Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:27][C:28]1[CH:29]=[C:30]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH:31]=[CH:32][C:33]=1[Cl:34]>CN(C=O)C>[Cl:27][C:28]1[CH:29]=[C:30]([N:35]2[CH2:40][CH2:39][N:38]([C:2]3[C:11]4[C:6](=[CH:7][C:8]([S:12]([NH:15][C:16]5[S:17][CH:18]=[CH:19][N:20]=5)(=[O:14])=[O:13])=[CH:9][CH:10]=4)[CH:5]=[CH:4][N:3]=3)[CH2:37][CH2:36]2)[CH:31]=[CH:32][C:33]=1[Cl:34]
Reactant: O=S(=O)(Nc1nccs1)c1ccc2c(Cl)nccc2c1
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=S(=O)(Nc1nccs1)c1ccc2c(N3CCN(c4ccc(Cl)c(Cl)c4)CC3)nccc2c1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
1-Chloro-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (from Example 73, step 2; 0.050 g, 0.153 mmol) and potassium carbonate (0.106 g, 0.767 mmol) were dissolved in DMF (1.023 ml). 1-(3,4-dichlorophenyl)piperazine (0.071 g, 0.307 mmol) was added and the reaction was stirred overnight at 120° C. The reaction was filtered through a syringe filter and purified via HPLC (Phenominex C18 column, 150×30 mm, 5 micron; gradient elution 25 to 70% MeCN:H2O with 0.1% TFA modifier). The product fractions were concentrated and passed through a SCX ion exchange column (pre-wetted with methanol). The column was flushed several times with methanol, then the product was liberated by flushing the column several times with 2.0 M ammonia in methanol. The product-containing filtrate was concentrated to afford 1-(4-(3,4-dichlorophenyl)piperazin-1-yl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=8.40 (d, J=1.8 Hz, 1H), 8.28 (d, J=8.9 Hz, 1H), 8.23 (d, J=5.7 Hz, 1H), 7.88 (dd, J=1.9, 8.8 Hz, 1H), 7.63 (d, J=5.8 Hz, 1H), 7.44 (d, J=9.0 Hz, 1H), 7.28 (d, J=4.6 Hz, 1H), 7.22 (d, J=2.9 Hz, 1H), 7.02 (dd, J=2.8, 9.1 Hz, 1H), 6.87 (d, J=4.6 Hz, 1H), 3.46 (s, 8H). m/z (ESI) 521.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([CH3:8])=[C:4]([O:9][C:10]2[C:11]([NH2:16])=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:3]=1.C([O-])=O.[NH4+]>[Pd].CO>[CH3:8][C:5]1[N:6]=[N:7][CH:2]=[CH:3][C:4]=1[O:9][C:10]1[C:11]([NH2:16])=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: Cc1nnc(Cl)cc1Oc1cccnc1N
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1nnccc1Oc1cccnc1N
Temperature: 65 °C
Yield: 72 %

Procedure:
3-(6-Chloro-3-methylpyridazin-4-yloxy)pyridin-2-amine (3.0 g, 12.7 mmol) was charged with MeOH (150 mL). Pd/C (0.67 g, 0.63 mmol) was added followed by ammonium formate (2.23 g, 35.5 mmol). The mixture was heated at 65° C. overnight. The solution was cooled and filtered through GF/F paper. The filtrate was concentrated and the residue was dissolved in dichloromethane and saturated NaHCO3. The organic layer was separated and the aqueous layer was extracted twice with dichloromethane. The combined organics were dried and concentrated to give 3-(3-methylpyridazin-4-yloxy)pyridin-2-amine (1.85 g, 72%) as a solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[N:12]=[C:11]([CH2:13][OH:14])[CH:10]=[C:9]([C:15]([O:17][CH2:18][CH3:19])=[CH2:16])[N:8]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[CH3:1][S:2]([O:14][CH2:13][C:11]1[CH:10]=[C:9]([C:15]([O:17][CH2:18][CH3:19])=[CH2:16])[N:8]=[C:7]([Cl:6])[N:12]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: C=C(OCC)c1cc(CO)nc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=C(OCC)c1cc(COS(C)(=O)=O)nc(Cl)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 108.3 %

Procedure:
Methanesulfonyl chloride (0.369 mL, 4.73 mmol) was added to an ice-cold solution of (2-chloro-6-(1-ethoxyvinyl)pyrimidin-4-yl)methanol (846 mg, 3.94 mmol) in DCM (8 mL) containing N,N-diisopropylethylamine (1.0 mL, 5.91 mmol). The mixture was stirred at 0° C. for 10 min. DCM (30 mL) was added and the mixture was washed with water (5 mL). The organic phase was dried over sodium sulfate, filtered and the solvent was evaporated to give the title compound (2-chloro-6-(1-ethoxyvinyl)pyrimidin-4-yl)methyl methanesulfonate (1249 mg, quant.).
Reaction SMILES: [O:1]([C:8]([NH:10][C@H:11]([C:19]([OH:21])=[O:20])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:9])C1C=CC=CC=1.[C:22]1(O)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CC(=O)CC>[C:8]([NH:10][C@H:11]([C:19]([O:21][C:19](=[O:20])[C@H:11]([CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH:10][C:8]([OH:1])=[O:9])=[O:20])[CH2:12][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([OH:9])=[O:1]
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)Oc1ccccc1
Reactant: Oc1ccccc1
Solvent: CCC(C)=O
Product: O=C(O)N[C@@H](Cc1ccccc1)C(=O)OC(=O)[C@H](Cc1ccccc1)NC(=O)O
Temperature: 80 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
Under a nitrogen atmosphere, a solution prepared by dissolving 571 mg (2 mmol) of N-phenoxycarbonyl-L-phenylalanine and 184 mg (2 mmol) of phenol in 20 mL of 2-butanone was charged into a two-necked round bottom flask having a volume of 100 mL and mounted with a Dimroth condenser, and was then stirred at 80° C. for 8 hours. The fact that N-carboxy-phenylalanine anhydride was obtained in a yield of 99% or more was confirmed by subjecting the reaction mixture to NMR determination.
Reaction SMILES: [S-:1][C:2]#[N:3].[Na+].[C:5]([N:9]=[N:10][C:11]1(Cl)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([CH3:8])([CH3:7])[CH3:6].O.[Cl-].[Na+]>C(O)(C)C>[C:5]([N:9]=[N:10][C:11]1([N:3]=[C:2]=[S:1])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([CH3:8])([CH3:6])[CH3:7]
Reactant: CC(C)(C)N=NC1(Cl)CCCCC1
Reactant: N#C[S-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CC(C)(C)N=NC1(N=C=S)CCCCC1
Temperature: 5 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 91.5 grams (1.05 moles) of sodium thiocyanate in 450 ml of 75% aqueous isopropanol in a 2 liter jacketed reactor, cooled to 5° C., was added 203.2 grams (1.0 moles) of 1-t-butylazo-1-chlorocyclohexane holding the reaction temperature at 10°-20° C. After the addition was complete, the reaction mixture was stirred an additional 90 minutes at room temperature, 900 ml of water added and the reaction stirred until the sodium chloride dissolved. The product was extracted with 300 ml pentane, the pentane extract washed successively with water, 10% NaHCO3 solution, water, dried over anhydrous sodium sulfate, filtered and the pentane evaporated under reduced pressure to leave 173 grams (75% crude yield) of a yellow liquid. The product had a broad band at approximately 2040 cm-1 in its infrared spectrum which is indicative of the isothiocyano band in these compounds. There was no band at 2170 cm-1 (thiocyano band).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:10]([O-])=O>CC(O)=O.[Fe]>[NH2:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[F:1])[C:6]#[N:7]
Reactant: N#Cc1ccc(F)c([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CC(=O)O
Product: N#Cc1ccc(F)c(N)c1
Temperature: 80 °C

Procedure:
A mixture of 4-fluoro-3-nitrobenzonitrile (5.0 g, 30.1 mmol) and Fe powder (5.05 g, 90.3 mmol) in AcOH (100 mL) was heated at 80° C. for 1 hour under N2. Then the solvent was removed under vacuum and water (200 mL) was added to the residue. The solution was adjusted to pH 6 by addition of Na2CO3 and extracted with DCM (2×200 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated to yield 3-amino-4-fluorobenzonitrile (48), which was used without further purification. MS m/z 137.0 (M+1)+.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([C:14]2[S:15][C:16]([C:19]3[C:23]([CH3:24])=[C:22]([C:25]([F:28])([F:27])[F:26])[O:21][N:20]=3)=[CH:17][CH:18]=2)=[O:13])[CH2:7]1)=[O:4].C([O-])([O-])=O.[K+].[K+].[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>C(#N)C>[CH3:35][N:36]1[CH2:41][CH2:40][N:39]([CH2:2][C:3]([NH:5][C@H:6]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([C:14]3[S:15][C:16]([C:19]4[C:23]([CH3:24])=[C:22]([C:25]([F:28])([F:27])[F:26])[O:21][N:20]=4)=[CH:17][CH:18]=3)=[O:13])[CH2:7]2)=[O:4])[CH2:38][CH2:37]1
Reactant: CN1CCNCC1
Reactant: Cc1c(-c2ccc(C(=O)N3CCC[C@H](NC(=O)CCl)C3)s2)noc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1c(-c2ccc(C(=O)N3CCC[C@H](NC(=O)CN4CCN(C)CC4)C3)s2)noc1C(F)(F)F
Reaction time: 72 h
Yield: 85.1 %

Procedure:
2-Chloro-N—{(S)-1-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carbonyl]-piperidin-3-yl}-acetamide (35 mg, 0.08 mmol, as prepared in Example 56) was dissolved in acetonitrile (3 mL) containing anhydrous K2CO3, treated with N-methylpiperazine (18 μL, 0.16 mmol), and stirred for 3 days. The reaction mixture was then evaporated and treated with water to provide a homogeneous solution which was extracted with EtOAc (2×4 mL), dried over MgSO4, filtered, and evaporated to afford product as an foam (34 mg, 85%). 1H NMR (CDCl3) 1.60-1.76 (m, 3 H), 1.88-1.98 (m, 1 H), 2.22 (s, 3 H), 2.29 (d, J=1.3, 3 H), 2.32-2.52 (m, 8 H), 2.92 (s, 2 H), 3.52 (br s, 1 H), 3.48 (br s, 2 H), 3.72-4.46 (m, 3 H), 7.32-7.44 (br m, 3 H). 19F NMR −63.1. LC/MS 4.59 min, [M+1]+ 500.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:14]=[C:13](OS(C(F)(F)F)(=O)=O)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:23])[CH:11]=2)[CH:6]=1.[CH3:25][S:26]([C:29]1[CH:34]=[CH:33][C:32]([NH2:35])=[CH:31][CH:30]=1)(=[O:28])=[O:27].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:14]=[C:13]([NH:35][C:32]2[CH:31]=[CH:30][C:29]([S:26]([CH3:25])(=[O:28])=[O:27])=[CH:34][CH:33]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:23])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc(OS(=O)(=O)C(F)(F)F)c2cc(F)ccc2c1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cc(Nc2ccc(S(C)(=O)=O)cc2)c2cc(F)ccc2c1
Temperature: 160 °C
Yield: 69.9 %

Procedure:
To a solution of (6-fluoro-4-trifluoromethanesulfonyloxy-naphthalen-2-yl)-acetic acid methyl ester (115 mg, 0.31 mmol) and 4-methanesulfonyl-phenylamine (59 mg, 0.35 mmol) in N,N-dimethylformamide (3 mL), was added (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (39 mg, 0.063 mmol), tris(dibenzylideneacetone)dipalladium(0) (14 mg, 0.016 mmol), and cesium carbonate (102 mg, 0.31 mmol). After being heated under microwave conditions (160° C., 15 minutes), the resulting mixture was diluted with water (10 mL) and extracted with ethyl acetate (15 mL×3). The organic layer was washed with brine, then dried over sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography (gradient elution with 0-50% ethyl acetate in hexanes) to afford [6-fluoro-4-(4-methanesulfonyl-phenylamino)-naphthalen-2-yl]-acetic acid methyl ester (84.0 mg, 69% yield) as a yellow solid.
Reaction SMILES: [C:1]([C:5]12[CH2:12][O:11][C:8]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[CH:18])([O:9][CH2:10]1)[O:7][CH:6]2[C:19]#[N:20])([CH3:4])(C)C.[C:21](C(CO)(CO)CO)(C)(C)[CH3:22]>>[CH2:1]([C:5]12[CH2:10][O:9][C:8]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[CH:18])([O:11][CH2:12]1)[O:7][CH:6]2[C:19]#[N:20])[CH2:4][CH2:21][CH3:22]
Reactant: C#CCCCCC12OCC(C(C)(C)C)(CO1)C(C#N)O2
Reactant: CC(C)(C)C(CO)(CO)CO
Product: C#CCCCCC12OCC(CCCC)(CO1)C(C#N)O2

Procedure:
4-t-Butyl-1-(hex-5-ynyl)-2,6,7-trioxabicyclo[2.2.2]octane-3-carbonitrile (Preparation of 2-t-butyl-2-hydroxymethylpropan-1,3-diol,
Reaction SMILES: [OH:1][C:2]1[C:13]2=[C:14]3[CH:9]([CH2:10][C:11]4[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[CH:15][C:12]=42)[NH:8][CH2:7][CH2:6][C:5]3=[CH:4][C:3]=1[O:23][CH3:24].C(=O)(O)[O-].[Na+].[CH2:30](Br)[C:31]#[CH:32]>C(O)C>[CH2:32]([N:8]1[CH:9]2[C:14]3=[C:13]([C:2]([OH:1])=[C:3]([O:23][CH3:24])[CH:4]=[C:5]3[CH2:6][CH2:7]1)[C:12]1[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:11]=1[CH2:10]2)[C:31]#[CH:30]
Reactant: C#CCBr
Reactant: COc1cc2c(cc1OC)-c1c(O)c(OC)cc3c1C(C2)NCC3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: C#CCN1CCc2cc(OC)c(O)c3c2C1Cc1cc(OC)c(OC)cc1-3
Temperature: 25 °C
Reaction time: 1 h

Procedure:
12.0 g. (2.7 mmol) (±)-5,6,6a,7-Tetrahydro-1-hydroxy-2,9,10-trimethoxy-4H-dibenzo(de,g)quinoline are dissolved in 25 ml. ethanol and mixed with 560 mg. sodium bicarbonate and 0.26 ml. (2.95 mmol) propargyl bromide. The reaction mixture is stirred for 1 hour at ambient temperature and then for 2 hours at 80° C. under reflux. The usual working up and crystallisation from ethanol gives (±)-6-propargyl-5,6,6a,7-tetrahydro-1-hydroxy-2,9,10-trimethoxy-4H-dibenzo(de,g)quinoline;
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[C:4]([O:14][CH2:15][C:16]([CH3:21])([CH3:20])[C:17]([OH:19])=[O:18])=[CH:3][CH:2]=1.C1C2NC3C(=CC=CC=3)C=2C(OC(C)(C)C(O)=O)=CC=1.Cl[CH2:43][C:44]1[CH:63]=[CH:62][C:47]([O:48][CH2:49][C:50]2[N:51]=[C:52]([C:56]3[CH:61]=[CH:60][N:59]=[CH:58][CH:57]=3)[O:53][C:54]=2[CH3:55])=[C:46]([O:64][CH3:65])[CH:45]=1.ClCC1C=CC(OCC2N=C(C3C=CC=CC=3)OC=2C)=C(OC)C=1>>[CH3:65][O:64][C:46]1[CH:45]=[C:44]([CH:63]=[CH:62][C:47]=1[O:48][CH2:49][C:50]1[N:51]=[C:52]([C:56]2[CH:57]=[CH:58][N:59]=[CH:60][CH:61]=2)[O:53][C:54]=1[CH3:55])[CH2:43][N:12]1[C:13]2[CH:1]=[CH:2][CH:3]=[C:4]([O:14][CH2:15][C:16]([CH3:21])([CH3:20])[C:17]([OH:19])=[O:18])[C:5]=2[C:6]2[C:11]1=[CH:10][CH:9]=[CH:8][CH:7]=2
Reactant: CC(C)(COc1cccc2[nH]c3ccccc3c12)C(=O)O
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccncc2)oc1C
Agent: CC(C)(Oc1cccc2[nH]c3ccccc3c12)C(=O)O
Agent: COc1cc(CCl)ccc1OCc1nc(-c2ccccc2)oc1C
Product: COc1cc(Cn2c3ccccc3c3c(OCC(C)(C)C(=O)O)cccc32)ccc1OCc1nc(-c2ccncc2)oc1C

Procedure:
The subject compound was prepared by performing the same operation as that of the example 3 by using 3-(9H-carbazole-4-yloxy)-2,2-dimethylpropionic acid prepared by the reference 30 instead of 2-(9H-carbazole-4-yloxy)-2-methylpropionic acid used in the example 3, and using 4-((4-(chloromethyl)-2-methoxyphenoxy)methyl)-2-(pyridine-4-yl)-5 methyloxazole prepared by the reference 4 instead of 4-((4-(chloromethyl)-2-methoxyphenoxy)methyl)-5-methyl-2-phenyloxazole.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].BrN1C(=[O:18])CCC1=O.C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>ClCCl.CCCCCC.[N+]([O-])([O-])=O.[Ag+].O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[CH:11]=[O:18]
Reactant: Cc1ccc([N+](=O)[O-])c(F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: [Ag+]
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=[N+]([O-])[O-]
Solvent: CCCCCC
Solvent: ClCCl
Solvent: O
Product: O=Cc1ccc([N+](=O)[O-])c(F)c1
Temperature: 25 °C
Yield: 34.9 %

Procedure:
In a round bottom flask under nitrogen was combined 3-Fluoro-4-nitrotoluene (15 g, 96.7 mMol), N-bromosuccinimide (37.9 g, 212.7 mMol), and carbon tetrachloride (300 mL). The mixture was stirred at room temperature and benzoyl peroxide added (2.34 g, 9.67 mMol). A water-cooled reflux condenser was attached and the solution heated to reflux and stirred overnight. Upon arrival the solution was cooled to room temperature, diluted with dichloromethane (300 mL) and washed with 1N sodium hydroxide solution (2×200mL). The organic layer was then washed with water (200 mL) and concentrated to dryness on a rotary evaporator. The crude material was then redissolved in dioxane (450 mL) and water (50 mL) and stirred at room temperature. Silver nitrate (65.7 g, 387 mMol) was added and the material allowed to stir overnight. Upon arrival the reaction mixture was filtered and the solids washed with ethyl acetate. The filtrate was extracted with ethyl acetate (3×200 mL). The organics were dried with magnesium sulfate, filtered, and concentrated on a rotary evaporator. Purification by flash column silica gel chromatography 30% ethyl acetate in hexane as the eluant yielded a still impure product that was recolumned using 50% dichloromethane in hexane to give 5.7 g (35% yield) of 3-Fluoro-4-nitro-benzaldehyde. 1H NMR (DMSO-d6): δ=10.09 (s, 1H), 8.36 (m, 1H), 8.07 (dd, 1H, J=11, 1.5 Hz), 7.96 (dd, 1H, J=8.3, 1.5 Hz).
Reaction SMILES: Cl.[CH:2]12[CH2:7][CH:6]1[CH2:5][NH:4][CH2:3]2.C(N(CC)CC)C.O.[F:16][C:17]1[CH:18]=[C:19]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH2:20][NH:21][C:22]1[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][N:25]=[C:24](S(C)=O)[N:23]=1>C(Cl)Cl>[CH:2]12[CH2:7][CH:6]1[CH2:5][N:4]([C:24]1[N:23]=[C:22]([NH:21][CH2:20][C:19]3[CH:36]=[CH:37][C:38]([O:39][CH3:40])=[C:17]([F:16])[CH:18]=3)[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][N:25]=1)[CH2:3]2
Reactant: C1NCC2CC12
Reactant: CCOC(=O)c1cnc(S(C)=O)nc1NCc1ccc(OC)c(F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)c1cnc(N2CC3CC3C2)nc1NCc1ccc(OC)c(F)c1
Reaction time: 18 h

Procedure:
In DCM (50 mL) was dissolved the above product ethyl 4-((3-fluoro-4-methoxybenzyl)amino)-2-(methylsulfinyl)pyrimidine-5-carboxylate. To the solution were added 3-azabicyclo[3.1.0]hexan hydrochloride salt (0.8 g, 6.67 mmol) and triethylamine (4 mL, 28.8 mmol). The reaction was conducted at ambient temperature for 18 h, followed by addition of water and extraction with DCM. The organic phase was dried over sodium sulfate, and the solvent was removed by rotary evaporation to give ethyl 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-fluoro-4-methoxybenzyl)amino)pyrimidine-5-carboxylate as a faint yellow oil (3.1 g). The product was used in the subsequent procedure without further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:20])([O:4][C:5]([N:7]1[CH2:12][CH2:11][N:10]([C:13]2[C:18]([NH2:19])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:9][CH2:8]1)=[O:6])[CH3:3].Br[CH2:22][CH2:23][CH2:24][CH2:25]Br.C(=O)([O-])[O-].[K+].[K+].BrC(C(Br)C)C>C(#N)C.O>[CH3:3][C:2]([CH3:20])([O:4][C:5]([N:7]1[CH2:8][CH2:9][N:10]([C:13]2[C:18]([N:19]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:11][CH2:12]1)=[O:6])[CH3:1]
Reactant: BrCCCCBr
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncccc2N)CC1
Agent: CC(Br)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(c2ncccc2N2CCCC2)CC1
Reaction time: 72 h

Procedure:
1-[1,1-Dimethylethoxycarbonyl]-4-[3-amino-2-pyridinyl]piperazine (International Publication No. WO 88/08424, 0.50 g), 1,4-dibromobutane (0.21 ml) and potassium carbonate (0.30 g) are refluxed in 4 ml of acetonitrile for 1 week. After 1 week, additional dibromobutane (0.21 ml) is added and refluxing is continued for 3 days. The reaction mixture is poured into water, extracted with methylene chloride, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate is purified by flash column chromatography eluting with ethyl acetate/hexane (10/90) to ethyl acetate/hexane (25/75). The appropriate fractions are pooled and concentrated to give the title compound, NMR (300 MHz, CDCl3) 7.78, 6.98, 6.78, 3.52, 3.20-3.10, 1.87 and 1.44δ.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:15].[Na+].[CH:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[S:26]([O-:29])(=[O:28])=[O:27])=O.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCCl>[CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:18][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[S:26]([OH:29])(=[O:28])=[O:27])=[C:6]1[CH3:15]
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Reactant: O=Cc1ccccc1S(=O)(=O)[O-]
Agent: CC[SiH](CC)CC
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: COC(=O)Cn1c(C)c(Cc2ccccc2S(=O)(=O)O)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 73.6 %

Procedure:
A mixture of (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester (1.0 g), 2-formylbenzensulfonic acid sodium salt (0.94 g) and 1,2-dichloroethane (15 mL) at 0° C. was treated dropwise with a mixture of triethylsilane (4.3 mL), trifluoroacetic acid (1.0 mL) and 1,2-dichloroethane (10 mL), and the resulting mixture was stirred at room temperature for 6 hours. The mixture was extracted with ethyl acetate and the combined organic extract was dried over sodium sulfate. The solvent was removed under reduced pressure and the residue purified by column chromatography on silica gel, eluting with a mixture of methanol and dichloromethane (0:1 to 1:9 by volume) to afford the title compound as a purple gum (1.3 g).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].[CH2:8](Cl)[CH:9]=[CH2:10]>>[CH2:10]([NH:5][CH2:4][CH:3]([O:6][CH3:7])[O:2][CH3:1])[CH:9]=[CH2:8]
Reactant: COC(CN)OC
Reactant: C=CCCl
Product: C=CCNCC(OC)OC

Procedure:
Aminoacetaldehyde dimethyl acetal was reacted with allyl chloride to give N-allyl-N-dimethoxyethyl amine, which was then acetylated with acetyl chloride to give N-allyl-N-dimethoxyethylacetamide, according to the following reactions: ##STR3##
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]([C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)=O)=[CH:4][CH:3]=1.Cl.O([NH2:19])C.B.C1COCC1.[OH-].[Na+]>N1C=CC=CC=1>[CH3:1][C:2]1[S:6][C:5]([CH:7]([NH2:19])[C:9]2[CH:10]=[C:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: Cc1cccc(C(=O)c2ccc(C)s2)c1
Reactant: CON
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cc1cccc(C(N)c2ccc(C)s2)c1
Temperature: 0 °C
Reaction time: 14 h

Procedure:
(5-Methyl-thiophen-2-yl)-m-tolyl-methanone (5.00 g, 23.12 mmol) was mixed with methoxylamine hydrochloride (3.00 g, 35.92 mmol) in pyridine and the resulting reaction mixture was stirred for 14 hours. The reaction mixture was concentrated on a rotary evaporator, the residue was washed with ether and the combined ether layers were concentrated. The residue was dissolved in BH3.THF (100.00 mL, 1.0 M in THF, 0.10 mol) and the resulting mixture was refluxed for 3 hours. The reaction mixture was then cooled to 0° C., 20% NaOH was added and the resulting mixture was refluxed for 14 hours. After cooling to room temperature, the reaction mixture was extracted with hexane and the combined organic extracts were dried with K2CO3 and concentrated to give the desired title amine. Spectroscopic data: 1H NMR (300 MHz, DMSO-d6) δ ppm 2.26 (s, 3H) 2.32 (s, 3H) 3.30 (br s, 2H) 5.14 (s, 1H) 6.48-6.58 (m, J=14.36 Hz, 1H) 6.58-6.67 (m, 1H) 6.93-7.08 (m, 1H) 7.11-7.27 (m, 3H).
Reaction SMILES: Br[C:2]1[C:3]([N:22]([CH2:24][CH2:25][CH2:26][N:27]([CH3:29])[CH3:28])[CH3:23])=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:30]1[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[CH:31]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:28][N:27]([CH3:29])[CH2:26][CH2:25][CH2:24][N:22]([CH3:23])[C:3]1[C:2]([C:32]2[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=2)=[CH:21][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)=[O:8])=[CH:5][N:4]=1
Reactant: OB(O)c1cccnc1
Reactant: CN(C)CCCN(C)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Solvent: O
Product: CN(C)CCCN(C)c1ncc(C(=O)Nc2ccc(OC(F)(F)F)cc2)cc1-c1cccnc1
Temperature: 125 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5-bromo-6-((3-(dimethylamino)propyl)(methyl)amino)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 165.1, 88 mg, 0.185 mmol), pyridin-3-ylboronic acid (22.7 mg, 0.185 mmol) and Na2CO3 (59 mg, 0.555 mmol) in a mixture of DME (4.0 mL), EtOH (0.54 mL) and water (0.80 mL) was flushed with argon for 5 min. Pd(PPh3)2Cl2 was added (6.5 mg, 0.0093 mmol) and the mixture was subjected to MW irradiation at 125° C. (MW irradiation) for 30 min. Additional pyridin-3-ylboronic acid (22.7 mg, 0.185 mmol), Na2CO3 (59 mg, 0.555 mmol) and Pd(PPh3)2Cl2 (6.5 mg, 0.0093 mmol) were added and the mixture stirred at 125° C. for further 30 min. The vial was cooled to RT and the RM was evaporated to dryness under reduced pressure to give a residue that was triturated with THF and filtered. The filtrate was evaporated to dryness under reduced pressure and the crude product was purified by preparative LC-MS. TFA was removed using a SPE PL-HCO3 (StratoSpheres™ VariPure IPE) cartridge to afford the title compound. LC-MS (Condition 6) tR=1.33 min, m/z=474.0 [M+H]+.