Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:19]=[CH:18][C:17]3[C:16]4[C:11](=[CH:12][C:13]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)=[CH:14][CH:15]=4)[CH2:10][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH2:31]([O:34][C:35]1[C:40]([C:41]([CH3:44])([CH3:43])[CH3:42])=[CH:39][C:38]([CH3:45])=[CH:37][C:36]=1[Si:46](Cl)([CH2:49][CH3:50])[CH2:47][CH3:48])[CH:32]=[CH2:33].C(=O)([O-])O.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.C1(C)C=CC=CC=1.CCCCCC>[CH2:31]([O:34][C:35]1[C:40]([C:41]([CH3:42])([CH3:43])[CH3:44])=[CH:39][C:38]([CH3:45])=[CH:37][C:36]=1[Si:46]([CH:10]1[C:11]2[CH:12]=[C:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:14]=[CH:15][C:16]=2[C:17]2[C:9]1=[CH:8][C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[CH:19][CH:18]=2)([CH2:47][CH3:48])[CH2:49][CH3:50])[CH:32]=[CH2:33]
Reactant: c1ccc(-c2ccc3c(c2)Cc2cc(-c4ccccc4)ccc2-3)cc1
Reactant: C=CCOc1c(C(C)(C)C)cc(C)cc1[Si](Cl)(CC)CC
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C=CCOc1c(C(C)(C)C)cc(C)cc1[Si](CC)(CC)C1c2cc(-c3ccccc3)ccc2-c2ccc(-c3ccccc3)cc21
Temperature: -78 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
There was dissolved 3.00 g (9.42 mmol) of 2,7-diphenylfluorene in 60 mL of THF, and the obtained solution was cooled down to −78° C. To the solution, 6.12 mL of a 1.54 M-concentration hexane solution of n-butyllithium was added slowly, 6.12 mL of said hexane solution containing 9.42 mmol of n-butyllithium. Temperature of the resultant mixture was raised up to a room temperature, and the mixture was stirred for 2 hours at a room temperature. The mixture was cooled down to −78° C., and a solution of 3.06 g (9.42 mmol) of (2-allyloxy-3-tert-butyl-5-methylphenyl)chlorodiethylsilane in 14 mL of toluene was added to the mixture. Temperature of the resultant mixture was raised up to a room temperature, and the mixture was stirred for 3 hours, thereby obtaining a reaction solution. A mixture of 50 mL of a 10% aqueous solution of sodium hydrogen carbonate and 50 mL of a 10% aqueous solution of sodium carbonate was added to the reaction solution at 0° C. To the obtained mixture, 58 mL of toluene was added, and the mixture was separated to the toluene solution and the aqueous solution. The toluene solution was dried over sodium sulfate, and the mixture was filtered. The obtained filtrate was concentrated under a reduced pressure. A small amount of toluene was added the concentrated filtrate to obtain a solution, and hexane was further added thereto, thereby obtaining 3.66 g (yield: 64.0%) of (2-allyloxy-3-tert-butyl-5-methylphenyl)(2,7-diphenyl fluoren-9-yl)diethylsilane as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][C:17]([F:20])([F:19])[F:18].CN(C=O)C>[Na+].[Cl-]>[CH3:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:7][N:6]=1
Reactant: FC(F)(F)CBr
Reactant: Cc1ccc(O)cn1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(OCC(F)(F)F)cn1
Temperature: 95 °C
Yield: 70.1 %

Procedure:
Add 5-hydroxy-2-methyl-pyridine (3.3 g, 30.6 mmol), potassium carbonate (17 g, 122.4 mmol) and 2-bromo-1,1,1-trifluoroethane (10 g, 61.2 mmol) to a flask containing DMF (60 mL) and heat to 95° C. for 20 h. Cool the mixture, dilute with aqueous 10% NaCl (20 mL) and extract with hexane/EtOAc (1:1, 100 mL). Filter the bi-phasic mixture through Celite®, separate and wash the organic layer with aqueous 10% NaCl (3×50 mL) and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1 to 1:1) to obtain the desired intermediate (4.1 g, 70%).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][C:11]([NH:13][C@@H:14]([C:37]([O:39]C)=[O:38])[CH2:15][O:16][C@@H:17]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:18][N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:21]1[CH2:23][CH2:22]1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>O1CCCC1>[CH2:3]([O:10][C:11]([NH:13][C@@H:14]([C:37]([OH:39])=[O:38])[CH2:15][O:16][C@@H:17]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:18][N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:21]1[CH2:22][CH2:23]1)=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)[C@@H](CO[C@H](CN(CC1CC1)C(=O)OC(C)(C)C)c1ccccc1)NC(=O)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CC1CC1)C[C@@H](OC[C@@H](NC(=O)OCc1ccccc1)C(=O)O)c1ccccc1
Reaction time: 18 h

Procedure:
Aqueous sodium hydroxide (1N; 3.81 mL, 3.81 mmol) was added to a solution of methyl N-[(benzyloxy)carbonyl]-O-{(1S)-2-[(tert-butoxycarbonyl)(cyclopropylmethyl)amino]-1-phenylethyl}-D-serinate (1.30 g, 2.46 mmol) in tetrahydrofuran (20 mL). After 18 h, aqueous hydrochloric acid (1N; 3.81 mL, 3.81 mmol) was added. The mixture was extracted with dichloromethane (3×), and the combined organic extracts were dried over magnesium sulfate, filtered, and concentrated to give the title compound. (1.27 g) MS 535 (M+Na).
Reaction SMILES: C[O:2][C:3](=[O:42])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][C:12]([C@H:14]2[C@H:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=3[F:26])[C@:17]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=3[F:36])([C:27]#[N:28])[C@H:16]([CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[NH:15]2)=[O:13])=[CH:6][CH:5]=1.[OH-].[Na+]>CO>[Cl:25][C:21]1[C:20]([F:26])=[C:19]([C@@H:18]2[C@:17]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=3[F:36])([C:27]#[N:28])[C@H:16]([CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[NH:15][C@H:14]2[C:12]([NH:11][CH2:10][C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:42])=[O:2])=[CH:9][CH:8]=2)=[O:13])[CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)c1ccc(CNC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)NCc2ccc(C(=O)O)cc2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Reaction time: 1.5 h

Procedure:
rac 4-({[(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-methyl)-benzoic acid methyl ester (40 mg) was dissolved in MeOH (10 mL) with help of slight heating. To the stirred solution was added NaOH (1N, 2 mL) and the mixture was stirred for 1.5 hrs. The solvent was removed and the residue was treated with 1 N HCl to make the mixture acidic. The white suspension was extracted with EtOAc (3×10 mL) and the extracts combined and dried with sodium sulfate. The solvent was removed and the residue was freeze dried to give a white powder. 38 mg.
Reaction SMILES: C(O)C.Cl.[C:5]([C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=1)[O:12][C:13]1[C:18]([CH3:19])=[CH:17][C:16]([N+:20]([O-])=O)=[CH:15][N:14]=1)([CH3:8])([CH3:7])[CH3:6]>[Fe].O>[C:5]([C:9]1[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=1)[O:12][C:13]1[N:14]=[CH:15][C:16]([NH2:20])=[CH:17][C:18]=1[CH3:19])([CH3:8])([CH3:6])[CH3:7]
Reactant: Cc1cc([N+](=O)[O-])cnc1Oc1cccc(C(C)(C)C)c1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1cc(N)cnc1Oc1cccc(C(C)(C)C)c1
Temperature: 50 °C
Yield: 54.4 %

Procedure:
A 100 ml two-necked round-bottomed flask equipped with a KPG-stirrer, a thermometer and a reflux condenser is charged with ethanol (50 ml), water (5 ml), iron (1.43 g) and hydrochloric acid 37% (0.2 ml). The reaction mixture is heated at 50° C. 2-(3-tert-Butyl-phenoxy)-3-methyl-5-nitro-pyridine (2.26 g) was added portionwise. The mixture is heated at reflux for 3 hours. After cooling the mixture to 50° C. it is filtered through celite. The filtrate is poured into water (200 ml) and extracted with ethylacetate (2×50 ml). The combined organic layers are washed with brine (100 ml), dried over sodium sulfate, filtered and the solvent is removed in vacuo. Purification by flash chromatography over silica gel with hexane/ethyl acetate 1:1 (v:v) gives 1.10 g of the compound as a brownish solid (MP: 83-84° C.).
Reaction SMILES: [CH:1]1([S:4](Cl)(=[O:6])=[O:5])[CH2:3][CH2:2]1.N1C=CC=CC=1.[CH2:14]([OH:18])[CH2:15][CH2:16][CH3:17]>>[CH:1]1([S:4]([O:18][CH2:14][CH2:15][CH2:16][CH3:17])(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: CCCCO
Reactant: O=S(=O)(Cl)C1CC1
Solvent: c1ccncc1
Product: CCCCOS(=O)(=O)C1CC1
Temperature: -10 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
Cyclopropanesulfonyl chloride (5 g, 35 mmol, 1 eq) was dissolved in an excess BuOH (20 ml), the reaction mixture was cooled at −10° C. and pyridine (5.8 mL, 70 mmol, 2 eq) was slowly added dropwise. The mixture was slowly warmed at room temperature and stirred overnight. The solvent was removed under reduced pressure and the resulting white solid was dissolved in CHCl3. The organic phase was washed with water, brine and dried (MgSO4) and concentrated to give an oil (4.8 g, 24.9 mmol, 71%). 1H NMR (300 MHz, CDCl3): δ 4.25 (t, 2H), 2.46 (m, 1H), 1.74 (m, 2H), 1.45 (m, 2H), 1.25 (dd, 2H), 1.09 (dd, 2H), 93 (t, 3H).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([CH3:9])[C:7]3[CH:10]=[C:11]([N:14]4[CH:19]=[CH:18][C:17](O)=[CH:16][C:15]4=[O:21])[CH:12]=[CH:13][C:6]=3[N:5]=2)[CH2:3][CH2:2]1.P(Br)(Br)([Br:24])=O.C([O-])(O)=O.[Na+]>CN(C=O)C>[Br:24][C:17]1[CH:18]=[CH:19][N:14]([C:11]2[CH:12]=[CH:13][C:6]3[N:5]=[C:4]([CH:1]4[CH2:3][CH2:2]4)[N:8]([CH3:9])[C:7]=3[CH:10]=2)[C:15](=[O:21])[CH:16]=1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(O)cc3=O)cc21
Reactant: O=P(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(Br)cc3=O)cc21
Temperature: 50 °C
Reaction time: 8 h
Yield: 69.5 %

Procedure:
To a suspension of 1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (2 g) in DMF (35 ml) was added phosphoryltribromide (2.45 g) at room temperature, and the mixture was stirred at 50° C. overnight. The mixture was poured into saturated NaHCO3 solution, and extracted with EtOAc. The organic layer was washed with water and brine successively, dried over MgSO4 and concentrated in vacua. The resulting residual solid was recrystallized from EtOH-hexane to give the title compound (1.70 g) as a brown solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[O:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[O:12][CH2:13][C:14]#[C:15][CH2:16][OH:17].O.[Na+].[Cl-]>C(Cl)Cl>[S:2]([O:17][CH2:16][C:15]#[C:14][CH2:13][O:12][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][O:6]1)(=[O:4])(=[O:3])[CH3:1]
Reactant: CS(=O)(=O)Cl
Reactant: OCC#CCOC1CCCCO1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CS(=O)(=O)OCC#CCOC1CCCCO1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 55 %

Procedure:
Methanesulfonyl chloride (1.0 mL, 12.80 mmol) was added dropwise to a stirred solution of 4-(tetrahydro-pyran-2-yloxy)-but-2-yn-1-ol (1.9232 g, 11.30 mmol) and TEA (2.5 mL, 17.85 mmol) in DCM (40 mL) at ° C. for five minutes. And then the resulting mixture was stirred at room temperature for 5.5 hours. Water (20 mL) was added, followed by addition of saturated aqueous NaCl solution (70 mL). The organic phase was separated and washed again with brine (60 mL), dried over Na2SO4, concentrated. The residue was separated by flash column chromatography on silica gel using 5-25% EtOAc/hexane to afford 1.542 g of product (yield 55%, oil), along with 400 mg of Di-4-(tetrahydro-pyran-2-yloxy)-but-2-ynyl ether (yield 22%). 1H-NMR (CDCl3): δ 4.88 (t, J=1.8 Hz, 2 H), 4.76 (t, J=3.0-3.3 Hz, 1 H), 4.37-4.24 (m, 2 H), 180-3.76 (m, 1 H), 3.54-3.50 (m, 1 H), 3.11 (s, 3 H), 1.78-1.51 (m, 6 H).
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[CH:13]=[CH:12][S:11][CH:10]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C([Li])CCC.[CH2:19]([Sn:23](Cl)([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH3:22].P([O-])([O-])(O)=O.[Na+].[Na+].P([O-])(O)(O)=O.[Na+]>C1COCC1>[CH2:28]([Sn:23]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:24][CH2:25][CH2:26][CH3:27])[C:10]1[S:11][CH:12]=[CH:13][C:9]=1[P:4]([O:6][CH2:7][CH3:8])([O:3][CH2:1][CH3:2])=[O:5])[CH2:29][CH2:30][CH3:31]
Reactant: CCOP(=O)(OCC)c1ccsc1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: O=P([O-])(O)O
Agent: O=P([O-])([O-])O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1sccc1P(=O)(OCC)OCC
Temperature: -78 °C
Reaction time: 3 h
Yield: 96 %

Procedure:
In THF, 1.96 g (8.90 mmols) of 3-(diethoxyphosphoryl)thiophene was dissolved and cooled down to −78° C. Commercially available n-butyl lithium (1.59 M hexane solution, 8.90 mmols) was slowly dropped, followed by stirring for 3 hours at a standing temperature. Thereafter, 3.19 g (9.80 mmols) of commercially available tributylstannyl chloride was dropped and stirred for 1.5 hours. After completion of the reaction, a disodium hydrogen phosphate/sodium dihydrogen phosphate buffer solution, adjusted to pH=7, was added so as to complete the reaction, followed by extraction with ethyl acetate. The organic phase was washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was removed, and the resulting crude product was purified with a silica gel column (ethyl acetate:hexane=1:2) to obtain the specified substance in the form of a transparent oil at a yield of 4.35 g (yield: 96%). The thus obtained substance was used as it is for reaction in Example 12(3).
Reaction SMILES: CO.C(OC(=O)[N:9]([CH2:30][C:31]1[CH:40]=[CH:39][C:34]2[O:35][CH2:36][CH2:37][O:38][C:33]=2[CH:32]=1)[CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([CH3:28])[CH:26]=3)[CH:21]=[CH:20][C:19]2=[O:29])[CH2:12][CH2:11]1)(C)(C)C.[ClH:42].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:42].[O:35]1[C:34]2[CH:39]=[CH:40][C:31]([CH2:30][NH:9][CH:10]3[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][N:18]4[C:27]5[C:22](=[CH:23][CH:24]=[C:25]([CH3:28])[CH:26]=5)[CH:21]=[CH:20][C:19]4=[O:29])[CH2:14][CH2:15]3)=[CH:32][C:33]=2[O:38][CH2:37][CH2:36]1
Reactant: Cc1ccc2ccc(=O)n(CCN3CCC(N(Cc4ccc5c(c4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc2ccc(=O)n(CCN3CCC(NCc4ccc5c(c4)OCCO5)CC3)c2c1
Reaction time: 0.5 h

Procedure:
To 2.0 mL of a methanol solution containing 0.25 g of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(7-methyl-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 2.0 mL of 4 mol/L hydrogen chloride/ethyl acetate solution was added and stirred for 30 min. Ethyl acetate was added, and the resulting solid was filtered to afford 0.18 g of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methylquinolin-2(1H)-one hydrochloride as a white solid.
Reaction SMILES: [N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7](B(O)O)[CH:8]=[CH:9][C:2]=12.Br[C:14]1[CH:15]=[C:16]([NH:20][CH3:21])[CH:17]=[CH:18][CH:19]=1>>[N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([C:14]3[CH:15]=[C:16]([NH:20][CH3:21])[CH:17]=[CH:18][CH:19]=3)[CH:8]=[CH:9][C:2]=12
Reactant: OB(O)c1ccc2nonc2c1
Reactant: CNc1cccc(Br)c1
Product: CNc1cccc(-c2ccc3nonc3c2)c1

Procedure:
Starting from 5-benzo[1,2,5]oxadiazoleboronic acid and (3-bromo-phenyl)-methyl-amine. Yellow powder. MS(ES+): 226 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][Se:15][C:11]=2[C:10]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([O:24]C)=[O:23])=[CH:18][CH:17]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C2C=C[Se]C=2C(C2OC(C(OC)=O)=CC=2)=N1)C1C=CC=CC=1.C(N1C2C=C[Se]C=2C(C2OC(C(O)=O)=CC=2)=N1)C1C=CC=CC=1>>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][Se:15][C:11]=2[C:10]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18][CH:17]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(-c2nn(Cc3ccccc3)c3cc[se]c23)cc1
Agent: COC(=O)c1ccc(-c2nn(Cc3ccccc3)c3cc[se]c23)o1
Agent: O=C(O)c1ccc(-c2nn(Cc3ccccc3)c3cc[se]c23)o1
Product: O=C(O)c1ccc(-c2nn(Cc3ccccc3)c3cc[se]c23)cc1

Procedure:
Compound 67 (0.792 g, 0.002 mole) was used to replace compound 55 in the preparation of compound 59 to afford compound 70. Yield: 0.649 g (85.2%); white crystals; mp 288-290° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([C:9]([O:11]C)=O)=[N:7][CH:8]=1.[NH3:13]>>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([C:9]([NH2:13])=[O:11])=[N:7][CH:8]=1
Reactant: N
Reactant: COC(=O)c1cnc(OC)cn1
Product: COc1cnc(C(N)=O)cn1
Temperature: 50 °C

Procedure:
To a 100-mL round-bottomed flask was added methyl 5-methoxypyrazine-2-carboxylate (0.811 g, 4.82 mmol, synthesized according to Journal of Heterocyclic Chemistry, 19(2), 407-8; 1982) and ammonia (2 M in MeOH; 25 mL, 50.0 mmol). The reaction mixture was heated to 50° C. overnight. The reaction mixture was allowed to cool to ambient temperature, filtered and dried to afford 5-methoxypyrazine-2-carboxamide as a white crystalline solid. MS m/z=154.0 [M+H]+. Calculated for C6H7N3O2: 153.14.
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][C:8]1[CH:9]=[N:10][CH:11]=[N:12][CH:13]=1.F[C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[C:17]#[N:18].Cl>O.CS(C)=O>[C:17]([C:16]1[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=1[NH:7][C:8]1[CH:9]=[N:10][CH:11]=[N:12][CH:13]=1)#[N:18]
Reactant: N#Cc1ccccc1F
Reactant: Nc1cncnc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1ccccc1Nc1cncnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
To 10 ml of dimethyl sulfoxide was added 1.40 g (12.5 mmol) of potassium tert-butoxide, and to the solution was added 951 mg (10.0 mmol) of 5-aminopyrimidine while cooling with water. After stirring at room temperature for 1 hour, 0.54 ml (5.0 mmol) of 2-fluorobenzonitrile was added thereto while cooling with water, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into ice-water, and the mixture was adjusted to pH 7.0 with 1 N hydrochloric acid, and filtered. The filter residue was dissolved in 200 ml of acetone, and the acetone solution was filtered. The filtrate was dried over magnesium sulfate, and the solvent was removed by distillation under reduced pressure to obtain 0.53 g (2.70 mmol) of 5-[N-(2cyanophenyl)amino]pyrimidine.
Reaction SMILES: C(OC([NH:8][CH2:9][C@@H:10]([N:12]1[C:16]2=[N:17][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:20]=[C:15]2[CH:14]=[C:13]1[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:11])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][CH2:9][C@@H:10]([N:12]1[C:16]2=[N:17][C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:20]=[C:15]2[CH:14]=[C:13]1[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH3:11]
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)n([C@@H](C)CNC(=O)OC(C)(C)C)c2n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc2cc(C(=O)OCC)n([C@@H](C)CN)c2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 95 %

Procedure:
To a solution of diethyl 1-{(2S)-1-[(tert-butoxycarbonyl)amino]propan-2-yl}-1H-pyrrolo[2,3-b]pyridine-2,6-dicarboxylate (3.00 g, 7.15 mmol) in CH2Cl2 (20 mL) is added TFA (10 mL). The mixture is stirred at room temperature for 3 hr then is concentrated under reduced pressure. The residue is taken up in ethyl acetate and is washed with brine, is dried (Na2SO4) and concentrated in vacuo to afford the title compound (2.17 g) which is used in the next step without purification.
Reaction SMILES: [CH3:1][C:2]1([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[NH:18][C:17]3=O)[CH2:12][CH2:11]2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.P(Cl)(Cl)([Cl:28])=O.N>>[Cl:28][C:17]1[N:16]([CH:13]2[CH2:14][CH2:15][N:10]([C:2]3([CH3:1])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]3)[CH2:11][CH2:12]2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC1(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CCCCCCC1
Agent: N
Product: CC1(N2CCC(n3c(Cl)nc4ccccc43)CC2)CCCCCCC1
Temperature: 25 °C
Yield: 66.3 %

Procedure:
A mixture of 4-(2-keto-1-benzimidazolinyl)piperidine (5.10 g, 23.5 mmol) and HCl solution in MeOH (20 ml) was stirred at room temperature for 10 minutes. After evaporation of the solvent, the residue was triturated in Et2O to give HCl salt as off-white powder. To this HCl salt was added cyclooctanone (3.33 ml, 28.2 mmol) followed by addition of aqueous solution of KCN (1.92 g, 29.5 mmol) in water (7 ml) at room temperature. After 18 hour stirring, the resulting solid was collected by filtration, washed with water, and dried in vacuo to give 6.81 g (85.7%) of nitrile derivative as white powder. To a solution of this nitrile derivative (5.12 g, 15.1 mmol) in THF (40 ml) was added a solution of methylmagnesium bromide in Et2O (3.0 M solution, 25 ml) at 0° C. Then the reaction mixture was stirred at room temperature for 18 hours. Aqueous NH4Cl solution was added to the reaction mixture and the resulting solid appeared was collected by filtration, washed with water and Et2O, and dried in vacuo at 70° C. to give 4.88 g (82.8%) of 1-[1-(1-methylcyclooctyl)-4-piperidinyl]-1,3-dihydro-2H-1,3-benzimidazol-2-one as white powder. A mixture of 1-[1-(1-methylcyclooctyl)-4-piperidinyl]-1,3-dihydro-2H-1,3-benzimidazol-2-one (2.316 g, 5.95 mmol) and phosphoryl chloride (15 ml, 165.5 mmol) was heated to reflux for 1.5 h. After cooling down to room temperature, the reaction mixture was poured into ice cooled 25% ammonia solution and extracted with CH2Cl2. The extracts combined were washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (silica gel: 200 g, hexane/ethyl acetate: 4/1) to give 1.42 g(58.7%) of a colorless amorphous solid.
Reaction SMILES: [CH2:1]([N:8]([CH3:26])[C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23]Br)=[CH:19][CH:18]=2)[C:11](=[O:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>CN(C=O)C>[CH2:1]([N:8]([CH3:26])[C:9]1[CH:14]=[CH:13][N:12]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([CH2:23][N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)=[CH:19][CH:18]=2)[C:11](=[O:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: CN(Cc1ccccc1)c1ccn(CCc2ccc(CBr)cc2)c(=O)c1
Solvent: CN(C)C=O
Product: CN(Cc1ccccc1)c1ccn(CCc2ccc(CN3CCCC3)cc2)c(=O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 150 mg (0.37 mmol) 4-(benzyl-methyl-amino)-1-[2-(4-bromomethyl-phenyl)-ethyl]-1H-pyridin-2-one (preparation 14d) in 2.0 mL DMF is added 152 μL (1.82 mmol) pyrrolidine at RT. The reaction mixture is stirred for 1 h at RT and is directly transferred to a reverse HPLC for purification (Waters symmetry, C18; water (0.15% formic acid)/acetonitrile 95:5 to 10:90).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]([C@H:7]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9][CH2:8]1)([CH3:6])[CH3:5].[H-].[Na+].[CH3:17]I>O1CCCC1>[CH3:1][O:2][C:3](=[O:14])[C:4]([C@H:7]1[CH2:8][CH2:9][C@@H:10]([O:13][CH3:17])[CH2:11][CH2:12]1)([CH3:6])[CH3:5]
Reactant: COC(=O)C(C)(C)[C@H]1CC[C@@H](O)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)[C@H]1CC[C@@H](OC)CC1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
0.500 g of 2-(cis-4-hydroxy-cyclohexyl)-2-methyl-propionic acid methyl ester (Example 87b) are dissolved in 5 ml of dry tetrahydrofuran. 0.120 g of sodium hydride (60% dispersion) is added in portions and the mixture stirred at 40° C. for 1 hour. Methyl iodide (0.233 ml) is added and the mixture heated to 40° C. for 5 hours. The reaction mixture is then cooled to room temperature, quenched with 5 ml of water and extracted with tert-butyl methyl ether (2×50 ml). The combined organic phases are dried over sodium sulphate and concentrated by evaporation. The title compound is identified from the residue by means of flash chromatography (SiO2 60F) based on its Rf value.