Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)=[CH:5][CH:4]=[N:3]1.[C:16]1([C:22]2[N:26]=[C:25]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[S:24][N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[CH3:1][N:2]1[C:6]([NH:7][C:8]([N:30]2[CH2:31][CH2:32][N:27]([C:25]3[S:24][N:23]=[C:22]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[N:26]=3)[CH2:28][CH2:29]2)=[O:15])=[CH:5][CH:4]=[N:3]1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: Cn1nccc1NC(=O)OCC(Cl)(Cl)Cl
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nccc1NC(=O)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 70 °C
Reaction time: 15 h
Yield: 46.7 %

Procedure:
A mixture of 2,2,2-trichloroethyl (1-methyl-1H-pyrazol-5-yl)carbamate (243 mg, 0.893 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and diisopropylethylamine (0.156 ml, 0.893 mmol) in dimethylsulfoxide (2.5 ml) was stirred at 70° C. for 15 hours. Water was poured into the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and ethyl acetate to obtain the desired product (140 mg, 46.8%) as a solid.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[NH:37]1[CH2:43][CH2:42][CH2:41][C@H:38]1[CH2:39][OH:40].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:37]3[CH2:43][CH2:42][CH2:41][C@H:38]3[CH2:39][OH:40])=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: OC[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(F)ccc1-c1cc(N2CCC[C@H]2CO)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 180 °C
Yield: 79.3 %

Procedure:
A mixture of 0.20 g (0.38 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, 0.23 g (2.3 mmol) L-prolinol and 0.15 g (1.1 mmol) potassium carbonate in 0.5 ml dimethyl sulfoxide was heated at 180° C. under microwave irradiation for 30 min. in a sealed tube. After cooling to room temperature the reaction mixture was diluted with water and extracted with three portions of tert-butyl methyl ether. The combined organic extracts were washed with water and brine, dried over sodium sulfate and concentrated in vacuo. Flash column chromatography gave 0.18 g (78%) of the title compound as an off-white solid.
Reaction SMILES: [C:1](=[S:6])([O:3]CC)[NH2:2].Br[CH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([O:16][CH3:17])=[O:15])[C:9]1=O>O1CCOCC1>[C:14]([CH:10]1[C:9]2[NH:2][C:1](=[O:3])[S:6][C:8]=2[CH2:13][CH2:12][CH2:11]1)([O:16][CH3:17])=[O:15]
Reactant: CCOC(N)=S
Reactant: COC(=O)C1CCCC(Br)C1=O
Solvent: C1COCCO1
Product: COC(=O)C1CCCc2sc(=O)[nH]c21

Procedure:
A mixture of 10.5 g of ethyl thiocarbamate, 25.9 g of methyl 3-bromo-2-oxo-cyclohexanecarboxylate and 200 ml of dioxane was refluxed for 16 hours and was then distilled to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with a 1-1 cyclohexane-ethyl acetate mixture to obtain 4-carbomethoxy-2,3,4,5,6,7-hexahydrobenzothiazoline-2-one melting at 95° C.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH:14](O)[CH2:15][CH2:16][C:17]2[N:18]=[CH:19][N:20]([C:22]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:21]=2)=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(Cl)([Cl:44])=O>C(Cl)Cl>[C:1]([NH:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]([Cl:44])[CH2:15][CH2:16][C:17]2[N:18]=[CH:19][N:20]([C:22]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:21]=2)=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)c1ccc(C(O)CCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1ccc(C(Cl)CCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Temperature: 0 °C

Procedure:
A solution of 3.21 g of 4-[3-(4-tert-butylaminocarbonylphenyl)-3-hydroxyprop-1-yl]-1-tritylimidazole and 1.5 ml of thionyl chloride in 50 ml of methylene chloride is refluxed for 1 h, cooled and poured into 50 ml of ice-cold sodium bicarbonate solution. The organic phase is separated, dried over sodium sulfate and evaporated to yield 4-[3-(4-tert-butylaminocarbonylphenyl)-3-chloroprop-1-yl]-1-tritylimidazole as a white foam. NMR (CDCl3): δ=1.45 (s, 9H), 4.30 (t, J=6.0 Hz, 2H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH2:12][CH3:13])[CH2:10][OH:11])[C:5]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([S:26]([C:34]2[CH:39]=[CH:38]C=CC=2)(=[N:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:27])=[CH:22][CH:21]=1>>[CH2:32]([O:31][C:29]([N:28]=[S:26]([C:23]1[CH:22]=[CH:21][C:20]([NH:19][C:2]2[N:7]=[C:6]([NH:8][C@@H:9]([CH2:10][OH:11])[CH2:12][CH3:13])[C:5]([C:14]3[S:15][CH:16]=[CH:17][CH:18]=3)=[CH:4][N:3]=2)=[CH:25][CH:24]=1)([CH:34]1[CH2:39][CH2:38]1)=[O:27])=[O:30])[CH3:33]
Reactant: CCOC(=O)N=S(=O)(c1ccccc1)c1ccc(N)cc1
Reactant: CC[C@H](CO)Nc1nc(Cl)ncc1-c1cccs1
Product: CCOC(=O)N=S(=O)(c1ccc(Nc2ncc(-c3cccs3)c(N[C@H](CC)CO)n2)cc1)C1CC1
Yield: 49 %

Procedure:
In the reaction of (R)-2-(2-chloro-5-(2-thienyl)pyrimidine-4-ylamino)butan-1-ol (151 mg, 0.53 mmol) with (RS)—S-(4-aminophenyl)-N-(ethoxycarbonyl)-S-phenylsulfoximide (147 mg, 0.48 mmol) according to procedure 5c, the desired product is obtained in 49% yield (130 mg) after chromatographic purification (silica gel, dichloromethane/ethanol (0%-20% ethanol)).
Reaction SMILES: C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C([O-])(=O)C.[Na+].I[C:29]1[C:30]([NH:35][C:36]2[CH:37]=[C:38]([C:42]3[C:47]([CH3:48])=[CH:46][CH:45]=[C:44]([C:49]([OH:51])=[O:50])[CH:43]=3)[CH:39]=[CH:40][CH:41]=2)=[N:31][CH:32]=[N:33][CH:34]=1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:48][C:47]1[CH:46]=[CH:45][C:44]([C:49]([OH:51])=[O:50])=[CH:43][C:42]=1[C:38]1[CH:37]=[C:36]2[C:41]([C:29]3[CH:34]=[N:33][CH:32]=[N:31][C:30]=3[NH:35]2)=[CH:40][CH:39]=1
Reactant: Cc1ccc(C(=O)O)cc1-c1cccc(Nc2ncncc2I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)O)cc1-c1ccc2c(c1)[nH]c1ncncc12
Temperature: 20 °C
Reaction time: 0.08 h

Procedure:
tri-o-Tolylphosphine (18 mg, 0.060 mmol) was stirred in DMF (3 mL). The mixture was degassed by bubbling nitrogen through it until all additions were complete. To the mixture was added palladium acetate (6.8 mg, 0.030 mmol), and the resulting mixture was stirred at 20° C. for 5 min. To this mixture was added sodium acetate (37.1 mg, 0.452 mmol) and 3′-[(5-iodopyrimidin-4-yl)amino]-6-methylbiphenyl-3-carboxylic acid (0.13 g, 0.30 mmol). The resulting mixture was heated to reflux for 2 h. LCMS showed complete reaction to give the desired product, M+H 304; and a small amount of reduction product (M+H 306). The mixture was cooled to 20° C. The product was isolated by prep HPLC/MS using a 30 mm×100 mm C18 column; 25% CH3CN—H2O (0.1% TFA), 1.75 min, to 40% at 6 min; 60 mL/min; detector set at m/z 304; retention time, 3.2 min; reduction product, 4.3 min. The HPLC fractions were freeze dried to yield 45 mg of the TFA salt, a white solid. 1H NMR (d6-DMSO) δ 13.0 (br s, 1H, NH); 9.6 (s, 1H); 9.1 (s, 1H); 8.3 (d, 1H); 7.8 (m, 2H); 7.5 (s, 1H); 7.4 (m, 2H); 2.3 (s, 3H).
Reaction SMILES: [CH:1]([CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:20]=[C:21]1[C:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:24][CH2:23][N:22]1[CH2:38][C:39](O)=[O:40]>ClCCl.CN(C)C1C=CN=CC=1>[CH:1]([CH:14]1[CH2:19][CH2:18][N:17]([C:39](=[O:40])[CH2:38][N:22]2[CH2:23][CH2:24][C:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:21]2=[O:20])[CH2:16][CH2:15]1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(C(c2ccccc2)C2CCNCC2)cc1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)N1CCC(C(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-benzhydrylpiperidine (0.25 g, 1.00 mmol) in dichloromethane (20 mL) was added 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.30 g, 1.00 mmol) under nitrogen. To the reaction was added N1-(ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.38 g, 2.00 mmol) and N,N-dimethylpyridin-4-amine (6.1 mg, 0.005 mmol), and the reaction mixture was stirred overnight at room temperature. The reaction was concentrated, and the residue was partitioned in ethyl acetate:water (8:2). The organic layer was separated, washed with water and then brine, dried over MgSO4, filtered and concentrated. Silica gel chromatography eluting with ethyl acetate/hexane (1:1) gave the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.14-7.39 (m, 20H), 4.23-4.31 (m, 1H), 4.19 (d, J=16.5 Hz, 1H), 4.08 (d, J=16.3 Hz, 1H), 3.73-3.80 (m, 1H), 3.58 (d, J=11.0 Hz, 1H), 3.35 (t, J=6.7 Hz, 2H), 2.86-3.00 (m, 1H), 2.71 (t, J=6.5 Hz, 2H), 2.50-2.62 (m, 2H), 1.37-1.47 (m, 2H), 0.81-1.07 (m, 2H); MS (DCI+) m/z 529 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]([N:16]3[CH2:20][CH2:19][S:18](=[O:21])[CH2:17]3)=[O:15])[O:11][C:10]=2[C:22]2[CH:23]=[C:24]([C:28]#[N:29])[CH:25]=[CH:26][CH:27]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.ClC1C=C(C2C=C(C(N3CCSC3)=O)[O:40]C=2C2C=C(C#N)C=CC=2)C=C(F)C=1.ClC1C=CC=C(C(OO)=O)C=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]([N:16]3[CH2:20][CH2:19][S:18](=[O:40])(=[O:21])[CH2:17]3)=[O:15])[O:11][C:10]=2[C:22]2[CH:23]=[C:24]([C:28]#[N:29])[CH:25]=[CH:26][CH:27]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: N#Cc1cccc(-c2oc(C(=O)N3CCS(=O)C3)cc2-c2cc(F)cc(Cl)c2)c1
Reactant: N#Cc1cccc(-c2oc(C(=O)N3CCSC3)cc2-c2cc(F)cc(Cl)c2)c1
Agent: O=C(OO)c1cccc(Cl)c1
Product: N#Cc1cccc(-c2oc(C(=O)N3CCS(=O)(=O)C3)cc2-c2cc(F)cc(Cl)c2)c1

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 3 starting with the compound from Example 1. Instead of 1.0 equivalent of meta-chloroperbenzoic acid, 2.2 equivalents are used. 80.0 mg (78% of theory) of the title compound are obtained.
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[C:12]3[CH2:15][CH2:16][CH2:17][CH2:18][C:11]=3[C:10]2=[O:19])=[CH:5][C:4]=1[CH:20]=[C:21]([Cl:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]>C(#N)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:19])[C:11]2[CH2:18][CH2:17][CH2:16][CH2:15][C:12]=2[C:13]([NH2:1])=[O:14])=[CH:5][C:4]=1[CH:20]=[C:21]([Cl:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C(Cl)=Cc1cc(N2C(=O)C3=C(CCCC3)C2=O)ccc1Cl
Reactant: N
Solvent: CC#N
Product: CCOC(=O)C(Cl)=Cc1cc(NC(=O)C2=C(C(N)=O)CCCC2)ccc1Cl
Reaction time: 19 h

Procedure:
Ammonia gas was passed into a solution of 5.9 g of N-[4-chloro-3-(2-chloro-2-ethoxycarbonylethenyl)-phenyl]-3,4,5,6-tetrahydrophthalimide in 150 ml of acetonitrile until saturation was reached. The reaction mixture obtained was then stirred for a further 19 hours at 20°-25° C., after which the solid formed was separated off and then washed with petroleum ether. Mp.: 185°-186° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.C(O)(=O)C.[OH:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[O:32][CH3:33])[CH:27]=O.[BH3-]C#N.[Na+]>CO.CN1C(=O)N(C)CC1>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([NH:1][CH2:27][C:26]4[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:24]([OH:23])[CH:25]=4)[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccc(C=O)cc1O
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CN1CCN(C)C1=O
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(CNc2n[nH]c3ncnc(Nc4cccc(Cl)c4)c23)cc1O

Procedure:
Analogously to Example 21, 1.00 mmol of 3-amino-4-(3-chloro-phenylamino)-1H-pyrazolo[3,4-d]pyrimidine in 26 ml of methanol, 13 ml of DMEU and 3.0 mmol of acetic acid are first reacted with 3-hydroxy-4-methoxy-benzaldehyde and then reduced with 7.00 mmol of NaCNBH3 (5-7 days). 4-(3-Chloro-phenylamino)-3-(3-hydroxy-4-methoxy-benzylamino)-1H-pyrazolo[3,4-d]pyrimidine is obtained; m.p. 225-227° C.; HPLC: TRet (Grad5-40)=17.6.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][CH:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:3]=1C=O.CC(C)=[O:22]>>[O:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2](=[O:22])[CH2:3][CH:4]1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=CC1=C(Cl)c2ccccc2OC1c1ccccc1
Reactant: CC(C)=O
Product: O=C1CC(c2ccccc2)Oc2ccccc21

Procedure:
(+)-4H-2-carboxamido-4-phenyl-thieno[3,2-c][1]benzopyran, [α]43625 =+110° (c=0.5, acetone), is prepared according to example 30 in the same manner as the corresponding racemate, but starting from the pure enantiometric 4-chloro-3-formyl-flav-3-ene which is obtained by chloroformylation of (+)-flavanone [(+) at 436 nm] according to EP-A-139615.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=O.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH:24]=[CH:23][CH:22]([C:26]([OH:28])=[O:27])[CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].CO.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(Cl)Cl>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH:24]=[CH:23][CH:22]([C:26]([O:28][CH3:1])=[O:27])[CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CC=CC(C(=O)O)C1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)C1C=CCN(C(=O)OC(C)(C)C)C1
Reaction time: 1 h

Procedure:
1,1'-Carbonyldiimidazole (4 g, 24.7 mmol) in methylene chloride (100 ml) was added dropwise to a solution of 1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridine-3-carboxylic acid (5 g, 22 mmol) in methylene chloride (200 ml) under a nitrogen atmosphere. Stirring was continued for 1 h followed by addition of methanol (300 ml), and reflux for 26 h. 10% aqueous citric acid (100 ml) was added and the mixture extracted with methylene chloride. The organic layer was dried over magnesium sulphate, evaporated to dryness in vacuo and purified on a silica gel column (Eluent: methylene chloride/methanol (90/1)) to give methyl 1-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridine-3-carboxylate as yellow oil. (Yield: 3.9 g, 73%)
Reaction SMILES: [CH2:1]([Li])CCC.[CH2:6]([O:13][C:14]1[CH:15]=[CH:16][C:17]([OH:22])=[C:18]([CH:21]=1)[CH:19]=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.ClCCl>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:6]([O:13][C:14]1[CH:15]=[CH:16][C:17]([OH:22])=[C:18]([CH:19]=[CH2:1])[CH:21]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: [Li]CCCC
Reactant: O=Cc1cc(OCc2ccccc2)ccc1O
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: C=Cc1cc(OCc2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.3 %

Procedure:
To a flame dried 500 mL 3-neck flask under an atmosphere of argon, was charged methyltriphenylphosphonium bromide (43.8 mmol) dissolved in anhydrous THF (120 mL), followed by the dropwise addition of n-butyllithium (21.9 mL, 35.04 mmol). The dark red mixture was stirred at ambient temperature for 1 h. Next 5-benzyloxy-2-hydroxybenzaldehyde (2.0 g, 8.76 mmol) (Acta. Chem. Scand., Ser. B, B40(5), 400-1, (1986) was added followed by the addition of anhydrous dichloromethane (40 mL). The mixture was stirred at ambient temperature for 18 h. The solvents were removed in vacuo, and the residue was partitioned between EtOAc and water (500 mL each). The organic layer was washed with brine (500 mL), dried (Na2SO4), and concentrated in vacuo. The crude product was purified using the Biotage FlashElute chromatography system using a 65M normal phase cartridge, eluting with 15% EtOAc/Hexanes to give a yellow solid (1.75 g, 88%). 1H NMR (400 MHz, CDCl3) δ 7.44-7.30, (m, 4H), 7.14 (d, J=2.9 Hz, 1H), 6.94-6.87 (m, 1H), 6.79 (dd, J=8.8, 2.9 Hz, 2H), 6.72 (d, J=8.8 Hz, 1H), 5.71 (dd, J=17.6, 1.5 Hz, 1H), 5.35 (dd, J=11.2, 0.98 Hz, 1H), 5.02 (s, 2H), 4.60 (s, 1H); MS (FIA) m/e 227 (M+1)
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[C:5]1([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Br:18][C:19]([CH3:24])([CH3:23])[C:20](Br)=[O:21]>ClCCl>[Br:18][C:19]([CH3:24])([CH3:23])[C:20]([C:15]1[CH:14]=[CH:13][C:12]([O:11][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[CH:17][CH:16]=1)=[O:21]
Reactant: CC(C)(Br)C(=O)Br
Reactant: c1ccc(Oc2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)(Br)C(=O)c1ccc(Oc2ccccc2)cc1

Procedure:
39.19 g of aluminium trichloride (0.294 mol) were added, between 0° C. and 5° C. In 45′ to a solution of 50 g of diphenylether (0.294 mol) and 37.27 ml of α-bromoisobutyrylbromide in 250 ml of dichloromethane.
Reaction SMILES: [CH3:1][C:2]([CH3:47])([CH3:46])[C@H:3]([NH:15][C:16]([C@H:18]([CH2:30]/[CH:31]=[CH:32]/[C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[C:35]([CH3:45])[CH:34]=1)[C@H:19]([CH2:27][CH2:28][CH3:29])[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:17])[C:4]([NH:6][C@@H:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8])=[O:5]>C(O)C.[Pd]>[CH3:47][C:2]([CH3:1])([CH3:46])[C@H:3]([NH:15][C:16]([C@H:18]([CH2:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[C:35]([CH3:45])[CH:34]=1)[C@H:19]([CH2:27][CH2:28][CH3:29])[C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])=[O:17])[C:4]([NH:6][C@@H:7]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH3:8])=[O:5]
Reactant: CCC[C@H](C(=O)OC(C)(C)C)[C@@H](C/C=C/c1ccc(-c2ccccc2)c(C)c1)C(=O)N[C@H](C(=O)N[C@H](C)c1ccccc1)C(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CCC[C@H](C(=O)OC(C)(C)C)[C@@H](CCCc1ccc(-c2ccccc2)c(C)c1)C(=O)N[C@H](C(=O)N[C@H](C)c1ccccc1)C(C)(C)C
Yield: 90636.2 %

Procedure:
tert-Butyl (2S,3R,5E)-3-({[(1s)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]amino}carbonyl)-6-[3-methyl-(4-phenyl)phenyl]-2-(1-propyl)hex-5-enoate (437 gm, 0.68 mmol) in ethanol (50 mL) was hydrogenated over 10% palladium on charcoal (50 mg) at 3 bar and 20° C. for 17 h. The mixture was filtered through Arbocel filter aid and concentrated under reduced pressure. Flash chromatography (gradient elution with hexane:ethyl acetate) gave tert-butyl (2S,3R)-3-({[(1S)-2,2-dimethyl-1-({[(1R)-1-phenylethyl]amino}carbonyl)propyl]amino}carbonyl)-6-[3-methyl-(4-phenyl)phenyl]-2-(1-propyl)hexanoate (395 gm, 62%), as a colourless foam.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]([CH2:12][CH2:13][CH2:14][CH3:15])[C:9](O)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OCC)(=O)C.O>O1CCCC1>[CH:1]1([CH2:7][CH:8]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCCC(CC1CCCCC1)C(=O)O
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCC(CO)CC1CCCCC1
Yield: 107.1 %

Procedure:
A solution of 2-(cyclohexylmethyl)hexanoic acid (1.4 g) in 50 ml of dry tetrahydrofuran at 0° C. under nitrogen was treated with stirring with 10 ml of 1 molar borane-tetrahydrofuran complex. The mixture was stirred for 30 minutes, allowed to come to room temperature, and poured into ethyl acetate. After careful addition of water, the organic layer was separated, washed with brine, dried (MgSO4) and evaporated to give 1.4 g of 2-(cyclohexylmethyl)hexan-1-ol.
Reaction SMILES: [CH3:1][O:2][C:3]1[S:7][C:6]([N:8]2[CH:13]([OH:14])[CH2:12][CH2:11][N:10]([CH2:15][CH3:16])[C:9]2=[O:17])=[N:5][N:4]=1.[CH:18]1([N:21]=[C:22]=[O:23])[CH2:20][CH2:19]1>C(N(CC)CC)C>[CH3:1][O:2][C:3]1[S:7][C:6]([N:8]2[CH:13]([O:14][C:22](=[O:23])[NH:21][CH:18]3[CH2:20][CH2:19]3)[CH2:12][CH2:11][N:10]([CH2:15][CH3:16])[C:9]2=[O:17])=[N:5][N:4]=1
Reactant: O=C=NC1CC1
Reactant: CCN1CCC(O)N(c2nnc(OC)s2)C1=O
Solvent: CCN(CC)CC
Product: CCN1CCC(OC(=O)NC2CC2)N(c2nnc(OC)s2)C1=O
Reaction time: 1 h

Procedure:
Tetrahydro-1-(5-methoxy-1,3,4-thiadiazol-2-yl)-3-ethyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole) and cyclopropyl isocyanate (3.5 ml; 0.07 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer. The mixture is stirred and triethylamine (1 drop) is added thereto. After the addition is completed the reaction mixture is allowed to stand for a period of about 1 hour. The mixture is then washed with hexane and is dried to yield the desired product tetrahydro-1-(5-methoxy-1,3,4-thiadiazol-2-yl)-3-ethyl-6-(N-cyclopropylcarbamoyloxy)-2(1H)-pyrimidinone.
Reaction SMILES: O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH:23]([CH3:24])[CH2:22][C:21]([NH:25][CH:26]=O)=[N:20]2)=[CH:15][CH:14]=1.[OH-].[Na+]>O>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]2[CH:23]([CH3:24])[CH2:22][C:21]([NH:25][CH3:26])=[N:20]2)=[CH:17][CH:18]=1
Reactant: CC1CC(NC=O)=NN1c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CNC1=NN(c2ccc(Cl)cc2)C(C)C1

Procedure:
To a stirred solution of 250 ml. of freshly distilled tetrahydrofuran under nitrogen is added cautiously 3.3 g. of lithium aluminum hydride, then 3.3 g. of N-[1-(p-chlorophenyl)-5-methyl-2-pyrazolin-3-yl]formamide is added and the mixture is refluxed under nitrogen for 4 hours. The reaction mixture is cooled. Then with stirring, 3.3 ml. of water is cautiously added dropwise, followed by 3.3 ml. of 15% aqueous sodium hydroxide solution and 10.0 ml. of water. The mixture is filtered and the residue is washed with ether. The combined filtrate and wash is evaporated to dryness giving a gum which solidifies. The solid is collected, washed with hexane and dried. The product of the Example is recrystallized from dichloromethane-hexane to give 2.3 g. of white crystals, m.p. 102°-103° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](/[CH:17]=[CH:18]/[C:19]([OH:21])=O)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:22]([NH:25][NH:26][C:27](=[O:35])[C:28]1[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=1)([CH3:24])[CH3:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.CCOC(C)=O>[CH:22]([N:25]([C:19](=[O:21])/[CH:18]=[CH:17]/[C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:9]=1)[NH:26][C:27](=[O:35])[C:28]1[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=1)([CH3:24])[CH3:23]
Reactant: CC(C)(C)OC(=O)n1cc(/C=C/C(=O)O)c2ccccc21
Reactant: Cc1ccc(C(=O)NNC(C)C)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NN(C(=O)/C=C/c2cn(C(=O)OC(C)(C)C)c3ccccc23)C(C)C)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To solution containing (E)-3-(1-(tert-butoxycarbonyl)-1H-indol-3-yl)acrylic acid (150.0 mg, 0.52 mmol), N′-isopropyl-4-methylbenzohydrazide (150.0 mg, 0.78 mmol) and HATU (296.6 mg, 0.78 mmol) dissolved in DMF (3.0 ml), N,N-diisopropylethylamine (DIPEA)(0.14 ml, 0.78 mmol) was slowly drop-wise added and stirred at room temperature for 12 hr. The reaction mixture was diluted with EtOAc, washed with water and brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was separated through silica gel chromatography (30% EtOAc) for refinement and dried so that white (E)-tert-butyl 3-(3-(1-isopropyl-2-(4-methylbenzoyl)hydrazinyl)-3-oxoprop-1-enyl)-1H-indole-1-carboxylate was obtained (141.0 mg, 58.8%).