Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:8]=[S:9]1[CH:15]2[N:12]([C:13](=[O:17])[C:14]2=O)[CH:11]([C:18]([OH:20])=[O:19])[C:10]1([CH3:22])[CH3:21].[CH3:23][S:24]([CH2:27][C:28]([CH:30]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:29])(=[O:26])=[O:25]>C1C=CC=CC=1>[C:1]([OH:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:8]=[S:9]1[C@H:15]2[N:12]([C:13](=[O:17])[C:14]2=[CH:30][C:28](=[O:29])[CH2:27][S:24]([CH3:23])(=[O:26])=[O:25])[C@@H:11]([C:18]([OH:20])=[O:19])[C:10]1([CH3:22])[CH3:21]
Reactant: C=S1C2C(=O)C(=O)N2C(C(=O)O)C1(C)C
Reactant: CS(=O)(=O)CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)C(=O)O
Solvent: c1ccccc1
Product: C=S1[C@@H]2C(=CC(=O)CS(C)(=O)=O)C(=O)N2[C@@H](C(=O)O)C1(C)C
Reaction time: 0.17 h

Procedure:
A solution of 2.3 g of methylene-6,7-dioxo-3,3-dimethyl-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate pivalate in 75 ml of benzene is treated at room temperature with 4 g of methylsulphonylacetylmethylenetriphenylphosphorane. After 10 minutes, the reaction mixture is evaporated. The residue is chromatographed on silica gel while eluting with cyclohexane/ethyl acetate (1:1). There is obtained methylene-(2S,5R)-3,3-dimethyl-7-oxo-6-[3-methylsulphonyl-2-oxopropylidene]-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate pivalate as an orange oil [Rf: 0.23; cyclohexane/ethyl acetate (1:1); NMR (CDCl3), δ (ppm): 1.22 (9H); 1.5 (3H); 1.56 (3H); 3.03 (3H, CH3 --SO2); 4.24 (2H, --CH2 --SO2); 4.59 (1H); 6.02 (1H); 6.79 (1H)].
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[N:4][C:3]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[CH:14]1([C:17]2[N:22]=[C:21]([NH2:23])[CH:20]=[CH:19][CH:18]=2)[CH2:16][CH2:15]1>C(#N)C>[Cl:8][C:6]1[N:5]=[N:4][C:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:2]([NH:23][C:21]2[CH:20]=[CH:19][CH:18]=[C:17]([CH:14]3[CH2:16][CH2:15]3)[N:22]=2)[CH:7]=1
Reactant: CCOC(=O)c1nnc(Cl)cc1Cl
Reactant: Nc1cccc(C2CC2)n1
Solvent: CC#N
Product: CCOC(=O)c1nnc(Cl)cc1Nc1cccc(C2CC2)n1
Temperature: 140 °C
Yield: 33.4 %

Procedure:
A pressure tube charged with ethyl 4,6-dichloropyridazine-3-carboxylate (300 mg, 1.36 mmol), 6-cyclopropylpyridin-2-amine (273 mg, 2.04 mmol), and acetonitrile (8 mL) was heated at 140° C. for 20 h. After cooling to room temperature, the mixture was concentrated in vacuo and the residue obtained was purified by chromatography (silica, 50 μm, 80 g, Analogix, 0 to 10% acetone in dichloromethane, 20 min) to give ethyl 6-chloro-4-(6-cyclopropylpyridin-2-ylamino)pyridazine-3-carboxylate (145 mg, 34%) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 10.64 (br. s., 1H) 9.39 (s, 1H) 7.63 (t, J=7.83 Hz, 1H) 6.94 (d, J=7.58 Hz, 1H) 6.78 (d, J=8.08 Hz, 1H) 4.12 (s, 3H) 1.99-2.10 (m, 1H) 1.06-1.12 (m, 4H). LCMS (EI/CI) m/z: 319 [M+H].
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:13]([Cl:14])=[CH:12][C:7]([C:8]([O:10]C)=[O:9])=[C:6]([OH:15])[CH:5]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([CH3:23])[S:21][CH:22]=1.O>CN(C)C=O>[NH2:3][C:4]1[C:13]([Cl:14])=[CH:12][C:7]([C:8]([OH:10])=[O:9])=[C:6]([O:15][CH2:17][C:18]2[N:19]=[C:20]([CH3:23])[S:21][CH:22]=2)[CH:5]=1
Reactant: Cc1nc(CCl)cs1
Reactant: COC(=O)c1cc(Cl)c(N)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(COc2cc(N)c(Cl)cc2C(=O)O)cs1
Reaction time: 0.5 h
Yield: 65.6 %

Procedure:
A suspension of 60% sodium hydride/oil dispersion (0.5 g, 12.5 mmoles) in anhydrous dimethylformamide (20 ml) under nitrogen was treated with methyl 4-amino-5-chloro-2-hydroxybenzoate (2.02 g, 10 mmoles), stirred for 30 minutes, then treated with 4-chloromethyl-2-methylthiazole (1.85 g, 12.5 mmoles). The mixture was heated to 95°±5° C. for 1.5 hours, then cooled and added to water (150 ml). The aqueous mixture was extracted with ether (2×100 ml), and the combined ethereal solution was dried (MgSO4), concentrated in vacuo, and taken up in 95% ethanol (20 ml). Water (10 ml) and 50% sodium hydroxide (10 ml) were added, and the mixture was refluxed for one hour, cooled in on ice, and concentrated in vacuo to remove most of the ethanol. Water was added to a total volume of 100 ml, and the aqueous solution was extracted with ether (2×50 ml), cooled in an ice bath, and adjusted to pH 4 with concentrated hydrochloric acid (16 ml). A resultant precipitate was filtered, washed with water, air dried, and recrystallized from 95% ethanol to yield 1.96 g (64%) of tan crystals, mp 188°-189° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@:9]2([CH2:24][CH2:25]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:23])[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:32]1([C:38]2([C:44]([NH2:46])=[O:45])[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C@@:9]2([CH2:24][CH2:25][N:41]3[CH2:40][CH2:39][C:38]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=4)([C:44]([NH2:46])=[O:45])[CH2:43][CH2:42]3)[CH2:13][CH2:12][N:11]([C:14](=[O:23])[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Reactant: COc1ccc(C(=O)N2CC[C@@](CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc1
Agent: Cl
Product: COc1ccc(C(=O)N2CC[C@](CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc1

Procedure:
Prepare by the method of Example 88.6 using (S)-2-[3-(3,4-dichloro-phenyl)-1-(4-methoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride to give the title compound: Rf =0.35 (silica gel, 10% methanol/dichloromethane).
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[CH:3][CH:2]1[C:11]([OH:13])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O=S1(=O)C2C=CC=CC=2N=CC1C(O)=O>CN(C=O)C.C(OC(=O)C)C>[CH2:26]([NH:33][C:11]([CH:2]1[CH:3]=[N:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[S:1]1)=[O:13])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NCc1ccccc1
Reactant: O=C(O)C1C=Nc2ccccc2S1
Agent: O=C(O)C1C=Nc2ccccc2S1(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(NCc1ccccc1)C1C=Nc2ccccc2S1
Temperature: 80 °C
Yield: 34.4 %

Procedure:
A solution of 1,4-benzothiazine-2-carboxlic acid (70 mg, 0.36 mmol) and 1,1′-carbonyldiimidazole (70 mg, 0.43 mmole) in DMF ( 5 mL) is stirred at 80° C. for 30 mins. It is then treated with benzylamine (0.05 mL, 0.43 mmol) and heated at 80° C. for 1 h. The reaction mixture is cooled to room temperature, taken up with ethylacetate, and extracted with water (3×10 mL). The organic layer is dried over sodium sulfate and concentrated. The solid is filtered and washed with ethylacetate to give N-benzyl-1,4-benzothiazine-2-carboxamide (35 mg, 35% yield) as a white solid (compound 1), m.p. 160-162° C.
Reaction SMILES: [C:1]([C:3]1[C:11]2[CH:10]=[CH:9][S:8][C:7]=2[C:6]([O:12]C)=[CH:5][CH:4]=1)#[N:2].C([S-])C.[Na+].C(OCC)(=O)C.Cl>CN(C=O)C>[C:1]([C:3]1[C:11]2[CH:10]=[CH:9][S:8][C:7]=2[C:6]([OH:12])=[CH:5][CH:4]=1)#[N:2]
Reactant: COc1ccc(C#N)c2ccsc12
Agent: CC[S-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc(O)c2sccc12
Temperature: 150 °C
Yield: 99.3 %

Procedure:
To a solution of 4-cyano-7-methoxy benzo[b]thiophene (450 mg, 2.38 mmol, 1 equiv.) in dry DMF (20 mL) was added sodium ethanethiolate (80% technical grade, 1.34 g, ˜13 mmol, ˜5 equiv.) and the reaction mixture was heated at 150° C. for 2 hr. The mixture was cooled to room temperature and ethyl acetate and 1N HCl were added and the layers were separated. The aqueous layer was extracted with ethyl acetate and the combined organic extracts were washed with brine (3 times), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The acquired material thus obtained was purified via medium pressure liquid chromatography eluting with 30% ethyl acetate/70% hexanes to afford the title compound (414 mg, 99%) as a colorless solid; □H (400 MHz, CD3OD) 6.80 (1H, d, J=8 Hz), 7.47 (1H, d, J=6 Hz), 7.64 (1H, d, J=8 Hz), 7.83 (1H, d, J=6 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][N:7]2[C:15]3[CH:14]=[CH:13][NH:12][C:11](=[O:16])[C:10]=3[N:9]=[C:8]2[CH2:17][CH2:18][CH2:19][CH3:20])=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:30][C:31]([F:46])([F:45])[S:32]([NH:35][C:36]1[CH:44]=[CH:43][CH:42]=[CH:41][C:37]=1[C:38](Cl)=[O:39])(=[O:34])=[O:33]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH2:17]([C:8]1[N:7]([CH2:6][C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:38](=[O:39])[C:37]3[CH:41]=[CH:42][CH:43]=[CH:44][C:36]=3[NH:35][S:32]([C:31]([F:46])([F:30])[F:45])(=[O:34])=[O:33])=[CH:22][CH:21]=2)[C:15]2[CH:14]=[CH:13][NH:12][C:11](=[O:16])[C:10]=2[N:9]=1)[CH2:18][CH2:19][CH3:20]
Reactant: CCCCc1nc2c(=O)[nH]ccc2n1Cc1ccc(N)cc1
Reactant: O=C(Cl)c1ccccc1NS(=O)(=O)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1nc2c(=O)[nH]ccc2n1Cc1ccc(NC(=O)c2ccccc2NS(=O)(=O)C(F)(F)F)cc1
Reaction time: 16 h

Procedure:
A mixture of 2.96 g of 1-p-aminobenzyl-2-butyl-4,5-dihydro-4-oxo-1H-imidazo[4,5-c]pyridine, 3 ml of triethylamine, 0.5 g of 4-dimethylaminopyridine and 120 ml of CH2Cl2 is cooled to 5° and a solution of 2.88 g of o-trifluoromethanesulphonamidobenzoyl chloride in 20 ml of CH2Cl2 is added dropwise. The mixture is stirred at 20° for a further 16 hours, evaporated and worked up in conventional manner to give 2-butyl-4-oxo-1-[4-(2-trifluoromethanesulphonamidobenzamido)benzyl]-4,5-dihydro-1H-imidazo[4,5-c]pyridine.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]([C@@H:12]([C@H:21]([CH2:23][O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[OH:22])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>C(Cl)Cl>[CH3:39][S:40]([O:11][CH2:10][C@H:9]([C@@H:12]([C@H:21]([CH2:23][O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[O:22][S:40]([CH3:39])(=[O:42])=[O:41])[O:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:42])=[O:41]
Reactant: CS(=O)(=O)Cl
Reactant: OC[C@@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@@H](O)COCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@@H](OCc1ccccc1)[C@H](OCc1ccccc1)[C@H](COCc1ccccc1)OS(C)(=O)=O
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
2,3,5-Tri-O-benzyl-L-xylitol (10.2 g, 24.17 nmmol) is dissolved in dry methylene chloride (100 ml) containing triethylamine (10.1 mL, 72.5 mmol). The mixture is cooled to -10° C. and methane sulfonylchloride (3.93 mL, 50.75 mmol) is added dropwise. The mixture is stirred 30 minutes at -10° C. and washed with water. The organic layer is dried over sodium sulfate, filtered and put to dryness under reduced pressure to afford an oil. Flash chromatography on silica gel and elution with a 4:6 mixture of ethyl acetate and cyclohexane yield 1,4-di-O-methanesulfonyl-2,3,5-tri-O-benzyl-L-xylitol as an oil (13.9 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:27])=[C:6]([C:8]2[N:9]=[C:10]([NH:17][C:18]3[C:23]([C:24]([OH:26])=O)=[CH:22][N:21]=[CH:20][CH:19]=3)[C:11]3[O:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:7]=1.[CH2:28]([N:30](CC)CC)C.CN.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:27])=[C:6]([C:8]2[N:9]=[C:10]([NH:17][C:18]3[C:23]([C:24]([NH:30][CH3:28])=[O:26])=[CH:22][N:21]=[CH:20][CH:19]=3)[C:11]3[O:16][CH2:15][CH2:14][C:12]=3[N:13]=2)[CH:7]=1
Reactant: O=C(O)c1cnccc1Nc1nc(-c2cc(Cl)ccc2F)nc2c1OCC2
Reactant: CCN(CC)CC
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CNC(=O)c1cnccc1Nc1nc(-c2cc(Cl)ccc2F)nc2c1OCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.3 %

Procedure:
To a suspension of 4-[2-(5-chloro-2-fluorophenyl)-6,7-dihydrofuro[3,2-d]pyrimidin-4-ylamino]-nicotinic acid (75 mg, 0.19 mmol, 1 eq) in DMF (2 ml) was added triethylamine (30 μl, 0.21 mmol, 1.1 eq) followed by methylamine (1.17 ml, 3.89 mmol, 2 M solution in THF, 20 eq). To the suspension was added a solution of PyBrOP (100 mg, 0.21 mmol, 1.2 eq) in DMF (1 ml) dropwise. The reaction mixture was stirred at room temperature for 16 h. The reaction was concentrated in vacuo and the residue was triturated with ether (2×20 ml). The crude residue was purified by flash column chromatography (5% MeOH in CHCl3) to afford 4-[2-(5-chloro-2-fluorophenyl)-6,7-dihydrofuro[3,2-d]pyrimidin-4-ylamino]-N-methyl nicotinamide, i.e. compound of formula (44) (20 mg, 26%) as a white solid.
Reaction SMILES: Br[C:2]1[C:31]2=[N:32][C:28]3=[CH:29][N:30]2[C:5]([N:6]2[CH2:37][CH2:36][C:9]([CH3:38])([O:10][CH2:11][CH2:12][CH2:13][CH2:14][C@H:15]([CH3:35])[O:16][C:17]4[CH:18]=[CH:19][C:20]([F:34])=[CH:21][C:22]=4[C:23]4[CH:33]=[C:27]3[CH:26]=[CH:25][CH:24]=4)[CH2:8][CH2:7]2)=[C:4]([C@H:39]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])[C:40]([O:42][CH3:43])=[O:41])[C:3]=1[CH3:49].[C:50](O[C@@H](C1C(C)=C(C=C)C2=NC3=CN2C=1N1CCC(C)(OCCCC[C@H](C)OC2C=CC(F)=CC=2C2C=C3C=CC=2)CC1)C(OC)=O)(C)([CH3:52])[CH3:51]>>[C:45]([O:44][C@@H:39]([C:4]1[C:3]([CH3:49])=[C:2]([C:50]([CH3:52])=[CH2:51])[C:31]2=[N:32][C:28]3=[CH:29][N:30]2[C:5]=1[N:6]1[CH2:37][CH2:36][C:9]([CH3:38])([O:10][CH2:11][CH2:12][CH2:13][CH2:14][C@H:15]([CH3:35])[O:16][C:17]2[CH:18]=[CH:19][C:20]([F:34])=[CH:21][C:22]=2[C:23]2[CH:33]=[C:27]3[CH:26]=[CH:25][CH:24]=2)[CH2:8][CH2:7]1)[C:40]([O:42][CH3:43])=[O:41])([CH3:47])([CH3:48])[CH3:46]
Reactant: C=Cc1c(C)c([C@H](OC(C)(C)C)C(=O)OC)c2n3cc(nc13)-c1cccc(c1)-c1cc(F)ccc1O[C@@H](C)CCCCOC1(C)CCN2CC1
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(Br)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)cc1-c1cccc-3c1
Product: C=C(C)c1c(C)c([C@H](OC(C)(C)C)C(=O)OC)c2n3cc(nc13)-c1cccc(c1)-c1cc(F)ccc1O[C@@H](C)CCCCOC1(C)CCN2CC1
Yield: 80 %

Procedure:
Prepared in 80% yield from methyl(2S)-2-[(22S)-5-bromo-17-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]-2-(tert-butoxy)acetate following the procedure for methyl(2S)-2-(tert-butoxy)-2-[(22S)-5-ethenyl-17-fluoro-4,22,28-trimethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate. LCMS (ESI, M+1): 698.4.
Reaction SMILES: [C:1]([NH:20][C@@H:21]([CH2:24][CH3:25])[CH:22]=[O:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([Mg]Br)[CH3:27].O>CCOCC>[C:1]([NH:20][C@@H:21]([CH2:24][CH3:25])[CH:22]([OH:23])[CH2:26][CH3:27])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[C@@H](C=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC[Mg]Br
Solvent: O
Solvent: CCOCC
Product: CCC(O)[C@H](CC)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (S)-2-(trityl-amino)-butyraldehyde (1.5 g, 1 eq, 4.53 mmol) in ether (150 mL) under an argon atmosphere at −78° C., was added ethylmagnesium bromide (3 M in ether, 1.51 mL, 1 eq, 4.53 mmol) dropwise. The solution was stirred at −78° C. for 2 h, then allowed to warm to room temperature over 16 h. The mixture was re-cooled to 0° C., H2O (150 mL) added, and the organic phase separated. The aqueous phase was extracted with more ether (2×50 mL), and the combined organic phase washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by silica gel column chromatography, eluted with hexane:ether (90:10) to afford the title compound as a light yellow oil; Yield: 1.19 g (73%). (65% de 3R,4S: 35% de 3S,4S) 1H-NMR(d6-DMSO, 250 MHz): δ 0.46+0.69 (t+m, 6H, J=7.34 Hz, —NHCH(CH2CH3)CH(CH2CH3)OH), 1.13-1.29 (m, 4H, —NHCH(CH2CH3)CH(CH2CH3)OH), 2.17 (m, 1H, —NHCH(CH2CH3)CH(CH2CH3)OH), 2.55 (m, 1H, —NHCH(CH2CH3)CH(CH2CH3)OH), 3.20-3.39 (m, 1H, —NHCH(CH2CH3)CH(CH2CH3)OH), 4.29+4.39 (2×d, 1H, J=4.74+5.53 Hz, —NHCH(CH2CH3)CH(CH2CH3)OH), 7.15-7.52 (m, 15H, 3×Bz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17](S(C)=O)[O:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1.[NH2:24][C@@H:25]1[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]1[OH:31].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17]([NH:24][C@@H:25]5[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]5[OH:31])[O:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cc(Br)cnc43)cc2o1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(Br)cnc43)cc2o1
Temperature: 120 °C
Yield: 37.7 %

Procedure:
A stirred mixture of 6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]oxazole (150 mg, 0.384 mmol) from Step 3 of this Example, (1R,2R)-(−)-2-aminocyclohexanol (88 mg, 0.768 mmol), and DIEA (99 mg, 0.768 mmol) in anhydrous DMA (3 mL) in a sealed vial was heated in a Biotage microwave synthesizer at 120° C. for 30 min. After the reaction mixture was cooled to rt, it was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C-18 column as the stationary phase to afford (1R,2R)-2-((6-((6-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanol (64 mg, 38%) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.49 (d, J=2.0 Hz, 1H), 8.38 (d, J=1.7 Hz, 1H), 7.81 (d, J=7.6 Hz, 1H), 7.39 (s, 1H), 7.10-7.16 (m, 2H), 5.48 (s, 2H), 4.69 (d, J=4.2 Hz, 1H), 3.30-3.40 (m, 2H), 1.83-1.97 (m, 2H), 1.57-1.67 (m, 2H), 1.15-1.30 (m, 4H). LCMS (ESI) m/z 442 and 444 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:19])[N:3]1[C:7](=[O:8])[N:6]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([O:16][CH3:17])[CH:10]=2)[N:5]=[C:4]1[CH3:18].S(Cl)([Cl:23])(=O)=O>C(Cl)(Cl)Cl.C(Cl)Cl>[Cl:23][C:14]1[CH:13]=[C:12]([CH3:15])[C:11]([O:16][CH3:17])=[CH:10][C:9]=1[N:6]1[C:7](=[O:8])[N:3]([CH:2]([F:1])[F:19])[C:4]([CH3:18])=[N:5]1
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1cc(-n2nc(C)n(C(F)F)c2=O)ccc1C
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: COc1cc(-n2nc(C)n(C(F)F)c2=O)c(Cl)cc1C
Yield: 97 %

Procedure:
A solution of 15.0 g (0.056 mole) of 4-difluoromethyl-4,5-dihydro-1-(4-methyl-3-methoxyphenyl)-3-methyl-1,2,4-triazol-5(1H)-one and 7.5 g (0.056 mole) of sulfuryl chloride in 100 mL of chloroform was stirred at room temperature for two hours. The reaction mixture was concentrated under reduced pressure to leave a residue. This residue was dissolved in methylene chloride and washed with an aqueous 10% sodium hydroxide solution. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to yield 16.5 g of 1-(2-chloro-4-methyl-5-methoxyphenyl)-4-difluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one as a solid.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1.[CH3:13][O-:14].[Na+]>C1(C)C=CC=CC=1.CO>[CH3:13][O:14][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1
Reactant: NCc1ccc(OCCCl)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COCCOc1ccc(CN)cc1
Reaction time: 2 h

Procedure:
4-(2-Chloroethoxy)benzylamine (2.0 g; 0,11 mol) was dissolved in anhydrous toluene (50 ml). The reaction mixture was ice-cooled and sodium methoxide (0.59 g; 0.011 mol) dissolved in methanol (5 ml) was added thereto. When the addition was complete the mixture was left to stand for 2 hours at room temperature and filtered. Solvent was evaporated from the filtrate, to give an oily residue of good purity.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:43][O:44][C:45]1[C:46]2[N:59]=[C:58]([NH2:60])[S:57][C:47]=2[C:48]([N:51]2[CH2:56][CH2:55][O:54][CH2:53][CH2:52]2)=[N:49][CH:50]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:60][C:58]2[S:57][C:47]3[C:48]([N:51]4[CH2:56][CH2:55][O:54][CH2:53][CH2:52]4)=[N:49][CH:50]=[C:45]([O:44][CH3:43])[C:46]=3[N:59]=2)=[O:9])=[CH:10][CH:11]=1
Reactant: COc1ccc(C(=O)O)cc1
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2nc3c(OC)cnc(N4CCOCC4)c3s2)cc1

Procedure:
From 4-methoxybenzoic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 401 (M+H+, 100).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[CH2:13](O)[CH2:14][OH:15].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:15][CH2:14][CH2:13][O:6]1
Reactant: O=C(CCCCl)c1ccccc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: ClCCCC1(c2ccccc2)OCCO1
Reaction time: 20 h

Procedure:
A mixture of γ-chlorobutyrophenone (33.2 g; 0.182 mol), ethylene glycol (20.3 ml; 0.363 mol), p-toluenesulfonic acid (a pinch) and toluene (300 ml) is heated at reflux for 40 hours, and the water formed in the reaction is azeotroped off. After 20 hours, more ethylene glycol (20.3 ml; 0.363 mol) is added. On completion of the reaction the mixture is extracted with saturated aqueous sodium bicarbonate solution (300 ml), the organic layer is washed with 1 N sodium hydroxide solution and then with water, and is evaporated to afford 37.0 g of a cream colored solid, m.p. 54°-55.5° C.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1.[CH3:24][NH:25][CH3:26]>[OH-].[Na+].Cl>[CH3:24][N:25]([CH3:26])[C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1
Reactant: CNC
Reactant: CCCOc1ccccc1-c1nc2nc(SC)ncc2c(=O)[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCOc1ccccc1-c1nc2nc(N(C)C)ncc2c(=O)[nH]1

Procedure:
7-Methylthio-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (0.60 g) was treated with a solution of dimethylamine in industrial methylated spirit (33%; 20 ml) in a pressure vessel for 18 hours at 90° C. The cooled reaction mixture was evaporated under reduced pressure to yield a solid which was dissolved in aqueous sodium hydroxide. The filtered aqueous solution was neutralized with a few drops of concentrated hydrochloric acid to yield a pale yellow solid which was recrystallized from 2-propanol to yield the title compound, 0.33 g, m.p. 177.5-178.5° C.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]2[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=2)[O:22][CH2:23][C:24]#[N:25])=[CH:15][CH:14]=1.[N-:31]=[N+:32]=[N-:33].[Na+].[Cl-].[NH4+]>CN(C)C=O.C(OCC)(=O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:30]=[CH:29][C:16]([O:17][CH2:18][C:19]2[CH:20]=[C:21]([CH:26]=[CH:27][CH:28]=2)[O:22][CH2:23][C:24]2[NH:33][N:32]=[N:31][N:25]=2)=[CH:15][CH:14]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#CCOc1cccc(COc2ccc(OCc3ccc4ccccc4n3)cc2)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: c1cc(COc2ccc(OCc3ccc4ccccc4n3)cc2)cc(OCc2nnn[nH]2)c1

Procedure:
α-(3-(4-(2-quinolinylmethyloxy)phenoxymethyl)phenoxy)acetonitrile (8.12 mmol), sodium azide (24.4 mmol) and ammonium chloride (24.4 mmol) in dimethylformamide (10 ml) are heated at 115°-120° C. for 6 hrs. After cooling, the reaction mixture is diluted with ethyl acetate (150 ml), washed with water (6×100 ml) then dried and evaporated. The residue is chromatographed on a column of silica gel (360 g) and eluted with a gradient of isopropanol in methylene chloride to give 5-(3-(4-(2-quinolinylmethyloxy)phenoxymethyl)phenoxymethyl)tetrazole (M.P. 131°-132° C.)