Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]([O:12][CH:13]2[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.C(N(CC)CC)C.[CH:27]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[Cl:1][C:2]1[C:11]([O:12][CH:13]2[CH2:18][CH2:17][CH:16]([NH:33][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[CH2:15][CH2:14]2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2
Reactant: O=C1CCC(Oc2ccc3cnccc3c2Cl)CC1
Reactant: NC1CCCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: CCN(CC)CC
Product: Clc1c(OC2CCC(NC3CCCCC3)CC2)ccc2cnccc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.4 %

Procedure:
100 mg (0.36 mmol) 4-(5-Chloro-isoquinolin-6-yloxy)-cyclohexanone (79) were dissolved in 10 ml methanol. After adding 73 mg (0.73 mmol) triethyl amine, 108 mg (1.09 mmol) cyclohexylamine, 218 mg (3.63 mmol) acetic acid and freshly dried molecular sieves, the reaction was stirred at room temperature. After 30 minutes, a solution of 68 mg (1.09 mmol) sodium cyanoborohydride in 2 ml methanol was added and the reaction was kept at room temperature until complete conversion was achieved. For working up, the reaction mixture was filtered and the filtrate was brought to alkaline pH by adding solid NaHCO3. After evaporation of the solvent, the residue was taken up in H2O and extracted three times with dichloromethane. The combined organic layers were dried over MgSO4 and evaporated. Final purification by preparative HPLC gave 69 mg of the desired product as trifluoroacetate, which was dissolved in 2 N HCl and lyophilized, to yield 45 mg of the corresponding HCl-salt. Rt=1.08/1.15 min (Method #1). Detected mass: 359.3/361.3 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[C:4](F)[CH:3]=1.[C-:15]#[N:16].[Na+]>CS(C)=O.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[C:4]([CH:3]=1)[C:15]#[N:16]
Reactant: [C-]#N
Reactant: Fc1cc(Br)ccc1-c1ccccn1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#Cc1cc(Br)ccc1-c1ccccn1
Temperature: 180 °C
Yield: 79.2 %

Procedure:
2-(4-Bromo-2-fluorophenyl)pyridine (1.0 g, 3.9 mmol) and sodium cyanide (214 mg, 4.3 mmol) were combined in DMSO (20 mL) under argon. The reaction mixture was heated at 180° C. overnight. TLC analysis showed no starting material present. The reaction mixture was diluted with EtOAc (100 mL), and washed with H2O (3×100 mL), brine (100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to afford a dark oil. The crude product was purified by column chromatography eluting with 1:9 EtOAc:Hexane. to afford 5-bromo-2-pyridin-2-ylbenzonitrile (800 mg, 80%). MS 262.1 (M++H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([NH2:14])=[S:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].Br[CH2:16][C:17](=[O:25])[C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[F:23][C:18]([F:24])([C:19]([F:22])([F:21])[F:20])[C:17](=[O:25])[CH2:16][S:13][C:12](=[NH:14])[CH2:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([CH3:1])[CH:3]=1
Reactant: O=C(CBr)C(F)(F)C(F)(F)F
Reactant: Cc1cc(CC(N)=S)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(CC(=N)SCC(=O)C(F)(F)C(F)(F)F)ccc1[N+](=O)[O-]
Yield: 73.8 %

Procedure:
2-(3-Methyl-4-nitrophenyl)-thioacetamide (1.00 g), 1-bromo-3,3,4,4,4-pentafluoro-2-butanone (1.15 g) and potassium carbonate (0.79 g) were stirred in DMF (10 ml) at room temperature for 1 hour. The reaction solution was diluted with ethyl acetate and washed with water and saturated aqueous solution of sodium chloride. After drying the organic layer with magnesium sulfate, the solvent was distilled off under the reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain 2-(3-Methyl-4-nitro-phenyl)-thioacetimidic acid 3,3,4,4,4-pentafluoro-2-oxo-butyl ester (1.30 g).
Reaction SMILES: C([Li])CCC.[CH:6]1[N:7]=[CH:8][N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=12.[CH2:15]=[O:16].Cl>CCCCCC.CCOCC>[OH:16][CH2:15][C:8]1[N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=[CH:6][N:7]=1
Reactant: c1ncn2c1CCCC2
Reactant: C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: OCc1ncc2n1CCCC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1.58 molar n-butyl lithium in n-hexane (49 ml.) was added over 0.5 hour to a stirred solution of 5,6,7,8-tetrahydroimidazo[1,5-a]pyridine (8.9 g.) in dry ether at -60° under nitrogen. After 3 hours, gaseous formaldehyde generated by the thermal condensation of paraformaldehyde (6.9 g.) was passed into the red solution. The mixture was allowed to warm to room temperature overnight, acidified with hydrochloric acid and extracted with chloroform. The aqueous layer was basified with an excess of saturated sodium carbonate solution and extracted with chloroform. Concentration and recrystallisation of the residue from ethanol-ethyl acetate-petroleum ether afforded 3-hydroxymethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine (7.7 g.) m.p. 188°-199°.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[F:15])=O.[NH2:16][C:17]([NH2:19])=[S:18]>CO>[BrH:1].[F:15][C:6]1[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[CH:10][C:5]=1[C:3]1[N:16]=[C:17]([NH2:19])[S:18][CH:2]=1
Reactant: NC(N)=S
Reactant: O=C(CBr)c1cc(C(F)(F)F)ccc1F
Solvent: CO
Product: Br
Product: Nc1nc(-c2cc(C(F)(F)F)ccc2F)cs1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 5.8 g of 2-bromo-1-(2-fluoro-5-trifluoromethyl-phenyl)-ethanone in 44 ml of methanol was treated at room temperature with 2.2 g of thiourea and boiled for 1 hour. 2.8 g of 4-(2-fluoro-5-trifluoromethyl-phenyl)-thiazol-2-ylamine hydrobromide separated as colorless crystals upon cooling to 0° C. and after the addition of 15 ml of diethyl ether.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[C:15]=2[OH:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:22][CH2:23][S:24](Cl)(=[O:26])=[O:25].N1C=CC=CC=1>C1COCC1.CCOCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][S:24]([CH2:23][Cl:22])(=[O:26])=[O:25])[C:15]=2[OH:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(N)c2O)CC1
Reactant: O=S(=O)(Cl)CCl
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(NS(=O)(=O)CCl)c2O)CC1
Yield: 46.8 %

Procedure:
In a dry roundbottom flask, 4-(3-amino-2-hydroxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (293 mg., 1 mmol) was dissolved in dry THF (3 mL) under nitrogen. While stirring, chloro-methanesulfonyl chloride (149 mg., 1 mmol) was added dropwise over 10 minutes and the solution was stirred 30 minutes. Pyridine (0.121 mL., 1.5 mmol) was then added dropwise over 5 minutes and the solution was stirred for 18 hours. The reaction mixture was diluted with 40 mL Et2O and washed with 40 mL of 10% aqueous HCl, 50 mL water, and 50 mL brine. The organic fraction was dried over MgSO4 and concentrated in vacuo. The residue is purified by flash chromatography (20% to 40% EtOAc in hexanes) to give 190 mg of 4-(3-Chloromethanesulfonylamino-2-hydroxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester as an amber oil (45%). (M−H)−=404.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:17]([C:18]3[N:26]=[C:25]([CH3:27])[N:24]=[C:23]4[C:19]=3[N:20]=[CH:21][N:22]4[CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][O:29]3)=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][N:11]=2)=[CH:5][CH:4]=1.[C:34]([Mg]Cl)([CH3:37])([CH3:36])[CH3:35].Cl>C1COCC1.CO>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[CH:12][C:13]([CH:14]([OH:15])[C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:16][C:17]=2[C:18]2[N:26]=[C:25]([CH3:27])[N:24]=[C:23]3[C:19]=2[N:20]=[CH:21][N:22]3[CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Nc2ncc(C=O)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Reactant: CC(C)(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(Nc2ncc(C(O)C(C)(C)C)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.8 %

Procedure:
6-(6-methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)nicotinaldehyde (95.0 mg, 0.213 mmol) was dissolved in THF (2.5 mL) and the flask was cooled in an ice water bath. Then, tert-butylmagnesium chloride (1.0 M solution in tetrahydrofuran, 0.60 mL, 0.60 mmol) was added via syringe, turning the reaction red. The reaction was stirred under nitrogen while being warmed to room temperature, and after 70 min the reaction was treated with MeOH (1.0 mL) and 5 N HCl (0.50 mL). The flask was fitted with a reflux condenser and put in a preheated oil bath (about 50° C.), and stirring was continued for 1 h. Then, the reaction was cooled to room temperature, diluted with MeOH, concentrated, and purified by prep HPLC (10% to 100% MeCN/water with 0.1% TFA over 28 min using a total flow rate of 100 mL/min) to give 1-(6-(6-methoxypyridin-3-ylamino)-5-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-3-yl)-2,2-dimethylpropan-1-ol (45.9 mg, 97.4% purity, 52% yield). 1H NMR (d6-DMSO, 400 MHz) δ 12.62 (br s, 1H), 9.61 (s, 1H), 8.63 (s, 1H), 8.53 (d, J=2.74 Hz, 1H), 8.21-8.14 (m, 2H), 6.88 (d, J=9.0 Hz, 1H), 4.31 (s, 1H), 3.86 (s, 3H), 2.85 (s, 3H), 0.91 (s, 9H). m/z (ESI, pos. ion) 420 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([NH:11][CH2:12][C@@H:13]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]1([CH2:7][O:8][C:9](=[O:10])[NH:11][CH2:12][C@@H:13]2[CH2:17][CH2:16][NH:15][CH2:14]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CNC(=O)OCc2ccccc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC[C@@H]1CCNC1)OCc1ccccc1
Reaction time: 2 h
Yield: 94 %

Procedure:
To a solution of 1,1-dimethylethyl(3S)-3-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]-1-pyrrolidinecarboxylate in DCM (100 mL) at RT was added TFA (50 mL). After 2 h, the reaction solution was concentrated under vacuum and purified on silica (CHCl3/MeOH, 9:1 containing 5% NH4OH) to give the title compound (2.93 g, 94%) as a light yellow oil: LC-MS (ES) m/e 235 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][CH2:9][C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][C:15]([Cl:21])=[CH:16][CH:17]=3)[N:12]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:11]=2)=[O:7])=[CH:4][N:3]=1.[OH:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[Cl:21][C:15]1[CH:14]=[C:13]2[C:18]([C:19](=[O:20])[C:10]([CH2:9][NH:8][C:6](=[O:7])[C:5]3[CH:28]=[CH:29][C:2]([N:36]4[CH2:37][CH2:38][N:33]([CH2:32][CH2:31][OH:30])[CH2:34][CH2:35]4)=[N:3][CH:4]=3)=[CH:11][N:12]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[CH:17][CH:16]=1
Reactant: OCCN1CCNCC1
Reactant: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(Cl)nc1
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc(N2CCN(CCO)CC2)nc1

Procedure:
N-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-6-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-nicotinamide was prepared starting from intermediate E and N-(2-hydroxyethyl)piperazine. MS calcd. for C28H28ClN5O3 [(M+H)+] 518.2, obsd. 518.0.
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[CH2:3][C@H:4]([NH:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:5]O.O=S(Cl)[Cl:15]>C1(C)C=CC=CC=1>[ClH:15].[Cl:15][CH2:5][C@@H:4]([NH:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH2:3][CH:2]([CH3:12])[CH3:1]
Reactant: O=S(Cl)Cl
Reactant: CC(C)CN[C@H](CO)CC(C)C
Solvent: Cc1ccccc1
Product: CC(C)CN[C@H](CCl)CC(C)C
Product: Cl
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a solution of (2S)-4-methyl-2-(isobutylamino)pentan-1-ol (Method B4c; 256 g, 1.5 mol) and toluene (2.5 L) was added SOCl2 (167 mL) over 15 min. After the addition of SOCl2 was complete the reaction was heated at 90° C. overnight. The reaction solution was then cooled to room temp. and concentrated under reduced pressure. The dark oily residue was dissolved in CH2Cl2 (2 L) and concentrated under reduced pressure. The red-brown residue was dissolved in Et2O (1 L), and hexane (750 mL) was added dropwise over a period of 8 h. The resulting slurry was stirred overnight, filtered, and washed with a 40% EtOAc/hex solution to give N-(1S)-(1-(chloromethyl)-3-methylbutyl)-N-(isobutyl)amine HCl salt as a dark brown solid (276 g): 1H NMR (CDCl3) δ0.93-1.00 (m, 6H), 1.10-1.12 (m, 6H), 1.85 (m, 4H), 2.24-2.34 (m, 2H), 2.80-2.88 (m, 1H), 2.90-3.02 (m, 1H), 3.50-3.57 (m, 1H), 3.96 (dd, J=12.9, 5.6 Hz, 1H), 4.10 (dd, J=13.2, 3.6 Hz, 1H).
Reaction SMILES: [OH-].[Na+].[C:3]1(=[O:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]C[NH:4]1.N[CH:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:15]([OH:17])=[O:16].NCCCCCCCC(O)=[O:33].Cl>O.O1CCOCC1>[C:3]([NH:4][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:14][C:15]([OH:17])=[O:16])(=[O:12])[C:11]1[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:33]
Reactant: NCCCCCCCC(=O)O
Reactant: CCCCCCC(N)C(=O)O
Reactant: O=C1CCCCCCCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CCCCCCCNC(=O)c1ccccc1O
Temperature: 25 °C

Procedure:
Sodium hydroxide (1.68 g, 42.0 mmol, 1.2 eq), 2-azacyclononanone (5.0 g, 35.5 mmol, 1.0 eq) and 20 mL of water were placed a 100 mL round bottom flask equipped with a magnetic stir bar and cold water condenser to prepare aminocaprylic acid. The reaction mixture was heated to reflux for 2.5 hours (at which time the reaction was determined to have finished, by TLC) and cooled to 25 degrees C. A solution of oligosalicylate (4.87 g, 40 mmol, 1.1 eq) and dioxane (50 mL) was added to the aqueous solution of 8-aminocaprylic acid. This mixture was heated to reflux for 2.25 hours (at which time the reaction was determined to have finished, by HPLC). The clear orange reaction mixture was cooled to 25 degrees C. and acidified to pH=1 with 3% (by vol.) aqueous hydrochloric acid. All the dioxane and some of the water were stripped (60 degrees C., 50 min). The aqueous phase was decanted from the brown oil while still warm. Crystallization of the oil from ethanol-water yielded a white precipitate. The solid was recovered by filtration and was dried over 4 hours in a 50 degrees C. vacuum oven. The N-(salicyloyl)-8-aminocaprylic acid was isolated as a white solid (5.73 g, 59%).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH:6]1([O:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][C:11]=2[CH2:21][OH:22])[CH2:8][CH2:7]1.C(N(CC)CC)C.O>ClCCl>[CH3:1][S:2]([O:22][CH2:21][C:11]1[CH:12]=[C:13]([O:16][C:17]([F:19])([F:20])[F:18])[CH:14]=[CH:15][C:10]=1[O:9][CH:6]1[CH2:7][CH2:8]1)(=[O:4])=[O:3]
Reactant: OCc1cc(OC(F)(F)F)ccc1OC1CC1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1cc(OC(F)(F)F)ccc1OC1CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methanesulfonyl chloride (0.31 mL, 0.46 g, 4.0 mmol) was added dropwise to a stirred, cooled (−10° C.) solution of 2-(cyclopropyloxy)-5-(trifluoromethoxy)benzenemethanol (WO9900368, 0.5 g, 2.0 mmol) and triethylamine (0.56 mL, 0.40 g, 4.0 mmol) in dichloromethane (10 mL) and the mixture was stirred at 0° C. for 30 minutes, then at room temperature for 2 hours. Water (50 mL) was added and the mixture was extracted with ethyl acetate (2×50 mL). The combined organic fractions were washed with aqueous citric acid (10%, 20 mL), aqueous sodium hydrogen carbonate (saturated, 50 mL) and brine (50 mL), dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound. 1H NMR (400 MHz, CDCl3) δ 7.28-7.22 (3H, m), 5.20 (2H, s), 3.80-3.77 (1H, m), 3.01 (3H, s), and 0.85-0.79 (4H, m).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5]Br)[CH3:2].C(=O)([O-])[O-].[K+].[K+].[OH:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[I:24])[C:17]([O:19][CH3:20])=[O:18].O>C(C(C)=O)C.C(OCC)(=O)C>[CH2:1]([O:3][CH2:4][CH2:5][O:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23]=1[I:24])[C:17]([O:19][CH3:20])=[O:18])[CH3:2]
Reactant: COC(=O)c1ccc(I)c(O)c1
Reactant: CCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOCCOc1cc(C(=O)OC)ccc1I
Temperature: 80 °C
Yield: 84.7 %

Procedure:
3.15 g (20 mmol) of 2-bromoethyl ethyl ether and 3.4 g (24.6 mmol) of potassium carbonate are added to a solution of 5.7 g (20 mmol) of methyl 3-hydroxy-4-iodobenzoate (prepared according to Example 19d) in 50 mL of methyl ethyl ketone. The reaction mixture is heated at 80° C. for 12 hours. The reaction is stopped by addition of 50 mL of water and extraction with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then purified by chromatography on a column of silica eluted with an 80/20 heptane/ethyl acetate mixture. 5.93 g (83%) of methyl 3-(2-ethoxyethoxy)-4-iodobenzoate are obtained in the form of a colorless oil.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]=[C:8]2[CH:10]=[CH:11][N:12]([CH3:13])[C:7]2=[CH:6][C:5]=1[NH:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)[CH3:3].[NH2:28][C:29]1[N:34]=[C:33](Cl)[C:32]([C:36]#[N:37])=[C:31]([CH3:38])[N:30]=1.CCN(C(C)C)C(C)C>CC(O)=O.C(#N)C>[NH2:28][C:29]1[N:34]=[C:33]([NH:1][C@H:2]([C:4]2[N:9]=[C:8]3[CH:10]=[CH:11][N:12]([CH3:13])[C:7]3=[CH:6][C:5]=2[NH:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:17][CH2:16]2)[CH3:3])[C:32]([C:36]#[N:37])=[C:31]([CH3:38])[N:30]=1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1NC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1nc(N)nc(Cl)c1C#N
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2NC2CCN(C(=O)OC(C)(C)C)CC2)c1C#N
Temperature: 75 °C
Reaction time: 1 h

Procedure:
To crude tert-butyl (S)-4-((5-(1-aminoethyl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-6-yl)amino)piperidine-1-carboxylate was added HOAc (2 drops), followed by ACN (2 mL), 2-amino-4-chloro-6-methylpyrimidine-5-carbonitrile (0.083 g, 0.493 mmol), and DIPEA (0.344 mL, 1.970 mmol). The reaction mixture was stirred at 75° C. for 1 hour. LCMS showed the reaction was complete, though messy. The volatiles were removed by N2 flow. The crude title compound was used without further purification. ESI-MS m/z [M+H]+ calc'd for C26H35N9O2, 506. found 506.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[CH:21][N:20]=[C:19]3[C:15]=2[N:16]=[CH:17][N:18]3[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]#[N:31])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:32]N1C(=O)CCC1=O.C(OCC)(=O)C.O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:22]=[CH:21][N:20]=[C:19]3[C:15]=2[N:16]=[C:17]([Cl:32])[N:18]3[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]#[N:31])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncnc3c2ncn3Cc2ccccc2C#N)CC1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc3c2nc(Cl)n3Cc2ccccc2C#N)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 22.1 %

Procedure:
4-[9-(2-Cyanobenzyl)-9H-purin-6-yl]-piperazine-1-carboxylic acid t-butyl ester (0.419 g) was suspended in N,N-dimethylformamide (80 mL), and then N-chlorosuccinimide (0.160 g) was added. This was stirred at room temperature for 72 hours. N-chlorosuccinimide (0.160 g) was added again, and this was then heated at 60° C. for 18 hours. Ethyl acetate (200 mL) and water (100 mL) were then added, and the organic layer was washed twice with 50 mL of water and then once with 5 mL of saturated aqueous sodium chloride solution. This was then dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure, and then the residue was purified by silica gel chromatography. The dichloromethane:ethyl acetate 7:3 fraction gave the title compound (0.100 g).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)=[CH:4][C:3]=1[C:16]#[N:17].[N:18]1[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=1.CC([O-])(C)C.[K+]>CS(C)=O>[CH3:15][O:14][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:24][C:21]3[CH:22]=[CH:23][N:18]=[CH:19][CH:20]=3)=[C:3]([C:16]#[N:17])[CH:4]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccncc1
Reactant: COc1cccc(-c2ccc(F)c(C#N)c2)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cccc(-c2ccc(Nc3ccncc3)c(C#N)c2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 79.9 %

Procedure:
To a solution of 4-fluoro-3′-methoxybiphenyl-3-carbonitrile (0.50 g, 2.20 mmol) in DMSO (4 mL) was added pyridine-4-amine (0.23 g, 2.42 mmol) and KOtBu (0.15 g, 1.38 mmol). The reaction stirred under nitrogen at room temperature for 12 h. The reaction mixture was partitioned between water and ethyl acetate, the layers were separated, the organics were washed with water, brine solution, dried over Na2SO4 and concentrated to give the crude product. The crude material was purified by silica gel column chromatography (DCM/(2M)NH4-MeOH=100/0−95/5) to afford 0.53 g of 3′-methoxy-4-(pyridine-4-ylamino)biphenyl-3-carbonitrile. MS (ESI) m/z 302.2 (M+H). 1H NMR MeOD) d ppm 8.24 (2H, d, J=6.41 Hz), 8.01 (1H, d, J=2.44 Hz), 7.93 (1H, dd, J=8.70, 2.29 Hz), 7.61 (1H, d, J=8.55 Hz), 7.40 (1H, t, J=7.93 Hz), 7.17-7.30 (2H, m), 6.92-7.05 (3H, m), 3.88 (3H, s).
Reaction SMILES: [CH:1](=[N:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].[C:18]([O-])(O)=O.[Na+].O.[C:24]1([CH3:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(O)C>[CH:1](=[N:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH:24]([CH3:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH3:18])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: Oc1ccc(N=Cc2ccccc2)cc1
Reactant: Cc1ccccc1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCC(C)Oc1ccc(N=Cc2ccccc2)cc1

Procedure:
Benzylidene-p-hydroxyaniline as a known substance (m.p.: 185° C.) (140 g) was dissolved in ethanol (700 ml) containing KOH (43 g), followed by dropwise adding S(+)-2-octyl p-toluenesulfonate (218 g) at 70° C., heating the mixture under reflux for 20 hours, adding a 5% aqueous solution of NaHCO3 (50 ml), water (200 ml) and toluene (800 ml), separating the toluene layer, washing with a 2N aqueous solution of NaOH, distilling off toluene and recrystallizing from ethanol to obtain optically active benzylidene-p-(1-methyl-heptyloxy)aniline (m.p. 47.3° C.)(105 g).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[N:5]2[C:10]=1[CH:9]=[CH:8][CH:7]=[N:6]2.[Cu][C:20]#[N:21]>CS(C)=O>[F:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][C:4]1[N:5]2[N:6]=[CH:7][CH:8]=[CH:9][C:10]2=[C:2]([C:20]#[N:21])[N:3]=1
Reactant: N#C[Cu]
Reactant: Fc1ccccc1Cc1nc(Br)c2cccnn12
Solvent: CS(C)=O
Product: N#Cc1nc(Cc2ccccc2F)n2ncccc12
Temperature: 170 °C

Procedure:
1.00 g (3.266 mmol) of the compound obtained in Example 5A were initially charged in dry DMSO (25 ml), 1.170 g (13.066 mmol) of copper(I) cyanide were then added and, with stirring, the mixture was heated to 170° C. for 3.5 h. The mixture was filtered through Celite, and the filter cake was washed with ethyl acetate and tetrahydrofuran. The filtrate was then extracted four times with a mixture of saturated aqueous ammonium chloride solution/aqueous ammonia (33%) (3:1, v/v) and washed once with saturated aqueous sodium chloride solution. The phases were separated and the organic phase was dried with sodium sulfate, filtered and concentrated. The residue was treated with ethanol in an ultrasonic bath, and water was then added. The precipitate formed was filtered off, washed with ethanol and then dried under high vacuum. This gave 586 mg of the target compound (71% of theory).