Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]([O:18][CH:19]([CH3:21])[CH3:20])[C:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4].ClC1C=C(C=CC=1)C(OO)=[O:27].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:1]([C:5]1[N:6]([O:18][CH:19]([CH3:20])[CH3:21])[C:7]2[C:16]3[N:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:10]([O-:27])=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cnc3cccnc3c2n1OC(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCc1nc2c[n+]([O-])c3cccnc3c2n1OC(C)C
Temperature: 0 °C
Yield: 99.9 %

Procedure:
A solution of 2-butyl-1-isopropoxy-1H-imidazo[4,5-c][1,5]naphthyridine (0.40 g, 1.4 mmol) in dichloromethane (25 mL) was cooled to approximately 0° C., and 3-chloroperoxybenzoic acid (0.42 g of approximately 77% pure material, 1.9 mmol) was added. The reaction was stirred for ten minutes at 0° C., stirred for 1.5 hours at room temperature, and then stirred with saturated aqueous sodium bicarbonate (25 mL) for 15 minutes. The organic layer was separated and dried over potassium carbonate, filtered, and concentrated under reduced pressure to provide 0.42 g of 2-butyl-1-isopropoxy-5-oxido-1H-imidazo[4,5-c][1,5]naphthyridine as a yellow oil.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[CH2:29]([CH:33]1[CH2:37][CH2:36][NH:35][CH2:34]1)[CH:30]([CH3:32])[CH3:31]>>[CH2:29]([CH:33]1[CH2:37][CH2:36][N:35]([CH2:2][C:3]2[N:4]([CH3:28])[C:5]3[C:10]([N:11]=2)=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:8]=[C:7]([N:18]2[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[N:20]=[C:19]2[CH3:27])[N:6]=3)[CH2:34]1)[CH:30]([CH3:32])[CH3:31]
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Reactant: CC(C)CC1CCNC1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(CC(C)C)C3)n(C)c2n1

Procedure:
4-(8-(Bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with 3-isobutylpyrrolidine via General Procedure E to give 27 mg of 302 following reverse phase purification. MS (Q1) 489.2 (M)+
Reaction SMILES: [F:1][C:2]([C:5]1[NH:6][C:7]2[C:12]([CH:13]=1)=[C:11]([C:14]([F:17])([F:16])[F:15])[C:10]([C:18]#[N:19])=[CH:9][CH:8]=2)([F:4])[CH3:3].C([O-])([O-])=O.[Cs+].[Cs+].Cl[CH2:27][C:28]1[N:32]=[C:31]([C:33]2[CH:38]=[C:37]([F:39])[CH:36]=[C:35]([F:40])[CH:34]=2)[O:30][N:29]=1.CC#N>CCOC(C)=O>[F:4][C:2]([C:5]1[N:6]([CH2:27][C:28]2[N:32]=[C:31]([C:33]3[CH:38]=[C:37]([F:39])[CH:36]=[C:35]([F:40])[CH:34]=3)[O:30][N:29]=2)[C:7]2[C:12]([CH:13]=1)=[C:11]([C:14]([F:15])([F:17])[F:16])[C:10]([C:18]#[N:19])=[CH:9][CH:8]=2)([F:1])[CH3:3]
Reactant: Fc1cc(F)cc(-c2nc(CCl)no2)c1
Reactant: CC(F)(F)c1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(F)(F)c1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(F)cc(F)c2)n1
Temperature: 70 °C
Reaction time: 24 h
Yield: 77.1 %

Procedure:
A mixture of the indole (0.050 g, 0.18 mmol) from step A, Cs2CO3 (0.065 g, 0.20 mmol), 3-(chloromethyl)-5-(3,5-difluorophenyl)-1,2,4-oxadiazole (0.046 g, 0.20 mmol) and CH3CN (4 mL) was stirred at 70° C. for 24 h. The mixture was diluted with EtOAc (25 mL), washed with water (15 mL), brine (15 mL), dried over (MgSO4) and concentrated. Added 10% Et2O in hexanes (10 mL) and stirred for 2 h. The resulting solid was filtered, rinsed with hexanes and dried to afford the title compound (0.065 g, 76%) as a light tan solid: 1H NMR (400 MHz, DMSO-d6) δ 8.23 (d, J=8.6 Hz, 1H), 7.98 (d, J=8.6 Hz, 1H), 7.74-7.64 (m, 3H), 7.23 (s, 1H), 5.99 (s, 2H), 2.24 (t, 3H); MS m/z 467 (M−H).
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9]/[N:10]=[C:11](\[CH3:20])/[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=O>Cl.O1CCOCC1>[CH3:20][C:11]1[N+:10]([O-:9])=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[O:8][C:12]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C/C(=N\O)C(=O)c1ccccc1
Reactant: O=Cc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1c(-c2ccccc2)oc(-c2ccccc2)[n+]1[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 51.6 %

Procedure:
To a solution of benzaldehyde (325 mg, 311 μL, 3.06 mmol) in HCl (4M in dioxane, 10 mL was added (E)-2-(hydroxyimino)-1-phenylpropan-1-one (500 mg, 3.06 mmol) at 0-5° C. The ice bath was removed and the mixture was stirred at RT for 24 h. All volatiles were removed and the residue was dissolved in HCl (4M in dioxane, 10 mL). The reaction mixture was stirred at RT for 6 h and concentrated. The obtained suspension was filtered, washed with diethyl ether and dried in vacuo to give the product as colorless solid (398 mg, 1.58 mmol, 51.7%).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]([CH2:16][C:17]([OH:19])=O)[C:4]=2[CH:3]=1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH3:42][NH:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.[OH-].[Na+]>C1COCC1.O.C(Cl)Cl>[CH2:44]([N:43]([CH3:42])[C:17](=[O:19])[CH2:16][N:5]1[C:4]2[CH:3]=[C:2]([Cl:1])[CH:15]=[CH:14][C:13]=2[S:12][C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: CNCc1ccccc1
Reactant: O=C(O)CN1c2ccccc2Sc2ccc(Cl)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CN(Cc1ccccc1)C(=O)CN1c2ccccc2Sc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.6 %

Procedure:
(2-Chlorophenothiazin-10-yl)acetic acid (480 mg, 1.65 mmol) was dissolved in THF (10 mL). To this solution, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.58 g, 8.25 mmol), 1-hydroxybenzotriazole (220 mg, 1.65 mmol), and N-methyl benzyl amine (2.0 mL, 16.5 mmol) were added. The mixture was stirred at room temperature overnight and was then diluted with water and methylene chloride. The aqueous layer was made basic with sodium hydroxide (1N), and the layers were separated. The aqueous layer was extracted with methylene chloride. The organic layers were combined, washed with water and brine, dried (Na2SO4), filtered, and concentrated to provide a mixture of N-methyl benzyl amine and product (3.8 g). The residue was purified with a plug of SiO2. The product was recrystallized from hexane and ethyl acetate to provide N-benzyl-2-(2-chlorophenothiazin-10-yl)-N-methylacetamide as a white solid (258 mg, 40%).
Reaction SMILES: [C:1]([C:3]1[C:4]2[S:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)=[CH:10][C:5]=2[C:6](=O)[NH:7][CH:8]=1)#[N:2].P(Cl)(Cl)([Cl:25])=O>>[Cl:25][C:6]1[C:5]2[CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[S:12][C:4]=2[C:3]([C:1]#[N:2])=[CH:8][N:7]=1
Reactant: CC(C)(C)c1ccc(-c2cc3c(=O)[nH]cc(C#N)c3s2)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: CC(C)(C)c1ccc(-c2cc3c(Cl)ncc(C#N)c3s2)cc1
Reaction time: 1 h

Procedure:
7-Cyano-2-(4′-t-butylphenyl)-4-oxo-4,5-dihydrothieno[3,2-c]-pyridine was dissolved in phosphorus oxychloride (25 mL) and the resulting solution heated at reflux for 2 h. After this time the mixture was poured into ice and stirred for 1 h. The precipitated solid was filtered and washed with water, drying by suction in air at room temperature affording 1.05 g of 101. 1H NMR (300 MHz, d6-DMSO) δ 8.83 (s, 1H), 8.11 (s, 1H), 7.92 (d, 2H), 7.56 (d, 2H), 1.34 (s, 9H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]=[C:10]=[S:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.C(OCC)(=O)C>CN1CCCC1=O>[C:1]1([CH2:7][CH2:8][NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[S:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: S=C=NCCC1=CCCCC1
Reactant: Nc1ccccn1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: S=C(NCCC1=CCCCC1)Nc1ccccn1
Temperature: 25 °C
Reaction time: 16.5 h
Yield: 50.1 %

Procedure:
A solution of 2-(1-cyclohexenyl)ethyl isothiocyanate (1.67 g, 10 mmol) and 2-aminopyridine (941 mg, 10 mmol) in N-methylpyrrolidinone (20 mL) was heated to 100° C. After 16.5 h, the reaction was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with water (4×) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. The solid obtained was purified by recrystallization from ethyl acetate to provide 1.31 g of the titled product (50%) as a white crystalline solid: mp 153°-155° C.;
Reaction SMILES: [CH2:1]([NH:8][C:9]([CH:11]1[CH2:16][N:15]([NH2:17])[CH2:14][CH2:13][N:12]1[C:18](=[O:20])[CH3:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1>ClCCl>[C:18]([N:12]1[CH2:13][CH2:14][N:15]([NH:17][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][C:29]([F:28])=[CH:30][CH:31]=2)[CH2:16][CH:11]1[C:9](=[O:10])[NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:20])[CH3:19]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CC(=O)N1CCN(N)CC1C(=O)NCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(NC(=O)c2ccc(F)cc2)CC1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of rac-N-benzyl-1-acetyl-4-aminopiperazine-2-carboxamide (274 mg) and triethylamine (0.28 ml) in dichloromethane (5 ml) was added 4-fluorobenzoyl chloride (0.13 ml) at 0° C. The mixture was stirred at ambient temperature for 1 hour, washed with water and brine. The organic layer was dried over magnesium sulfate, and concentrated. The residue was purified by column chromatography eluting with a mixture of methanol and chloroform (1:9) to give crystals. Recrystallization of methanol, ethyl acetate and n-hexane gave rac-N-[4-acetyl-3-(N-benzylcarbamoyl)-1-piperazinyl]-4-fluorobenzamide (104 mg).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@@H:10]1[CH2:11][CH2:12][C@@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([N:23](CC)CC)C.ClC(OCC(C)C)=O.N>ClCCl.CCCCCC.C(OCC)(=O)C.O>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@@H:10]1[CH2:11][CH2:12][C@@H:13]2[C:18]([NH2:23])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@H]1CC[C@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Agent: N
Solvent: ClCCl
Solvent: O
Solvent: CCCCCC
Product: NC(=O)[C@H]1CC[C@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 87.3 %

Procedure:
230 mg (0.84 mmol) of (2R,5S)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid was dissolved in dehydrated dichloromethane (4.2 mL), and 110 mg of triethylamine was added, followed by cooling to 0° C. 137 mg of isobutyl chloroformate was added to the mixture, followed by stirring at the same temperature for 20 minutes. 0.6 mL of aqueous ammonia was added to the reaction mixture, followed by stirring at room temperature for 1 hour. Subsequently, water (10 mL) was added and the organic layer was aliquoted, followed by sequential washing with water and saturated brine and drying over anhydrous magnesium sulfate. The residue resulting from concentration of the solvent under reduced pressure was applied to silica gel column chromatography (hexane/ethyl acetate=1/3), and subsequently crystallized with chloroform/hexane=1:3 to afford 202 mg of the title compound as a colorless crystalline powder (yield 87%). Enantiomeric excess: 99.9% ee or more (CHIRALPAK AD-H, 4.6×150 mm, hexane/ethanol=4/1, UV 210 nm, flow rate 1 mL/min., retention time 10.3 min.).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]1[N:16]=[CH:15][C:14]([CH3:18])([CH3:17])[CH2:13][S:12]1)([CH3:3])[CH3:2].C(N(CC)CC)C.ClCCl.[C:29](Cl)(=[O:33])[O:30][CH2:31][CH3:32]>O>[CH2:31]([O:30][C:29]([N:16]1[CH2:15][C:14]([CH3:18])([CH3:17])[CH2:13][S:12][C:11]1=[N:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH:1]([CH3:3])[CH3:2])=[O:33])[CH3:32]
Reactant: CCOC(=O)Cl
Reactant: CC(C)c1ccccc1N=C1N=CC(C)(C)CS1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)N1CC(C)(C)CSC1=Nc1ccccc1C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.9 %

Procedure:
To a mixture of 2-(2-isopropylphenyl)imino-5,5-dimethyl-1,3-thiazine (0.26 g), triethylamine (0.15 g) and dichloromethane (5 ml) was added dropwise for 5 minutes ethyl chlorocarbonate (0.13 g). The mixture was stirred at room temperature for 2 hours. To the solution was added water (30 ml). The mixture was extracted with diethylether (60 ml), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to give 3-(ethoxycarbonyl)-2-(2-isopropylphenyl)imino-5,5-dimethyl-1,3-thiazine (0.23 g, yield: 68%) as a white crystal. M.p. 84-86° C.
Reaction SMILES: COC[O:4][C:5]1[C:6]([C:19]#[C:20][C:21]2[CH:22]=[C:23]([CH:33]=[C:34]([O:38][CH3:39])[C:35]=2[O:36][CH3:37])[CH2:24][C:25]2[C:26]([NH2:32])=[N:27][C:28]([NH2:31])=[N:29][CH:30]=2)=[CH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([O:15]COC)[CH:11]=[CH:10][CH:9]=2.O.Cl>C1COCC1>[NH2:31][C:28]1[N:27]=[C:26]([NH2:32])[C:25]([CH2:24][C:23]2[CH:33]=[C:34]([O:38][CH3:39])[C:35]([O:36][CH3:37])=[C:21]([C:20]#[C:19][C:6]3[CH:7]=[C:8]4[C:13](=[CH:14][C:5]=3[OH:4])[C:12]([OH:15])=[CH:11][CH:10]=[CH:9]4)[CH:22]=2)=[CH:30][N:29]=1
Reactant: COCOc1cc2c(OCOC)cccc2cc1C#Cc1cc(Cc2cnc(N)nc2N)cc(OC)c1OC
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Cc2cnc(N)nc2N)cc(C#Cc2cc3cccc(O)c3cc2O)c1OC
Yield: 48.5 %

Procedure:
146 mg of 5-[3-(3,5-bis-methoxymethoxy-naphthalen-2-ylethynyl)-4,5-dimethoxybenzyl]-pyrimidin-2,4-diamine (Example 12ap)) in 2.5 ml of THF, 2.5 ml of water and 2.5 ml of 6N hydrochloric acid are held at 50° for 7.5 hrs. The mixture is concentrated and the residue is chromatographed on silica gel with methylene chloride/methanol 9:1. 59 mg of 6-[5-(2,4-diamino-pyrimidin-5-ylmethyl)-2,3-dimethoxy-phenylethynyl]-naphthalene-1,7-diol are isolated as a yellowish solid. Yield: 48%. Mass spectrum: peaks inter alia at 443 (M++H, 100%).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[N:4][CH:3]=1.C([BH3-])#N.[Na+].[CH:11]1([O:16][C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=2[O:25][CH3:26])[CH:20]=O)[CH2:15][CH2:14][CH2:13][CH2:12]1>CO.Cl>[CH:11]1([O:16][C:17]2[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=2[O:25][CH3:26])[CH2:20][NH:1][C:2]2[NH:6][N:5]=[N:4][CH:3]=2)[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: Nc1cnn[nH]1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COc1ccc(CNc2cnn[nH]2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 64 h
Yield: 27.9 %

Procedure:
To a stirred solution of 5-amino-1,2,3-triazole (3.0 g, 0.036 mol) in 100 ml of methanol and 15 ml of 1N HCl was added sodium cyanoborohydride (1.89 g, 0.030 mol) and 3-cyclopentyloxy-4-methoxybenzaldehyde (6.6 g, 0.30 mol). The reaction mixture was stirred at room temperature for 64 hours and then acidified to pH 2 with concentrated HCl. The solution was evaporated at reduced pressure and the residue was treated with water (100 ml) and extracted twice with 100 ml portions of ethyl acetate. The ethyl acetate extracts were combined and extracted twice with 50 ml portions of 3N HCl and then discarded. The aqueous extracts were combined with the original aqueous layer and basified to pH 12 with potassium hydroxide pellets. The alkaline solution was extracted twice with 100 ml portions of ethyl acetate. The ethyl acetate extracts were combined and evaporated to give a solid which was crystallized from ethyl acetate to give 2.9 g (34%) of the title compound mp 113-114° C. collected in two crops.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH2:6][CH2:7][OH:8])[CH3:5].Cl[C:10]1[CH:15]=[C:14]([N:16]2[C:20]3[N:21]=[C:22]([N:50]4[CH2:55][CH2:54][O:53][CH2:52][CH2:51]4)[N:23]=[C:24]([C:25]4[CH:26]=[N:27][C:28]([N:31]([CH2:41][C:42]5[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=5)[CH2:32][C:33]5[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=5)=[N:29][CH:30]=4)[C:19]=3[CH2:18][CH2:17]2)[CH:13]=[CH:12][N:11]=1>C1(C)C=CC=CC=1>[CH3:3][N:4]([CH3:5])[CH2:6][CH2:7][O:8][C:12]1[CH:13]=[C:14]([N:16]2[C:20]3[N:21]=[C:22]([N:50]4[CH2:51][CH2:52][O:53][CH2:54][CH2:55]4)[N:23]=[C:24]([C:25]4[CH:30]=[N:29][C:28]([N:31]([CH2:32][C:33]5[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=5)[CH2:41][C:42]5[CH:43]=[CH:44][C:45]([O:48][CH3:49])=[CH:46][CH:47]=5)=[N:27][CH:26]=4)[C:19]=3[CH2:18][CH2:17]2)[CH:15]=[CH:10][N:11]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccnc(Cl)c3)cn2)cc1
Reactant: CN(C)CCO
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccnc(OCCN(C)C)c3)cn2)cc1
Reaction time: 0.25 h
Yield: 100 %

Procedure:
Sodium hydride (15 mg, 60% mineral oil dispersion, 5 equivalents) and N,N-dimethylaminoethanol (39 μl, 5 equivalents) were added to toluene (1.3 ml). After refluxing for 5 minutes, stirring was carried out at 50° C. for 15 minutes. {5-[7-(2-Chloro-pyridin-4-yl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrimidin-2-yl}-bis-(4-methoxy-benzyl)-amine (50 mg) obtained in Step A in Example 1-H-31 was added, followed by refluxing overnight, and the reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (dichloromethane/methanol=30/1 to 10/1), to obtain a colorless solid (54 mg, 100%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7]/[N:8]=[CH:9]/[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:16][C:17]1[CH:22]=[C:21]([F:23])[C:20](/[C:24](=[CH:27]/[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:29]=2F)/[C:25]#[N:26])=[C:19]([F:36])[CH:18]=1.C(N(CC)CC)C.C1CCN2C(=NCCC2)CC1>ClCCl.C(O)(C)(C)C>[C:1]([O:5][C:6]([CH:7]1[CH:27]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=2)[C:24]([C:20]2[C:19]([F:36])=[CH:18][C:17]([Cl:16])=[CH:22][C:21]=2[F:23])([C:25]#[N:26])[CH:9]([CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:8]1)=[O:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)C/C=N/CC(=O)OC(C)(C)C
Reactant: N#C/C(=C\c1cccc(Cl)c1F)c1c(F)cc(Cl)cc1F
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(C)(C)O
Solvent: ClCCl
Product: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2)C1(C#N)c1c(F)cc(Cl)cc1F
Yield: 43 %

Procedure:
In a manner similar to the method described in Example 1c, [3-methyl-but-(E)-ylideneamino]-acetic acid tert-butyl ester prepared in Example 1a (1 g, 5 mmol) was reacted with (Z)-2-(4-chloro-2,6-difluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-acrylonitrile (1.3 g, 4 mmol) prepared in Example 109a, AgF (0.77 g, 6 mmol), and triethylamine (1.4 mL, 10 mmol) in dichloromethane (120 mL) at room temperature for 18 h, followed by the reaction with DBU (4.8 ml) in tert-butanol (20 mL) at 100° C. for 2 h to give rac-(2R,3R,4R,5S)-4-(4-chloro-2,6-difluoro-phenyl)-3-(3-chloro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester as a white gum (0.9 g, 41%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:12]([C@:16]12[CH2:24][CH2:23][C@@H:22]3[C@@H:25]4[C:30]([CH2:31][CH2:32][C@H:21]3[C@@H:20]1[CH2:19][CH2:18][C@@H:17]2[OH:34])=[CH:29][C:28](=[O:33])[CH2:27][CH2:26]4)[CH:13]([CH3:15])[CH3:14].O>C1C=CC=CC=1.N1C=CC=CC=1>[CH2:12]([C@:16]12[CH2:24][CH2:23][C@@H:22]3[C@@H:25]4[C:30]([CH2:31][CH2:32][C@H:21]3[C@@H:20]1[CH2:19][CH2:18][C@@H:17]2[O:34][C:9](=[O:10])[CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[CH:29][C:28](=[O:33])[CH2:27][CH2:26]4)[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2O
Reactant: O=C(Cl)CCc1ccccc1
Solvent: c1ccncc1
Solvent: c1ccccc1
Solvent: O
Product: CC(C)C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CC[C@@H]2OC(=O)CCc1ccccc1
Reaction time: 18 h

Procedure:
Add 3-phenylpropionyl chloride (0.5 g.) in benzene (1.5 cc.) with swirling to 13β-isobutyl-17β-hydroxy-gon-4-en-3-one (0.5 g.) in pyridine (2 cc.) at -20°. Store the mixture at -10° for 18 hours, add water and extract the product with ether. Wash, dry and evaporate the extracts to give a residue and recrystallize from methanol to give the title compound, m.p. 101°-106°; ultraviolet absorption peak at 240 mμ (ε15,300); infrared absorption peaks at 5.75, 5.95 μ.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH2:39][CH2:40][C:41]([F:44])([F:43])[F:42])[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[CH:36][N:37]([CH2:39][CH2:40][C:41]([F:42])([F:43])[F:44])[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3cn(CCC(F)(F)F)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2c(C)cc(-c3cn(CCC(F)(F)F)cn3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 88 from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(1-(3,3,3-trifluoropropyl)-imidazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [C:1]1([N:11]=[C:12]=[S:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[N-:14]=[N+:15]=[N-:16].[Na+].Cl>C(O)C>[C:1]1([N:11]2[C:12]([SH:13])=[N:16][N:15]=[N:14]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: S=C=Nc1cccc2ccccc12
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Sc1nnnn1-c1cccc2ccccc12
Temperature: 79 °C
Yield: 85 %

Procedure:
To a solution of 1-naphthalenylisothiocyanate (500 mg, 2.7 mmol) in ethanol (150 mL) was added sodium azide (2.8 g, 43 mmol) and the mixture was heated to 79° C. for 2 hours. The reaction mixture was then cooled to room temperature, aqueous HCl solution (12N, 1.5 mL) added and the mixture concentrated. The resulting residue was diluted with ethyl acetate and extracted with aqueous NaOH solution (1N) and the aqueous layer acidified with aqueous HCl solution (12N) until a precipitate formed. The precipitate was collected and used in the next step without further purification (520 mg, 85% yield).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].Cl[C:25]1[N:26]=[N:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=1>>[F:18][C:16]1[CH:15]=[CH:14][C:13]([N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)=[C:12]([C:10]([N:4]2[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:9])[C@H:3]2[CH2:2][NH:1][C:25]2[N:26]=[N:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=2)=[O:11])[CH:17]=1
Reactant: C[C@@H]1CCCN(C(=O)c2cc(F)ccc2-n2nccn2)[C@@H]1CN
Reactant: FC(F)(F)c1ccc(Cl)nn1
Product: C[C@@H]1CCCN(C(=O)c2cc(F)ccc2-n2nccn2)[C@@H]1CNc1ccc(C(F)(F)F)nn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A45 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 3-chloro-6-(trifluoromethyl)pyridazine. MS (ESI) 464 (M+H).