Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[OH:2][C:3]([CH3:8])([CH3:7])[CH2:4][C:5]#[N:6].[CH2:9]([O:11]CC)[CH3:10]>>[CH2:9]([O:11][C:5](=[NH:6])[CH2:4][C:3]([OH:2])([CH3:8])[CH3:7])[CH3:10]
Reactant: CC(C)(O)CC#N
Reactant: CCOCC
Agent: Cl
Product: CCOC(=N)CC(C)(C)O
Yield: 72 %

Procedure:
HCl (g) was bubbled through a solution of 3-hydroxy-3-methylbutyronitrile (5.0 g, 50.4 mmol) in diethyl ether (20 mL) and IMS (3.48 g, 75.6 mmol) at 0° C. for 30 minutes before leaving to stand at −5° C. over night. The solution was concentrated under vacuum affording 6.48 g (72%) of 3-hydroxy-3-methyl-butyrimidic acid ethyl ester. 1H NMR (400 MHz, CDCl3) δ: 11.36 (m br, 1H), 4.66 (q, 2H), 2.89 (s, 2H), 1.51 (t, 3H), 1.36 (s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].[F-].[K+].Br[C:15]([CH3:25])([CH3:24])[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=O.O>CN(C)C=O>[CH3:24][C:15]1([CH3:25])[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:1][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[O:11]1
Reactant: CC(C)(Br)C(=O)c1ccccc1
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)Oc2cc([N+](=O)[O-])ccc2N=C1c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66.4 %

Procedure:
To a suspension of 2-amino-5-nitrophenol (3.00 g) in N,N-dimethyl-formamide (30 mL) was added potassium fluoride (3.40 g), and the mixture was stirred at room temperature for 15 minutes, and thereto was added 2-bromo-2-methylpropiophenone (4.42 g). The mixture was stirred at room temperature for 0.5 hour, at 60° C. for 20 hours and at 80° C. for 3 days. After cooling, to the reaction mixture was added cold water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and brine, dried over sodium sulfate and concentrated in vacuo. The resultant residue was purified by column chromatography on silica gel (solvent; n-hexane/ethyl acetate=10/1) to give 2,2-dimethyl-7-nitro-3-phenyl-2H-1,4-benzoxazine (3.65 g) as a pale yellow powder.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]([F:28])([F:27])[C:10]([NH:12][C:13]([C@@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1C(OC(C)(C)C)=O)=[O:14])=[O:11]>ClCCl>[F:28][C:9]([F:8])([F:27])[C:10]([NH:12][C:13]([C@@H:15]1[CH2:19][CH2:18][CH2:17][NH:16]1)=[O:14])=[O:11]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)NC(=O)C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC(=O)C(F)(F)F)[C@@H]1CCCN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57 %

Procedure:
A solution of trifluoroacetic acid (14 mL) in 48 mL of dichloromethane was added dropwise in 45 min into a stirring mixture of (S)-tert-butyl 2-(2,2,2-trifluoroacetylcarbamoyl)pyrrolidine-1-carboxylate (1.15 g, 3.70 mmol) and 28 mL of dichloromethane at room temperature. The solution was stirred for 2 h at room temperature, and the volatiles were removed under reduced pressure. The remaining viscous product was treated with ethyl ether (3×20 mL) to provide a white solid in 57% yield. (441 mg, 2.10 mmol). 1H NMR (500 MHz, CD3OD): δ 4.57 (t, 1H, J=7.5 Hz), 3.36-3.24 (m, 2H), 2.39-2.33 (m, 1H), 2.21-2.14 (m, 1H), 2.12-1.97 (m, 2H). 13C NMR (125 MHz, CD3OD): δ 163.5, 163.3, 163.0, 162.7, 121.6, 119.3, 116.9, 116.5, 114.6, 47.9, 47.0, 31.2, 24.5.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][C:18]=2[N:19]=1.[CH3:29][O:30][CH2:31][CH2:32][NH2:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:29][O:30][CH2:31][CH2:32][NH:33][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[CH:22][C:21]([O:24][C:25]([F:27])([F:28])[F:26])=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:13]
Reactant: COCCN
Reactant: Cn1c(Nc2nc3cc(OC(F)(F)F)ccc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COCCNC(=O)c1ccc2c(c1)nc(Nc1nc3cc(OC(F)(F)F)ccc3s1)n2C

Procedure:
1-Methyl-2-(5-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid (2-methoxy-ethyl)-amide (35 mg) was prepared by following General Procedure F using 1-methyl-2-(5-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benz-imidazole-5-carboxylic acid (41 mg), 2-methoxy-ethylamine (0.1 ml), HBTU (38 mg), and DIEA (0.1 ml). LCMS: m/z 467.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[N:9]([S:35]([C:38]3[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=3)(=[O:37])=[O:36])[C:10]([C:12]3[C:16]4=[N:17][C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=[C:15]4[N:14]([CH2:25][CH2:26][CH2:27][N:28]4[CH2:33][CH2:32]N(C)[CH2:30][CH2:29]4)[CH:13]=3)=[CH:11][C:3]=12.ClC1C(F)=CN=C2N(S(C3C=CC(C)=CC=3)(=O)=O)C(C3C4=NC(OC)=C([O:65]C)C=C4N(CC(I)C)C=3)=CC=12.C(=O)([O-])[O-].[K+].[K+].CN1CCNCC1>C(#N)C>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[N:9]([S:35]([C:38]3[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=3)(=[O:37])=[O:36])[C:10]([C:12]3[C:16]4=[N:17][C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=[C:15]4[N:14]([CH2:25][CH2:26][CH2:27][N:28]4[CH2:33][CH2:32][O:65][CH2:30][CH2:29]4)[CH:13]=3)=[CH:11][C:3]=12
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(Cl)c(F)cnc3n1S(=O)(=O)c1ccc(C)cc1)cn2CCCN1CCN(C)CC1
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(Cl)c(F)cnc3n1S(=O)(=O)c1ccc(C)cc1)cn2CC(C)I
Agent: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc2c(nc1OC)c(-c1cc3c(Cl)c(F)cnc3n1S(=O)(=O)c1ccc(C)cc1)cn2CCCN1CCOCC1

Procedure:
3-[4-Chloro-5-fluoro-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-5,6-dimethoxy-1-[3-(4-methylpiperazin-1-yl)propyl]-1H-pyrrolo[3,2-b]pyridine can be prepared as in example 2, stage 2(c), but starting with 0.300 g of 3-[4-chloro-5-fluoro-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-1-(2-iodopropyl)-5,6-dimethoxy-1H-pyrrolo[3,2-b]pyridine, 0.068 g of potassium carbonate and 0.090 g of 1-methylpiperazine in 50 cm3 of acetonitrile. 0.192 g of 3-[4-chloro-5-fluoro-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-5,6-dimethoxy-1-(3-morpholin-4-ylpropyl)-1H-pyrrolo[3,2-b]pyridine is obtained as a resin with the following characteristics:
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[C:13]([O:25][CH3:26])[C:14]([O:23][CH3:24])=[C:15]([O:21][CH3:22])[C:16]=2[O:19][CH3:20])[CH2:11]1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]2[CH2:18][C:17]3[C:12](=[C:13]([O:25][CH3:26])[C:14]([O:23][CH3:24])=[C:15]([O:21][CH3:22])[C:16]=3[O:19][CH3:20])[CH2:11]2)=[CH:30][CH:29]=1
Reactant: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCI)C2
Reactant: Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCOc1ccc(Cl)cc1)C2
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.4 %

Procedure:
The mixture of 2-(8-iodooctyl)-4,5,6,7-tetramethoxyindan (830 mg), 4-chlorophenol (269 mg), and potassium carbonate (481 mg) in DMF (8 ml) was stirred at room temperature for 12 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo. The residue was purified by alumina column chromatography (hexane to hexane:ethyl acetate=10:1) to yield the entitled compound (776 mg) as crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3([CH2:19][O:20][C:5]=2[CH:4]=1)[C:17]1[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=1)[NH:11][C:10]3=[O:18].CC1C=CC(S(O[CH2:32][C@H:33]2[CH2:37][CH2:36][CH2:35][O:34]2)(=O)=O)=CC=1.BrCC1CCCCO1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[C:9]3([CH2:19][O:20][C:5]=2[CH:4]=1)[C:17]1[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=1)[N:11]([CH2:32][C@H:33]1[CH2:37][CH2:36][CH2:35][O:34]1)[C:10]3=[O:18]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Reactant: COc1ccc2c(c1)OCC21C(=O)Nc2ccccc21
Agent: BrCC1CCCCO1
Product: COc1ccc2c(c1)OCC21C(=O)N(C[C@H]2CCCO2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 6-methoxyspiro[1-benzofuran-3,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, and (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace 2-(bromomethyl)tetrahydro-2H-pyran, 6-methoxy-1′-[(2R)-tetrahydrofuran-2-ylmethyl]spiro[1-benzofuran-3,3′-indol]-2′(1′H)-one was obtained (54%) as a colorless liquid: 1H NMR (300 MHz, CDCl3) (diastereomers) δ 7.32-7.25 (m, 1H), 7.16-6.99 (m, 3H), 6.61 (d, J=8.1 Hz, 1H), 6.52 (d, J=2.1 Hz, 1H), 6.36 (dd, J=8.1, 2.1 Hz, 1H), 4.94 (d, J=9.0 Hz, 1H), 4.69 (d, J=9.0 Hz, 1H), 4.32-4.22 (m, 1H), 4.00-3.66 (m, 4H), 3.77 (s, 3H), 2.10-1.66 (m, 4H); 13C NMR (75 MHz, CDCl3) (diastereomers) δ178.0, 177.9, 162.0, 161.4, 142.9, 142.8, 132.4, 132.3, 128.7, 128.6, 123.6, 123.5 (2C), 123.4, 123.2, 121.0, 120.9, 109.6, 109.3, 107.4 (2C), 96.5, 80.5, 80.4, 76.8, 76.7, 68.2, 68.1, 57.5, 55.5, 44.5 (2C), 29.2, 28.9, 25.6, 25.5; MS (ES+) m/z 352.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7](=O)[C:8]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[S:11][C:9]=3[S:10][C:4]=2[CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1.[CH3:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[CH3:1][C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([N:39]3[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]3)[C:8]3[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[S:11][C:9]=3[S:10][C:4]=2[CH:3]=1
Reactant: Cc1ccc2c(c1)Sc1sc3ccccc3c1C(=O)N2
Reactant: CN1CCNCC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: Cc1ccc2c(c1)Sc1sc3ccccc3c1C(N1CCN(C)CC1)=N2

Procedure:
In the same manner as in Example 80 and using 8-methyl-1benzothieno[2,3-b][1,5]benzothiazepin-12(11H)-one, phosphorus oxychloride, N,N-dimethylaniline, 1-methylpiperazine, 8-methyl-12-(4-methylpiperazin-1-yl)-[1]benzothieno[2,3-b][1,5]benzothiazepine is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[N:5]([C:14]1[CH:19]=[C:18]([CH:20]=C)[N:17]=[C:16]([NH2:22])[C:15]=1[N+:23]([O-:25])=[O:24])[CH2:6][C:7]1[CH:8]=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=1)[CH3:2].I([O-])(=O)(=O)=[O:28].[Na+]>CC(C)=O.O.[Os](=O)(=O)(=O)=O>[CH2:1]([O:3][C:4](=[O:26])[N:5]([C:14]1[CH:19]=[C:18]([CH:20]=[O:28])[N:17]=[C:16]([NH2:22])[C:15]=1[N+:23]([O-:25])=[O:24])[CH2:6][C:7]1[CH:8]=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=1)[CH3:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=Cc1cc(N(Cc2ccc(C)nc2)C(=O)OCC)c([N+](=O)[O-])c(N)n1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)N(Cc1ccc(C)nc1)c1cc(C=O)nc(N)c1[N+](=O)[O-]
Reaction time: 0.08 h
Yield: 81.1 %

Procedure:
(2-Amino-3-nitro-6-vinyl-pyridin-4-yl)-(6-methyl-pyridin-3-ylmethyl)-carbamic acid ethyl ester (270 mgs/0.755 mmols) was dissolved in acetone (5 mls)/water (5 mls) and osmium tetroxide (2.5% wt in tBuOH) (0.10 mls/0.008 mmols) was added. Stirred for 5 mins to give brown solution then added sodium metaperiodate (500 mgs/3.47 mmols). Orange suspension stirred for 1 hour. Partitioned between EtOAc (100 mls) and sodium thiosulfate pentahydrate (20% wt in H2O) (50 mls). Organic collected, washed with brine, dried over Na2SO4, filtered and concentrated to a brown resin. Purification by column chromatography eluting with EtOAc gave the title compound (220 mgs) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].[I:10]I.S([O-])([O-])=O.[Na+].[Na+]>CO.O>[I:10][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]([CH3:1])=[CH:3][C:4]=1[OH:9]
Reactant: Cc1ccc(O)cc1C
Reactant: II
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1cc(O)c(I)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.3 %

Procedure:
3,4-Dimethylphenol (0.68 g) and iodine (1.82 g) were dissolved in methanol/water (10 ml/5 ml), and the mixture was stirred at room temperature overnight. An aqueous sodium sulfite solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography using ethyl acetate-hexane to give 2-iodo-4,5-dimethylphenol (833 mg, yield 64%).
Reaction SMILES: [OH:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[Cl:29][C:30]1[CH:31]=[C:32](O)[CH:33]=[CH:34][CH:35]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.N>C1COCC1.C(Cl)(Cl)Cl>[Cl:29][C:30]1[CH:35]=[C:34]([CH:33]=[CH:32][CH:31]=1)[O:1][C@@H:2]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](O)c3ccccc3)CC2)c1
Reactant: Oc1cccc(Cl)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@@H](Oc3cccc(Cl)c3)c3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 35.7 %

Procedure:
A mixture of N-(3-{1-[(3S)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide (5.20 mg, 0.0137 mmol), 3-chlorophenol (100 mg), triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days. Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (2.4 mg, 35.8% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 7.30 (m, 2H), 7.30-7.20 (m, 3H), 7.20 (m, 3H), 6.90 (apparent d, 1H, J=7.7 Hz), 6.71 (apparent d, 1H, J=2.9 Hz), 6.69 (apparent t, 1H, J=2.9 Hz), 6.67 (apparent t, 1H, J=2.9 Hz), 6.65 (apparent d, 1H, J=2.9 Hz), 5.09 (apparent dd, 1H, J=4.8, 8.1 Hz), 3.18 (m, 2H), 2.73 (m, 2H), 2.50 (apparent sept, partially hidden, 2H, J=7.1 Hz), 2.30-2.10 (m, 6H), 1.89 (m, 2H), 1.25 (d, 6H, overlapped); ESMS m/e: 491.1 (M+H)+.
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([C:23](=[O:26])[NH:24][CH3:25])=[CH:19][C:18]=4[O:27][CH3:28])[N:12]=[CH:11][C:10]=3[N:9]3[CH:29]=[N:30][C:31]([C:32]([OH:34])=[O:33])=[C:8]3[C@H:7]2[CH2:35][CH3:36])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:49](O)[CH:50]=[CH2:51]>CN(C=O)C>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([C:23](=[O:26])[NH:24][CH3:25])=[CH:19][C:18]=4[O:27][CH3:28])[N:12]=[CH:11][C:10]=3[N:9]3[CH:29]=[N:30][C:31]([C:32]([O:34][CH2:51][CH:50]=[CH2:49])=[O:33])=[C:8]3[C@H:7]2[CH2:35][CH3:36])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: C=CCO
Reactant: CC[C@@H]1c2c(C(=O)O)ncn2-c2cnc(Nc3ccc(C(=O)NC)cc3OC)nc2N1C1CCCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1ncn2c1[C@@H](CC)N(C1CCCC1)c1nc(Nc3ccc(C(=O)NC)cc3OC)ncc1-2
Temperature: 42.5 °C
Reaction time: 0.67 h
Yield: 77.3 %

Procedure:
(R)-5-cyclopentyl-6-ethyl-3-(2-methoxy-4-(methylcarbamoyl)phenylamino)-5,6-dihydroimidazo[1,5-f]pteridine-7-carboxylic acid 1-2 (44 mg, 0.09 mmol) in DMF (0.5 mL) was treated with carbonyldiimidazole (19 mg, 0.12 mmol) and stirred at 40-45° C. for 40 minutes. Allyl alcohol (1 ml, 14.7 mmol) was then added and the reaction mixture was stirred at 40° C. for 18 hours. The mixture was partitioned between an aqueous solution of sodium carbonate and ethyl acetate. The organic phase was washed with brine, dried over magnesium sulphate and concentrated to give the desired compound as a pale brown solid (37 mg, 77% yield); LC/MS M+1 (obs.) 532.68, LC/MS M-1 (obs.) 530.81.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][CH2:12][CH:13]1[O:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15][CH:14]1[C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=1.C(N(CC)CC)C.O>C1COCC1>[Cl:34][C:29]1[CH:28]=[C:27]([CH:14]2[CH:13]([CH2:12][NH:11][S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[O:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]2)[CH:32]=[CH:31][C:30]=1[Cl:33]
Reactant: CC(C)(C)OC(=O)N1CCOC(CN)C(c2ccc(Cl)c(Cl)c2)C1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCOC(CNS(=O)(=O)c2ccccc2)C(c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51.4 %

Procedure:
Benzenesulfonyl chloride (130 mg) was added dropwise to a solution of tert-butyl (6SR,7RS)-7-(aminomethyl)-6-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (280 mg) and triethylamine (0.14 mL) in THF (5 mL), and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (195 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[N:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:4][CH2:3]1.CC(C[AlH]CC(C)C)C.CO.O>C1COCC1>[CH3:1][N:2]1[CH2:3][CH2:4][CH:5]([NH:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:7]1
Reactant: CN1CCC(=NNC(=O)OC(C)(C)C)CC1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CN1CCC(NNC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.4 %

Procedure:
To a solution of tert-butyl 2-(1-methylpiperidin-4-ylidene)hydrazinecarboxylate (500 mg, 2.20 mmol) in THF (50 mL) was added DIBAl-H (22 mL, 22 mmol) under nitrogen atmosphere. The resulting mixture was stirred at 25° C. overnight. Methanol (5 mL) was added to quench the reaction at −78° C. After being stirred at room temperature for 1 h, water (10 mL) was added. The solid was filtered off and washed with EtOAc. The combined filtrate was partitioned and extracted with EtOAc (3×50 mL), dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography eluting with EtOAc/petroleum ether (1:10) to give tert-butyl 2-(1-methylpiperidin-4-yl)hydrazinecarboxylate (350 mg, 69% yield) as a colorless oil. LCMS (ESI) m/z: 230.4 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:13])[CH2:9][CH:10]2[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[CH3:14]CCCCC.IC.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:13])[CH:9]([CH:10]2[CH2:11][CH2:12]2)[CH3:14])=[CH:6][CH:7]=1
Reactant: CCCCCC
Reactant: O=C(CC1CC1)c1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CC(C(=O)c1ccc(Cl)cc1)C1CC1
Temperature: -30 °C

Procedure:
Crude 1-(4-chlorophenyl)-2-cyclopropylethanone (from the previous reaction) in dry dimethylformamide (150 ml) was added dropwise to a stirred suspension of hexane-washed sodium hydride (4.57 g of a 60% dispersion in oil, 114 mmol) in dry dimethylformamide (35 ml) under nitrogen. After 1 hour the mixture was cooled to -30° C. and iodomethane (16.2 g, 114 mmol) in dry dimethylformamide (35 ml) added very slowly. The mixture was then poured into water and the resultant mixture extracted with ether. The extracts were washed with brine, dried and evaporated in vacuo. Chromatography [SiO2, hexane-ethyl acetate (95:5)] gave 1-(4-chlorophenyl)-2-cyclopropylpropan-1-one (7.66 g, approximately 70% pure, approximately 28% based on 1-(4-chlorophenyl)-2-cyclopropylethanol).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:11]O.S(Cl)([Cl:15])=O>C(OCC)C>[ClH:15].[CH3:11][O:6][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([NH2:1])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CO
Reactant: Nc1cccc(C(=O)O)c1
Solvent: CCOCC
Product: COC(=O)c1cccc(N)c1
Product: Cl

Procedure:
The title compound is prepared according to the method of Example 9 using 13.7 g (0.1 mole) of m-aminobenzoic acid, 250 ml of methanol, and 21.9 ml (0.29 mole) of thionyl chloride, except that the mixture is not heated. After concentration of reduced pressure, the product is shaken with diethyl ether, producing 18.7 g (0.10 mole) of crystalline solid. Structure is confirmed by NMR spectrum.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][S:9]([N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][NH2:19])[CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:21]1[N:29]=[C:28]2[C:24]([N:25]=[CH:26][NH:27]2)=[CH:23][N:22]=1>>[C:1]1([CH2:7][CH2:8][S:9]([N:12]2[CH2:13][CH2:14][CH:15]([CH2:18][NH:19][C:21]3[N:29]=[C:28]4[C:24]([N:25]=[CH:26][NH:27]4)=[CH:23][N:22]=3)[CH2:16][CH2:17]2)(=[O:10])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCC1CCN(S(=O)(=O)CCc2ccccc2)CC1
Reactant: Clc1ncc2nc[nH]c2n1
Product: O=S(=O)(CCc1ccccc1)N1CCC(CNc2ncc3nc[nH]c3n2)CC1

Procedure:
EXAMPLE 82 was prepared from C-[1-(2-phenyl-ethanesulfonyl)-piperidin-4-yl]-methylamine and 2-chloro-9H-purine (2-chloro-9H-purine was prepared according to S. R. Brashears, S. S. Wang, S. G. Bechtolt, B. E. Christensen, J. Am. Chem. Soc., 81:3789–3792(1959)): MS (m+1)=401.
Reaction SMILES: [Si]([O:8][C@H:9]([CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[C@H:10]([CH3:21])[O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1)(C(C)(C)C)(C)C.Br[C:31]1[CH:32]=[C:33]([CH2:37][C:38]([NH:40][CH3:41])=[O:39])[CH:34]=[CH:35][CH:36]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:8][C@H:9]([CH2:22][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[C@H:10]([CH3:21])[O:11][C:12]1[CH:13]=[CH:14][C:15]([C:36]2[CH:35]=[CH:34][C:33]([CH2:37][C:38]([NH:40][CH3:41])=[O:39])=[CH:32][CH:31]=2)=[CH:16][CH:17]=1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@@H](CCc1cccnc1)O[Si](C)(C)C(C)(C)C
Reactant: CNC(=O)Cc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CNC(=O)Cc1ccc(-c2ccc(O[C@@H](C)[C@H](O)CCc3cccnc3)cc2)cc1
Temperature: 110 °C
Reaction time: 18 h

Procedure:
Prepared according to the method described in Example 12b) from (1S,2R)-4-[2-(tert-butyldimethylsilanyloxy)-1-methyl-4-pyridin-3-ylbutoxy]benzeneboronic acid (0.20 g, Example 11)), 2-(3-bromophenyl)-N-methyl-acetamide (0.244 g, Example 24a)), 2M aqueous sodium carbonate (0.265 ml) and tetrakis(triphenylphosphine)palladium (0) (0.1 g) in toluene (5 ml) and ethanol (2 ml). The reaction was heated at 110° C. for 6 hours. After cooling, the solution was concentrated under reduced pressure the residue was dissolved in methanol (10 ml), concentrated hydrochloric acid (1 ml) was added and the solution stirred at room temperature for 18 hours. The mixture was concentrated under reduced pressure the residue was neutralised using saturated sodium hydrogen carbonate and extracted with ethyl acetate. The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by normal-phase HPLC eluting with a gradient of 0-10% ethanol in dichloromethane to give the title compound as an oil which was converted to the oxalic acid salt by treatment with a saturated ethereal solution of oxalic acid to give the title compound as a gum (0.123 g).