Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[NH:7][CH:8]=1.C(N(CC)CC)C.Cl[CH2:18][O:19][C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1>C(Cl)Cl>[CH:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:28]=[CH:29][C:20]=1[O:19][CH2:18][N:5]1[CH:4]=[C:3]([Cl:2])[CH:8]=[N:7][C:6]1=[O:9]
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: ClCOc1ccc2ccccc2c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1ncc(Cl)cn1COc1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
5-Chloropyrimidine-2-one hydrochloride (5 mmol) and triethylamine were stirred together in CH2Cl2 (30 ml). When all the solid had dissolved there was added a solution of 2-chloromethoxynaphthalene [see Preparation 13] (5 mmol) in CH2Cl2 (10 ml) with stirring at room temperature for 5 minutes. The mixture was stirred at room temperature for 24 hours before the solvent was distilled off. The residue was triturated with water, extracted into CHCl3, dried (MgSO4) and evaporated to give a mixture of the tite compound and the O-alkylated isomer in the ratio 4:1. Yield 1.27 g (86%). The O-isomer was removed from the product by extraction with ether followed by recrystallization of the N-isomer from acetone m.p. 168° C. 1H NMR (CDCl3 δ): 5.85 (s, CH2), 7.10-8.1 (m, 8H. Ar+H-4), 8.48 (H-6, d7 =4 Hz) IR (KBr, cm -1): 1675 (CO).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.C([Mg]Cl)(C)C.[CH:14]([C:17]1[CH:21]=[C:20]([NH:22][C:23]2[C:24]3[CH2:40][C:39]([CH3:42])([CH3:41])[CH2:38][C:25]=3[N:26]=[C:27]([N:29]3[CH2:33][CH2:32][CH2:31][C@H:30]3[C:34](OC)=[O:35])[N:28]=2)[NH:19][N:18]=1)([CH3:16])[CH3:15]>C1COCC1>[F:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][C:34]([C@@H:30]2[CH2:31][CH2:32][CH2:33][N:29]2[C:27]2[N:28]=[C:23]([NH:22][C:20]3[NH:19][N:18]=[C:17]([CH:14]([CH3:16])[CH3:15])[CH:21]=3)[C:24]3[CH2:40][C:39]([CH3:42])([CH3:41])[CH2:38][C:25]=3[N:26]=2)=[O:35])=[CH:3][CH:4]=1
Reactant: COC(=O)[C@@H]1CCCN1c1nc2c(c(Nc3cc(C(C)C)n[nH]3)n1)CC(C)(C)C2
Reactant: Nc1ccc(F)nc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)c1cc(Nc2nc(N3CCC[C@H]3C(=O)Nc3ccc(F)nc3)nc3c2CC(C)(C)C3)[nH]n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17.9 %

Procedure:
To a stirred solution of 5-amino-2-fluoropyridine (79 mg, 0.703 mmol) in dry THF (2 mL) was added isopropyl magnesium chloride 2M in THF (0.43 mL, 0.86 mmol) dropwise under nitrogen atmosphere at 0° C. The resultant mixture was stirred at 0° C. for 30 min. To this was added a solution of (S)-methyl 1-(4-(3-isopropyl-1H-pyrazol-5-ylamino)-6,6-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxylate (70 mg, 0.175 mmol) in THF (2 mL) dropwise at 0° C. and the reaction mixture was allowed to stir at RT for 2 h. The reaction mixture was cooled to 0° C. and quenched by saturated ammonium chloride solution (10 mL). The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (2×20 mL). The organic layer was washed with brine (20 mL) and dried over anhydrous sodium sulfate. Removal of EtOAc under vacuum gave a crude oil which was purified by reverse phase HPLC to afford 15 mg of (S)—N-(6-fluoropyridin-3-yl)-1-(4-(3-isopropyl-1H-pyrazol-5-ylamino)-6,6-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyrrolidine-2-carboxamide. 1H NMR (400 MHz, CD3OD, freebase) δ (ppm): 1.15-1.25 (m, 6H), 1.20 (s, 6H), 2.02-2.18 (m, 2H), 2.22-2.3.8 (m, 2H), 2.58 (s, 2H), 2.62 (s, 2H), 2.79-2.90 (m, 1H), 3.60-3.70 (m, 1H), 3.78-3.87 (m, 1H), 4.77 (dd, 1H), 6.25 (brs, 1H), 6.99 (dd, 1H), 7.97 (brs, 1H), 8.20 (s, 1H). The other enantiomer was obtained using the chiral (R) starting material.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C@H:11]([N:12]([CH3:22])[C:13](=[O:21])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3.[OH-].[K+].[CH2:25](I)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>CS(C)=O.O>[CH2:25]([O:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C@H:11]([N:12]([CH3:22])[C:13](=[O:21])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CN1C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](O)CC[C@H]4[C@@H]3CC[C@@H]12
Reactant: CCCCCCI
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCCO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4N(C)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 8 h

Procedure:
To a solution of 17β-hydroxy-4-methyl-5α-4-azaandrostan-3-one (102 mg, 0.336 mmol) in DMSO (3 ml) was added powdered KOH (300 mg) followed by n-hexyliodide (400 μl). After stirring the reaction mixture overnight, the reaction was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, then brine, then dried (MgSO4), and concentrated in vacuo. The residue was then purified by preparative thin layer chromatography to afford the title compound, characterized by H1NMR.
Reaction SMILES: Br[CH2:2][C:3]1([C:6]2[CH:7]=[CH:8][C:9]([CH3:12])=[N:10][CH:11]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.Cl.[CH3:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28]N)=[CH:24][CH:23]=1.[CH3:30][N:31]1[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]1>>[CH3:30][N:31]1[CH2:36][CH2:35][C:34]2[N:28]([CH2:2][C:3]3([C:6]4[CH:11]=[N:10][C:9]([CH3:12])=[CH:8][CH:7]=4)[CH2:5][CH2:4]3)[C:25]3[CH:24]=[CH:23][C:22]([CH3:21])=[CH:27][C:26]=3[C:33]=2[CH2:32]1
Reactant: Cc1ccc(C2(CBr)CC2)cn1
Reactant: CN1CCC(=O)CC1
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1)c1c(n2CC2(c3ccc(C)nc3)CC2)CCN(C)C1

Procedure:
The title compound is prepared by following Method 8 by using 5-(1-(bromomethyl)cyclopropyl)-2-methylpyridine, (4-methylphen ylhydrazine hydrochloride triethylamine and N-methyl-4-piperidone.
Reaction SMILES: Cl.[C:2]1([CH:8]([O:15][C:16]([C:18]2[N:23]3[C:24](=[O:27])[C@@H:25]([NH2:26])[C@H:22]3[S:21][CH2:20][C:19]=2[O:28][S:29]([CH3:32])(=[O:31])=[O:30])=[O:17])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]([O:37][C:38]([NH:40][C:41]1[S:42][CH:43]=[C:44](/[C:46](=[N:50]/[O:51][CH:52]2[CH2:56][CH2:55][CH2:54][CH2:53]2)/[C:47](O)=[O:48])[N:45]=1)=[O:39])([CH3:36])([CH3:35])[CH3:34].CN1CCOCC1.P(Cl)(Cl)(OC1C=CC=CC=1)=O.Cl>ClCCl.O>[C:2]1([CH:8]([O:15][C:16]([C:18]2[N:23]3[C:24](=[O:27])[C@@H:25]([NH:26][C:47](=[O:48])/[C:46](/[C:44]4[N:45]=[C:41]([NH:40][C:38]([O:37][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:39])[S:42][CH:43]=4)=[N:50]\[O:51][CH:52]4[CH2:56][CH2:55][CH2:54][CH2:53]4)[C@H:22]3[S:21][CH2:20][C:19]=2[O:28][S:29]([CH3:32])(=[O:31])=[O:30])=[O:17])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2CCCC2)C(=O)O)cs1
Reactant: CS(=O)(=O)OC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cl
Agent: O=P(Cl)(Cl)Oc1ccccc1
Solvent: CN1CCOCC1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2CCCC2)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(OS(C)(=O)=O)CS[C@H]23)cs1
Reaction time: 0.02 h
Yield: 77.7 %

Procedure:
To a suspension of 7β-amino-3-methanesulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester hydrochloride (1.49 g: 3 mMol.) and (Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-cyclopentyloxyimino-acetic acid (1.23 g: 3.5 mMol.) in dichloromethane (30 ml) at -30° C. are added N-methylmorpholine (1.1 ml: 10 mMol.) and, after 1 minute, phenyl dichlorophosphate (0.49 ml: 3.3 mMol.), and the mixture is stirred at the same temperature for 2 hours. The reaction mixture is mixed with 1N-hydrochloric acid (6 ml) and water (50 ml) and extracted with ethyl acetate. The extract is washed with water, 5% aqueous sodium hydrogen carbonate, and water, dried over sodium sulfate, and purified by silica gel chromatography (toluene: ethyl acetate=5:1, containing 0.5% acetic acid) to give 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-cyclopentyloxyiminoacetamido]-3-methanesulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester (1.86 g) as white foam. Yield: 78%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C@H:14]([NH:30][S@:31]([C:33]([CH3:36])([CH3:35])[CH3:34])=[O:32])[CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[Si:50]([O:67][CH2:68][CH2:69][N:70]([CH2:100][CH3:101])[CH2:71][CH2:72][C@@H:73]([NH:82][C:83]1[CH:88]=[CH:87][C:86]([S:89]([NH2:92])(=[O:91])=[O:90])=[CH:85][C:84]=1[S:93]([C:96]([F:99])([F:98])[F:97])(=[O:95])=[O:94])[CH2:74][S:75][C:76]1[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=1)([C:63]([CH3:66])([CH3:65])[CH3:64])([C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Si:50]([O:67][CH2:68][CH2:69][N:70]([CH2:100][CH3:101])[CH2:71][CH2:72][C@@H:73]([NH:82][C:83]1[CH:88]=[CH:87][C:86]([S:89]([NH:92][C:25](=[O:26])[C:24]2[CH:28]=[CH:29][C:21]([N:18]3[CH2:19][CH2:20][CH:15]([C@H:14]([C:9]4[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=4[C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:30][S@:31]([C:33]([CH3:36])([CH3:35])[CH3:34])=[O:32])[CH2:16][CH2:17]3)=[CH:22][CH:23]=2)(=[O:90])=[O:91])=[CH:85][C:84]=1[S:93]([C:96]([F:98])([F:99])[F:97])(=[O:94])=[O:95])[CH2:74][S:75][C:76]1[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=1)([C:63]([CH3:64])([CH3:66])[CH3:65])([C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1
Reactant: CCN(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CC[C@H](CSc1ccccc1)Nc1ccc(S(N)(=O)=O)cc1S(=O)(=O)C(F)(F)F
Reactant: CC(C)(C)[S@](=O)N[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)O)cc2)CC1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CC[C@H](CSc1ccccc1)Nc1ccc(S(=O)(=O)NC(=O)c2ccc(N3CCC([C@@H](N[S@@](=O)C(C)(C)C)c4ccccc4-c4ccc(Cl)cc4)CC3)cc2)cc1S(=O)(=O)C(F)(F)F
Reaction time: 0.25 h
Yield: 103.6 %

Procedure:
4-(4-((R)-(4′-chlorobiphenyl-2-yl)((S)-1,1-dimethylethylsulfinamido)methyl)piperidin-1-yl)benzoic acid (INTERMEDIATE 130, 0.12 g, 0.23 mmol), DMAP (56 mg, 0.46 mmol), and EDC (88 mg, 0.46 mmol) were placed in a 40 ml vial and flushed with nitrogen. DCM (3.0 ml) and DIPEA (0.08 ml, 0.46 mmol) were added, and the solution was stirred at r.t for 15 min. A solution of (R)-4-(4-((2-(tert-butyldiphenylsilyloxy)ethyl)(ethyl)amino)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide (INTERMEDIATE 25, 0.18 g, 0.23 mmol) in DCM (1.5 ml) was added to the solution and the reaction mixture was stirred at r.t overnight. The reaction mixture was diluted with DCM and washed with sodium bisulfate (1N, aq.) followed by sodium bicarbonate (saturated, aq). The organic layer was dried (Na2SO4), filtered, and evaporated under reduced pressure to give a residue that was dried under vacuum to provide N-(4-((R)-4-((2-(tert-butyldiphenylsilyloxy)ethyl)(ethyl)amino)-1-(phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)phenylsulfonyl)-4-(4-((R)-(4′-chlorobiphenyl-2-yl)((S)-1,1-dimethylethylsulfinamido)methyl)piperidin-1-yl)benzamide (EXAMPLE 12, STEP 1, 0.31 g) which was used in the preparation of EXAMPLE 12, STEP 2 without further purification.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[F:8][C:7]1[C:2]([CH:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:9]([O:17][CH2:18][CH3:19])=[O:16])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Fc1cccnc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCOC(=O)C(C(=O)OCC)c1ncccc1F
Temperature: 100 °C
Reaction time: 3 h
Yield: 72.8 %

Procedure:
A mixture of 3.95 g of 2,3-difluoropyridine, 13.2 g of diethyl malonate, 38 ml of dimethyl sulfoxide and 26.85 g of cesium carbonate was stirred for 3 hours at 100° C. under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, then, to this was added ice water and extracted with ethyl acetate. The organic layer was washed with saturated brine twice, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure. 12.18 g of the resultant residue was subjected to silica gel column chromatography, to obtain 6.38 g of diethyl (3-fluoro-2-pyridyl)malonate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[N:11]([CH3:27])[C:12]2[C:21]3[C:20](=[O:22])[NH:19][C:18]([CH:23]=[O:24])=[C:17]([CH3:25])[C:16]=3[CH:15]=[CH:14][C:13]=2[N:26]=1.[CH:28]([Mg]Br)=[CH2:29]>C1COCC1>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[NH:9][C:10]1[N:11]([CH3:27])[C:12]2[C:21]3[C:20](=[O:22])[NH:19][C:18]([CH:23]([OH:24])[CH:28]=[CH2:29])=[C:17]([CH3:25])[C:16]=3[CH:15]=[CH:14][C:13]=2[N:26]=1
Reactant: C=C[Mg]Br
Reactant: Cc1c(C=O)[nH]c(=O)c2c1ccc1nc(Nc3c(Cl)cccc3Cl)n(C)c12
Solvent: C1CCOC1
Product: C=CC(O)c1[nH]c(=O)c2c(ccc3nc(Nc4c(Cl)cccc4Cl)n(C)c32)c1C
Temperature: -78 °C

Procedure:
A suspension of 2-(2,6-dichlorophenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1-H-imidazo[4,5-h]isoquinoline-7-carbaldehyde (2) (100 mg, 0.25 mmol) in THF (3ml) was cooled to −78° C. Vinylmagnesium bromide (1M in THF, 2.0 mmol) was added dropwise, and the brown suspension was warmed gradually to −10° C. over 2 h. The solution was quenched with saturated ammonium chloride and extracted with ethyl acetate, and concentrated in vacuo to provide the title compound, which was used in the next step without purification, mp 235-236° C., MS (ES) 429 (MH+).
Reaction SMILES: [C:1]1([P:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:8]C2C=CC=CC=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:21](=O)[CH2:22][CH2:23][CH3:24].[CH3:26][C:27]1[CH:28]=[CH:29][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:31][CH:32]=1>ClC1C=CC=CC=1>[C:15]1([P:7](=[O:8])([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:21]([NH:36][S:33]([C:30]2[CH:31]=[CH:32][C:27]([CH3:26])=[CH:28][CH:29]=2)(=[O:34])=[O:35])[CH2:22][CH2:23][CH3:24])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: c1ccc(OP(c2ccccc2)c2ccccc2)cc1
Reactant: CCCC=O
Reactant: Cc1ccc(S(N)(=O)=O)cc1
Solvent: Clc1ccccc1
Product: CCCC(NS(=O)(=O)c1ccc(C)cc1)P(=O)(c1ccccc1)c1ccccc1
Temperature: 105 °C

Procedure:
A white solid (60.6 g, 71% yield) separates when a mixture of 0.2 mole each of phenyl diphenylphosphinite, n-butyraldehyde, and p-toluenesulfonamide in 125 g of chlorobenzene is warmed at 105° C. for 1 hr. Recrystallization three times from o-dichlorobenzene gives a white solid product: mp 254°-263°; 31P nmr (CF3CO2H)- 44.7 ppm.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16]([OH:18])=[O:17])=[O:13])=[C:4]1[CH3:23])[CH3:2].S(Cl)(Cl)=O.CO.N1C=CC=C[CH:31]=1>C(Cl)CCl>[CH3:31][O:13][C:12]1([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:3]([CH2:1][CH3:2])[C:4]=2[CH3:23])[C:14]2[C:15](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:16](=[O:18])[O:17]1
Reactant: CCn1c(C)c(C(=O)c2ccccc2C(=O)O)c2ccccc21
Reactant: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: CO
Solvent: ClCCCl
Product: CCn1c(C)c(C2(OC)OC(=O)c3ccccc32)c2ccccc21

Procedure:
Proceeding in a manner similar to that described in Example 1 above, 5.1 g of 2-(1-ethyl-2-methylindol-3-yl)carbonylbenzoic acid, 1.2 ml of thionyl chloride and 5.0 ml of methyl alcohol were interacted in 30.0 ml of ethylene dichloride in the presence of 1.3 ml of pyridine to obtain 2.1 g of 3-methoxy-3-(1-ethyl-2-methylindol-3-yl)phthalide (Formula III: R0 =R=R1 =R2 =R8 =H; R6 =C2H5 ; R7 =Y=CH3 ; X=O), a dark brown-colored oil. Significant infrared maxima appeared at 1770 (C=O; s) and 740 cm-1 (C=O; s). Analysis by mass spectrum showed m/e peaks at 321 (M+) and 290 (M+ -OCH3). A toluene solution of the product spotted on an acidic clay-coated paper developed a red-purple-colored image.
Reaction SMILES: [CH2:1]([N:9]=[N+:10]=[N-:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:12]1([C:18]#[CH:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C[C-]1C(C)=C(C)C(C)=C1C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Ru+].C1COCC1>[CH2:1]([N:9]1[C:18]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:19][N:11]=[N:10]1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: [N-]=[N+]=NCCc1ccccc1
Reactant: C#Cc1ccccc1
Agent: Cl[Ru+]
Agent: Cc1c(C)c(C)[c-](C)c1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1ccc(CCn2nncc2-c2ccccc2)cc1
Yield: 89 %

Procedure:
Phenethyl azide (148 mg, 1 mmol), phenylacetylene (113 mg, 1.1 mmol), Cp*RuCl(PPh3)2 (8 mg, 0.01 mmol, 1 mol %). Solvent: THF, 10 mL, 60° C., 2 hours. Off-white product obtained in 89% yield (221 mg). ESI-MS: m/z 250, [M+H].
Reaction SMILES: [CH3:1][C:2]1[C:7]([N:8]2[CH2:13][C@@H:12]3[CH2:14][C@H:9]2[CH2:10][N:11]3C(OC(C)(C)C)=O)=[CH:6][CH:5]=[CH:4][N:3]=1.C(Cl)[Cl:23]>FC(F)(F)C(O)=O>[ClH:23].[CH3:1][C:2]1[C:7]([N:8]2[CH2:13][C@@H:12]3[CH2:14][C@H:9]2[CH2:10][NH:11]3)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ncccc1N1C[C@@H]2C[C@H]1CN2C(=O)OC(C)(C)C
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ncccc1N1C[C@@H]2C[C@H]1CN2
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
tert-Butyl (1S,4S)-5-(2-methyl-3-pyridyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (230 mg, 0.8 mmol) was dissolved in a mixture of DCM (5 ml) and trifluoroacetic acid (5 ml) and stirred at room temperature overnight. The mixture was concentrated under reduced pressure, the residue was dissolved in DCM and evaporated again. The last step was repeated, the residue was dissolved in THF (10 ml) and hydrochloric acid was added (4N in dioxane, 4 ml). The precipitate was isolated by centrifugation and decantation, washed with THF (2×) and dried under reduced pressure to yield 170 mg of a brown solid (0.75 mmol, yield 94%) MS (ESI) m/z=190.1 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.N1C=CC=C([C:25]2[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=2)C=1>C1(C)C=CC=CC=1>[OH:12][C:3]1[C:2]([NH:1][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][C:25]([C:16]3[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=3)=[CH:26][CH:27]=2)=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cccc(N)c1O
Reactant: O=C(Cl)c1ccc(-c2cccnc2)cc1
Reactant: c1ccncc1
Solvent: Cc1ccccc1
Product: COC(=O)c1cccc(NC(=O)c2ccc(-c3ccncc3)cc2)c1O
Temperature: 70 °C
Reaction time: 4 h
Yield: 71.8 %

Procedure:
Thionyl chloride (10 mL) was added to 4-(pyridin-4-yl)benzoic acid (1.6 g, 8 mmol) and the mixture was stirred under reflux overnight. The solvent was evaporated under reduced pressure and the residue was dried in vacuum giving 4-(pyridin-3-yl)benzoyl chloride. To a solution of methyl 3-amino-2-hydroxybenzoate (1 g, 6 mmol) and pyridine (480 mg, 6 mmol) in toluene (50 mL) was added 4-(pyridin-3-yl)benzoyl chloride (1.3 g, 6 mmol) portion wise at 0° C. and then stirred at 70° C. for 4 h. The resulting mixture was extracted with ethyl acetate (100 mL×4), the organic phase was washed with water and saturated sodium bicarbonate, dried with anhydrous sodium sulfate and evaporated under reduced pressure to obtain methyl 2-hydroxy-3-(4-(pyridin-4-yl)benzamido)benzoate as yellow solid (1.5 g, yield 71%). 1H-NMR (400 MHz, CDCl3) δ 4.00 (s, 3H), 6.97-7.01 (t, J=8.2 Hz, 1H), 7.57-7.63 (m, 3H), 7.78-7.80 (d, J=8.0 Hz, 2H), 8.05-8.07 (d, J=8.8 Hz, 2H), 8.67-8.78 (m, 4H), 11.44 (s, 1H); LC-MS (ESI) m/z: 349 (M+1)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([C:28]([NH2:30])=[O:29])=[CH:5][C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([CH2:15][C@@H:16]([NH2:26])[CH2:17][O:18]CC3C=CC=CC=3)[C:7]=2[N:27]=1.I[Si](C)(C)C.Cl>C(Cl)(Cl)Cl.CO>[NH2:2][C:3]1[C:4]([C:28]([NH2:30])=[O:29])=[CH:5][C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([CH2:15][C@@H:16]([NH2:26])[CH2:17][OH:18])[C:7]=2[N:27]=1
Reactant: NC(=O)c1cc2c3ccccc3n(C[C@@H](N)COCc3ccccc3)c2nc1N
Agent: C[Si](C)(C)I
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: NC(=O)c1cc2c3ccccc3n(C[C@@H](N)CO)c2nc1N
Temperature: 25 °C
Yield: 50.1 %

Procedure:
To a cooled (0° C.) solution of 2-amino-9-[(2R)-2-amino-3-(benzyloxy)propyl]-9H-pyrido[2,3-b]indole-3-carboxamide (61, 81 mg, 0.160 mmol) in chloroform (2 mL) was added iodotrimethylsilane (140 uL, 0.990 mmol). The reaction was stirred under argon, allowed to warm slowly to room temperature and then stirred an additional 16 h. The reaction mixture was filtered and concentrated in vacuo. The crude mixture was purified by reverse phase HPLC (Phenomenex Luna 15 μm C18, aqueous NH4OAc/CH3CN) to provide the product which was then converted to the hydrochloride salt by stirring with a solution of excess hydrochloric acid in methanol to afford 2-amino-9-[(2R)-2-amino-3-hydroxypropyl]-9H-pyrido[2,3-b]indole-3-carboxamide (65, 24 mg, 45%). NH4OAc standard conditions. DAD Retention time=4.76 min. M+H=300. 1H NMR (300 MHz, MeOD-d4): 8.97 (s, 1H), 8.01 (d, J=7.0 Hz, 1H) 7.67 (d, J=7.4 Hz, 1H), 7.52 (t, J=6.9, 1H), 7.38 (t, J=6.9 Hz, 1H), 4.75-4.69 (m, 2H), 3.96-3.81 (m, 2H), 3.71-3.62 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([OH:26])=O)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][NH2:34])[CH:28]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23][C:24]([NH:34][CH2:33][C:29]3[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=3)=[O:26])[N:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:3]=12
Reactant: NCc1cccnc1
Reactant: O=C(O)Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21)NCc1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 30.1 %

Procedure:
To a suspension of 2-(4-chloro-3,5-diphenyl-1H-pyrazolo[3,4-c]pyridazin-1-yl)acetic acid (100 mg, 0.27 mmol) in DMF (2 mL) were added pyridin-3-ylmethanamine (33 mg, 0.30 mmol), diisopropylethylamine (DIPEA) (105 μL, 0.60 mmol) and 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (125 mg, 0.33 mmol). The solution obtained was stirred at room temperature for 18 h then diluted with EtOAc. The organic phase was washed with water and brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was purified by preparative HPLC yielding Compound 57 as a solid (37 mg).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([CH2:11]O)[CH:6]=1)[CH3:3].S(Cl)([Cl:15])=O>ClCCl>[ClH:15].[Cl:15][CH2:11][C:7]1[CH:6]=[C:5]([CH2:4][N:2]([CH3:3])[CH3:1])[CH:10]=[CH:9][N:8]=1
Reactant: CN(C)Cc1ccnc(CO)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CN(C)Cc1ccnc(CCl)c1
Product: Cl
Reaction time: 1 h

Procedure:
4-Dimethylaminomethyl-2-hydroxymethylpyridine (13.45 g) in dichloromethane (200 ml) was added dropwise to a stirred solution of thionyl chloride (30 ml) in dichloromethane (150 ml). The resulting red mixture was stirred for 1 hour then concentrated in vacuo. The residue was treated with ether (300 ml) to yield a crystalline solid. Recrystallisation from methanol/ether (1:3) yielded 2-chloromethyl-4-dimethylaminomethylpyridine hydrochloride (20.04 g) as an orange solid m.p. 202°-204°.