Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[NH2:2][C:3]([NH2:5])=[O:4].C([O:8][C:9]([C:11]1([C:38](OCC)=[O:39])[CH2:15][CH2:14][CH2:13][N:12]1[C:16]1[CH:17]=[N:18][C:19]([O:22][C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[N:28]([C:32]2C=NC=CC=2)[N:27]=[CH:26]3)=[CH:20][CH:21]=1)=O)C>C(O)C>[CH3:32][N:28]1[C:29]2[C:25](=[CH:24][C:23]([O:22][C:19]3[N:18]=[CH:17][C:16]([N:12]4[C:11]5([C:9](=[O:8])[NH:5][C:3](=[O:4])[NH:2][C:38]5=[O:39])[CH2:15][CH2:14][CH2:13]4)=[CH:21][CH:20]=3)=[CH:31][CH:30]=2)[CH:26]=[N:27]1
Reactant: NC(N)=O
Reactant: CCOC(=O)C1(C(=O)OCC)CCCN1c1ccc(Oc2ccc3c(cnn3-c3cccnc3)c2)nc1
Agent: [Na]
Solvent: CCO
Product: Cn1ncc2cc(Oc3ccc(N4CCCC45C(=O)NC(=O)NC5=O)cn3)ccc21
Temperature: 80 °C

Procedure:
To a flame dried flask is added ethanol (6 mL) and freshly cut sodium metal (62.4 mg, 2.71 mmol). The solution is stirred until homogenous. Recrystallized urea (98 mg, 1.63 mmol) is added and the solution is stirred at room temperature for 5 minutes. 1-[6-(1-Pyridin-3-yl-1H-indazol-5-yloxy)-pyridin-3-yl]-pyrrolidine-2,2-dicarboxylic acid diethyl ester (0.54 mmol) is added, and the solution is heated to 80° C. for 30 minutes, then cooled to 50° C. and stirred for 16 hours. The reaction is then quenched by the addition of 10 mL water, and 1N hydrochloric acid is added to adjust the pH to 5. The aqueous layer is extracted with ethyl acetate (3×20 mL). The combined ethyl acetate layers are washed with saturated sodium chloride, dried with magnesium sulfate, filtered, and concentrated under vacuum to produce crude product. This material is chromatographed on silica gel (ISCO MPLC purification, 30 minutes, 50-100% ethyl acetate gradient, Biotage flash 40s column) to provide 1-[6-(1-Methyl-1H-indazol-5-yloxy)-pyridin-3-yl]-1,7,9-triaza-spiro[4.5]decane-6,8,10-trione.
Reaction SMILES: [CH:1]1[CH2:5][CH:4]=[CH:3][CH:2]=1.[C:6]([O:10][CH2:11][CH2:12][OH:13])(=[O:9])[CH:7]=[CH2:8]>C1COCC1>[CH:2]12[CH2:1][CH:5]([CH:7]([C:6]([O:10][CH2:11][CH2:12][OH:13])=[O:9])[CH2:8]1)[CH:4]=[CH:3]2
Reactant: C1=CCC=C1
Reactant: C=CC(=O)OCCO
Solvent: C1CCOC1
Product: O=C(OCCO)C1CC2C=CC1C2
Yield: 81.3 %

Procedure:
Cyclopentadiene (66 g) and 140 g of 2-hydroxyethyl acrylate were dissolved in 500 g of THF solvent. After the reaction at 30° C. for 24 hours, the solvent was removed by rotary evaporator. The residue was distilled under reduced pressure to obtain 148 g of 2-hydroxyethyl 5-norbornene-carboxylate as a mixture of endo and exo (yield: 72%). NMR spectral data of the resulting compound (21) is shown in FIG. 4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.C1C[O:14][CH2:13]C1.CN(C=O)C>O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([CH:13]=[O:14])[S:10][C:3]=12
Reactant: Clc1ccnc2ccsc12
Reactant: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc2nccc(Cl)c2s1
Reaction time: 1 h
Yield: 85.5 %

Procedure:
To a solution of 7-chlorothieno[3,2-b]pyridine (2) (2 g, 11.83 mmol) in THF (40 mL) n-BuLi (2.5M in hexanes, 5.7 mL, 14.2 mmol) was added dropwise at −78° C. and the reaction mixture stirred 1 h. DMF (2.7 mL, 35.5 mmol) was added and stirring continued 1 h more. The reaction mixture was poured into water, extracted with EtOAc, the combined organics dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was triturated with ether and filtered affording title compound 232 (2 g, 10.12 mmol, 86% yield). MS (m/z): 197.9 (36%), (M+MeOH+1) 230.0 (100%).
Reaction SMILES: C([O:4][C@@H:5]1[C@H:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@:8]([CH2:21][O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([CH:18]([F:20])[F:19])[O:7][C@H:6]1[N:30]1[CH:35]=[CH:34][C:33](=[O:36])[NH:32][C:31]1=[O:37])(=O)C.CO.O1CCOCC1>N>[CH2:11]([O:10][C@@H:9]1[C@:8]([CH2:21][O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([CH:18]([F:19])[F:20])[O:7][C@@H:6]([N:30]2[CH:35]=[CH:34][C:33](=[O:36])[NH:32][C:31]2=[O:37])[C@@H:5]1[OH:4])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)O[C@H]1[C@H](n2ccc(=O)[nH]c2=O)O[C@@](COCc2ccccc2)(C(F)F)[C@H]1OCc1ccccc1
Agent: N
Solvent: C1COCCO1
Solvent: CO
Product: O=c1ccn([C@@H]2O[C@@](COCc3ccccc3)(C(F)F)[C@@H](OCc3ccccc3)[C@H]2O)c(=O)[nH]1
Yield: 66.2 %

Procedure:
A solution of compound 6 (0.52 g, 1 mmol) in NH3.MeOH/dioxane (6 mL/6 mL) was stirred at 20° C. After 18 h the reaction mixture was evaporated to dryness under reduced pressure. Purification by silica gel chromatography [petroleum ether:ethyl acetate (4:1 to 1.5:1)] provided 32 (0.314 g, 61%) as a white solid.
Reaction SMILES: O=[C:2]1[C:11]2[CH:10]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.Cl.[NH2:17][OH:18].C([O-])(=O)C.[Na+]>CO>[OH:18]/[N:17]=[C:2]1\[CH2:3][CH2:4][CH2:5][C:6]2[CH:7]=[CH:8][C:9]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][C:11]\1=2
Reactant: NO
Reactant: COC(=O)c1ccc2c(c1)C(=O)CCC2
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc2c(c1)/C(=N/O)CCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a solution of methyl 8-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate (10 g, 0.048 mol) in MeOH (100 ml) was added hydroxylamine hydrochloride (5 g, 0.07 mol), followed by sodium acetate (6 g, 0.072 mol). The reaction mixture was stirred at rt for 1 h and heated to 50° C. for 15 h. The solvent was removed under vacuum and the residue was diluted with water. The product was extracted with EtOAc (2×150 ml), dried and evaporated to yield 10 g (93%) of the titled compound as a solid. TLC-Chloroform/MeOH (9/1), Rf=0.3.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([NH:16][C:17]1[CH:29]=[C:28]([C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:32][CH:31]=2)[CH:27]=[CH:26][C:18]=1[C:19]([O:21]C(C)(C)C)=[O:20])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:8]([NH:16][C:17]1[CH:29]=[C:28]([C:30]2[CH:35]=[CH:34][C:33]([O:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:32][CH:31]=2)[CH:27]=[CH:26][C:18]=1[C:19]([OH:21])=[O:20])(=[O:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccc(Oc3ccccc3)cc2)cc1NC(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(-c2ccc(Oc3ccccc3)cc2)ccc1C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5.0 mL of trifluoroacetic acid was added to the obtained tert-butyl 2-(benzamido)-4-(4-phenoxyphenyl)benzoate and stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and the obtained residue was purified with silica gel column chromatography [PSQ100B (spherical) manufactured by Fuji Silysia Chemical Ltd., eluent; hexane:ethyl acetate=1:2] to obtain 8.0 mg of 2-(benzamido)-4-(4-phenoxyphenyl)benzoic acid as white solid.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]3([CH2:14][CH2:13]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:64][N:65]1[CH2:70][CH2:69][N:68]([CH:71]2[CH2:76][CH2:75][CH:74]([NH2:77])[CH2:73][CH2:72]2)[CH2:67][CH2:66]1>CN(C=O)C>[CH:1]1([N:6]2[CH2:12][C:11]3([CH2:14][CH2:13]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:77][C@H:74]5[CH2:73][CH2:72][C@H:71]([N:68]6[CH2:67][CH2:66][N:65]([CH3:64])[CH2:70][CH2:69]6)[CH2:76][CH2:75]5)=[O:28])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CCN(C2CCC(N)CC2)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N[C@H]2CC[C@H](N3CCN(C)CC3)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-(9′-Cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-3-methoxybenzoic acid (Intermediate 5) (66 mg, 0.15 mmol, 1 eq), DIPEA (52 μl, 0.3 mmol, 2 eq) and TBTU (54 mg, 0.17 mmol, 1.1 eq) were added to 1 mL DMF and the resulting solution was stirred at rt for 20 min before the addition of 4-(4-methylpiperazin-1-yl)cyclohexanamine (Intermediate 17) (35 mg, 0.18 mmol, 1.2 eq) dissolved in DMF (0.5 mL). The RM was then stirred at rt for 2 hours before purifying by preparative RP-HPLC-MS (Preparative—2 and Preparative—3) to provide 4-(9′-cyclopentyl-5′-methyl-6′-oxo-5′,6′,8′,9′-tetrahydrospiro[cyclopropane-1,7′-pyrimido[4,5-b][1,4]diazepine]-2′-ylamino)-N-((trans)-4-(4-methylpiperazin-1-yl)cyclohexyl)-3-methoxybenzamide (white solid, 17 mg, 18%).
Reaction SMILES: NC1C2N=C(C[O:19]CC)N(CCC)C=2C2C=CC(O)=CC=2N=1.[CH2:23]([O:25][CH2:26][C:27]1[N:28]([CH2:50][CH2:51][CH3:52])[C:29]2[C:38]3[CH:37]=[CH:36][C:35]([O:39][CH2:40][CH2:41][N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)=[CH:34][C:33]=3[N:32]=[C:31]([NH2:48])[C:30]=2[N:49]=1)[CH3:24]>O>[CH2:23]([O:25][CH2:26][C:27]1[N:28]([CH2:50][CH2:51][CH3:52])[C:29]2[C:38]3[CH:37]=[CH:36][C:35]([O:39][CH2:40][C:41]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)=[O:19])=[CH:34][C:33]=3[N:32]=[C:31]([NH2:48])[C:30]=2[N:49]=1)[CH3:24]
Reactant: CCCn1c(COCC)nc2c(N)nc3cc(O)ccc3c21
Reactant: CCCn1c(COCC)nc2c(N)nc3cc(OCCN4CCOCC4)ccc3c21
Solvent: O
Product: CCCn1c(COCC)nc2c(N)nc3cc(OCC(=O)N4CCOCC4)ccc3c21
Reaction time: 1 h

Procedure:
A modification on the procedure described in Example 646 was used to convert 4-amino-2-(ethoxymethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-ol (prepared as described in Parts A and B of Example 51) into 2-(ethoxymethyl)-7-(2-morpholin-4-ylethoxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine. The reaction mixture was heated overnight then was poured slowly into water. After the mixture was stirred for 1 hour, a tan solid was isolated by filtration and recrystallized from acetonitrile to afford 2-(ethoxymethyl)-7-(2-morpholin-4-yl-2-oxoethoxy)-1-propyl-1H-imidazo[4,5-c]quinolin-4-amine as off-white crystals, mp 213° C.
Reaction SMILES: CO[CH:3](OC)[CH2:4][CH2:5][N:6]1[CH:11]=[C:10]([C:12]2[C:13]([F:18])=[N:14][CH:15]=[CH:16][CH:17]=2)[C:9](=[O:19])[NH:8][C:7]1=[O:20].Cl.C(N(CC)CC)C.C(O)(=O)C.[F:35][C:36]([F:50])([F:49])[C:37]1[CH:42]=[CH:41][C:40]([C@:43]23[CH2:48][C@H:47]2[CH2:46][NH:45][CH2:44]3)=[CH:39][CH:38]=1.[Na]>O1CCCC1.C([O-])(O)=O.[Na+]>[F:18][C:13]1[C:12]([C:10]2[C:9](=[O:19])[NH:8][C:7](=[O:20])[N:6]([CH2:5][CH2:4][CH2:3][N:45]3[CH2:46][C@H:47]4[C@:43]([C:40]5[CH:39]=[CH:38][C:37]([C:36]([F:35])([F:50])[F:49])=[CH:42][CH:41]=5)([CH2:48]4)[CH2:44]3)[CH:11]=2)=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: FC(F)(F)c1ccc([C@@]23CNC[C@@H]2C3)cc1
Reactant: COC(CCn1cc(-c2cccnc2F)c(=O)[nH]c1=O)OC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: O=c1[nH]c(=O)n(CCCN2C[C@@H]3C[C@]3(c3ccc(C(F)(F)F)cc3)C2)cc1-c1cccnc1F
Temperature: 0 °C
Reaction time: 5 h
Yield: 93.1 %

Procedure:
To a solution of 1-[3,3-bis(methyloxy)propyl]-5-(2-fluoro-3-pyridinyl)-2,4(1H,3H)-pyrimidinedione (Prep89, 133 mg, 0.430 mmol) in Tetrahydrofuran (THF) (4 ml) at ambient temperature under an Argon atmosphere, hydrochloric acid 2M solution (0.5 ml, 1.000 mmol) was added and the reaction mixture stirred for 5 h. Volatiles were evaporated at rotary (cold bath) and the residue was taken up with triethylamine (0.240 ml, 1.720 mmol) and 4 ml of THF and the slurry was re-evaporated to dryness. The crude obtained was directly used in the next step without any further purification. It was diluted with Acetonitrile (4.00 ml) and to the mixture was added acetic acid (0.025 ml, 0.430 mmol) followed by (1S,5R)-1-(4-trifluoromethyl-phenyl)-3-aza-bicyclo[3.1.0]hexane (Prep4, 98 mg, 0.430 mmol). The resulting mixture stirred at ambient temperature under an Argon atmosphere for 20 minutes then the mixture was cooled down to 0° C. and sodium triacetoxyboronhydride (137 mg, 0.645 mmol) was added in one portion. The reaction mixture was stirred overnight allowing the Temperature to reach gradually ambient. Reaction mixture was diluted with NaHCO3 saturated solution (5 mL) and extracted with AcOEt (3×20 mL). Combined organics were dried over Na2SO4 and evaporated to dryness to get crude material as thick yellow oil (300 mg) that was purified by SiO2 flash chromatography eluting with AcOEt/NH4OH from 100/0 to 96/4 (TLC Rf=0.35 AcOEt/NH4OH 96/4). Evaporation of the solvent afforded the title compound (190 mg) as white foam.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:25]2[C:26](=[O:31])[NH:27][CH:28]=[CH:29][CH:30]=2)[CH:8]=[C:9](/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2C(F)(F)F)[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[F:32]C1C=CC=CC=1Br.FC(F)(F)C1C=CC=CC=1Br>>[C:1]([C:5]1[CH:6]=[C:7]([C:25]2[C:26](=[O:31])[NH:27][CH:28]=[CH:29][CH:30]=2)[CH:8]=[C:9](/[CH:13]=[CH:14]/[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:32])[C:10]=1[O:11][CH3:12])([CH3:2])([CH3:4])[CH3:3]
Reactant: Fc1ccccc1Br
Reactant: COc1c(/C=C/c2ccccc2C(F)(F)F)cc(-c2ccc[nH]c2=O)cc1C(C)(C)C
Agent: FC(F)(F)c1ccccc1Br
Product: COc1c(/C=C/c2ccccc2F)cc(-c2ccc[nH]c2=O)cc1C(C)(C)C

Procedure:
3-{3-tert-Butyl-4-methoxy-5-[(E)-2-(2-trifluoromethyl-phenyl)-vinyl]-phenyl}-1H-pyridin-2-one (I-239)) was prepared analogously except in step 2, o-fluoro-bromobenzene was replaced with o-trifluoromethyl-bromobenzene: MS (CI) mz/=429 (M+H).
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:7]=[N:8][C:9]3[C:14]([C:15]=2[NH:16][C@H:17]2[CH2:22][CH2:21][C@H:20]([CH2:23][NH:24]C(=O)OC(C)(C)C)[CH2:19][CH2:18]2)=[CH:13][C:12]([C:32]2[CH:37]=[C:36]([Cl:38])[C:35]([OH:39])=[C:34]([Cl:40])[CH:33]=2)=[CH:11][CH:10]=3)=[O:5])[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>>[NH2:24][CH2:23][C@H:20]1[CH2:21][CH2:22][C@H:17]([NH:16][C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:32]4[CH:37]=[C:36]([Cl:38])[C:35]([OH:39])=[C:34]([Cl:40])[CH:33]=4)[CH:13]=3)[N:8]=[CH:7][C:6]=2[C:4]([CH:1]2[CH2:2][CH2:3]2)=[O:5])[CH2:18][CH2:19]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: NC[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)cc23)CC1

Procedure:
Following general procedure A-2, tert-butyl {trans-4-[3-(cyclopropanecarbonyl)-6-(3,5-dichloro-4-hydroxyphenyl)quinolin-4-ylamino]cyclohexyl}methylcarbamate (0.123 mmol) was reacted with TFA (2 mL) to afford the desired product (24 mg, 40% over two steps) as a yellow solid: 1H NMR (300 MHz, CD3OD+TFA-d) δ 9.36 (s, 1H), 8.47 (s, 1H), 8.27 (d, J=8.4 Hz, 1H), 7.98 (d, J=8.4 Hz, 1H), 7.74 (s, 2H), 4.54-4.48 (m, 1H), 2.92-2.76 (m, 3H), 2.50-2.37 (m, 2H), 2.08-2.02 (m, 2H), 1.83-1.64 (m, 3H), 1.41-1.15 (m, 6H); ESI MS m/z 484 [C26H27Cl2N3O2+H]+; HPLC>99% (AUC), tR=11.38 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[CH:12]([OH:15])[CH2:13][OH:14])=[N:9][C:8]([O:16][CH3:17])=[CH:7][CH:6]=2.C(N(CC)CC)C.[S:25](Cl)([C:28]1[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=1)(=[O:27])=[O:26]>ClCCl.O.C(=O)(O)[O-].[Na+].C([Sn](=O)CCCC)CCC>[CH3:32][C:31]1[CH:33]=[CH:34][C:28]([S:25]([O:14][CH2:13][CH:12]([C:11]2[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([O:16][CH3:17])[N:9]=3)[N:4]=[CH:3][C:2]=2[F:1])[OH:15])(=[O:27])=[O:26])=[CH:29][CH:30]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc2ncc(F)c(C(O)CO)c2n1
Agent: CCCC[Sn](=O)CCCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2ncc(F)c(C(O)COS(=O)(=O)c3ccc(C)cc3)c2n1
Reaction time: 3 h
Yield: 74.7 %

Procedure:
To a solution of 1-[3-fluoro-6-(methoxy)-1,5-naphthyridin-4-yl]-1,2-ethanediol (16.5 g, 71 mmol)) in dichloromethane (200 mL), triethylamine (10 mL) and dibutyltin oxide (350 mg) was added tosyl chloride (13.2 g). After 3 hours, the mixture was diluted with water/sodium bicarbonate and extracted several times with chloroform. The combined organic extracts were dried over magnesium sulfate and evaporated under vacuum. The residue was chromatographed on silica gel eluting with 20-30% ethyl acetate in chloroform to afford the desired product (20.3 g, 75%). MS (+ve ion electrospray) m/z 393 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([CH3:9])[CH:3]=1.C[C:11](C)=[CH:12][C:13](O)=[O:14].CS(O)(=O)=O>>[OH:1][C:2]1[CH:7]=[C:6]2[C:5]([CH2:11][CH2:12][C:13](=[O:14])[O:8]2)=[C:4]([CH3:9])[CH:3]=1
Reactant: Cc1cc(O)cc(O)c1
Reactant: CC(C)=CC(=O)O
Agent: CS(=O)(=O)O
Product: Cc1cc(O)cc2c1CCC(=O)O2
Yield: 104.5 %

Procedure:
3 grams of 1,5-dihydroxy-3-methylbenzene are admixed with 3 grams of dimethylacrylic acid. There was then added 20 ml. of methanesulfonic acid and the mixture stirred for 1 hour at 70° C. The mixture was cooled and extracted with ether. The ether solution was washed twice with a saturated aqueous sodium bicarbonate solution and once with a saturated sodium chloride solution. The ether layer was dried over sodium sulfate and then evaporated to yield the corresponding 7-hydroxy-5-methylchromanone (4.5 g).
Reaction SMILES: [CH:1]1([C:4]2[S:8][C:7]([N:9]3[CH:14]([OH:15])[CH2:13][CH2:12][N:11]([CH3:16])[C:10]3=[O:17])=[N:6][N:5]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:25](Cl)(=[O:28])[CH:26]=[CH2:27]>C1C=CC=CC=1>[CH:1]1([C:4]2[S:8][C:7]([N:9]3[CH:14]([O:15][C:25](=[O:28])[CH:26]=[CH2:27])[CH2:13][CH2:12][N:11]([CH3:16])[C:10]3=[O:17])=[N:6][N:5]=2)[CH2:2][CH2:3]1
Reactant: C=CC(=O)Cl
Reactant: CN1CCC(O)N(c2nnc(C3CC3)s2)C1=O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: C=CC(=O)OC1CCN(C)C(=O)N1c1nnc(C2CC2)s1

Procedure:
Tetrahydro-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. Acryloyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction mixture is filtered and the filtrate is stripped of solvent under reduced pressure to yield the desired product tetrahydro-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-acryloyloxy-2(1H)-pyrimidinone as the residue.
Reaction SMILES: Cl[C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3.[CH3:19][O:20][C:21]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:22]=1[NH2:23]>>[CH3:16][O:15][C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[C:6]1=[CH:17][C:2]([NH:23][C:22]3[C:24]([CH3:28])=[CH:25][CH:26]=[CH:27][C:21]=3[O:20][CH3:19])=[N:3][C:4](=[O:18])[N:5]1[CH2:14][CH2:13]2
Reactant: COc1cccc(C)c1N
Reactant: COc1ccc2c(c1)CCn1c-2cc(Cl)nc1=O
Product: COc1ccc2c(c1)CCn1c-2cc(Nc2c(C)cccc2OC)nc1=O

Procedure:
The title compound was prepared from 2-chloro-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (4) and 2-methoxy-6-methyl-aniline as in Example 1 d. 1H-NMR (400 MHz, d6-DMSO) δ 8.71 (br, 1H), 7.71 (br, 1H), 7.35-6.80 (5H), 6.39 (br, 1H), 3.92 (br, 2H), 3.83 (br, 3H), 3.74 (br, 3H), 2.94 (t, 2H) and 2.14 (br, 3H); MS (ESI) (M+H)+ 364.
Reaction SMILES: I[C:2]1[C:3]([C:7]([F:13])([F:12])[C:8]([F:11])([F:10])[F:9])=[N:4][NH:5][CH:6]=1.I[C:15]([F:20])([F:19])[CH:16]([F:18])[F:17]>[Cu].CN(C=O)C>[F:12][C:7]([F:13])([C:3]1[C:2]([C:15]([F:20])([F:19])[CH:16]([F:18])[F:17])=[CH:6][NH:5][N:4]=1)[C:8]([F:11])([F:10])[F:9]
Reactant: FC(F)(F)C(F)(F)c1n[nH]cc1I
Reactant: FC(F)C(F)(F)I
Agent: [Cu]
Solvent: CN(C)C=O
Product: FC(F)C(F)(F)c1c[nH]nc1C(F)(F)C(F)(F)F
Temperature: 122.5 °C
Reaction time: 8 h
Yield: 10.5 %

Procedure:
4-Iodo-3-pentafluoroethyl-1H-pyrazole (6.24 g), copper powder (3.81 g), Iodo-1,1,2,2-tetrafluoroethane (9.12 g) and DMF (30 ml) were set in an autoclave and heated and stirred for 8 hours, maintaining the inside temperature of 120-125° C. After cooling to room temperature, the insoluble material was filtered off through Celite and washed with diethyl ether. The filtrate was diluted with water and extracted with diethyl ether. The organic phase was washed with water and dried over sodium sulfate, and concentrated under the reduced pressure. The crude product was distilled under reduced pressure to obtain 3-pentafluoroethyl-4-(1,1,2,2-tetrafluoroethyl)-1H-pyrazole (0.60 g), bp. 125-135° C./20 mbar.
Reaction SMILES: B(Cl)([C@H]1[C@H](C)C2C(C)(C)C(CC2)C1)[C@H]1[C@H](C)C2C(C)(C)C(CC2)C1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([C:33](=[O:40])[CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37])[CH:30]=[CH:31][CH:32]=1.N(CCO)CCO>C1COCC1>[OH:40][C@H:33]([C:29]1[CH:30]=[CH:31][CH:32]=[C:27]([O:26][CH3:25])[CH:28]=1)[CH2:34][CH2:35][C:36]([O:38][CH3:39])=[O:37]
Reactant: COC(=O)CCC(=O)c1cccc(OC)c1
Agent: C[C@@H]1C2CCC(C[C@H]1B(Cl)[C@@H]1CC3CCC([C@H]1C)C3(C)C)C2(C)C
Solvent: C1CCOC1
Solvent: OCCNCCO
Product: COC(=O)CC[C@H](O)c1cccc(OC)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 78 %

Procedure:
A dried, 25 mL round-bottom flask equipped magnetic stirring bar is cooled to room temperature under a stream of nitrogen. To this is added (−)-DIP-Chloride (6.76 mmol, 2.17 g, 1.2 eq) and THF (10 mL), and the mixture is cooled to −25° C., followed by the addition of methyl 4-(3-methoxyphenyl)-4-oxobutanoate (5.63 mmol). The resulting mixture is then stirred at −20° C. to −30° C. for 10 h. Then, diethanolamine (12.39 mmol, 2.2 eq) is added at −20° C., and the mixture is warmed to room temperature and stirred overnight. This mixture is then filtered, evaporated, and the residue is purified on silica gel (0-33% ethyl acetate in hexane) to give (S)-methyl 4-hydroxy-4-(3-methoxyphenyl)butanoate (985 mg, 79%; >95% based on recovered starting material) as a clear colorless oil. 1H NMR (CDCl3) δ 7.33-7.27 (m, 1H), 6.92-6.84 (m, 3H), 5.52-5.46 (m, 1H), 3.82 (s, 1H), 3.48 (s, 1H), 2.71-2.61 (m, 3H), 2.26-2.12 (m, 1H).
Reaction SMILES: [O:1]=[S:2]1(=[O:25])[CH2:7][CH:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]=[N+]=[N-])[O:16][C:15]3=[O:23])=[CH:10][C:9]=2[F:24])[CH2:4][CH2:3]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C.O>[O:25]=[S:2]1(=[O:1])[CH2:3][CH:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][NH2:20])[O:16][C:15]3=[O:23])=[CH:10][C:9]=2[F:24])[CH2:6][CH2:7]1
Reactant: [N-]=[N+]=NC[C@H]1CN(c2ccc(C3=CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Product: NC[C@H]1CN(c2ccc(C3=CCS(=O)(=O)CC3)c(F)c2)C(=O)O1
Yield: 95.7 %

Procedure:
(5R)-3-[4-(1,1-Dioxo-3,6-dihydro-2H-thiopyran-4-yl)-3-fluorophenyl]-5-(azidomethyl) oxazolidin-2-one (Intermediate 2) (3 g, 8.2 mmol) was dissolved in acetonitrile/water (10:1, 50 ml). Triphenylphosphine (2.6 g, 9.9 mmol) was added and the resulting mixture was stirred over night with evolution of nitrogen. The reaction mixture was applied onto a silica gel column and eluted with acetonitrile/water (15:1 to 5:1) to give the title compound (2.67 g).
Reaction SMILES: CC(S[CH:5]1[CH:9]2[O:10][C:11]([CH3:14])([CH3:13])[O:12][CH:8]2[O:7][CH:6]1[CH:15]1[O:19][C:18]([CH3:21])([CH3:20])[O:17][CH2:16]1)=O>CO.[Ni].[Al].[Ni]>[CH3:20][C:18]1([CH3:21])[O:19][C@@H:15]([C@H:6]2[O:7][C@@H:8]3[O:12][C:11]([CH3:14])([CH3:13])[O:10][C@@H:9]3[CH2:5]2)[CH2:16][O:17]1
Reactant: CC(=O)SC1C(C2COC(C)(C)O2)OC2OC(C)(C)OC21
Agent: [Ni]
Agent: [Al]
Solvent: CO
Product: CC1(C)O[C@H]2O[C@H]([C@H]3COC(C)(C)O3)C[C@H]2O1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
The crude reaction mixture obtained by the procedure described in Example 2 containing 3-S-Acetyl-1,2:5,6-di-O-isopropylidene-3-thio-α-D-allofuranose E2 (7.5 g, 23.58 mmole) was dissolved in methanol and added to a slurry of freshly prepared Raney nickel (prepared from nickel-aluminium alloy, 60 g) in methanol (100 ml). The reaction mixture was stirred at room temperature for 15 h and filtered. The filtrate was concentrated under reduced pressure to give the title product E3; yield: 5 g, 88%, which was subjected to the following step without further purification.