Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(=O)N[C@@H](C(C)C)C(N1[C@H](C2NC(C3C=CC(C4C=CC5C(=CC=C(C6NC([C@@H]7CCCN7[C:48](=[O:61])[C@H:49]([NH:56][C:57]([O:59][CH3:60])=[O:58])[C:50]7[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=7)=NC=6)C=5)C=4)=CC=3)=CN=2)CC2(OCCO2)C1)=O.Cl.Cl.Cl.[C@H:69]12[CH2:75][C@H:72]([CH2:73][CH2:74]1)[C@@H:71]([C:76]1[NH:77][C:78]([C:81]3[CH:82]=[C:83]4[C:88](=[CH:89][CH:90]=3)[CH:87]=[C:86]([C:91]3[CH:92]=[C:93]5[C:118](=[CH:119][CH:120]=3)[C:97]3[NH:98][C:99]([C@@H:101]6[CH2:105][CH2:104][CH2:103][N:102]6[C:106](=[O:117])[C@@H:107]([NH:112][C:113](=[O:116])[O:114][CH3:115])[C@H:108]([O:110][CH3:111])[CH3:109])=[N:100][C:96]=3[CH:95]=[CH:94]5)[CH:85]=[CH:84]4)=[CH:79][N:80]=1)[NH:70]2>>[CH3:115][O:114][C:113](=[O:116])[NH:112][C@@H:107]([C@H:108]([O:110][CH3:111])[CH3:109])[C:106]([N:102]1[CH2:103][CH2:104][CH2:105][C@H:101]1[C:99]1[NH:98][C:97]2[C:118]3[C:93]([CH:94]=[CH:95][C:96]=2[N:100]=1)=[CH:92][C:91]([C:86]1[CH:85]=[CH:84][C:83]2[C:88](=[CH:89][CH:90]=[C:81]([C:78]4[NH:77][C:76]([C@@H:71]5[C@@H:72]6[CH2:75][C@@H:69]([CH2:74][CH2:73]6)[N:70]5[C:48](=[O:61])[C@H:49]([NH:56][C:57]([O:59][CH3:60])=[O:58])[C:50]5[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=5)=[N:80][CH:79]=4)[CH:82]=2)[CH:87]=1)=[CH:120][CH:119]=3)=[O:117]
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc(-c4ccc5cc(-c6cnc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)ccc5c4)cc3)[nH]1)OCCO2)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4ccc5cc(-c6cnc([C@H]7N[C@@H]8CC[C@H]7C8)[nH]6)ccc5c4)ccc3c2[nH]1)[C@@H](C)OC
Agent: Cl
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4ccc5cc(-c6cnc([C@@H]7[C@H]8CC[C@H](C8)N7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)ccc5c4)ccc3c2[nH]1)[C@@H](C)OC

Procedure:
The title compound was prepared according to the method employed to prepare (S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamic acid methyl ester, except that methyl (2S,3R)-1-((S)-2-(7-(6-(2-((1R,3S,4S)-2-azabicyclo[2.2.1]heptan-3-yl)-1H-imidazol-5-yl)naphthalen-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)-3-methoxy-1-oxobutan-2-ylcarbamate 3HCl salt was used instead of methyl (S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate 3HCl salt. MS (ESI) m/z 889.43 [M+H]+. (100 mg, 43%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]1[N:11]([CH3:30])[C:12](=[O:29])[C:13]([O:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=1.N1C=CC=CC=1.[C:37]1([C:43](Cl)=[O:44])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C1COCC1>[C:43]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10]1[N:11]([CH3:30])[C:12](=[O:29])[C:13]([O:20][C:21](=[O:28])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=1)(=[O:44])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)c1nc(C2Cc3ccccc3N2)n(C)c(=O)c1OC(=O)c1ccccc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COC(=O)c1nc(C2Cc3ccccc3N2C(=O)c2ccccc2)n(C)c(=O)c1OC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
THF was added to the crude product of Step 1, followed by pyridine (2 eq.) and PhCOCl (1 eq.). After being stirred at room temperature overnight, the reaction mixture was evaporated to give the crude title product.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]([B:22]2[O:26][C:25]([CH3:28])(C)C(C)[O:23]2)=[C:15]([CH:18]=[C:19]([Cl:21])[CH:20]=1)C=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:30](C)([O-:32])=[O:31].[OH-].[Na+].Cl>C1COCC1.CCOC(C)=O>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:14]2[B:22]([OH:23])[O:26][CH:25]([CH2:28][N+:30]([O-:32])=[O:31])[C:15]=2[CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[N+](=O)[O-]
Reactant: CC1OB(c2c(C=O)cc(Cl)cc2OCCCOCc2ccccc2)OC1(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=[N+]([O-])CC1OB(O)c2c(OCCCOCc3ccccc3)cc(Cl)cc21
Reaction time: 12 h

Procedure:
To a solution of 3-(3-benzyloxy-propoxy)-5-chloro-2-(4,4,5-trimethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (3.4 g, 7.8 mmol) and nitromethane (1.7 mL, 31.3 mmol) in THF (20 mL) was added a solution of NaOH (0.025 M, 40 mL). After 12 h, 2 N HCl was added until pH was 1. The solution was diluted with EtOAc (150 mL), washed with water, dried over Na2SO4, filtered and concentrated under reduced pressure. The product was purified by silica gel column chromatography (4:1 hexanes-EtOAc mobile phase) to give the title compound product (1.7 g, 56%) as a colorless gel. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.39-7.28 (m, 5H), 6.92 (s, 1H), 6.83 (s, 1H), 5.85 (br s, 1H), 5.81 (dd, J=8.5, 3.9 Hz, 1H), 4.70 (dd, J=13.2, 3.9 Hz, 1H), 4.59 (s, 2H), 4.47 (dd, J=13.0, 8.7 Hz, 1H), 4.21-4.07 (m, 2 H), 3.71-3.60 (m, 2H), 2.10 (quin, J=5.7 Hz, 2H).
Reaction SMILES: [CH2:1]([C:12]1[N:16]=[C:15]([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)[O:14][N:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].[O:25]1[C:29]2[CH:30]=[CH:31][C:32]([NH2:34])=[CH:33][C:28]=2[O:27][CH2:26]1>>[O:25]1[C:29]2[CH:30]=[CH:31][C:32]([NH:34][CH2:21][C:20]3[CH:23]=[CH:24][C:17]([C:15]4[O:14][N:13]=[C:12]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[N:16]=4)=[CH:18][CH:19]=3)=[CH:33][C:28]=2[O:27][CH2:26]1
Reactant: CCCCCCCCCCCc1noc(-c2ccc(C=O)cc2)n1
Reactant: Nc1ccc2c(c1)OCO2
Product: CCCCCCCCCCCc1noc(-c2ccc(CNc3ccc4c(c3)OCO4)cc2)n1

Procedure:
The same procedure as employed in the preparation of Example 357 (step a) but using 4-(3-undecyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 1,3-benzodioxol-5-ylamine gave the title compound as an oil. HPLC (Condition A), Rt: 5.15 min (HPLC purity: 97.2%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7](=[N:16][OH:17])[NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=2)=[N:4][O:5][N:6]=1.C1N=CN([C:23](N2C=NC=C2)=[O:24])C=1>O1CCCC1.C(OCC)(=O)C>[NH2:1][C:2]1[C:3]([C:7]2[N:8]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[CH:10]=3)[C:23](=[O:24])[O:17][N:16]=2)=[N:4][O:5][N:6]=1
Reactant: Nc1nonc1C(=NO)Nc1cccc(Cl)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1nonc1-c1noc(=O)n1-c1cccc(Cl)c1
Yield: 95.4 %

Procedure:
A solution of 4-amino-N-(3-chlorophenyl)-N′-hydroxy-1,2,5-oxadiazole-3-carboximidamide (540 mg, 2.1 mmol) and N,N-carbonyldiimidazole (380 mg, 2.3 mmol) in tetrahydrofuran (10 mL) was heated at 80° C. for 1 h. The reaction mixture was diluted with ethyl acetate (150 mL) and washed with 0.1 N HCl (3×75 mL) and brine (75 mL). The organic layer was dried with sodium sulfate, filtered, and concentrated to give the desired product (560 mg, 94%) as a white solid which was used without further purification. LCMS for C10H7ClN5O3 (M+H)+: m/z=279.9.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:15]([C:16]([NH:18][CH3:19])=[O:17])=[C:14]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)[O:13][C:5]2=[N:6][C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].Br[CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[Cl:36].C(=O)([O-])[O-].[Cs+].[Cs+]>>[Cl:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[CH2:29][CH2:28][N:8]([C:7]1[N:6]=[C:5]2[O:13][C:14]([C:20]3[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=3)=[C:15]([C:16]([NH:18][CH3:19])=[O:17])[C:4]2=[CH:3][C:2]=1[I:1])[S:9]([CH3:12])(=[O:10])=[O:11]
Reactant: CNC(=O)c1c(-c2ccc(C)cc2)oc2nc(NS(C)(=O)=O)c(I)cc12
Reactant: Clc1ccccc1CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CNC(=O)c1c(-c2ccc(C)cc2)oc2nc(N(CCc3ccccc3Cl)S(C)(=O)=O)c(I)cc12
Temperature: 150 °C

Procedure:
To 5-iodo-N-methyl-6-(methylsulfonamido)-2-(p-tolyl)furo[2,3-b]pyridine-3-carboxamide (150 mg, 0.309 mmol) was added 1-(2-bromoethyl)-2-chlorobenzene (678 mg, 3.09 mmol) and CESIUM CARBONATE (101 mg, 0.309 mmol) was heated at 150° C. μwave 10 min. LCMS showed 1:1 SM/Prod and 1:2 styrene/Br. Added CESIUM CARBONATE (101 mg, 0.309 mmol) and heated additional 10 min at 150° C. μwave. Added water and extracted with EtOAc. Conc. on vac. Added ACN/water and filtered with 0.45 μPTFE filter
Reaction SMILES: CC(C)([O-])C.[K+].C([Li])CCC.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20].[C:21](=[O:23])=[O:22]>O.O1CCCC1>[F:12][C:13]1[C:14]([O:19][CH3:20])=[CH:15][CH:16]=[CH:17][C:18]=1[C:21]([OH:23])=[O:22]
Reactant: O=C=O
Reactant: COc1ccccc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(C(=O)O)c1F
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 51 %

Procedure:
A mixture of potassium tert-butoxide (30.80 g, 274 mmol) and anhydrous tetrahydrofuran (300 mL) was cooled to -78° C. and treated with a 1.6M solution of n-butyllithium (172 mL, 275 mmol) in hexanes. After stirring for 15 minutes, 2-fluoroanisole (31.35 g, 248 mmol) was added and the reaction was stirred an additional 1.8 hours. The reaction was poured into a 2 L Erlenmeyer flask containing dry ice and warmed to room temperature. Water (250 mL) was added and after extracting with ether (160 mL), the aqueous layer was acidified with concentrated hydrochloric acid, and filtered to give 2-fluoro-3-methoxybenzoic acid (21.43 g, 51%) as a yellow solid: mp 155°-160° C.; 1H NMR (acetone-d6) 300 MHz 7.46 (ddd, J=6.0 Hz J=1.8 Hz J=1.4 Hz, 1H) 7.36 (dt, J=1.6 Hz J=8.1 Hz, 1H) 7.20 (dt, J=1.4 Hz J=8.1 Hz, 1H) 3.92 (s, 3H); 19F NMR (acetone-d6) 300 MHz -134.04(m). Mass spectrum: M+H=171.
Reaction SMILES: [CH2:1]([N:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH2:15][CH2:14]2)[CH3:5])[CH:2]=[CH2:3].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28](Cl)=[S:29])=[CH:23][CH:22]=1>O1CCOCC1>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][C:28]([N:16]2[C:17]3[C:13](=[CH:12][C:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][N:4]([CH2:1][CH:2]=[CH2:3])[CH3:5])=[CH:19][CH:18]=3)[CH2:14][CH2:15]2)=[S:29])=[CH:23][CH:22]=1
Reactant: C=CCN(C)CCCCCc1ccc2c(c1)CCN2
Reactant: S=C(Cl)Oc1ccc(Cl)cc1
Solvent: C1COCCO1
Product: C=CCN(C)CCCCCc1ccc2c(c1)CCN2C(=S)Oc1ccc(Cl)cc1
Reaction time: 0.25 h
Yield: 42.9 %

Procedure:
130 mg (0.5 mmol) Allyl-[5-(2,3-dihydro-1H-indol-5-yl)-pentyl]-methyl-amine in 0.5 ml dioxane were treated with 0.072 ml (0.5 mmol) chlorothio-formicacid-O-(4-chlorophenyl)-ester at 15° C. The mixture was stirred for 15 min, concentrated and purified by column chromatography on silica gel with a gradient of CH2Cl2MeOH 99:1 to 97:3 to yield 92 mg 5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carbothioic acid O-(4-chloro-phenyl)ester as colorless oil. The corresponding acetic acid salt was prepared by treatment with acetic acid in CH2Cl2 to yield 101 mg 5-[5-(Allyl-methyl-amino)-pentyl]-2,3-dihydro-indole-1-carbothioic acid O-(4-chloro-phenyl)esteracetic acid as light brown viscous oil, MS: 429 (MH+, 1Cl).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]([O:12][CH3:13])=[O:11])=[CH:2]1.Br[C:15]1[S:16][CH:17]=[CH:18][N:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1C(=O)CCC1>[S:16]1[CH:17]=[CH:18][N:19]=[C:15]1[N:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]([O:12][CH3:13])=[O:11])=[CH:2]1
Reactant: Brc1nccs1
Reactant: COC(=O)c1c[nH]c2ncccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COC(=O)c1cn(-c2nccs2)c2ncccc12
Temperature: 130 °C

Procedure:
A mixture of methyl 1H-pyrrolo[2,3-b]pyridine-3-carboxylate (200 mg, 1.135 mmol), 2-bromothiazole (205 μl, 2.271 mmol) and cesium carbonate (1110 mg, 3.41 mmol) in NMP (1135 μl) was heated at 130° C. for 2 h. The mixture was then purified by HPLC to afford the title compound as a brownish-white solid.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[N:23]=[C:22]([CH2:24][S:25]([CH2:28][CH2:29][OH:30])(=[O:27])=[O:26])[CH:21]=[C:20]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][C@@H:32]3[CH3:37])[N:19]=2)=[CH:14][CH:13]=1.C(=O)(O)[O-].[Na+].O>O1CCOCC1>[OH:30][CH2:29][CH2:28][S:25]([CH2:24][C:22]1[CH:21]=[C:20]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][C@@H:32]2[CH3:37])[N:19]=[C:18]([C:15]2[CH:14]=[CH:13][C:12]([NH:11][C:2](=[O:3])[O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:17][CH:16]=2)[N:23]=1)(=[O:26])=[O:27]
Reactant: C[C@H]1COCCN1c1cc(CS(=O)(=O)CCO)nc(-c2ccc(N)cc2)n1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H]1COCCN1c1cc(CS(=O)(=O)CCO)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 123.6 %

Procedure:
Phenyl chloroformate (0.046 mL, 0.36 mmol) was added to 2-[[2-(4-aminophenyl)-6-[(3S)-3-methylmorpholin-4-yl]pyrimidin-4-yl]methylsulfonyl]ethanol (0.143 g, 0.36 mmol) and sodium bicarbonate (0.046 g, 0.55 mmol) in dioxane (20 mL) at RT under air. The resulting slurry was stirred at RT for 2 hours. Water was added and the mixture extracted with DCM three times. The combined organics were dried (MgSO4), filtered and concentrated in vacuo to give the desired material as a yellow solid (0.228 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[CH:11][C:12]=2[S:13]([C:16]([F:19])([F:18])[F:17])(=[O:15])=[O:14])=[CH:4][CH:3]=1.[Br:20]Br>C(Cl)(Cl)Cl>[Br:20][C:10]1[NH:9][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[C:12]([S:13]([C:16]([F:17])([F:19])[F:18])(=[O:14])=[O:15])[CH:11]=1
Reactant: BrBr
Reactant: O=S(=O)(c1cc[nH]c1-c1ccc(Cl)cc1)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=S(=O)(c1cc(Br)[nH]c1-c1ccc(Cl)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.7 %

Procedure:
A solution of 2-(p-chlorophenyl)-3-[(trifluoromethyl)sulfonyl]pyrrole (1.0 g, 0.00323 mol) in chloroform is cooled, treated with a solution of bromine (0.52 g, 0.00323 mol) in chloroform, stirred at room temperature overnight, diluted with chloroform, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a dark syrup. Flash chromatography of the syrup using silical gel and a 1:5 ethyl acetate/hexanes solution gives the title product as an off-white solid (0.31 g, mp 73°-76° C.) which is identified by 1HNMR spectral analysis.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5](OC)=[O:6].O.[NH2:13][NH2:14]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:13][NH2:14])=[O:6]
Reactant: COC(=O)c1cccc(Br)c1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)c1cccc(Br)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
Methyl 3-bromobenzoate (2 g, 9.3 mmol) was dissolved in 25 ml ethanol. Hydrazine hydrate (4.5 ml, 92.9 mmol) was added and the reaction was stirred at 80° C. overnight. The reaction mixture was evaporated under reduced pressure and a white solid was formed. This solid was washed with water and diethyl ether and dried in the vacuum oven to afford 1.8 g (90% yield) of the title compound. Purity 100%.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:8][CH2:7][O:6][CH:5]([C:9]([OH:11])=O)[CH2:4]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:45]1[C:53]2[C:48](=[C:49]([C:54]3[CH:55]=[C:56]([NH2:63])[C:57]4[CH:58]=[N:59][NH:60][C:61]=4[CH:62]=3)[CH:50]=[CH:51][CH:52]=2)[CH:47]=[CH:46]1>CN(C=O)C>[NH:45]1[C:53]2[C:48](=[C:49]([C:54]3[CH:62]=[C:61]4[C:57]([CH:58]=[N:59][NH:60]4)=[C:56]([NH:63][C:9]([CH:5]4[O:6][CH2:7][CH2:8][N:3]([CH3:2])[CH2:4]4)=[O:11])[CH:55]=3)[CH:50]=[CH:51][CH:52]=2)[CH:47]=[CH:46]1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12
Reactant: CN1CCOC(C(=O)O)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCOC(C(=O)Nc2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)C1
Reaction time: 0.08 h

Procedure:
4-Methyl-2-morpholinecarboxylic acid hydrochloride (40 mg, 0.22 mmol) was treated with HATU (84 mg, 0.22 mmol) in DMF (0.250 mL) and DIPEA (0.069 mL, 0.40 mmol). The mixture was shaken for five minutes prior to treatment with 6-(1H-indol-4-yl)-1H-indazol-4-amine (25 mg, 0.1 mmol) in DMF (0.25 mL). Reaction mixture was left to stand at room temperature for 18 hrs. Solvent was removed in vacuo and the product re-dissolved in chloroform (0.3 mL) prior to application on to a pre-conditioned (methanol then chloroform) NH2 cartridge (0.5 g). Product was eluted after 2 hr with ethyl acetate/methanol (1:1, 3 mL), and concentrated under a stream of nitrogen using blow down apparatus. Purification by MDAP (Method D) afforded the title compound.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:13])[CH:11]=2)[C:6]([CH2:14]Br)=[N:5]1)(=[O:3])[CH3:2].Cl.Cl.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:13])[CH:11]=2)[C:6]([CH2:14][N:29]2[CH2:28][CH2:27][N:26]([C:23]3[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][CH:24]=3)[CH2:31][CH2:30]2)=[N:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)n1nc(CBr)c2ccc(F)cc21
Reactant: COc1ccc(N2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N2CCN(Cc3nn(C(C)=O)c4cc(F)ccc34)CC2)cc1
Temperature: 20 °C
Reaction time: 16 h
Yield: 53.3 %

Procedure:
1-Acetyl-3-bromomethyl-6-fluoro-1-H-indazole (0.63 g, 2.33 mmol) in CH2Cl2 (10 mL) was treated with 4-methoxyphenylpiperazine dihydrochloride (0.593 g, 2.33 mmol) and Hunig's base (1.32 mL, 7.5 mmol) and the mixture stirred at 20° C. for 16 h. The mixture was poured into saturated aqueous sodium bicarbonate solution (25 mL) and extracted with CH2Cl2 (3×25 mL). The combined organic extracts were dried (MgSO4), concentrated and the residue purified by flash chromatography (25% EtOAc in hexane) to give the title compound as a white solid (475 mg, 53%); mp 94°-95° C. (from Et2O/hexane); 1H NMR (360 MHz, d6 -DMSO) δ8.12 (dd, J=8.4, 2.9 Hz, 1H, indazole), 8.00 (d, J=9.8 Hz, 1H, indazole), 7.34 (t, J=9.8 Hz, 1H, indazole), 6.87 (d, J=9.2 Hz, 2H, Ph), 6.80 (d, J=9.2 Hz, 2H, Ph), 3.93 (s, 2H, Ar--CH2N), 3.67 (s, 3H, OMe), 3.02 (m, 4H, piperazine), 2.70 (s, 3H, Ac), 2.63 (m, 4H, piperazine); MS (CI+) m/e 383 (M+H+); Anal. calcd for C21H23FN4O2 : C, 65.95; H, 6.06; N, 14.65. Found: C, 66.38; H, 5.79; N, 14.59.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5]/[C:6]/2=[CH:11]\[C:12](Cl)=[O:13].[OH-].[NH4+:16].CCCCCC>ClCCl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5]/[C:6]/2=[CH:11]\[C:12]([NH2:16])=[O:13]
Reactant: [NH4+]
Reactant: O=C(Cl)/C=C1\CCc2c(F)cccc21
Agent: [OH-]
Solvent: CCCCCC
Solvent: ClCCl
Product: NC(=O)/C=C1\CCc2c(F)cccc21
Temperature: 0 °C
Reaction time: 18 h
Yield: 58.1 %

Procedure:
An ice cold solution of (E)-2-(4-fluoro-1-indanylidene)acetyl chloride (2.11 g, 0.01 mol) in dichloromethane (65 mL) was treated with a 30% aqueous solution of ammonium hydroxide (2.63 ml, 0.02 mol), and the mixture was stirred for 18 h. Hexane was added to the mixture, and the solids were collected by filtration to give 1.63 g of crude product. Recrystallization from acetonitrile:water mixtures gave 1.11 g (58%) of (E)-2-(4-fluoro-1-indanylidene)-acetamide as a white solid; m.p., 198-200° C.
Reaction SMILES: [Na].[NH:2]1[C:6]([C:7]2[CH:8]=[CH:9][C:10]3[C:11](=[O:23])[C:12]4[C:17]([S:18](=[O:22])(=[O:21])[C:19]=3[CH:20]=2)=[CH:16][CH:15]=[CH:14][CH:13]=4)=[N:5][N:4]=[N:3]1.Br[CH2:25][C:26]([O:28]CC)=[O:27]>C(O)C>[C:26]([CH2:25][N:4]1[N:3]=[N:2][C:6]([C:7]2[CH:8]=[CH:9][C:10]3[C:11](=[O:23])[C:12]4[C:17]([S:18](=[O:21])(=[O:22])[C:19]=3[CH:20]=2)=[CH:16][CH:15]=[CH:14][CH:13]=4)=[N:5]1)([OH:28])=[O:27]
Reactant: O=C1c2ccccc2S(=O)(=O)c2cc(-c3nnn[nH]3)ccc21
Reactant: CCOC(=O)CBr
Agent: [Na]
Solvent: CCO
Product: O=C(O)Cn1nnc(-c2ccc3c(c2)S(=O)(=O)c2ccccc2C3=O)n1
Reaction time: 2 h

Procedure:
Sodium (0.46 g) was dissolved in ethanol (20 ml) and 3-(5-tetrazolyl)thioxanthone-10,10-dioxide (6.24 g) was added. Ethyl bromoacetate (3.34 g) was added to the mixture, which was boiled under reflux for 1.5 hours. The ester intermediate was deposited during this time, and after cooling was filtered off, washed with water and dried, m.p. 194°-195° C. The ester was boiled with concentrated hydrochloric acid (40 ml) and acetic acid (120 ml) for 2 hr. On cooling 3-(2-carboxymethyl-5-tetrazolyl)thioxanthone-10,10-dioxide crystallised out, and was filtered off, recrystallised from acetic acid, and dried, m.p. 252° C. with decomposition.
Reaction SMILES: [NH2:1][C@@H:2]1[C:17](=[O:18])[N:4]2[C:5]([C:14]([OH:16])=[O:15])=[C:6]([CH2:9]OC(=O)C)[CH2:7][S:8][C@H:3]12.C(=O)(O)[O-].[Na+].[OH-].[Na+].[N-:26]=[N+:27]=[N-:28].[Na+]>CC(C)=O.O>[NH2:1][C@@H:2]1[C:17](=[O:18])[N:4]2[C:5]([C:14]([OH:16])=[O:15])=[C:6]([CH2:9][N:26]=[N+:27]=[N-:28])[CH2:7][S:8][C@H:3]12
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: [N-]=[N+]=NCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.1 %

Procedure:
To 7β-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid (27.2 g, 99.9 mmol) was added water (500 ml) and sodium bicarbonate (9.3 g, 111 mmol); the pH of the mixture was adjusted to 6.5 with 10% sodium hydroxide solution. Sodium azide (13.1 g, 201 mmol) was added to the mixture followed by acetone (350 ml). The mixture was heated at 60° C. for 6h and left stirring at room temperature overnight. Acetone was removed under reduced pressure and the mixture was cooled in an ice-bath, acidified with concentrated hydrochloric acid to pH 3.5; the precipitated solid was filtered off, dried overnight over P205 to give 14.3 g (56%) of 7β-amino-3-azidomethyl-3-cephem-4-carboxylic acid. IR (Nujol) max 2095, 1796, 1732 cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[C:4]([CH2:10][CH2:11]Cl)[CH:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:8][CH:9]=1)[CH2:6][N:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:11][CH2:10]2
Reactant: ClCCc1cc(Cl)ccc1CCl
Reactant: Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Clc1ccc2c(c1)CCN(c1ccccc1)C2

Procedure:
4-chloro-2-(2-chloroethyl)benzyl chloride (5 g), aniline (2.1 g) and triethylamine (5.7 g), were dissolved in chloroform (40 ml) and the mixture heated at reflux for 18 hr. The reaction mixture was cooled and washed with 2M sodium hydroxide solution (100 ml), 2M hydrochloric acid (100 ml) and water (100 ml), then dried (sodium sulphate) and evaporated to dryness in vacuo. The residue was chromatographed on silica gel to give the product, 6-chloro-2-phenyl-1,2,3,4-tetrahydroisoquinoline m.pt. 67°-70°.