Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(C(F)(F)F)=CC=1N.C1N=C[N:16]([C:19](N2C=NC=C2)=[O:20])C=1.[CH3:26][NH:27][C:28]([C:30]1[CH:35]=[C:34]([O:36][C:37]2[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=2)[CH:33]=[CH:32][N:31]=1)=[O:29].O>C(Cl)Cl>[CH3:26][NH:27][C:28]([C:30]1[CH:35]=[C:34]([O:36][C:37]2[CH:43]=[CH:42][C:40]([NH:41][C:19]([NH2:16])=[O:20])=[CH:39][CH:38]=2)[CH:33]=[CH:32][N:31]=1)=[O:29]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Agent: COc1ccc(C(F)(F)F)cc1N
Solvent: ClCCl
Solvent: O
Product: CNC(=O)c1cc(Oc2ccc(NC(N)=O)cc2)ccn1
Reaction time: 16 h

Procedure:
To a solution of 2-methoxy-5-(trifluoromethyl)aniline (0.15 g) in anh CH2Cl2 (15 mL) at 0° C. is added CDI (0.13 g). The resulting solution is allowed to warm to room temp. over 1 h, is stirred at room temp. for 16 h, then is treated with 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline (0.18 g) from Step 2. The resulting yellow solution is stirred at room temp. for 72 h, then is treated with H2O (125 mL). The resulting aqueous mixture is extracted with EtOAc (2×150 mL). The combined organics are washed with a saturated NaCl solution (100 mL), dried (MgSO4) and concentrated under reduced pressure. The residue is triturated (90% EtOAc/10% hexane). The resulting white solids are collected by filtration and washed with EtOAc. The filtrate is concentrated under reduced pressure and the residual oil purified by column chromatography (gradient from 33% EtOAc/67% hexane to 50% EtOAc/50% hexane to 100% EtOAc) to give N-(2-methoxy-5-(trifluoromethyl)phenyl)-N)-(4-(2-(N-methylcarbamoyl)-4-pyridyloxy)phenyl)urea as a light tan solid: TLC (100% EtOAc) Rf 0.62; 1H NMR (DMSO-d6) δ 2.76 (d, Hz, 3H), 3.96 (s, 3H), 7.1-7.6 and 8.4-8.6 (m, 11H), 8.75 (d, J=4.8 Hz, 1H), 9.55 (s, 1H); FAB-MS m/z 461 ((M+H)+).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[CH:12]1[CH:17]=[CH:16][C:15]([O:18][C:19](OC2C=CC=CC=2)=[N:20][C:21]#[N:22])=[CH:14][CH:13]=1.C(N(CC)CC)C>ClCCl>[F:1][C:2]([F:10])([F:11])[C:3]1[CH:4]=[C:5]([NH:6][C:19](=[N:20][C:21]#[N:22])[O:18][C:15]2[CH:16]=[CH:17][CH:12]=[CH:13][CH:14]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: N#CN=C(Oc1ccccc1)Oc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#CN=C(Nc1cccc(C(F)(F)F)c1)Oc1ccccc1
Reaction time: 23 h
Yield: 46.5 %

Procedure:
To a solution of 3-trifluoromethylaniline (11 mmol, 1.37 ml) in dichloromethane (25 ml), diphenylcyanocarbonimidate (10 mmol, 2.38 g), and triethylamine (11 mmol, 1.53 ml) were added. The mixture was stirred under nitrogen for 23 h. After concentration the residue was stirred with water, the water was decanted followed by concentration. The residue was stirred with toluene and the solid was collected by filtration giving 1.42 g of N-(3-trifluoromethylphenyl)-N'-cyano-O-phenylisourea (50%);
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([CH:6]1[CH2:11][CH2:10][N:9](C)[CH2:8][CH2:7]1)=[O:5].C(=O)([O-])[O-].[K+].[K+].[C:23]1([O:29][C:30](Cl)=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CCCCCC>C1(C)C=CC=CC=1>[O:29]([C:30]([N:9]1[CH2:10][CH2:11][CH:6]([C:4](=[O:5])[C:3]2[CH:13]=[CH:14][CH:15]=[CH:16][C:2]=2[F:1])[CH2:7][CH2:8]1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CN1CCC(C(=O)c2ccccc2F)CC1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: O=C(c1ccccc1F)C1CCN(C(=O)Oc2ccccc2)CC1
Temperature: 25 °C
Yield: 57.1 %

Procedure:
To a solution of 57.5 g of 4-(2-fluorobenzoyl)-1-methyl piperidine and 68.7 g of potassium carbonate in 750 ml of toluene was added with stirring 47 g of phenylchloroformate. The reaction mixture was heated under reflux for 5 hrs, cooled to room temperature, filtered, and the solvent removed under reduced pressure to give an oil. Trituration of the oil with hexane gave 48.6 g (46%) of product. Recrystallization of 1.0 g of product from ethanol-water (2×) and from ethanol gave the analytical sample, mp 95°-96° C.
Reaction SMILES: [H-].[Na+].[CH:3]1(Br)[CH2:7][CH2:6][CH2:5][CH2:4]1.CN(C=O)C.[CH:14]1([N:19]2[CH2:24][CH2:23][CH:22]([O:25][C:26]3[N:31]=[CH:30][C:29]([C:32]4[CH:33]=[CH:34][C:35](=[O:38])[NH:36][CH:37]=4)=[CH:28][N:27]=3)[CH2:21][CH2:20]2)[CH2:18][CH2:17][CH2:16][CH2:15]1>O>[CH:14]1([N:19]2[CH2:24][CH2:23][CH:22]([O:25][C:26]3[N:27]=[CH:28][C:29]([C:32]4[CH:33]=[CH:34][C:35]([O:38][CH:3]5[CH2:7][CH2:6][CH2:5][CH2:4]5)=[N:36][CH:37]=4)=[CH:30][N:31]=3)[CH2:21][CH2:20]2)[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: O=c1ccc(-c2cnc(OC3CCN(C4CCCC4)CC3)nc2)c[nH]1
Reactant: BrC1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: c1cc(OC2CCCC2)ncc1-c1cnc(OC2CCN(C3CCCC3)CC2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
60% sodium hydride (21 mg) and cyclopentyl bromide were added to a DMF solution (4 ml) of 2-(1-cyclopentylpiperidin-4-yloxy)-5-(1H-pyridin-2-on-5-yl)pyrimidine (120 mg), and stirred at room temperature for 2 hours. Water was added to the reaction mixture, and extracted with ethyl acetate. The organic layer was washed with saturated saline solution, dried with anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified through silica gel column chromatography (chloroform:methanol=9:1) to obtain the entitled compound.
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[C:3]1[CH:4]=[C:5]([CH:40]=[CH:41][CH:42]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=2)[C:34](O)=[O:35])=[O:30])[CH:11]=1)=[O:9].CN(CCN1CCOCC1)C(=O)C1C=CC=[C:50]([C:51]([NH:53][C:54]2C=CC(N3CCCCC3)=C[C:55]=2[C:66]2C=C(C(=O)NCC3C=CC=C(C(F)(F)F)C=3)C=[CH:68][N:67]=2)=[O:52])C=1.CC#N.N1CC[C@H](NC(=O)C)C1>CN(C=O)C>[C:51]([NH:53][C@H:54]1[CH2:55][CH2:66][N:67]([C:34]([C:33]2[CH:32]=[C:31]([CH:39]=[CH:38][CH:37]=2)[C:29]([NH:28][C:17]2[CH:18]=[CH:19][C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:21][C:16]=2[C:12]2[CH:11]=[C:10]([CH:15]=[CH:14][N:13]=2)[C:8]([NH:7][CH2:6][C:5]2[CH:40]=[CH:41][CH:42]=[C:3]([C:2]([F:1])([F:44])[F:43])[CH:4]=2)=[O:9])=[O:30])=[O:35])[CH2:68]1)(=[O:52])[CH3:50]
Reactant: O=C(O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reactant: CN(CCN1CCOCC1)C(=O)c1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: CC(=O)N[C@H]1CCNC1
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC(=O)N[C@H]1CCN(C(=O)c2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)C1

Procedure:
This compound was prepared from 3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)carbamoyl)benzoic acid 4.1e using the procedure described for the preparation of N1-methyl-N1-(2-morpholinoethyl)-N3-(4-(piperidin-1-yl)-2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)phenyl)isophthalamide 4.8, except that CH3CN was substituted for DMF as the reaction solvent and (S)—N-(pyrrolidin-3-yl)acetamide was used as the amine component. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.88 (d, J=3.5 Hz, 1H), 8.69˜8.663 (m, 1H), 8.33 (s, 1H), 8.10˜8.05 (m, 2H), 8.00˜7.97 (m, 1H), 7.76 (d, J=5.2 Hz, 1H), 7.71˜7.66 (m, 1H), 7.60˜7.43 (m, 6H), 4.60 (s, 2H), 4.40˜4.16 (m, 1H), 3.71˜3.21 (m, 8H), 2.22˜1.71 (m, 11H). MS (ES, m/z): 713 [M+H]+.
Reaction SMILES: CC([N:5]([CH2:9][C:10]([NH:12][N:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[Cl:18])=[O:11])C(=O)[O-])(C)C.Cl>CCOC(C)=O.CCOCC>[ClH:18].[NH2:5][CH2:9][C:10]([NH:12][N:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[Cl:18])=[O:11]
Reactant: CC(C)(C)N(CC(=O)Nn1cccc1Cl)C(=O)[O-]
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: NCC(=O)Nn1cccc1Cl
Reaction time: 19 h
Yield: 62.8 %

Procedure:
To a stirred solution of 1,1-dimethylethyl-[2-(2-chloro-1H-pyrrol-1-ylamino)-2-oxoethyl]carbamate (3.1 g) in EtOAc (20 ml) and ether (20 ml) was added ethereal HCl (excess) at room temperature. The reaction mixture was allowed to stir for 19 hours at which time the precipitated product was faltered and washed with EtOAc. Recrystallization from ethanol/ether afforded 0.75 g of the product as a solid, m.p. 220° C. (dec.).
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C@:3]21[CH2:26][C:25]1[C:20](=[CH:21][CH:22]=[C:23]([SH-:27]C(=S)OCC)[CH:24]=1)[CH2:19]2.[OH-].[Na+].O>CCO>[SH:27][C:23]1[CH:24]=[C:25]2[C:20](=[CH:21][CH:22]=1)[CH2:19][C@:3]1([C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[N:10]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:16])([CH3:17])[CH3:18])[C:2]1=[O:1])[CH2:26]2
Reactant: CCOC(=S)[SH-]c1ccc2c(c1)C[C@@]1(C2)C(=O)N(COCC[Si](C)(C)C)c2ncccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: C[Si](C)(C)CCOCN1C(=O)[C@@]2(Cc3ccc(S)cc3C2)c2cccnc21
Temperature: 60 °C

Procedure:
To a stirred solution of O-ethyl S-[(2R)-2′-oxo-1′-{[2-(trimethylsilyl)ethoxy]methyl}-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-yl]carbonodithioate from Step B (740 mg, 1.52 mmol) in EtOH (4 mL) was added 1 N NaOH (3.0 mL, 3.0 mmol). The resulting suspension was heated at 60° C. for 90 min, then cooled and poured into H2O (50 mL). The mixture was extracted with EtOAc (2×70 mL), and the combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated in vacuo to yield the title compound. MS: m/z=462 (M+Na+CH3CN).
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([Mg]Br)=[CH:3][CH:2]=1.[CH3:10][Sn:11](Cl)([CH3:13])[CH3:12].[Cl-].[NH4+].O>O1CCCC1>[C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([Sn:11]([CH3:13])([CH3:12])[CH3:10])=[CH:3][CH:2]=1
Reactant: C[Sn](C)(C)Cl
Reactant: Cc1ccc([Mg]Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc([Sn](C)(C)C)cc1
Temperature: 25 °C
Yield: 82.5 %

Procedure:
p-Tolylmagnesium bromide solution (Aldrich) (1.0M solution in diethyl ether) (53 ml, 0.0530 mol) was added dropwise to trimethyltin chloride (6.92 g, 0.0347 mol) in tetrahydrofuran (50 ml) under nitrogen at -10° C. The suspension was allowed to warm slowly to room temperature over 3 hours; then saturated ammonium chloride solution (10 ml) was added, followed by sufficient water to dissolve the precipitate. The solution was extracted three times with diethyl ether-hexane (1:1). The combined organic phase was washed with brine, dried (magnesium sulfate) and the solvents removed in vacuo. Vacuum distillation of the residue afforded a colorless liquid (bp 39°-40° C., 0.1 mm Hg) which was further purified by flash chromatography (silica gel, hexane) to give p-tolyltrimethyltin (7.30 g, 82%) as a colorless liquid; 1H NMR (300 MHz, CDCl3) δ7.40 (d, J=7.7 Hz, 2H), 7.19 (d, J=7.7 Hz, 2H), 2.34 (s, 3H), 0.30 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30](=[O:50])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[C:41]([CH2:42][O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][O:45]3)=[CH:40][N:39]=[N:38]2)[CH:32]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30](=[O:50])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]2[C:41]([CH2:42][O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][O:45]3)=[CH:40][N:39]=[N:38]2)[CH:32]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J6) (160 mg, 0.5 mmol) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionic acid tert-butyl ester (Example K5) (201 mg, 0.5 mmol) according to the general procedure M. Obtained as an amorphous yellow substance (247 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[C:4]([O:11][CH3:12])[CH:3]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH:17]=O.C[O-].[Na+]>CO>[Cl:1][C:2]1[CH:10]=[CH:9][C:5](/[C:6](=[CH:17]/[C:16]2[CH:19]=[CH:20][CH:21]=[C:14]([Cl:13])[CH:15]=2)/[C:7]#[N:8])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1cc(Cl)ccc1CC#N
Reactant: O=Cc1cccc(Cl)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(Cl)ccc1/C(C#N)=C/c1cccc(Cl)c1
Yield: 62.5 %

Procedure:
In a manner similar to the method described in Example 1b, 4-chloro-2-methoxybenzyl cyanide (2 g, 10 mmol) prepared in Example 58a Step B was reacted with 3-chlorobenzaldehyde (2 g, 14 mmol), methanolic solution (25 wt %) of sodium methoxide (15 mL, 66 mmol) in methanol (50 mL) at 50° C. for 5 h to give (Z)-2-(4-chloro-2-methoxy-phenyl)-3-(3-chloro-phenyl)-acrylonitrile as a white powder (1.9 g, 63%).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[CH2:12][CH2:11][C:10](=[O:13])[NH:9][C:5]2=[N:6][C:7]=1[Cl:8].Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[N:3]=[C:4]2[CH2:12][CH2:11][C:10](=[O:13])[N:9]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:5]2=[N:6][C:7]=1[Cl:8]
Reactant: O=C1CCc2nc(Br)c(Cl)nc2N1
Reactant: CCOC(=O)CCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCCCN1C(=O)CCc2nc(Br)c(Cl)nc21

Procedure:
A solution of 2-bromo-3-chloro-7,8-dihydro-5H-pyrido[2,3-b]pyrazin-6-one (Intermediate J) (3.9 g, 14.86 mmol) and ethyl 7-bromoheptanoate (7.05 g, 29.7 mmol) in DMF (75 ml) under nitrogen was treated with potassium carbonate (10.27 g, 74.3 mmol) and the resultant solution was stirred at room temperature for 96 hours. The mixture was diluted with water and extracted with EtOAc (×2). The combined organic extracts were washed with water, brine, dried (MgSO4) and concentrated in vacuo. Purification of the crude product by chromatography on silica eluting with 0-60% EtOAc/iso-hexane 0-60% afforded the title compound;
Reaction SMILES: [OH:1][CH:2]1[CH2:25][NH:24][CH2:23][CH2:22][C:3]21[C:7](=[O:8])[N:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH:16]([CH3:21])[C:17]([F:20])([F:19])[F:18])=[CH:11][CH:10]=1)[CH2:5][CH2:4]2.[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33](Cl)(=[O:35])=[O:34]>>[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[S:33]([N:24]1[CH2:23][CH2:22][C:3]2([C:7](=[O:8])[N:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH:16]([CH3:21])[C:17]([F:20])([F:18])[F:19])=[CH:11][CH:10]=3)[CH2:5][CH2:4]2)[CH:2]([OH:1])[CH2:25]1)(=[O:35])=[O:34]
Reactant: CC(Oc1ccc(N2CCC3(CCNCC3O)C2=O)cc1)C(F)(F)F
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Product: CC(Oc1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4Cl)CC3O)C2=O)cc1)C(F)(F)F

Procedure:
The title compound was prepared in analogy to example 2 step B from a mixture of (5SR,6RS)-6-hydroxy-2-[4-((rac)-2,2,2-trifluoro-1-methyl-ethoxy)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one and 2-chloro-benzenesulfonyl chloride. Light yellow solid. MS (ESI): 533.1 (MH+)
Reaction SMILES: NN1CCCC1.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([N:17]2[CH2:21][CH2:20][C@H:19]([NH:22][C:23]3[N:32]=[C:31]([N:33]4[CH2:38][CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34]4)[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=3)[CH2:18]2)=[O:16])=[CH:10][CH:9]=1.[ClH:46]>CO.C(OCC)(=O)C>[ClH:7].[ClH:46].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][C:15]([N:17]2[CH2:21][CH2:20][C@H:19]([NH:22][C:23]3[N:32]=[C:31]([N:33]4[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]4)[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[N:24]=3)[CH2:18]2)=[O:16])=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(N[C@H]3CCN(C(=O)Cc4ccc(Cl)cc4)C3)nc3ccccc23)CC1
Agent: Cl
Agent: NN1CCCC1
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(Cc1ccc(Cl)cc1)N1CC[C@H](Nc2nc(N3CCNCC3)c3ccccc3n2)C1
Reaction time: 8 h

Procedure:
To a mixture of t-butyl 4-(2-((S)-pyrrolidin-3-ylamino)quinazolin-4-yl)piperazine-1-carboxylate (0.30 g), p-chlorophenylacetic acid (0.13 g), and chloroform (5 mL) were added HOBt.H2O (0.18 g) and EDC.HCl (0.18 g), and the mixture was stirred at room temperature for 2 days. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate, and the mixture was extracted with chloroform. The organic layer was dried with anhydrous sodium sulfate, the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, hexane/ethyl acetate=3:2) to obtain t-butyl 4-(2-((S)-1-(2-(4-chlorophenyl)ethanoyl)pyrrolidin-3-ylamino)quinazolin-4-yl)piperazine-1-carboxylate (0.29 g). (2) To a solution of t-butyl 4-(2-((S)-1-(2-(4-chlorophenyl)ethanoyl)pyrrolidin-3-ylamino)quinazolin-4-yl)piperazine-1-carboxylate (0.28 g) in methanol (5 mL) was added a solution (1.3 mL) of 4 M HCl in ethyl acetate, and the mixture was stirred overnight. The solvent was evaporated under reduced pressure, and the residue was crystallized in diethyl ether to obtain the title compound (0.15 g).
Reaction SMILES: [ClH:1].NC(=O)[C@@H:4]([NH:11][C:12](=[O:32])[CH2:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH2:30])[CH:25]=2)=[C:19]([F:31])[CH:18]=1)=[O:15])[C:5]1C=C[CH:8]=[CH:7][CH:6]=1.C1(N)CCCC1>>[ClH:1].[NH2:30][C:26]1[CH:25]=[C:24]([O:23][C:20]2[CH:21]=[CH:22][C:17]([NH:16][C:14](=[O:15])[CH2:13][C:12]([NH:11][CH:4]3[CH2:5][CH2:6][CH2:7][CH2:8]3)=[O:32])=[CH:18][C:19]=2[F:31])[CH:29]=[CH:28][N:27]=1
Reactant: NC(=O)[C@@H](NC(=O)CC(=O)Nc1ccc(Oc2ccnc(N)c2)c(F)c1)c1ccccc1
Agent: Cl
Agent: NC1CCCC1
Product: Nc1cc(Oc2ccc(NC(=O)CC(=O)NC3CCCC3)cc2F)ccn1
Yield: 44 %

Procedure:
3-(4-(2-Aminopyridin-4-yloxy)-3-fluorophenylamino)-3-oxopropanoic acid (Compound C of Example 102, 30 mg, 0.10 mmol) was coupled with cyclopentanamine (Aldrich, 17 mg, 0.2 mmol) in a manner similar to that which is described in Step C of Example 1 to give N1-(4-(2-aminopyridin-4-yloxy)-3-fluorophenyl)-N3-cyclopentylmalonamide, hydrochloride salt (18 mg, 44% yield). 1H NMR (DMSO-d6) δ 13.34 (s, 1H), 10.66 (s, 1H), 8.15 (d, 1H, J=7.0 Hz), 7.96 (d, 1H, J=7.0 Hz), 7.77-7.88 (m, 3H), 7.42 (m, 2H), 6.70 (d, 1H, J=7.5 Hz), 6.12 (s, 1H), 3.98 (m, 1H), 3.69 (s, 2H), 1.78 (m, 2H), 1.63 (m, 2H), 1.49 (m, 2H), 1.37 (m, 2H); MS (ESI+) m/z 373.30 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[CH2:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH:22]1[NH2:30].C(N(C(C)C)CC)(C)C.C(O)CC(C)C>C(OCC)(=O)C>[CH2:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:23][CH:22]1[NH:30][C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11]
Reactant: Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: NC1Cc2ccccc2C1
Solvent: CCOC(C)=O
Solvent: CC(C)CCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc(NC2Cc3ccccc3C2)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O

Procedure:
A mixture of 1.0 g of 2-chloroadenosine, 1.2 g of 2-indanylamine, and 1.6 ml of diisopropylethylamine and 1.0 ml of isoamyl alcohol is refluxed for 16 hours. The reaction mixture is diluted with ethyl acetate and washed with saturated sodium bicarbonate solution. After drying over magnesium sulfate the solvent is removed in vacuo and the residue is chromatographed on silica gel with 10:1 methylene chloride/ammonia saturated methanol as the eluent. The resulting product is recrystallized from methanol to afford 2-(2-indanylamino)-adenosine melting at 129°-132°.
Reaction SMILES: [O:1]([CH2:8][C:9]1[NH:10][CH:11]=[C:12]([C:14]2[CH:27]=[CH:26][C:17]([O:18][C:19]3[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=3)=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:28]([N:31]=[C:32]=[O:33])([CH3:30])[CH3:29].O.C(OCC)(=O)C>CN(C)C=O>[CH:28]([NH:31][C:32]([NH:23][C:22]1[CH:21]=[CH:20][C:19]([O:18][C:17]2[CH:26]=[CH:27][C:14]([C:12]3[N:13]=[C:9]([CH2:8][O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[NH:10][CH:11]=3)=[CH:15][CH:16]=2)=[CH:25][CH:24]=1)=[O:33])([CH3:30])[CH3:29]
Reactant: CC(C)N=C=O
Reactant: Nc1ccc(Oc2ccc(-c3c[nH]c(COc4ccccc4)n3)cc2)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)NC(=O)Nc1ccc(Oc2ccc(-c3c[nH]c(COc4ccccc4)n3)cc2)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
A mixture containing 4-{4-[2-(phenoxymethyl)-1H-imidazol-4-yl]phenoxy}aniline (0.2 g, 0.56 mmol) and isopropylisocyanate (0.155 g, 1.8 mmol) in 3 ml of dimethylformamide is heated at 100° C. for two hours then stirred at ambient temperature for two hours. 20 ml of water and 30 ml of ethyl acetate are added, followed by extraction, then the organic phase is washed with a saturated sodium chloride solution. The organic phase is dried over sodium sulfate. After evaporation to dryness, the oil obtained is triturated in isopentane. After filtration then drying, the solid obtained is purified on a silica column (eluent dichloromethane-ethanol-ammonia 96/2/2) and a pink-cream coloured powder is obtained with a yield of 20%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][C:12]=1[OH:20].[OH-].[Na+].[CH3:23][C:24]([CH3:49])([CH2:37]C1C=C(C)C=CC=1S([O-])(=O)=O)[CH2:25]C1C=C(C)C=CC=1S([O-])(=O)=O>CN(C=O)C>[CH3:23][C:24]1([CH3:49])[CH2:37][O:20][C:12]2[CH:13]=[C:14]([C:17](=[O:19])[CH3:18])[CH:15]=[CH:16][C:11]=2[C:3]2[CH:4]=[CH:5][C:6]([C:8](=[O:10])[CH3:9])=[CH:7][C:2]=2[O:1][CH2:25]1
Reactant: Cc1ccc(S(=O)(=O)[O-])c(CC(C)(C)Cc2cc(C)ccc2S(=O)(=O)[O-])c1
Reactant: CC(=O)c1ccc(-c2ccc(C(C)=O)cc2O)c(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2c(c1)OCC(C)(C)COc1cc(C(C)=O)ccc1-2
Temperature: 150 °C
Reaction time: 20 h
Yield: 31.9 %

Procedure:
To a solution of 1,1′-(2,2′-dihydroxy-[1,1′-biphenyl]-4,4′-diyl)-diethanone (0.2 g, 0.74 mmol) (synthesized according to WO 2010/111673) in anhydrous DMF (10 mL), NaOH (0.08 g, 1.85 mmol) and 2,2-dimethylpropane-1,3-diyl-bis-(4-methylbenzenesulfonate) (0.37 g, 0.89 mmol) (synthesized according to US 2005/0113374) were added successively and the suspension was stirred at 150° C. for 20 h under nitrogen atmosphere. The reaction mixture was brought to room temperature, crushed ice was added and stirred vigorously for 15 min. The contents were extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and purified by flash column chromatography (20% Ethyl acetate-Hexane) to yield a white solid (0.08 g, 32%). m/z 339.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][CH:3]=1.N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>ClCCl.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1ccc(Br)cc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (4-bromophenyl)methanol (3.0 g, 16.04 mmol) and imidazole (1.42 g, 20.85 mmol) in dichloromethane was added tert-butyl dimethylsilyl chloride (3.14 g, 20.85 mmol) and the mixture was stirred at room temperature overnight. The reaction was diluted with water, extracted with ethyl acetate (2×) and concentrated. The residue was absorbed onto silica and purified by flash column chromatography (silica gel, ethyl acetate/hexanes) to give the desired product. 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J=8.4 Hz, 2H), 7.20 (d, J=8.3 Hz, 2H), 4.68 (s, 2H), 0.94 (s, 9H), 0.09 (s, 6H).