Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=O)=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:15][C:16]([S@:19]([NH2:21])=[O:20])([CH3:18])[CH3:17].O>C1COCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Cl:1][C:2]1[C:11](/[CH:12]=[N:21]/[S@@:19]([C:16]([CH3:18])([CH3:17])[CH3:15])=[O:20])=[CH:10][C:9]2[C:4](=[C:5]([CH3:14])[CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: Cc1cccc2cc(C=O)c(Cl)nc12
Reactant: CC(C)(C)[S@](N)=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccc2cc(/C=N/[S@](=O)C(C)(C)C)c(Cl)nc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77.7 %

Procedure:
To a solution of 2-chloro-8-methylquinoline-3-carboxaldehyde (2.05 g, 10 mmol) in dry THF (20 mL) under nitrogen was added titanium isopropoxide (5.68 g, 20 mmol) and the mixture stirred at r.t. for 10 minutes. (R)-(+)-2-Methyl-2-propanesulfinamide (1.21 g, 10 mmol) was added to the reaction which was stirred at r.t. for 72 h. Water (20 mL) was added and the mixture was extracted with DCM (150 mL). The organic layer was separated, dried (MgSO4), filtered and the solvent removed in vacuo to afford the title compound (2.4 g, 72%) as a pale yellow solid. δH (CDCl3) 9.12 (s, 1H), 8.79 (s, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.67 (d, J=6.8 Hz, 1H), 7.51 (t, J=7.8 Hz, 1H), 2.79 (s, 3H), 1.32 (s, 9H). LCMS (ES+) 309, 311 (M+H)+.
Reaction SMILES: Cl[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=O.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([NH:23][C:24]([NH2:26])=[S:25])[CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1>C(O)C>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([NH:23][C:24]2[S:25][C:2]3[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=3[N:26]=2)[CH:14]=[CH:15][C:16]=1[N:17]1[CH:21]=[C:20]([CH3:22])[N:19]=[CH:18]1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Reactant: O=C1CCCCC1Cl
Solvent: CCO
Product: COc1cc(Nc2nc3c(s2)CCCC3)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared in analogy to example 1 step e) from 46 mg (0.33 mmol) 2-chlorocyclohexanon and 79 mg (0.3 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea in ethanol (3 ml). The crude product was purified on silica gel with methylene chloride/methanol 19/1 yielding 40 mg (39%) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-(4,5,6,7-tetrahydro-benzothiazol-2-yl)-amine as a yellow solid. MS ISP (m/e): 341.4 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.16 (s, 1H), 7.63 (s, 1H), 7.49 (s, 1H), 7.28 (d, 1H), 7.22 (d, 1H), 7.01 (s, 1H), 3.77 (s, 3H), 2.57 (br s, 4H), 2.14 (s, 3H), 1.71 (br s, 4H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[C:8]([NH2:10])[C:7]([S:11][CH2:12]C[Si](C)(C)C)=[C:6]([Cl:18])[C:5]=1[NH2:19].COC(=O)C1C=C(N)C([SH:31])=C(Cl)C=1N.C(=S)=S.[OH-].[Na+]>CCO>[CH3:1][O:2][C:3]([C:4]1[C:5]([NH2:19])=[C:6]([Cl:18])[CH:7]2[S:11][C:12]([SH:31])=[N:10][CH:8]2[CH:9]=1)=[O:20]
Reactant: COC(=O)c1cc(N)c(S)c(Cl)c1N
Reactant: COC(=O)c1cc(N)c(SCC[Si](C)(C)C)c(Cl)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: S=C=S
Product: COC(=O)C1=CC2N=C(S)SC2C(Cl)=C1N

Procedure:
This compound is synthesized as reported in U.S. Pat. No. 4,454,148. 2,5-Diamino-3-chloro-4-(2-trimethylsilanyl-ethylsulfanyl)-benzoic acid methyl ester (step d in example H17) is used as starting material and after thiol deprotection (step f in example H17), the crude 2,5-diamino-3-chloro-4-mercapto-benzoic acid methyl ester is cyclized with CS2, NaOH in EtOH at 70° C. The crude is directly used in the next step without further purification; LC/MS: 275/277 (M+1)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([C:42]([N:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)=[O:43])=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]2>>[CH3:29][O:28][C:14]1[CH:15]=[C:16]([CH:26]=[CH:27][C:13]=1[NH:12][C:4]1[N:3]=[C:2]([NH:30][C:31]2[CH:32]=[CH:33][C:34]([C:42]([N:44]3[CH2:45][CH2:46][CH2:47][CH2:48]3)=[O:43])=[C:35]3[C:39]=2[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]3)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=1)[CH2:17][P:18](=[O:25])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]
Reactant: CN1Cc2c(C(=O)N3CCCC3)ccc(N)c2C1=O
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(C(=O)N4CCCC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared using the procedure for Example 102 with diethyl (4-{[4-chloro-5-(trifluoromethyl) pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and Compound 116A. MS (ES+): m/z 677.46 (100) [MH+]; HPLC: tR=0.98 min (UPLC, purity).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[N:7]([C:19]1[CH:24]=[CH:23][C:22]([CH:25]=[O:26])=[CH:21][N:20]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH:28]([Si:31]([CH:45]([CH3:47])[CH3:46])([CH:42]([CH3:44])[CH3:43])[O:32][C:33]1[CH:34]=[C:35]2[CH:41]=[CH:40][NH:39][C:36]2=[N:37][CH:38]=1)([CH3:30])[CH3:29].[OH-].[K+].O>CO>[C:1]([O:5][C:6](=[O:27])[N:7]([C:19]1[CH:24]=[CH:23][C:22]([CH:25]([OH:26])[C:41]2[C:35]3[C:36](=[N:37][CH:38]=[C:33]([O:32][Si:31]([CH:42]([CH3:44])[CH3:43])([CH:45]([CH3:47])[CH3:46])[CH:28]([CH3:29])[CH3:30])[CH:34]=3)[NH:39][CH:40]=2)=[CH:21][N:20]=1)[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:13][CH:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(C(F)(F)F)cc1)c1ccc(C=O)cn1
Reactant: CC(C)[Si](Oc1cnc2[nH]ccc2c1)(C(C)C)C(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)[Si](Oc1cnc2[nH]cc(C(O)c3ccc(N(Cc4ccc(C(F)(F)F)cc4)C(=O)OC(C)(C)C)nc3)c2c1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.8 %

Procedure:
A mixture of (5-Formyl-pyridin-2-yl)-(4-trifluoromethyl-benzyl)-carbamic acid tert-butyl ester (19, 41 mg, 0.11 mmol, prepared as described in Example 30), 5-triisopropylsilanyloxy-1H-pyrrolo[2,3-b]pyridine (83, 34 mg, 0.12 mmol) and potassium hydroxide (9.8 mg, 0.17 mmol) in methanol (10 mL) was stirred at room temperature overnight. The reaction mixture was poured into water, extracted with ethyl acetate, washed with brine and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as a viscous liquid (84, 0.05 g, 70%). MS (ESI) [M+H+]+=671.38.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[CH2:6][CH2:7][N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[C:12]([NH2:21])[C:11]=2[N:10]=[C:9]1[CH2:22][O:23][CH2:24][CH3:25].O>CN(C)C=O>[N:1]([CH2:6][CH2:7][N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[C:12]([NH2:21])[C:11]=2[N:10]=[C:9]1[CH2:22][O:23][CH2:24][CH3:25])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CCCl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCN=[N+]=[N-]
Temperature: 25 °C

Procedure:
Sodium azide (14.7 g) was added to a solution of 1-(2-chloroethyl)-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4amine (22.8 g prepared according to the method of Part F) in N,N-dimethylformamide (75 mL). The reaction mixture was heated at reflux for several hours and then allowed to cool to ambient temperature overnight. The reaction mixture was poured into water (100 ml) and then extracted 3 times with ethyl acetate. The extracts were combined, washed 3 times with water, dried over magnesium sulfate, filtered and then concentrated to dryness under vacuum to provide crude 1-(2-azidoethyl)-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin4-amine as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]3[CH:26]=[N:27][NH:28][CH:29]=3)[CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][C:22]([C:25]5[CH:29]=[N:28][NH:27][CH:26]=5)=[CH:21][CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2ccc(-c3cn[nH]c3)cc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2cc(-c3cn[nH]c3)ccc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-7-(1H-pyrazol-4-yl)-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:7][CH:8]=1)=O.[O:15]=[C:16]1[CH2:20][CH2:19][S:18][CH2:17]1>>[O:15]=[C:16]1[CH2:20][CH2:19][S:18][C:17]1=[CH:1][C:3]1[CH:4]=[C:5]([CH:9]([CH3:14])[C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)C(C)c1cccc(C=O)c1
Reactant: O=C1CCSC1
Product: COC(=O)C(C)c1cccc(C=C2SCCC2=O)c1
Yield: 11.6 %

Procedure:
By using methyl 2-(3-formylphenyl)propionate (720 mg) obtained in Example 66 and 3-oxothiolane (580 mg), the title compound (120 mg, 12%) was obtained in the same manner as that of Example 1.
Reaction SMILES: [Na].[CH2:2]([OH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:10][C:11]1[N:16]=[C:15](Cl)[CH:14]=[C:13]([NH2:18])[N:12]=1>>[NH2:10][C:11]1[N:16]=[C:15]([O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:14]=[C:13]([NH2:18])[N:12]=1
Reactant: Nc1cc(Cl)nc(N)n1
Reactant: OCc1ccccc1
Agent: [Na]
Product: Nc1cc(OCc2ccccc2)nc(N)n1
Temperature: 150 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
Sodium (0.41 g, 17.8 mmol) was added to benzyl alcohol (15 ml) under a nitrogen atmosphere and the mixture was heated at 150° C. for 1.5 h. 2,6-Diamino-4-chloropyrimidine (2.16 g, 14.94 mmol) was added and the reaction mixture was stired at 180° C. for a further 2 h. Volatiles were removed in vacuo and the resulting residue was chromatographed on silia with dichloromethane: methanol (9:1) as eluent, to yield the title product as a white solid (1.98 g, 62%); νmax/cm−1 3347 (NH), 1498 (C6H5), 1608 (C6H5); δH (200 MHz, d6-DMSO) 5.20 (1H, s, C(5)H), 5.32 (2H, s, OCH2), 6.05 (2H, br s, NH2), 6.17 (2H, br s, NH2), 7.41-7.48 (5H, m, C6H5); m/z (+EI) 216 (M+, 100%), 139 (M+-C6H5, 33), 91 (94).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH:23]4[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]4)=[CH:19][CH:18]=3)=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.ClC1N=NC(N2CC(C(NC3C=CC(C4CCN(C([O-])=O)CC4)=CC=3)=O)C2)=CC=1>>[N:7]1[CH:2]=[CH:3][CH:4]=[C:5]([N:8]2[CH2:9][CH2:10][CH:11]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH:23]4[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]4)=[CH:19][CH:18]=3)=[O:15])[CH2:12][CH2:13]2)[N:6]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(=O)C3CCN(c4ccc(Cl)nn4)CC3)cc2)CC1
Agent: O=C(Nc1ccc(C2CCN(C(=O)[O-])CC2)cc1)C1CN(c2ccc(Cl)nn2)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(NC(=O)C3CCN(c4cccnn4)CC3)cc2)CC1

Procedure:
The title compound was prepared as described in Example 147B, tert-butyl 4-(4-(1-(6-chloropyridazin-3-yl)piperidine-4-carboxamido)phenyl)piperidine-1-carboxylate for 4-(4-(1-(6-chloropyridazin-3-yl)azetidine-3-carboxamido)phenyl)piperidine-1-carboxylate.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Br:28][C:29]1[CH:30]=[C:31]([CH:35]=[CH:36][CH:37]=1)[C:32](O)=[O:33].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:32](=[O:33])[C:31]4[CH:35]=[CH:36][CH:37]=[C:29]([Br:28])[CH:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: O=C(O)c1cccc(Br)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)c4cccc(Br)c4)cc3)cc2)CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1-[4′-(4-Amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (0.181 g, 0.5 mmol), 3-bromo-benzoic acid (0.100 g, 0.5 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl uronium hexafluorophosphate (0.228 g, 0.6 mmol) and N-methylmorpholine (0.110 mL, 1.0 mmol) were combined in DMF and stirred at room temperature for 2 days. The reaction was submitted to standard aqueous workup and purified by silica gel chromatography to afford the title compound.
Reaction SMILES: [F:1][C:2]1([CH2:15][OH:16])[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.[ClH:17].CCOCC>CCOCC>[ClH:17].[F:1][C:2]1([CH2:15][OH:16])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(CO)CC1
Agent: Cl
Solvent: CCOCC
Product: OCC1(F)CCNCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of tert-butyl 4-fluoro-4-(hydroxymethyl)piperidine-1-carboxylate (21 g, 0.09 mol) in dry ether (200 mL) was added HCl/ether (4M, 100 mL) drop-wise at 0° C. under N2. After addition, the mixture was allowed to warm to RT and stirred overnight. The reaction mixture was concentrated to remove solvent and the residue was washed with ether. 1H NMR (400 MHz, D2O): δ 1.78 (m, 2H), 2.05 (m, 2H), 3.15 (m, 2H), 3.31 (m, 2H), 3.57 (d, 2H), m/z 134 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](/[CH:10]=[CH:11]/[CH:12]=[C:13](\[O:18][CH3:19])/[C:14]([O:16]C)=[O:15])=[CH:7][C:6]=2[CH:20]=1.CCO.O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](/[CH:10]=[CH:11]/[CH:12]=[C:13](\[O:18][CH3:19])/[C:14]([OH:16])=[O:15])=[CH:7][C:6]=2[CH:20]=1
Reactant: COC(=O)/C(=C/C=C/c1cc2cc(Cl)ccc2o1)OC
Solvent: CCO
Solvent: O
Product: CO/C(=C\C=C\c1cc2cc(Cl)ccc2o1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
To a stirred solution of methyl (2Z,4E)-5-(5-chlorobenzofuran-2-yl)-2-methoxy-2,4-pentadienoate (530 mg, 1.81 mmol) in EtOH/water 1/1 (40 ml) potassium hydroxide (0.43 g, 7.66 mmol) was added. The solution was stirred at RT overnight, then it was treated as seen in example 2. Pure title compound (330 mg, 1.18 mmol, yield 65.4%) was obtained as bright yellow crystals.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:6]#[N:7].Cl.[C:13]([O:17][C:18](=[O:22])[CH2:19][NH:20][CH3:21])([CH3:16])([CH3:15])[CH3:14]>>[Cl:11][C:9]1[CH:10]=[C:3]([CH:4]=[C:5]([C:6]#[N:7])[CH:8]=1)[CH2:2][N:20]([CH3:21])[CH2:19][C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:22]
Reactant: CNCC(=O)OC(C)(C)C
Reactant: N#Cc1cc(Cl)cc(CBr)c1
Agent: Cl
Product: CN(CC(=O)OC(C)(C)C)Cc1cc(Cl)cc(C#N)c1

Procedure:
The title compound was prepared following general procedure 10, starting from 3-(bromomethyl)-5-chlorobenzonitrile and sarcosine tert-butyl ester hydrochloride. It was isolated as a yellow oil (570 mg, 78%). LC/MS (Method B): 295.1 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:21]([CH2:22][O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[S:20][CH:11](SCC2C=CC=CC=2)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si]([N:35]1[CH:43]=[C:41]([CH3:42])[C:39](=[O:40])[NH:38][C:36]1=[O:37])(C)(C)C>C(=O)([O-])[O-].[Cd+2].C1(C)C=CC=CC=1>[CH2:1]([O:8][C@@H:9]1[C@@H:21]([CH2:22][O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[S:20][C@@H:11]([N:35]2[CH:43]=[C:41]([CH3:42])[C:39](=[O:40])[NH:38][C:36]2=[O:37])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COC[C@H]2SC(SCc3ccccc3)C[C@@H]2OCc2ccccc2)cc1
Reactant: Cc1cn([Si](C)(C)C)c(=O)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [Cd+2]
Solvent: Cc1ccccc1
Product: Cc1cn([C@H]2C[C@H](OCc3ccccc3)[C@@H](COCc3ccccc3)S2)c(=O)[nH]c1=O
Reaction time: 0.5 h

Procedure:
A suspension of benzyl 3,5-di-O-benzyl-2-deoxy-1,4-dithio-D-erythro-pentofuranoside (22.5 g, 51.6 mmol), his TMS-thymine (46 g, 170 mmol), mercuric bromide (20.5 g, 56.7 mmol), cadmium carbonate (29.3 g, 170 mmol) and dry toluene (1L) was boiled under reflux, with stiring, for 24 hours. The hot mixture was then filtered and the solids were washed with toluene. The filtrate was successively washed with potassium iodide solution (30%) and water and then evaporated. The residue was taken up in 4:1 methanol-water, stirred for 30 minutes, the suspension filtered and the filtrate evaporated. The residue was applied to a silica gel column (hexane-ethyl acetate (1:1)) and combination of the appropriate fractions gave the title product as a clear colourless syrup. 1H NMR indicated the ratio of α- to β- anomers to be 2.8:1. Further column chromatography gave more of the separated anomers. The first compound to be eluted from the column was 3',5'-di-O-benzyl-4'-thio-thymidine as a colourless syrup. This could be crystallised from methanol to give colourless crystals m.p. 140°-142° C.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7]([OH:10])(=[O:9])=[O:8])=[CH:3][CH:2]=1.C1([C@@H]([NH:20][C@H:21]2[CH2:30][CH2:29][C:24]3([O:28][CH2:27][CH2:26][O:25]3)[CH2:23][C@H:22]2[C:31]([O:33][CH2:34][CH3:35])=[O:32])C)C=CC=CC=1.[H][H]>[Pd].C(O)C>[C:1]1([CH3:11])[CH:2]=[CH:3][C:4]([S:7]([OH:10])(=[O:8])=[O:9])=[CH:5][CH:6]=1.[NH2:20][C@H:21]1[CH2:30][CH2:29][C:24]2([O:28][CH2:27][CH2:26][O:25]2)[CH2:23][C@H:22]1[C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: [H][H]
Reactant: CCOC(=O)[C@@H]1CC2(CC[C@@H]1N[C@@H](C)c1ccccc1)OCCO2
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)[C@@H]1CC2(CC[C@@H]1N)OCCO2
Temperature: 40 °C
Reaction time: 10 h
Yield: 83 %

Procedure:
Example 1, 2nd Alternative Preparation, Step 1a: To a hydrogenator were charged ethyl (7R,8S)-8-((S)-1-phenyl-ethylamino)-1,4-dioxa-spiro [4.5]decane-7-carboxylate 4-toluenesulfonate salt 1A (1417 g, 2.8 moles, c.f.: WO2004098516, prepared analogous to U.S. Pat. No. 6,835,841), ethanol (200 proof, 11.4 L), and 10% Pd/C catalyst (50% wet, 284 g). The mixture was inerted with nitrogen, then pressurized with hydrogen gas (45 psig) and agitated vigorously at approx. 40° C. until starting material was consumed (HPLC). The suspension was cooled, purged with nitrogen gas and the catalyst was removed by filtration while inerted. The spent catalyst was washed with ethanol (4.3 L). The filtrate and washings were combined and concentrated under vacuum to a volume of 2-3 L while maintaining the batch between 40°-60° C. Isopropyl acetate (5 L) was charged and the mixture was concentrated to a volume of ˜2 L until most ethanol was removed (<0.5%) and residual moisture content was <1,000 ppm. Batch volume was adjusted to ˜7.5 L by the addition of isopropyl acetate. The mixture was heated to 80° C. until clear, then cooled 65°-70° C. Seed crystals of 1 (5 g) were added and the batch was cooled to 50° C. over 2 hours, then further cooled to 20° C. over 4 hours and held for ˜10 hours. The resulting slurry was filtered and the cake was washed with isopropyl acetate (2 L). The product was dried under vacuum at ˜35° C. until volatiles were reduced below ˜1% (LOD). Ethyl (7R,8S)-8-amino-1,4-dioxa-spiro[4.5]decane-7-carboxylate 4-toluenesulfonate salt 1 was obtained as a white, crystalline solid (936 g, 83% yield; HPLC purity: 99.8%). 1H-NMR: (300 MHz, CDCl3) 8.14-7.89 (brs, 3H), 7.75 (d, J 9.0 Hz, 2H), 7.15 (d, J 8.0 Hz, 2H), 4.22-4.04 (m, 2H), 4.01-3.77 (m, 4H), 3.55-3.43 (m, 1H,), 3.20-3.13 (m, 1H), 2.40-2.27 (m, 4H), 2.21-1.94 (m, 2H), 1.81-1.51 (m, 3H), 1.23 (t, J 7.0 Hz, 3H); HPLC: Waters Xterra MS C18 4.6 mm×150 mm i.d., 3.5 μm particle size, 0.05% NH40H (5% ACN, 95% H2O, solvent A), to 0.05% NH4OH (95% ACN, 5% H2O, solvent B), 5% B to 20% B in 10 minutes, changed to 95% B in 25 minutes, and then changed to 5% B in 1 minute; 11.1 minutes (aminoester 1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)(=O)=O)[N:3]=1.[CH3:19][O:20][CH2:21][CH2:22][OH:23].C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([O:23][CH2:22][CH2:21][O:20][CH3:19])[N:3]=1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: COCCO
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: COCCOc1nc(N)nc(-c2ccco2)c1C#N

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile, 2-methoxyethanol and DBU in DME. ES-MS m/e (%): 283 (M+Na+, 15), 261 (M+H+, 100).
Reaction SMILES: C(OC([NH:8][CH:9]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH3:27])[CH:19]=1)[CH2:10][C:11](=[O:17])[CH2:12][C:13]([O:15]C)=O)=O)(C)(C)C.C([O-])([O-])=O.[K+].[K+].[CH2:34](Br)[CH:35]([CH3:37])[CH3:36]>CC(C)=O.CCCC[N+](CCCC)(CCCC)CCCC.[I-]>[CH3:27][O:26][C:20]1[CH:19]=[C:18]([CH:9]2[NH:10][C:11](=[O:17])[CH:12]=[C:13]([O:15][CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:8]2)[CH:23]=[CH:22][C:21]=1[O:24][CH3:25]
Reactant: COC(=O)CC(=O)CC(NC(=O)OC(C)(C)C)c1ccc(OC)c(OC)c1
Reactant: CC(C)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Product: COc1ccc(C2CC(OCC(C)C)=CC(=O)N2)cc1OC

Procedure:
With reference to Scheme 1, compound 4 (0.5 g, 1.3 mmol) and K2CO3 (0.5 g) was suspended in acetone (10 ml) followed by addition of TBAI (50 mg). To this mixture, isobutyl bromide (0.3 ml, 2.8 mmol) was added slowly. The reaction was refluxed for 3 h and quenched with water (50 ml). The aqueous phase was extracted with ethyl acetate (20 ml) twice. The combined organics was washed with brine and dried over sodium sulfate. Removal of the solvent gave a yellow oil residue, which was purified by chromatography on silica gel (elute with CH2Cl2/EtOAc 1:1) to give a mixture of compound 5 and 6 as light yellow oil (0.45 g, 78%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12](Cl)=[O:13])=[CH:4][N:3]=1.[CH3:15][O:16][C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[C:19]([N+:24]([O-:26])=[O:25])[CH:18]=1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([C:12]([NH:21][C:20]2[CH:22]=[CH:23][C:17]([O:16][CH3:15])=[CH:18][C:19]=2[N+:24]([O-:26])=[O:25])=[O:13])=[CH:4][N:3]=1
Reactant: O=C(Cl)c1cnc(Cl)nc1C(F)(F)F
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Product: COc1ccc(NC(=O)c2cnc(Cl)nc2C(F)(F)F)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared from 2-chloro-4-(trifluoromethyl)pyrimidine-5-carbonyl chloride and 4-methoxy-2-nitroaniline and was obtained as a light yellow solid as described in Example 1. 1H NMR (CDCl3): 10.52 (s, 1H), 9.04 (s, 1H), 8.68 (d, J=9.3, 1H), 7.76 (d, J=3.0, 1H), 7.35-7.31 (m, 1H), 3.91 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:22][CH3:23])=[C:9]([O:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:24][C:25]1[CH:29]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[Se:27][C:26]=1[C:34]([NH2:36])=[O:35].CN(C=O)C.[OH-].[Na+]>>[O:19]1[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][CH2:13][O:12][C:9]2[CH:10]=[C:11]3[C:6](=[CH:7][C:8]=2[O:22][CH3:23])[N:5]=[CH:4][N:3]=[C:2]3[NH:24][C:25]2[CH:29]=[C:28]([C:30]([CH3:33])([CH3:31])[CH3:32])[Se:27][C:26]=2[C:34]([NH2:36])=[O:35])[CH2:17][CH2:18]1
Reactant: COc1cc2ncnc(Cl)c2cc1OCCCN1CCOCC1
Reactant: CC(C)(C)c1cc(N)c(C(N)=O)[se]1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(Nc3cc(C(C)(C)C)[se]c3C(N)=O)c2cc1OCCCN1CCOCC1

Procedure:
The reaction of 4-chloro-7-methoxy-6-(3-morpholinopropoxy)quinazoline with 3-amino-5-tert-butylselenophene-2-carboxamide in the presence of DMF/NaOH as described in Example 1 gave title compound a pale yellow color solid, mp 208-212° C. IR (KBr) vmax 3438, 3158, 2949, 1618, 1570, 1385, 1228, 1127, 1027, 859 cm−1; 1H NMR (400 MHz, CDCl3): δ 12.01 (1H, s, exchangeable with D2O), 8.86 (1H, s), 8.72 (1H, s), 7.38 (1H, s), 7.23 (1H, s), 5.37 (2H, br s), 4.32 (2H, t, J=6.4 Hz), 4.01 (3H, s), 3.73 (4H, t, J=4.6 Hz), 2.65 (2H, t, J=7.2 Hz), 2.51-2.52 (4H, m), 2.14 (2H, pentet, J=7.0 Hz), 1.47 (9H, s); 13C NMR (100 MHz, CDCl3): δ 168.9, 168.7, 155.2, 154.5, 153.4, 149.3, 148.2, 147.6, 121.8, 109.8, 109.2, 107.7, 101.4, 67.5, 67.0, 56.2, 55.5, 53.7, 37.2, 32.6, 26.2; LC-MS (negative ion mode): m/z 544, 546 (M−H)−.