Product: COC(=O)c1cc(Cl)cc(N)c1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
2,5-Dichloro-3-aminobenzoic acid, 206 mg (1.0 mmol), was dissolved in 4 ml of acetone, and 0.7 ml (1.4 mmol) of 2.0 M trimethylsilyl diazomethane solution in hexane was added to the solution. The mixture was stirred at room temperature for 1.5 hours. The solvent was removed by distillation to give methyl 2,5-dichloro-3-aminobenzoate.
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[O:12][C:11]3[CH:13]=[CH:14][C:15]([NH2:17])=[CH:16][C:10]=3[O:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[O:18]([C:25]1[CH:35]=[CH:34][CH:33]=[C:27]2[C:28]([O:30]C(=O)[C:26]=12)=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(C(C)C)C[CH2:41][O:42]C1C=CC(N)=CC=1OC)(C)C>>[O:18]([C:25]1[CH:26]=[C:27]2[C:33](=[CH:34][CH:35]=1)[C:41](=[O:42])[N:17]([C:15]1[CH:14]=[CH:13][C:11]3[O:12][CH:7]([CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:8][O:9][C:10]=3[CH:16]=1)[C:28]2=[O:30])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: COc1cc(N)ccc1OCCN(C(C)C)C(C)C
Reactant: O=C1OC(=O)c2c(Oc3ccccc3)cccc21
Reactant: Nc1ccc2c(c1)OCC(CN1CCCC1)O2
Product: O=C1c2ccc(Oc3ccccc3)cc2C(=O)N1c1ccc2c(c1)OCC(CN1CCCC1)O2

Procedure:
2-Pyrrolidin-1-ylmethyl-2,3-dihydro-benzo[1,4]dioxin-6-ylamine (WO 0121577 A2] was treated with 3-phenoxyphthalic anhydride in the same manner as for 4-(2-diisopropylamino-ethoxy)-3-methoxy-phenylamine in Example A4 to give the title compound.
Reaction SMILES: Cl.Cl.Cl.[CH3:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.C(N(CC)CC)C.Cl[C:31]1[N:36]([CH3:37])[C:35](=[O:38])[CH:34]=[C:33]([C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)[N:32]=1>O1CCCC1>[CH3:37][N:36]1[C:35](=[O:38])[CH:34]=[C:33]([C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)[N:32]=[C:31]1[N:19]1[CH2:20][CH2:21][CH2:22][CH:17]([C:14]2[CH:13]=[CH:12][C:11]([N:8]3[CH2:9][CH2:10][N:5]([CH3:4])[CH2:6][CH2:7]3)=[CH:16][CH:15]=2)[CH2:18]1
Reactant: Cn1c(Cl)nc(-c2ccncc2)cc1=O
Reactant: CN1CCN(c2ccc(C3CCCNC3)cc2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN1CCN(c2ccc(C3CCCN(c4nc(-c5ccncc5)cc(=O)n4C)C3)cc2)CC1
Reaction time: 12 h
Yield: 70.7 %

Procedure:
To a solution of 3-(4-(4-methylpiperazin-1-yl)-phenyl)-piperidine trihydrochloride salt (0.4 g, 1.08 mmol) and triethylamine (0.6 g, 5.93 mmol) in tetrahydrofuran (10 mL) was added 2-chloro-3-methyl-6-(pyridin-4-yl)-3H-pyrimidin-4-one (0.22 g, 0.99 mmol) portionwise. After stirring for 12 h, the resulting suspension was partitioned between chloroform and 1N sodium hydroxide. The aqueous layer was extracted with chloroform. The combined organic layer was washed with brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting 5-10% methanol in chloroform to furnish 3-methyl-2-(3-(4-(4-methylpiperazin-1-yl)-phenyl)-piperidin-1-yl)-6-(piridin-4-yl)-3H-pyrimidin-4-one (0.31 g, 0.70 mmol; 71%) as white crystals.
Reaction SMILES: FC1C=C(N)C=C[C:3]=1[C:4](OCC)=[O:5].[F:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[CH3:24].[OH:25]S(O)(=O)=O.[OH-].[Na+]>CC(O)=O.C(OCC)(=O)C>[F:14][C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[CH:17][C:16]=1[C:24]([O:5][CH2:4][CH3:3])=[O:25]
Reactant: Cc1ccc([N+](=O)[O-])cc1F
Reactant: O=S(=O)(O)O
Reactant: CCOC(=O)c1ccc(N)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc([N+](=O)[O-])cc1F
Temperature: 90 °C
Reaction time: 2 h

Procedure:
Ethyl 4-Amino-2-fluorobenzoate (Compound G) To a mixture of 2-fluoro-4-nitrotoluene (1.0 g, 6.4 mmol, Aldrich) and Na2Cr2O7 (2.74 g, 8.4 mmol) in 13.7 ml of HOAc was added slowly 6.83 ml of H2SO4. This mixture was slowly heated to 90° C. for 1 hour to give a greenish heterogeneous solution. The mixture was cooled to room temperature and diluted with ethyl acetate. The pH of the solution was adjusted to 4 with aqueous NaOH. The mixture was extracted with more ethyl acetate. The combined organic layers were washed with NaHCO3 (sat.), then brine and dried over Na2SO4. After filtration, the solution was concentrated to dryness which then was dissolved in 6 ml of SOCl2, and heated at 80° C. for 1 hour. The excess of SOCl2 was removed under reduced pressure and the residue was dissolved in 5 ml of CH2Cl2, 2 ml of EtOH and 2 ml of pyridine. The mixture was stirred at room temperature for 2 hours and concentrated to dryness. Ethyl 2-fluoro-4-nitrobenzoate was obtained as a white solid after column chromatography of the residue with ethyl acetate/hexane (1/9). This solid was then dissolved in 10 ml of ethyl acetate, and Pd/C (50 mg) was added. Hydrogenation converted ethyl 2-fluoro-4-nitrobenzoate into the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]4[NH:23][CH:24]=[CH:25][C:18]=34)=[C:12]([F:26])[CH:11]=2)[CH:3]=1.C(N(C(C)C)C(C)C)C.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.CN(C=O)C>C(C(CCCC)CO)C>[F:26][C:12]1[CH:11]=[C:10]([NH:9][C:4]2[CH:3]=[C:2]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[N:7]=[C:6]([NH2:8])[N:5]=2)[CH:15]=[CH:14][C:13]=1[O:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]2[NH:23][CH:24]=[CH:25][C:18]=12
Reactant: Nc1nc(Cl)cc(Nc2ccc(Oc3ccnc4[nH]ccc34)c(F)c2)n1
Reactant: C1COCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCC(CC)CO
Solvent: CN(C)C=O
Product: Nc1nc(Nc2ccc(Oc3ccnc4[nH]ccc34)c(F)c2)cc(N2CCOCC2)n1
Temperature: 150 °C

Procedure:
52 mg (0.14 mmol) of 6-chloro-N4-[3-fluoro-4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)-phenyl]pyrimidine-2,4-diamine (from example 60) are dissolved in 2.5 ml of 2-ethylhexanol. 0.24 ml of N-ethyldiisopropylamine and 36 mg (0.42 mmol) of morpholine are added, and the mixture is heated at 150° C. bath temperature for 20 hours. After cooling, a little DMF is added and the mixture is chromatographed on silica gel 60 (gradient column: mobile phase: DCM:methanol=50:1, then 3:1). This gives an oil which is purified by preparative HPLC.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[O:13]([CH2:20][C:21]([NH:23][C:24]1[C:25]2[N:26]=[CH:27][N:28]([C:37]=2[N:38]=[CH:39][N:40]=1)[C@@H:29]1[O:36][C@H:33]([CH2:34][OH:35])[C@@H:31]([OH:32])[CH2:30]1)=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([O:35][CH2:34][C@H:33]2[O:36][C@@H:29]([N:28]3[C:37]4[N:38]=[CH:39][N:40]=[C:24]([NH:23][C:21](=[O:22])[CH2:20][O:13][C:14]5[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=5)[C:25]=4[N:26]=[CH:27]3)[CH2:30][C@@H:31]2[OH:32])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(COc1ccccc1)Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(COc1ccccc1)Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](COC(=O)c2ccc([N+](=O)[O-])cc2)O1

Procedure:
The synthesis of this product is carried out by reacting 1.1 eq of p-nitrobenzoyl chloride with 6-N-phenoxyacetyldeoxyadenosine for 4 hours in pyridine. After hydrolysis of the excess reagent, almost complete evaporation of the pyridine, and ethyl acetate/sodium bicarbonate extraction, the ethyl acetate phase is evaporated to dryness. The product is obtained by column chromatography with a gradient of methanol in chloroform (elution 4% methanol).