Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1>>[CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1ccc(O)cc1
Reactant: O=C(O)c1cc(NC2CCCCC2)ncn1
Product: O=C(Nc1ccc(O)cc1)c1cc(NC2CCCCC2)ncn1

Procedure:
Following the general method as outlined in Example 1, starting from 6-(cyclohexylamino)pyrimidine-4-carboxylic acid (Intermediate 4) and 4-aminophenol (Aldrich), the title compound was obtained as a slightly yellow solid.
Reaction SMILES: [C:1]1([C:7]2[C:11]3[CH:12]=[CH:13][C:14]4[O:18][CH:17]([CH2:19][OH:20])[CH2:16][C:15]=4[C:10]=3[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:24])(=O)=O>C(Cl)Cl>[Cl:24][C:13]1[C:14]2[O:18][CH:17]([CH2:19][OH:20])[CH2:16][C:15]=2[C:10]2[O:9][N:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:11]=2[CH:12]=1
Reactant: OCC1Cc2c(ccc3c(-c4ccccc4)noc23)O1
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: OCC1Cc2c(c(Cl)cc3c(-c4ccccc4)noc23)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.2 %

Procedure:
A portion (10 g) of the 7,8-dihydro-3-phenylfuro[2,3-g]-1,2-benzisoxazole-7-methanol prepared in Example 1 was dissolved in 300 ml of methylene chloride. To the ice-cooled solution, sulfuryl chloride (9 g) was added over time under agitation. The mixture was thereafter stirred for 8 hours at room temperature. The solvent was distilled off and the resulting residue was purified by column chromatography using methylene chloride as an eluant, whereupon 3.3 g of 5-chloro-7,8-dihydro-3-phenylfuro[2,3-g]-1,2benzisoxazole-7-methanol was obtained. This compound (3.3 g) was dissolved in 100 ml of acetone and, to the stirred solution, a mixture of chromium (VI) oxide (4 g), water (6 ml) and concentrated sulfuric acid (5.9 g) was added dropwise over time, and the solution was stirred for 2.5 hours at room temperature. The insolubles were filtered off by suction. After distilling off the acetone, water was added to the residue and the mixture was subjected to extraction with ether. The ether layer was washed with water and dried, followed by distilling off of the solvent. The residue was recrystallized with acetonitrile to yield 1 g of 5-chloro-7,8-dihydro-3-phenylfuro[2,3-g]-1,2-benzisoxazole-7-carboxylic acid. m.p. 221°-224° C. This compound exhibited a mass spectrum having a molecular ion peak at m/e 315.
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:45])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:26]5[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=5[OH:33])[CH:23]=[CH:24][CH:25]=4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:34])[C:12]=2[C@H:35]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[C:36]([O:38][CH3:39])=[O:37])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[CH3:46][C@@H:47](O)[CH2:48][CH:49]=[CH2:50].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1.CCOCC>[CH2:1]([O:4][C:5]1([CH3:45])[CH2:6][CH2:7][N:8]([C:11]2[N:16]3[N:17]=[C:18]([C:20]4[CH:21]=[C:22]([C:26]5[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=5[O:33][C@H:49]([CH2:48][CH:47]=[CH2:46])[CH3:50])[CH:23]=[CH:24][CH:25]=4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:34])[C:12]=2[C@H:35]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[C:36]([O:38][CH3:39])=[O:37])[CH2:9][CH2:10]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc3cc(-c4cccc(-c5cc(F)ccc5O)c4)nn23)CC1
Reactant: C=CC[C@@H](C)O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc3cc(-c4cccc(-c5cc(F)ccc5O[C@@H](C)CC=C)c4)nn23)CC1
Reaction time: 2 h
Yield: 80.1 %

Procedure:
To a solution of (S)-methyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(5′-fluoro-2′-hydroxy-[1,1′-biphenyl]-3-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.19 g, 0.31 mmol, 1 equiv), (R)-pent-4-en-2-ol (0.095 mL, 0.92 mmol, 3 equiv), and PPh3 (0.16 g, 0.62 mmol, 2 equiv) in THF (1.54 mL) was added DEAD (0.098 mL, 0.62 mmol, 2 equiv). After stirring 2 h, dilute with ether and wash with water. The ether layer was dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash column chromatography (0-60% EtOAc in hexane) to provide the product as a white foam (0.17 g, 81%). 1H NMR (500 MHz, CDCl3) [note: 4H of piperidine not observed and are likely very broad] δ 8.16 (s, 1H), 8.08-7.99 (m, 1H), 7.61-7.56 (m, 1H), 7.51 (d, J=7.6 Hz, 1H), 7.16 (dd, J=9.1, 2.8 Hz, 1H), 7.04-6.95 (m, 2H), 6.92-6.82 (m, 1H), 6.08-5.97 (m, 1H), 5.74 (s, 1H), 5.42 (d, J=17.3 Hz, 1H), 5.22-5.08 (m, 2H), 5.06-4.99 (m, 2H), 4.27 (d, J=6.0 Hz, 1H), 4.03 (d, J=4.7 Hz, 2H), 3.77 (s, 3H), 2.65 (br. s., 3H), 2.45-2.35 (m, 1H), 2.28 (s, 1H), 2.06-1.95 (m, 3H), 1.79-1.69 (m, 1H), 1.38 (br. s., 3H), 1.27 (s, 9H), 1.21 (d, J=6.0 Hz, 3H). LCMS (M+1)=685.4.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=O)[C:11](OCC(C)C)=[O:12])=[CH:2]1.[BH4-].[Na+]>C(O)(C)C.O>[OH:12][CH2:11][CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: CC(C)COC(=O)C(=O)c1c[nH]c2ccccc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: OCCc1c[nH]c2ccccc12
Reaction time: 5 h

Procedure:
A stirred suspension of isobutyl 3-indolylglyoxylate (48.5 g.) and sodium borohydride (22.7 g.) in isopropanol (500 ml.) was slowly heated to reflux and held for 5 hours. The cooled mixture was diluted with water (2 l.) and extracted with dichloromethane. The extract was washed with water, dried over magnesium sulphate and concentrated under reduced pressure to an oil which crystallised on cooling. Recrystallisation from toluene (100 ml.) gave 3-(2-hydroxyethyl)indole as a cream-coloured crystalline powder, mp. 55°-56°. Yield 23.3 g. (72.3%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[NH:17][C:16]3[C:18]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:19][CH:20]=[CH:21][C:15]=3[N:14]=2)[CH3:12])[N:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[F:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Br)=[CH:35][CH:34]=1>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][C@H:11]([C:13]2[N:14]([CH2:37][C:36]3[CH:39]=[CH:40][C:33]([F:32])=[CH:34][CH:35]=3)[C:15]3[CH:21]=[CH:20][CH:19]=[C:18]([S:22]([CH3:25])(=[O:24])=[O:23])[C:16]=3[N:17]=2)[CH3:12])[N:5]=[CH:4][N:3]=1
Reactant: C[C@H](Nc1ncnc(N)c1C#N)c1nc2cccc(S(C)(=O)=O)c2[nH]1
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2c(S(C)(=O)=O)cccc2n1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 4-amino-6-(((1S)-1-(7-(methylsulfonyl)-1H-benzimidazol-2-yl)ethyl)amino)-5-pyrimidinecarbonitrile (36 mg, 0.10 mmol), potassium carbonate (21 mg, 0.15 mmol) and 4-fluorobenzyl bromide (15 μL, 0.12 mmol) in DMF (3 mL) was stirred at rt in a sealed flask for 18 h. The reaction mixture was diluted with EtOAc, washed with water, brine, dried over magnesium sulfate, and concentrated under reduced pressure. Purification of the residue by flash chromatography over silica gel, using 2.5% MeOH in DCM as eluent gave 4-amino-6-(((1S)-1-(1-(4-fluorobenzyl)-4-(methylsulfonyl)-1H-benzimidazol-2-yl)ethyl)amino)-5-pyrimidinecarbonitrile: 1H NMR (400 MHz, CDCl3) δ 8.08 (1H, s), 7.88 (1H, d, J=8.0 Hz), 7.44 (1H, d, J=8.0 Hz), 7.31 (1H, t, J=8.0 Hz), 6.93 (4H, t, J=8.0 Hz), 6.19 (1H, t, J=8.0 Hz), 5.80-5.71 (1H, m), 5.52 (1H, d, J=16.0 Hz), 5.50 (1H, d, J=16.0 Hz), 5.31 (2H, br), 3.47 (3H, s), 1.62 (3H, d, J=8.0 Hz); LC-MS (ESI) m/z 466.0 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])[CH:5]=[CH:6][CH:7]=1.CC(C)([O-])C.[K+].Cl[CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28]>C1COCC1>[C:10]1([C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([O:1][CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:3]=2)=[O:9])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=C(c1ccccc1)c1cccc(O)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCOc1cccc(C(=O)c2ccccc2)c1
Reaction time: 2 h

Procedure:
To a solution of (3-hydroxyphenyl)(phenyl)methanone (30.0 g, 151 mmole) in anhydrous THF (300 mL) at 0° C. was slowly added a solution of potassium-t-butoxide (200 mL-1 M in THF, 0.200 mmole), followed by a slow addition of [2-(chloromethoxy)ethyl](trimethyl)silane (32.1 mL, 182 mmole). After stirring the mixture for 2 h, the solvent was removed in vacuo and the residue redissolved in a mixture of H2O (200 mL) and EtOAc (200 mL). The aqueous layer was further extracted with EtOAc (2×100 mL). The combined extracts were washed with H2O (200 mL), 0.1 N HCl (500 mL), brine (100 mL), dried over MgSO4, filtered and concentrated in vacuo to give an orange oil. The crude product was redissolved in hexanes and filtered through a silica-gel plug to give the product as an impure pale yellow oil which is carried on without further purification: ESHRMS m/z 329.1586 (M+H, C19H25O3Si, Calc'd 329.1567).
Reaction SMILES: [CH3:1]CN=C=NCCCN(C)C.[C:12]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([N:29]2[CH2:34][CH2:33][CH2:32][N:31]([CH2:35][C:36](O)=[O:37])[C:30]2=[O:39])[CH2:25][CH2:24]1)=[O:22])(=O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CN.C1C=CC2N(O)N=NC=2C=1>C1COCC1.C1COCC1.ClCCl>[CH3:1][C:36]([CH2:35][N:31]1[CH2:32][CH2:33][CH2:34][N:29]([CH:26]2[CH2:27][CH2:28][N:23]([C:21]([O:20][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[O:22])[CH2:24][CH2:25]2)[C:30]1=[O:39])=[O:37]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)CN1CCCN(C2CCN(C(=O)OC(=O)c3ccccc3)CC2)C1=O
Agent: CN
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(=O)CN1CCCN(C2CCN(C(=O)OCc3ccccc3)CC2)C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.3 %

Procedure:
WSC (0.39 g) was added to a solution of [3-{1-[(benzoyloxy)carbonyl]piperidin-4-yl}-2-oxotetrahydropyrimidin-1(2H)-yl]acetic acid (0.70 g) obtained in Example 36a), a solution of methylamine in THF (1.85 mL) and HOBt (0.31 g) in THF/dichloromethane (1/1, 30 mL) and the mixture was stirred at room temperature overnight. The solvent were distilled off under reduced pressure, and the residue was diluted with ethyl acetate. The mixture was washed with an aqueous saturated sodium bicarbonate solution and saturated saline solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified with basic silica gel column chromatography (ethyl acetate) to obtain the title compound (0.70 g, 97%) as a white powder.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[N:18]=[C:17]([NH2:19])[C:16]([C:20](=[O:31])[C:21]3[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[C:23]([F:29])[C:22]=3[F:30])=[CH:15][N:14]=2)[CH2:9]1)=O)(C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[NH2:19][C:17]1[C:16]([C:20]([C:21]2[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[C:23]([F:29])[C:22]=2[F:30])=[O:31])=[CH:15][N:14]=[C:13]([NH:12][CH:10]2[CH2:11][NH:8][CH2:9]2)[N:18]=1
Reactant: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CN(C(=O)OC(C)(C)C)C2)nc1N
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(F)c(F)c1C(=O)c1cnc(NC2CNC2)nc1N
Reaction time: 2 h

Procedure:
To a stirred suspension of the protected amine (940 mg, 2.16 mmol, Example 319) in methylene chloride (30 mL), trifluoroacetic acid (20 mL) was added at 0° C. and the mixture stirred for 2 hours. The solvent was removed and the residue was partitioned between ethyl acetate and 5% sodium carbonate solution. The aqueous layer was extracted with ethyl acetate/tetrahydrofuran (1:1, 3×10 ml). The extracts were combined and the solution was dried with sodium sulfate. Removal of solvent gave a yellow solid. 711 mg, 98%. MS (ES) MH+=336.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([OH:13])=[C:8]([C:14]1[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=1)[CH:7]=[CH:6]2.F[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1.ClCCl>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1)=[C:8]([C:14]1[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=1)[CH:7]=[CH:6]2
Reactant: COc1ccc2c(O)c(-c3ccc(SC)cc3)ccc2c1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc2c(Oc3ccc([N+](=O)[O-])cc3)c(-c3ccc(SC)cc3)ccc2c1
Yield: 71.1 %

Procedure:
Stir a solution of 6-methoxy-2-(4-methylsulfanyl-phenyl)-naphthalen-1-ol (1.98 g, 6:68 mmol), 4-fluoro-nitrobenzene (0.78 mL, 7.34 mmol) and phosphazene base P4-t-butyl (6.7 mL of 1M in hexane, 6.7 mmol) in N,N-dimethylformamide (30 mL) at ambient temperature for 4 hours. Dilute the reaction with dichloromethane, wash with 1N aqueous hydrochloric acid, water, dry with solid magnesium sulfate and chromatograph on silica gel with hexane/ethyl acetate mixtures to give 2.18 g of 6-methoxy-2-(4-methylsulfanyl-phenyl)-1-(4-nitro-phenoxy)-naphthalene (78%)
Reaction SMILES: [F:1][C@@H:2]1[C@@H:6]([CH2:7][OH:8])[O:5][C@@H:4]([N:9]2[C:19]3[N:18]=[C:16]([NH2:17])[NH:15][C:13](=[O:14])[C:12]=3[N:11]=[CH:10]2)[CH2:3]1.C1C=CC2N(O)N=NC=2C=1.[C:30]([NH:40][C@H:41]([C:45]([O:47][CH2:48][CH:49]([O:69][C:70](=[O:76])[CH2:71][CH2:72][C:73](O)=[O:74])[CH2:50][O:51][C:52](=[O:68])[C@H:53]([CH:65]([CH3:67])[CH3:66])[NH:54][C:55]([O:57][CH2:58][C:59]1[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=1)=[O:56])=[O:46])[CH:42]([CH3:44])[CH3:43])([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.CN(C=O)C>[F:1][C@@H:2]1[C@@H:6]([CH2:7][O:8][C:73](=[O:74])[CH2:72][CH2:71][C:70]([O:69][CH:49]([CH2:50][O:51][C:52](=[O:68])[C@H:53]([CH:65]([CH3:67])[CH3:66])[NH:54][C:55]([O:57][CH2:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][CH:60]=2)=[O:56])[CH2:48][O:47][C:45](=[O:46])[C@H:41]([CH:42]([CH3:44])[CH3:43])[NH:40][C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])=[O:76])[O:5][C@@H:4]([N:9]2[C:19]3[N:18]=[C:16]([NH2:17])[NH:15][C:13](=[O:14])[C:12]=3[N:11]=[CH:10]2)[CH2:3]1
Reactant: Nc1nc2c(ncn2[C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)OC(=O)CCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OCC(COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)OC(=O)CCC(=O)OC[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(N)nc32)C[C@@H]1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2′,3′-dideoxy-3′-fluoroguanosine (17.8 g, 66 mmole), HOBT (10.64 g, 78.8 mmole), succinic acid 1,3-bis-(N-CBZ-L-valyloxy)-2-propyl ester (52 g, 78.8 mmole) and DMAP (0.96 g, 7.88 mmole) was coevaporated two times with DMF and reduced to about 500 ml. DCC (17.3 g, 84 mmole) was added and the mixture was stirred overnight at room temperature. The mixture was warmed for six hours at 60° C. and then cooled to about 110° C. The mixture was filtered and the solution was reduced under reduced pressure. 1200 ml of ethyl acetate was added and the organic phase was washed twice with 5% acetic acid, 5% sodium hydrogen carbonate and water. The organic phase was dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography. Yield: 42 g.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[C:8]([CH3:17])=[N:9][C:10]2[N:11]([N:14]=[CH:15][CH:16]=2)[C:12]=1O>>[Cl:6][C:7]1[C:8]([CH3:17])=[N:9][C:10]2[N:11]([N:14]=[CH:15][CH:16]=2)[C:12]=1[Cl:3]
Reactant: Cc1nc2ccnn2c(O)c1Cl
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nc2ccnn2c(Cl)c1Cl
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Phosphorous oxychloride (excess) is added to 6-chloro-5-methylpyrazolo[1,5-a]pyrimidin-7-ol (1.00 equivalent) and heated to 80° C. After 2 hours, the reaction mixture is concentrated under reduced pressure. The resulting residue is poured onto ice and, carefully neutralized with saturated NaHCO3 (pH 8), and diluted with EtOAc. After stirring for 17 hours, the organic layer was separated and the aqueous layer was re-extracted with EtOAc, repeatedly. The combined organic extracts are dried (MgSO4) and concentrated. The product is purified by flash chromatography as necessary.
Reaction SMILES: [CH3:1][CH:2]([NH2:6])[CH:3]([CH3:5])[CH3:4].[CH2:7]1[CH2:13][S:10](=[O:12])(=[O:11])[O:9][CH2:8]1>O1CCCC1>[CH3:1][CH:2]([NH:6][CH2:8][CH2:7][CH2:13][S:10]([OH:12])(=[O:11])=[O:9])[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)C(C)N
Reactant: O=S1(=O)CCCO1
Solvent: C1CCOC1
Product: CC(C)C(C)NCCCS(=O)(=O)O
Temperature: 25 °C

Procedure:
To a solution of 1,2-dimethylpropylamine (10.0 g, 115 mmol) in tetrahydrofuran (80 mL) was slowly added a solution of 1,3-propane sultone (13.7 g, 110 mmol) in THF (20 mL). The solution was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid product was collected by filtration, washed with THF (50 mL) and EtOH (50 mL). The resulting solid was dried in vacuo, to afford compound DQ (17.5 g, 76%). 1H NMR (D2O, 500 MHz) δ ppm 3.07 (m, 3H), 2.88 (t, 2H, J=7.3 Hz), 1.97 (m, 3H), 1.10 (d, 3H, J=6.8 Hz), 0.85 (d, 3H, J=6.8 Hz), 0.81 (d, 3H, J=6.8 Hz). 13C NMR (D2O, 125 MHz) δ ppm 59.79, 48.19, 44.18, 29.72, 21.51, 18.44, 15.02, 10.71. ES-MS 232 (M+Na).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH3:11])[CH:5]=[CH:4][C:3]=1[C@H:12]1[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][CH:20]2OCCC[O:21]2)[CH2:14][CH2:13]1.C(O)=O>C1(C)C=CC=CC=1>[F:1][C:2]1[C:7]([F:8])=[C:6]([O:9][CH2:10][CH3:11])[CH:5]=[CH:4][C:3]=1[C@H:12]1[CH2:17][CH2:16][C@H:15]([CH2:18][CH2:19][CH:20]=[O:21])[CH2:14][CH2:13]1
Reactant: CCOc1ccc([C@H]2CC[C@H](CCC3OCCCO3)CC2)c(F)c1F
Solvent: O=CO
Solvent: Cc1ccccc1
Product: CCOc1ccc([C@H]2CC[C@H](CCC=O)CC2)c(F)c1F

Procedure:
The 2-(2-(trans-4-(2,3-difluoro-4-ethoxyphenyl)-cyclohexyl)-ethyl)-1,3-dioxane (19.8 mmol) obtained by the reaction of Step 4 was dissolved in 100 ml of toluene, 87% formic acid (198 mmol) was added, and the solution was heated to reflux for 4 hours. The reaction solution was twice washed with 50 ml of a saturated aqueous solution of sodium hydrogen carbonate, then three times with 50 ml of water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, to form crude 3-(trans-4-(2,3-difluoro-4-ethoxyphenyl)-cyclohexyl)-propanal (19.8 mmol).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[C:7]([C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=1)[C:13]([NH:15][CH3:16])=[O:14])[CH:6]=[N:5]2.C1C(=O)N([Br:27])C(=O)C1>CN(C=O)C.CCOC(C)=O>[Br:27][C:3]1[N:4]2[N:5]=[CH:6][C:7]([C:10]3[CH:11]=[C:12]([CH:17]=[CH:18][CH:19]=3)[C:13]([NH:15][CH3:16])=[O:14])=[CH:8][C:9]2=[N:1][CH:2]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CNC(=O)c1cccc(-c2cnn3ccnc3c2)c1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)c1cccc(-c2cnn3c(Br)cnc3c2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-Imidazo-[1,2-b]-pyridazin-7-yl-N-methyl-benzamide (1 eq, 0.595 mmol, 150 mg) is dissolved in DMF (5 ml) at 0° C. and NBS (1.1 eq, 0.654 mmol, 116 mg) is added. The reaction mixture is stirred for 1 h at 0° C. and then is diluted with EtOAc. The reaction mixture is washed with NaHCO3 and brine, dried over MgSO4, filtered and evaporated to yield 3-(3-Bromo-imidazo-[1,2-b]-pyridazin-7-yl)-N-methyl-benzamide as a pale yellow solid which did not require further purification; [M+H]+=333
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6](O)=[O:7].C(Cl)(=O)C([Cl:18])=O>ClCCl.CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[C:6]([Cl:18])=[O:7]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(C(=O)O)ccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(C(=O)Cl)ccc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
To a solution of 3-methoxy-4-nitrobenzoic acid (5.7 g, 30 mmol) in dichloromethane (100 mL) and N,N-dimethylformamide (5 mL) at 0° C. was added slowly oxalyl chloride (5.08 mL, 60 mmol). After stirring for 2 hours, the mixture was concentrated and the residue was used without further purification.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[N:13]=[CH:12][N:11]=[C:10]([NH2:14])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].[C:17](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:18]>CN(C=O)C>[F:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]([N:14]=[C:17]=[S:18])[N:11]=[CH:12][N:13]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1cc(-c2cccnc2F)ncn1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ncccc1-c1cc(N=C=S)ncn1
Reaction time: 1.5 h
Yield: 36.3 %

Procedure:
To a solution of 6-(2-fluoropyridin-3-yl)pyrimidin-4-amine (0.3 g, 1.577 mmol) in DMF was added NaH (0.126 g, 3.15 mmol). Stirring was continued for 1.5 h and 1,1′-thiocarbonyldipyridin-2(1H)-one (0.366 g, 1.577 mmol) was added. The mixture was stirred at rt for 2 h and purified on silica gel using 10-15% ethyl acetate in hexanes to give an orange solid (0.133 g, 0.573 mmol, 36%). MS (LC/MS) R.T.=2.48; [M+H]+=233.08.
Reaction SMILES: C(C[N:5]1[C:9]([SH:10])=[N:8][N:7]=[N:6]1)(O)=O.CC(O[CH2:15][C:16]1[CH2:25][S:24][C@@H:19]2[C@H:20]([NH2:23])[C:21](=[O:22])[N:18]2[C:17]=1[C:26]([OH:28])=[O:27])=O>>[NH2:23][CH:20]1[C:21](=[O:22])[N:18]2[C:17]([C:26]([OH:28])=[O:27])=[C:16]([CH:15]([S:10][C:9]3[NH:5][N:6]=[N:7][N:8]=3)[CH2:17][C:26]([OH:28])=[O:27])[CH2:25][S:24][C@H:19]12
Reactant: O=C(O)Cn1nnnc1S
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Product: NC1C(=O)N2C(C(=O)O)=C(C(CC(=O)O)Sc3nnn[nH]3)CS[C@H]12

Procedure:
7-Amino-3-(1-carboxymethyltetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid was prepared as described in Example 17 from reaction of 1-carboxymethyltetrazole-5-thiol and 7-aminocephalosporanic acid.
Reaction SMILES: [OH:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C@@H:9]2[CH2:13][C@H:12]([S:14][C:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11][N:10]2[C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=2)=[O:35])[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:54][S:55](Cl)(=[O:57])=[O:56]>ClCCl>[CH3:54][S:55]([O:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C@@H:9]2[CH2:13][C@H:12]([S:14][C:15]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:11][N:10]2[C:34]([O:36][CH2:37][C:38]2[CH:43]=[CH:42][C:41]([N+:44]([O-:46])=[O:45])=[CH:40][CH:39]=2)=[O:35])[CH2:4][CH2:3]1)(=[O:57])=[O:56]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)N1C[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1CN1CCN(O)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)ON1CCN(C[C@@H]2C[C@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 1 h

Procedure:
To a solution of (2S,4S)-2-[(4-hydroxypiperizin-1-yl)methyl]-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (5.4 g) and triethylamine (1.54 ml) in dichloromethane (60 ml) was added methanesulfonyl chloride (0.72 ml) under ice-cooling and the mixture was stirred under the same condition for 1 hour. The reaction mixture was washed successively with aqueous sodium hydrogen carbonate and aqueous sodium chloride, dried over magnesium sulfate, and evaporated in vacuo to give (2S,4S)-2-[(4-methanesulfonyloxypiperizin-1-yl)-methyl]-1-(4-nitrobenzyloxycarbonyl)-4-(triphenylmethylthio)pyrrolidine (6.06 g).