Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:22][CH2:23][C@@H:24]3[O:26][CH2:25]3)=[CH:12][C:13]=2[O:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:8]=[CH:7][N:6]=1.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[Cl:1][C:2]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:3]=1[NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:22][CH2:23][C@H:24]([OH:26])[CH2:25][N:37]3[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]3)=[CH:12][C:13]=2[O:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:8]=[CH:7][N:6]=1
Reactant: CN1CCNCC1
Reactant: COc1ccc(Cl)c(Nc2ncnc3cc(OC[C@H]4CO4)cc(OC4CCOCC4)c23)c1
Product: COc1ccc(Cl)c(Nc2ncnc3cc(OC[C@H](O)CN4CCN(C)CC4)cc(OC4CCOCC4)c23)c1

Procedure:
Using an analogous procedure to that described in Example 22, 4-(2-chloro-5-methoxyanilino)-7-[(2R)-2,3-epoxypropoxy]-5-tetrahydropyran-4-yloxyquinazoline (0.07 g) was reacted with 1-methylpiperazine (0.05 ml) to give the title compound (0.04 g); NMR Spectrum: (DMSOd6) 1.8-1.9 (m, 2H), 2.2 (s, 3H), 2.2 (d, 2H), 2.25-2.6 (m, 10H), 3.55 (t, 2H), 3.8 (s, 3H), 3.92 (m, 2H), 4.05 (m, 2H), 4.2 (m, 1H), 4.9 (d, 1H), 5.1 (m, 1H), 6.8 (m, 1H), 6.85 (d, 1H), 6.95 (d, 1H), 7.5 (d, 1H), 8.12 (d, 1H), 8.5 (s, 1H), 9.9 (s, 1H); Mass Spectrum: M+H+ 558 and 560.
Reaction SMILES: [CH:1]1([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:12]([F:15])([F:14])[F:13])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:16]Br.OS(O)(=O)=O>C(O)(=O)C>[Br:16][C:9]1[CH:10]=[CH:11][C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[C:7]([C:12]([F:13])([F:14])[F:15])[CH:8]=1
Reactant: FC(F)(F)c1ccccc1C1CCCC1
Reactant: BrBr
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: FC(F)(F)c1cc(Br)ccc1C1CCCC1
Temperature: 0 °C
Yield: 36.5 %

Procedure:
To a solution of 1-cyclopentyl-2-(trifluoromethyl)benzene (0.5 g, 2.334 mmol) in acetic acid (2.5 mL) was added bromine (1.202 mL, 23.34 mmol). The mixture was stirred well, added concentrated H2SO4 (2.5 mL), and stirred at 40° C. for 1.5 h. The reaction mixture was poured into ice-water and extracted with CH2Cl2. The CH2Cl2 layer was washed with water, followed by a solution of sodium thiosulfate, then with water. The organic layer was dried over Na2SO4 and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography to give the title compound (250 mg). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.52-1.75 (m, 4H), 1.78-1.88 (m, 2H), 1.95-2.04 (m, 2H), 3.16-3.26 (m, 1H), 7.57 (d, J=8.4 Hz, 1H), 7.76 (d, J=2 Hz, 1H), 7.81 (dd, J=8.4 Hz, 2 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.[H-].[Na+].Cl[C:10]1[N:15]=[C:14]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:13]=[C:12]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[N:11]=1>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[N:4][N:5]([C:10]2[N:15]=[C:14]([N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)[N:13]=[C:12]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[N:11]=2)[CH:6]=1
Reactant: Brc1cn[nH]c1
Reactant: Clc1nc(N2CCOCC2)nc(N2CCOCC2)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cnn(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)c1
Temperature: 25 °C
Yield: 92.1 %

Procedure:
To a cooled (0° C.) solution of 4-bromopyrazole (0.29 g, 2.0 mmol) in anhydrous DMF (4 ml) was added NaH (60% dispersion in mineral oil, 0.088 g, 2.2 mmol) in a portionwise fashion over 10 minutes. The mixture allowed to warm to room temperature where it was stirred for 30 minutes before the adition of 2-Chloro-4,6-di-morpholin-4-yl-[1,3,5]triazine (3b)(0.571 g, 2.00 mmol). The mixture was then heated under the influence of microwave radiation (120° C., 14 minutes). Upon cooling the reaction was diluted with water (10 ml) and filtered. The filtercake was washed with more cold water (10 ml), collected and dried to give the title compound (92.4%, 0.73 g) in suitably pure form to be used without any further purification. m/z (LC-MS, ESP): 396 [M+H]+, R/T=3.56 mins.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Cl)[C:3]=1[C:9]([C:11]1[C:16]([CH3:17])=[CH:15][C:14]([O:18][CH3:19])=[C:13]([O:20][CH3:21])[C:12]=1[OH:22])=[O:10].[Na].[CH2:24](COC)[O:25]C>CO>[CH3:19][O:18][C:14]1[CH:15]=[C:16]([CH3:17])[C:11]2[C:9](=[O:10])[C:3]3[C:4]([O:22][C:12]=2[C:13]=1[O:20][CH3:21])=[CH:5][CH:6]=[CH:7][C:2]=3[O:25][CH3:24]
Reactant: COCCOC
Reactant: COc1cc(C)c(C(=O)c2c(Cl)cccc2Cl)c(O)c1OC
Agent: [Na]
Solvent: CO
Product: COc1cc(C)c2c(=O)c3c(OC)cccc3oc2c1OC
Temperature: 80 °C
Reaction time: 72 h

Procedure:
At about 0-5° C. under a protective atmosphere, 37.5 g (0.11 mol) of the benzophenone derivative from Example 1a in 100 ml of dimethoxyethane were added to a solution of 2.6 g (110 mol) of sodium in 50 ml of methanol. After about 72 hours of stirring at 80° C., the title compound was precipitated by adding a 1:1 mixture of water and ethyl acetate. 33.4 g (100% of theory) of product of m.p. 158° C. were isolated by filtration.
Reaction SMILES: C([N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]1(N)C)(OC(C)(C)C)=O.C([Li])CCC.[CH3:21][N:22](OC)[C:23]([CH:25]1[CH2:27][CH2:26]1)=O.Cl>C1COCC1>[CH:25]1([C:23]2[NH:22][C:21]3=[N:8][CH:9]=[CH:10][CH:11]=[C:12]3[CH:13]=2)[CH2:27][CH2:26]1
Reactant: CC(C)(C)OC(=O)N1C=CC=CC1(C)N
Reactant: CON(C)C(=O)C1CC1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: c1cnc2[nH]c(C3CC3)cc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 100.8 %

Procedure:
To a stirred mixture of N-boc-2-aminopicoline (10.4 g) in dry THF (70 ml) in an ice/salt bath was added, under an atmosphere of nitrogen, n-butyl lithium (2M solution in cyclohexane, 50 ml), keeping the temperature below 0° C. The reaction was stirred below 0° C. for 1 h before the addition of a solution of N-methyl-N-(methyloxy)cyclopropanecarboxamide (7.5 g) (available from Pfaltz-Bauer) in dry THF (20 ml). The reaction mixture was stirred at 0° C. for 2 h then warmed to 10° C. and poured into 5M hydrochloric acid (130 ml). The mixture was heated at 60° C. for 2 h, cooled and the aqueous layer separated. The aqueous layer was basified by the addition of 10M sodium hydroxide, with ice/water cooling, until the pH was 10-12. The resulting mixture was extracted with DCM (2×100 ml) and the combined organic extracts were washed with water (50 ml), dried using a hydrophobic frit and evaporated to give the title compound (7.89 g).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][CH2:14][C:15]1[S:16][C:17]([C:20]([OH:22])=O)=[CH:18][N:19]=1.[NH2:23][CH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[O:27]1[CH2:28][CH2:29][CH:24]([NH:23][C:20]([C:17]2[S:16][C:15]([CH2:14][CH2:13][C:3]3[C:4]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:19][CH:18]=2)=[O:22])[CH2:25][CH2:26]1
Reactant: NC1CCOCC1
Reactant: Cc1onc(-c2ccccn2)c1CCc1ncc(C(=O)O)s1
Product: Cc1onc(-c2ccccn2)c1CCc1ncc(C(=O)NC2CCOCC2)s1
Yield: 46 %

Procedure:
As described for example 22b, 2-[2-(5-methyl-3-pyridin-2-yl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid (77 mg, 0.24 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (45 mg, 46%) which was obtained as a white solid MS: m/e=399.1 [M+H]+.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[C:12](O)(=[O:32])/[CH:13]=[CH:14]\[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=[CH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl.O>[CH3:7][O:6][C:5]1[CH:4]=[C:3]([CH:11]=[CH:10][C:8]=1[O:9][C:12](=[O:32])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=[CH:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH:2]=[O:1]
Reactant: COc1cc(C=O)ccc1O
Reactant: CCCCCCCCCC=CC=CC=CC=C/C=C\C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCCC=CC=CC=CC=CC=CC(=O)Oc1ccc(C=O)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 73.9 %

Procedure:
To a solution of vanillin (330 mg, 2.2 mmol), cis-eicosapentaenoic acid (800 mg, 2.65 mmol) and catalytic amount of 4-(dimethylamino)pyridine in dichloromethane (DCM, 15 mL) was added a solution of N,N′-dicyclohexylcarbodiimide (720 mg, 3.53 mmol) in DCM (5 mL) for 5 min at ice cold temperature. The mixture was stirred at rt for 16 h and diluted with water. DCM layer was separated and the aqueous layer was extracted with DCM (3×100 mL). The combined DCM layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and the residue was chromatographed over silica gel column using hexane-ethyl acetate (95:5) as an eluent to give the product as an oil (710 mg, 75%). IR (neat) νmax 3012, 2961, 2931, 2855, 1767, 1701, 1600, 1271, 1149, 1119, 1032 cm−1; 1H NMR (400 MHz, CDCl3) δ 9.94 (1H, s, —CHO), 7.49 (1H, d, J=1.6 Hz, H-2), 7.47 (1H, dd, J=8.0, 1.6 Hz, H-6), 7.20 (1H, d, J=8.0 Hz, H-5), 5.30-5.48 (10H, m, H-5′, 6′, 8′, 9′, 11′, 12′, 14′, 15′, 17′, 18′), 3.89 (3H, s, —OCH3), 2.80-2.88 (8H, m, H-7′, 10′, 13′, 16′), 2.58-2.67 (2H, m, H-2′), 2.22-2.25 (2H, m, H-19′), 2.05-2.11 (2H, m, H-4′), 1.81-189 (2H, m, H-3′), 0.97 (3H, t, J=7.4 Hz, H-20′).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:36])([CH3:35])[O:4][NH:5][C:6]([C:8]1[C:9]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([I:33])=[CH:29][C:28]=2[F:34])=[C:10]2[CH:16]=[N:15][N:14](CC3C=CC(OC)=CC=3)[C:11]2=[N:12][CH:13]=1)=[O:7]>C(O)(C(F)(F)F)=O>[OH:1][CH2:2][C:3]([CH3:36])([CH3:35])[O:4][NH:5][C:6]([C:8]1[C:9]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([I:33])=[CH:29][C:28]=2[F:34])=[C:10]2[CH:16]=[N:15][NH:14][C:11]2=[N:12][CH:13]=1)=[O:7]
Reactant: COc1ccc(Cn2ncc3c(Nc4ccc(I)cc4F)c(C(=O)NOC(C)(C)CO)cnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CO)ONC(=O)c1cnc2[nH]ncc2c1Nc1ccc(I)cc1F
Temperature: 65 °C
Yield: 6.3 %

Procedure:
4-(2-Fluoro-4-iodophenylamino)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid (2-hydroxy-1,1-dimethylethoxy)-amide (420 mg, 0.69 mmol) was dissolved in TFA (5 mL) and the reaction mixture heated at 65° C. for 3 hours. The reaction mixture was concentrated in vacuo and the resultant residue was dissolved in dichloromethane (10 mL) and methanol (2 mL) before being washed with aqueous saturated sodium bicarbonate solution (3×10 mL). The aqueous layer was extracted with dichloromethane (2×10 mL) and the combined organic extracts filtered through a hydrophobic frit then concentrated in vacuo. The resultant residue was purified by reverse-phase HPLC (gradient 10-95% methanol/water+0.1% formic acid, Phenominex gemini PhC6, 5 micron, 250×20 mm) to yield the title compound as a white solid (21 mg, 11%). LCMS (Method A): RT=7.71 min, [M+H]+=486. 1H NMR (DMSO-d6, 400 MHz) 13.53 (1H, s), 11.20 (1H, s), 10.15 (1H, s), 8.49 (1H, s), 7.80 (1H, d, J=9.68 Hz), 7.63 (1H, d, J=8.38 Hz), 7.25 (1H, t, J=8.38 Hz), 6.70 (1H, s), 4.65 (1H, s), 1.17 (6H, s).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([N:8]2[C:12]([NH2:13])=[C:11]([C:14](=O)[NH2:15])[CH:10]=[N:9]2)=[CH:6][CH:7]=1.[CH3:17][NH:18][NH2:19]>CN(C)C=O>[CH3:17][N:18]([C:2]1[N:3]=[N:4][C:5]([N:8]2[C:12]([NH2:13])=[C:11]([C:14]#[N:15])[CH:10]=[N:9]2)=[CH:6][CH:7]=1)[NH2:19]
Reactant: NC(=O)c1cnn(-c2ccc(Cl)nn2)c1N
Reactant: CNN
Solvent: CN(C)C=O
Product: CN(N)c1ccc(-n2ncc(C#N)c2N)nn1

Procedure:
A mixture of 2.2 g. (10 mmoles) of 3-chloro-6-(4-cyano-5-amino-1-pyrazolyl)-pyridazine (prepared according to Example 24), 1.38 g. (30 mmoles) of methylhydrazine and 25 ml. of dimethylformamide is heated at 120°-130° C. for 7.5 hours, and after cooling the mixture is poured onto ice. The separated crystals are filtered, washed with water and triturated with 5 ml. of hot ethanol, filtered and dried. Yield: 2.1 g. (91%); m.p.: 260° C. (with decomposition).
Reaction SMILES: [C:1]([C:3]1[N:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1)#[CH:2].I[C:13]1[CH:14]=[C:15]([C:20]2[NH:24][C:23]3[CH:25]=[C:26]([CH2:29][N:30]4[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]4)[CH:27]=[CH:28][C:22]=3[N:21]=2)[CH:16]=[CH:17][C:18]=1[CH3:19]>>[CH3:19][C:18]1[CH:17]=[CH:16][C:15]([C:20]2[NH:24][C:23]3[CH:25]=[C:26]([CH2:29][N:30]4[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]4)[CH:27]=[CH:28][C:22]=3[N:21]=2)=[CH:14][C:13]=1[C:2]#[C:1][C:3]1[N:7]2[N:8]=[CH:9][CH:10]=[CH:11][C:6]2=[N:5][CH:4]=1
Reactant: C#Cc1cnc2cccnn12
Reactant: Cc1ccc(-c2nc3ccc(CN4CCN(C)CC4)cc3[nH]2)cc1I
Product: Cc1ccc(-c2nc3ccc(CN4CCN(C)CC4)cc3[nH]2)cc1C#Cc1cnc2cccnn12

Procedure:
The title compound was synthesized from 3-ethynylimidazo[1,2-b]pyridazine and 2-(3-iodo-4-methylphenyl)-6-((4-methylpiperazin-1-yl)methyl)-1H-benzo[d]imidazole (as prepared in Example 1) in a manner similar to that described for in Example 1. The intermediate compound 3-ethynylimidazo[1,2-b]pyridazin was made as for Example 1 (Step 1 to 3) with the spectra below: 1H NMR (300 MHz, DMSO-d6) δ: 8.63-8.64 (1H, m), 8.18-8.21 (1H, m), 8.10 (1H, s), 7.32-7.35 (1H, m), 4.94 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[OH:21])=[CH:4][CH:3]=1.Br[CH2:23][C:24]1[C:33]([O:34][CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:42])([CH3:41])[CH3:40])=[CH:32][C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:10][CH:9]2[O:21][CH2:23][C:24]2[C:33]([O:34][CH2:35][O:36][CH2:37][CH2:38][Si:39]([CH3:40])([CH3:42])[CH3:41])=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(F)cc2)C(O)C1
Reactant: C[Si](C)(C)CCOCOc1cc2ccccc2cc1CBr
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(F)cc2)C(OCc2cc3ccccc3cc2OCOCC[Si](C)(C)C)C1

Procedure:
In an analogous manner to that described in Example 3(c), by alkylating tert-butyl (3RS,4RS)-4-(4-fluorophenyl)-3-hydroxy-piperidine-1-carboxylate with 2-bromomethyl-3-(2-trimethylsilylethoxy-methoxy)-naphthalene there was obtained tert-butyl (3RS,4RS)-4-(4-fluorophenyl)-3-[3-(2-trimethylsilyl-ethoxy-methoxy)-naphthalen-2-ylmethoxy]-piperidine-1-carboxylate as a light yellow oil; MS: 523 [M-(C2H4 +CH2O)]+.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH2:7][C:8]2[CH:16]=[CH:15][C:11]([C:12](O)=[O:13])=[CH:10][C:9]=2[C:17]([O:19][CH3:20])=[O:18])=[CH:4][CH:3]=1.O1CCCC1.B>CO>[F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH2:7][C:8]2[CH:16]=[CH:15][C:11]([CH2:12][OH:13])=[CH:10][C:9]=2[C:17]([O:19][CH3:20])=[O:18])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc(C(=O)O)ccc1CCc1ccc(F)cc1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc(CO)ccc1CCc1ccc(F)cc1
Temperature: 25 °C
Yield: 82.8 %

Procedure:
A mixture of 4-(4-fluorophenethyl)-3-methoxycarbonylbenzoic acid (16.5 g, 54.88 mmol), tetrahydrofuran (500 ml) and borane in tetrahydrofuran (1M. complex, 218 mls, 218 mmol) was stirred under an inert atmosphere at reflux for 6 hours. The reaction was cooled to ambient temperature and methanol (1 L) was added. It was then evaporated to dryness to give a dark oil which was purified by flash column chromatography using iso-hexane/ethyl acetate (1:1) as eluant to give, as a clear gum, methyl 2-(4-fluorophenethyl)-5-hydroxymethylbenzoate (13.10 g).
Reaction SMILES: [OH:1][CH:2]1[CH2:19][C:5]2([C:20]3[CH:21]=[C:22]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=4)[CH:23]=[CH:24][CH:25]=3)[N:6]=[C:7]([NH:10][C:11](=[O:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[S:8][CH2:9][CH:4]2[CH2:3]1.CC(O)C.C(=O)=O>>[OH:1][C@H:2]1[CH2:19][C@:5]2([C:20]3[CH:21]=[C:22]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=4)[CH:23]=[CH:24][CH:25]=3)[N:6]=[C:7]([NH:10][C:11](=[O:18])[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[S:8][CH2:9][C@@H:4]2[CH2:3]1
Reactant: COc1cccc(-c2cccc(C34CC(O)CC3CSC(NC(=O)c3ccccc3)=N4)c2)c1
Agent: O=C=O
Solvent: CC(C)O
Product: COc1cccc(-c2cccc([C@]34C[C@H](O)C[C@H]3CSC(NC(=O)c3ccccc3)=N4)c2)c1
Yield: 35.2 %

Procedure:
Racemic N-((4aRS,6RS,7aSR)-6-hydroxy-7a-(3′-methoxybiphenyl-3-yl)-4,4a,5,6,7,7a-hexahydrocyclopenta[d][1,3]thiazin-2-yl)benzamide (0.689 g, 1.50 mmol) is purified by chiral HPLC: 2.1×25 cm Chiralpak AD-H, 5 micron, 35% IPA/CO2, flow rate: 70 mL/min, UV: 225 nm. The first eluting isomer is isolated to provide the enantiomerically enriched title compound (0.242 g, 35%). ES/MS m/e: 459 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([C:9]2([CH2:12][OH:13])[CH2:11][CH2:10]2)[CH:8]=1)([O-])=O>C(O)C>[NH2:1][C:4]1[CH:5]=[N:6][N:7]([C:9]2([CH2:12][OH:13])[CH2:10][CH2:11]2)[CH:8]=1
Reactant: O=[N+]([O-])c1cnn(C2(CO)CC2)c1
Solvent: CCO
Product: Nc1cnn(C2(CO)CC2)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.6 %

Procedure:
To a solution of (1-(4-nitro-1H-pyrazol-1-yl)cyclopropyl)methanol (300 mg) obtained in Step B of Example 128 in ethanol (20 mL) was added palladium-activated carbon ethylene diamine complex (Pd: 8.5-11.5%) (100 mg), and the mixture was stirred at room temperature for 5 hr under hydrogen atmosphere (at normal pressures). The palladium-activated carbon ethylene diamine complex was removed by filtration through Celite, and the solvent was evaporated under reduced pressure to give the title compound (250 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].Br[C:12]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:13]=1[C:14]([OH:16])=[O:15].CCOC(C)=O.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[Br:21][C:18]1[CH:19]=[CH:20][C:12]([O:10][C:3]2[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=2[F:1])=[C:13]([CH:17]=1)[C:14]([OH:16])=[O:15]
Reactant: O=C(O)c1cc(Br)ccc1Br
Reactant: COc1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(Oc2ccc(Br)cc2C(=O)O)c(F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A three-neck RBF equipped with a reflux condenser and overhead stirrer was charged with 2-fluoro-4-methoxyphenol (14.24 g, 100 mmol), 2,5-dibromobenzoic acid (25.5 g, 91 mmol), EtOAc (0.446 mL, 4.55 mmol), copper (I) triflate toluene complex (2:1) (0.484 g, 2.27 mmol) and toluene (300 mL). Cesium carbonate (59.4 g, 182 mmol) was carefully added portion-wise. The mixture was stirred for 10 minutes at RT then heated at 95° C. for 3 hours. The toluene was cooled to RT then extracted twice with 300 ml of water. The combined water extracts were acidified with 6 N HCl at which time a precipitate formed. The mixture was extracted with EtOAc (3×500 mL) and the combined organic fractions were dried over sodium sulfate and concentrated in vacuo. The resulting solid was triturated with minimal 1:1 Hexanes:EtOAc and filtered. The collected solid was dried in vacuo to afford 5-bromo-2-(2-fluoro-4-methoxyphenoxy)benzoic acid as a grey solid. The mother liquors were set aside for later recrystallizatio. MS m/z=341.0 [M+H].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:15]2=[N:16][C:17]([C:27]3[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=3)=[C:18]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)[N:19]=[C:14]2[CH:13]=[CH:12]1)[CH3:2].C([O-])=O.[NH4+]>CCO.[Pd]>[C:23]1([CH3:26])[CH:22]=[CH:21][C:20]([C:18]2[N:19]=[C:14]3[CH2:13][CH2:12][N:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:34])[C:15]3=[N:16][C:17]=2[C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)=[CH:25][CH:24]=1
Reactant: CCOC(=O)CCCCCCn1ccc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)CCCCCCN1CCc2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Temperature: 25 °C

Procedure:
7-(2,3-Di-p-tolyl-pyrrolo[2,3-b]pyrazin-5-yl)-heptanoic acid ethyl ester (Intermediate B) (35 mg, 0.077 mmol) in dry EtOH (1 ml) under nitrogen at RT was treated with ammonium formate (24.22 mg, 0.384 mmol) followed by Pd on carbon (8.18 mg, 7.68 μmol). The resulting black suspension was heated at reflux for 16 hours, overnight. The reaction mixture was cooled to RT and then loaded onto a Celite® (filter material) column. The column was eluted with 1:1 MeOH/DCM and the filtrate concentrated under reduced pressure. The resultant residue was dissolved in DCM (50 ml), washed with water (×2) and the organic solvent removed under reduced pressure. Purification by chromatography on silica eluting with 0-30% EtOAc in iso-hexane afforded the titled compound;
Reaction SMILES: C[O:2][C:3](=[O:25])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]#[C:18][C:19]2[CH:20]=[N:21][CH:22]=[N:23][CH:24]=2)=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.O1CCCC1.[OH-].[Li+]>CO.O>[CH:6]1([CH2:5][CH:4]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[C:18][C:19]3[CH:20]=[N:21][CH:22]=[N:23][CH:24]=3)=[CH:13][CH:12]=2)[C:3]([OH:25])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)c1ccc(C#Cc2cncnc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C(CC1CCCC1)c1ccc(C#Cc2cncnc2)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 92.2 %

Procedure:
A solution of 3-cyclopentyl-2-(4-pyrimidin-5-ylethynyl-phenyl)-propionic acid methyl ester (440 mg, 1.32 mmol) in methanol (3 mL), water (2 mL), and tetrahydrofuran (0.5 mL) was treated with lithium hydroxide (38 mg, 0.90 mmol). The reaction mixture was stirred at 25° C. for 60 h. At this time, additional lithium hydroxide (38 mg, 0.90 mmol) was added. The reaction was stirred at 25° C. for 4 h. At this time, the reaction was diluted with water (5 mL) and then concentrated in vacuo. The resulting aqueous layers were washed with ethyl acetate (2×10 mL), acidified with a 1N aqueous hydrochloric acid solution, and then extracted with ethyl acetate (2×25 mL). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 3-cyclopentyl-2-(4-pyrimidin-5-ylethynyl-phenyl)-propionic acid (390 mg, 92%) as an amber foam: EI-HRMS m/e calcd for C20H20N2O2 (M+) 320.1524, found 320.1526.
Reaction SMILES: C1(=O)[N:5]([CH2:6][CH2:7][S:8][CH2:9][CH2:10][C:11]2[O:12][C:13]([CH2:16][N:17]([CH3:19])[CH3:18])=[CH:14][CH:15]=2)C(=O)C2=CC=CC=C12.NN.[C:28]([N:30]=[C:31]([S:34][CH3:35])SC)#[N:29]>>[C:28]([NH:30][C:31](=[N:5][CH2:6][CH2:7][S:8][CH2:9][CH2:10][C:11]1[O:12][C:13]([CH2:16][N:17]([CH3:18])[CH3:19])=[CH:14][CH:15]=1)[S:34][CH3:35])#[N:29]
Reactant: CN(C)Cc1ccc(CCSCCN2C(=O)c3ccccc3C2=O)o1
Reactant: CSC(=NC#N)SC
Agent: NN
Product: CSC(=NCCSCCc1ccc(CN(C)C)o1)NC#N

Procedure:
When 1-phthalimido-2-[2-(5-dimethylaminomethyl-2-furyl)ethylthio]ethane is treated with hydrazine and the resultant substituted ethylamine is reacted with dimethyl cyanodithioimidocarbonate there is produced N-cyano-N'-{2-[2-(5-dimethylaminomethyl-2-furyl)ethylthio]ethyl}-S-methylisothiourea, and when this is reacted with propargylamine according to the general procedure of Example 3 the title compound is produced.
Reaction SMILES: [C:1]([C:3]1[C:4]([O:8][CH3:9])=[N:5][S:6][CH:7]=1)#[N:2].S(=O)(=O)(O)[OH:11]>>[C:1]([C:3]1[C:4]([O:8][CH3:9])=[N:5][S:6][CH:7]=1)(=[O:11])[NH2:2]
Reactant: O=S(=O)(O)O
Reactant: COc1nscc1C#N
Product: COc1nscc1C(N)=O

Procedure:
A solution of 2.8 g. (0.02 mole) of 4-cyano-3-methoxyisothiazole prepared as in Example 18 in 30 ml. of 75% sulfuric acid was heated at 70° C. for 0.5 hour. The solution was then cooled and poured into ice to give after filtration and drying 0.95 g. of 4-carbamoyl-3-methoxyisothiazole, m.p. 165°-168° C. By continuous ether extraction of the aqueous filtrate an addition 1.13 g. of 4-carbamoyl-3-methoxyisothiazole was obtained to give a total yield of 2.08 g. (66%).