Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([N:17]2[CH2:22][CH2:21][C@:20]([CH2:30][CH2:31][N:32](C)[C:33](=O)OC(C)(C)C)([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[O:19][C:18]2=[O:41])[CH3:16])=[CH:11][CH:10]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([N:17]2[CH2:22][CH2:21][C@@:20]([C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)([CH2:30][CH2:31][NH:32][CH3:33])[O:19][C:18]2=[O:41])[CH3:16])=[CH:11][CH:10]=1
Reactant: C[C@@H](c1ccc(-c2ccc(F)cc2F)cc1)N1CC[C@](CCN(C)C(=O)OC(C)(C)C)(c2ccc(F)cc2)OC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)c2ccc(-c3ccc(F)cc3F)cc2)C(=O)O1
Yield: 21.3 %

Procedure:
A solution of tert-butyl 2-((R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)ethyl(methyl)carbamate (73 mg, 0.13 mmol) in TFA/CH2Cl2 (20%, 6 mL) was stirred at 0° C. for 1 h. After the material was consumed, the solution was concentrated to give residue, which was purified by preparative TLC followed by preparative HPLC to give (R)-3-((S)-1-(2′,4′-difluorobiphenyl-4-yl)ethyl)-6-(4-fluorophenyl)-6-(2-(methylamino)ethyl)-1,3-oxazinan-2-one (13 mg, 21%). LC-MS Method 3 tR=1.10, min, m/z=469; 1H NMR (CDCl3): 1.50 (d, 3H), 2.25 (m, 4H), 2.37 (m, 1H), 2.60 (m, 3H), 2.81 (m, 1H), 2.98 (m, 2H) 6.85 (m, 2H), 7.00 (m, 4H), 7.18 (m, 2H), 7.28 (m, 3H).
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[O:11])=[CH:2]1.[C:12]1([Mg]Cl)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[C:12]1([CH:10]([C:3]2[C:4]3[C:5](=[CH:6][N:7]=[CH:8][CH:9]=3)[NH:1][CH:2]=2)[OH:11])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cl[Mg]c1ccccc1
Reactant: O=Cc1c[nH]c2cnccc12
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1c[nH]c2cnccc12
Temperature: -40 °C
Yield: 43 %

Procedure:
A mixture of 1H-pyrrolo[2,3-c]pyridine-3-carboxaldehyde (100 mg, 0.68 mmol) and THF (6.8 mL) was cooled to −40° C. and phenylmagnesium chloride (0.68 mL, 1.36 mmol) was added. The reaction mixture was warmed to room temperature and refluxed for 1 h. The reaction mixture was cooled to room temperature and quenched with saturated NH4Cl and then water was added. The aqueous layer was extracted with EtOAc (1×), dried (MgSO4) and filtered, and the solvent was removed. The crude material was purified by Biotage chromatography (90:10 to 85:15 methylene chloride/methanol) to give phenyl(1H-pyrrolo[2,3-c]pyridin-3-yl)methanol as a yellow solid (65.5 mg, 43%): Rf 0.11 (90:10 methylene chloride/methanol); 1H NMR (300 MHz, CD3OD) (6.09 (1H, s), 7.25-7.27 (1H, m), 7.32-7.35 (3H, m), 7.46-7.48 (3H, m), 7.96-7.97 (1H, d, J=5.6 Hz), 8.64 (1H, s); ESI MS m/z 225 [C14H12N2O+H]+; Estimated Purity: >90% by 1H NMR analysis.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.Cl.Cl.[NH2:37][CH:38]1[CH:43]2[CH2:44][CH2:45][N:40]([CH2:41][CH2:42]2)[CH2:39]1.C(N(CC)CC)C>C(#N)C.CN(C1C=CN=CC=1)C>[N:40]12[CH2:45][CH2:44][CH:43]([CH2:42][CH2:41]1)[CH:38]([NH:37][C:17]([C:16]1[C:10]3[O:9][C:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[N:12][C:11]=3[CH:13]=[CH:14][CH:15]=1)=[O:19])[CH2:39]2
Reactant: NC1CN2CCC1CC2
Reactant: O=C(O)c1cccc2nc(-c3ccc(F)cc3)oc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(NC1CN2CCC1CC2)c1cccc2nc(-c3ccc(F)cc3)oc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.2 %

Procedure:
A solution of 2-(4-fluorophenyl)benzoxazole-7-carboxylic acid (0.100 g, 0.39 mmol) in acetonitrile (10 mL) was treated with DCC (0.089 g, 0.43 mmol) and the mixture stirred at room temperature for 1 h. After this time a thick granular precipitate had formed. 3-Aminoquinuclidine dihydrochloride (0.086 g, 0.43 mmol) and DMAP (0.010 g, 0.08 mmol) were then added to the reaction followed by the dropwise addition of triethylamine (0.10 g, 1.00 mmol) over 15 min. The reaction was then stirred at room temperature overnight. Subsequent concentration of the reaction mixture and purification of the resulting solid residue by column chromatography afforded 0.100 g (70% yield) of N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-fluorophenyl)benzoxazole-7-carboxamide as a white solid: mp 185-187° C.; 1H NMR (500 MHz, DMSO-d6) δ 8.46 (d, J=6.7 Hz, 1H), 8.24 (m, 2H), 7.95 (m, 1H), 7.70 (m, 1H), 7.51 (m, 3H), 4.06 (m, 1H), 3.21 (m, 1H), 2.92 (m, 1H), 2.74 (m, 4H), 1.96 (m, 2H), 1.64 (m, 2H), 1.44 (m, 1H); MS (ESI) m/z 366 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14]OC.CN(C)C=O.[CH3:22][N:23]([CH3:28])[CH2:24][CH2:25][CH2:26][NH2:27]>CCOCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:27][CH2:26][CH2:25][CH2:24][N:23]([CH3:28])[CH3:22]
Reactant: CN(C)CCCN
Reactant: COC=C1C(=O)NC(=O)c2ccc(Br)cc21
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CN(C)CCCN/C=C1\C(=O)NC(=O)c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
A mixture of 6-bromo-4-(methoxymethylene)-isoquinoline-1,3(2H,4H)-dione (70.5 mg, 0.25 mmole), dimethylformamide (2 mL) and N1,N1-dimethylpropane-1,3-diamine (25.6 mg, 0.25 mmole) is stirred at room temperature for one hour. The reaction mixture is diluted with ether, filtered and washed with fresh ether and dried to give a light brown solid, 65.8 mg, (66% yield) MS (ES+): 352.2, (M+H).
Reaction SMILES: C([BH3-])#[N:2].[Na+].[CH2:5]([N:7]([CH2:22][CH3:23])[CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=O)[CH2:18][CH2:19][CH3:20])=[CH:13][CH:12]=1)[CH3:6].C([O-])(=O)C.[NH4+]>CO.C(OCC)(=O)C>[CH2:5]([N:7]([CH2:22][CH3:23])[CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]([NH2:2])[CH2:18][CH2:19][CH3:20])=[CH:13][CH:12]=1)[CH3:6]
Reactant: CCCC(=O)c1ccc(OCCN(CC)CC)cc1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCC(N)c1ccc(OCCN(CC)CC)cc1
Temperature: 40 °C
Yield: 59.4 %

Procedure:
Sodium cyanoborohydride (155 mg, 3.5 mmol) was added to a suspension of 1-(4-(2-(diethylamino)ethoxy)phenyl)butan-1-one (21; 186 mg, 0.7 mmol) and ammonium acetate (1.63 g, 21.2 mmol) in methanol (2 mL). The resulting mixture was then heated at 40° C. for 72 hours. The reaction mixture was diluted with ethyl acetate, washed with sat. aqueous NaHCO3 (2×) and sat. brine, dried over sodium sulfate and concentrated to give crude 25 (110 mg, 59%) as a yellow oil: MS (ES+) m/z 265.1 (M+H)+. This material was taken to the next step without further purification.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]([CH3:38])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]([S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH3:20])=[C:15]([C:30]#[C:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:14]=1)=[O:11])C)(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:24]1([S:21]([N:19]([CH3:20])[C:16]2[CH:17]=[CH:18][C:13]([NH:12][C:10](=[O:11])[CH:9]([NH:7][CH3:6])[CH3:38])=[N:14][C:15]=2[C:30]#[C:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)(=[O:22])=[O:23])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C(=O)Nc1ccc(N(C)S(=O)(=O)c2ccccc2)c(C#Cc2ccccc2)n1)N(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(C)C(=O)Nc1ccc(N(C)S(=O)(=O)c2ccccc2)c(C#Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of tert-butyl-N-[1-[[5-[benzenesulfonyl(methyl)amino]-6-(2-phenylethynyl)pyridin-2-yl]amino]-1-oxopropan-2-yl]-N-methylcarbamate F5a (25 mg) and DCM:TFA (9:1, 3 ml) is stirred at RT for 2 h. The mixture is diluted with DCM and extracted with a saturated aqueous solution of NaHCO3. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by RP HPLC. Yield: 7 mg. HPLC-MS: M+H=449; tR=1.49 min (*Method—1).
Reaction SMILES: CO[C@H]1CC[C@H](C[N:10]2C(=O)CNC3N=CC(C4C(C)=CC(C(N)=O)=NC=4)=[N:20][C:11]2=3)CC1.[CH3:31][O:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([CH2:39][N:40]2[C:45](=[O:46])[CH2:44][NH:43][C:42]3[N:47]=[CH:48][C:49]([C:51]4[C:52]([CH3:59])=[CH:53][C:54]([C:57]#[N:58])=[N:55][CH:56]=4)=[N:50][C:41]2=3)[CH2:35][CH2:34]1.FC(F)(F)C(O)=O.S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:31][O:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([CH2:39][N:40]2[C:41]3=[N:50][C:49]([C:51]4[CH:56]=[N:55][C:54]([C:57]5[N:20]=[CH:11][NH:10][N:58]=5)=[CH:53][C:52]=4[CH3:59])=[CH:48][N:47]=[C:42]3[NH:43][CH2:44][C:45]2=[O:46])[CH2:35][CH2:34]1
Reactant: CO[C@H]1CC[C@H](CN2C(=O)CNc3ncc(-c4cnc(C(N)=O)cc4C)nc32)CC1
Reactant: CO[C@H]1CC[C@H](CN2C(=O)CNc3ncc(-c4cnc(C#N)cc4C)nc32)CC1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CO[C@H]1CC[C@H](CN2C(=O)CNc3ncc(-c4cnc(-c5nc[nH]n5)cc4C)nc32)CC1
Temperature: 65 °C

Procedure:
5-(8-(((trans)-4-Methoxycyclohexyl)methyl)-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin-2-yl)-4-methylpicolinamide. 5-(8-(((trans)-4-Methoxycyclohexyl)methyl)-7-oxo-5,6,7,8-tetrahydropyrazino[2,3-b]pyrazin -2-yl)-4-methylpicolinonitrile (0.607 g, 1.55 mmol), trifluoroacetic acid (2.0 mL, 26.0 mmol) and sulfuric acid (0.5 mL, 9.38 mmol) were combined and heated at 65° C. for 1 h. Reaction pH was adjusted to 10 with sodium carbonate and the resulting solution was extracted with ethyl acetate (3×15 mL). Organic layers were collected, dried over magnesium sulfate, concentrated and purified using reverse-phase preparatory HPLC (10-100% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min). Clean fractions were combined and condensed under reduced pressure and dried under high vacuum to afford the title compound as a yellow solid (0.425 g, 1.04 mmol, 67% yield). MS (ESI) m/z 411.5 [M+1]+.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].C(OC([NH:27][CH:28]1[CH2:32][CH2:31][NH:30][CH2:29]1)=O)(C)(C)C.N12CCCN=C1CCCCC2>C(#N)C>[NH2:27][CH:28]1[CH2:32][CH2:31][N:30]([C:2]2[N:11]=[C:10]3[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]3[CH:12]3[CH2:14][CH2:13]3)=[CH:4][C:3]=2[F:19])[CH2:29]1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: NC1CCN(c2nc3c(cc2F)c(=O)c(C(=O)O)cn3C2CC2)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 97.8 %

Procedure:
A suspension of 5.65 g (20 mmole) of 7-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 4.65 g (25 mmole) of 3-t-butoxycarbonylaminopyrrolidine, 7.9 g (50 mmole) of 1,8-diazabicyclo[5.4.0]undec-7-ene and 150 ml of acetonitrile was stirred at 60° C. for one hour. The solvent was removed in vacuo and the residue was dissolved in 100 ml of trifluoroacetic acid. After stirring at room temperature for one hour, the solvent was removed in vacuo and the residue was suspended in water and the pH adjusted to 11.5 with 50% sodium hydroxide. After filtering through a fiber glass pad to clarify, the filtrate was acidified to 6.6 with 6M hydrochloric acid. The resulting precipitate was removed by filtration, washed with water, 2-propanol, ether and dried in vacuo to give 6.5 g (98%) of the title compound, mp 284°-286° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]=[CH2:9])=[N:6][CH:7]=1.[C:10]([N+:14]#[C-:15])([CH3:13])([CH3:12])[CH3:11]>CO.FC(F)(F)C(O)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:15]([NH:14][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:9][N:8]=2)[CH:7]=1
Reactant: C=Nc1ccc(Br)cn1
Reactant: [C-]#[N+]C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: CC(C)(C)Nc1cnc2ccc(Br)cn12
Temperature: 25 °C
Yield: 78 %

Procedure:
To a suspension of 5-bromo-N-methylenepyridin-2-amine (0.85 g, 4.6 mmol) in methanol (20 mL) was added tert-butyl isocyanide (1.14 mL, 10.1 mmol) and trifluoroacetic acid (˜3 drops). The reaction mixture was heated at reflux for 2 h, after which point a clear solution was obtained. The mixture was allowed to cool to ambient temperature and was concentrated in vacuo. The residue was purified by column chromatography eluting with a 0-100% gradient ethyl acetate in hexanes to afford 6-bromo-N-(tert-butyl)imidazo[1,2-a]pyridin-3-amine as a beige solid in 78% yield (0.956 g): 1H NMR (300 MHz, CDCl3) δ8.31 (br s, 1H), 7.41-7.33 (m, 1H), 7.29 (s, 1H), 7.17-7.10 (m, 1H), 2.70 (br s, 1H), 1.16 (s, 9H); MS (ES+) m/z 267.9 (M+1), 270.0 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([C:16]2[CH:38]=[CH:37][C:19]3[N:20]([CH3:36])[C:21]([C:23]4[N:33]([CH2:34][CH3:35])[C:26]5=[N:27][CH:28]=[C:29]([O:31][CH3:32])[CH:30]=[C:25]5[CH:24]=4)=[N:22][C:18]=3[CH:17]=2)=[O:15])[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([C:16]2[CH:38]=[CH:37][C:19]3[N:20]([CH3:36])[C:21]([C:23]4[N:33]([CH2:34][CH3:35])[C:26]5=[N:27][CH:28]=[C:29]([O:31][CH3:32])[CH:30]=[C:25]5[CH:24]=4)=[N:22][C:18]=3[CH:17]=2)=[O:15])[CH2:9]1
Reactant: CCn1c(-c2nc3cc(C(=O)N4CCC[C@@H](NC(=O)OC(C)(C)C)C4)ccc3n2C)cc2cc(OC)cnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCn1c(-c2nc3cc(C(=O)N4CCC[C@@H](N)C4)ccc3n2C)cc2cc(OC)cnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.8 %

Procedure:
To a stirred solution of (R)-tert-butyl(1-(2-(1-ethyl-5-methoxy-1H-pyrrolo[2,3-b]pyridin-2-yl)-1-methyl-1H-benzo[d]imidazole-5-carbonyl)piperidin-3-yl)carbamate (24 mg, 0.045 mmol) in DCM (2 mL) was added TFA (2 mL, 26.0 mmol) dropwise with continuous stirring. The reaction was stirred at room temperature under nitrogen for 1 h. The reaction mixture was concentrated in vacuo before being dissolved in MeOH and purified by SPE on sulfonic acid (SCX) 1 g, first washing with MeOH and then eluting using a 10% NH3/MeOH solution to give the free base of the product. The appropriate fractions were combined and evaporated in vacuo before being azeotroped with cyclohexane to give the title compound as a pale yellow solid (13 mg).
Reaction SMILES: CS(O[CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([NH:13][C:14]2[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][N:17]=[C:16]3[CH:23]=[CH:24][S:25][C:15]=23)[CH2:9][CH2:8]1)(=O)=O.[C-:26]#[N:27].[Na+]>CS(C)=O.CCOC(C)=O>[N+:20]([C:19]1[C:14]([NH:13][C@H:10]2[CH2:11][CH2:12][C@H:7]([CH2:6][C:26]#[N:27])[CH2:8][CH2:9]2)=[C:15]2[S:25][CH:24]=[CH:23][C:16]2=[N:17][CH:18]=1)([O-:22])=[O:21]
Reactant: CS(=O)(=O)OC[C@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3ccsc23)CC1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#CC[C@H]1CC[C@H](Nc2c([N+](=O)[O-])cnc3ccsc23)CC1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
A mixture of {trans-4-[(6-nitrothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}methyl methanesulfonate (0.20 g, 0.52 mmol) and sodium cyanide (0.057 g, 1.2 mmol) in dimethyl sulfoxide (2 mL) was stirred at 90° C. for 4 h. After diluting with EtOAc, the resulting mixture was washed with sat. NaHCO3 solution, water and brine, then concentrated. The residue was purified on silica gel (eluting with 0 to 5% MeOH in dichloromethane) to give the desired product. LCMS calculated for C15H17N4O2S (M+H)+: m/z=317.1. Found: 317.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5][OH:6].[C:11](Cl)([Cl:13])=[O:12]>>[Cl:13][C:11]([O:6][CH2:5][C:4]1[CH:3]=[C:2]([F:1])[CH:9]=[C:8]([F:10])[CH:7]=1)=[O:12]
Reactant: OCc1cc(F)cc(F)c1
Reactant: O=C(Cl)Cl
Product: O=C(Cl)OCc1cc(F)cc(F)c1

Procedure:
Prepared according to the procedure described in Example 56, Step 1, using the following starting materials: 3,5-difluorobenzyl alcohol and phosgene (20% in toluene).
Reaction SMILES: C([C@@:4]1([OH:29])[C@:8](C(=O)C)([OH:9])[C@@H:7]([CH2:13][O:14]C(=O)C)[O:6][C@H:5]1[N:18]1[CH:26]=[N:25][C:24]2[C:19]1=[N:20][C:21]([Cl:28])=[N:22][C:23]=2Cl)(=O)C.[OH-].[NH4+:31]>O1CCCC1>[Cl:28][C:21]1[N:22]=[C:23]([NH2:31])[C:24]2[N:25]=[CH:26][N:18]([C:19]=2[N:20]=1)[C@@H:5]1[O:6][C@H:7]([CH2:13][OH:14])[C@@H:8]([OH:9])[C@H:4]1[OH:29]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@@](O)(C(C)=O)[C@@]1(O)C(C)=O
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of the compound of Example 3 (271 g, 606 M), concentrated ammonium hydroxide (4 L) and tetrahydrofuran (0.5 L) is stirred at room temperature under nitrogen for 4 days. The solvent volume is reduced in vacuo and the resulting residue is triturated with absolute ethanol. The title compound is precipitated out of the ethanolic solvent to yield a light brown solid, (159 g, 87%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[C:12]1[N:20]([S:21]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[CH:13]=1.[H-].[Na+].Cl[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>CN(C)C=O>[CH2:38]([O:37][C:35](=[O:36])[CH2:34][N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[C:6]([C:12]2[N:20]([S:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)(=[O:23])=[O:22])[C:15]3=[N:16][CH:17]=[CH:18][CH:19]=[C:14]3[CH:13]=2)=[CH:7]1)[CH3:39]
Reactant: CCOC(=O)CCl
Reactant: COc1ccc2[nH]cc(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cc(-c2cc3cccnc3n2S(=O)(=O)c2ccc(C)cc2)c2cc(OC)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.5 %

Procedure:
A solution of 2-(5-methoxy-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine [6.6 g, Reference Example 12(a)] in dimethylformamide (100 mL), under a nitrogen atmosphere, was treated with sodium hydride (700 mg, 60% dispersion in oil). After stirring at ambient temperature for 30 minutes the mixture was treated dropwise with ethyl chloroacetate (2.0 mL, 23.75 mmol) and stirring was continued for an additional 4 hours. The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, then dried over sodium sulfate and then evaporated to give the title compound (5.77 g) as a yellow solid, MS: 504(MH+). HPLC (METHOD A):: RT=11.88 minutes.
Reaction SMILES: [NH2:1][CH:2]1[C:24](=[O:25])[N:4]2[C:5]([C:17]([O:19]C(C)(C)C)=[O:18])=[C:6]([CH2:9][S:10][C:11]3[S:12][C:13]([CH3:16])=[N:14][N:15]=3)[CH2:7][S:8][C@H:3]12.[C:26]([CH2:28][S:29]([CH2:32][C:33](O)=[O:34])(=[O:31])=[O:30])#[N:27].C1(N=C=NC2CCCCC2)CCCCC1>>[C:26]([CH2:28][S:29]([CH2:32][C:33]([NH:1][CH:2]1[C:24](=[O:25])[N:4]2[C:5]([C:17]([OH:19])=[O:18])=[C:6]([CH2:9][S:10][C:11]3[S:12][C:13]([CH3:16])=[N:14][N:15]=3)[CH2:7][S:8][C@H:3]12)=[O:34])(=[O:31])=[O:30])#[N:27]
Reactant: N#CCS(=O)(=O)CC(=O)O
Reactant: Cc1nnc(SCC2=C(C(=O)OC(C)(C)C)N3C(=O)C(N)[C@H]3SC2)s1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)CS(=O)(=O)CC#N)[C@H]3SC2)s1
Reaction time: 2.5 h

Procedure:
t-Butyl 7-amino-3-(5-methyl-1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylate (8.0 g, 20 mmol), cyanomethylsulfonylacetic acid (3.3 g, 20 mmol) and dicyclohexylcarbodiimide (4.1 g. 20 mmol) were reacted by the procedure of Example 5. The crude ester was chromatographed on silica gel using ethyl acetate as eluent. The purified t-butyl ester (6.2 g) was dissolved in hot acetonitrile (40 ml) and trifluoroacetic acid (40 ml) was added. The solution was allowed to stand 2.5 hours and then was added slowly to ether (100 ml) with stirring. The precipitated title compound was collected, triturated with ether and dried.
Reaction SMILES: CCN(CC)CC.Br[CH2:9][CH2:10][OH:11].[OH:12][C@@H:13]1[C:29]([CH3:31])([CH3:30])[C:28](=[O:32])[C@H:27]([CH3:33])[C@@H:26]([OH:34])[C@@H:25]([CH3:35])[CH2:24][CH2:23][CH2:22][C@@H:21]2[C@@H:19]([NH:20]2)[CH2:18][C@@H:17](/[C:36](/[CH3:44])=[CH:37]/[C:38]2[N:39]=[C:40]([CH3:43])[S:41][CH:42]=2)[O:16][C:15](=[O:45])[CH2:14]1>C(#N)C>[OH:12][C@@H:13]1[C:29]([CH3:31])([CH3:30])[C:28](=[O:32])[C@H:27]([CH3:33])[C@@H:26]([OH:34])[C@@H:25]([CH3:35])[CH2:24][CH2:23][CH2:22][C@@H:21]2[C@@H:19]([N:20]2[CH2:9][CH2:10][OH:11])[CH2:18][C@@H:17](/[C:36](/[CH3:44])=[CH:37]/[C:38]2[N:39]=[C:40]([CH3:43])[S:41][CH:42]=2)[O:16][C:15](=[O:45])[CH2:14]1
Reactant: OCCBr
Reactant: C/C(=C\c1csc(C)n1)[C@@H]1C[C@@H]2N[C@@H]2CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C/C(=C\c1csc(C)n1)[C@@H]1C[C@H]2[C@@H](CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1)N2CCO
Temperature: 72.5 °C
Reaction time: 20 h
Yield: 68.2 %

Procedure:
Et3N (4.95 mL, 35.52 mmol) and 2-bromoethanol (3.02 mL, 42.62 mmol) were added to (1S,3S,7S,10R,11S,12S,16R)-7,11-dihydroxy-8,8,10,12-tetramethyl-3-((E)-1-(2-methylthiazol-4-yl)prop-1-en-2-yl)-4-oxa-17-azabicyclo[14.1.0]heptadecane-5,9-dione (3.50 g, 7.10 mmol) in acetonitrile (35 mL) and heated to 72.5° C. After 20 hr, the reaction mixture was cooled to room temperature, concentrated to dryness through rotary vacuum distillation. The crude was dissolved in ethyl acetate (50 mL) and mixed with deionized water (35 mL). The mixture was extracted with ethyl acetate (3×35 mL), dried over Na2SO4, filtered, concentrated, crystallized in acetonitrile (35 mL), washed with acetonitrile (2×5 mL), and dried in vacuum oven at 45.5° C. overnight to isolate (1S,3S,7S,10R,11S,12S,16R)-7,11-dihydroxy-17-(2-hydroxyethyl)-8,8,10,12-tetramethyl-3-((E)-1-(2-methylthiazol-4-yl)prop-1-en-2-yl)-4-oxa-17-azabicyclo[14.1.0]heptadecane-5,9-dione as a white crystalline powder (2.60 g, HPLC AP 97.1, 68.2% yield).
Reaction SMILES: [CH:1]([C:3]1[CH:14]=[CH:13][C:6]([CH:7]=[CH:8][C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1)=O.Cl.[NH2:16][OH:17].C([O-])(=O)C.[Na+]>CO.O>[OH:17][N:16]=[CH:1][C:3]1[CH:14]=[CH:13][C:6]([CH:7]=[CH:8][C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1
Reactant: NO
Reactant: COC(=O)C=Cc1ccc(C=O)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)C=Cc1ccc(C=NO)cc1
Reaction time: 8 h

Procedure:
4.0 g of methyl 4-formylcinnamate are dissolved in 40 ml methanol and then 1.6 g hydroxylamine-hydrochloride and 1.9 g sodium acetate are added. The mixture is stirred overnight and then diluted with 300 ml water. The precipitate is filtered by suction, dried in vacuo and crystallized from ethyl acetate/petrolether. This gives 3.56 g of the title compound.
Reaction SMILES: [C:1]([CH2:3][C@@H:4]1[CH2:8][C@H:7]([NH:9][C:10]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH:21]([CH3:23])[CH3:22])[N:13]=2)=[O:11])[CH2:6][N:5]1[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])#[N:2].[OH-].[NH4+]>CO.[Ni]>[NH2:2][CH2:1][CH2:3][C@@H:4]1[CH2:8][C@H:7]([NH:9][C:10]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH:21]([CH3:23])[CH3:22])[N:13]=2)=[O:11])[CH2:6][N:5]1[C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25]
Reactant: CC(C)n1nc(C(=O)N[C@H]2C[C@@H](CC#N)N(C(=O)OC(C)(C)C)C2)c2ccccc21
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: CC(C)n1nc(C(=O)N[C@H]2C[C@@H](CCN)N(C(=O)OC(C)(C)C)C2)c2ccccc21
Yield: 28.5 %

Procedure:
The mixture of tert-butyl (2S,4S)-2-(cyanomethyl)-4-{[(1-isopropyl-1H-indazol-3-yl)carbonyl]amino}pyrrolidine-1-carboxylate (0.40 g, 0.97 mmol, Step 1 of Example 19) and catalytic Raney-Ni in methanol (16 mL) and 25% ammonium hydroxide (4.0 mL) was stirred under hydrogen (4 atom) at room temperature for 7 h. The mixture was filtered through a pad of Celite. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate 1:1 to dichloromethane/methanol 10:1) to give 115 mg (65%) of the title compound as a colorless oil.