Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[F:23][C:24]1[CH:25]=[CH:26][C:27]([CH3:42])=[C:28]([CH:41]=1)[C:29]([NH:31][C:32]1[N:37]=[CH:36][C:35]([C:38](Cl)=[O:39])=[CH:34][CH:33]=1)=[O:30]>ClCCl.O>[CH:1]1[C:6]2[CH2:7][N:8]([C:38]([C:35]3[CH:34]=[CH:33][C:32]([NH:31][C:29](=[O:30])[C:28]4[CH:41]=[C:24]([F:23])[CH:25]=[CH:26][C:27]=4[CH3:42])=[N:37][CH:36]=3)=[O:39])[C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)Cl)cn1
Reactant: c1ccc2c(c1)CNc1ccccc1O2
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3Oc3ccccc32)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 37.4 %

Procedure:
To a stirred solution of 0.39 g of 10,11-dihydrodibenz[b,f][1,4]-oxazepine, 1.1 ml of triethylamine in 5 ml of dichloromethane is added 1.17 g of 6-[(5-fluoro-2-methylbenzoyl)amino]-pyridine-3-carbonyl chloride. The mixture is stirred under argon at room temperature for 16 hours, and diluted with 50 ml of dichloromethane and 20 ml of water. The organic layer is separated, washed with 20 ml each of 1M NaHCO3, brine and dried (Na2SO4). The solution is filtered through a thin pad of hydrous magnesium silicate and the filtrate is concentrated to dryness under vacuum. The residue is chromatographed on silica gel with ethyl acetate-hexane (1:1) as solvent to give a solid. Crystallization from ethyl acetate gives 0.335 g of off-white crystals, m.p. 180°-186° C.
Reaction SMILES: [CH3:1][C:2]([O-])(C)[CH3:3].[K+].C1COCC1.[OH:12][CH2:13][CH2:14][C:15]1[S:19][CH:18]=[N:17][C:16]=1[CH3:20].C(Br)C=C>O>[CH2:3]([O:12][CH2:13][CH2:14][C:15]1[S:19][CH:18]=[N:17][C:16]=1[CH3:20])[CH:2]=[CH2:1]
Reactant: Cc1ncsc1CCO
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCOCCc1scnc1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
An oven-dried 100 mL round bottom flask was charged with t-BuOK (20.8 mmol), dry THF (25 mL), purged with argon and cooled to 0° C. in an ice bath. 5-(2-Hydroxyethyl)-4-methylthiazole (16 mmol) was then added dropwise to the solution and the reaction stirred at 0° C. for 1 h under argon. Allyl bromide (20.8 mmol) was added dropwise, and the solution was warmed to R.T. and allowed to stir for 20 h under argon. Deionized water (4 mL) was then added and the reaction stirred for 10 min. All liquid were then removed in vacuo and the residue redissolved in ethyl acetate (50 mL). The organic phase was washed three times with water (20 mL), dried over Na2SO4, filtered over Celite, and then concentrated in vacuo to yield a yellow oil (96%). 1HNMR (400 MHz, CDCl3): δ=8.52 (s, 1H), 5.89 (m, 1H), 5.23 (dd, 1H, 3JHHtrans=17.4 Hz, 2JHHgems=1.8 Hz), 5.13 (dd, 1H, 3JHHcis=10.3 Hz, 2JHHgems=1.6 Hz), 3.96 (dt, 2H, 3JHH=5.7 Hz, 4JHH=1.4 Hz), 3.57 (t, 2H, 3JHH=6.9 Hz), 2.99 (t, 2H, 3JHH=6.9 Hz), 2.37 (s, 3H) ppm. 13CNMR (400 MHz, CDCl3): δ=149.6, 149.2, 134.5, 127.9, 17.0, 71.9, 70.0, 27.0, 14.9 ppm. HRMS-ESI: Calculated [M+H]+: 184.0791. found: 184.0787.
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH2:11].Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].C([O-])(=O)C.[K+]>O.C(O)C.COCCOC>[CH2:16]([O:15][C:13]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCCCCN
Reactant: O=C(Cl)OCc1ccccc1
Agent: CC(=O)[O-]
Agent: CS(=O)(=O)O
Agent: [K+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: NCCCCNC(=O)OCc1ccccc1
Reaction time: 1.5 h
Yield: 37.6 %

Procedure:
A solution of 46 g of methane sulfonic acid in 50 ml of water was added without exceeding 30° C. to a mixture of 23 g of 1,4-diamino butane and 50 ml of water and the reaction medium was diluted with 140 ml of ethanol. A solution of 39 g of benzyl chloroformate in 50 ml of 1,2-dimethoxy ethane and 100 ml of a 50% aqueous solution of potassium acetate were added alternately at pH 3.5 to 5.0. The additions were made alternately to maintain the pH value between 3.5 and 5.0. The mixture was stirred for 90 minutes at 20° to 25° C. and evaporated under reduced pressure. The residue was poured over 500 ml of water and the insoluble part was filtered off. The filtrate was washed 3 times with 150 ml of benzene, and then 100 ml of 30% sodium hydroxide saturated with sodium chloride were added. After extraction with benzene, the extracts were evaporated to dryness under reduced pressure to obtain 19.10 g of the expected product.
Reaction SMILES: C(OC([N:8]1[CH2:13][C@H:12]([CH3:14])[NH:11][C@H:10]([CH3:15])[CH2:9]1)=O)(C)(C)C.C(=O)(O)[O-].[Na+].[N:21]#[C:22]Br.[Cl:24]CCl>>[ClH:24].[CH3:15][C@H:10]1[CH2:9][NH:8][CH2:13][C@@H:12]([CH3:14])[N:11]1[C:22]#[N:21]
Reactant: N#CBr
Reactant: ClCCl
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1
Agent: O=C([O-])O
Agent: [Na+]
Product: C[C@@H]1CNC[C@H](C)N1C#N
Product: Cl

Procedure:
4.00 g of cis-3,5-dimethylpiperazine-1-carboxylic acid tert-butyl ester (prepared according to the method E. Jon Jacobson et. al. J. Med. Chemistry. 1999, Vol. 42, 1123-144) in 91 mL of dichloromethane was treated with sodium bicarbonate (4.7 g) followed by addition of cyanogen bromide (7.5 mL). The reaction mixture was heated at reflux overnight, was filtered, and was purified by column chromatography (0 to 50% ethyl acetate/hexanes) to afford 3.9 g of the title compound as a white solid. 1H NMR (CDCl3, 300 MHz) δ ppm 1.33 (d, 6H, J=6.5 Hz), 1.44 (s, 9H), 2.54 (m, 2H), 3.09 (m, 2H), 4.09 (m, 2H); 13C NMR (CDCl3, 75 MHz) 16.70 (2C), 28.54 (3C), 53.86 (4C), 80.86, 114.10, 154.22.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][S:6][CH:7]([CH3:13])[C:8](OCC)=O.[CH3:15]C(C)([O-])C.[K+].C([O-])=O.[NH4+:24]>C1(C)C=CC=CC=1.C(O)C.C(OCC)C>[NH2:24][C:13]1[CH:7]([CH3:8])[S:6][CH2:5][C:4]=1[C:3]([O:2][CH2:1][CH3:15])=[O:14]
Reactant: CC(C)(C)[O-]
Reactant: [NH4+]
Reactant: CCOC(=O)C(C)SCCC(=O)OC
Agent: O=C[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)C1=C(N)C(C)SC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of the product of Step A (17.24 g, 73 mmol) in toluene (160 mL) was treated with potassium t-butoxide (18.4 g, 164 mmol) and the mixture was heated at reflux for 1.5 h. Upon cooling to ambient temperature, the mixture was washed twice with 1 N hydrochloric acid, dried over magnesium sulfate and concentrated. To a solution of the resulting residue (11.0 g) in ethanol (150 mL) was added ammonium formate (32.3 g, 0.51 mol) and the mixture was heated at reflux for 7 h and then stirred at ambient temperature overnight. The mixture was diluted with ethyl ether, washed with water (2×) and dried over magnesium sulfate to give the title product as a yellow oil, 7.05 g. The material was a mixture of methyl and ethyl esters.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][N:8]=[C:7]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[C:6]=2[CH:16]=1.Cl[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=1[O:31][CH3:32].C([O-])([O-])=O.[K+].[K+].C(#N)C>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][N:8]=[C:7]([CH:10]3[CH2:11][CH2:12][N:13]([CH2:18][CH2:19][CH2:20][O:21][C:22]4[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[CH:24][C:23]=4[O:31][CH3:32])[CH2:14][CH2:15]3)[C:6]=2[CH:16]=1
Reactant: Fc1ccc2onc(C3CCNCC3)c2c1
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1cc(C(C)=O)ccc1OCCCN1CCC(c2noc3ccc(F)cc23)CC1
Yield: 93.8 %

Procedure:
A mixture of 5-fluoro-3-(-4-piperidinyl)-1,2benzisoxazole (2.2 g, 0.01 mole), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (24g, 0.01 mole), K2CO3 (1.4 g), a few crystals of KI and acetonitrile (100 ml) was stirred and refluxed for 8hours. The reaction was poured into water and the aqueous mixture was extracted with ethyl acetate . The ethyl acetate extract was washed (brine), dried (MgSO4) and concentrated to afford 4.0 g of a white solid. The solid was chromatographed on a Waters Prep 500 HPLC utilizing silica gel columns and eluting with methylene chloride/methanol (5%). Concentration of the appropriate fractions afforded 2.0 g (47%) of 1-[4-[3-[4-(5-fluoro-1,2-benzisoxazol-[3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone as a white crystalline solid, m.p.=103°-105° C.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][C@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:25]1.C(N(C(C)C)CC)(C)C>CC(O)C>[C:33]([O:32][C:30]([N:26]1[CH2:27][CH2:28][CH2:29][C@H:24]([NH:23][C:18]2[C:17]([N+:20]([O-:22])=[O:21])=[CH:16][N:15]=[C:14]3[N:10]([S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])[CH:11]=[CH:12][C:13]=23)[CH2:25]1)=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](N)C1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H](Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)C1
Temperature: 110 °C
Yield: 84.9 %

Procedure:
A mixture of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (0.6769 g, 2.004 mmol), (S)-3-amino-1-Boc-piperidine (0.4269 g, 2.132 mmol), and diisopropylethylamine (0.45 mL, 2.6 mmol) in propan-2-ol (12 ml) was heated in a microwave reactor at 110° C. for 20 minutes. The solvent was evaporated in vacuo and then purified by column chromatography on silica gel (gradient: 0 to 30% ethyl acetate in heptanes) affording 853.7 mg (85%) of (S)-3-(1-Benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester. LCMS (Method F, ESI): RT=1.19 min, m+H=502.3.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[N:6]=[CH:5]2.[Li]CCCC.[CH2:23]([N:26]1[CH:30]=[C:29]([C:31](=[O:36])[C:32]([F:35])([F:34])[F:33])[CH:28]=[C:27]1[C:37]#[N:38])[CH:24]=[CH2:25]>C1COCC1>[CH2:23]([N:26]1[CH:30]=[C:29]([C:31]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:6]=[CH:5]3)([OH:36])[C:32]([F:35])([F:33])[F:34])[CH:28]=[C:27]1[C:37]#[N:38])[CH:24]=[CH2:25]
Reactant: Fc1ccc(-n2ncc3cc(Br)ccc32)cc1
Reactant: C=CCn1cc(C(=O)C(F)(F)F)cc1C#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCn1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)cc1C#N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To a chilled (−78° C.) solution of 5-bromo-1-(4-fluorophenyl)-1H-indazole (1.3 g, 4.3 mmol, 1.1 equiv.) in 20 mL of THF was added n-BuLi (2.5 M in hexanes, 1.7 ml, 4.3 mmol, 1.1 equiv.) followed by a chilled (−78° C.) solution of 1-allyl-4-(2,2,2-trifluoroacetyl)-1H-pyrrole-2-carbonitrile (0.9 g, 3.9 mmol, 1 equiv.) in 3 mL of THF. After 30 minutes, the mixture was warmed to 0° C., quenched with water, diluted with brine, and extracted with EtOAc. The combined organics were dried, filtered, and concentrated in vacuo. The residue was purified by flash chromatography using EtOAc-hexanes (5-30% gradient) to afford 1.15 g (66%) of the title compound as an off-white solid. MS m/z 441.26 (MH+).
Reaction SMILES: [N+](C1C=CC(N2CCNCC2)=CC=1)([O-])=O.[N+:16]([C:19]1[CH:20]=[C:21]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:22]=[CH:23][CH:24]=1)([O-])=O.CS(C1N=CC2=CC=C([C:43]3C=CC=[CH:45][C:44]=3[O:49]C)N2N=1)=O.CS([C:54]1[N:59]=[CH:58][C:57]2=[CH:60][CH:61]=[C:62]([C:63]3[CH:68]=[CH:67][C:66]([S:69]([CH3:72])(=[O:71])=[O:70])=[CH:65][CH:64]=3)[N:56]2[N:55]=1)=O>>[CH3:72][S:69]([C:66]1[CH:67]=[CH:68][C:63]([C:62]2[N:56]3[C:57]([CH:58]=[N:59][C:54]([NH:16][C:19]4[CH:20]=[C:21]([N:25]5[CH2:30][CH2:29][N:28]([CH2:43][C@H:44]([OH:49])[CH3:45])[CH2:27][CH2:26]5)[CH:22]=[CH:23][CH:24]=4)=[N:55]3)=[CH:60][CH:61]=2)=[CH:64][CH:65]=1)(=[O:71])=[O:70]
Reactant: CS(=O)c1ncc2ccc(-c3ccc(S(C)(=O)=O)cc3)n2n1
Reactant: O=[N+]([O-])c1cccc(N2CCNCC2)c1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Agent: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Product: C[C@@H](O)CN1CCN(c2cccc(Nc3ncc4ccc(-c5ccc(S(C)(=O)=O)cc5)n4n3)c2)CC1

Procedure:
The compound was prepared in an analogous fashion to Example 73 replacing 1-(4-Nitro-phenyl)-piperazine with 1-(3-Nitro-phenyl)-piperazine and 2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine with 2-Methanesulfinyl-7-(4-methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazine to afford 44.32 mg of (R)-1-(4-{3-[7-(4-Methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-piperazin-1-yl)-propan-2-ol as a lyophilized powder. (M+H)=507.10. 1H NMR (400 MHz, DMSO, d6) δ 9.49 (s, 2H), 9.08 (s, 1H), 8.51 (d, 2H, J=8.52 Hz), 8.03 (d, 2H, J=8.56 Hz), 7.42 (m, 1H), 7.37 (d, 1H, J=4.80 Hz), 7.26 (m, 2H), 7.01 (d, 1H, J=4.80 Hz), 6.67 (d, 1H, J=6.72 Hz), 4.15 (m, 2H), 3.70 (m, 4H), 3.31 (s, 3H), 3.13 (m, 5H), 1.13 (d, 3H, J=6.16 Hz).
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]2[NH:6][C:7]([CH2:9][CH2:10][N:11]3[CH2:15][CH2:14][CH2:13][CH:12]3[CH3:16])=[N:8][C:4]=2[CH:3]=1.[C:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)#[N:20]>>[CH3:16][CH:12]1[CH2:13][CH2:14][CH2:15][N:11]1[CH2:10][CH2:9][C:7]1[NH:6][C:5]2[CH:17]=[CH:18][C:2]([C:24]3[CH:25]=[CH:26][C:21]([C:19]#[N:20])=[CH:22][CH:23]=3)=[CH:3][C:4]=2[N:8]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CC1CCCN1CCc1nc2cc(Br)ccc2[nH]1
Product: CC1CCCN1CCc1nc2cc(-c3ccc(C#N)cc3)ccc2[nH]1

Procedure:
Compounds of formula (55) and (55a) can be prepared from 2(R)-methylpyrrolidine HCl (50) and ethyl acrylate (51) as shown in Scheme 6. 2(R)-Methylpyrrolidine HCl can be treated with potassium carbonate to provide 2(R)-methylpyrrolidine (41), which is reacted with ethyl acrylate (51) to provide 3-(2-methyl-pyrrolidin-1-yl)-propionic acid ethyl ester (52). Compound (52) is reacted with 4-bromo-benzene-1,2-diamine (53), which is produced by controlled hydrogenation of 2-amino-5-bromo-nitrobenzene, Chemical Abstracts number 875-514, to provide 5-bromo-2-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-1H-benzoimidazole (54). Compound (54) can be reacted with a 4-cyanophenylboronic acid to provide 4-{2-[2-(2-methyl-pyrrolidin-1-yl)-ethyl]-1H-benzoimidazol-5-yl}-benzonitrile (55). As previously described for Scheme 5, the amine compound (41) can be any amine of the formula HNRaRb, wherein Ra and Rb are as defined for R4 and R5. Also, the 4-cyanophenylboronic acid can be replaced with any boronic acid of the formula RcB(OH)2, wherein Rc is aryl or heteroaryl to provide compounds of general structure (55a). Additionally, compounds (55) and (55a) may be alkylated on the benzimidazole nitrogen by treatment with a base, such as cesium carbonate, and an alkylating agent, such as methyl iodide.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:27]([OH:29])=O)[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].O[N:31]=[C:32]([NH2:37])[C:33]([CH3:36])([CH3:35])[CH3:34]>>[C:33]([C:32]1[N:37]=[C:27]([CH:13]2[CH2:14][CH:15]([C:17]3[CH:18]=[CH:19][C:20]([C:23]([F:25])([F:24])[F:26])=[CH:21][CH:22]=3)[CH2:16][N:11]([C:9]([N:6]3[CH2:5][CH2:4][CH:3]([C:1]#[N:2])[CH2:8][CH2:7]3)=[O:10])[CH2:12]2)[O:29][N:31]=1)([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)C(N)=NO
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)CC1
Product: CC(C)(C)c1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCC(C#N)CC3)C2)n1

Procedure:
100 mg (0.244 mmol) of 1-[(4-cyanopiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 100A) and 31.2 mg (0.269 mmol) of N′-hydroxy-2,2-dimethylpropanimidamide were reacted according to the General Method 1. Yield: 79.1 mg (66% of theory).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[N:8]2[CH:9]=[N:10][CH:11]=[C:7]2[N:6]=[C:5]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:4]=1.C([O-])(=O)C.[Na+].[I:29]Cl>C(O)(=O)C.O>[I:29][C:11]1[N:10]=[CH:9][N:8]2[C:3]([C:2]([F:1])([F:22])[F:23])=[CH:4][C:5]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=3)=[N:6][C:7]=12
Reactant: ClI
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3cncc3n2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3cnc(I)c3n2)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 100.1 %

Procedure:
To a stirred solution of 4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine (1.05 g, 3.17 mmol) in acetic acid (4 mL) was added at room temperature sodium acetate (0.29 g, 3.58 mmol) and drop wise a solution of iodine monochloride (0.53 g, 3.58 mmol) in acetic acid (4 mL). The reaction mixture was stirred at room temperature for 19 h, diluted slowly with water (100 mL), stirred at room temperature for 30 min, the precipitate was filtered off, washed with water and dried to give 8-iodo-4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine (1.45 g, 100%) as an orange solid. MS (EI) 457.0 [(M)+]; mp 141° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](=O)[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][CH2:20][CH:21]([OH:24])[CH2:22][NH2:23].[H][H]>[Pt]=O.C(O)C>[NH2:19][CH2:20][CH:21]([OH:24])[CH2:22][NH:23][CH:9]([CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCC(O)CN
Reactant: O=C(CCc1ccccc1)CCc1ccccc1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Product: NCC(O)CNC(CCc1ccccc1)CCc1ccccc1

Procedure:
A solution of 1,5-di-(phenyl)-3-pentanone (9.5 g., 0.04 mole) in 50 cc. of anhydrous ethanol is added dropwise over about 20 minutes to a stirred solution of 1,3-diamino-2-hydroxypropane (25 g., 0.27 mole) in 200 cc. of ethanol. The resulting mixture is then heated at reflux for about two hours, allowed to cool, 1.0 g. platinum oxide added, and the mixture reduced under a 40 psi hydrogen atmosphere until hydrogen uptake ceases. The mixture is then filtered from the catalyst, concentrated in vacuo to remove the ethanol, the residue taken up in ether (250 cc.), washed with water, dried over sodium sulfate, filtered and concentrated in vacuo to yield the product 1-amino-3-[1,5-di-(phenyl)-3-pentylamino]-2-propanol.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].Cl.Cl.[CH3:21][N:22]1[CH2:28][CH:27]2[NH:29][CH:24]([CH2:25][CH2:26]2)[CH2:23]1.N12CCCN=C1CCCCC2>C(#N)C>[ClH:1].[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([F:18])=[C:2]([CH:23]3[N:22]([CH3:21])[CH2:28][CH:27]4[NH:29][CH:24]3[CH2:25][CH2:26]4)[N:11]=2)[C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8]1)[CH3:13]
Reactant: CN1CC2CCC(C1)N2
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(C3C4CCC(CN3C)N4)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
A mixture of 0.54 g (2.0 mmol) of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 0.50 g (2.5 mmol) of 3-methyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride [P. A. Sturm, et al, J. Med. Chem., 17, 481 (1974)], 0.75 ml (5.0 ml) 1,8-diazabicyclo[5.4.0]undec-7-ene and 20 ml of acetonitrile was heated under reflux for 1.5 hours and stirred overnight at room temperature. The reaction mixture was filtered and the solid washed with ethanol to give 0.46 g of the title compound, mp>310°.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4](C(OCC)=O)[C:3]=1[C:17]([C:19]1[CH:20]=[C:21]([S:25]([NH2:28])(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1)=[O:18]>CC(O)C.C1(C)C=CC=CC=1>[NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:17]([C:19]1[CH:20]=[C:21]([S:25]([NH2:28])(=[O:26])=[O:27])[CH:22]=[CH:23][CH:24]=1)=[O:18]
Reactant: CCOC(=O)n1c(C(=O)c2cccc(S(N)(=O)=O)c2)c(N)c2ccc(Cl)cc21
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: Nc1c(C(=O)c2cccc(S(N)(=O)=O)c2)[nH]c2cc(Cl)ccc12

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 employing 3-[3-amino-6-chloro-1-(ethoxycarbonyl)indole-2-carbonyl]benzenesulfonamide (step 1). m.p.: 125-127° C. (2-propanol/toluene)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8](OCC)=O)[CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH2:19]>O1CCCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([OH:19])[CH3:8])[CH:2]=1
Reactant: O
Reactant: CCOC(=O)Cc1cccnc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)c1cccnc1
Reaction time: 0.5 h

Procedure:
Ethyl 3-pyridylacetate (2.0 ml) was dissolved in tetrahydrofuran (66 ml). Under ice cooling, lithium aluminum hydride (0.5 g) was added thereto followed by stirring for 30 min. After adding water (0.5 ml), a 5 N aqueous solution of sodium hydroxide (0.5 ml) and further water (1.5 ml), the resulting precipitate was filtered off and washed with ethyl acetate. The filtrate was concentrated under reduced pressure to give the title compound (1.636 g) as a pale yellow oil (1.636 g) (yield: quantitative).
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].Br[CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[C:14]([O:18][C:19]([NH:21][C@H:22]1[C@@H:25]([CH3:26])[NH:24][C:23]1=[O:27])=[O:20])([CH3:17])([CH3:16])[CH3:15]>CN(C)C=O>[C:14]([O:18][C:19]([NH:21][C@H:22]1[C@@H:25]([CH3:26])[N:24]([C:2]([NH:3][CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[O:1])[C:23]1=[O:27])=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: C[C@H]1NC(=O)[C@H]1NC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)CBr
Reactant: N#C[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1C(=O)NCC(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a suspension of potassium cyanate (558 mg, 6.9 mmol) in 6 ml of dimethylformamide was added t-butyl bromoacetate (1.1 ml, 6.6 mmol). The mixture was heated to 100° C. for 1 hour and cooled to room temperature. (3s-cis)-3-[[(t-butyloxy)carbonyl]amino]-4-methyl-2-azetidinone (1.2 g, 6.0 mmol) was then added, and the mixture was heated to 65° C. After being stirred at 65° C. for 1 hour, the mixture was heated to 100° C. and stirred for an additional hour. Additional isocyanate was prepared (using 558 mg potassium cyanate and 1.1 ml of t-butyl bromoacetate as described above) and added to the reaction mixture at room temperature. After being heated at 65° C. for 1 hour and 100° C. for 1 hour, the reaction mixture was stirred at room temperature overnight.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[C:6]([NH:13][C@H:14]([C:19]([OH:21])=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]>>[N-:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[C:6]([NH:13][C@H:14]([C:19]([OH:21])=[O:20])[CH2:15][CH:16]([CH3:17])[CH3:18])([O:8][C:9]([CH3:11])([CH3:10])[CH3:12])=[O:7]
Reactant: c1c[nH]cn1
Agent: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: c1c[n-]cn1

Procedure:
The N-BOC-L-leucine imidazolide was prepared from 136 g of imidazole and 115 g of N-BOC-L-leucine following the method described in paragraph B above. Similarly, the magnesium enolate of methyl acid malonate was prepared from 236 g of methyl acid malonate following the method described in paragraph D above.