Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[CH:14])=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:15]1[O:17][CH2:16]1.S(=O)(=O)(O)O>C1COCC1>[CH:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:13]#[C:14][CH2:15][CH2:16][OH:17])=[CH:11][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C1CO1
Reactant: C#Cc1ccc(C2CCCCC2)cc1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Product: OCCC#Cc1ccc(C2CCCCC2)cc1
Reaction time: 1 h

Procedure:
To a solution of 153 g of ethylbromide in 160 ml of abs. THF, is added a suspension of 36 g of magnesium turning in 330 ml of THF, (to obtain a solution of ethyl magnesium bromide) and the reaction mixture cooled to 0° to 5°. To the reaction mixture is then added, dropwise, a solution of 214 g of p-cyclohexylphenylacetylene in 420 ml of abs. THF, over a period of one hour. The resulting thick suspension is diluted with 200 of abs. THF and then refluxed for 1.5 hours. The reaction mixture is then cooled to 0°, and a solution of 62 g ethylene oxide in 420 ml of abs. THF added thereto, dropwise, over a period of one hour. After addition is completed, the reaction mixture is refluxed for 2.5 hours, then decomposed by adding dilute sulfuric acid (5%), and extracted with ether. The combined ether extracts are washed with water, then brine, and evaporated i.v. to dryness to obtain a residue from which is crystallized 4-(p-cyclohexylphenyl)-3-butyn-1 -ol, m.p. 56° - 59° from pentane.
Reaction SMILES: [Cl:1][C:2]1[C:38]([C:39]([F:42])([F:41])[F:40])=[CH:37][CH:36]=[CH:35][C:3]=1[CH2:4][N:5]([CH2:21][CH:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH2:16][C:17]([O:19]C)=[O:18])[CH:13]=[CH:14][CH:15]=1.[Li+].[OH-].CC(O)=O.Cl.CCOCC>O1CCCC1.O.CCOCC.O.CCOC(C)=O>[ClH:1].[Cl:1][C:2]1[C:38]([C:39]([F:40])([F:41])[F:42])=[CH:37][CH:36]=[CH:35][C:3]=1[CH2:4][N:5]([CH2:21][CH:22]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH2:16][C:17]([OH:19])=[O:18])[CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)Cc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C(O)Cc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 110.6 %

Procedure:
A solution of methyl (3-{3-[[2-chloro-3-(trifluoromethyl)benzyl](2,2-diphenylethyl)amino]propoxy}phenyl)acetate (113 mg, 0.19 mmol) in 1.5 mL of tetrahydrofuran and 1 mL of water was treated with 1 N aqueous LiOH (0.29 mL, 0.29 mmol). After stirring at room temperature for 2 hours, additional 1N aqueous LiOH (0.29 mL, 0.29 mmol) was added and stirring was continued for 2 hours. The reaction was neutralized with AcOH (66 μL, 0.58 mmol) and poured into H2O/EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with brine (1×), dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude material was purified by preparative thin layer chromatography (silica gel, 1 mm plates, Merck 20×20 cm silica gel 60 F254) eluting with CH2Cl2:MeOH (95:5) to afford an oil. The oil was dissolved in Et2O and acidified with excess HCl/Et2O. The reaction was concentrated in vacuo and dried under reduced pressure to give 65 mg (56% yield) of the title compound as a white solid: H NMR (C5D5N, 400 MHz) δ 7.60-7.05 (m, 15 H), 7.01 (t, 1 H, J=7.6), 6.84 (dd, 1 H, J=8.4, 2.4), 4.32 (t, 1 H, J=7.6), 3.89 (s, 2 H), 3.77 (s, 2 H), 3.71 (t, 2 H, J=5.6), 3.16 (d, 2 H, J=7.6), 2.65 (t, 2 H, J=6.4), 1.88-1.78 (m, 2 H).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26]O[CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.N1CC[S:53]CC1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][S:53][CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CSCCN1
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Product: CC(C)(C)c1nc(N2CCSCC2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and thiomorpholine and isolated as light-yellow gum (10.2 mg, 54%). MS (m/e): 403.4 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:3]=1[NH2:4].Br[C:13](C)(C)[C:14]([O:16][CH2:17][CH3:18])=[O:15].C(N(C(C)C)CC)(C)C>>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][NH:4][C:3]1[C:2]([CH3:1])=[CH:8][CH:7]=[CH:6][C:5]=1[N+:9]([O-:11])=[O:10])[CH3:18]
Reactant: Cc1cccc([N+](=O)[O-])c1N
Reactant: CCOC(=O)C(C)(C)Br
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNc1c(C)cccc1[N+](=O)[O-]

Procedure:
A mixture of 2-methyl-6-nitroaniline (XIV, 2.00 g), ethyl bromoacetate (III, 3.5 ml) and diisopropylethylamine (3.5 ml) is heated at reflux (140°) for 8 hr. The resultant solution is allowed to cool to 20°-25°. After dilution with aqueous sodium bicarbonate, extraction several times with ethyl acetate, drying with magnesium sulfate and concentration the residue is resubmitted to the above reaction conditions for an additional 16 hr. After workup, purification by flash chromatography eluting with a gradient of hexane/ethyl acetate (10/1→5/1), pooling and concentrating the appropriate fractions, the title compound is obtained, mp 49°-52°; IR (mineral oil) 3365, 2953, 2925, 1731, 1536, 1475, 1461, 1374, 1344, 1236, 1207, 1104 and 1022 cm-1 ; NMR (CDCl3) 7.88, 7.33, 6.8-7.0, 6.86, 4.17, 3.94, 2.39 and 1.23 δ.
Reaction SMILES: CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[S:27][C:28]([C:36]([OH:38])=O)=[C:29]([CH2:31][C:32]([O:34][CH3:35])=[O:33])[N:30]=2)=[CH:22][CH:21]=1.[C:39]([O:43][C:44]([N:46]1[CH2:49][CH:48]([O:50][C:51]2[CH:56]=[CH:55][C:54]([NH2:57])=[CH:53][C:52]=2[O:58][CH3:59])[CH2:47]1)=[O:45])([CH3:42])([CH3:41])[CH3:40].CN1CCOCC1>C1COCC1>[C:39]([O:43][C:44]([N:46]1[CH2:47][CH:48]([O:50][C:51]2[CH:56]=[CH:55][C:54]([NH:57][C:36]([C:28]3[S:27][C:26]([C:23]4[CH:22]=[CH:21][C:20]([Cl:19])=[CH:25][CH:24]=4)=[N:30][C:29]=3[CH2:31][C:32]([O:34][CH3:35])=[O:33])=[O:38])=[CH:53][C:52]=2[O:58][CH3:59])[CH2:49]1)=[O:45])([CH3:42])([CH3:41])[CH3:40]
Reactant: COC(=O)Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)O
Reactant: COc1cc(N)ccc1OC1CN(C(=O)OC(C)(C)C)C1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COC(=O)Cc1nc(-c2ccc(Cl)cc2)sc1C(=O)Nc1ccc(OC2CN(C(=O)OC(C)(C)C)C2)c(OC)c1
Temperature: 5 °C
Yield: 89.8 %

Procedure:
Mix 1-propanephosphonic acid cyclic anhydride (50% in EtOAc) (528.7 g, 831.3 mmol) and THF (1110 mL) and chill to 5° C. Add 2-(4-chloro-phenyl)-4-methoxycarbonylmethyl-thiazole-5-carboxylic acid (185.0 g, 593.43 mmol) followed by 3-(4-amino-2-methoxy-phenoxy)-azetidine-1-carboxylic acid tert-butyl ester (192.2 g, 914.4 mmol). Charge N-methylmorpholine (99 mL, 1247 mmol) dropwise over 15 min and remove the ice bath immediately after the addition. Heat the reaction to 65° C. for 16 h and quench with water (555 mL). Dilute with EtOAc (1110 mL) and partition the layers. Wash with saturated sodium bicarbonate (555 mL) and with brine (555 mL). Distill the organic solvent until <5% THF remains and then back-add with ethyl acetate as needed to a total of 740 mL solvent at the end of the distillation. Add heptane (230 mL) at 75° C. and seed with authentic product at 55° C. Allow to cool to room temperature, filter, and rinse twice with heptane-EtOAc (2×100 mL, 1:1). Dry in a vacuum oven at 40° C. to obtain 313.5 g (90%) of the title compound as an orange-brown solid. ES/MS m/z (35Cl) 586 [M−1]−.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[CH2:13]([C:15]1[S:19][CH:18]=[C:17]([C:20]([OH:22])=O)[CH:16]=1)[CH3:14].[CH3:23][C:24]12[CH2:31][CH:28]([NH:29][CH2:30]1)[CH2:27][C:26]([CH3:33])([CH3:32])[CH2:25]2.O>C(Cl)Cl>[CH2:13]([C:15]1[S:19][CH:18]=[C:17]([C:20]([N:29]2[CH2:30][C:24]3([CH3:23])[CH2:31][CH:28]2[CH2:27][C:26]([CH3:33])([CH3:32])[CH2:25]3)=[O:22])[CH:16]=1)[CH3:14]
Reactant: CCc1cc(C(=O)O)cs1
Reactant: CC1(C)CC2CC(C)(CN2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CCc1cc(C(=O)N2CC3(C)CC2CC(C)(C)C3)cs1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 61.6 %

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.06 g; 1.2 eq) was added to a solution of 5-ethyl-thiophene-3-carboxylic acid (0.04 g; 1 eq.) in DCM (1 mL/100 mg of starting material). This mixture was stirred at room temperature for 5 minutes, then 1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane (0.043 g; 1.1 eq.) added and the mixture allowed to stir for 18 hours. Water (1 mL/100 mg of starting material) was then added and the organic layer separated, dried and evaporated to give the crude product which was purified by column chromatography (EtOAc/iso-hexane) to give the title compound (0.046 g). LCMS m/z 292 [M+H]+ RT=4.28 min (Analytical Method 3).
Reaction SMILES: [CH2:1]([O:8][N:9]([C@H:22]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:25]([C:35]2[S:39][N:38]=[CH:37][N:36]=2)[CH2:24][CH2:23]1)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[Li].O.SCC(O)=O>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:8][NH:9][C@H:22]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C@H:25]([C:35]2[S:39][N:38]=[CH:37][N:36]=2)[CH2:24][CH2:23]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H](N(OCc2ccccc2)S(=O)(=O)c2ccccc2[N+](=O)[O-])CC[C@H]1c1ncns1
Agent: O=C(O)CS
Agent: [Li]O
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@H](NOCc2ccccc2)CC[C@H]1c1ncns1
Temperature: 30 °C
Reaction time: 24 h
Yield: 71.7 %

Procedure:
To a mixture of (2S,5R)-tert-butyl 5-(N-(benzyloxy)-2-nitrophenylsulfonamido)-2-(1,2,4-thiadiazol-5-yl)piperidine-1-carboxylate (1.17 g, 2.0 mmol) in dry DMF (30 mL) at rt was added LiOH.H2O (640 mg, 16.0 mmol), followed by addition of 2-mercaptoacetic acid (920 mg, 10.0 mmol). The mixture was stirred at 30° C. for 24 hrs., then the mixture was diluted with EtOAc (200 mL), washed with water (4×), dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (3:1 petroleum ether/EtOAc) to give (2S,5R)-tert-butyl 5-(benzyloxyamino)-2-(1,2,4-thiadiazol-5-yl)piperidine-1-carboxylate (560 mg, 75%) as an oil. ESI-MS (EI+, m/z): 413 [M+Na]+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.C(N(CC)CC)C.Cl[C:26]1[O:27][C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=1.O>O1CCCC1>[O:27]1[C:28]2[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=2[N:30]=[C:26]1[NH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1
Reactant: COC(=O)[C@@H]1C[C@@H](N)CN1C(=O)OC(C)(C)C
Reactant: Clc1nc2ccccc2o1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@@H](Nc2nc3ccccc3o2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Methyl (2S,4R)-4-amino-1-tert-butoxycarbonylpyrrolidine-2-carboxylate [product of Reference Example 4(2), 3.32 g] and triethylamine (1.4 mL) were dissolved in tetrahydrofuran (20 mL). 2-Chlorobenzoxazole (0.86 mL) was added thereto and the mixture was stirred at room temperature for 48 hr. The reaction mixture was added to water and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogencarbonate solution and brine, and dried. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography to give methyl (2S,4R)-4-(2-benzoxazolyl)amino-1-tert-butoxycarbonylpyrrolidine-2-carboxylate (1.48 g) as a white solid.
Reaction SMILES: [Cl:1][CH2:2][CH:3]=O.[NH2:5][C:6]1[CH:7]=[CH:8][C:9]([Cl:26])=[C:10]([CH:25]=1)[C:11]([NH:13][CH2:14][C:15]12[CH2:24][CH:19]3[CH2:20][CH:21]([CH2:23][CH:17]([CH2:18]3)[CH2:16]1)[CH2:22]2)=[O:12].Cl.C([BH3-])#N.[Na+]>CO>[Cl:26][C:9]1[CH:8]=[CH:7][C:6]([NH:5][CH2:3][CH2:2][Cl:1])=[CH:25][C:10]=1[C:11]([NH:13][CH2:14][C:15]12[CH2:16][CH:17]3[CH2:23][CH:21]([CH2:20][CH:19]([CH2:18]3)[CH2:24]1)[CH2:22]2)=[O:12]
Reactant: O=CCCl
Reactant: Nc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(NCCCl)ccc1Cl
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Chloroacetaldehyde (50% solution in water) (0.705 ml) was added to a solution of amino amide from Example 55 (1.5 g) in methanol (15 ml). After 10 minutes hydrochloric acid (0.77 ml of a 50% solution in methanol) was added. Solid sodiumcyanoborohydride (0.317 g) was added and the mixture stirred at ambient temperature for two days. The solvent was removed under reduced pressure, the residue was dissolved in dichloromethane (50 ml) and washed with aqueous sodium hydrogen carbonate (3×50 ml). The organic extracts were dried over magnesium sulphate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluting with hexane:diethylether (1:1) to give the title compound as a yellow solid (1.13 g).
Reaction SMILES: C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C.[CH2:31]([O:38][C:39]1[CH:44]=[C:43](Br)[CH:42]=[C:41]([F:46])[C:40]=1[F:47])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[O:48]1CCOCC1>O.[OH-].[K+].CCOC(C)=O>[CH2:31]([O:38][C:39]1[CH:44]=[C:43]([OH:48])[CH:42]=[C:41]([F:46])[C:40]=1[F:47])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: Fc1cc(Br)cc(OCc2ccccc2)c1F
Reactant: C1COCCO1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: Oc1cc(F)c(F)c(OCc2ccccc2)c1
Temperature: 90 °C
Yield: 60 %

Procedure:
To a solution of potassium hydroxide (2246.7 mg, 40.12 mmol) in 1,4-dioxane (5 mL) and Water (5 mL) was added 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (212.63 mg, 0.5015 mmol). The reaction mixture was degassed with nitrogen and then treated with tris(dibenzylideneacetone)dipalladium-[0](183.54 mg, 0.2006 mmol) and 1-benzyloxy-5-bromo-2,3-difluoro-benzene [CAS: 1035155-54-4](3 g, 10.03 mmol) the reaction was then heated at 90° C. for 16 hours. The reaction was diluted with aq. KOH solution (2M, 150 mL) and EtOAc (150 mL). The aqueous was separated, and acidified to pH 1 with aq. HCl (2M). The organics were then extracted into EtOAc (150 mL). The organics were separated, washed with brine (150 mL), dried over MgSO4, filtered and concentrated in vacuo to give crude 3-benzyloxy-4,5-difluoro-phenol ˜60% pure);
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:11]1[C:12]([O:25][CH3:26])=[C:13](/[CH:19]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22])[C:14]([CH3:18])=[C:15]([Cl:17])[CH:16]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].N12CCCN=C1CCCCC2.O.[N+:39]([CH3:42])([O-:41])=[O:40]>ClCCl>[C:1]([O:5][C:6]([NH:8][CH:9]([C:11]1[C:12]([O:25][CH3:26])=[C:13]([CH:19]([CH2:42][N+:39]([O-:41])=[O:40])[CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:14]([CH3:18])=[C:15]([Cl:17])[CH:16]=1)[CH3:10])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: C[N+](=O)[O-]
Reactant: COC(=O)/C=C/c1c(C)c(Cl)cc(C(C)NC(=O)OC(C)(C)C)c1OC
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: ClCCl
Product: COC(=O)CC(C[N+](=O)[O-])c1c(C)c(Cl)cc(C(C)NC(=O)OC(C)(C)C)c1OC
Temperature: 25 °C
Yield: 53 %

Procedure:
A solution of methyl (2E)-3-(3-{1-[(tert-butoxycarbonyl)amino]ethyl}-5-chloro-2-methoxy-6-methylphenyl)acrylate (1.5 g, 3.9 mmol) in nitromethane (11 mL) at 0° C. was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (0.59 mL, 3.9 mmol) and allowed to warm to room temperature. The reaction mixture was heated at 60° C. for 21 h, cooled to room temperature, poured into water (100 ml) and extracted with EtOAc (2×75 mL). The organic layer was separated, washed with brine solution, dried over anhydrous sodium sulfate, filtered, and concentrated to give a orange foam. The crude material was dissolved in dichloromethane and purified by flash column chromatography using EtOAc in hexanes (0%-30% over 30 min) to give the desired product (0.93 g, 53%) as a white foam. LCMS for C20H29ClN2O7Na (M+Na)+: m/z=467.2. Found: 467.1.
Reaction SMILES: C(O[C:4](=[O:14])[CH2:5][C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.Cl.[C:16]([NH2:24])(=[NH:23])[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1>>[C:7]1([C:6]2[N:24]=[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[N:23]=[C:4]([OH:14])[CH:5]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: N=C(N)c1ccncc1
Agent: Cl
Product: Oc1cc(-c2ccccc2)nc(-c2ccncc2)n1

Procedure:
The title compound was prepared from 3-oxo-3-phenyl-propionic acid ethyl ester and isonicotinamidine hydrochloride according to general procedure 1. 1H NMR (DMSO-d6, 400 MHz) δ 7.08 (s, 1H), 7.50-7.55 (m, 3H), 8.17-8.25 (m, 4 H), 8.88 (d, J=4.4 Hz, 2H), 10-12 (br s, 1H); MS: m/z(ESI) 250 (M+H).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C:11](=[CH:12][CH2:13][C@@H:14]3[C@@H:23]2[CH2:22][CH2:21][C@@:19]2([CH3:20])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[OH:28])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:29](OC=C)[CH3:30]>>[Si:1]([O:8][C@H:9]1[CH2:26][CH2:25][C@@:24]2([CH3:27])[C:11](=[CH:12][CH2:13][C@@H:14]3[C@@H:23]2[CH2:22][CH2:21][C@@:19]2([CH3:20])[C@H:15]3[CH2:16][CH2:17][C@@H:18]2[O:28][CH:29]=[CH2:30])[CH2:10]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C=COCC
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H](O)[C@@]4(C)CC[C@@H]32)C1
Product: C=CO[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4 g of 3β-(t-butyldimethylsilyloxy)androst-5-en-17β-ol in 50 ml of vinyl ethyl ether, there was added 0.25 g of mercuric acetate. The mixture was stirred at room temperature for 24 hours, quenched with triethylamine, and then poured into dilute aqueous potassium carbonate solution. The aqueous mixture was extracted 3 times with 100 ml-portions of diethyl ether and the combined organic extracts were washed with saturated aqueous sodium chloride solution and then dried over sodium sulfate. The solvent was then removed under reduced pressure and the residue was purified by flash chromatography using ethyl acetate/hexane, 1:4, to give 3β-(t-butyldimethylsilyloxy)-17β-ethenyloxyandrost-5-ene.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([C:8]#[C:9][CH2:10][OH:11])[CH:5]=[CH:6][CH:7]=1>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([CH2:8][CH2:9][CH2:10][OH:11])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(Cl)cccc1C#CCO
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1c(Cl)cccc1CCCO
Temperature: 60 °C
Reaction time: 11 h
Yield: 80 %

Procedure:
A suspension of Compound 54-1 (2.58 g) and chlorotris(triphenylphosphine)rhodium(I) (1.50 g) in toluene (80 ml) was stirred under a hydrogen atmosphere at 60° C. for 11 hr. The reaction mixture was filtered through celite and concentrated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=99:1-80:20) to give the object product (2.11 g) as a brown oil.
Reaction SMILES: Cl.Cl[C:3]([C:5]1[CH:6]=[CH:7][N:8]2[C:12]=1[CH2:11][S:10][CH:9]2[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:4].[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:27]=[C:28]([CH:30]=[CH:31][CH:32]=2)[NH2:29])[CH:20]=1.C(N(CC)CC)C.C>O1CCOCC1.C(#N)C>[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]2[CH:27]=[C:28]([NH:29][C:3]([C:5]3[CH:6]=[CH:7][N:8]4[C:12]=3[CH2:11][S:10][CH:9]4[C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)=[O:4])[CH:30]=[CH:31][CH:32]=2)[CH:20]=1
Reactant: Nc1cccc(Oc2cccnc2)c1
Reactant: O=C(Cl)c1ccn2c1CSC2c1cccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: C1COCCO1
Product: O=C(Nc1cccc(Oc2cccnc2)c1)c1ccn2c1CSC2c1cccnc1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 41.2 %

Procedure:
7-Chloroformyl-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole hydrochloride (6 g) is added, at a temperature between 65° and 72° C., to a solution of 3-(3-pyridyloxy)aniline (3.9 g) and triethylamine (4.05 g) in dioxane (150 cc) which is heated to a temperature in the vicinity of 65° C., in the course of 5 minutes. The suspension obtained is heated, with stirring, at a temperature in the vicinity of 100° C. for 6 hours and 30 minutes and then stirred at a temperature in the vicinity of 20° C. for 16 hours. The solvent is evaporated off under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 60° C. The residue is dissolved in methylene chloride (300 cc). The solution obtained is washed twice with distilled water (300 cc in total), twice with an aqueous 1N sodium hydroxide solution (300 cc in total) and twice with distilled water (300 cc in total) and then dried over anhydrous magnesium sulphate, treated with decolourizing charcoal (0.5 g), filtered and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 60° C. A crude product (8.2 g) is thereby obtained, which is dissolved in boiling acetonitrile (50 cc). Decolourizing charcoal (0.5 g) is added to the solution obtained and the suspension is filtered in the heated state. The filtrate is cooled at a temperature in the vicinity of 20 ° C. for 2 hours. The crystals formed are separated by filtration, washed 3 times with acetonitrile (30 cc in total) and 3 times with diethyl ether (90 cc in total) and then dried under reduced pressure (20 mm Hg; 2.7 kPa) at a temperature in the vicinity of 20° C. in the presence of potassium hydroxide pellets. N-[3-(3-pyridyloxy)phenyl]-3-(3-pyridyl)-1H, 3H-pyrrolo[1,2-c]thiazole-7-carboxamide (3.4 g) in the form of cream-coloured crystals, m.p. 154° C., is thereby obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:22])=[C:6]([NH:8][C:9]2[N:10]=[CH:11][C:12]3[N:17]=[C:16]([NH:18][C:19](=[O:21])[CH3:20])[S:15][C:13]=3[N:14]=2)[CH:7]=1.[Cl:23][C:24]1[C:32]([C:33]([C:36]#[N:37])([CH3:35])[CH3:34])=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](O)=[O:27].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:19]([NH:18][C:16]1[S:15][C:13]2[N:14]=[C:9]([NH:8][C:6]3[CH:7]=[C:2]([NH:1][C:26](=[O:27])[C:25]4[CH:29]=[CH:30][CH:31]=[C:32]([C:33]([C:36]#[N:37])([CH3:35])[CH3:34])[C:24]=4[Cl:23])[CH:3]=[CH:4][C:5]=3[CH3:22])[N:10]=[CH:11][C:12]=2[N:17]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)Nc1nc2cnc(Nc3cc(N)ccc3C)nc2s1
Reactant: CC(C)(C#N)c1cccc(C(=O)O)c1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2cnc(Nc3cc(NC(=O)c4cccc(C(C)(C)C#N)c4Cl)ccc3C)nc2s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
A solution of N-{5-[(5-amino-2-methylphenyl)amino][1,3]thiazolo[5,4-d]pyrimidin-2-yl}acetamide (120 mg, 382 μmol), 2-chloro-3-(1-cyano-1-methylethyl)benzoic acid (111 mg, 500 μmol) produced in Example D18(v) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (189 mg, 500 μmol) in pyridine (4 mL) was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (15 mL), and the mixture was extracted with ethyl acetate (20 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/methanol=100/0→95/5), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate to give the title compound (133 mg, 67%) as colorless crystals.