Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8](I)=[CH:9][CH:10]=3)[C@@:5]3([CH2:20][O:19][C:18]([NH2:21])=[N:17]3)[C:4]=2[CH:3]=1.[C:22]([O:26][CH3:27])(=[O:25])[CH:23]=[CH2:24].P.C(N(CC)CC)C>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:21][C:18]1[O:19][CH2:20][C@@:5]2([N:17]=1)[C:4]1[CH:3]=[C:2]([Br:1])[CH:15]=[CH:14][C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8](/[CH:24]=[CH:23]/[C:22]([O:26][CH3:27])=[O:25])=[CH:9][CH:10]=1
Reactant: NC1=N[C@]2(CO1)c1cc(Br)ccc1Oc1ccc(I)cc12
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: P
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1ccc2c(c1)[C@@]1(COC(N)=N1)c1cc(Br)ccc1O2
Temperature: 120 °C

Procedure:
A mixture of (R)-2′-bromo-7′-iodo-5H-spiro[oxazole-4,9′-xanthen]-2-amine (3.00 g, 6.56 mmol), methyl acrylate (0.621 mL, 6.89 mmol), phosphine, tri-o-tolyl (0.400 g, 1.313 mmol), palladium(ii) acetate (0.295 g, 1.313 mmol), and triethylamine 99.5% (1.826 mL, 13.13 mmol) in DMF (12 mL) in a microwave vial was purged with argon for 5 min, capped, and heated to 120° C. for 40 min in a microwave. The reaction mixture was diluted with EtOAc (100 mL) and washed with water, dried over Na2SO4, and concentrated. The product was purified with ISCO using 0-70% EtOAc in hexanes to give (S,E)-methyl 3-(2-amino-2′-bromo-5H-spiro[oxazole-4,9′-xanthene]-7′-yl)acrylate. MS (ESI pos. ion) m/z: 416.9 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1[N:13]([CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:6]2[N:7]=[C:8]([C:11]#[N:12])[N:9]=[CH:10][C:5]=2[CH:4]=1.[C:22]([O:26][C:27]([N:29]1[CH2:33][CH2:32][C:31]2([CH2:38][CH2:37][NH:36][CH2:35][CH2:34]2)[CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[C:22]([O:26][C:27]([N:29]1[CH2:33][CH2:32][C:31]2([CH2:38][CH2:37][N:36]([CH2:2][C:3]3[N:13]([CH2:14][CH2:15][CH:16]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]4)[C:6]4[N:7]=[C:8]([C:11]#[N:12])[N:9]=[CH:10][C:5]=4[CH:4]=3)[CH2:35][CH2:34]2)[CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Reactant: N#Cc1ncc2cc(CBr)n(CCC3CCCCC3)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CCN(Cc3cc4cnc(C#N)nc4n3CCC3CCCCC3)CC2)C1
Temperature: 25 °C
Reaction time: 14 h
Yield: 71 %

Procedure:
To a solution of 6-bromomethyl-7-(2-cyclohexyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (290 mg, 0.84 mmol) in DMF (1.7 ml), 2,8-Diaza-spiro[4.5]decane-2-carboxylic acid tert-butyl ester (201 mg, 0.84 mmol) and potassium carbonate (138 mg, 1.0 mmol) are added. The mixture is stirred at room temperature under nitrogen atomosphere for 14 h. The reaction mixture is diluted with water and extracted with AcOEt (twice). The combined organic layer is washed with water and brine, dried over MgSO4, and concentrated in vacuo. The residue is purified by silica gel column chromatography (n-hexane:AcOEt=1:1) to give 8-[2-Cyano-7-(2-cyclohexyl-ethyl)-7H-pyrrolo[2,3-d]pyrimidin-6-ylmethyl]-2,8-diaza-spiro[4.5]decane-2-carboxylic acid tert-butyl ester in 71% yield. Rf=0.45(n-hexane:AcOEt=1:1).
Reaction SMILES: C1(C)C=CC(S([O:10][C@H:11]2[CH2:30][CH2:29][C@@:28]3([CH3:31])[C@@H:13]([CH2:14][CH2:15][C@@H:16]4[C@@H:27]3[C:26](=[O:32])[CH2:25][C@@:24]3([CH3:33])[C@H:17]4[CH2:18][CH:19]=[C:20]3[C:21](=[O:23])[CH3:22])[CH2:12]2)(=O)=O)=CC=1.C([O-])(=O)C.[K+].CN(C)C=O>O>[OH:10][C@@H:11]1[CH2:30][CH2:29][C@@:28]2([CH3:31])[C@@H:13]([CH2:14][CH2:15][C@@H:16]3[C@@H:27]2[C:26](=[O:32])[CH2:25][C@@:24]2([CH3:33])[C@H:17]3[CH2:18][CH:19]=[C:20]2[C:21](=[O:23])[CH3:22])[CH2:12]1
Reactant: CC(=O)C1=CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](OS(=O)(=O)c5ccc(C)cc5)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)C1=CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
A stirred mixture of 3β-toluene-p-sulphonyloxy-5α-pregn-16-ene-11,20-dione (627 g.), potassium acetate (918 g.), dimethylformamide (4.25 l.) and water (425 ml.) was heated on the steam bath for 4 hr. Most of the dimethylformamide was removed under reduced pressure and water was added to the residue with stirring. The solid (420 g.) was collected, washed and dried at 40° in vacuo. This material in peroxide free dioxan (7 l.) was flushed with nitrogen and a solution of potassium hydroxide (200 g.) in water (2 l.) was added. The mixture was stirred and heated at 50°-60° for 7 hr. and then left at room temperature overnight. Acetic acid (50 ml.) was added and the precipitated solid was filtered off, washed with water and dried. The dry solid was heated under reflux with benzene (2 l.) for 2 hr. the mixture cooled and filtered to give 3α-hydroxy-5α-pregn-16-ene-11,20-dione (215 g.).
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[O:19][C:18](=[O:21])[C:17]([C:22]([OH:24])=O)=[CH:16]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:49][O:50][C:51]1[CH:56]=[CH:55][C:54]([C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([NH2:63])[CH:58]=2)=[CH:53][CH:52]=1>CN(C=O)C>[CH3:49][O:50][C:51]1[CH:52]=[CH:53][C:54]([C:57]2[CH:62]=[CH:61][CH:60]=[C:59]([NH:63][C:22]([C:17]3[C:18](=[O:21])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[CH:12][C:11]=4[OH:10])=[O:24])[CH:58]=2)=[CH:55][CH:56]=1
Reactant: O=C(O)c1cc2cccc(O)c2oc1=O
Reactant: COc1ccc(-c2cccc(N)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cccc(NC(=O)c3cc4cccc(O)c4oc3=O)c2)cc1
Temperature: 25 °C
Yield: 51.6 %

Procedure:
DIEA (0.0144 mL, 0.083 mmol) was added to 8-hydroxy-3-carboxy-coumarin (0.016 g, 0.075 mmol) and HATU (0.032 g, 0.083 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 4′-Methoxy-biphenyl-3-ylamine (0.015 g, 0.075 mmol) was added and allowed to react overnight. DMF was removed under vacuum and the reaction was resuspended in DMSO. The crude product was purified on a Parallex Flex parallel preparative reverse phase HPLC instrument (Biotage) using a solvent gradient of 10-95% ACN/H2O with 0.05% TFA at a flow rate of 20 mL/min. UV absorbance was monitored at 254 nm and the fractions corresponding to the product peak were collected and the solvent removed under vacuum to give 0.015 g of product in 52% yield: LCMS (ESI) m/z 388 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2Cl.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([CH3:27])([CH3:26])[C:24]#[N:25])=[CH:19][CH:18]=1.O>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([N+:12]([O-:14])=[O:13])=[C:5]2[NH:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]([CH3:27])([CH3:26])[C:24]#[N:25])=[CH:21][CH:22]=1
Reactant: O=[N+]([O-])c1cnc2ccc(Br)cc2c1Cl
Reactant: CC(C)(C#N)c1ccc(N)cc1
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C#N)c1ccc(Nc2c([N+](=O)[O-])cnc3ccc(Br)cc23)cc1
Reaction time: 2 h

Procedure:
18 g (62.6 mmol) of 6-bromo-4-chloro-3-nitro-quinoline (Example 1c) and 11 g (68.9 mmol) of (2-(4-amino-phenyl)-2-methyl-propionitrile (Example 1e) are dissolved in 350 ml of acetic acid and stirred for 2 h. After this time, water is added and the yellow precipitate is filtered off and washed with H2O. The solid is dissolved in EtOAc-THF (1:1), washed with sat. aqueous NaHCO3 and dried over MgSO4. The organic phase is evaporated to dryness to give the title compound as a yellow solid. ES-MS: 411, 413 (M+H)+, Br pattern; analytical HPLC: tret=3.69 min (Grad 1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:15](=[S:16])[N:14]([C:17]3[CH:18]=[C:19]([C:25]([F:28])([F:27])[F:26])[C:20]([C:23]#[N:24])=[N:21][CH:22]=3)[C:13](=[O:29])[C:9]32[CH2:12][CH2:11][CH2:10]3)=[CH:4][CH:3]=1.Cl[C:31]1[N:36]=[CH:35][CH:34]=[CH:33][N:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>C1COCC1>[O:29]=[C:13]1[C:9]2([CH2:12][CH2:11][CH2:10]2)[N:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][C:31]3[N:36]=[CH:35][CH:34]=[CH:33][N:32]=3)=[CH:3][CH:4]=2)[C:15](=[S:16])[N:14]1[C:17]1[CH:18]=[C:19]([C:25]([F:28])([F:27])[F:26])[C:20]([C:23]#[N:24])=[N:21][CH:22]=1
Reactant: Clc1ncccn1
Reactant: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(O)cc3)C2=S)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ncc(N2C(=O)C3(CCC3)N(c3ccc(Oc4ncccn4)cc3)C2=S)cc1C(F)(F)F
Temperature: 25 °C
Yield: 50.4 %

Procedure:
A mixture of 5-(5-(4-hydroxyphenyl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile (Compound 63, 50 mg, 0.12 mmol), 2-chloropyrimidine (17 mg, 0.15 mmol), and cesium carbonate (60 mg, 0.18 mmol) in anhydrous THF (1.2 mL) was heated at reflux overnight. The reaction mixture was cooled to room temperature and water was added. The aqueous was extracted with EtOAc (3×), the organics combined and washed with brine, dried (MgSO4) and concentrated. Purification by column chromatography on silica gel eluting with 0 to 60% EtOAc/hexanes provided 30 mg of 5-(8-oxo-5-(4-(pyrimidin-2-yloxy)phenyl)-6-thioxo-5,7-diazaspiro[3.4]octan-7-yl)-3-(trifluoromethyl)picolinonitrile as an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.24 (d, 1H), 8.78 (d, 1H), 8.73 (d, 2H), 7.48 (dd, 4H), 7.35 (t, 1H), 2.72-2.61 (m, 2H), 2.54-2.42 (m, 2H), 2.10-1.93 (m, 1H), 1.69-1.52 (m, 1H). LCMS [M+1]+ 497.8.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH:28]1([CH2:34][C@H:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40]2=[O:48])[C:36]([OH:38])=O)[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[NH2:49][C:50]1[CH:55]=[CH:54][C:53]([Br:56])=[CH:52][N:51]=1.C1(C[C@@H](N2CC3C(=CC=CC=3)C2=O)C(NC2SC=CN=2)=O)CCCCC1>>[Br:56][C:53]1[CH:54]=[CH:55][C:50]([NH:49][C:36](=[O:38])[C@@H:35]([N:39]2[CH2:47][C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:40]2=[O:48])[CH2:34][CH:28]2[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]2)=[N:51][CH:52]=1
Reactant: Nc1ccc(Br)cn1
Reactant: O=C(O)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(Nc1nccs1)[C@@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Product: O=C(Nc1ccc(Br)cn1)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Yield: 54.9 %

Procedure:
BOP coupling of (S)-3-Cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (prepared in Example 1, Step A; 287 mg; 1.00 mmol) and 2-amino-5-bromopyridine (173 mg; 1.00 mmol) in a manner similar to that used for the preparation of (R)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide (outlined in Example 9, Step B) provided after flash chromatography (Merck Silica gel 60, 230-400 mesh, eluent: 30% ethyl acetate/hexanes) 243 mg (55%)of (S)-N-(5-Bromo-pyridin-2-yl)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide as a white foam: EI-HRMS m/e calcd for C22H24BrN3O2 (M+) 441.1052, found 441.1036.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C)C=O>[CH2:13]([N:9]1[C:10]2[C:6](=[CH:5][C:4]([Br:3])=[CH:12][CH:11]=2)[CH:7]=[CH:8]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: ClCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1ccc2c(ccn2Cc2ccccc2)c1
Temperature: 30 °C
Yield: 80 %

Procedure:
In a suspension of 26.6 g of KOH in 200 ml of dimethylformamide, 20.1 g of solid 5-bromoindole was incorporated while being stirred. The mixture was stirred for 50 minutes at room temperature, and 25.4 g of benzyl chloride was dropwise added to the mixture over a period of 16 minutes at a temperature of not higher than 30° C. The reaction mixture was maintained at 30° C. in an oil bath for 5 hours with stirring. After completion of the reaction, 200 ml of water was added and the thus-formed aqueous phase was extracted with 120 ml of ether three times. The thus-obtained organic phase was washed with water and dried over sodium sulfate overnight. The dried product was concentrated to dryness and then recrystallized from isopropyl ether to give 23.5 g of N-benzyl-5-bromoindole. The yield was 80% by mole.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([NH2:9])=[C:4]([NH:10][C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)[N:3]=1.[CH3:18][C:19](C)(C)C([O-])([O-])[O-].C(S(O)(=O)=O)C>CN(C)C=O>[NH2:1][C:2]1[N:3]=[C:4]2[C:5]([N:9]=[C:18]([CH3:19])[N:10]2[C@@H:11]2[CH2:15][C@H:14]([CH2:16][OH:17])[CH:13]=[CH:12]2)=[C:6]([Cl:8])[N:7]=1
Reactant: CC(C)(C)C([O-])([O-])[O-]
Reactant: Nc1nc(Cl)c(N)c(N[C@H]2C=C[C@@H](CO)C2)n1
Agent: CCS(=O)(=O)O
Solvent: CN(C)C=O
Product: Cc1nc2c(Cl)nc(N)nc2n1[C@H]1C=C[C@@H](CO)C1
Reaction time: 24 h

Procedure:
(±)-cis-4-[(2,5-Diamino-4-chloro-6-pyrimidinyl)amino]-2-cyclopentene-1-methanol prepared as in Example 3 (1.12 g, 4.38 mmol) was stirred in N,N-dimethylformamide (5 mL) with trimethylorthoacetate (30 mL) and ethane sulfonic acid (0.66 g, 5.7 mmol) at 70° C. for 3 days. The resulting solution was evaporated to a yellow syrup. Acetic anhydride (20 mL) was added and this solution was refluxed for 2.5 hours. The resulting dark solution was evaporated to a syrup, which was dissolved in 1N hydrochloric acid (50 mL). After 24 hours, the pH was adjusted to 6 with sodium hydroxide and most of the water evaporated. Crude product was extracted into 20% isopropyl alcohol-chloroform. This solution was dried (MgSO4) and solvent evaporated to leave (±)-cis-4-(2-amino-6-chloro-8-methyl-9H-purin-9-yl)-2-cyclopentene-1-methanol as a pale yellow glass (0.30 g); structure confirmed by 1H-NMR. This sample was dissolved in methanol (10 mL) and stirred in a Parr bomb with cyclopropylamine (1 mL) at 70° C. for 12 hours. Evaporation and chromatography on silica gel gave title compound, eluted as a cream-colored solid foam (136 mg) with 5% methanol-chloroform.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=3)[C:12](F)=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[Br:24]C1C(Cl)=NC(Cl)=NC=1.NC1C=C(O)C=CC=1>>[OH:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=3)[C:12]([Br:24])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(Nc2ncc(F)c(Nc3cccc(O)c3)n2)c1
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: Nc1cccc(O)c1
Product: Oc1cccc(Nc2ncc(Br)c(Nc3cccc(O)c3)n2)c1

Procedure:
In a manner similar to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 5-bromo-2,4-dichloropyrimidine and 3-aminophenol were reacted to yield N2,N4-bis(3-hydroxyphenyl)-5-bromo-2,4-pyrimidinediamine. 1H NMR (DMSO-d6): δ 9.99 (bs, 1H), 9.34 (bs, 1H), 8.30 (s, 1H), 7.15 (t, 1H, J=8.4 Hz), 7.06-6.97 (m, 2H), 6.94-6.92 (m, 2H), 6.80 (bs, 1H), 6.62 (s, 1H, J=8.1 Hz), 6.43 (d, 1H, J=7.8 Hz); LCMS: ret. time: 18.48 min.; purity: 97%; MS (m/e): 374 (MH+).
Reaction SMILES: CCCP(=O)=O.[CH3:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][C:9]=1[NH:17][C:18]1[N:23]=[C:22]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH:21]=[CH:20][N:19]=1.[CH2:30]([NH2:36])[C:31]1[O:35][CH:34]=[CH:33][CH:32]=1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[O:35]1[CH:34]=[CH:33][CH:32]=[C:31]1[CH2:30][NH:36][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][C:8]([CH3:7])=[C:9]([NH:17][C:18]2[N:23]=[C:22]([C:24]3[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=3)[CH:21]=[CH:20][N:19]=2)[CH:10]=1
Reactant: NCc1ccco1
Reactant: Cc1ccc(C(=O)O)cc1Nc1nccc(-c2cccnc2)n1
Agent: CCCP(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NCc2ccco2)cc1Nc1nccc(-c2cccnc2)n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution containing ˜50% of propylphosphonic anhydride in N,N-dimethylformamide (Fluka, Buchs, Switzerland; 674 μL, ˜1 mmol) is added within 20 minutes to a stirred mixture of 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzoic acid (214.4 mg, 0.7 mmol), furfurylamine (Aldrich, Buchs, Switzerland; 61.8 μL, 0.7 mmol) and triethylamine (776 μL, 5.6 mmol) in 2 mL N,N-dimethylformamide. After stirring for 24 hours at room temperature, the mixture is treated with a half-saturated aqueous solution of sodium hydrogen carbonate and extracted three times with ethyl acetate. The solvent is evaporated off under reduced pressure and the residue dried in vacuo. The crude product is crystallised from dichloromethane to give the title compound as a crystalline solid.
Reaction SMILES: I[CH3:2].[CH:3]1([N:6]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[N:9][N:8]=[C:7]2[SH:17])[CH2:5][CH2:4]1>C(O)C.[OH-].[Na+]>[CH:3]1([N:6]2[C:7]([S:17][CH3:2])=[N:8][N:9]=[C:10]2[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH2:5][CH2:4]1
Reactant: Sc1nnc(-c2ccncc2)n1C1CC1
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CSc1nnc(-c2ccncc2)n1C1CC1
Reaction time: 8 h
Yield: 68.5 %

Procedure:
A solution of iodomethane (0.457 mL, 7.33 mmol) in ethanol (3 mL) was added to a solution of 4-cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazole-3-thiol (1 g, 4.58 mmol) in 1M sodium hydroxide (10 mL) at room temperature. After stirring overnight, the reaction mixture was extracted with dichloromethane and then the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford the titled compound (729.1 mg, 69%, beige solid). 1H NMR (CDCl3) δ (ppm): 8.77 (d, 2H), 7.75 (m 2H), 3.23 (m, 1H), 2.82 (s, 3H), 1.17 (m, 2H), 0.80 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S([O-])(=O)(=O)C.[N:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH2:30]O)=[CH:23][CH:22]=1>CN(C)C=O.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:30][CH2:29][CH2:28][CH2:27][C:24]2[CH:25]=[CH:26][N:21]=[CH:22][CH:23]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: OCCCCc1ccncc1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COC(=O)C(=O)c1ccc(OCCCCc2ccncc2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 30.9 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (1.086 g) in dimethylformamide (10 mL) under argon was treated with 55% sodium hydride (0.261 g), stirred for 15 minutes and treated with the mesylate prepared from 0.906 g of 4-pyridinebutanol. The mixture was heated under argon at 60° C. for 4 hours. The cooled mixture was treated with glacial acetic acid (2 drops) and the volatiles were removed under vacuum. The residue was mixed with dichloromethane and dilute cold sodium bicarbonate solution. The dichloromethane extracts were dried (Na2SO4), filtered, and evaporated to give crude product. The material was purified by HPLC (hexane-acetone; 2: 1) to provide 0.58 g of alpha-oxo-4-[4-(4-pyridinyl)butoxy]benzeneacetic acid methyl ester as a colorless oil whose NMR was compatible with the desired product.
Reaction SMILES: C[O:2][C:3]([NH:5][C:6]([CH3:17])([CH2:9][CH2:10][C:11]1[S:12][C:13]([Br:16])=[CH:14][CH:15]=1)[CH2:7][OH:8])=O.CC(C)([O-])C.[K+]>CN(C)C=O>[Br:16][C:13]1[S:12][C:11]([CH2:10][CH2:9][C:6]2([CH3:17])[CH2:7][O:8][C:3](=[O:2])[NH:5]2)=[CH:15][CH:14]=1
Reactant: COC(=O)NC(C)(CO)CCc1ccc(Br)s1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(CCc2ccc(Br)s2)COC(=O)N1
Temperature: 0 °C
Reaction time: 3 h
Yield: 95.5 %

Procedure:
2-Methoxycarbonylamino-2-methyl-4-(5-bromothiophen-2-yl)butan-1-ol (12.4 g, 38.6 mmol) obtained in Example 1 (e) was dissolved in dimethylformamide (125 ml), and potassium t-butoxide (6.50 g, 57.9 mmol) was added thereto in an ice bath under a nitrogen atmosphere followed by stirring for 3 hours at the same temperature. The reaction mixture was poured into ice-cold 10% hydrochloric acid (300 ml), and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was concentrated in vacuo, and the residue was purified by flash chromatography on a silica gel column (elution solvent; hexane:ethyl acetate=4:1-1:2) to afford the title compound (10.7 g, 95% yield) as a white crystalline solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([OH:14])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2].[CH3:15]N(C=O)C.C(=O)([O-])[O-].[K+].[K+].CI>O>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:14][CH3:15])=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2]
Reactant: CN(C)C=O
Reactant: COC(=O)c1cc(C(C)=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: COC(=O)c1cc(C(C)=O)ccc1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methyl 5-acetyl-2-hydroxybenzoate (95.3 g, 490.6 mmol) was added to DMF (381 mL) and potassium carbonate (82.2 g, 588.8 mmol) at RT under an atmosphere of nitrogen. To the resulting suspension was added methyl iodide (90.5 g, 637.8 mmol) whilst maintaining good agitation. After stirring at RT for 30 minutes, the crude reaction mixture was analysed by GC demonstrating complete reaction. Water (380 mL) was added followed by further water (380 mL) and the resulting white solid filtered off to afford 82.5 g of the desired, water wet product (7).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]2[O:13][CH:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14][C@@H:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]([OH:13])[C@H:11]([NH:22][C@@H:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:14])[CH2:12]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](N)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC2OC2C1
Solvent: CCO
Product: C[C@@H](N[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1O)c1ccccc1

Procedure:
A solution of 29.7 g of 1-tert-butoxycarbonyl-3.4-epoxypyrrolidine and 41 ml of (R)-(+)-α-methylbenzylamine in 250 ml of ethanol was heated under reflux for 16 hours. The solvent was removed under reduced pressure, and a residue was subjected to silica gel column chromatography. From an eluant of a mixture of chloroform and methanol (98:2 by volume.), an oily titled compound weighing 15.3 g was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:25])[N:5]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([F:24])([F:23])[F:22])[C:6]([CH2:12]Cl)=[N:7]2.[I:26][C:27]1[C:35]2[C:30](=[N:31][CH:32]=[N:33][C:34]=2[NH2:36])[NH:29][N:28]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[NH2:36][C:34]1[N:33]=[CH:32][N:31]=[C:30]2[N:29]([CH2:12][C:6]3[N:5]([CH2:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[C:21]([F:24])([F:23])[F:22])[C:4](=[O:25])[C:3]4[C:8](=[CH:9][CH:10]=[CH:11][C:2]=4[Br:1])[N:7]=3)[N:28]=[C:27]([I:26])[C:35]=12
Reactant: Nc1ncnc2[nH]nc(I)c12
Reactant: O=c1c2c(Br)cccc2nc(CCl)n1Cc1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1ncnc2c1c(I)nn2Cc1nc2cccc(Br)c2c(=O)n1Cc1ccccc1C(F)(F)F

Procedure:
To a solution of the quinazolinone, obtained as described above, (100 g, 90% pure, 210 mmol) and 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (50.4 g, 193 mmol) in DMF (600 mL) at RT was added potassium carbonate (80.0 g, 580 mmol) and after 18 hr the reaction mixture was poured into water (1.2 L). The resulting precipitate was collected by filtration, and was washed sequentially with water (500 mL), with EtOAc (600 mL) and finally with Et2O (400 mL). The resulting cake was dried in vacuo to afford the title compound, Intermediate A, as an off white solid (115 g, 89%); Rt 2.28 min, m/z 656/658 (M+H)+ (ES+).