Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:21](=[O:22])[N:12]2[C:13]([C:18]([O-:20])=[O:19])=[C:14]([CH3:17])[CH2:15][S:16][C@H:11]12)=[O:8].C1([O:29]C)C=CC=CC=1.FC(F)(F)C(O)=O>>[OH:29][CH:6]([C:2]1[O:1][CH:5]=[CH:4][CH:3]=1)[C:7]([NH:9][CH:10]1[C:21](=[O:22])[N:12]2[C:13]([C:18]([OH:20])=[O:19])=[C:14]([CH3:17])[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: CC1=C(C(=O)[O-])N2C(=O)C(NC(=O)Cc3ccco3)[C@H]2SC1
Reactant: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(O)c3ccco3)[C@H]2SC1
Yield: 57.3 %

Procedure:
Diphenylmethyl (6R,7R,2'R and S)-7-(2'-[fur-2-yl]-acetamido)-3-methylceph-3-em-4-carboxylate (463mg, 1.365 mmole) was treated with anisole and trifluoroacetic acid in the manner described previously [see Example 10 (b)] to give (6R,7R,2'R and S)-7-[2'-hydroxy-2'-(fur-2-yl)-acetamido]-3-methylceph-3-em-4-carboxylic acid as a foam (368mg, 1.09mmole, 57.3%). The title compound was obtained from the acid (368mg, 1.1mole) by treatment with sodium 2-ethylhexanoate in acetone and ether, as a pale-brown solid containing 21/2mole-equivalents of water (i.r. and microanalysis), (221mg, 0.545mmole, 50%); λmax (pH6 buffer) 220 and 258nm (ε10,780 and 8,000 respectively); νmax (Nujol) 3370 (OH,NH, and H2 0), 1755 (azetidin-2-one), 1675 and 1518 (CONH), and 1590 cm-1 (CO2 -); τ(Me2SO-D6) 1.57 and 1.63 (total 1H,2d, J9Hz, NH), 2.37 (1H,s) and 3.59 (2H,m) (furyl protons), 4.44 (1H,m, C7 -H), 4.81 and 4.83 (total 1H, 2s, -CHOH), 4.97 (1H,d,J5Hz, C6 -H), 6.47 and 6.86 (2H, Abq, J18Hz, C2 -H2), 8.00 (3H,s,C3 -CH3). (Found: C, 41.2, 41.5; H,3.4, 3.6; N,6.4, 6.5; S,7.8; Na,5.9. C14H13N2NaO6S.2.5 H2O (405.3) requires: C, 41.6; H,4.5; N,6.9; S,7.9; Na,5.7%).
Reaction SMILES: [C:1]1([CH:7]=[C:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:21].[Na+]>CO>[C:1]1(/[CH:7]=[C:8]2/[CH:9]([NH2:21])[CH2:10][CH2:11][CH2:12][CH2:13]/2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [BH3-]C#N
Reactant: O=C1CCCCC1=Cc1ccccc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: NC1CCCC/C1=C\c1ccccc1
Temperature: 10 °C
Reaction time: 19 h

Procedure:
Molecular sieve (size 3A, 2 g) was added to a solution of 2-(phenylmethylene)cyclohexanone (1.86 g, 0.01 mole) in 20 ml of methanol, followed by a solution of ammonium acetate (7.7 g, 0.1 mole) in 20 ml of methanol. The mixture was cooled to about 10° C., and a solution of sodium cyanoborohydride in 20 ml of methanol was added during five minutes. The mixture was stirred at ambient temperature for 19 hours. The mixture was filtered, and the filtrate was cooled and brought to pH 11 by the addition of 20% aqueous sodium hydroxide. The methanol was evaporated and the mixture was extracted with ether. The extract was washed with water (water layer discarded) and then with three 10 ml portions of 10% aqueous hydrochloric acid. Water was added to dissolve the resulting solid. The aqueous acidic layer was cooled, basified with sodium hydroxide and extracted with chloroform. The chloroform extract was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated to give 1.2 g of (±)-(E)-2-(phenylmethylene)cyclohexylamine which was identical (by tlc, UV, and nmr comparison) to the amine prepared in Part D of Example 1 above.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[C:36]1([C:42]2([C:48]([NH2:50])=[O:49])[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:45]3[CH2:44][CH2:43][C:42]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)([C:48]([NH2:50])=[O:49])[CH2:47][CH2:46]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:16]=[C:17]([O:25][CH3:26])[C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC

Procedure:
2-[3-(3,4-Dichloro-phenyl)-1-(3,4,5-trimethoxybenzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (7.87 mmol) and THF/H20 (3/1, 80 mL) were combined. 4-Phenylpiperidine-4-carboxylic acid amide hydrochloride (2.8 g, 11.64 mmol, 1.5 eq.) and potassium carbonate (3.3 g, 23.88 mmol, 3 eq.) were added. The mixture was heated to reflux for 72 h. The mixture was concentrated in vacuo. The aqueous residue was extracted with dichloromethane. The organic phase was extracted with H20 (50 mL). The organic phase was dried over MgSO4, filtered, and concentrated in vacuo to obtain a residue. The residue was purified by chromatography on silica gel (350 g) eluting sequentially with ethyl acetate, 6% methanol in dichloromethane, and then 10% methanol in dichloromethane to give the title compound:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23](C(OC(C)(C)C)=O)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.Cl>CO.CCOCC>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:24]=[N:23][NH:22][CH:21]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)n1cc(-c2cn(S(=O)(=O)c3ccccc3)c3cc(F)ccc23)cn1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: O=S(=O)(c1ccccc1)n1cc(-c2cn[nH]c2)c2ccc(F)cc21
Reaction time: 0.5 h
Yield: 97.9 %

Procedure:
To a solution of tert-butyl 4-(6-fluoro-1-(phenylsulfonyl)-1H-indol-3-yl)-1H-pyrazole-1-carboxylate (Intermediate 4; 310 mg; 0.70 mmol) in methanol (2 mL) was added saturated HCl in Et2O (10 mL). The resulting mixture was stirred for 30 minutes. The reaction was concentrated to dryness under reduced pressure, diluted with water (10 mL), neutralized with saturated aqueous NaHCO3, and extracted with EtOAc (10 mL×3). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated to afford 234 mg (89%) of the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:32])[N:4]([CH2:19][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24](=[O:29])[C:23]3(Br)Br)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]>C(O)(=O)C.O.[Zn]>[Cl:1][C:2]1[C:3](=[O:32])[N:4]([CH2:19][C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[NH:25][C:24](=[O:29])[CH2:23]3)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1Cc1ccc2c(c1)C(Br)(Br)C(=O)N2
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1Cc1ccc2c(c1)CC(=O)N2
Reaction time: 48 h
Yield: 81.9 %

Procedure:
5-[3-Chloro-4-(2,4-difluorobenzyloxy)-6-methyl-2-oxo-2H-pyridin-1-ylmethyl]-3,3-dibromo-1H-indol-2-one (0.2 g, 0.34 mmol) was suspended in 5 mL of acetic acid, and zinc metal (0.22 g, 3.4 mmol) was added. The reaction was stirred for 48 hours. The reaction was diluted with water, and washed 2 times with ethyl acetate. The combined organics were washed 1 time with brine, dried (MgSO4), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 100% EtOAc) gave a white solid (0.12 g, 82%): 1H NMR (300 MHz, DMSO-d6) δ 10.37 (br s, 1H), 7.65 (app q, J=6.9 Hz, 1H), 7.34 (dt, J=8.2, 2.5 Hz, 1H), 7.18 (dt, J=7.1, 1.9, 1H), 6.98 (br s, 2H), 6.77 (d, J=8.4 Hz, 1H), 6.57 (s, 1H), 5.28 (s, 2H), 5.23 (s, 2H), 3.44 (s, 2H), 2.34 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21]([O:23]CC)=O)[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:27][S:28][CH2:29][CH2:30][CH2:31][NH2:32]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:26])=[C:14]([C:21]([NH:32][CH2:31][CH2:30][CH2:29][S:28][CH3:27])=[O:23])[C:15](=[O:20])[N:16]3[CH3:19])=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(C)c1=O
Reactant: CSCCCN
Product: CSCCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(C)c1=O
Yield: 43 %

Procedure:
In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (30 mg, 0.084 mmol) described in example 92 and [3-(methylthio)propyl]amine (0.02 mL, 0.589 mmol) was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-methyl-N-[3-(methylthio)propyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (15 mg, 43% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.25 (br s, 1 H), 8.57 (s, 1 H), 7.39 (s, 1 H), 7.18-7.14 (m, 2 H), 7.05-7.00 (m, 2 H), 4.14 (s, 2 H), 3.59-3.54 (m, 5 H), 2.59 (m, 2 H), 2.12 (s, 3 H), 1.95 (m, 2 H); HRMS m/z calcd for C21H23FN3O3S: 416.1438. Found: 416.1447.
Reaction SMILES: [C:1]([N:4]1[C:8]([CH2:15]O)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:7][C:6]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])=[N:5]1)(=[O:3])[CH3:2].[CH3:25]C(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+].[O-]S([O-])=O.[Na+].[Na+].[Li]CCCC>C(Cl)Cl.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:1]([N:4]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)([CH:15]=[CH2:25])[CH2:7][C:6]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[F:24])=[N:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1N=C(c2cc(F)ccc2F)CC1(CO)c1ccccc1
Reactant: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: C=CC1(c2ccccc2)CC(c2cc(F)ccc2F)=NN1C(C)=O
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a solution of 3.96 g (12.0 mmol) 1-3 in 200 mL CH2Cl2 was added 5.6 g (13.2 mmol) Dess-Martin Periodinane and the mixture was stirred for 3 h. To this was then added a saturated aqueous solution of NaHCO3 and also some solid Na2SO3, and the biphasic mixture was stirred vigorously for 1 h. The layers were separated, the organic was washed with saturated NaHCO3, water, dried over Na2SO4 and concentrated to provide the crude aldehyde. In a separate flask, 6.4 g (18.0 mmol) methyl triphenylphosphonium bromide was suspended in 100 mL of THF, cooled to −78° C., and 7.2 mL (18.0 mmol) 2.5M nBuLi in hexanes was added. After stirring for 30 min, the above aldehyde dissolved in 30 mL of THF was cannulated into the reaction flask and stirring was continued for 30 min at −78° C. The cooling bath was removed and the reaction was allowed to stir for 1 h while coming to room temperature. The reaction was quenched with saturated aqueous NH4Cl, the mixture was dumped into a separatory funnel with EtOAc, the layers were separated, the aqueous layer was extracted with EtOAc, the combined organics were washed with brine, dried over Na2SO4, and concentrated. The residue was purified by silica gel chromatography with EtOAc/hexanes to provide 1-4 as a pale yellow solid. Data for 1-4: 1HNMR (500 MHz, CDCl3) δ 7.7 (m, 1H), 7.35-7.25 (m, 5H), 7.05 (m, 2H), 6.8 (m, 1H), 5.45 (m, 1H), 5.35 (m, 1H), 3.9 (m, 1H), 3.4 (m, 1H), 2.4 (s, 3H) ppm. HRMS (ES) calc'd M+H for C19H16F2N2O: 327.1304. Found: 327.1294.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([OH:8])[CH2:3]1.C(N(CC)C(C)C)(C)C.[Cl:18][C:19]1[C:20]([C:32](Cl)=[O:33])=[N:21][O:22][C:23]=1[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[C:26]([F:31])[CH:25]=1>ClCCl>[Cl:18][C:19]1[C:20]([C:32]([NH:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][C@H:4]([OH:8])[CH2:3]2)=[O:33])=[N:21][O:22][C:23]=1[C:24]1[CH:29]=[CH:28][C:27]([F:30])=[C:26]([F:31])[CH:25]=1
Reactant: N[C@@H]1CCC[C@H](O)C1
Reactant: O=C(Cl)c1noc(-c2ccc(F)c(F)c2)c1Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H]1CCC[C@H](O)C1)c1noc(-c2ccc(F)c(F)c2)c1Cl
Reaction time: 2 h

Procedure:
A suspension of (1S,3R)-3-aminocyclohexanol (46 mg, 0.40 mmol), N,N-diisopropylethylamine (0.21 mL, 1.20 mmol) and dichloromethane (15 mL) under argon was treated with a dichloromethane (15 mL) solution of 4-chloro-5-(3,4-difluorophenyl)-isoxazole-3-carbonyl chloride (112 mg, 0.40 mmol) at room temperature. After stirring for 2 hours the volatiles were removed in vacuo, and the residue was purified initially by silica gel chromatography, eluting with dichloromethane to 4% methanol in dichloromethane followed by RP HPLC (H2O/MeCN/MeOH 48/48/4 [vol./vol.]) to afford the title compound: (86 mg, 0.24 mmol).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:12]=[N:13][C:14]([O:17]C)=[CH:15][CH:16]=2)=[CH:6][CH:5]=1.I[Si](C)(C)C>C(#N)C.O>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[N:13][C:14]([OH:17])=[CH:15][CH:16]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(Oc2ccc(OC)nc2)cc1
Agent: C[Si](C)(C)I
Solvent: CC#N
Solvent: O
Product: COC(=O)c1ccc(Oc2ccc(O)nc2)cc1
Yield: 96.8 %

Procedure:
To a solution of 4-(6-methoxy-pyridin-3-yloxy)-benzoic acid methyl ester (0.2 g, 0.8 mmol) in acetonitrile (6 ml) was added iodotrimethylsilane (0.346 g, 1.73 mmol) and the mixture was allowed to reflux for 1 h. The reaction mixture was diluted with water (8 ml) and extracted with chloroform. The extract was washed with 10% aqueous Na2S2O3 and water and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure to afford 0.19 g (87%) of 4-(6-hydroxy-pyridin-3-yloxy)-benzoic acid methyl ester as yellowish crystals.
Reaction SMILES: [H-].C(O[Al](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].[C:19]([OH:22])(=[O:21])[CH3:20].[C:23]([OH:26])(=[O:25])[CH3:24].O[C@H:28]1[CH2:33][CH2:32][C@H:31]2[C@H:34]3[C@H:45]([CH2:46][CH2:47][C@:29]12[CH3:30])[C@:42]1([CH2:43]O)[C:37](=[CH:38][C:39](=[O:48])[CH2:40][CH2:41]1)[CH2:36][CH2:35]3.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>O1CCCC1>[C:19]([O:22][C@H:28]1[CH2:33][CH2:32][C@H:31]2[C@H:34]3[C@H:45]([CH2:46][CH2:47][C@:29]12[CH3:30])[C@:42]1([CH2:43][O:25][C:23](=[O:26])[CH3:24])[C:37](=[CH:38][C@@H:39]([OH:48])[CH2:40][CH2:41]1)[CH2:36][CH2:35]3)(=[O:21])[CH3:20]
Reactant: CC(=O)O
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO)[C@@H]1CC[C@@H]2O
Agent: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(=O)OC[C@]12CC[C@H](O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](OC(C)=O)CC[C@@H]12

Procedure:
To a solution of lithium tri-t-butoxyaluminum hydride in tetrahydrofuran is added a tetrahydrofuran solution of 17β,19-dihydroxy-4-androsten-3-one diacetate. The resulting mixture is stirred at 20° C. for a period of about 18 hours after which an aqueous solution of sodium potassium tartrate is added. The mixture is filtered and concentrated to a small volume under reduced pressure. The concentrate is taken up in ether and washed well with water. The ether solution is dried over magnesium sulfate, filtered and the ether removed under vacuum to yield a residue which is crystallized from acetone-hexane to yield androst-4-ene-3β, 17β,19-triol 17,19-diacetate.
Reaction SMILES: Br[CH2:2][C:3](=O)[C:4]([O:6][CH2:7][CH:8]=C)=[O:5].[C:11]1([CH2:17][C:18]([NH2:20])=[S:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O)C>N1C=CC=CC=1>[CH2:17]([C:18]1[S:19][CH:2]=[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[N:20]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NC(=S)Cc1ccccc1
Reactant: C=CCOC(=O)C(=O)CBr
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)c1csc(Cc2ccccc2)n1

Procedure:
40 g of allyl bromopyruvate were progressively added to a mixture of 30.2 gof phenylthioacetamide, 120 ml of ethanol and 20 ml of pyridine and the mixture was refluxed for 16 hours. The mixture was evaporated to dryness under reduced pressure and the residue was added to a water-ether mixture.The mixture was stirred and the decanted aqueous phase was extracte with ether. The combined organic phases were evaporated to dryness and the residue was chromatographed over silica gel. Elution with a 7-3 hexane-ethyl acetate mixture yielded 22.5 g of ethyl 2-benzyl-thiazole-4-carboxylate melting at 78°-79° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](F)=[O:6].[BH4-].[Na+].Cl>C(O)(C)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[CH2:5][OH:6]
Reactant: O=C(F)c1ccc(F)c(Br)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: OCc1ccc(F)c(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.5 %

Procedure:
221 g (1 mol) of 3-bromo-4-fluoro-benzoyl fluoride were added dropwise to a mixture of 30.4 g (0.8 mol) of sodium tetrahydridoborate and 840 ml of isopropanol at 20°-25° C. in the course of 3 hours. The reaction mixture was stirred for about a further 30 minutes and then poured into 2 liters of ice-water. The pH was adjusted to 1 by adding concentrated hydrochloric acid, and the organic layer was then separated off. The aqueous phase was subsequently extracted with 200 ml of methylene chloride. The combined organic phases were dried and filtered and the filtrate was distilled. 163 g (79.5% of theory) of 3-bromo-4-fluoro-benzyl alcohol of boiling point 137° C./16 mbars and of refractive index nD20 =1.5623 were obtained.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.C([O:15][C:16](=O)[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)C.C(O)(=O)C>O1CCCC1.CCCCCC>[O:15]=[C:16]([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: CCOC(=O)CCc1ccccc1
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(=O)O
Product: COP(=O)(CC(=O)CCc1ccccc1)OC
Reaction time: 2 h

Procedure:
To a solution of dimethyl methylphosphonate (115.5 g.) in tetrahydrofuran (2.1 l.) at -65°, there is added 660 ml. of a 1.6 M solution of n-butyl lithium in hexane, and then there is added a solution of ethylhydrocinnamate (93.5 g.) in tetrahydrofuran (225 ml.). The mixture is stirred at -65° for 2 hrs. and then stirring is continued at 25° for 16 hrs. Acetic acid (70 ml.) is added, the solution is concentrated under reduced pressure and the residue is partitioned between methylene chloride and water. The organic layer is dried, concentrated, and distilled at 2 mm. to give 121.5 g. of the title compound; b.p. 184-195; mass spectrum 256 (M+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][N:39]1[CH2:43][CH2:42][CH2:41][CH:40]1[CH2:44][CH2:45][NH2:46]>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([NH:46][CH2:45][CH2:44][CH:40]3[CH2:41][CH2:42][CH2:43][N:39]3[CH3:38])[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Reactant: CN1CCCC1CCN
Product: CN1CCCC1CCNc1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and 2-(1-methyl-pyrrolidin-2-yl)ethylamine according to conditions described in general procedure C. Mp: 112-114° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.30-1.61 (m, 10 H), 1.37-2.10 (m, 5 H), 2.84 (bs, 2 H), 3.11-3.36 (m, 7 H), 6.15-6.30 (m, 1 H), 6.96 (d, J=12.4 Hz, 1 H), 7.08-7.20 (m, 2 H), 7.37 (d, J=8.0 Hz, 1 H), 7.43 (s, 1 H), 7.52-7.59 (m, 3 H), 7.79 (d, J=8.4 Hz, 1 H), 7.96 (d, J=7.7 Hz, 1 H), 8.21 (s, 1 H), 10.40 (s, 1 H).
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:10]1[CH:11]=[C:12]2[C:17]([NH:18][C@@H:19]([C:21]3([F:24])[CH2:23][CH2:22]3)[CH3:20])=[C:16]([C:25]([NH2:27])=[O:26])[CH:15]=[N:14][N:13]2[CH:28]=1.[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:24][C:21]1([C@H:19]([NH:18][C:17]2[C:12]3[N:13]([CH:28]=[C:10]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:11]=3)[N:14]=[CH:15][C:16]=2[C:25]([NH2:27])=[O:26])[CH3:20])[CH2:23][CH2:22]1
Reactant: C[C@@H](Nc1c(C(N)=O)cnn2cc(Br)cc12)C1(F)CC1
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Product: C[C@@H](Nc1c(C(N)=O)cnn2cc(-c3ccccc3)cc12)C1(F)CC1
Temperature: 140 °C
Yield: 20.4 %

Procedure:
Potassium phosphate (2M aqueous solution, 0.11 mL, 0.22 mmol) was added in one portion to a stirred solution of (R)-6-bromo-4-(1-(1-fluorocyclopropyl)ethylamino)-pyrrolo[1,2-b]pyridazine-3-carboxamide (Intermediate 6, 10 mg, 0.029 mmol), phenyl boronic acid (5.4 mg, 0.044 mmol), X-Phos ligand (1.4 mg, 0.0029 mmol) and palladium acetate (0.3 mg, 0.0015 mmol) in anhydrous 1,4-dioxane (0.12 mL). The resulting biphasic mixture was then heated in the CEM microwave at 140° C. for 30 min. The reaction was allowed to cool to rt and the phases separated. The aqueous phase was extracted with ethyl acetate (2×5 mL). The combined organics were then dried (MgSO4) and evaporated in vacuo before purifying by reverse-phase Prep HPLC (condition A). The fraction containing the major product was concentrated on the rotovap to afford 2 mg (20%) of the title compound as a white solid. HPLC (condition B): retention time=4.00 min. LCMS (condition B): MH+ m/z 339.2. 1H NMR (400 MHz, MeOD) δ ppm 8.20 (1 H, s), 8.02 (1 H, d, J=1.76 Hz), 7.71 (1 H, dd, J=8.36, 1.10 Hz), 7.57 (1 H, d, J=1.98 Hz), 7.45 (2 H, t, J=7.70 Hz), 7.31 (2 H, t, J=7.37 Hz), 5.07 (1 H, br. s.), 1.40-1.64 (4 H, m), 1.35 (3 H, br. s.).
Reaction SMILES: [CH2:1]([C:5]1[S:9][C:8]([NH:10][C:11]2[N:16]=[CH:15][C:14]([C:17]([OH:19])=O)=[CH:13][CH:12]=2)=[C:7]([C:20]([OH:22])=O)[CH:6]=1)[CH2:2][CH2:3][CH3:4].O.[NH2:24][C:25]1[NH:29][N:28]=[N:27][N:26]=1>CN(C)C=O>[CH2:1]([C:5]1[S:9][C:8]2[N:10]=[C:11]3[CH:12]=[CH:13][C:14]([C:17]([NH:24][C:25]4[NH:29][N:28]=[N:27][N:26]=4)=[O:19])=[CH:15][N:16]3[C:20](=[O:22])[C:7]=2[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Nc1nnn[nH]1
Reactant: CCCCc1cc(C(=O)O)c(Nc2ccc(C(=O)O)cn2)s1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1cc2c(=O)n3cc(C(=O)Nc4nnn[nH]4)ccc3nc2s1

Procedure:
A mixture of 6-[(5-butyl-3-carboxy-2-thienyl)amino]-3-pyridinecarboxylic acid (Example 39), 3.2 g (0.01 mol) and 9.93 g (0.06 mol) of 1, 11 -carbonyldiimidazole (Aldrich Chemical Company) in 100 ml of dimethylformamide is heated in a wax bath under a nitrogen atmosphere with stirring at 100° to 108° C. for seventy minutes, cooled and stirred at room temperature for one hour. To the previous mixture is added 5-aminotetrazole monohydrate (Aldrich Chemical Company), 2.06 g (0.02 mol) and the mixture is heated at 100°-108° C. for ninety minutes. The solvent is evaporated and the residue dissolved in dimethylformamide, filtered, cooled and the precipitate collected and washed with methanol to give 1.2 g of 2-butyl-4-oxo-N-1H-tetrazol-5-yl-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxamide; mp 293° C. (dec) after recrystallization from pyridine.
Reaction SMILES: Cl[CH2:2][CH2:3][C@@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].[I-:12].[Na+]>C(N(CC)CC)C.C(C(C)=O)C>[I:12][CH2:2][CH2:3][C@@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5]
Reactant: O[C@@H](CCCl)c1ccccc1
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: CCN(CC)CC
Product: O[C@@H](CCI)c1ccccc1
Yield: 74.9 %

Procedure:
Commercially available (S)-3-chloro-1-phenyl-1-propanol (6 g) was heated with excess sodium iodide (4 equiv., 18 g) and a few drops of triethylamine in 30 mL of methyl ethyl ketone at 100° C. for 20 h. A sample was taken and monitored by NMR to determine the extent of conversion. The solvent was removed in vacuo and the residue was taken up in dichloromethane and filtered to remove the salts and the iodoalcohol was purified by flash chromatography to yield 6.9 g of product.