Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([NH2:13])[S:11][CH:12]=2)=[CH:4][CH:3]=1.[C:14](Cl)(Cl)=[O:15].Cl.[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([C:26]2[CH:31]=[C:30]([C:32]3[CH:41]=[C:40]4[C:35]([CH2:36][CH2:37][NH:38][CH2:39]4)=[CH:34][CH:33]=3)[N:29]=[C:28]([NH2:42])[N:27]=2)[CH2:22][CH2:21]1>>[NH2:42][C:28]1[N:29]=[C:30]([C:32]2[CH:41]=[C:40]3[C:35]([CH2:36][CH2:37][N:38]([C:14]([NH:13][C:10]4[S:11][CH:12]=[C:8]([C:5]5[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=5)[N:9]=4)=[O:15])[CH2:39]3)=[CH:34][CH:33]=2)[CH:31]=[C:26]([N:23]2[CH2:22][CH2:21][N:20]([CH3:19])[CH2:25][CH2:24]2)[N:27]=1
Reactant: O=C(Cl)Cl
Reactant: Nc1nc(-c2ccc(Cl)cc2)cs1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(C(=O)Nc3nc(-c5ccc(Cl)cc5)cs3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 40 starting from 4-(4-chlorophenyl)-1,3-thiazol-2-amine (Aldrich, Cat. #339369), phosgene and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt. Analytic LCMS (M+H)+: m/z=561.2/563.2.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[S:4].[NH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:13]([CH3:19])[NH:14][C:15](=[O:18])[NH:16][N:17]=2)=[CH:8][CH:7]=1.C>CN(C)C=O>[CH3:1][NH:2][C:3](=[S:4])[NH:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:13]([CH3:19])[NH:14][C:15](=[O:18])[NH:16][N:17]=2)=[CH:10][CH:11]=1
Reactant: CN=C=S
Reactant: CC1NC(=O)NN=C1c1ccc(N)cc1
Solvent: CN(C)C=O
Product: CNC(=S)Nc1ccc(C2=NNC(=O)NC2C)cc1
Temperature: 110 °C
Reaction time: 4 h
Yield: 99.4 %

Procedure:
Methyl isothiocyanate (0.788 g) was added to a solution of 6-(4-aminophenyl)-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (2 g) in N,N-dimethylformamide (20 ml) and the mixture was stirred for 4 hours at 110° C. After cooling, the mixture was treated with activated charcoal and evaporated in vacuo. The residual solid was washed with water and dried to give 6-[4-(3-methylthioureido)phenyl]-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (2.7 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5](OS(C(F)(F)F)(=O)=O)=[C:6]([C:8]2[N:13]=[C:12]([N:14]3[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[N:15]3)[CH:11]=[CH:10][CH:9]=2)[CH:7]=1.[CH3:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][SH:45])=[CH:40][CH:39]=1.CCN(C(C)C)C(C)C.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.CCCCCC.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]>[CH3:36][O:37][C:38]1[CH:43]=[CH:42][C:41]([CH2:44][S:45][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][C:6]=2[C:8]2[N:13]=[C:12]([N:14]3[C:18]([C:19]([F:22])([F:21])[F:20])=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:16]=[N:15]3)[CH:11]=[CH:10][CH:9]=2)=[CH:40][CH:39]=1
Reactant: COc1ccc(CS)cc1
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3cc(C)ccc3OS(=O)(=O)C(F)(F)F)n2)c1C(F)(F)F
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CCCCCC
Product: CCOC(=O)c1cnn(-c2cccc(-c3cc(C)ccc3SCc3ccc(OC)cc3)n2)c1C(F)(F)F
Temperature: 90 °C
Reaction time: 15 h

Procedure:
To a solution of title compound from Example 243 Step A (2.74 g, 5.23 mmol), 4-methoxy α-toluenethiol (0.88 mL, 6.28 mmol) in 1,4-dioxane (75 mL) were added DIEA (1.83 mL, 10.5 mmol), Xantphos (0.61 g, 1.05 mmol) and tris(dibenzylideneacetone)dipalladium (0) (0.48 g, 0.52 mmol), and the reaction mixture was heated at 90° C. After 15 h, the reaction mixture was allowed to cool to ambient temperature, then was diluted with hexane. The resulting yellow solid was removed by filtration, and the collected organic filtrate was concentrated in vacuo. Purification by flash chromatography on silica gel (5 to 20% ethyl acetate in hexanes) provided the title compound: LCMS m/z 528.6 [M+H]+; 1H NMR (500 MHz, CD2Cl2) δ 8.11 (s, 1H), 7.94 (t, J=7.9 Hz, 1H), 7.72 (d, J=7.8 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.36 (m, 2 H), 7.17 (d, J=8.0 Hz, 1H), 7.04 (d, J=8.5 Hz, 2H) 6.74 (d, J=8.7 Hz, 2H) 4.35 (q, J=7.1 Hz, 2H), 3.87 (s, 2H), 3.73 (s, 3H), 2.37 (s, 3H), 1.37 (t, J=7.1 Hz, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=1)[O:9][CH2:8][CH2:7][CH:6]2[C:23]([O:25][CH3:26])=[O:24])#[N:2].C(Cl)(=O)C(Cl)=O.[NH2:33][C:34]1[CH:35]=[N:36][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:38][CH:39]=1.C(N(C(C)C)CC)(C)C>ClCCl.CN(C=O)C>[F:43][C:40]([F:41])([F:42])[C:37]1[N:36]=[CH:35][C:34]([NH:33][C:18]([C:17]2[CH:21]=[CH:22][C:14]([O:13][C:12]3[CH:11]=[C:10]4[C:5]([CH:6]([C:23]([O:25][CH3:26])=[O:24])[CH2:7][CH2:8][O:9]4)=[CH:4][C:3]=3[C:1]#[N:2])=[CH:15][CH:16]=2)=[O:20])=[CH:39][CH:38]=1
Reactant: Nc1ccc(C(F)(F)F)nc1
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(C#N)cc21
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4ccc(C(F)(F)F)nc4)cc3)c(C#N)cc21
Reaction time: 0.17 h
Yield: 100.2 %

Procedure:
4-(6-cyano-4-(methoxycarbonyl)chroman-7-yloxy)benzoic acid (100 mg, 0.283 mmol) was diluted with dichloromethane (1 mL) followed by the addition of oxalyl chloride in dichloromethane (2M) (0.156 mL, 0.311 mmol) and 1 drop of DMF. After stirring for 10 minutes, 3-amino-6-(trifluoromethyl)pyridine (91.8 mg, 0.566 mmol) and diisopropylethylamine (0.123 mL, 0.708 mmol) were added and the reaction was stirred for 5 hours. The reaction was loaded onto a biotage 25 column and eluted with 5% ethyl acetate/hexanes to 100% ethyl acetate to provide the desired product (141 mg, 100% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[F:11][C:12]([F:18])([F:17])[C:13](OC)=[O:14].O>CO>[C:8]([C:4]1[CH:3]=[C:2]([NH:1][C:13](=[O:14])[C:12]([F:18])([F:17])[F:11])[CH:7]=[CH:6][CH:5]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1cccc(N)c1
Reactant: COC(=O)C(F)(F)F
Solvent: O
Solvent: CO
Product: CC(=O)c1cccc(NC(=O)C(F)(F)F)c1
Reaction time: 0.5 h
Yield: 85 %

Procedure:
10 mmol of 3′-aminoacetophenone as a starting material was dissolved in a methanol solvent in a 100 mL round-bottomed flask and 1.2 equivalents (eq) of methyl trifluoroacetate was added dropwise thereto over 30 minutes at room temperature, and subsequently the reaction mixture was stirred for 2 hours. After the completion of the reaction was confirmed by TLC, a small amount of water was added to terminate the reaction. Then, the solvent was removed under reduced pressure. The residue was dissolved in 50 mL of ethyl acetate and washed twice with 30 mL of water, dried over anhydrous sodium sulfate, and distilled under reduced pressure to obtain the desired 3-acetyl-trifluoroacetylaminobenzene (85%) as a brown oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:4][CH:3]=1.[F-:17].[K+].C(OCC)(=O)C.O>CS(C)=O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:17][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:4][CH:3]=1
Reactant: N#Cc1nc(Cl)cnc1Sc1ccccc1
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1nc(F)cnc1Sc1ccccc1
Temperature: 55 °C
Reaction time: 2.5 h
Yield: 53.6 %

Procedure:
In 3.6 mL of dimethyl sulfoxide was dissolved 0.20 g of 6-chloro-3-(phenylsulfanyl)-2-pyrazinecarbonitrile. After adding 0.42 g of potassium fluoride and 0.16 g of tetra-n-butylammonium bromide successively, the mixture thus obtained was stirred at 50-60° C. for 2.5 hours. The reaction mixture was poured into a mixture of 20 mL of ethyl acetate and 20 mL of water, and the organic layer was separated. The organic layer was washed successively with water and saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent: toluene:n-hexane=1:2] to obtain 0.10 g of 6-fluoro-3-(phenylsulfanyl)-2-pyrazinecarbonitrile as a light yellow-colored oily product.
Reaction SMILES: [Cl-].[N+]([C:5]1[CH:10]=C([N+]([O-])=O)C=C[C:6]=1[N+:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[C:22]([O:29][CH2:30][CH3:31])[CH:21]=2)=[CH:16][CH:15]=1)([O-])=O.C(N)CC.C[OH:37]>CC(C)=O>[C:30]([O-:37])(=[O:29])[CH3:31].[CH2:30]([O:29][C:22]1[CH:21]=[C:20]([C:17]2[CH:16]=[CH:15][N+:14]([CH2:6][CH2:5][CH3:10])=[CH:19][CH:18]=2)[CH:25]=[CH:24][C:23]=1[N+:26]([O-:28])=[O:27])[CH3:31]
Reactant: CO
Reactant: CCOc1cc(-c2cc[n+](-c3ccc([N+](=O)[O-])cc3[N+](=O)[O-])cc2)ccc1[N+](=O)[O-]
Agent: [Cl-]
Solvent: CC(C)=O
Solvent: CCCN
Product: CC(=O)[O-]
Product: CCC[n+]1ccc(-c2ccc([N+](=O)[O-])c(OCC)c2)cc1
Temperature: 100 °C
Yield: 94 %

Procedure:
To 1-(2,4-dinitrophenyl)-4-[3-(ethyloxy)-4-nitrophenyl]pyridinium chloride (1.2 g, 2.57 mmol) in 10 mL of MeOH was added, propylamine (0.151 g, 2.57 mmol). The mixture was heated to 100° C. for 4 h. The mixture was cooled and rotovaped down. The product was taken up in acetone. This solution was loaded onto a short silica gel column and eluted with EtOAc (˜500 mL) to remove the aniline by product. The product was then eluted with 300 mL of (10% HOAc/10% MeOH/80% DCM). The solvent was rotovaped down to give the title compound of step C (0.84 g, 2.42 mmol, 94%). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.23 (d, J=6.96 Hz, 2H), 8.63 (d, J=6.96 Hz, 2H), 8.07 (d, J=8.42 Hz, 1H), 7.90 (d, J=1.65 Hz, 1H), 7.74 (dd, J=8.42, 1.83 Hz, 1H), 4.59 (t, J=7.23 Hz, 2H), 4.38 (q, J=7.08 Hz, 2H), 1.91-2.00 (m, 2H), 1.86 (s, 3H), 1.35 (t, J=6.96 Hz, 3H), 0.89 (t, J=7.33 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][C:14]=1[N+:22]([O-:24])=[O:23].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C>CN(C=O)C.O>[NH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:9][NH:8][C:6](=[O:7])[C:5]2[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:18])=[CH:15][C:14]=1[N+:22]([O-:24])=[O:23]
Reactant: NNC(=O)c1ccc(Cl)cc1
Reactant: Nc1ccc(C(=O)O)cc1[N+](=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ccc(C(=O)NNC(=O)c2ccc(Cl)cc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 4-Chloro-benzoic acid hydrazide (5.0 g, 29 mmol) and 4-Amino-3-nitro-benzoic acid (5.3 g, 29 mmol) in DMF (100 mL) was added HOBT (3.9 g, 29 mmol), and EDCI (5.5 g, 29 mmol), followed by triethylamine (12.1 mL, 87 mmol). The mixture was stirred at ambient temperature for 18 hours. Water (50 mL) was added to the reaction mixture. The precipitate was collected by filtration, washed with water, and dried under vacuum to provide the title compound as a yellow solid. 1H NMR (DMSO-d6, 400 MHz) δ ppm 7.08 (d, J=8.97 Hz, 1H) 7.61 (m, 2H) 7.82-7.97 (m, 5H) 8.66 (d, J=2.15 Hz, 1H) 10.52 (s, 1H) 10.57 (s, 1H; (M+H)+=335.0
Reaction SMILES: O[C:2]1[C:3]([C:8]([OH:10])=O)=[N:4][CH:5]=[CH:6][N:7]=1.P(Cl)(Cl)([Cl:13])=O.[NH2:16][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[CH:19]([CH3:28])[CH2:20][C:21]2([CH3:27])[CH3:26].C(N(CC)CC)C>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:13][C:2]1[C:3]([C:8]([NH:16][C:17]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:18]=2[CH:19]([CH3:28])[CH2:20][C:21]3([CH3:27])[CH3:26])=[O:10])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: O=C(O)c1nccnc1O
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC1CC(C)(C)c2cccc(N)c21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CC1CC(C)(C)c2cccc(NC(=O)c3nccnc3Cl)c21
Yield: 61 %

Procedure:
A mixture of 0.5 g (3.57 mmols) of 3-hydroxypyrazine-2-carboxylic acid, 3 ml of phosphorus oxychloride, and one drop of pyridine was refluxed for 3 hours. The resultant reaction solution was distilled to remove excess phosphorus oxychloride. To the residue 5 ml of ethyl acetate was added. The solution was added dropwise to 10 ml of an ethyl acetate solution of 0.53 g (3 mmols) of 4-amino-1,1,3-trimethylindane and 0.4 g (3.96 mmols) of triethylamine. The resultant mixture was stirred at room temperature for 2 hours and then sequentially washed with water, sodium hydrogen carbonate, water, and a saturated brine. The washed solution was dried with magnesium sulfate and then concentrated under reduced pressure. The concentrated residue was separated and purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/4), to obtain 0.58 g of light yellow crystals (Compound No. 10 shown in Table 5). The yield was 61%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:14]=[CH:13][C:12]([C:15](=O)[CH3:16])=[CH:11][C:10]=2[CH3:18])=[CH:4][CH:3]=1.[CH3:19][C:20]([S@:23]([NH2:25])=[O:24])([CH3:22])[CH3:21]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:14]=[CH:13][C:12]([CH:15]([NH:25][S@@:23]([C:20]([CH3:22])([CH3:21])[CH3:19])=[O:24])[CH3:16])=[CH:11][C:10]=2[CH3:18])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cnc(Sc2ccc(F)cc2)c(C)c1
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)cnc1Sc1ccc(F)cc1
Yield: 74 %

Procedure:
The title compound is prepared in 74% yield (2.82 g, white solid) from 1-(6-((4-fluorophenyl)thio)-5-methylpyridin-3-yl)ethanone (2.71 g, 10.4 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide (1.89 g, 15.6 mmol) in a similar manner to Step-4 of Amine-1.
Reaction SMILES: [CH3:1][CH:2]([CH3:17])[CH2:3][CH2:4][NH:5][C:6]([C:8]1([C:13](OC)=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]1)=O.Cl.[OH-].[Na+]>C1COCC1.O>[CH3:1][CH:2]([CH3:17])[CH2:3][CH2:4][NH:5][CH2:6][C:8]1([CH2:13][OH:14])[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: COC(=O)C1(C(=O)NCCC(C)C)CCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CCNCC1(CO)CCCC1
Temperature: 75 °C
Reaction time: 5 h

Procedure:
To a solution of methyl 1-[N-(3-methylbutyl)-carbamoyl]-cyclopentanecarboxylate (900 mg, 3.7 mmol) in THF at rt was added BH3/THF complex ) 7.4 mL, 7.4 mmol) and stirred at 75° C. for 5 hours. To this reaction mixture was added 6N HCl (10 mL) and the mixture was further stirred for 30 min before the solution was neutralized by 1N NaOH. The solution was diluted with water and extracted with EtOAc. The combined extracts were dried over magnesium sulfate, and concentrated to a crude oil (700 mg, 95%). MS [M+H]+200.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[C:17]2=[C:18]3[C:10]([C:11]4[C:16]2=[CH:15][CH:14]=[CH:13][CH:12]=4)=[CH:9][CH:8]=[CH:7][C:6]3=[CH:5][CH:4]=1.[NH2:19][C:20]([CH3:25])([CH2:23][OH:24])[CH2:21][OH:22].C([O-])([O-])=O.[K+].[K+].CCO>O.Cl>[ClH:1].[C:3]1([CH2:2][NH:19][C:20]([CH3:25])([CH2:23][OH:24])[CH2:21][OH:22])[C:17]2=[C:18]3[C:10]([C:11]4[C:16]2=[CH:15][CH:14]=[CH:13][CH:12]=4)=[CH:9][CH:8]=[CH:7][C:6]3=[CH:5][CH:4]=1
Reactant: ClCc1ccc2cccc3c2c1-c1ccccc1-3
Reactant: CC(N)(CO)CO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CC(CO)(CO)NCc1ccc2cccc3c2c1-c1ccccc1-3
Yield: 43.8 %

Procedure:
To a RB flask equipped with magnetic stirring bar, condenser and N2 inlet line with bubbler was added crude 1-chloromethylfluoranthene (3C, 13.01 g, 52 mmol), 2-amino-2-methyl-1,3-propanediol (Aldrich, 5.46 g, 52 mmol), K2CO3 (MCB, 14.37 g, 0.104 mol) and abs. EtOH (300 mL). The reaction was stirred at reflux overnight, filtered hot, and the solvent removed by rotary evaporation to give a crude dark oil. This was acidified with 1N HCl and dissolved in H2O, filtered, basified with 5N NaOH solution and filtered to give a crude white solide. The material was dissolved in ethanolic HCl solution, filtered and precipitated with Et2O. Filtration followed by crystallization (abs. EtOH/Et2O, 1:4) gave after filtration and drying a 43.8% yield of 2-[(1-fluorantheneylmethyl)amino]-2-methyl-1,3-propanediol hydrochloride 0.3 H2O, mp 185-188 (dec), (C,H,N,Cl).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:18]=[C:17]([C:19]([OH:21])=O)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)[C:33]2[CH:34]=[CH:35][CH:36]=C[C:32]=2[N:31]=N1.C([O-])(O)=[O:50].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:18]=[C:17]([C:19]([N:31]3[CH2:32][CH2:33][CH2:34][C@@H:35]3[CH2:36][OH:50])=[O:21])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: O=C([O-])O
Reactant: O=C(O)c1cc(-c2ccc(F)c(F)c2)nc2ccccc12
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1cc(-c2ccc(F)c(F)c2)nc2ccccc12)N1CCC[C@@H]1CO
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-(3,4-difluoroPhenyl)-4-quinoline carboxylic acid (100 mg), BOP (220 mg) and (R)-(−)-pyrrolidine methanol (0.1 mL) in 1 ml of DMF is stirred at room temperature for 18 hours. The mixture is added to saturated aqueous NaHCO3 solution and extracted three times with EtOAc. The combined EtOAc layers are washed with brine and water, dried over Na2SO4, filtered and concentrated to afford a foam. The foam is purified by preparative silica gel thin layer chromatography, using 10% methanol in methylene chloride as the developing solvent. The desired product is obtained as a free base. 1H NMR (CDCl3) d 1.77 -1.87(3H, m), 2.16-2.22 (1H, m), 3.18-3.26 (2H, m), 3.83-3.95 (2H, m), 4.52-4.56 (1H, m), 7.23-7.30 (1H, m), 7.57 (1H, m), 7.73-7.78 (2H, m), 7.83 (1H, d), 7.87 (1H, m), 8.03-8.10 (1H, m), 8.15 (1H, d). The hydrochloride salt was prepared by treating the free base in EtOAc with a solution of hydrogen chloride in ether and collecting the resulting solid by filtration.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2.[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[N:15]1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CC(CC(C)C)=O>[S:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]([N:23]2[CH2:24][CH2:25][N:26]([CH2:2][CH2:3][C:4]3[CH:5]=[C:6]4[C:10](=[CH:11][CH:12]=3)[NH:9][C:8](=[O:13])[CH2:7]4)[CH2:27][CH2:28]2)=[N:15]1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: O=C1Cc2cc(CCCl)ccc2N1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: O=C1Cc2cc(CCN3CCN(c4nsc5ccccc45)CC3)ccc2N1

Procedure:
To a 125 ml round-bottomed flask equipped with N2 inlet and condenser were added 0.62 g (3.20 mmol) 5-(2-chloroethyl)-oxindole, 0.70 g (3.20 mmol) N-(1,2-benzisothiazol-3-yl)piperazine, 0.68 g (6.40 mmol) sodium carbonate, 2 mg sodium iodide, and 30 ml methylisobutyl ketone. The reaction was refluxed 40 hours, cooled, filtered, and evaporated. The residue was chromatographed on silica gel, eluting the byproducts with ethyl acetate (1 l) and the product with 4% methanol in ethyl acetate (1.5 l). The product fractions (Rf =0.2 in 5% methanol in ethyl acetate) were evaporated, taken up in methylene chloride, and precipitated by addition of ether saturated with HCl; the solid was filtered and washed with ether, dried, and washed with acetone. The latter was done by slurrying the solid with acetone and filtering. The title compound was obtained as a high melting, non-hygroscopic solid product, m.p. 288°-288.5° C., 0.78 g (59%).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([OH:17])=O)[CH:11]=2)[C:6]1=[O:18].[CH3:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][N:25]1[CH2:30][CH2:31][CH2:32][NH2:33]>>[Cl-:1].[Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([NH:33][CH2:32][CH2:31][CH2:30][NH+:25]3[CH2:26][CH2:27][CH2:28][CH2:29][CH:24]3[CH3:23])=[O:17])[CH:11]=2)[C:6]1=[O:18]
Reactant: CC1CCCCN1CCCN
Reactant: O=C(O)c1ccc2c(c1)C(=O)N(Cc1ccccc1Cl)C2=O
Product: CC1CCCC[NH+]1CCCNC(=O)c1ccc2c(c1)C(=O)N(Cc1ccccc1Cl)C2=O
Product: [Cl-]

Procedure:
2-(2-chloro-benzyl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-carboxylic acid (100 mg, 0.316 mmol) and 3-(2-methylpiperidin-1-yl)propan-1-amine (138 μL, 0.792 mmol) were reacted with each other. Target compound in the amount of 92 mg (60%) was obtained by following the procedure described in Example 1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH2:21])[C:11]([NH2:20])=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[CH:6][CH:7]=1.[CH:22](OCC)(OCC)OCC>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[NH:21][CH:22]=[N:20][C:11]3=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1nc(-c2ccncc2)c(-c2cccc(F)c2)nc1N
Reactant: CCOC(OCC)OCC
Product: Fc1cccc(-c2nc3[nH]cnc3nc2-c2ccncc2)c1
Temperature: 140 °C
Yield: 44 %

Procedure:
A mixture of 5-(3-fluorophenyl)-6-pyridin-4-ylpyrazine-2,3-diamine (Example 72, 300 mg, 1.07 mmol) in 1,1′,1″-[methanetriyltris(oxy)]triethane (3 mL) was stirred and heated at 140° C. overnight. The solvent was removed under vacuum and the residue was triturated with diethyl ether. The resulting solid was purified by silica gel column chromatography (CH2Cl2/MeOH 9:1) to afford the title compound as a yellow solid (136 mg, 44%)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH:5]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]#[N:25])=[CH:20][CH:19]=1)[C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[CH:9]=[C:8]([OH:15])[C:7]=1[F:16])[CH3:2].O[C@H:28]1[CH2:32][CH2:31][O:30][CH2:29]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:1]([O:3][C:4](=[O:26])[CH:5]([NH:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]#[N:25])=[CH:22][CH:23]=1)[C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[CH:9]=[C:8]([O:15][C@@H:28]2[CH2:32][CH2:31][O:30][CH2:29]2)[C:7]=1[F:16])[CH3:2]
Reactant: O[C@H]1CCOC1
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(OCC)cc(O)c1F
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(OCC)cc(O[C@@H]2CCOC2)c1F
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 7.38 g (RS)-(4-cyano-phenylamino)-(5-ethoxy-2-fluoro-3-hydroxy-phenyl)-acetic acid ethyl ester described in example 3.5 in 220 ml THF were added 1.68 ml (S)-(+)-3-hydroxy-tetrahydrofurane and 6.48 g triphenylphosphine. The mixture was cooled to 0° C. Subsequently, 3.84 ml of diethyl azodicarboxylate were added. The solution was stirred for 3 hrs at room temperature, then evaporated. The crude product was purified by chromatography on silica gel (cyclohexane/EtOAc) to give 6.53 g of (RS)-(4-cyano-phenylamino)-[5-ethoxy-2-fluoro-3-[(R)-tetrahydro-furan-3-yloxy]-phenyl]-acetic acid ethyl ester as an off-white solid.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][NH:3]1.FC(F)(F)S(O[C:25]1[CH:26](C)[O:27][C:28](=[O:31])[C:29]=1[F:30])(=O)=O.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.O>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:30][C:29]1[C:28](=[O:31])[O:27][CH2:26][C:25]=1[N:3]1[CH2:4][CH2:5][C:6]2([CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[C:2]1=[O:1]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNC2=O)CC1
Reactant: CC1OC(=O)C(F)=C1OS(=O)(=O)C(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(C1=C(F)C(=O)OC1)C2=O

Procedure:
A mixture of tert-butyl 1-oxo-2,8-diazaspiro[4.5]decane-8-carboxylate (150 mg, 0.590 mmol), 4-fluoro-2-methyl-5-oxo-2,5-dihydrofuran-3-yl trifluoromethanesulfonate (148 mg, 0.590 mmol), xantphos (34.1 mg, 0.059 mmol), water (0.032 mL, 1.77 mmol) in toluene (20 mL) was degassed by nitrogen followed by addition of palladium acetate (6.6 mg, 0.029 mmol).