Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:43])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C@@H:13]2[NH:17][C@@H:16]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C@:15]3([C:30]4[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=4)[NH:24][C:23]3=[O:32])[C@H:14]2[C:33]2[CH:38]=[C:37]([F:39])[CH:36]=[C:35]([Cl:40])[CH:34]=2)=[O:12])=[C:6]([O:41][CH3:42])[CH:5]=1.[OH-].[Na+].Cl>CO.C1COCC1.O>[Cl:31][C:27]1[CH:26]=[C:25]2[NH:24][C:23](=[O:32])[C@:15]3([C@@H:14]([C:33]4[CH:38]=[C:37]([F:39])[CH:36]=[C:35]([Cl:40])[CH:34]=4)[C@H:13]([C:11]([NH:10][C:7]4[CH:8]=[CH:9][C:4]([C:3]([OH:43])=[O:2])=[CH:5][C:6]=4[O:41][CH3:42])=[O:12])[NH:17][C@H:16]3[CH2:18][C:19]([CH3:21])([CH3:20])[CH3:22])[C:30]2=[CH:29][CH:28]=1
Reactant: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Cl)ccc43)[C@H]2c2cc(F)cc(Cl)c2)c(OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@@]2(C(=O)Nc3cc(Cl)ccc32)[C@H]1c1cc(F)cc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of rac-4-{[(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-5-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-3-methoxy-benzoic acid methyl ester (0.17 g, 0.27 mmol) in MeOH (3 mL) and THF (9 mL) was added an aqueous solution (1N) of NaOH (6 mL, 6 mmol). The reaction mixture was stirred at room temperature for 18 h. The crude mixture was diluted with water (5 mL), and acidified to “pH” 5-6 by dilute aqueous HCl solution. The mixture was then extracted with ethyl acetate three times. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated. The residue was triturated with dichlormethane and hexanes to give rac-4-{[(2′S,3′R,4′R,5′R)-6-chloro-4′-(3-chloro-5-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]amino}-3-methoxy-benzoic acid as a white powder (Yield, 0.14 g, 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]([CH:17]=1)[C:7](=[O:16])[CH:8]=[CH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:17]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:18][CH:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:8][C:7]2=[O:16]
Reactant: O=C(C=Cc1ccccc1)c1cc(Cl)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C1CC(c2ccccc2)Oc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
5'-Chloro-2'-hydroxychalcone (25.0 g) was dissolved in ethanol (125 ml.) and and aqueous solution of 1.5% sodium hydroxide (375 ml.) was added. The mixture was stirred at room temperature for 4 hrs. and the solid filtered off, washed with water and dried to give 6-chloroflavanone (16.65. g), mp. 90°-93° C. A sample recrystallised from 60°-80° C. petroleum ether had m.pt 95°-96° C. The flavanone (4.0 g) was dissolved in acetic acid (160 ml.) and concentrated hydrochloric acid (20 ml.) and added to amalgamated zinc (from zinc dust (40 g.) and mercuric chloride (0.5 g). The mixture was stirred for 1 hr., and allowed to stand overnight. The residual zinc was filtered off, and the filtrate diluted with water. The oily precipitate was extracted into either and the extract washed with water and saturated sodium bicarbonate solution, dried over magnesium sulphate, filtered and evaporated. The residue was chromatographed on alkaline alumina, eluting with 60°-80° C. petroleum either, to give 6-chloroflavan (0.52 g.), m.p. 71°-72° C.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][O:6][CH2:7][C:8]2[N:13]=[C:12]([NH2:14])[CH:11]=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[Cl:15][C:16]1[CH:17]=[C:18]([S:22](Cl)(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=1>>[Cl:15][C:16]1[CH:17]=[C:18]([S:22]([NH:14][C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([CH2:7][O:6][CH2:5][CH2:4][CH:1]3[CH2:3][CH2:2]3)[N:13]=2)(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: Nc1cccc(COCCC2CC2)n1
Product: O=S(=O)(Nc1cccc(COCCC2CC2)n1)c1cccc(Cl)c1

Procedure:
This material was prepared in analogy to example 1 from 6-(2-cyclopropyl-ethoxymethyl)-pyridin-2-ylamine (0.08 g) and 3-chloro-benzenesulfonyl chloride (0.095 g) as a light yellow gum (0.096 g). MS (ESI−): 365.0 ([M−H]−).
Reaction SMILES: C(C1C=C(B(O)O)C=CC=1)(=O)C.Br[C:14]1[CH:15]=[CH:16][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[N:18][CH:19]=1.C(NC(C1C(=O)C2C(=NC=CC=2)[N:32]([C:41]2[CH:46]=[CH:45][CH:44]=[C:43](Br)[CH:42]=2)C=1)=O)(C)C>>[NH2:32][C:41]1[CH:42]=[C:43]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[N:18][CH:19]=2)[CH:44]=[CH:45][CH:46]=1
Reactant: CC(C)NC(=O)c1cn(-c2cccc(Br)c2)c2ncccc2c1=O
Reactant: CC(C)(O)c1ccc(Br)cn1
Agent: CC(=O)c1cccc(B(O)O)c1
Product: CC(C)(O)c1ccc(-c2cccc(N)c2)cn1

Procedure:
Following the procedure of Step 5 of Example 1, but substituting 3-aminophenylboronic acid for 3-acetyl phenylboronic acid and 5-bromo-2-(1-hydroxy-1-methylethyl)pyridine from Step 1 of Example 30 for N-isopropyl-1-(3-bromophenyl)-1,4-dihydro[1,8]naphthyridin-4-one-3-carboxamide, the 5-(3-Aminophenyl)-2-(1-hydroxy-1-methylethyl)pyridine compound was obtained as a solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[CH3:13][S:14](Cl)(=[O:16])=[O:15]>C(Cl)Cl>[CH3:13][S:14]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:11][CH:12]=1)(=[O:16])=[O:15]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(CN)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(CNS(C)(=O)=O)cc1
Yield: 45.1 %

Procedure:
By the procedure outlined in scheme example 929, starting from 4-(aminomethyl)benzoic acid (2.00 g, 13.24 mmol) was treated with sulfuric acid to form methyl 4-(aminomethyl)benzoate (1.20 g, 55%). Methyl 4-(aminomethyl)benzoate (0.600 g, 3.63 mmol) was treated with methanesulfonyl chloride (0.832 g, 7.26 mmol)) in DCM (20 ml) to give crude methyl 4-{[(methylsulfonyl)amino]methyl}benzoate (0.398 g, 45%). Methyl 4-{[(methylsulfonyl)amino]methyl}benzoate (0.398 g, 1.63 mmol) was treated with NaOH and methanol to give 4-{[(methylsulfonyl)amino]methyl}benzoic acid hydrochloride (0.370 g, 98%). The title compound, N-({4-[(4-(3-fluorophenyl)-4-{2-[(1R,5S)-3-(2-methyl-1H-benzimidazol-1-yl)-8-azabicyclo[3.2.1]oct-8-yl]ethyl}-1-piperidinyl)carbonyl]phenyl}methyl) methanesulfonamide (0.128 g, 50%) was obtained as a oil from 4-{[(methylsulfonyl)amino]methyl}benzoic acid hydrochloride (0.132 g, 0.461), 1-(8-{2-[4-(3-Fluoro-phenyl)-piperidin-4-yl]-ethyl}-8-aza-bicyclo[3.2.1]oct-3-yl)-2-methyl-1H-enzoimidazole dihydrochloride (0.200 g, 0.39 mmol) and HATU (0.150 g, 0.46 mmol) following the procedure outlined in example 5. ES-LCMS m/z 658 (M+1).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([F:14])([F:13])[F:12])=O.[CH3:15][O:16][C:17](=[O:25])[CH2:18][CH2:19][CH2:20][CH2:21][C:22](=[O:24])[NH2:23]>O>[CH3:15][O:16][C:17](=[O:25])[CH2:18][CH2:19][CH2:20][CH2:21][C:22]1[O:24][CH:2]=[C:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:11]([F:14])([F:13])[F:12])[N:23]=1
Reactant: O=C(CBr)c1ccccc1C(F)(F)F
Reactant: COC(=O)CCCCC(N)=O
Solvent: O
Product: COC(=O)CCCCc1nc(-c2ccccc2C(F)(F)F)co1

Procedure:
Combine 2-bromo-1-(2-trifluoromethyl-phenyl)-ethanone (6.6 g, 24.7 mmol) with 5-carbamoyl-pentanoic acid methyl ester (7.8 g, 49 mmol) and heat the neat mixture in a sealed vessel at 140-150° C. for about 4.5 hours. Cool the mixture, dilute with water, and extract with EtOAc. Dry the combined extracts over Na2SO4 and concentrate. Chromatography over silica gel (CH2Cl2) allows for recovery of 5-[4-(2-trifluoromethyl-phenyl)-oxazol-2-yl]-pentanoic acid methyl ester (3.47 g, 43%). MS (ES): (M+1)+ 328.2
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]([NH:6][CH2:7][CH2:8][NH:9][C:10](=[O:32])[CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21]/[CH:22]=[CH:23]\[CH2:24]/[CH:25]=[CH:26]\[CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH3:31])=[O:5].C(OC([NH:40][C:41](=NC(=O)OC(C)(C)C)[N:42]1C=CC=N1)=O)(C)(C)C.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[CH3:1][N:2]([CH2:3][C:4]([NH:6][CH2:7][CH2:8][NH:9][C:10](=[O:32])[CH2:11][CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21]/[CH:22]=[CH:23]\[CH2:24]/[CH:25]=[CH:26]\[CH2:27]/[CH:28]=[CH:29]\[CH2:30][CH3:31])=[O:5])[C:41]([NH2:42])=[NH:40]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCCNC(=O)CNC
Reactant: CC(C)(C)OC(=O)N=C(NC(=O)OC(C)(C)C)n1cccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCCNC(=O)CN(C)C(=N)N
Temperature: 25 °C
Reaction time: 24 h
Yield: 43 %

Procedure:
(4Z,7Z,10Z,13Z,16Z,19Z)—N-(2-(2-(Methylamino)acetamido)ethyl)docosa-4,7,10,13,16,19-hexaenamide (416 mg, 1.2 mmol) was taken up in 10 mL of DMF along with tert-butyl (((tert-butoxycarbonyl)amino)(1H-pyrazol-1-yl)methylene)carbamate (154 mg, 1.2 mmol) and DIEA (154 mg, 1.2 mmol). The resulting reaction mixture was stirred at room temperature for 24 h. It was then diluted with EtOAc and washed with water. The organic layer was washed with brine, dried (Na2SO4) and concentrated under reduced pressure. Purification by silica gel chromatography (pentane/EtOAc) afforded 350 mg of the di-Boc derivative of (4Z,7Z,10Z,13Z,16Z,19Z)—N-(2-(2-(1-methylguanidino)acetamido)ethyl)docosa-4,7,10,13,16,19-hexaenamide (43% yield). MS (EI) calcd for C32H51N3O4 541.39. found 542 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=1.Cl.[CH2:17]([O:20][NH2:21])[CH:18]=[CH2:19].[OH-].[Na+]>O1CCOCC1.O>[CH2:17]([O:20][NH:21][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=1)[CH:18]=[CH2:19]
Reactant: C=CCON
Reactant: CCCNc1nc(Cl)nc(NCCC)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: C=CCONc1nc(NCCC)nc(NCCC)n1
Temperature: 60 °C
Yield: 88.4 %

Procedure:
A mixture of 2-chloro-N-(4,6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV) (2.00 g, 8.71 mmol), O-allyl-hydroxylamine hydrochloride (1.91 g, 17.42 mmol) and NaOH (0.70 g, 17.42 mmol) in 1,4-dioxane (25 mL) and water (5 mL) was heated at 60° C. for 4 h. The volatiles were removed under reduced pressure. Saturated NaHCO3 solution (100 mL) was added to the residue and the mixture was extracted with EtOAc (3×25 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography using gradient elution from CH2Cl2/EtOH (99:1) to CH2Cl2/EtOH (95:5) to yield O-allyl-N-(4,6-bis-propylamino-[1,3,5]triazin-2-yl)-hydroxylamine (XLIII, 2.05 g, 88% yield). ESI-MS (m/z) 267 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[C@H:27]([CH2:28][OH:29])[CH2:26][CH2:25][S:24]3(=[O:31])=[O:30])=[CH:19][C:18]=2[F:32])=[O:16])[CH2:11][CH2:10]1.S(C1C=CC(C)=CC=1)(O[CH3:37])(=O)=O>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[C@H:27]([CH2:28][O:29][CH3:37])[CH2:26][CH2:25][S:24]3(=[O:30])=[O:31])=[CH:19][C:18]=2[F:32])=[O:16])[CH2:13][CH2:14]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(N4[C@H](CO)CCS4(=O)=O)cc3F)CC2)c(C)c1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Product: COC[C@@H]1CCS(=O)(=O)N1c1ccc(C(=O)N2CCN(c3ccc(C)cc3C)CC2)c(F)c1

Procedure:
Using (S)-[4-(2,4-dimethylphenyl)piperazin-1-yl][2-fluoro-4-(3-hydroxymethyl-1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl]methanone (550 mg) described in Example 39 and methyl tosylate (0.18 mL) and by the reaction and treatment in the same manner as in Example 36, the title compound (48 mg) was obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:26]=[CH:25][C:24]4=[CH:27][CH:28]=[C:29]([C:30]5[CH:35]=[CH:34][CH:33]=[C:32]([S:36](=[O:43])(=[O:42])[NH:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH:31]=5)[N:23]4[N:22]=3)=[C:16]([O:44][CH3:45])[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(OCC)(=O)C>C(Cl)Cl>[C:38]([NH:37][S:36]([C:32]1[CH:33]=[CH:34][CH:35]=[C:30]([C:29]2[N:23]3[C:24]([CH:25]=[N:26][C:21]([NH:20][C:17]4[CH:18]=[CH:19][C:14]([CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)=[CH:15][C:16]=4[O:44][CH3:45])=[N:22]3)=[CH:27][CH:28]=2)[CH:31]=1)(=[O:43])=[O:42])([CH3:41])([CH3:40])[CH3:39]
Reactant: COc1cc(C2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc2ccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2n1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc(C2CCNCC2)ccc1Nc1ncc2ccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)n2n1
Yield: 39.2 %

Procedure:
To 4-{4-[7-(3-tert-Butylsulfamoyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-3-methoxy-phenyl}-piperidine-1-carboxylic acid tert-butyl ester (207.0 mg, 0.31 mmol) in 6.0 mL of DCM at room temperature was added hydrogen chloride gas. When deprotection was complete, ethyl acetate was added, and the precipitate was filtered and washed with ethyl acetate. The orange solid was taken up in water, treated with sat. NaHCO3 until aq. layer pH=13, and extracted with DCM. The organic layers were combined, dried with sodium sulfate, filtered, and conc. in vacuo to afford N-tert-Butyl-3-[2-(2-methoxy-4-piperidin-4-yl-phenylamino)-pyrrolo[2,1-f][1,2,4]triazin-7-yl]-benzenesulfonamide as a burnt orange solid (65 mg, 39%). MP 201-202° C. LCMS (E/I+) 535.21 (M+H). 1H NMR (DMSO-d6)-9.01 (s, 1H), 8.56 (s, 1H), 8.36 (d, 1H, J=7.76 Hz), 7.99 (d, 1H, J=8.56 Hz), 7.85 (s, 1H), 7.83 (s, 1H), 7.69 (t, 1H, J=7.84 Hz), 7.23 (d, 1H, J=4.76 Hz), 7.01 (d, 1H, J=4.72 Hz), 6.95-6.89 (m, 2H), 3.32 (s, 3H), 3.10-2.98 (m, 2H), 2.69-2.52 (m, 2H), 1.78-1.69 (m, 2H), 1.69-1.44 (m, 2H), 1.12 (s, 9H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:24])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([NH:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][CH:16]=1)=[O:13].C(N(CC)C(C)C)(C)C.C1(N=C=NC2CCCCC2)CCCCC1.O.ON1C2C=CC=CC=2N=N1.[NH2:60][CH2:61][C:62]1[C:67]([CH2:68][CH3:69])=[N:66][C:65]2[N:70]([CH2:73][CH3:74])[N:71]=[CH:72][C:64]=2[C:63]=1[NH:75][CH:76]1[CH2:81][CH2:80][O:79][CH2:78][CH2:77]1>CN(C)C=O>[CH2:73]([N:70]1[C:65]2=[N:66][C:67]([CH2:68][CH3:69])=[C:62]([CH2:61][NH:60][C:19](=[O:21])[C:18]3[CH:17]=[CH:16][C:15]([NH:14][C:12](=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:3][CH2:2][OH:1])[CH3:24])=[CH:23][CH:22]=3)[C:63]([NH:75][CH:76]3[CH2:77][CH2:78][O:79][CH2:80][CH2:81]3)=[C:64]2[CH:72]=[N:71]1)[CH3:74]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CN
Reactant: CN(CCO)CCCCCCCC(=O)Nc1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1ccc(NC(=O)CCCCCCCN(C)CCO)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of 4-({8-[(2-hydroxyethyl)(methyl)amino]octanoyl}amino)benzoic acid (7.38 g, 19.8 mmol, 1.2 equivalents, e.g. which can be as prepared in Intermediate 39) in N,N-dimethylformamide (75 ml, about 10 volumes cf. the weight of the acid) was treated with N,N-diisopropylethylamine (4.89 ml, 3.62 g, 28.1 mmol, 1.7 equivalents) resulting in a clear yellow solution. N,N′-Dicyclohexylcarbodiimide (4.42 g, 21.45 mmol, 1.3 equivalents) and then 1-hydroxybenzotriazole hydrate (3.28 g, 21.45 mmol, 1.3 equivalents) were added, and the mixture was stirred at room temperature for 15 minutes. 5-(Aminomethyl)-1,6-diethyl-N-(tetrahydro-2H-pyran-4-yl)-1H-pyrazolo[3,4-b]pyridin-4-amine (5 g, 16.5 mmol, 1 equivalent, e.g. which can optionally be as prepared in Intermediate 7 including alternative preparation no. 1 thereof) was then added, resulting in a cloudy yellow/orange solution which was allowed to stir at room temperature overnight. As much N,N-dimethylformamide as possible was evaporated off, the residue was partitioned between dichloromethane and sodium bicarbonate solution, and then the separated aqueous phase was extracted with more dichloromethane. The combined organic extracts were washed with lithium chloride solution, water and brine, were dried (MgSO4), and were concentrated by evaporation, to give the crude product (15.5 g). 1.73 g of this crude product was removed. The remainder of the crude product was purified by column chromatography on silica gel (about 600 g), eluting with 10% methanol in dichloromethane, followed by 20% methanol in dichloromethane, 20% methanol in dichloromethane containing triethylamine, and finally 30% methanol in dichloromethane containing triethylamine. The majority of the fractions containing the product were combined and evaporated to give the title compound (6.68 g) as a white foam. LCMS showed MH+=622; TRET=2.21 min. The apparently-more-pure fractions containing the product were combined and evaporated to give more of the title compound (0.48 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:12][C:13]([F:16])([F:15])[F:14])=[C:8]([CH2:10][OH:11])[CH:9]=1)([O-])=O>CCOC(C)=O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:12][C:13]([F:14])([F:15])[F:16])=[C:8]([CH2:10][OH:11])[CH:9]=1
Reactant: O=[N+]([O-])c1ccc(OC(F)(F)F)c(CO)c1
Solvent: CCOC(C)=O
Product: Nc1ccc(OC(F)(F)F)c(CO)c1
Reaction time: 3 h
Yield: 96 %

Procedure:
(5-Nitro-2-trifluoromethoxy-phenyl)-methanol (2 g, 8.4 mmol) was dissolved in EtOAc (50 mL) and was degassed. Pd/C (200 mg) was then added and the mixture was degassed again. The solution was hydrogenated with a balloon for 3 h. After the reaction was complete, the solution was filtered through diatomaceous earth and the residue was chromatographed with 95:5 CH2Cl2:MeOH as an eluent to give 1.67 g (96%) of (5-amino-2-trifluoromethoxy-phenyl)-methanol as a yellow solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([CH2:10][C:11]1([CH2:26][C:27](O)=[O:28])[CH2:16][CH2:15][CH:14]([CH:17]2[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24][CH3:25])[CH2:19][CH2:18]2)[CH2:13][CH2:12]1)(O)=[O:8].O.Cl>C1COCC1>[OH:8][CH2:7][CH2:10][C:11]1([CH2:26][CH2:27][OH:28])[CH2:16][CH2:15][CH:14]([CH:17]2[CH2:22][CH2:21][CH:20]([CH2:23][CH2:24][CH3:25])[CH2:19][CH2:18]2)[CH2:13][CH2:12]1
Reactant: CCCC1CCC(C2CCC(CC(=O)O)(CC(=O)O)CC2)CC1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CCCC1CCC(C2CCC(CCO)(CCO)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
10.0 g (0.26 mol) of lithium aluminium hydride are suspended in 200 ml of THF, and a solution of 24.0 g (74.0 mmol) of (4-carboxymethyl-4′-propylbicyclohexyl-4-yl)acetic acid in 300 ml of THF is metered in. When the addition is complete, the mixture is stirred at RT for 1 h and at the reflux temperature for 3 h. The reaction mixture is hydrolysed using water and neutralised using dil. hydrochloric acid. The salts are filtered off, and the filtrate is diluted with MTBE. The solution is washed with saturated sodium chloride solution and dried using sodium sulfate. The solid remaining after removal of the solvents is recrystallised from acetonitrile, giving 2-[4-(2-hydroxyethyl)-4′-propylbicyclohexyl-4-yl]ethanol as a beige solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].[Br:11]Br>C1(Cl)C=CC=CC=1.[Fe](Br)(Br)Br>[Br:11][C:8]1[CH:9]=[CH:10][C:3]([S:2][CH3:1])=[C:4]([CH:7]=1)[CH:5]=[O:6]
Reactant: CSc1ccccc1C=O
Reactant: BrBr
Agent: Br[Fe](Br)Br
Solvent: Clc1ccccc1
Product: CSc1ccc(Br)cc1C=O
Temperature: 70 °C
Reaction time: 5 h

Procedure:
In a 100 mL 2-neck round-bottomed flask 2-(methylthio)benzaldehyde (5 grams, 32.8 mmol) and iron(III) bromide (0.485 grams, 1.642 mmol) were dissolved in PhCl (10 ml) to give a brown solution. The reaction mixture was heated to 70° C. and treated dropwise with a solution of bromine (1.78 mL, 34.5 mmol) in PhCl (8 mL) via an addition funnel. The mixture was heated at 70° C. After 5 hours, the heating source was removed and the reaction was cooled to room temperature. The reaction mixture was quenched with a 1:1 mixture of aqueous saturated NaHCO3/Na2SO3 solution (30 mL total). The aqueous layer was separated and extracted with CH2Cl2 (50 mL). The combined organic layers were dried (MgSO4), filtered and concentrated using a rotary evaporator. The residual solution was cooled in the freezer overnight. The crude product precipitated and was isolated by decanting the excess PhCl and drying the product under high vacuum overnight. The structure was confirmed by 1H and 13C NMR spectroscopy. Yield 4.5 grams (60%).
Reaction SMILES: [C:1]([O-:4])([O-])=O.[K+].[K+].[Cl:7][C:8]1[C:18]2[N:17]3[CH2:19][CH2:20][CH2:21][C@@H:22]([NH:23][C:24](=O)[C:25](F)(F)F)[C@H:16]3[C:15]3[CH:30]=[CH:31][CH:32]=[CH:33][C:14]=3[O:13][C:12]=2[CH:11]=[CH:10][C:9]=1[Cl:34]>CO.O>[Cl:7][C:8]1[C:18]2[N:17]3[CH2:19][CH2:20][CH2:21][C@@H:22]([NH:23][CH2:24][CH2:25][O:4][CH3:1])[C@H:16]3[C:15]3[CH:30]=[CH:31][CH:32]=[CH:33][C:14]=3[O:13][C:12]=2[CH:11]=[CH:10][C:9]=1[Cl:34]
Reactant: O=C(N[C@@H]1CCCN2c3c(ccc(Cl)c3Cl)Oc3ccccc3[C@H]12)C(F)(F)F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COCCN[C@@H]1CCCN2c3c(ccc(Cl)c3Cl)Oc3ccccc3[C@H]12
Yield: 90.2 %

Procedure:
K2CO3 (537 mg, 3.9 mmol) was added to a solution of trans-N-(6,7-dichloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepin-1-yl)-2,2,2-trifluoroacetamide (322 mg, 0.75 mmol) in methanol (28 mL) and water (1.7 mL). The reaction mixture was stirred at reflux temperature for 2 h whereafter the methanol was removed under reduced pressure. Water was added to the remaining product and the water layer was extracted with CH2Cl2 (3×). The combined organic layers were washed with brine, dried (Na2SO4) and evaporated to give the crude title compound (266 mg, 100%).
Reaction SMILES: Cl.[C:2]12([O:12][C:13]3[C:19]([CH3:20])=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=3[CH3:21])[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.[OH-].[Na+].Br[CH2:25][CH2:26][CH2:27][CH2:28]Br.C([O-])([O-])=O.[K+].[K+]>C(O)C.O>[C:2]12([O:12][C:13]3[C:14]([CH3:21])=[CH:15][C:16]([N:17]4[CH2:28][CH2:27][CH2:26][CH2:25]4)=[CH:18][C:19]=3[CH3:20])[CH2:9][CH:8]3[CH2:7][CH:6]([CH2:5][CH:4]([CH2:10]3)[CH2:3]1)[CH2:11]2
Reactant: Cc1cc(N)cc(C)c1OC12CC3CC(CC(C3)C1)C2
Reactant: BrCCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: Cc1cc(N2CCCC2)cc(C)c1OC12CC3CC(CC(C3)C1)C2

Procedure:
The amine obtained by washing a CH2Cl2 solution of 2.1 g. (6.82 mmole) of 4-(1-adamantyloxy)-3,5-dimethylaniline hydrochloride with three 25 ml. portions of 10% aq. NaOH followed by a water wash, drying (anhydrous MgSO4) and concentration, was combined with 1.47 g. (6.82 mmole) of 1,4-dibromobutane and 2.07 g. (15.0 mmole) of K2CO3 in 20 ml. of absolute ethanol and refluxed for approximately 18 hours.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18]3[N:19]([CH2:23][CH2:24][CH2:25][C:26]([O:28]C(C)(C)C)=[O:27])[CH:20]=[CH:21][N:22]=3)[C:15](=[O:33])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O>>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH:17][C:18]3[N:19]([CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])[CH:20]=[CH:21][N:22]=3)[C:15](=[O:33])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(Nc3nccn3CCCC(=O)OC(C)(C)C)[C@H]2SC1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(Nc3nccn3CCCC(=O)O)[C@H]2SC1

Procedure:
3-Acetoxymethyl-7-[1-(3-t-butoxycarbonylpropyl)imidazol-2-yl]aminoceph-3-em-4-carboxylic acid was treated with TFA according to the process of Example 39, except that product was isolated by trituration, to give 3-acetoxymethyl-7-[1-(3-carboxypropyl)imidazol-2-yl]amino ceph-3-em-4-carboxylic acid, having the following n.m.r. spectrum in d6DMSO+CD3CO2D: 1.6-2.4 (m, 4H); 2.0 (s, 3H); 3.5 (d, 1H); 3.7 (d, 1H); 4.0 (t, 2H); 4.7 (d, 1H); 5.0 (d, 1H); 5.2 (d, 1H); 5.6 (s, 1H); 7.1 (m, 2H).