Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[C:21]([O-])([O-])=O.[Cs+].[Cs+].IC.Cl>CN(C=O)C>[CH3:21][O:11][C:10](=[O:12])[C@H:9]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(Br)cc1)C(=O)O
Agent: Cl
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)[C@@H](Cc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (R)-3-(4-Bromo-phenyl)-2-tert-butoxycarbonylamino-propionic acid (1.0 g, 2.91 mmol) in DMF (5 mL) is added Cs2CO3 (1.041 g, 3.2 mmol) and the mixture is stirred at room temperature for 30 minutes. Then iodomethane (1.031 g, 7.26 mmol) is added and the mixture is stirred at room temperature about 72 hours. The pH is adjusted to 5˜6 by adding 1N HCl then the mixture is extracted with EtOAc. The combined organic layers were washed with water and brine, dried over MgSO4, filtered and concentrated to give (R)-3-(4-bromo-phenyl)-2-tert-butoxycarbonylamino-propionic acid methyl ester. HPLC Retention time 1.49 minutes (condition C): MS 358.3 (M−1).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:13]=1)[C:7]([N:9]([O:11][CH3:12])[CH3:10])=[O:8].[C:14](=[NH:27])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:15]1([C:14](=[N:27][C:2]2[CH:3]=[N:4][CH:5]=[C:6]([CH:13]=2)[C:7]([N:9]([O:11][CH3:12])[CH3:10])=[O:8])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CON(C)C(=O)c1cncc(Br)c1
Product: CON(C)C(=O)c1cncc(N=C(c2ccccc2)c2ccccc2)c1

Procedure:
Prepared according to the method described for Preparation 51 using 5-bromo-N-methoxy-N-methylnicotinamide and benzophenone imine.
Reaction SMILES: [N:1]1([CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:11]([OH:14])[CH2:12][OH:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>N1C=CC=CC=1.O>[OH:14][CH:11]([CH:10]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:12][O:13][S:27]([C:24]1[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=1)(=[O:29])=[O:28]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC(O)C(c1ccccc1)n1ccc2ccccc21
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC(O)C(c2ccccc2)n2ccc3ccccc32)cc1
Yield: 69.1 %

Procedure:
A solution of (2RS,3RS)-3-indol-1-yl-3-phenyl-propane-1,2-diol (1.83 g, 6.8 mmol) and p-toluenesulfonyl chloride (1.31 g, 6.8 mmol) in anhydrous pyridine (10 mL) was stirred at room temperature under nitrogen for 15 hours. The mixture was then diluted with water (10 mL), quenched with a 2N aqueous solution of hydrochloric acid in an ice/water bath until the solution was pH=3, and extracted with dichloromethane. The organic layer was washed with water again, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified via Biotage chromatography (FlasH40i, silica, 10%, 25% EtOAc/hexane) to yield 1.98 g (69%) of (2RS,3RS)-toluene-4-sulfonic acid 2-hydroxy-3-indol-1-yl-3-phenyl-propyl ester as a white solid. 1HNMR (DMSO): δ3.70 and δ3.85 (dd and dd, 2H, CH2OTs), δ4.80 (m, 1H, CHOH), δ5.52 (d, 1H, CHPh), δ5.82 (d, 1H, CHOH); MS (ESI) m/z 422 ([M+H]+).
Reaction SMILES: [CH2:1]([O:3]C([Sn](CCCC)(CCCC)CCCC)=C)[CH3:2].Br[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][N:21]=1.Cl.[OH-].[Na+]>C(#N)C.[Cu](I)I.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[Pd]Cl.C(OCC)C>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([CH:1]([OH:3])[CH3:2])=[N:21][CH:22]=1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Clc1ccc(Br)nc1
Agent: Cl[Pd]Cl
Agent: I[Cu]I
Agent: Cl
Solvent: CC#N
Solvent: CCOCC
Product: CC(O)c1ccc(Cl)cn1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
Copper iodide (148 mg), 1-ethoxyvinyltri-n-butyltin (2.97 mL), and bis(triphenylphosphine)palladium (II) chloride (183 mg) were added to a solution of 2-bromo-5-chloropyridine (1 g) in acetonitrile (30 mL), and the reaction solution was stirred in a nitrogen atmosphere at 100° C. for three hours. The reaction solution was returned to room temperature. 10 mL of 5 N hydrochloric acid was added, and the reaction solution was heated under reflux for 30 minutes. The reaction solution was returned to room temperature and neutralized with a 5 N sodium hydroxide solution. Diethyl ether was added to the reaction solution, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (30 mL) and methanol (10 mL). Sodium borohydride (492 mg) was added, and the reaction solution was stirred at room temperature for one hour. Water and diethyl ether were added to the reaction solution, and the organic layer was separated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: hexane-diethyl ether) to obtain 503 mg of the title compound.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH2:13][Si:14]([CH2:17][CH2:18][CH2:19][CH3:20])([CH3:16])[CH3:15])(=O)=O)=CC=1.[C:22]1([CH:29]=[CH:28][C:26]([OH:27])=[CH:25][CH:24]=1)[OH:23].[OH-].[K+].Cl>O.C(O)C.CO>[CH2:17]([Si:14]([CH3:16])([CH3:15])[CH2:13][CH2:12][CH2:11][O:23][C:22]1[CH:29]=[CH:28][C:26]([OH:27])=[CH:25][CH:24]=1)[CH2:18][CH2:19][CH3:20]
Reactant: Oc1ccc(O)cc1
Reactant: CCCC[Si](C)(C)CCCOS(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Solvent: O
Product: CCCC[Si](C)(C)CCCOc1ccc(O)cc1
Temperature: 65 °C
Yield: 50.6 %

Procedure:
The above-obtained 3-(butyldimethylsilyl)propyl p-toluenesulfonate was added dropwise in 45 min. to a mixture of 2.32 g (21.1 mM) of hydroquinone, 1.13 g (17.1 mM) of 85 %-potassium hydroxide, 6 ml of methanol and 30 ml of ethanol under stirring at 65° C., followed by stirring for 0.5 hour and further stirring for 6 hour at 80° C. After the reaction, the reaction mixture was poured into cold water, acidified with hydrochloric acid (pH≈2) and extracted with ethyl acetate, followed by washing with water and drying with anhydrous magnesium sulfate. The magnesium sulfate in the resultant mixture was filtered off and the filtrate was condensed into a solid, followed by purification by silica gel column chromatography (eluent: toluene) to obtain 2.05 g of 4-[3-(butyldimethylsilyl)propoxy]phenol (Yield: 50.6 %).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[CH:15]=[C:16](I)[S:17][C:10]=23)[C:5]([F:19])=[CH:4][C:3]=1[C:20]1[C:21](=[O:34])[N:22]([CH3:33])[C:23]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:24][CH:25]=1.[N:35]1([C:41]([C:43]2[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=2)=[O:42])[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.[Cl-].[Li+]>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[CH:15]=[C:16]([C:46]4[CH:45]=[CH:44][C:43]([C:41]([N:35]5[CH2:40][CH2:39][O:38][CH2:37][CH2:36]5)=[O:42])=[CH:48][CH:47]=4)[S:17][C:10]=23)[C:5]([F:19])=[CH:4][C:3]=1[C:20]1[C:21](=[O:34])[N:22]([CH3:33])[C:23]([NH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[N:24][CH:25]=1
Reactant: O=C(c1ccc(B(O)O)cc1)N1CCOCC1
Reactant: Cn1c(Nc2ccccc2)ncc(-c2cc(F)c(Oc3ccnc4cc(I)sc34)cc2F)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: C1COCCO1
Product: Cn1c(Nc2ccccc2)ncc(-c2cc(F)c(Oc3ccnc4cc(-c5ccc(C(=O)N6CCOCC6)cc5)sc34)cc2F)c1=O
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A suspension of 5-(2,5-difluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)phenyl)-3-methyl-2-(phenylamino)pyrimidin-4(3H)-one (0.0105 g, 0.0178 mmol), 4-(morpholine-4-carbonyl)phenylboronic acid (0.005 g, 0.021 mmol), Pd(PPh3)4 (0.001 g, 0.001 mmol) and lithium chloride (0.003 g, 0.071 mmol) in dioxane (0.5 mL) and 2M aqueous Na2CO3 (0.5 mL) was stirred at 100° C. for 30 minutes. The reaction mixture was cooled to room temperature and then partitioned between EtOAc and H2O. The layers were separated and the aqueous layer was re-extracted with EtOAc (1×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude product was purified by flash column chromatography, eluting with 20:1 CH2Cl2/MeOH. The product was obtained (4.5 mg; 39%) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ 8.54 (br s, 1H), 7.96 (s, 1H), 7.84-7.77 (m, 3H), 7.57-7.46 (m, 5H), 7.42 (t, 2H), 7.24 (m, 1H), 7.08 (m, 1H), 6.71-6.62 (m, 2H), 3.99-3.40 (m, 8H), 3.68 (s, 3H). LRMS (APCI pos) m/e 652 (M+1).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:18](=O)[CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:26].[Na+].O>C(Cl)Cl.CO>[NH2:26][CH:18]1[C:13]2[C:14]3[C:15](=[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[NH:8][C:9]=3[CH:10]=[CH:11][CH:12]=2)[CH2:16][CH2:17]1
Reactant: [BH3-]C#N
Reactant: O=C1CCc2c(-c3ccccc3)[nH]c3cccc1c23
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: NC1CCc2c(-c3ccccc3)[nH]c3cccc1c23
Temperature: 25 °C
Reaction time: 72 h
Yield: 52 %

Procedure:
A portion (2.3 g) of the compound obtained in Example 41 was dissolved in a mixed solvent of methylene chloride (450 ml) and methanol (450 ml) and to the solution were added ammonium acetate (7.12 g) and sodium cyanoborohydride (0.76 g). The mixture was stirred for 3 days at room temperature. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate-ethyl acetate/methanol=9:1) to yield 1.2 g (52%) of the titled compound as pale brown crystals.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([S:12]([OH:15])(=[O:14])=[O:13])[CH:8]=[CH:7]2.N([O-])=O.[Na+].[ClH:20]>O.[NH4+].[Cl-].Cl[Cu].[Cu]>[Cl:20][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([S:12]([OH:15])(=[O:14])=[O:13])[CH:8]=[CH:7]2
Reactant: Cl
Reactant: Nc1cccc2ccc(S(=O)(=O)O)cc12
Agent: Cl[Cu]
Agent: [Cu]
Agent: O=N[O-]
Solvent: O
Product: O=S(=O)(O)c1ccc2cccc(Cl)c2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
A solution of 8-amino-2-naphthalenesulfonic acid (Aldrich, 1.00 g, 4.48 mmol) in water (3.0 mL) and conc. HCl (7.0 mL) was cooled to 0° C. A solution of NaNO2 (143 μL, 4.48 mmol) in water (3.0 mL) was added dropwise while maintaining the temperature below 5° C. The reaction mixture was stirred at 0° C. for 1 h. In a separate flask, CuCl (214 μL, 8.96 mmol) was dissolved in conc. HCl (7.0 mL) and the solution was cooled to 0° C. The copper solution was added to the diazonium solution at 0° C. in portions to control the gas evolution. The reaction mixture was allowed to stir at 0° C. for 1 h and then at room temperature for 12 h. The reaction mixture was then diluted with 10% aq. NH4Cl solution and extracted with EtOAc (3×). The combined organic extracts were washed again with aq. 10% NH4Cl solution, dried over Na2SO4, filtered and concentrated in vacuo to give the title compound (740 mg, 65%). 1H NMR (DMSO-d6) δ 8.43 (s, 1H), 7.95 (dd, J=17.1, 8.5 Hz, 2H), 7.80 (dd, J=8.4, 1.5 Hz, 1H), 7.71 (dd, J=7.5, 1.1 Hz, 1H), 7.57-7.45 (m, 1H); MS(ESI−) m/z 241.2 (M−H)−.
Reaction SMILES: [CH3:1][N:2]([C@@H:10]([CH3:46])[C:11]([NH:13][C@H:14]1[C@H:20]([CH3:21])[N:19]([C:22](=[O:28])[CH2:23][S:24]([CH3:27])(=[O:26])=[O:25])[C:18]2[CH:29]=[CH:30][CH:31]=[CH:32][C:17]=2[N:16]([CH2:33][C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:37]=[CH:36][C:35]=2[CH3:44])[C:15]1=[O:45])=[O:12])C(=O)OC(C)(C)C.[ClH:47]>O1CCOCC1.CCOCC>[ClH:47].[CH3:21][C@@H:20]1[N:19]([C:22](=[O:28])[CH2:23][S:24]([CH3:27])(=[O:26])=[O:25])[C:18]2[CH:29]=[CH:30][CH:31]=[CH:32][C:17]=2[N:16]([CH2:33][C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[N:37]=[CH:36][C:35]=2[CH3:44])[C:15](=[O:45])[C@H:14]1[NH:13][C:11](=[O:12])[C@@H:10]([NH:2][CH3:1])[CH3:46]
Reactant: Cc1cnc2ccccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@H](C)N(C(=O)CS(C)(=O)=O)c2ccccc21
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CN[C@@H](C)C(=O)N[C@@H]1C(=O)N(Cc2c(C)cnc3ccccc23)c2ccccc2N(C(=O)CS(C)(=O)=O)[C@H]1C
Reaction time: 2 h
Yield: 90 %

Procedure:
A rt suspension of tert-butyl methyl((S)-1-((2S,3S)-2-methyl-5-((3-methylquinolin-4-yl)methyl)-1-(2-(methylsulfonyl)acetyl)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl)carbamate (140 mg, 215 μmol) in 4 M HCl in dioxane (1.07 ml) was stirred for 2 h. The reaction was diluted with Et2O and the solids were collected by vacuum filtration, taken up in MeCN—H2O, and lyophilized to provide (S)-N-((2S,3S)-2-methyl-5-((3-methylquinolin-4-yl)methyl)-1-(2-(methylsulfonyl)acetyl)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2-(methylamino)propanamide hydrochloride (113.4 mg, 90%) as a white solid. MS m/z 552 (MH)+.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[NH:8]C(=O)O[C:11](=[O:12])[C:6]=2[CH:5]=[C:4]([C:14]#[N:15])[CH:3]=1.Cl.[C:17]1([NH2:23])([CH:20]2[CH2:22][CH2:21]2)[CH2:19][CH2:18]1.C(N(CC)CC)C>C1COCC1>[NH2:8][C:7]1[C:2]([CH3:1])=[CH:3][C:4]([C:14]#[N:15])=[CH:5][C:6]=1[C:11]([NH:23][C:17]1([CH:20]2[CH2:22][CH2:21]2)[CH2:19][CH2:18]1)=[O:12]
Reactant: Cc1cc(C#N)cc2c(=O)oc(=O)[nH]c12
Reactant: NC1(C2CC2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C#N)cc(C(=O)NC2(C3CC3)CC2)c1N

Procedure:
236 mg (1.16 mmol) 8-methyl-2,4-dioxo-1,4-dihydro-2H-benzo[d][1,3]oxazine-6-carbonitrile, 234 mg (1.75 mmol) bicyclopropyl-1-ylamine hydrochloride and 177 mg (1.75 mmol) triethylamine in 25 ml THF are heated 4 h at reflux. The mixture is cooled down and evaporated. The residue is dissolved in ethyl acetate and extracted with water. After purification on a short path of silicagel, 63 mg of the title compound are isolated as yellow crystals. F: 171-172° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:39])[C@@H:13]([NH:23][C:24]([C:26]2[CH:31]=[C:30](Cl)[N:29]=[C:28]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:40]([NH2:43])[CH2:41][CH3:42].O>C1COCC1>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:39])[C@@H:13]([NH:23][C:24]([C:26]2[CH:31]=[C:30]([NH:43][CH2:40][CH2:41][CH3:42])[N:29]=[C:28]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCCN
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(Cl)nc(-c3ccccc3)n2)CC1
Solvent: O
Solvent: C1CCOC1
Product: CCCNc1cc(C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N2CCN(C(=O)OCC)CC2)nc(-c2ccccc2)n1
Temperature: 40 °C

Procedure:
4-{(S)-4-tert-butoxycarbonyl-2-[(6-chloro-2-phenyl-pyrimidine-4-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester (53 mg) and propylamine (31 μl) were dissolved in THF (0.5 ml). The mixture was stirred at 40° C. until reaction completion. Water was added and it was extracted with EA. The org. layers were dried (Na2SO4) and evaporated off to give 60 mg of the desired pure compound.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:4]=[C:5]2[CH2:10][NH:9][CH2:8][CH2:7][N:6]2[CH:11]=1.CCN(CC1C=CC=CC=1)CC.C=CC1C=CC=CC=1.C=CC1C=CC(C=C)=CC=1.[Cl:44][C:45]1[CH:53]=[C:52]([Cl:54])[CH:51]=[CH:50][C:46]=1[C:47](Cl)=[O:48]>ClCCl>[Cl:44][C:45]1[CH:53]=[C:52]([Cl:54])[CH:51]=[CH:50][C:46]=1[C:47]([N:9]1[CH2:8][CH2:7][N:6]2[CH:11]=[C:3]([C:2]([F:12])([F:1])[F:13])[N:4]=[C:5]2[CH2:10]1)=[O:48]
Reactant: FC(F)(F)c1cn2c(n1)CNCC2
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: C=Cc1ccc(C=C)cc1
Agent: CCN(CC)Cc1ccccc1
Solvent: C=Cc1ccccc1
Solvent: ClCCl
Product: O=C(c1ccc(Cl)cc1Cl)N1CCn2cc(C(F)(F)F)nc2C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.8 %

Procedure:
2-(Trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (0.096 g, 0.5 mmol, intermediate 4) and diethylaminomethyl polystyrene (0.469 g, 1.500 mmol) were slurried in dichloromethane (DCM) (5 ml). 2,4-Dichlorobenzoyl chloride (0.084 ml, 0.600 mmol) was added and the mixture stirred at room temperature for 24 h. The resin was filtered, washed with dichloromethane and the filtrate concentrated in vacuo to afford crude product which was purified by flash chromatography (Biotage SP4, 25+S, eluting with a 0-100% gradient of ethyl acetate/iso-hexane) to afford 7-[(2,4-dichlorophenyl)carbonyl]-2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (0.178 g, 0.489 mmol, 98% yield).
Reaction SMILES: CS[C:3](=[C:9]([C:12]#[N:13])[C:10]#[N:11])[C:4]1[S:5][CH:6]=[CH:7][CH:8]=1.[C:14]1([NH:20][NH2:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[NH2:11][C:10]1[N:20]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:21]=[C:3]([C:4]2[S:5][CH:6]=[CH:7][CH:8]=2)[C:9]=1[C:12]#[N:13]
Reactant: CSC(=C(C#N)C#N)c1cccs1
Reactant: NNc1ccccc1
Product: N#Cc1c(-c2cccs2)nn(-c2ccccc2)c1N

Procedure:
Using 2.06 g (10 mmol) of methylthio(thiophen-2-yl)methylenepropanedinitrile and 1.1 g (10 mmol) of phenylhydrazine, the entitled product having a melting point of 165° to 167° C. was obtained in the same manner as in Example 1-(1).
Reaction SMILES: [CH2:1]([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[N:19]=[C:18]2[CH:20]=[CH:21][N:22]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:17]2=[CH:16][CH:15]=1.CI>C1COCC1>[Cl:13][C:14]1[N:19]=[C:18]2[CH:20]=[C:21]([CH3:1])[N:22]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:17]2=[CH:16][CH:15]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2nc(Cl)ccc21
Reactant: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Cc1cc2nc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
1.6 M n-butyllithium in hexanes (24 mL, 39 mmol) was added to a solution of N,N-diisopropylamine (5.8 mL, 42 mmol) in THF (80 mL) at −78° C. Following complete addition, the mixture was allowed to stir at 0° C. for 30 minutes and was then re-cooled to −78° C. A solution of 5-chloro-1-(phenylsulfonyl)-1H-pyrrolo[3,2-b]pyridine (7.6 g, 26 mmol, from Step 1) in THF (38 mL) was added dropwise. After stirring at −78° C. for 1 hour, methyl iodide (3.2 mL, 52 mmol) was added. The mixture was allowed to slowly reach room temperature, at which time it was quenched by the addition of saturated NH4Cl. The product was extracted with EtOAc, and the extracts were washed with water (2×), brine, dried over sodium sulfate, filtered and concentrated to afford product as a yellow oil which was used without further purification (8.0 g, 100%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][C:29]=1[Cl:30])=[N+]=[N-].[OH-].[Na+].Cl>C1COCC1.[NH4+].[OH-].CCOCC>[NH2:20][CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][C:29]=1[Cl:30]
Reactant: [N-]=[N+]=NCc1cnccc1Cl
Agent: Cl
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: NCc1cnccc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 47.5 %

Procedure:
Triphenylphosphine (0.81 g, 3.1 mmol) was added to a solution of the above 3-azidomethyl-4-chloro-pyridine (0.47 g, 3.1 mmol) in anhydrous THF (10 mL) at 0° C. The reaction mixture was warmed to room temperature and stirred for 18 h. The reaction mixture was then diluted with NH4OH (3 mL) and stirred for another 3 h. 3M NaOH was then added to the reaction mixture and stirred for 1 h. The mixture was acidified to pH 2 by adding 4M HCl solution. The mixture was diluted with ether and the layers were separated. The aqueous layer was extracted with ether and then basified with 2M NaOH solution. The aqueous solution was extracted with CH2Cl2 (×3). The combined organic phase was dried over MgSO4 and concentrated in vacuo to afford a pale yellow oily solid. This product was diluted with ether and filtered. The filtrated was concentrated in vacuo to afford a pale yellow oil. The crude product was purified by silica gel column chromatography using 20:1 CH2Cl2:MeOH as an eluent to afford 0.21 g (53%) of 3-aminomethyl-4-chloropyridine as a colorless oil.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4(O)[C:38]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[C:32]([C:40]5[CH:45]=[CH:44][C:43]([C:46]6[CH:51]=[C:50]([C:52]7[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=7)[CH:49]=[C:48]([C:58]7[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=7)[CH:47]=6)=[CH:42][CH:41]=5)(O)[C:31]5[C:26]4=[CH:27][CH:28]=[CH:29][CH:30]=5)=[CH:21][CH:20]=3)[CH:10]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I.[PH2](O)=O>C(O)(=O)C>[C:1]1([C:7]2[CH:8]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:38]5[C:33]([C:32]([C:40]6[CH:45]=[CH:44][C:43]([C:46]7[CH:47]=[C:48]([C:58]8[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=8)[CH:49]=[C:50]([C:52]8[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=8)[CH:51]=7)=[CH:42][CH:41]=6)=[C:31]6[C:26]=4[CH:27]=[CH:28][CH:29]=[CH:30]6)=[CH:34][CH:35]=[CH:36][CH:37]=5)=[CH:21][CH:20]=3)[CH:10]=[C:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC1(c2ccc(-c3cc(-c4ccccc4)cc(-c4ccccc4)c3)cc2)c2ccccc2C(O)(c2ccc(-c3cc(-c4ccccc4)cc(-c4ccccc4)c3)cc2)c2ccccc21
Agent: I
Agent: O=[PH2]O
Solvent: CC(=O)O
Product: c1ccc(-c2cc(-c3ccccc3)cc(-c3ccc(-c4c5ccccc5c(-c5ccc(-c6cc(-c7ccccc7)cc(-c7ccccc7)c6)cc5)c5ccccc45)cc3)c2)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 92.3 %

Procedure:
9,10-bis(4-(3,5-Diphenylphenyl)phenyl)-9,10-dihydroxy-9,10-dihydroanthracene (6.0 g, 7.3 mmole) was suspended in acetic acid (70 ml). To the resultant suspension, a 57% hydroiodic acid (10 ml, 77 mmole, 10 eq) was added and the obtained mixture was stirred at 100° C. for 6 hours. To the reaction mixture, a 50% aqueous solution of hypophosphorous acid (50 ml) was added. The formed solid was separated by filtration and washed with water, methanol and acetone and a light yellow solid (5.3 g, 93%) was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH2:17][CH3:18])[C:13]([C:19](=[O:25])[CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])=[C:12]([O:26][CH2:27][CH3:28])[CH:11]=2)=[CH:4][N:3]=1.C(O)C.[BH4-].[Na+]>O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:11]=[C:12]([O:26][CH2:27][CH3:28])[C:13]([CH:19]([OH:25])[CH2:20][S:21]([CH3:24])(=[O:22])=[O:23])=[C:14]([O:16][CH2:17][CH3:18])[CH:15]=2)=[CH:4][N:3]=1
Reactant: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC)c1C(=O)CS(C)(=O)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOc1cc(Cc2cnc(N)nc2N)cc(OCC)c1C(O)CS(C)(=O)=O
Reaction time: 0.5 h

Procedure:
To a suspension of 1 g. of 4'-[(2,4-diamino-5-pyrimidinyl)-methyl]-2',6'-diethoxy-2-(methylsulfonyl)-acetophenone in a mixture of 25 ml. of ethanol and 10 ml. of water there is added portionwise with stirring over a period of 30 minutes 500 mg. of sodium borohydride. First the solution becomes clear, and after an additional 30 minutes of stirring, there crystallizes 4-[(2,4-diamino-5-pyrimidinyl)-methyl]-2,6-diethoxy-α-[(methylsulfonyl)-methyl]-benzyl alcohol, having a m.p. of 205°-206° after recrystallization from methanol.