Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:10][C:11]#[CH:12])[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].I[C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1>>[CH2:1]([O:3][C:4]([C:6]1([CH2:10][C:11]#[C:12][C:14]2[CH:15]=[CH:16][C:17]([O:20][C:21]([F:22])([F:23])[F:24])=[CH:18][CH:19]=2)[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: FC(F)(F)Oc1ccc(I)cc1
Reactant: C#CCC1(C(=O)OCC)CCC1
Product: CCOC(=O)C1(CC#Cc2ccc(OC(F)(F)F)cc2)CCC1

Procedure:
In analogy to the procedure described in example 24E], reaction of 1-prop-2-ynyl-cyclobutanecarboxylic acid ethyl ester and 1-iodo-4-trifluoromethoxybenzene gave the title compound as yellow oil.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([S:9][C:10]2[CH:22]=[CH:21][C:13]3[O:14][C:15]([CH3:20])([CH3:19])[C:16]([CH3:18])=[CH:17][C:12]=3[CH:11]=2)[CH:6]=[CH:7][CH:8]=1.[I-].[Li+]>N1C(C)=CC(C)=CC=1C.ClCCl>[OH:2][C:3]1[CH:4]=[C:5]([S:9][C:10]2[CH:22]=[CH:21][C:13]3[O:14][C:15]([CH3:19])([CH3:20])[C:16]([CH3:18])=[CH:17][C:12]=3[CH:11]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(Sc2ccc3c(c2)C=C(C)C(C)(C)O3)c1
Agent: [I-]
Agent: [Li+]
Solvent: ClCCl
Solvent: Cc1cc(C)nc(C)c1
Product: CC1=Cc2cc(Sc3cccc(O)c3)ccc2OC1(C)C
Yield: 67.3 %

Procedure:
6-(3-Methoxyphenyl)thio-2,2,3-trimethyl-2H-benzo[b]pyran (3.5 g) (see Preparation 6) was dissolved in dry 2,4,6-collidine (15 ml), anhydrous lithium iodide (3 g) was added and the mixture was heated under reflux under a nitrogen atmosphere for 24 hours. After cooling, the mixture was taken up in dichloromethane and washed with 2N aqueous hydrochloric acid solution (×3). The-organic layer was dried (anhydrous sodium sulphate), the solvent removed under reduced pressure and the residue chromatographed on silica eluting with a solvent gradient of 1:1 hexane:dichloromethane changing to dichloromethane to yield 6-(3-hydroxyphenyl)thio-2,2,3-trimethyl-2H-benzo[b]pyran (2.25 g) as an oil.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.Cl[CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1.ClC1C=CC(C2N(CC3C=NC=CC=3)N=C3C=2CCNCC3)=CC=1>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:27][C:28]3[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=3)[N:13]=2)=[CH:23][CH:22]=1
Reactant: ClCc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Agent: Cl
Agent: Clc1ccc(-c2c3c(nn2Cc2cccnc2)CCNCC3)cc1
Product: Clc1ccc(-c2nn(Cc3cccnc3)c3c2CCNCC3)cc1

Procedure:
The title compound was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 103, Step B; 0.3 mmol) using 3-chloromethyl-pyridine hydrogen chloride (0.5 mmol) in place of 2-chloromethyl-thiophene. The title compound was obtained as a 2:1 mixture (25 mg) with 3-(4-chloro-phenyl)-2-pyridin-3-ylmethyl-2,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene. Data for the mixture: MS (ESI): exact mass calculated for C19H19ClN4, 338.13; found, m/z 339.4 [M+H]+. 1H NMR (500 MHz, CDCl3): 8.47-8.14 (m, 2H), 7.42-7.03 (m, 6H), 5.39-5.07 (two s, 2H), 2.97-2.84 (m, 2H), 2.72-2.43 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1)([F:5])[F:4].[N-:13]=[N+:14]=[N-:15].[Na+]>CS(C)=O>[N:13]([CH2:2][C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=1)([F:5])[F:4])=[N+:14]=[N-:15]
Reactant: Fc1cccc(C(F)(F)CBr)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: [N-]=[N+]=NCC(F)(F)c1cccc(F)c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
To a solution of 14 (2.4 g, 10 mmol) in anhydrous DMSO (15 mL) was added NaN3 (1.0 g, 15.7 mmol). The reaction solution turned purple upon heating. After being stirred at 110° C. for 8 h, the reaction mixture was cooled to room temperature and partitioned between EtOAc (300 mL) and H2O (200 mL). The organic layer was washed with H2O (200 mL), brine (200 mL), and dried over Na2SO4. The solvents were removed by rotary evaporation. The crude product was purified by flash column chromatography (EtOAc/hexanes, 1:9) to yield azide 15 (1.7 g, 88%) as a yellow oil: 1H NMR (500 MHz, CDCl3) δ 3.60-3.75 (m, 2H), 7.00-7.15 (m, 2H), 7.15-7.35 (m, 1H), 7.40-7.60 (m, 1H); 13C NMR (125 MHz, CDCl3) δ 55.8, 56.1, 56.4, 112.95, 113.01, 113.06, 113.14, 113.19, 113.25, 117.89, 117.90, 118.06, 118.07, 118.08, 119.78, 119.81, 121.25, 121.28, 121.30, 121.33, 121.35, 121.38, 130.8, 130.9, 136.7, 161.9, 163.9; GC-MS calcd for C8H6F3N3 201. found 201. 2,2-Fifluoro-2-(3-fluorophenyl)ethanamine (4d). To a solution of 15 (2.0 g, 10.0 mmol) in EtOH (30 mL) was added 1 N HCl (15 mL) and Pd(OH)2/C (20%, 200 mg). The reaction mixture was allowed to stir under one atmosphere of H2 for 24 h. The catalyst was removed by filtration and the solvent was evaporated. The resulting yellowish solid was partitioned between diethyl ether (200 mL) and 1 N HCl (200 mL). The aqueous layer was washed with diethyl ether (200 mL) then concentrated to yield amine 4d as a white solid (1.6 g, 91%): 1H NMR (500 MHz, D2O) δ 3.60-4.66 (t, J=15.0 Hz, 2H), 7.17-7.30 (m, 3H), 7.40-7.45 (m, 1H); 13C NMR (125 MHz, D2O) δ 44.6, 44.8, 45.0, 112.6, 112.8, 118.5, 118.7, 121.3, 131.4, 131.5, 161.6, 163.6; LCQ-MS (M+H+) calcd for C8H9F3N 176. found 176; LC-TOF (M+H+) calcd for C8H9F3N 176.06816. found 176.06843.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:10])[CH2:7][CH2:8][CH2:9][C:2]1=2.[Br:11]Br>CCOCC.C(Cl)(Cl)(Cl)Cl>[Br:11][CH:7]1[CH2:8][CH2:9][C:2]2[S:1][CH:5]=[CH:4][C:3]=2[C:6]1=[O:10]
Reactant: O=C1CCCc2sccc21
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCC
Product: O=C1c2ccsc2CCC1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.2 %

Procedure:
Into a solution of 6,7-dihydrobenzo[b]thiophen-4(5H)-one (15.3 g, 100 mmol) in ether (600 mL) at −10° C. is added Br2 (16.0 g, 100 mmol) in carbon tetrachloride (CCl4) (100 mL) dropwise over 50 minutes. After an additional 15 minutes at −10° C., the cold bath is removed and the mixture is allowed to warm to ambient temperature. After 1 hour, the mixture is diluted with hexane (300 mL) and washed with water (2×500 mL), aqueous sodium chloride (150 mL) and concentrated under reduced pressure to yield the crude 5-bromo-6,7-dihydrobenzo[b]thiophen-4(5H)-one (22.7 g, 98%) to which is added DMF (˜200 mL), Li2CO3 (14.8 g, 200 mmol) and LiBr (17.4 g, 200 mmol). The mixture is heated for 5 hours at 90° C. and cooled. The crude mixture is poured into water, filtered and the filtrate extracted with EtOAc (600 mL), acidified to pH=1 with concentrated HCl and extracted with EtOAc (600 mL). The combined organic layers are concentrated under reduced pressure to yield a dark oil. The crude material is subjected to chromatography on silica gel, eluting with dichloromethane in hexanes 30-100%, to provide the title compound as an off-white solid (7.62 g, 51% yield).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:6](=[O:15])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:14])[CH3:3].[NH2:22][C:23]1[N:31]=[C:30]2[C:26]([NH:27][CH:28]=[N:29]2)=[C:25](Cl)[N:24]=1.C(N(CC)C(C)C)(C)C>CCCCO>[NH2:22][C:23]1[N:31]=[C:30]2[C:26]([N:27]=[CH:28][NH:29]2)=[C:25]([NH:1][C@H:2]([C:4]2[N:5]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:6](=[O:15])[C:7]3[C:12]([CH:13]=2)=[CH:11][CH:10]=[CH:9][C:8]=3[CH3:14])[CH3:3])[N:24]=1
Reactant: Cc1cccc2cc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cccc2cc([C@H](C)Nc3nc(N)nc4[nH]cnc34)n(-c3ccccc3)c(=O)c12
Temperature: 100 °C
Reaction time: 48 h

Procedure:
(S)-3-(1-Aminoethyl)-8-methyl-2-phenylisoquinolin-1(2H)-one (compound 4704) (100 mg, 0.36 mmol), 2-Amino-6-chloropurine (compound 5401) (60.9 mg, 0.36 mmol) and N,N-diisopropylethyl amine (69 μL, 0.40 mmol) were suspended in n-BuOH (4 mL) in a sealed tube, and the resulting mixture was stirred at 100° C. for 48 h and then at 120° C. for 24 h. The mixture was allowed to cool to room temperature and concentrate in vacuo to remove n-BuOH. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo. The residue was triturated with anhydrous ethyl ether and further purified by flash column chromatography on silica gel (eluting with 0-8% MeOH/DCM) to afford the desired product, (S)-3-(1-(2-amino-9H-purin-6-ylamino)ethyl)-8-methyl-2-phenylisoquinolin-1(2H)-one as a off white/yellow solid (compound 5402), (28 mg, 20%).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](=[O:22])[NH:19][C:18]4=[O:23])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[C:30]([O:34][C:35](=[O:46])[NH:36][C:37]1([CH2:43][CH2:44]O)[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)([CH3:33])([CH3:32])[CH3:31]>>[C:30]([O:34][C:35](=[O:46])[NH:36][C:37]1([CH2:43][CH2:44][N:19]2[C:18](=[O:23])[C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:24]=[CH:25][C:2]([Cl:1])=[CH:3][C:4]=3[C:26]([F:27])([F:29])[F:28])[N:8]=[CH:9]4)[S:21][C:20]2=[O:22])[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)([CH3:33])([CH3:32])[CH3:31]
Reactant: O=C1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CC(C)(C)OC(=O)NC1(CCO)CCOCC1
Product: CC(C)(C)OC(=O)NC1(CCN2C(=O)SC(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)CCOCC1

Procedure:
[4-(2-{5-[1-(4-Chloro-2-trifluoromethylbenzyl)-1H-indazol-5-ylmethylene]-2,4-dioxothiazolidin-3-yl}ethyl)tetrahydro-2H-pyran-4-yl]carbamic acid tert-butyl ester was prepared from 5-[1-(4-chloro-2-trifluoromethylbenzyl)-1H-indazol-5-ylmethylene]thiazolidine-2,4-dione (from Example 1) and ([4-(2-hydroxyethyl)-tetrahydro-2H-pyran-4-yl]-carbamic acid tert-butyl ester following General Procedure J.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=1)[CH2:5][C:6]1[C:7]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[N:8][C:9]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][CH:11]=1.S(=O)(=O)(O)O>C(O)(=O)C.C(OCC)(=O)C>[F:39][C:36]([F:38])([F:37])[C:28]1[CH:27]=[C:26]([CH:4]2[C:3](=[O:2])[N:19]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:7]3[N:8]=[C:9]([NH:12][C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:10]=[CH:11][C:6]=3[CH2:5]2)[CH:31]=[C:30]([C:32]([F:34])([F:35])[F:33])[CH:29]=1
Reactant: COC(=O)C(Cc1cnc(Nc2ccccc2)nc1Nc1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C1C(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cnc(Nc3ccccc3)nc2N1c1ccccc1
Temperature: 120 °C

Procedure:
To a solution of 3-(2,4-diphenylamino-pyrimidin-5-yl)-2-(3,5-bis-trifluoromethyl-phenyl)-propionic acid methyl ester (0.20 g, 0.36 mmol) (from Example 8c supra) was added 5% concentrated sulfuric acid in glacial acetic acid (3 mL) in one portion. The reaction mixture was heated at 120° C. for 3 hours. The reaction mixture was then diluted with ethyl acetate (100 mL) and quenched with 2 N aqueous sodium hydroxide solution. The organic layer was separated and successively washed with water (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product which was crystallized from ethyl acetate-hexanes to give 6-(3,5-bis-trifluoromethyl-phenyl)-8-phenyl-2-phenylamino-5,8-dihydro-6H-pyrido[2,3-d]pyrimidin-7-one as an off-white solid. (Yield 130.3 mg, 70.5%).
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]=[C:10]([CH:12]=[O:13])[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-:14].[Na+]>>[O:8]=[CH:9][CH:10]([NH:11][C:7](=[O:14])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH:12]=[O:13]
Reactant: O=Cc1coc(-c2ccccc2)n1
Reactant: [OH-]
Agent: [Na+]
Product: O=CC(C=O)NC(=O)c1ccccc1
Yield: 88 %

Procedure:
2-phenyloxazole-4-carbaldehyde (5.0 g, 28.9 mmol) and 2.0 M aqueous sodium hydroxide solution (50 ml) were heated to 70° C. in a 250 mL Erlenmeyer flask until dissolved. Some insoluble dark material remained which was removed by filtration. The reaction was cooled in an ice bath and acidified (sulfuric acid) with swirling. The resulting solid was collected by filtration, washed with water, and dried under vacuum to provide the title compound (4.85 g, 88%).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][N:5]=1)=[N+:2]=[N-:3].[H-].[Na+].[Cl:13][C:14]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([Cl:24])[C:15]=1[C:16](Cl)=[O:17]>CN(C=O)C.O>[N:1]([C:4]1[CH:9]=[C:8]([NH:10][C:16](=[O:17])[C:15]2[C:19]([Cl:24])=[CH:20][C:21]([Cl:23])=[CH:22][C:14]=2[Cl:13])[CH:7]=[CH:6][N:5]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=Nc1cc(N)ccn1
Reactant: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: [N-]=[N+]=Nc1cc(NC(=O)c2c(Cl)cc(Cl)cc2Cl)ccn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 14.2 %

Procedure:
To a cooled (0° C.) solution of 2-azidopyridin-4-amine (500 mg, 3.7 mmol) in dry DMF (10 ml) was added NaH (178 mg, 7.4 mmol). After stirring for 10 min, a solution 2,4,6-trichlorobenzoyl chloride (1.8 g, 7.4 mmol) in DMF (5 mL) was added dropwise. The reaction was warmed to 25° C. and stirring was continued for 30 min. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (3×10 mL). The combined organic extracts were washed with water (20 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica-gel chromatography (petroleum ether/ethyl acetate=1:1) to afford N-(2-azidopyridin-4-yl)-2,4,6-trichlorobenzamide (180 mg, yield: 14%). LCMS (ESI) m/z: 342.0 [M+H+].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH:11]=[N:10][N:9]=[C:8]2[C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[CH2:26][C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=1.O>CN(C)C=O>[N:1]1[CH:2]=[CH:3][C:4]([N:7]2[CH:11]=[N:10][N:9]=[C:8]2[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:26][C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[N:28]=3)=[CH:14][CH:13]=2)=[CH:5][CH:6]=1
Reactant: Oc1ccc(-c2nncn2-c2ccncc2)cc1
Reactant: ClCc1ccc2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc2nc(COc3ccc(-c4nncn4-c4ccncc4)cc3)ccc2c1
Temperature: 60 °C
Yield: 64.2 %

Procedure:
To a solution of 4-(4-Pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-phenol (44 mg) in dimethyl formamide (1 ml) in a 7 ml Teflon capped vial was added cesium carbonate (185 mg) and 2-Chloromethyl-quinoline (37 mg) and the reaction mixture heated on a shaker plate at 60° C. for 18 h. The reaction mixture was poured into water and extracted with methylene chloride, dried magnesium sulfate, filtered and concentrated to provide the title compound (45 mg). 1H NMR (400 MHz, CDCl3) δ 8.87 (s, 1H), 8.65 (d, J=6.0 Hz, 2H), 8.37 (d, J=8.3 Hz, 1H), 8.03 (d, J=8.7 Hz, 1H), 7.94 (d, J=7.9 Hz, 1H), 7.78 (m, 1H), 7.70 (d, J=8.3 Hz, 1H), 7.61 (t, J=5.8 Hz, 1H), 7.40 (m, 4H), 7.14 (d, J=9.1 Hz, 2H), 5.38 (s, 2H); MS: (M+H m/z=380.2).
Reaction SMILES: [Mg].[OH:2][C:3]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][C:5]([O:7][CH3:8])=[O:6].C1COCC1.[C:19](Cl)(=[O:23])[CH:20]([CH3:22])[CH3:21].Cl>C1(C)C=CC=CC=1>[C:19]([CH:9]([C:3](=[O:2])[CH2:4][C:5]([O:7][CH3:8])=[O:6])[C:10]([O:12][CH3:13])=[O:11])(=[O:23])[CH:20]([CH3:22])[CH3:21]
Reactant: COC(=O)C=C(O)CC(=O)OC
Reactant: CC(C)C(=O)Cl
Agent: Cl
Agent: [Mg]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COC(=O)CC(=O)C(C(=O)OC)C(=O)C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 167.9 %

Procedure:
A mixture of 12.15 g (0.03 mol) of product of Step A in 50 ml of toluene was refluxed using a Dean-Stark trap for 1 hour. The resulting clear solution was cooled to room temperature and 50 ml of anhydrous THF were added. To this solution 6.4 g (6.3 ml, 0.06 mol) of isobutyryl chloride was added and stirred for 18 hours. Crude was poured into 3.7% HCl, extracted with EtOAc, the EtOAc layer was washed again with 3.7% HCl and saturated NaCl. Organic layer was dried (MgSO4) and removed in vacuo affording 12.3 g of crude dimethyl 2-(isobutyryl)-3-oxo-1,5-pentanedioate. The crude was purified by HPLC using 10% EtOAc/cyclohexane as eluting solvent affording 8.87 g (61%) of this intermediate as a light yellow oil; nD25 1.4783.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5](=[O:54])[C@@H:6]([NH:23][C:24]([C@@H:26]1[CH2:35][C:34]2[CH:33]=[C:32]3[O:36][CH2:37][C@H:38]([C:40]4[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH:48]5[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]5)=[CH:42][CH:41]=4)[O:39][C:31]3=[CH:30][C:29]=2[CH2:28][NH:27]1)=[O:25])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[C:16]=2[CH3:22])=[CH:10][CH:9]=1.[CH:55](=O)[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>>[CH3:3][O:4][C:5](=[O:54])[C@@H:6]([NH:23][C:24]([C@@H:26]1[CH2:35][C:34]2[CH:33]=[C:32]3[O:36][CH2:37][C@H:38]([C:40]4[CH:45]=[CH:44][C:43]([O:46][CH2:47][CH:48]5[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]5)=[CH:42][CH:41]=4)[O:39][C:31]3=[CH:30][C:29]=2[CH2:28][N:27]1[CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)=[O:25])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[C:16]=2[CH3:22])=[CH:10][CH:9]=1
Reactant: COC(=O)[C@H](Cc1ccc(Oc2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCC2CCCCC2)cc1)CO3
Reactant: O=Cc1ccccc1
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(Oc2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1Cc1ccccc1)O[C@@H](c1ccc(OCC2CCCCC2)cc1)CO3

Procedure:
(S)-2-{[(3S,8S)-3-(4-Cyclohexylmethoxy-phenyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester di-hydrochloride (19 mg) was reacted with benzaldehyde according to General Procedure D. The reaction mixture was directly purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+1% MeOH to 1:1 hexanes EtOAc+2% MeOH up to 1:1 hexanes EtOAc+5% MeOH) to give (S)-2-{[(3S,8S)-7-benzyl-3-(4-cyclohexylmethoxy-phenyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yloxy)-phenyl]-propionic acid methyl ester. This ester was hydrolyzed according to General Procedure B to give the title compound (14 mg). LCMS (m/z): 783.
Reaction SMILES: [SH:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.Cl.Cl[CH2:14][CH2:15][NH2:16].[H-].[Na+]>O1CCCC1.CN(C)C=O>[S:1]1[C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=2[C:4](=[O:6])[NH:16][CH2:15][CH2:14]1
Reactant: NCCCl
Reactant: COC(=O)c1ccccc1S
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C1NCCSc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.9 %

Procedure:
To a cooled solution of methyl 2-sulfanylbenzoate (200 g, 1.19 mol) in tetrahydrofuran and N,N-dimethylformamide (2 L, V/V=1/1) was added 2-chloroethanamine hydrochloride (138 g, 1.19 mol) at 0° C. followed by sodium hydride (143 g, 3.57 mol, 60% in mineral oil) in portions. After being stirred at room temperature overnight, the reaction mixture was poured into ice-water and extracted with ethyl acetate (900 mL×4). The organic layers were combined, washed with brine (900 mL×3), dried over sodium sulfate and concentrated in vacuo. The residue was stirred in a mixture solution of ethyl acetate and petroleum ether (300 mL, V/V=1/1) for 1 hour. The solid was collected by filtration and dried in vacuo to afford 100 g of 3,4-dihydro-1,4-benzothiazepin-5(2H)-one (yield was 47%).
Reaction SMILES: C([NH:8][C@@H:9]([C@@H:13]([O:15][CH3:16])[CH3:14])[C:10](O)=O)(OC(C)(C)C)=O.[C:17]([C:21]1[CH:26]=[CH:25][C:24]([NH2:27])=[C:23]([NH2:28])[CH:22]=1)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([C:21]1[CH:26]=[CH:25][C:24]2[NH:27][C:10]([C@@H:9]([NH2:8])[C@@H:13]([O:15][CH3:16])[CH3:14])=[N:28][C:23]=2[CH:22]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)c1ccc(N)c(N)c1
Reactant: CO[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Product: CO[C@@H](C)[C@H](N)c1nc2cc(C(C)(C)C)ccc2[nH]1

Procedure:
The title compound was prepared according to Method 4 using N-boc-(2S,3S)-2-amino-3-methoxybutanoic acid and 4-tert-butyl-1,2-diaminobenzene.
Reaction SMILES: [CH:1]([O:3][CH2:4][CH:5]([CH3:7])[CH3:6])=[CH2:2].[C:8]([O:13][CH2:14][CH:15]([CH3:17])[CH3:16])(=[O:12])[C@@H:9]([CH3:11])[OH:10]>P(Cl)(Cl)(Cl)=O.C(OCC)(=O)C>[CH2:4]([O:3][CH:1]([O:10][C@H:9]([CH3:11])[C:8]([O:13][CH2:14][CH:15]([CH3:17])[CH3:16])=[O:12])[CH3:2])[CH:5]([CH3:7])[CH3:6]
Reactant: C=COCC(C)C
Reactant: CC(C)COC(=O)[C@@H](C)O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(C)COC(=O)[C@@H](C)OC(C)OCC(C)C
Temperature: 25 °C
Yield: 86.7 %

Procedure:
24.0 g of dehydrated isobutyl vinyl ether was dropwise added to a mixture of 32.7 g of isobutyl (R)-(+)-lactate and 0.3 g of phosphorus oxychloride which was being stirred at room temperature, so that the internal temperature of the reaction system could be kept at 40° C. or less. Then, the resulting mixture was stirred at room temperature overnight. After the reaction, thereto was added 200 ml of ethyl acetate, followed by washing with a saturated aqueous sodium hydrogen carbonate solution, water and a saturated aqueous sodium chloride solution in this order. The washed material was dried over anhydrous sodium sulfate and then subjected to vacuum distillation to remove the solvent. The resulting concentrate was subjected to distillation to obtain 47.8 g (yield: 96.9%) of an oily title compound (diastereomixture).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)[CH3:2].N1CCCCC1.C(O)(=O)[CH2:19][C:20]([OH:22])=[O:21].Cl>N1C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:11]=[CH:10][C:7](/[CH:8]=[CH:19]/[C:20]([OH:22])=[O:21])=[CH:6][CH:5]=1)[CH3:2]
Reactant: O=C(O)CC(=O)O
Reactant: CCOc1ccc(C=O)cc1
Agent: Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: CCOc1ccc(/C=C/C(=O)O)cc1
Temperature: 120 °C
Reaction time: 4 h

Procedure:
A solution of 4-ethoxybenzaldehyde (1.00 mL, 7.20 mmol) and piperidine (0.11 mL, 1.08 mmol) in 40 mL of pyridine was heated to 120° C. A solution of malonic acid (1.50 g, 14.40 mmol) in 40 mL of pyridine was added dropwise over 30 min and the reaction solution was stirred at 120° C. for 4 h. After cooling down to 0° C., excess amount of concentrated HCl was added carefully to make ˜pH 1. A white crystalline precipitate formed, and the solid was collected by filtration, washed with 0.1 N HCl aqueous solution, and dried to afford compound 19 in 99.5% (1.40 g) of pure 19 as a white solid.
Reaction SMILES: [CH3:1][C:2]1N=CN2[C:10]=1C=NNC2=S.CI.[CH2:14]([C:17]1[N:21]2[C:22](=[S:26])[NH:23][N:24]=[CH:25][C:20]2=[C:19]([CH3:27])[N:18]=1)[CH2:15][CH3:16].C(I)(C)C>>[CH2:14]([C:17]1[N:21]2[C:22]([S:26][CH:2]([CH3:10])[CH3:1])=[N:23][N:24]=[CH:25][C:20]2=[C:19]([CH3:27])[N:18]=1)[CH2:15][CH3:16]
Reactant: CCCc1nc(C)c2cn[nH]c(=S)n12
Reactant: Cc1ncn2c(=S)[nH]ncc12
Solvent: CI
Solvent: CC(C)I
Product: CCCc1nc(C)c2cnnc(SC(C)C)n12

Procedure:
The general procedure of Example 32 is repeated but replacing the 8-methyl-imidazo[1,5-d]-as-triazine-4(3H)-thione and methyl iodide employed in that example with 6-n-propyl-8-methyl-imidazo[1,5-d]-as-triazine-4(3H)-thione and isopropyl iodide.
Reaction SMILES: O[C:2]1([CH:8]([C:11]2[CH:12]=[N:13][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][CH:16]=2)[C:9]#[N:10])[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.S(Cl)(Cl)=O>CN(C=O)C>[O:5]1[CH2:4][CH2:3][C:2](=[C:8]([C:11]2[CH:12]=[N:13][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:15][CH:16]=2)[C:9]#[N:10])[CH2:7][CH2:6]1
Reactant: N#CC(c1ccc(C(F)(F)F)nc1)C1(O)CCOCC1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: N#CC(=C1CCOCC1)c1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Yield: 97 %

Procedure:
(4-Hydroxy-tetrahydro-pyran-4-yl)-(6-trifluoromethyl-pyridin-3-yl)-acetonitrile (1.15 g, 4.02 mmol) was dissolved in thionyl chloride (50 mL, 600 mmol). One drop of DMF was added and the mixture was heated at reflux for 1 hour and then cooled to room temperature and concentrated in vacuo. The resulting crude product was purified by flash chromatography to yield 2-(dihydro-2H-pyran-4(3H)-ylidene)-2-(6-(trifluoromethyl)pyridin-3-yl)acetonitrile (1.04 g, 3.9 mmol, 95%).