Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([C:8]2[CH:9]=[C:10]([CH2:14][C:15]([OH:17])=[O:16])[CH:11]=[CH:12][CH:13]=2)=[O:7])=[CH:4][CH:3]=1.O.[C:21]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:21][O:16][C:15](=[O:17])[CH2:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:19][CH:18]=2)[CH:9]=1
Reactant: O=C(O)Cc1cccc(C(=O)c2ccc(O)cc2)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: COC(=O)Cc1cccc(C(=O)c2ccc(O)cc2)c1
Yield: 573.5 %

Procedure:
A mixture of the acid (8.56 g, 33.4 mmole) of Step E and p-toluenesulfonic acid monohydrate (1.05 g, 5.6 mmole) in methanol (70 mL) is refluxed for 2.5 hours (TLC, methanol-toluene 1:9). The methanol is evaporated and the residue is dissolved in ethyl acetate and washed with brine. After drying (MgSO4) the solvent is removed to yield a tan solid (8.68 g, 96.2%, m.p. 111°-113° C.). The crude product is used as such in the next step.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])#[CH:2].Br[CH2:20][CH2:21][CH2:22][CH2:23]CC.BrCCCCCCCCCC>>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:20][CH2:21][CH2:22][CH3:23])#[CH:2]
Reactant: C#Cc1c(CCCCCC)ccc2ccccc12
Reactant: CCCCCCBr
Agent: CCCCCCCCCCBr
Product: C#Cc1c(CCCCCCCCCC)ccc2ccccc12

Procedure:
1-Ethynyl-2-n-decylnaphthalene was prepared in a similar manner to 1-ethynyl-2-hexylnaphthalene, except that bromohexane was replaced by bromodecane.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]([C:38](=[O:40])[CH3:39])[CH:30]=1)[C:9]([N:11]1[CH2:15][C@H:14]([F:16])[CH2:13][C@H:12]1[C:17](=[O:28])[NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[F:27])=[O:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:26][C:22]1[C:21]([F:27])=[C:20]([CH:25]=[CH:24][CH:23]=1)[CH2:19][NH:18][C:17]([C@@H:12]1[CH2:13][C@@H:14]([F:16])[CH2:15][N:11]1[C:9](=[O:10])[CH:8]([C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]([C:38](=[O:40])[CH3:39])[CH:30]=1)[NH2:7])=[O:28]
Reactant: CC(=O)n1cc(C(NC(=O)OC(C)(C)C)C(=O)N2C[C@H](F)C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)n1cc(C(N)C(=O)N2C[C@H](F)C[C@H]2C(=O)NCc2cccc(Cl)c2F)c2ccccc21
Temperature: 23 °C
Reaction time: 4 h

Procedure:
A solution of {1-(1-acetyl-1H-indol-3-yl)-2-[(2S,4R)-2-(3-chloro-2-fluoro-benzylcarbamoyl)-4-fluoro-pyrrolidin-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester (102 mg, 0.173 mmol) and TFA (66.7 μL, 0.866 mmol) in CH2Cl2 (0.58 mL) was stirred at 23° C. overnight. TFA (66.7 μL, 0.866 mmol) was again added and the reaction mixture was stirred at 23° C. for an additional 4 h to complete the reaction. Solvents were removed in vacuo and the crude residue was purified by preparative HPLC (Waters SunFire C180 DB, 5 μm, 19×50, eluent: 5% CH3CN/95% H2O to 100% CH3CN in 17 min, CH3CN and H2O containing 0.1% of TFA, flow 20 mL/min) to give after lyophilization of the purified fractions the desired material. MS (LC-MS): 487.1 [M−H]−; tR (HPLC conditions b): 3.19 min.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:9]=[C:10]([OH:17])[C:11](=[C:14]([Cl:16])[CH:15]=1)[CH:12]=[O:13].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[Cl:16][C:14]1[CH:15]=[C:8]([Cl:7])[CH:9]=[C:10]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:11]=1[CH:12]=[O:13]
Reactant: O=Cc1c(O)cc(Cl)cc1Cl
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1c(Cl)cc(Cl)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.1 %

Procedure:
Potassium carbonate (9.4 g, 67.8 mmole) was added to a stirred solution of 4,6-dichlorosalicylaldehyde (10.8 g, 56.5 mmole) in dimethylformamide (80 ml). The resulting mixture was stirred at 60° for 30 minutes and treated with benzyl bromide (10.6 g, 62.1 mmole). This mixture was stirred one hour at 60° C. and then poured into ice water (1000 ml) to give the title compound (15.9 g, 100%) which melted at 98°-100° C. after recrystallization from hexane. pmr (CDCl3) δ5.10 (2H, s), 7.33 (5H, s), 10.40 (H, s).
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:10]=2)[CH:5]1[N:17]1[CH2:22][CH2:21][N:20]([C:23]2([CH3:36])[CH2:28][CH2:27][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH2:24]2)[CH2:19][C@@H:18]1[CH3:37].I[CH2:39][CH3:40].O>CN(C=O)C>[CH2:39]([O:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:13]([F:16])([F:14])[F:15])[CH:10]=2)[CH:5]1[N:17]1[CH2:22][CH2:21][N:20]([C:23]2([CH3:36])[CH2:24][CH2:25][N:26]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:27][CH2:28]2)[CH2:19][C@@H:18]1[CH3:37])[CH3:40]
Reactant: CCI
Reactant: C[C@H]1CN(C2(C)CCN(C(=O)OC(C)(C)C)CC2)CCN1C1c2ccc(C(F)(F)F)cc2CC1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC1Cc2cc(C(F)(F)F)ccc2C1N1CCN(C2(C)CCN(C(=O)OC(C)(C)C)CC2)C[C@@H]1C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
Sodium hydride (5.225 g, 0.1306 mol) was mixed with dry DMF (150 mL) at 0° C. A solution of t-butyl 4-{(3S)-4-[2-hydroxy-5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]-3-methylpiperazin-1-yl}-4-methylpiperidine-1-carboxylate (50.0 g, 0.1005 mol) in DMF (100 mL) was added dropwise at 0° C over 20 min. After the addition, the mixture was stirred for another 20 min before iodoethane (12.06 mL, 0.1507 mol) was added at one portion. After being stirred for 1 h, the reaction content was carefully poured into 500 mL icy water. The mixture was extracted with methylene chloride (500 mL×3). The combined organic layer was washed with brine, and dried over magnesium sulfate. After the removal of the solvent, the residue was dissolved in methylene chloride, and passed through a silica plug with ethyl acetate/hexane/triethylamine 50:50:1 (the plug was presaturated with the same solvent system). After removal of the solvent, 48.4 g (91.6%) of product was obtained as a sticky solid, MS (EI) 526.2 (M+1).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@@:5]([CH3:17])([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:4](=[O:18])[C:3]=1[C:19]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][C:22]=2[S:21](=[O:35])(=[O:34])[N:20]=1.[OH-].[Na+:37].[CH3:38]I>O.CN(C)C=O>[CH3:17][C@@:5]1([CH2:12][CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([O-:1])=[C:3]([C:19]2[NH:24][C:23]3[CH:25]=[CH:26][C:27]([N:29]([CH3:38])[S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][C:22]=3[S:21](=[O:35])(=[O:34])[N:20]=2)[C:4]1=[O:18].[Na+:37]
Reactant: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N(C)S(C)(=O)=O)ccc3N2)=C([O-])c2ccccc21
Reaction time: 2 h

Procedure:
To a solution of Example 39I (104 mg, 0.193 mmol) in 3 mL of water was added 0.997 N NaOH (0.194 mL, 0.193 mmol). After stirring for 2 hours, the reaction mixture was concentrated to dryness. To a solution of the resulting residue in 3 mL of dimethylformamide was added methyl iodide (0.012 mL, 0.193 mmol). After stirring at room temperature overnight, the reaction solution was concentrated and chromatographed on silica gel eluting with hexane followed by 60% and 80% ethyl acetate in hexane. The resulting yellow solid was suspended in 3 mL of water and 0.997 N NaOH was added (0.160 mL, 0.160 mmol). After stirring for 4 hours, the suspension was lyophilized to 84 mg (79%) of a yellow solid. 1H NMR (300 MHz, DMSO-d6): δ ppm 0.46 (m, 1H) 0.69 (t, J=7.17 Hz, 6H) 0.82 (m, 1H) 1.28 (m, 1H) 1.39 (s, 3H) 1.73 (m, 1H) 2.15 (m, 1H) 2.97 (s, 3H) 3.27 (s, 3H) 7.33 (m, 2H) 7.46 (m, 2H) 7.57 (dd, J=8.82, 2.21 Hz, 1H) 7.66 (d, J=2.57 Hz, 1H) 8.05 (d, J=7.72 Hz, 1H) 15.64 (s, 1H). MS (ESI−) m/z 530 (M−H)−.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH2:20][OH:21])[C@H:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>N1C=CC=CC=1.CCOC(C)=O>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH2:20][O:21][S:23]([CH3:22])(=[O:25])=[O:24])[C@H:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])[CH3:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H](OC(C)(C)C)[C@@H](CO)NC(=O)OCc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C[C@@H](OC(C)(C)C)[C@@H](COS(C)(=O)=O)NC(=O)OCc1ccccc1
Reaction time: 5.5 h
Yield: 100.7 %

Procedure:
To a solution of (1R,2R)-N-(benzyloxycarbonyl)-1-(hydroxymethyl)-2-(tert-butoxy)propanamine (1.6 g, 5.4 mmol) in anh. pyridine (30 mL) at 4° C. was added methanesulfonyl chloride (0.75 mL, 9.7 mmol) dropwise. The reaction was stirred for 5.5 h, then was diluted with EtOAc (200 mL) and washed with a 1N HCl solution (4×200 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to yield (1R,2R)-N-(benzyloxycarbonyl)-1-(methanesulfonyloxymethyl)-2-(tert-butoxy)propanamine as an oil (2.03 g, 100%): TLC (25% EtOAc/hex) Rf0.31.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][NH2:13])[CH2:8][CH2:7]1)=[O:5].[C:14](OC(=O)C)(=[O:16])[CH3:15].Cl>N1C=CC=CC=1>[CH3:2][O:3][C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([CH2:12][NH:13][C:14](=[O:16])[CH3:15])[CH2:8][CH2:7]1)=[O:5]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)[C@H]1CC[C@H](CN)CC1
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)[C@H]1CC[C@H](CNC(C)=O)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of trans-4-(aminomethyl)cyclohexanecarboxylic acid methyl ester hydrochloride (1.5 mmol, 310 mg) in pyridine (2 mL) is added acetic anhydride (1.8 mmol, 0.31 mL) at room temperature. The mixture is stirred at room temperature for 4 hours, poured into 1M HCl and ice-water, and then extracted with ethyl acetate. The combined organic phase is washed with water and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain trans-4-(acetamidomethyl)-1-cyclohexanecarboxylic acid methyl ester (330 mg) as colorless oil. ESI-MS m/z: 214 [M+1]+, Retention time 1.97 min (condition B).
Reaction SMILES: [NH2:1][C@:2]1([CH2:9][C:10]#[C:11][C:12]2[N:17]=[C:16]([C:18]3[CH:23]=[C:22]([O:24][CH2:25][CH3:26])[CH:21]=[CH:20][C:19]=3[F:27])[CH:15]=[C:14]([CH3:28])[N:13]=2)[CH2:6][CH2:5][N:4]([CH3:7])[C:3]1=[O:8]>CC#N.CCOC(C)=O.FC(F)(F)S([O-])(=O)=O.[Ag+]>[CH2:25]([O:24][C:22]1[CH:21]=[CH:20][C:19]([F:27])=[C:18]([C:16]2[CH:15]=[C:14]([CH3:28])[N:13]=[C:12]([C:11]3[CH2:10][CH2:9][C@:2]4([CH2:6][CH2:5][N:4]([CH3:7])[C:3]4=[O:8])[N:1]=3)[N:17]=2)[CH:23]=1)[CH3:26]
Reactant: CCOc1ccc(F)c(-c2cc(C)nc(C#CC[C@@]3(N)CCN(C)C3=O)n2)c1
Agent: [Ag+]
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOc1ccc(F)c(-c2cc(C)nc(C3=N[C@]4(CC3)CCN(C)C4=O)n2)c1
Temperature: 40 °C
Reaction time: 66 h
Yield: 74.9 %

Procedure:
Silver trifluoromethanesulphonate (60.06 mg, 0.23 mmol) was added to a solution of (3R)-3-amino-3-[3-[4-(5-ethoxy-2-fluoro-phenyl)-6-methyl-pyrimidin-2-yl]prop-2-ynyl]-1-methyl-pyrrolidin-2-one (which may be prepared as described in Description 19) (447 mg, 1.17 mmol) in MeCN (20 mL) at 20° C. and the reaction was stirred for 66 hrs. An additional 10 mol % AgOTf was added, stirring was continued for an additional 3 days then the mixture was heated to 40° C. until no starting material remained. The solvent was evaporated and the residue was partitioned between water and EtOAc. The organic layer was dried (Na2SO4) and the solvent was evaporated to afford a brown oil. This was purified using a Biotage Isolera with a 25 g SNAP cartridge, eluting with a 0 to 50% mixture (9% MeOH; 89% EtOAc and 2% 880 NH3) in EtOAc affording the (5R)-2-[4-(5-ethoxy-2-fluoro-phenyl)-6-methyl-pyrimidin-2-yl]-7-methyl-1,7-diazaspiro[4.4]non-1-en-6-one (D20) (335 mg, 0.876 mmol, 74.9% yield) as a light brown solid.
Reaction SMILES: F[C:2]1[C:3]([CH3:22])=[N:4][C:5]2[C:10]([N:11]=1)=[C:9]([C:12]1[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=1)[CH:8]=[CH:7][CH:6]=2.[CH3:23][NH:24][CH:25]([CH3:27])[CH3:26]>CS(C)=O>[CH3:22][C:3]1[C:2]([N:24]([CH3:23])[CH:25]([CH3:27])[CH3:26])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[C:12]2[NH:20][C:19]3[CH2:18][CH2:17][NH:16][C:15](=[O:21])[C:14]=3[CH:13]=2)[N:4]=1
Reactant: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1F
Reactant: CNC(C)C
Solvent: CS(C)=O
Product: Cc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1N(C)C(C)C
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Prepared according to Example 127, using 2-(3-fluoro-2-methylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 126; 40 mg, 0.135 mmol), N-methylpropan-2-amine (29.6 mg, 0.405 mmol, Sigma Aldrich), and DMSO (1.4 mL) and stirring at 80° C. for 2 h. Purification by high throughput parallel purification (Rilas Technologies, Woburn, Mass.) provided 2-(2-methyl-3-(methyl(1-methylethyl)amino)-5-quinoxalinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one. 1H NMR (DMSO-d6) δ: 11.87 (br. s, 1H), 7.86-7.93 (m, 1H), 7.59-7.68 (m, 1H), 7.39-7.50 (m, 1H), 7.17 (s, 1H), 6.95 (br. s, 1H), 4.16-4.28 (m, 1H), 3.38-3.46 (m, 2H), 2.82-2.89 (m, 2H), 2.66 (s, 3H), 2.55 (s, 3H), 1.22-1.28 (m, 6H). m/z (ESI, +ve) 350.1 (M+H)+.
Reaction SMILES: CN(C)C=O.[C:6]1(=[O:26])[N:10]([C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][C:18]=3[Cl:20])[NH:13][N:12]=2)[C:9](=[O:21])[C:8]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:7]12.Br.Br[CH2:29][CH2:30][CH2:31][N:32]([CH2:35][CH3:36])[CH2:33][CH3:34].[K]>O>[CH2:33]([N:32]([CH2:35][CH3:36])[CH2:31][CH2:30][CH2:29][N:13]1[C:14]2[C:19](=[C:18]([Cl:20])[CH:17]=[CH:16][CH:15]=2)[C:11]([N:10]2[C:9](=[O:21])[C:8]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:7]3[C:6]2=[O:26])=[N:12]1)[CH3:34]
Reactant: O=C1c2ccccc2C(=O)N1c1n[nH]c2cccc(Cl)c12
Reactant: CCN(CC)CCCBr
Agent: Br
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)CCCn1nc(N2C(=O)c3ccccc3C2=O)c2c(Cl)cccc21
Yield: 59 %

Procedure:
To 60 ml of anhydrous N,N-dimethylformamide were added 4.54 g of 3-phthalimido-4-chloroindazole obtained in the same method as described in Example 1, 4.83 g of 3-bromopropyldiethylamine hydrobromide and 6.3 g of anhydrous potassium for 12 hours at 80° C. After cooling, the mixture was added with 80 ml of water and extracted with diethyl ether. The diethyl ether layer was extracted three times with 2N hydrochloric acid, and the hydrochloric acid layer was washed with diethyl ether. After the pH of the layer was adjusted to 14 with potassium carbonate, the layer was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate and chloroform was removed under reduced pressure to give 3.70 g of 1-(3-diethylaminopropyl)-3-phthalimido-4-chloroindazole having the following analytical values in a yield of 59 %.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[S:19](Cl)([CH3:22])(=[O:21])=[O:20]>ClCCl>[CH3:22][S:19]([O:9][CH2:8][CH2:7][N:4]1[CH2:5][CH2:6][O:1][CH2:2][CH2:3]1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: OCCN1CCOCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCCN1CCOCC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A flask was charged with 2-morpholinoethanol (1.0 g, 7.1 mmol), DIEA (2.4 mL, 14 mmol) and dichloromethane (100 mL). Mesylchloride (0.64 mL, 8.3 mmol) was added in a dropwise fashion to the dichloromethane mixture and the reaction mixture was stirred at room temperature for 15 hours. Concentration of the reaction mixture gave rise to a quantitative yield of 2-morpholinoethyl methanesulfonate, which was used in the next step without any without further purification. EI (MS); 210 (MH+).
Reaction SMILES: C([C:3]1[CH:18]=[CH:17][C:6]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])=[CH:5][CH:4]=1)=O.C1C[O:22][CH2:21]C1.CO.[BH4-].[Na+]>O>[OH:22][CH2:21][C:5]1[CH:4]=[CH:3][CH:18]=[CH:17][C:6]=1[C:7]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8]
Reactant: O=Cc1ccc(C(=O)OCc2ccccc2)cc1
Reactant: C1CCOC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(OCc1ccccc1)c1ccccc1CO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10.3 g (43 mmol) of benzyl 4-formylbenzoate, 50 ml of THF and 50 ml of methyl alcohol are introduced into a round-bottomed flask. While cooling in an icebath, 820 mg (21.5 mmol) of sodium borohydride are added in small portions and the mixture is stirred at room temperature for two hours. The reaction medium is poured into water, the mixture is extracted with ethyl ether and the organic phase is separated after settling has taken place, dried over magnesium sulphate and evaporated. 10.4 g (100%) of the expected product, melting point 55°-56° C., are collected.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=O.[O:19]([CH2:26][CH2:27][NH2:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:18]=[N:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:28][CH2:27][CH2:26][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:14]
Reactant: O=C(O)c1ccncc1Nc1ccc(I)cc1F
Reactant: NCCOc1ccccc1
Product: O=C(NCCOc1ccccc1)c1ccncc1Nc1ccc(I)cc1F

Procedure:
3-[(2-fluoro-4-iodophenyl)amino]-N-(2-phenoxyethyl)isonicotinamide was synthesized according to the procedure for General Method 1, outlined above, starting with 0.32 mmol of 3-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (intermediate 1) and 0.45 mmol of 2-phenoxyethylamine. LC/MS [10.10 min; 478 (M+1)]
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][CH:9](OS(C)(=O)=O)[CH2:10]2)=[O:5])[CH3:2].[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH:11]2[CH2:12][CH2:13][CH:7]1[CH2:8][CH:9]([N:19]=[N+:20]=[N-:21])[CH2:10]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1C2CCC1CC(OS(C)(=O)=O)C2
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)N1C2CCC1CC(N=[N+]=[N-])C2
Temperature: 100 °C
Reaction time: 5 h
Yield: 100.8 %

Procedure:
To a solution of 3-methanesulfonyloxy-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid ethyl ester (1.74 g, 6.28 mmol) in DMF (62 mL) was added sodium azide (813 mg, 12.5 mmol) portion-wise. The mixture was heated to 100° C., stirred for 5 hrs, cooled, and diluted with ethyl acetate. The solution was washed three times with water, sodium bicarbonate, brine; dried over Na2SO4, filtered, and concentrated to provide a yellow oil (1.42 g). 1H NMR (300 MHz, CDCl3) δ ppm 1.25 (t, J=7.1 Hz, 3H), 1.68 (m, 4H), 1.91 (m, 2H), 2.01 (m, 2H), 3.73 (m, 1H), 4.15 (q, J=7.0 Hz, 2H), 4.34 (m, 2H); MS (ESI+Q1MS) m/z 225 [M−H]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:18]=[C:17]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:23][CH:22]=3)[S:16][C:10]=2[NH:11][C:12](=O)[CH2:13][N:14]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:18]=[C:17]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH:28]([CH3:30])[CH3:29])=[CH:23][CH:22]=3)[S:16][C:10]=2[NH:11][C:12](=[S:40])[CH2:13][N:14]=1
Reactant: CC(C)Cc1ccc(CCc2cc3c(s2)NC(=O)CN=C3c2ccccc2Cl)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC(C)Cc1ccc(CCc2cc3c(s2)NC(=S)CN=C3c2ccccc2Cl)cc1
Yield: 155.8 %

Procedure:
A suspension of 9.8 g of 5-(2-chlorophenyl)-7-[2-(4-isobutylphenyl)ethyl]-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepin-2-one and 5.5 g of Lawesson reagent in 200 ml of toluene is stirred at 40°-43° C. for an hour. The resultant solution is concentrated under reduced pressure, and the residue is subjected to chromatography on silica gel and then eluted with chloroformmethanol (100:1 to 100:2). The objective fraction is concentrated under reduced pressure to give 9.6 g of 5-(2-chlorophenyl)-7-[2-(4-isobutylphenyl)ethyl]-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepine-2-thione, melting at 180°-182° C. with decomposition.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])[O:6][C:7](Cl)(Cl)Cl)Cl.[C:13]([O:17][C@H:18]([CH3:31])[C@H:19]([NH:22][C:23]1[CH:28]=[C:27]([CH3:29])[N:26]=[C:25]([Cl:30])[N:24]=1)CO)([CH3:16])([CH3:15])[CH3:14].N1C(C)=CC=CC=1C>C(Cl)Cl.[Cl-].[Na+]>[C:13]([O:17][C@@H:18]([C@H:19]1[CH2:7][O:6][C:5](=[O:11])[N:22]1[C:23]1[CH:28]=[C:27]([CH3:29])[N:26]=[C:25]([Cl:30])[N:24]=1)[CH3:31])([CH3:16])([CH3:14])[CH3:15]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cc(N[C@H](CO)[C@@H](C)OC(C)(C)C)nc(Cl)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: Cc1cc(N2C(=O)OC[C@@H]2[C@@H](C)OC(C)(C)C)nc(Cl)n1
Temperature: 25 °C
Yield: 151.4 %

Procedure:
Triphosgene (35 mg, 0.12 mmol, 0.4 equiv) was added to a solution of (2R,3R)-3-(tert-butoxy)-2-((2-chloro-6-methylpyrimidin-4-yl)amino)butan-1-ol (86 mg, 0.30 mmol) in DCM (3 mL) at −78° C., followed by the dropwise addition of 2,6-lutidine (0.14 mL, 1.2 mmol, 4 equiv). The solution was allowed to warm to room temperature and was then heated at 35° C. for 5 hours. The reaction was then cooled to room temperature and diluted with DCM (30 mL) and saturated aqueous sodium chloride (30 mL). The layers were separated and the organic layer was dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane) provided (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2-chloro-6-methylpyrimidin-4-yl)oxazolidin-2-one (0.057 g, white solid) in 61% yield. 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 4.73 (ddd, J=8.6, 4.1, 3.0 Hz, 1H), 4.65 (dd, J=9.4, 2.9 Hz, 1H), 4.48 (m, 1H), 4.41 (m, 1H), 2.52 (s, 3H), 1.26 (s, 9H), 1.03 (d, J=6.5 Hz, 3H); MS m/z 314.1 (M+H)+; Rt-1.02 min.
Reaction SMILES: C(C1C=C2C(=CC=1)N=C(C(OCC)=O)NC2=O)#N.[CH3:19][C:20]1[C:28]2[C:27](=[O:29])[NH:26][C:25]([C:30]([O:32]CC)=O)=[N:24][C:23]=2[S:22][CH:21]=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:42]2[CH:46]=[N:45][C:44]([S:47][CH2:48][CH2:49][CH2:50][CH2:51][O:52][C:53]3[CH:54]=[C:55]([CH2:59][NH2:60])[CH:56]=[CH:57][CH:58]=3)=[N:43]2)C=CC=CC=1>>[CH3:19][C:20]1[C:28]2[C:27](=[O:29])[NH:26][C:25]([C:30]([NH:60][CH2:59][C:55]3[CH:56]=[CH:57][CH:58]=[C:53]([O:52][CH2:51][CH2:50][CH2:49][CH2:48][S:47][C:44]4[N:45]=[CH:46][NH:42][N:43]=4)[CH:54]=3)=[O:32])=[N:24][C:23]=2[S:22][CH:21]=1
Reactant: CCOC(=O)c1nc2scc(C)c2c(=O)[nH]1
Reactant: NCc1cccc(OCCCCSc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Agent: CCOC(=O)c1nc2ccc(C#N)cc2c(=O)[nH]1
Product: Cc1csc2nc(C(=O)NCc3cccc(OCCCCSc4nc[nH]n4)c3)[nH]c(=O)c12

Procedure:
By a method similar to that in Example 15, and using, instead of ethyl 6-cyano-4-oxo-3,4-dihydroquinazoline-2-carboxylate, ethyl 5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-2-carboxylate obtained according to the method described in 034054656 and using, instead of 1-{3-[(3-{(1 (triphenylmethyl)-1H-1,2,4-triazol-3-yl]thiopropyl)oxy}phenyl}methaneamine, 1-{3-[(4-{[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]thio}butyl)oxy]phenyl}methanamine obtained in Reference Example 11, the title compound was obtained as a pales yellow powder (232 mg, 48%).