Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[N:14]([CH3:38])[C:15](=[O:37])[C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2[C:33]3[N:32]=[C:31]([CH3:34])[NH:30][C:29]=3[CH:28]=[CH:27][CH:26]=2)=[O:24])=[C:18]([O:35][CH3:36])[CH:17]=1.[CH2:39]=O.[C:41]([BH3-])#[N:42].[Na+]>CO.C(Cl)(Cl)Cl>[CH3:39][N:42]([CH3:41])[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:8]=1[N:14]([CH3:38])[C:15](=[O:37])[C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2[C:33]3[N:32]=[C:31]([CH3:34])[NH:30][C:29]=3[CH:28]=[CH:27][CH:26]=2)=[O:24])=[C:18]([O:35][CH3:36])[CH:17]=1
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCN)ccc1NC(=O)c1cccc2[nH]c(C)nc12
Reactant: C=O
Reactant: [BH3-]C#N
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCN(C)C)ccc1NC(=O)c1cccc2[nH]c(C)nc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 89.8 %

Procedure:
A mixture of N-[2-(4-aminobut-1-yloxy)-4-methylphenyl]-3-methoxy-N-methyl-4-(2-methyl-1H-benzimidazol-4-yl)carbonylaminobenzamide (150 mg), 37% formaldehyde solution (43.7 mg) and sodium cyanoborohydride (18.3 mg) in methanol (10 ml) was stirred at ambient temperature for 6 hours. The mixture was diluted with chloroform and the solution was washed with saturated aqueous sodium hydrogen carbonate and brine. The organic phase was dried over magnesium sulfate and the solvent was evaporated in vacuo. The crude product was purified by silica gel column (5% methanol in chloroform) to give N-[2-(4-dimethylaminobut-1-yloxy)-4-methylphenyl]-3-methoxy-N-methyl-4-(2-methyl-1H-benzimidazol-4-yl)carbonylaminobenzamide (142 mg).
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH:20][C:21](=[O:34])[CH:22]([O:31]C=O)[C:23]4[S:27][C:26]([NH:28]C=O)=[N:25][CH:24]=4)[C:18](=[O:35])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[N:5][N:4]=[N:3]1.P(Cl)(Cl)(Cl)=O.C(OCC)C>CO>[CH3:1][N:2]1[C:6]([S:7][CH2:8][C:9]2[CH2:10][S:11][C@@H:12]3[CH:19]([NH:20][C:21](=[O:34])[CH:22]([OH:31])[C:23]4[S:27][C:26]([NH2:28])=[N:25][CH:24]=4)[C:18](=[O:35])[N:13]3[C:14]=2[C:15]([OH:17])=[O:16])=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(OC=O)c3cnc(NC=O)s3)[C@H]2SC1
Agent: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(OC=O)c3c[nH]c(=NC=O)s3)[C@H]2SC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOCC
Solvent: CO
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(O)c3cnc(N)s3)[C@H]2SC1

Procedure:
To a mixture of 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-formyloxy-2-(2-formylamino-1,3-thiazol-5-yl)acetamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-formyloxy-2-(2-formylimino-2,3-dihydro-1,3-thiazol-5-yl)acetamido]-3-cephem-4-carboxylic acid, (1.5 g.) in methanol (30 ml.) was added phosphorus oxychloride (1.06 g.) under ice-cooling and stirring, and the mixture was stirred for 1 hour at the same temperature and then further stirred for 4 hours at room temperature. To the reaction mixture was added diethyl ether (150 ml.), and the precipitates were collected by filtration and then dried. Thus obtained pale yellow powder (1.30 g.) was added to water (30 ml.), and the mixture was adjusted to pH 1 to 2 with 10% hydrochloric acid. The resulting solution was treated with an activated charcoal, washed with ethyl acetate and then adjusted to pH 7 with a 5% sodium bicarbonate aqueous solution. The solution was washed with ethyl acetate, adjusted to pH 3 with 10% hydrochloric acid and then filtered. The aqueous solution was absorbed on a HP-20 (neutral resin) column, which was washed with water and then eluted with an aqueous methanol solution. The eluates containing the object compound were collected and then methanol was distilled off under reduced pressure. The remaining aqueous solution was lyophilized to give 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-hydroxy-2-(2-amino-1,3-thiazol-5-yl)acetamido]-3-cephem-4-carboxylic acid, which can be represented as 3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-7-[2-hydroxy-2-(2-imino-2,3-dihydro-1,3-thiazol-5-yl)acetamido]-3-cephem-4-carboxylic acid, (0.63 g.), mp. 130° to 200° C. (dec.).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[CH2:11]([O:13][C:14](=[O:28])[CH:15]([CH2:19][C:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:16](=O)[CH3:17])[CH3:12].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:11]([O:13][C:14]([C:15]1[CH:19]=[C:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:6]([C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N+:1]([O-:3])=[O:2])[C:16]=1[CH3:17])=[O:28])[CH3:12]
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: CCOC(=O)C(CC(=O)c1ccccc1)C(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccccc2)n(-c2ccccc2[N+](=O)[O-])c1C

Procedure:
o-Nitroaniline (15 mmol, 2.1 g), 3-oxo-2-(2-oxo-2-phenyl-ethyl)-butyric acid ethyl ester (15 mmol, 3.7 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. The resulting oil was purified over three silica gel columns to yield the named product, 1H-NMR (CDCl3, ppm): 1.36 t (3H), 2.36 s (3H), 4.31 q (2H), 6.80 s (1H), 7.03-7.66 bm (6H), 7.68 dt (2H), 7.97 dd (1H).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:10])[NH:4][C:5]([CH3:9])=[CH:6][C:7]=1[OH:8].C1CCN2C(=NCCC2)CC1.[F:22][C:23]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:24]=1[CH2:25]Br>CN1C(=O)CCC1>[Cl:1][C:2]1[C:3](=[O:10])[NH:4][C:5]([CH3:9])=[CH:6][C:7]=1[O:8][CH2:25][C:24]1[CH:27]=[CH:28][C:29]([F:31])=[CH:30][C:23]=1[F:22]
Reactant: Cc1cc(O)c(Cl)c(=O)[nH]1
Reactant: Fc1ccc(CBr)c(F)c1
Solvent: CN1CCCC1=O
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)[nH]1
Temperature: 80 °C
Yield: 12.8 %

Procedure:
3-Chloro-4-hydroxy-6-methyl-1H-pyridin-2-one (19.2 g, 0.12 mol) and DBU (19.9 mL, 0.13 mol) were dissolved in 70 mL of NMP. 2,4-Difluorobenzylbromide (17 mL, 0.13 mol) was added dropwise and the reaction was heated at 80° C. for 6 hours. The reaction was cooled to room temperature, the solid was filtered, and washed with NMP and hexanes. The solid was dried in a vacuum oven overnight to give a white solid (4.4 g, 13%): 1H NMR (300 MHz, DMSO-d6) δ 11.88 (br s, 1H), 7.63 (app q, J=9 Hz, 1H), 7.33 (app t, J=10 Hz, 1H), 7.16 (app t, J=9 Hz, 1H), 6.37 (s, 1H), 5.24 (s, 2H), 2.20 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)([O:26][CH3:27])C3C=CC(C#N)=CC=3)=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[N-:34]=[N+:35]=[N-:36].[Na+].Cl.C([N:41]([CH2:44][CH3:45])CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]([CH:17]([CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]3)[O:26][CH2:27][C:2]3[CH:7]=[CH:6][C:45]([C:44]4[N:34]=[N:35][NH:36][N:41]=4)=[CH:4][CH:3]=3)=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: [N-]=[N+]=[N-]
Reactant: COC(c1ccc(C#N)cc1)(c1c2ccccc2nn1-c1ccc(Cl)cc1)C1CCCCC1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(-n2nc3ccccc3c2C(OCc2ccc(-c3nn[nH]n3)cc2)C2CCCCC2)cc1

Procedure:
In analogy to the procedure described in example 31, [rac]-4-{[2-(4-chloro-phenyl)-2H-indazol-3-yl]-cyclohexyl-methoxymethyl}-benzonitrile (example 46) was reacted with sodium azide in the presence of triethylamine hydrochloride in DMF to obtain the title compound as brown solid. MS: m/e=499.3 [M+H+].
Reaction SMILES: [O:1]1[C@H:5]2[O:6][CH2:7][CH2:8][C@H:4]2[C@@H:3]([OH:9])[CH2:2]1.C(N(CC)CC)C.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:27]([CH2:32][C@@H:33]([OH:43])[C@@H:34]([NH2:42])[CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:28][CH:29]([CH3:31])[CH3:30])(=[O:26])=[O:25])=[CH:20][CH:19]=1.CN.[C:46](OCC)(=[O:48])C>C(#N)C.C(O)C>[CH2:2]([O-:1])[CH3:3].[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([N:27]([CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:32][C@@H:33]([OH:43])[C@@H:34]([NH:42][C:46](=[O:48])[O:9][C@@H:3]2[C@H:4]3[C@H:5]([O:6][CH2:7][CH2:8]3)[O:1][CH2:2]2)[CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)(=[O:26])=[O:25])=[CH:20][CH:19]=1
Reactant: CC(C)CN(C[C@@H](O)[C@@H](N)Cc1ccccc1)S(=O)(=O)c1ccc(N)cc1
Reactant: CCOC(C)=O
Reactant: O[C@H]1CO[C@H]2OCC[C@H]21
Agent: CN
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCO
Product: CC(C)CN(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc(N)cc1
Product: CC[O-]
Reaction time: 1 h

Procedure:
100 mmol (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-ol in ethyl acetate were added onto 120 mmol of disuccimidylcarbonate (95%) in acetonitrile. Following, a solution of 140 mmol triethylamine in ethylacetate was added and stirred. The mixture was cooled and treated with a suspension of 92 mmol of 4-Amino-N-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-N-(isobutyl)benzene sulfonamide in ethyl acetate. 20 mmol methylamine, 41% aqueous solution in ethanol were added and the mixture was warmed. The reaction was washed twice with 10% Na2CO3-solution and with water. Solvent was evaporated and ethanol was added. Another portion of solvent was distilled off. The temperature was kept around 40-45° C. and crystallization was initiated by seeding. After stirring the mixture was cooled, stirred for another 90 min stirred, cooled and again stirred for 60 min. The precipitate was filtered and washed with ethanol. The wet product was dried in vacuo at 40° C. 43.5 g of (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[[(4-aminophenyl)sulfonyl](isobutyl) amino]-1-benzyl-2-hydroxypropylcarbamate were suspended in ethanol abs. and dissolved. The clear solution was cooled and seeding was applied. Crystallization occurred while cooling the mixture. Stirring was continued for another 60 min, followed by cooling, stirring and filtering off the product, which was washed with cold ethanol abs. The wet product was dried in vacuo at 40° C. Yield: 42.1 g=71%.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18]>>[Br-:11].[CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N+:6]=1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: O=C(O)CCCCCBr
Reactant: Cc1nc2ccccc2s1
Product: Cc1sc2ccccc2[n+]1CCCCCC(=O)O
Product: [Br-]
Temperature: 120 °C
Yield: 212.9 %

Procedure:
2-methyl benzothiazole (19.5g, 0.1M) and 6-bromohexanoic acid (15.3g, 0.1M) were mixed and heated at 120° C. for 4 hours under continuous agitation. The resulting solid was broken up, ground with ether and then filtered. The filtrate was washed with more ether (250ml) to yield an off-white powder (57.5g).
Reaction SMILES: [CH:1]([CH:3]([CH:14]([CH3:16])[CH3:15])[CH2:4][C:5]1[CH:9]([C:10]([CH3:12])=[CH2:11])[CH2:8][CH2:7][C:6]=1[CH3:13])=[O:2].[Sn](Cl)(Cl)(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>[N+](C)([O-])=O>[O:2]1[CH:1]2[CH2:11][CH:10]([CH3:12])[C:9]31[C:5]([CH2:4][CH:3]2[CH:14]([CH3:16])[CH3:15])=[C:6]([CH3:13])[CH2:7][CH2:8]3
Reactant: C=C(C)C1CCC(C)=C1CC(C=O)C(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C[N+](=O)[O-]
Product: CC1=C2CC(C(C)C)C3CC(C)C2(CC1)O3
Yield: 78.8 %

Procedure:
To a solution, cooled to -40°, of 3.3 g of 2-(2-formyl-3-methylbutyl)-3-isopropenyl-1-methyl-1-cyclopentene in 225 ml of nitromethane were added 45 ml of a 0.5-M solution of tin tetrachloride in nitromethane. The reaction mixture became intensely yellow in colour and an initially resulting precipitate dissolved again. The mixture was treated immediately with excess 2-N sodium carbonate solution and extracted with ether. After washing, the ethereal phase was dried in a conventional manner and the solvent was removed. Distillation under a high vacuum yielded 2.6 g of crude 3a,6-epoxy-7-isopropyl-1,4-dimethyl-2,3,3a,4,5,6,7,8-octahydroazulene in the form of a colourless oil which could be separated by chromatography on 40 times the amount of Florisil (magnesium silicate gel) with hexane/ether (19.1) into two pairs of epimers (A and B). Epimer A: b.p.0.01 ca 75°; IR(film): νmax = 1465/40, 1380, 1345, 1245, 1162, 1125, 1108, 1080, 1050, 995, 965, 945, 910, 880 cm-1. The odour is camphorous, woody. Epimer B: b.p.0.01 ca 80° IR(film): νmax = 1465/35, 1380, 1340, 1295, 1245, 1200/1195, 1170, 1145, 1110, 1060, 1030, 1000, 990, 950, 925, 910, 878 cm-1. The odour is camphorous, dull.
Reaction SMILES: CC1C=CC(S([CH2:11][N+:12]#[C-:13])(=O)=O)=CC=1.[NH3:14].[CH3:15][C:16]([CH3:22])([CH2:20][CH3:21])[CH2:17][CH:18]=O.Cl>CO>[CH3:15][C:16]([CH3:22])([CH2:20][CH3:21])[CH2:17][C:18]1[N:14]=[CH:11][NH:12][CH:13]=1
Reactant: N
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CCC(C)(C)CC=O
Agent: Cl
Solvent: CO
Product: CCC(C)(C)Cc1c[nH]cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
TosMIC (154 g, 0.9 mol) was added to an ambient temperature, saturated solution of ammonia in methanol (7 L). After stirring at ambient temperature for 1 h, 3,3-dimethylpentanal (ca. 0.6 mol) was added over 20 min. After stirring at reflux for 3 h, the reaction mixture was poured into cold 1 N hydrochloric acid and washed with hexane. The aqueous layer was basified with 10 N aqueous sodium hydroxide and extracted with ether. The combined organic extracts were washed with brine, dried (magnesium sulfate), filtered and concentrated in vacuo. Chromatography over silica eluting with 5-10% methanol/methylene chloride afforded 4-(2,2-dimethylbutyl)-1H-imidazole.
Reaction SMILES: C(N(CC)CC)C.Cl.[Cl:9][CH2:10][CH2:11][CH2:12][NH2:13].[CH2:14]([N:20]=[C:21]=[O:22])[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>C(Cl)Cl>[Cl:9][CH2:10][CH2:11][CH2:12][NH:13][C:21]([NH:20][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:22]
Reactant: NCCCCl
Reactant: CCCCCCN=C=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCNC(=O)NCCCCl
Reaction time: 1 h
Yield: 86.1 %

Procedure:
Triethylamine (35 g; 35 mmole) was slowly added to a mixture of chloropropylamine hydrochloride (39 g; 0.3 mol), n-hexyl isocyanate (38.2 g; 0.3 mole) and methylene chloride (500 ml). The resulting solution was stirred for one hour, and then the solvent was removed in vacuo. The residue was treated with ether, and the colorless solid was filtered off. The ether solution was then washed with water, dried (magnesium sulfate) and concentrated to give pure 1-(3-chloropropyl)-3-n-hexylurea (57.0 g; 86% yield) as colorless crystals, m.p. 48°-50° C.
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([O:11][CH3:12])[CH:5]=1.O.[OH-].[Li+]>O1CCCC1.O>[F:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:13])=[O:2])=[CH:5][C:6]=1[O:11][CH3:12]
Reactant: COC(=O)c1ccc(F)c(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)ccc1F

Procedure:
4-Fluoro-3-methoxybenzoic acid methyl ester (2.55 g, 13.85 mmol) (from Example 34a supra) was dissolved in a mixture of tetrahydrofuran (140 mL) and water (70 mL). Lithium hydroxide monohydrate (5.8 g, 138.5 mmol) was added and the mixture was heated at reflux for 3.5 hours. After quenching with 1 N aqueous hydrochloric acid (150 mL), the solution was extracted with dichloromethane. The phases were separated and the organic layer was dried over anhydrous sodium sulfate. Concentration under reduced pressure gave 4-fluoro-3-methoxybenzoic acid as an off-white solid. (Yield 2.26 g, 96%).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:25]([O:29][C:30]([NH:32][C:33]1([C:48]([OH:50])=O)[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].[Cl:51][C:52]1[CH:57]=[CH:56][C:55]([CH:58]([NH2:84])[CH2:59][C:60]2[N:61]([C:65]([C:78]3[CH:83]=[CH:82][CH:81]=[CH:80][CH:79]=3)([C:72]3[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=3)[C:66]3[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=3)[CH:62]=[CH:63][N:64]=2)=[CH:54][CH:53]=1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[Cl:51][C:52]1[CH:57]=[CH:56][C:55]([CH:58]([NH:84][C:48]([C:33]2([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:26])([CH3:28])[CH3:27])[CH2:38][CH2:37][N:36]([C:39]3[C:40]4[CH:47]=[CH:46][NH:45][C:41]=4[N:42]=[CH:43][N:44]=3)[CH2:35][CH2:34]2)=[O:50])[CH2:59][C:60]2[N:61]([C:65]([C:78]3[CH:79]=[CH:80][CH:81]=[CH:82][CH:83]=3)([C:72]3[CH:73]=[CH:74][CH:75]=[CH:76][CH:77]=3)[C:66]3[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=3)[CH:62]=[CH:63][N:64]=2)=[CH:54][CH:53]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
Reactant: NC(Cc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1(C(=O)NC(Cc2nccn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.4 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (166 mg, 0.44 mmol) was added portionwise to 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (150 mg, 0.42 mmol), 1-(4-chlorophenyl)-2-(1-trityl-1H-imidazol-2-yl)ethanamine (Intermediate 88) (193 mg, 0.42 mmol) and N-ethyldiisopropylamine (0.087 mL, 0.50 mmol) in DMF (2.0 mL) at room temperature. The resulting solution was stirred at room temperature for 3 hours then quenched in water (10 mL) to give a pale yellow ppt. The precipitate was collected by filtration, washed with water and dried under vacuum to afford tert-butyl 4-(1-(4-chlorophenyl)-2-(1-trityl-1H-imidazol-2-yl)ethylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (320 mg, 95%) as a cream solid, which was used without further purification.
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([Cl:11])[C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:18][NH2:19]>CO>[Cl:11][C:4]1[C:3]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:2]([NH:19][CH3:18])[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[N:5]=1
Reactant: CN
Reactant: Clc1nc2nccn2c(Cl)c1-c1ccccc1
Solvent: CO
Product: CNc1c(-c2ccccc2)c(Cl)nc2nccn12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
850 mg 5,7-dichloro-6-phenylimidazo[1,2-a]pyrimidine (prepared as described for example 1) is dissolved in 18 ml of a 8M Solution of MeNH2 in methanol and stirred at room temperature for 1.5 h. The product precipitates upon dilution with water and cooling to 0° C. The solid material is collected by filtration and washed twice with water to yield the desired material.
Reaction SMILES: [CH2:1]([C:3]([O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1)([CH2:18][CH3:19])[C:4]#[C:5][CH2:6]OS(C1C=CC(C)=CC=1)(=O)=O)[CH3:2].[Br-:27].[Na+].CCOCC>CN(C=O)C.CCOCC.CCCCC>[Br:27][CH2:6][C:5]#[C:4][C:3]([CH2:18][CH3:19])([O:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][O:22]1)[CH2:1][CH3:2]
Reactant: CCC(C#CCOS(=O)(=O)c1ccc(C)cc1)(CC)OC1CCCCO1
Reactant: [Br-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCCCC
Product: CCC(C#CCBr)(CC)OC1CCCCO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.3 %

Procedure:
A mixture of Compound 402 (7.0 g) and sodium bromide (7.0 g) in DMF (50 ml) was stirred at r.t. for 4 h. Ether (300 ml) was added and the mixture was worked up with chromatography with ether/pentane 1:1 (v/v) as eluent to give the title compound (3.9 g). 1H NMR: 0.96 (t, 3H), 0.96 (t, 3H) 1.45-1.90 (m, 10E), 3.51 (m, 1H), 3.95 (m, 1H), 3.98 (s, 2H), 5.00 (m, 1H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][N:8]=1.[C:14]([O:18][C:19]([N:21]1[CH:26]2[CH2:27][CH2:28][CH:22]1[CH2:23][C:24](=[O:29])[CH2:25]2)=[O:20])([CH3:17])([CH3:16])[CH3:15].C(O)(=O)C>C(OCC)C>[C:14]([O:18][C:19]([N:21]1[CH:26]2[CH2:27][CH2:28][CH:22]1[CH2:23][C:24]([C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][N:8]=1)([OH:29])[CH2:25]2)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: Fc1cccnc1Br
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1C2CCC1CC(O)(c1ncccc1F)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.2 %

Procedure:
n-Butyl lithium (2.5M, 1 mL, 2.5 mmol) was added dropwise to a solution of 2-bromo-3-fluoro-pyridine (0.4 g, 2.27 mmol) in diethyl ether (8 mL), under nitrogen at −78° C. and stirred for 1 hour. 3-Oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester (0.51 g, 2.27 mmol) in diethyl ether (5 mL) was added dropwise at −78° C. and the reaction mixture stirred for 0.5 hours before warming to room temperature. The reaction mixture was poured onto ice, acidified with acetic acid and extracted into ethyl acetate. The remaining aqueous solution was basified with 1 M sodium hydroxide, extracted with DCM and the combined organics were dried over magnesium sulphate, filtered and the solvent removed by evaporation under vacuum. Methanol (10 mL) and sodium borohydride (0.14 g) were added to the residues and stirred for 2 hours to reduce any unreacted ketone. The solvent was removed by evaporation under vacuum, DCM added to the residues and the organics washed with water and brine, dried over magnesium sulphate, filtered and the solvent removed by evaporation under vacuum. The residue was purified by flash chromatography on silica eluting with 5-10% ethyl acetate/cyclohexane. The fractions containing the desired product were concentrated under vacuum to give the title compound (0.25 g). LCMS m/z 323 [M+H]+. R.T.=4.67 min (Analytical Method 3).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[O:12][CH2:13][CH3:14])[CH3:2].[Br:16]Br>O.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:15])[C:5]1[CH:10]=[C:9]([Br:16])[C:8]([Cl:11])=[CH:7][C:6]=1[O:12][CH2:13][CH3:14])[CH3:2]
Reactant: CCOC(=O)c1ccc(Cl)cc1OCC
Reactant: BrBr
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1cc(Br)c(Cl)cc1OCC
Reaction time: 72 h
Yield: 64 %

Procedure:
To a solution of 4-chloro-2-ethoxy-benzoic acid ethyl ester (1.46 g, 6.4 mmol) in 13 mL of water and methylene chloride (1:1 mixture) was added bromine (360 uL, 7 mmol). The reaction was stirred for three days. The organic layer was separated. It was washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. Purification of the crude residue by flash column chromatography (silica gel, eluting with a gradient of ethyl acetate in hexanes) gave 5-bromo-4-chloro-2-ethoxy-benzoic acid ethyl ester (1.26 g, 64%). LC-MS: 307.1 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]([F:16])([F:15])[F:14])[C:5](Cl)=[O:6].O[NH:18][C:19](=[NH:39])[C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][N:24]=[C:25]2[CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].C(N(CC)CC)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][N:18]=[C:19]([C:20]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:21]=3[CH:22]=[CH:23][N:24]=[C:25]4[CH2:30][CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[N:39]=2)[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]([F:16])([F:15])[F:14]
Reactant: CC(C)(C)OC(=O)CCc1nccc2c(C(=N)NO)cccc12
Reactant: O=C(Cl)c1ccc(OCC(F)(F)F)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCc1nccc2c(-c3noc(-c4ccc(OCC(F)(F)F)c(Cl)c4)n3)cccc12
Reaction time: 1.5 h
Yield: 90.2 %

Procedure:
A solution of 3-chloro-4-[(2,2,2-trifluoroethyl)oxy]benzoyl chloride (D21; 82 mg, 0.30 mmol) in dry DMF (1.5 ml) was added to a stirred solution of 1,1-dimethylethyl 3-{5-[(hydroxyamino)(imino)methyl]-1-isoquinolinyl}propanoate (D36; 85 mg, 0.270 mmol) and triethylamine (0.063 ml, 0.450 mmol) in dry DMF (1.5 ml) at 0° and the mixture was stirred at 0° for 1.5 h then at 100° with stirring under nitrogen for 16 h. The cooled mixture was partitioned between saturated aqueous sodium bicarbonate (30 ml) and ethyl acetate (3×20 ml), and the organic layer was washed with 50:50 brine:water and brine, dried (MgSO4) and evaporated in vacuo to give a brown oil (130 mg). The crude product was purified by flash chromatography on silica gel, eluting with 0-30% ethyl acetate-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound as a white solid (55 mg).