Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[OH:9][C:10]1[CH:22]=[CH:21][C:13](/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12][CH:11]=1.[CH2:23](Br)[CH:24]([CH3:26])[CH3:25]>CS(C)=O.O>[CH2:23]([O:9][C:10]1[CH:11]=[CH:12][C:13](/[CH:14]=[CH:15]/[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:21][CH:22]=1)[CH:24]([CH3:26])[CH3:25]
Reactant: CC(C)CBr
Reactant: CCOC(=O)/C=C/c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)/C=C/c1ccc(OCC(C)C)cc1
Temperature: 60 °C
Reaction time: 20 h
Yield: 86.3 %

Procedure:
13.8 g of potassium carbonate and 7.50 g of sodium iodide were added to a solution of 9.61 g of ethyl (E)-p-hydroxycinnamate and 8.22 g of isobutylbromide in 100 ml of dimethyl sulfoxide. The reaction mixture was then stirred for 20 hours at 60° C., after which it was cooled to the room temperature. The reaction mixture was then poured into 1 liter of water and extracted twice with ethyl acetate. The combined extracts were washed with water and dried over anhydrous sodium sulfate; the solvent was then removed by evaporation under reduced pressure. The residue was purified by flash column chromatography using 300 g of silica gel, eluted with a 5:1 by volume solution of hexane and ethyl acetate, to give 10.71 g of the title compound as a colorless oil (which solidified at low temperature).
Reaction SMILES: [CH:1]([C:5]1(C(OCC)=O)[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:11])=[CH:2][CH2:3][CH3:4].[Cl-].[Li+].CS(C)=O>O>[CH:1]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:11])=[CH:2][CH2:3][CH3:4]
Reactant: CCC=CC1(C(=O)OCC)CCCCC1=O
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: O
Product: CCC=CC1CCCCC1=O
Temperature: 25 °C
Yield: 72.3 %

Procedure:
The reagents (1-butenyl)-2-carboethoxy cyclohexanone (11.2 g, 50 mmol), lithium chloride (10.6 g, 250 mmol), water (0.99 g, 55mmol), and dimethyl sulfoxide, (250 ml) were combined under N2 and refluxed for 2 hours. The reaction was then cooled to 25° C. The reaction mixture was poured into water and extracted with two portions of 1:1 ether-hexane. The organic phases were combined and washed with two portions water followed by saturated brine and then dried over MgSO4. After filtering and stripping, the product was purified by fractional distillation at 1.5 mm Hg. (The product boils at 65 to 70° C. at 1 to 2 mm Hg.), giving 5.5 g of the desired title ketone.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=2)[C:31]([OH:33])=O)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:37][CH2:38][CH:39]=[CH2:40]>>[CH2:38]([NH:37][C:31](=[O:33])[C:30]1[CH:34]=[CH:35][CH:36]=[C:28]([S:27][CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:29]=1)[CH:39]=[CH2:40]
Reactant: C=CCN
Reactant: O=C(O)c1cccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Product: C=CCNC(=O)c1cccc(SCc2c(O[C@H](Cn3ccnc3)c3ccccc3)ccc3c2CCCC3=O)c1
Yield: 89.3 %

Procedure:
Using the method in Example 172, 3-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and 3-aminopropene (17 mg, 0.30 mmol, 0.6M in DMF) were combined to give 48 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 538 [M+H]+.
Reaction SMILES: CC(C)([O-])C.[K+].C(OP([CH2:15]/[C:16](/[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])(OCC)=O)C.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][C:32]=1[C:39](=[O:42])[CH:40]=O.O>O1CCCC1>[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][C:32]=1[C:39](=[O:42])/[CH:40]=[CH:15]/[C:16](/[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: COc1ccc(OC)c(C(=O)C=O)c1
Reactant: CCOC(=O)/C=C(/CP(=O)(OCC)OCC)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(/C=C/C(=O)c1cc(OC)ccc1OC)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.5 %

Procedure:
1.32 g (11.8 mmol) of potassium tert-butoxide and 30 ml of tetrahydrofuran are mixed together at 25° C. A solution of 3.85 g (11.8 mmol) of ethyl (E)-4-(diethoxyphosphoryl)-3-phenylbut-2-enoate in 30 ml of tetrahydrofuran is then added dropwise. A solution of 3 g (15.4 mmol) of (2,5-dimethoxyphenyl)-2-oxoacetaldehyde dissolved in 30 ml of tetrahydrofuran is added dropwise, at 25° C. The mixture is stirred for 16 hours at 25° C. It is poured into water and extracted with ether. The organic phase is dried (Na2SO4) and the solvents are evaporated off under reduced pressure. The 4 g of product obtained are purified by flash chromatography (80/20 heptane/ethyl acetate) (yellow oil: 0.46 g).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH2:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][C:14](O)=[O:15]>O1CCOCC1.C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>[C:20]([O:19][C:17](=[O:18])[NH:12][CH2:13][C:14](=[O:15])[NH:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: NCCCCc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(=O)NCCCCc1ccccc1
Reaction time: 16 h

Procedure:
Phenylbutylamine (8.2 g, 52 mmol) is added to a mixture of BOC-Gly-PNB (14.82 g, 50 mmol) in dioxane (60 mL) and 1 M K2CO3 (60 mL). The mixture is stirred 16 h and then diluted with CH2Cl2 and washed with a saturated NaHCO3 solution until the organic phase is colorless. The organics are dried (MgSO4) and concentrated to provide [(4-phenyl-butylcarbamoyl)-methyl]-carbamic acid tert-butyl ester which is used as is without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[CH3:11][C:12]1[N:13]=[CH:14][NH:15][CH:16]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:13]1[C:12]([CH3:11])=[CH:16][N:15]=[CH:14]1)[CH:5]=[O:6]
Reactant: Cc1c[nH]cn1
Reactant: O=Cc1ccc(F)c(F)c1
Product: Cc1cncn1-c1ccc(C=O)cc1F

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3,4-difluorobenzaldehyde and 4-methyl-1H-imidazole.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:27]=1[CH:28]=[O:29].[Cl-].[NH4+]>O1CCCC1>[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][CH:17]=[C:16]2[O:25][C:26]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:27]=1[CH:28]([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[OH:29]
Reactant: c1cscn1
Reactant: COc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C=O)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C(O)c2nccs2)c1
Reaction time: 2 h
Yield: 52 %

Procedure:
Thiazole (30 μl) was dissolved in tetrahydrofuran (1 ml) to prepare a solution which was cooled under an argon atmosphere to −78° C. n-Butyllithium (1.56 M hexane solution) (260 μl) was added to the cooled solution, and the mixture was stirred for 2 hr. A solution (2 ml) of 2-(6,7-dimethoxy-quinolin-4-yloxy)-5-methoxy-benzaldehyde (compound 26) (138 mg) in tetrahydrofuran was then added to the reaction solution, and the mixture was stirred at −78° C. for one hr. A saturated ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give [2-(6,7-dimethoxy-quinolin-4-yloxy)-5-methoxy-phenyl]-thiazol-2-yl-methanol (90 mg, yield 52%).
Reaction SMILES: [O:1]=[S:2]1(=[O:15])[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[C:16]([O:20][CH2:21][CH:22]1[O:24][CH2:23]1)([CH3:19])([CH3:18])[CH3:17]>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C>[O:15]=[S:2]1(=[O:1])[CH2:3][CH2:4][N:5]([C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:23][CH:22]([OH:24])[CH2:21][O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:12][CH:13]=2)[CH2:6][CH2:7]1
Reactant: CC(C)(C)OCC1CO1
Reactant: O=S1(=O)CCN(c2ccc(O)cc2)CC1
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: CC(C)(C)OCC(O)COc1ccc(N2CCS(=O)(=O)CC2)cc1
Yield: 78.3 %

Procedure:
4-(1,1-dioxo-thiomorpholin-4-yl)phenol (2.3 g, 10 mmol), t-butylglycidyl ether (1.56 g, 12 mmol) and ethyltriphenylphosphonium bromide (0.1 g) are reacted and purified as described for compound 102 to afford a light yellow liquid 2.8 g (78%).
Reaction SMILES: C[O:2][C:3](=[O:18])[CH2:4][C@@H:5]([NH2:17])[CH2:6][C@H:7]([CH3:16])[CH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>Cl>[NH2:17][C@@H:5]([CH2:6][C@H:7]([CH3:16])[CH2:8][CH2:9][CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1)[CH2:4][C:3]([OH:18])=[O:2]
Reactant: COC(=O)C[C@@H](N)C[C@H](C)CCC1CCCCC1
Agent: Cl
Product: C[C@H](CCC1CCCCC1)C[C@H](N)CC(=O)O
Temperature: 25 °C

Procedure:
A flask was charged with 0.356 g of (3S,5R)-3-amino-7-cyclohexyl-5-methyl-heptanoic acid methyl ester and 20 mL of 3 M HCl, and the mixture was heated at reflux overnight. The mixture was cooled to room temperature and the solvent was removed under reduced pressure. This provided 0.340 g (88%) of a white solid HCl salt: 1H NMR (400 MHz, CD3OD) δ ppm 0.87 (s, 2H) 0.95 (d, J=6.34 Hz, 3H) 1.21 (m, 6H) 1.35 (m, 1H) 1.43 (ddd, J=13.85, 8.24, 5.98 Hz, 1H) 1.55 (ddd, J=12.81, 6.34, 6.22 Hz, 1H) 1.64 (dd, J=8.30, 5.37 Hz, 2H) 1.71 (m, 5H) 2.57 (dd, J=17.45, 7.44 Hz, 1H) 2.70 (m, 1H) 3.59 (m, J=7.72, 7.72, 5.73, 5.43 Hz, 1H). MS (APCI) m+1/z=242.
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16].[Cl:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>>[Cl:17][C:18]1[CH:23]=[C:22]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=2[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:21]=[CH:20][CH:19]=1
Reactant: Nc1nnc(Br)c(-c2ccc(F)cc2F)n1
Reactant: OB(O)c1cccc(Cl)c1
Product: Nc1nnc(-c2cccc(Cl)c2)c(-c2ccc(F)cc2F)n1
Yield: 18 %

Procedure:
6-(3-Chlorophenyl)-5-(2,4-difluorophenyl)-1,2,4-triazin-3-amine (23 mg, 15%) was prepared from 6-bromo-5-(2,4-difluorophenyl)-1,2,4-triazin-3-amine (0.13 g, 0.40 mmol) and 3-chlorophenylboronic acid (0.07 g, 0.40 mmol) according to the general procedure of Example 1.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.CCN(CC)CC.[C:19](Cl)(=[O:21])[CH3:20].CCOC(C)=O>C1COCC1.CN(C1C=CN=CC=1)C>[CH3:1][N:2]([C:3]1[CH:4]=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1)[C:19](=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: CNc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N(C)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 108.1 %

Procedure:
To a solution of N-methyl-4-nitroaniline (200 mg, 1.31 mmol) in THF (5 ml) were successively added Et3N (0.364 ml, 2.63 mmol), acetyl chloride (0.14 ml, 1.97 mmol) and DMAP (8.0 mg, 0.066 mmol) at RT. The reaction mixture was stirred at RT for 2 h then diluted into AcOEt and washed with water. The organic layer was dried over Na2SO4, filtered and evaporated to dryness to yield the crude title compound (275 mg) as a brownish solid, which was used in the next step without further purification. HPLC: AtRet=1.17 min; LC-MS: m/z 195.4 [M+H]+; 1H NMR (400 MHz, CDCl3): 2.05 (br. s., 3H), 3.37 (s, 3H), 7.36-7.46 (m, 2H), 8.27-8.36 (m, 2H).
Reaction SMILES: [CH3:1][C@@H:2]([CH2:13][CH3:14])[CH2:3][O:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[C:7]#[N:8].[Br:15]Br>C(Cl)(Cl)Cl>[Br:15][C:10]1[CH:11]=[CH:12][C:5]([O:4][CH2:3][C@@H:2]([CH3:1])[CH2:13][CH3:14])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: BrBr
Reactant: CC[C@H](C)COc1ccccc1C#N
Solvent: ClC(Cl)Cl
Product: CC[C@H](C)COc1ccc(Br)cc1C#N
Reaction time: 24 h

Procedure:
A mixture of compound 39 (4.25 g, 0.022 mol), bromine (12.31 g, 0.077 mol) and chloroform (50 ml) was heated under reflux overnight. A further portion of bromine (12.31 g, 0.077 mol) was then added and heating continued for another 24 h. The resultant solution was washed with a saturated solution of sodium thiosulphate and finally with water. The dichloromethane solution was dried (MgSO4) and evaporated in vacuo and the crude oil was purified by column chromatography (10% petrol/dichloromethane) to yield a fawn oil.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C:13]([S:15][CH2:16][CH2:17][S:18][CH3:19])=[O:14]>C(Cl)Cl>[CH3:12][C:13]([S:15][CH2:16][CH2:17][S:18]([CH3:19])=[O:9])=[O:14]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCCSC(C)=O
Solvent: ClCCl
Product: CC(=O)SCCS(C)=O
Reaction time: 2 h
Yield: 38 %

Procedure:
m-Chloroperbenzoic acid (2.03 g., 0.01 mole, 85% pure) was added to a solution of 1.5 g (0.01 mole) 2-(methylcarbonylthio)-1-(methylthio)ethane in 40 ml. methylene chloride cooled to -10° C. After stirring at -10° for 2 hr., the solution was washed with two 30 ml. portions of saturated aqueous sodium bicarbonate solution, 30 ml. water and 30 ml. saturated aqueous saturated sodium chloride solution, dried with anhydrous sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography on silica gel, eluting with 10:1 ethyl acetate-methanol to yield 680 mg. (38% yield) of the title compound as an amorphous solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][C:14]([CH3:18])=[C:15]([CH3:17])[N:16]=2)[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+]>CCO>[CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[S:13][C:14]([CH3:18])=[C:15]([CH3:17])[N:16]=2)[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:30][CH:31]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2nc(C)c(C)s2)=CCC3(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(C2=CCC(C)(C)c3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)sc1C
Temperature: 50 °C

Procedure:
To a solution of ethyl 4-[5,6-dihydro-5,5-dimethyl-8-(4,5-dimethylthiazol-2-yl)-2-naphthalenyl]ethynylbenzoate (Compound 17) (58.0 mg, 0.13 mmol) and 4 ml of EtOH at room temperature was added aqueous NaOH (1 ml, 1M, 1 mmol). The resulting solution was warmed to 50° C. for 1 hour and concentrated in vacuo. The residue was suspended in a solution of CH2Cl2 and ether (5:1) and acidified to pH 5 with 1M aqueous HCl. The layers were separated and the organic layer was washed with brine, dried (Na2SO4), filtered and the solvents removed under reduced pressure to give the title compound as a white solid. 1H NMR (d6-DMSO): δ 7.94 (2H, d, J=8.4 Hz), 7.86 (1H, d, J=1.6 Hz), 7.61 (2H, d, J=8.3 Hz), 7.50 (1H, dd, J=1.6, 8.0 Hz), 7.45 (1H, d, J=8.0 Hz), 6.51 (1H, t, J=4.9 Hz), 2.37 (3H, s), 2.36 (2H, d, J=4.6 Hz), 2.32 (3H, s), 1.26 (6H, s).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:44])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH:35]([CH2:41][CH:42]=C)[C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].I([O-])(=O)(=O)=[O:46].[Na+].CC(C)=O.C(#N)C>[Os](=O)(=O)(=O)=O.O>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]2[C:17](=[O:44])[N:18]([C@H:28]3[CH2:29][CH2:30][C@H:31]([O:34][CH:35]([CH2:41][CH2:42][OH:46])[C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:32][CH2:33]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:13][CH:14]=1)#[N:2]
Reactant: C=CCC(O[C@H]1CC[C@H](n2c(=O)c(Cc3ccc(-c4ccccc4C#N)cc3)c(CCC)n3ncnc32)CC1)C(=O)OCC
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Solvent: CC#N
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OC(CCO)C(=O)OCC)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of ethyl 2-[(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]pent-4-enoate (0.98 g), sodium periodate (1.7 g), acetone (20 mL), acetonitrile (20 mL), water (20 mL) and osmium tetraoxide (0.30 g, 7% immobilized catalyst) was stirred at room temperature for 14 hr. The precipitate was filtered off, and the filtrate was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (5 mL) and methanol (10 mL), sodium tetrahydroborate (0.10 g) was added at 0° C., and the mixture was stirred at 0° C. for 2 hr. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture. After evaporation of the solvent under reduced pressure, the residue was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.37 g, 37%).
Reaction SMILES: [NH2:1][C:2]1([CH2:8][S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:15](=O)(O)[O-:16].[Na+]>ClCCl>[N:1]([C:2]1([CH2:8][S:9]([N:12]([CH3:14])[CH3:13])(=[O:11])=[O:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)=[C:15]=[O:16]
Reactant: O=C([O-])O
Reactant: CN(C)S(=O)(=O)CC1(N)CCCCC1
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)S(=O)(=O)CC1(N=C=O)CCCCC1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of amine hydrochloride 1200-D (520 mg) in 40 mL of dichloromethane was treated with 20 mL of aqueous saturated sodium bicarbonate solution and stirred vigorously for 10 min at 0° C. Stirring was stopped and layers were allowed to separate. Phosgene (10 mL of 20% solution in toluene) was added to the organic layer (lower layer) in one portion. The mixture was vigorously stirred immediately after addition for 10 min at 0° C. and further stirred at room temp for 3 h. The mixture was diluted with 100 mL of dichloromethane and layers were separated. The organic layer was washed with 50 mL of cold aqueous saturated sodium bicarbonate solution and dried over magnesium sulfate. The organic layer was filtered and diluted with 15 mL of toluene. The resulting solution was concentrated under reduced pressure and the product 1200-E was maintained as a 0.2M solution.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH:9]1[NH:17][C:18]1[N:19]=[CH:20][C:21]2[CH2:27][N:26]([C:28](=[O:39])[CH2:29][CH2:30][NH:31]C(=O)OC(C)(C)C)[CH2:25][CH2:24][C:22]=2[N:23]=1>ClCCl>[NH2:31][CH2:30][CH2:29][C:28]([N:26]1[CH2:25][CH2:24][C:22]2[N:23]=[C:18]([NH:17][CH:9]3[CH2:8][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[CH2:10]3)[N:19]=[CH:20][C:21]=2[CH2:27]1)=[O:39]
Reactant: CC(C)(C)OC(=O)NCCC(=O)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCC(=O)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Reaction time: 16 h
Yield: 97.7 %

Procedure:
Add trifluoroacetic acid (1 mL) to a solution of tert-butyl {3-[2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]-3-oxopropyl}carbamate (0.19 g; 1.0 equiv; 0.44 mmoles) in dichloromethane (1 mL) and stir for 16 hours. Concentrate the mixture and then partition the residue between dichloromethane and 1N sodium hydroxide. Separate the layers and further extract the aqueous layer with dichloromethane. Wash the combined organic extracts with brine, dry over sodium sulfate, filter, and concentrate to afford the desired 3-amino-1-[2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]propan-1-one (0.145 g; 98%): MS (m/z): 338(M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[N:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:6]=[N:7]2.[Se](=O)=[O:19]>C1C2C(=CC=CC=2)C=CC=1.C(Cl)Cl>[C:12]1([C:5]2[CH:6]=[N:7][C:8]3[CH:9]=[N:10][CH:11]=[C:2]([CH:1]=[O:19])[C:3]=3[CH:4]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cc1cncc2ncc(-c3ccccc3)cc12
Reactant: O=[Se]=O
Solvent: c1ccc2ccccc2c1
Solvent: ClCCl
Product: O=Cc1cncc2ncc(-c3ccccc3)cc12
Temperature: 200 °C
Reaction time: 5 h

Procedure:
36.2 g (164 mmol) of the compound from Example III are well stirred with 27.4 g of selenium dioxide in 130 g of naphthalene at 180° C. After 5 h, a further 3.65 g of SeO2 are added and the mixture is stirred for a further 3 h at 200° C. It is allowed to cool and is dissolved in CH2Cl2 and the solution is concentrated on a rotary evaporator after addition of 200 g of silica gel. The residue is applied to a large silica gel column and chromatographed (toluene→ethyl acetate). Yield: 18 g (47%) M.p.: 148° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[S:12]([C:15]1[N:19]=[CH:18][NH:17][N:16]=1)(=[O:14])=[O:13].[CH2:20]([N:22]([CH2:26][CH3:27])[C:23](Cl)=[O:24])[CH3:21].O>N1C=CC=CC=1>[CH2:20]([N:22]([CH2:26][CH3:27])[C:23]([N:17]1[CH:18]=[N:19][C:15]([S:12]([C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=2[Cl:1])(=[O:14])=[O:13])=[N:16]1)=[O:24])[CH3:21]
Reactant: CCN(CC)C(=O)Cl
Reactant: O=S(=O)(c1nc[nH]n1)c1ccc(C(F)(F)F)cc1Cl
Solvent: c1ccncc1
Solvent: O
Product: CCN(CC)C(=O)n1cnc(S(=O)(=O)c2ccc(C(F)(F)F)cc2Cl)n1
Reaction time: 5 h

Procedure:
3-(2-Chloro-4-trifluoromethylphenylsulfonyl)-1,2,4-triazole (3.12 g) and diethyl carbamoyl chloride (1.62 g) are dissolved in pyridine (10 ml) and reaction is performed at 50° C. for 5 h. After completion of the reaction, water (50 ml) is added to the reaction solution and the reaction product is extracted twice with ethyl acetate (100 ml). The ethyl acetate layer is washed first with 1N HCl, then with water, and subsequently dried with magnesium sulfate. The dried product is concentrated to form a crystal. Recrystallization from benzene/n-hexane produces the titled compound, 1-(diethylcarbamoyl)-3-(2-chloro-4-trifluoromethylphenylsulfonyl)-1,2,4-triazole, in an amount of 3.80 g; yield, 92.5%; m.p. 105.5°-107° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([C:12]1[NH:13][C:14]2[C:19]([CH:20]=1)=[CH:18][C:17]([O:21][CH2:22][C:23]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=O)=[CH:16][CH:15]=2)=O)C>O1CCCC1>[N:25]1([CH2:23][CH2:22][O:21][C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][CH:16]=2)[NH:13][C:12]([CH2:10][OH:9])=[CH:20]3)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: CCOC(=O)c1cc2cc(OCC(=O)N3CCOCC3)ccc2[nH]1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1cc2cc(OCCN3CCOCC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 105.5 %

Procedure:
Lithium aluminum hydride (0.46 g, 12 mmol) was added-5-(2-morpholin-4-yl-2-oxo-ethoxy)-1H-indole-2-carboxylic acid ethyl ester (0.8 g, 2.4 mmol) in tetrahydrofuran (50 mL). The mixture was stirred at room temperature for 16 hours and cooled to 0° C. It was then quenched with water (4.6 mL), 15% sodium hydroxide (4.6 mL) and water (4.6 mL). The precipitate was filtered off and the filtrate was concentrated to give 0.7 g of [5-(2-morpholin-4-yl-ethoxy)-1H-indol-2-yl]-methanol.