Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][C:8]([CH3:12])=[C:9]([CH3:11])[CH3:10])[CH2:3][CH:4]=[O:5].C(O)(=O)C1C=CC=CC=1>CCCCCCC>[CH3:1][CH:2]([CH2:6][CH2:7][C:8]([CH3:12])=[C:9]([CH3:11])[CH3:10])[CH2:3][CH2:4][OH:5]
Reactant: CC(C)=C(C)CCC(C)CC=O
Agent: O=C(O)c1ccccc1
Solvent: CCCCCCC
Product: CC(C)=C(C)CCC(C)CCO
Temperature: 100 °C

Procedure:
3,6,7-trimethyloct-6-enal (168 g, 1 mol.), heptane (168 g, 100 wt. %, technical grade), benzoic acid (3.05 g, 25 mmol, 2.5 mol.%) and (ethylenediamine)[1,2-bis(diphenylphosphino)ethane]ruthenium(bispivalate) (9.5 mg, 0.0125 mmol, 0.00125 mol.%) were loaded altogether in a 11 autoclave equipped with a mechanical stirring device. Sealed autoclave was then purged under stirring with nitrogen (3 times 5 bars) and hydrogen (3 times 5 bars) before being pressurized to 50 bars hydrogen. It was then heated to 100° C. and hydrogen pressure was maintained to 50 bars during all the reaction to afford desired product with complete selectivity. Upon reaction completion (checked by both hydrogen consumption and GC), autoclave was cooled down to 25° C. It was then depressurized and purged with nitrogen (3 times 5 bars) and reaction mixture was then transferred to a round-bottomed flask and solvent was removed under vacuum. After flash distillation, pure 3,6,7-trimethyloct-6-en-1-ol was obtained in 99% yield.
Reaction SMILES: [C:1]([C:3]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH:11]([CH3:13])[CH3:12])[CH2:4][CH2:5][CH:6]([OH:10])[CH2:7][CH2:8][CH3:9])#[N:2]>CS(C)=O.C(N(CC)CC)C>[C:1]([C:3]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([CH:11]([CH3:13])[CH3:12])[CH2:4][CH2:5][C:6](=[O:10])[CH2:7][CH2:8][CH3:9])#[N:2]
Reactant: CCCC(O)CCC(C#N)(c1ccccc1)C(C)C
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCCC(=O)CCC(C#N)(c1ccccc1)C(C)C
Reaction time: 1 h

Procedure:
7-Cyano-8-methyl-7-phenylnonane-4-ol, 70 mg 0.27 mmol, was dissolved in dimethyl sulfoxide 3.00 ml and triethylamine 0.70 ml. A sulfur trioxide-pyridine complex 64.7 mg was added thereto. After 1 hour, an additional sulfur trioxide-pyridine complex 80.0 mg was added thereto. The reaction mixture was partitioned by adding aqueous saturated sodium bicarbonate and ethyl acetate. The organic layer was washed with aqueous ammonium chloride and then with brine, dried over magnesium sulfate and evaporated. The residue was purified by silica gel column chromatography (ethyl acetate/hexane system), whereby the title compound, 50 mg 0.19 mmol, 72.0%, was obtained as a colorless syrup.
Reaction SMILES: [CH2:1]([Li])CCC.[CH:6]1([C:9]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=O)[CH2:8][CH2:7]1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH:6]1([C:9]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[CH2:1])[CH2:8][CH2:7]1
Reactant: [Li]CCCC
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)C2CC2)CC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C(C1CC1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 8 h
Yield: 83.5 %

Procedure:
Dissolve methyltriphenylphosphonium bromide (20.26 g, 55.6 mmol) in THF (200 mL) and cool to −78° C. Add butyllithium (20.2 mL, 50.5 mmol) and stir at −78° C. for 15 minutes. Warm to ambient temperature and add a solution of tert-butyl 4-(cyclopropylcarbonyl)piperidine-1-carboxylate in THF (5 mL) dropwise. Stir the mixture overnight at ambient temperature. Quench with 50% saturated sodium bicarbonate solution, extract twice with diethyl ether and twice with EtOAc. Combine the organic extracts; wash with brine; dry over sodium sulphate; collect the filtrate; and concentrate under vacuum. Add a mixture of 1:1 diethyl ether:hexane (20 mL) and filter. Concentrate the filtrate under vacuum and purify via flash column chromatography to give the title compound (5.3 g, 83.5%). MS (m/z): 196 (M+1-tBu)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18]CC)=[C:14]([CH3:21])[CH:13]=2)[C:6]=1[CH2:7][C:8]([OH:10])=[O:9]>Br>[Cl:1][C:2]1[N:3]=[C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([CH3:21])[CH:13]=2)[C:6]=1[CH2:7][C:8]([OH:10])=[O:9]
Reactant: CCOc1ccc(Cn2c(-c3ccccc3)nc(Cl)c2CC(=O)O)cc1C
Agent: Br
Product: Cc1cc(Cn2c(-c3ccccc3)nc(Cl)c2CC(=O)O)ccc1O
Yield: 32.4 %

Procedure:
4-Chloro-1-(4-ethoxy-3-methylbenzyl)-2-phenylimidazole-5-acetic acid (10 g) was stirred in 90 ml of 57% hydrobromic acid at 80°-90° C. for 6 hours. The reaction mixture was evaporated to dryness under reduced pressure and the residue was dissolved in 200 ml of ethyl acetate and washed three times with water. The ethyl acetate layer was evaporated to dryness under reduced pressure and the residue was purified by column chromatography using 210 g of silica gel. The desired fractions were recrystallized from acetone-diethyl ether to give 3 g of 4-chloro-1-(4-hydroxy-3-methylbenzyl)-2-phenylimidazole-5-acetic acid as colorless needles, m.p. 190°-192° C. (decompn.).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[C:7]12([CH3:17])[C:13]([CH3:15])([CH3:14])[CH:10]([CH2:11][CH2:12]1)[CH2:9][CH:8]2[NH2:16]>C(OC(C)C)(C)C>[C:7]12([CH3:17])[C:13]([CH3:14])([CH3:15])[CH:10]([CH2:11][CH2:12]1)[CH2:9][CH:8]2[NH:16][C:4](=[O:5])[CH2:3][C:2](=[O:6])[CH3:1]
Reactant: CC1(C)C2CCC1(C)C(N)C2
Reactant: C=C1CC(=O)O1
Solvent: CC(C)OC(C)C
Product: CC(=O)CC(=O)NC1CC2CCC1(C)C2(C)C
Temperature: 20 °C
Reaction time: 4 h
Yield: 83.9 %

Procedure:
16.8 g of diketene were added with stirring to a mixture of 30 g of 2-bornylamine and 200 ml of isopropyl ether and after stirring for 4 hours at 20° C., the mixture was evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and elution with a 9-1 methylene chloride-acetone mixture gave 39 g of N-(2-bornyl)-acetylacetamide. 30 g of the latter product and 1 g of p-toluene sulfonic acid were added to a mixture of 20 g of methyl orthoformate and 30 ml of methanol and the mixture stood at 20° C. for 16 hours. 2 ml of quinoline were added thereto and the mixture was evaporated to dryness under reduced pressure. The residue was added to toluene and the mixture was heated at 145° C. for 3 hours while distilling a toluene-methanol azeotrope. The mixture was evaporated to dryness under reduced pressure and the residue was chromatographed over silica gel. The product was eluted with an 8-2 methylene chloride-acetone mixture and was crystallized from isopropyl ether to obtain 19 g of N-(2'-bornyl)-3-methoxy-crotonamide melting at 149° C. The RMN spectra showed it was the E somer.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][S:5](=[O:38])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[N:6][C:7](=[O:31])[C:8]1[CH:13]=[C:12]([C:14]#[C:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:25]3[O:26][CH:27]=[CH:28][C:29]=3[CH3:30])=[O:24])[CH:17]=2)[CH:11]=[N:10][CH:9]=1.[F:39][CH:40]1[CH2:45][CH2:44][CH2:43][NH:42][CH2:41]1>>[F:39][CH:40]1[CH2:45][CH2:44][CH2:43][N:42]([CH2:2][CH2:3][CH2:4][S:5](=[O:38])([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[N:6][C:7](=[O:31])[C:8]2[CH:13]=[C:12]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23]([C:25]4[O:26][CH:27]=[CH:28][C:29]=4[CH3:30])=[O:24])[CH:17]=3)[CH:11]=[N:10][CH:9]=2)[CH2:41]1
Reactant: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(=O)(CCCBr)c3ccccc3)c2)c1
Reactant: FC1CCCNC1
Product: Cc1ccoc1C(=O)Nc1cccc(C#Cc2cncc(C(=O)N=S(=O)(CCCN3CCCC(F)C3)c3ccccc3)c2)c1

Procedure:
In a manner similar to that described for example 508, N-[(3-bromopropyl)(oxido)phenyl--sulfanylidene]-5-({3-[(3-methyl-2-furoyl)amino]phenyl}ethynyl)nicotinamide and 3-fluoropiperidine were converted to the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]3[CH2:22][CH2:23][CH2:24][C:18]=3[NH:17][C:16]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].S(OC)(O[CH3:30])(=O)=O.[Na]>C(O)(C)C>[Cl:1][C:2]1[CH:13]=[C:12]([Cl:14])[C:11]([N:15]2[C:20](=[O:21])[C:19]3[CH2:22][CH2:23][CH2:24][C:18]=3[N:17]([CH3:30])[C:16]2=[O:25])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5]
Reactant: COS(=O)(=O)OC
Reactant: CC(C)OC(=O)c1cc(-n2c(=O)[nH]c3c(c2=O)CCC3)c(Cl)cc1Cl
Agent: [Na]
Solvent: CC(C)O
Product: CC(C)OC(=O)c1cc(-n2c(=O)c3c(n(C)c2=O)CCC3)c(Cl)cc1Cl

Procedure:
using isopropyl 2,4-dichloro-5-(1,2,4,5,6,7-hexahydro-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate and dimethyl sulphate with sodium isopropylate in isopropanol there is obtained isopropyl 2,4-dichloro-5-(1,2,4,5,6,7-hexahydro-1-methyl-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate, 1H-NMR (CDCl3, 400 MHz, 7.78 ppm (s, 1H), 7.65 ppm (s, 1H), 5.23 ppm (m, 1H), 3.42 ppm (s, 3H), 2.96 ppm (m, 2H), 2.82 ppm (m, 2H), 2.17 ppm (m, 2H), 1.35 ppm (d, 6H),
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([O:11][C:12]([F:15])([F:14])[F:13])[CH:5]=1.Cl.[CH3:18][NH:19][CH3:20].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([N:19]([CH3:20])[CH3:18])=[C:6]([O:11][C:12]([F:15])([F:14])[F:13])[CH:5]=1
Reactant: COC(=O)c1ccc(F)c(OC(F)(F)F)c1
Reactant: CNC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(N(C)C)c(OC(F)(F)F)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a stirred solution of 5.36 g (22.5 mmol) 14a and 60.0 ml dimethylsulphoxid were added 2.23 g (27.0 mmol) dimethylamine hydrochloride and 6.54 g (47.3 mmol) potassium carbonate. The reaction mixture was stirred for 8 h at 60° C. in an autoclave and was reduced with high vacuum rotation evaporator at 65° C. The residue was diluted with dichloromethane, washed twice with water. The combined water phases were extracted with dichloromethane. The combined dichloromethane phases were washed with diluted sodium hydrogen carbonate solution, dried with sodium sulphate and concentrated. The oily crude was purified by column chromatography and the desired product 14b was obtained in 69% yield (4.09 g, 15.5 mmol).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[CH:19]=2)[CH:7]=1.[C:25]1([S:31](Cl)(=[O:33])=[O:32])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([S:31]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)(=[O:33])=[O:32])[CH2:14][C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[CH:19]=2)[CH:7]=1
Reactant: COC(=O)CCc1cccc(CNCc2cc3ccccc3o2)c1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)CCc1cccc(CN(Cc2cc3ccccc3o2)S(=O)(=O)c2ccccc2)c1

Procedure:
The title compound of Step B was prepared following the method describe in Step B of Example 1 from 3-(3-{[(benzofuran-2-ylmethyl)-amino]-methyl}-phenyl)-propionic acid methyl ester of Step A and benzenesulfonyl chloride using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 7.83 (m, 2H), 7.52-7.42 (m, 3H), 7.26-7.09 (m, 8H), 6.39 (d, 1H), 4.46 (s, 2H), 4.39 (s, 2H), 3.68 (s, 3H), 2.88 (t, 2H), 2.57 (t, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21]3[N:39]=[C:24]4[C:25]([C:29]5[CH:34]=[CH:33][C:32]([S:35]([CH3:38])(=[O:37])=[O:36])=[CH:31][CH:30]=5)=[CH:26][CH:27]=[CH:28][N:23]4[N:22]=3)[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl.C(=O)([O-])[O-].[Na+].[Na+]>[CH3:38][S:35]([C:32]1[CH:33]=[CH:34][C:29]([C:25]2[C:24]3[N:23]([N:22]=[C:21]([NH:20][C:16]4[CH:17]=[CH:18][CH:19]=[C:14]([N:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)[CH:15]=4)[N:39]=3)[CH:28]=[CH:27][CH:26]=2)=[CH:30][CH:31]=1)(=[O:36])=[O:37]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(Nc3nc4c(-c5ccc(S(C)(=O)=O)cc5)cccn4n3)c2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2cccn3nc(Nc4cccc(N5CCNCC5)c4)nc23)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 4-{3-[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperazine-1-carboxylic acid tert-butyl ester (250.0 mg, 0.4556 mmol) in dichloromethane (1 mL) was added dropwise trifluoroacetic acid (0.40 mL, 5.2 mmol) and the mixture was stirred at room temperature for 6 hours. The mixture was diluted with dichloromethane (20 mL) and saturated aqueous sodium carbonate (10 mL) was added dropwise. The mixture was stirred for 30 minutes. The layers were separated and the aqueous was washed with dichloromethane (3×10 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated under reduced pressure. [8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(3-piperazin-1-yl-phenyl)-amine was isolated as a yellow foam (0.168 g, 82%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.49 (d, J=6.7 Hz, 1H), 8.25 (d, J=8.4 Hz, 2H), 8.08 (d, J=8.4 Hz, 2H), 7.65 (d, J=7.2 Hz, 1H), 7.36 (s, 1H), 7.23 (t, J=8.3 Hz, 1H), 7.04-6.96 (m, 2H), 6.86 (s, 1H), 6.60 (d, J=8.3 Hz, 1H), 3.24-3.19 (m, 4H), 3.10 (s, 3H), 3.09-3.04 (m, 4H). MS=449 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]2[S:31][C:30]([S:32][CH3:33])=[N:29][CH:4]2[CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[N:13]([C:21]3[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=3)[N:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=1)[O:8][C:7]2=[O:28].[CH:34]1([CH2:37][NH2:38])[CH2:36][CH2:35]1>>[CH:34]1([CH2:37][NH:38][C:7]([C:6]2[C:11]([NH:10][C:9]([C:12]3[N:13]([C:21]4[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][N:22]=4)[N:14]=[C:15]([C:17]([F:18])([F:20])[F:19])[CH:16]=3)=[O:8])=[C:2]([Cl:1])[CH:3]3[S:31][C:30]([S:32][CH3:33])=[N:29][CH:4]3[CH:5]=2)=[O:28])[CH2:36][CH2:35]1
Reactant: CSC1=NC2C=c3c(nc(-c4cc(C(F)(F)F)nn4-c4ncccc4Cl)oc3=O)=C(Cl)C2S1
Reactant: NCC1CC1
Product: CSC1=NC2C=C(C(=O)NCC3CC3)C(NC(=O)c3cc(C(F)(F)F)nn3-c3ncccc3Cl)=C(Cl)C2S1

Procedure:
See step f) of example H2 using 4-chloro-6-[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-2-methylsulfanyl-3a,9a-dihydro-7-oxa-3-thia-1,5-diaza-cyclopenta[b]naphthalen-8-one as starting material and cyclopropanemethylamine. After overnight reaction and chromatography column purification, the expected product is obtained within 57%; LC/MS: 601/603 (M+1)+; m.p.: 221-223° C.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:9]([N+:10]([O-])=O)=[C:8]([Cl:13])[S:7][C:6]=1[Cl:14])=[O:4].[H][H]>C(O)C.[Ni]>[CH3:1][NH:2][C:3]([C:5]1[C:9]([NH2:10])=[C:8]([Cl:13])[S:7][C:6]=1[Cl:14])=[O:4]
Reactant: CNC(=O)c1c(Cl)sc(Cl)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: CNC(=O)c1c(Cl)sc(Cl)c1N
Yield: 102.3 %

Procedure:
A mixture of 2,5-dichloro-4-nitro-thiophene-3-carboxylic acid methylamide (565 mg) and Raney Ni (50 mg) in ethanol was stirred under 1 atm hydrogen for 5 hours. The reaction mixture was filtered and concentrated to afford 510 mg of 4-amino-2,5-dichloro-thiophene-3-carboxylic acid methylamide: 1H NMR (300 MHz, CDCl3) δ 3.8-3.6 (bs, 3H), 3.0 (d, 3H).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[CH:10]=[C:9]([C:12]([O:14]C)=[O:13])[N:8]=[CH:7][C:6]=2[C:5]([CH3:16])=[CH:4]1)[CH3:2].[OH-].[Na+]>C1COCC1>[CH2:1]([N:3]1[C:11]2[CH:10]=[C:9]([C:12]([OH:14])=[O:13])[N:8]=[CH:7][C:6]=2[C:5]([CH3:16])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C)c2cnc(C(=O)OC)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCn1cc(C)c2cnc(C(=O)O)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In a 200-ml round bottom flask, methyl 1-ethyl-3-methyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylate (1N, 6.0 g, 28 mmol) was dissolved in THF (50 ml). To the mixture was added a 2M NaOH (28 ml, 55 mmol) solution. The reaction was stirred at room temperature for 3 hrs. After completion, volatiles were removed and the residue was cooled in an ice bath and neutralized with dilute HCl to pH=4.0-4.5. The aqueous mixture washed with ethyl acetate (2×100 ml) and then lyophilized to give the crude product 1-ethyl-3-methyl-1H-pyrrolo[3,2-c]pyridine-6-carboxylic acid (1O) which is used in the next step without further purification.
Reaction SMILES: [CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]([NH2:18])=[N:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:23][C:24](=O)[C:25]#[C:26][CH2:27][S:28][CH2:29][CH3:30])C>C(O)(C)(C)C>[CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@H:13]3[O:17][C:16]4=[N:18][C:24](=[O:23])[CH:25]=[C:26]([CH2:27][S:28][CH2:29][CH3:30])[N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NC1=NC[C@@H](COc2ccc(C3CCCCC3)cc2)O1
Reactant: CCOC(=O)C#CCSCC
Solvent: CC(C)(C)O
Product: CCSCc1cc(=O)nc2n1C[C@@H](COc1ccc(C3CCCCC3)cc1)O2
Temperature: 170 °C
Yield: 57.1 %

Procedure:
To a solution of (S)-5-(4-cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine (0.5 g, 1.82 mmol) in t-butanol (5 mL) was added 4-ethylsulfanyl-but-2-ynoic acid ethyl ester (0.411 g, 2.39 mmol). The reaction mixture was heated in a microwave oven at 170° C. for 20 min. The solvent was removed under vacuum, and the residue purified by flash column chromatography (silica gel, MeOH/CH2Cl2) to afford 0.416 g of the title compound.
Reaction SMILES: [CH:1]1(N)[CH2:3][CH2:2]1.C(N(CC)CC)C.[N:12]1[C:19]([Cl:20])=[N:18][C:16](Cl)=[N:15][C:13]=1[Cl:14]>CC(C)=O>[CH:1]1([C:16]2[N:18]=[C:19]([Cl:20])[N:12]=[C:13]([Cl:14])[N:15]=2)[CH2:2][CH2:3]1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: NC1CC1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: Clc1nc(Cl)nc(C2CC2)n1

Procedure:
A mixture of 28.5 g of cyclopropylamine and 50.5 g of triethylamine was added drop-by-drop to a stirred solution of 92.3 g of cyanuric chloride in 1.5 liters of dry acetone at room temperature. Then the acetone was evaporated and the residue was treated with a 1:1 v:v mixture of ice water and ether. The ether phase was separated and dried (MgSO4), and the ether was evaporated to give 2-cyclopropyl-4,6-dichloro-1,3,5-triazine (9A), as a white solid, m.p.: 106°-107° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClC1C=CC=CC=1>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2([O:19][CH:20]=[CH:21][CH2:22]2)[CH:8]=[O:9])=[CH:16][CH:17]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc(-c2ccco2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: Clc1ccccc1
Product: O=CC1(c2ccc(Br)cc2)CC=CO1
Reaction time: 1 h

Procedure:
(Vilsmeir procedure) Phosphorous oxychloride POCL3 (12.5 g) and Dimethyl formamide (7 ml) were added to a mixture of 2(4-bromophenyl)furan (20.4 g) in chlorobenzene (100 ml). The mixture was stirred at 10° for one hour. A further addition of POCl3 (1.5 g) and DMF (0.7 g) was then made and the reaction stirred for a further one hour at RT. The mixture was poured onto ice, neutralised with sodium carbonate and the precipitated solid crystalised from chloroform (119). This solid was chromatographed on silica gel in chloroform to give 2(4-bromophenyl)furfural (11 g) m.p. 153.5°.
Reaction SMILES: C1(CCCC2CCN([CH2:16][C@@H:17]3[C@@H:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=4)[CH2:20][N:19]([C@H:29]([CH2:33][CH:34]4[CH2:37][CH2:36][CH2:35]4)[C:30]([OH:32])=[O:31])[CH2:18]3)CC2)C=CC=CC=1.[F:38][C:39]1[CH:44]=[CH:43][CH:42]=[C:41]([F:45])[C:40]=1[CH2:46][CH2:47][CH2:48][CH:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1>>[F:45][C:41]1[CH:42]=[CH:43][CH:44]=[C:39]([F:38])[C:40]=1[CH2:46][CH2:47][CH2:48][CH:49]1[CH2:50][CH2:51][N:52]([CH2:16][C@@H:17]2[C@@H:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)[CH2:20][N:19]([C@H:29]([CH2:33][CH:34]3[CH2:35][CH2:36][CH2:37]3)[C:30]([OH:32])=[O:31])[CH2:18]2)[CH2:53][CH2:54]1
Reactant: O=C(O)[C@@H](CC1CCC1)N1C[C@H](CN2CCC(CCCc3ccccc3)CC2)[C@@H](c2cccc(F)c2)C1
Reactant: Fc1cccc(F)c1CCCC1CCNCC1
Product: O=C(O)[C@@H](CC1CCC1)N1C[C@H](CN2CCC(CCCc3c(F)cccc3F)CC2)[C@@H](c2cccc(F)c2)C1

Procedure:
The title compound was prepared from 2-(R)-(3-(R)-formyl-4-(S)-(3-fluorophenyl)pyrrolidin-1-yl)-3-(cyclobutyl)propanoic acid, benzyl ester (from EXAMPLE 26, Step A) and 4-(3-(2,6-difluorophenyl)propyl) piperidine.HCl (from EXAMPLE 114, Step A) using procedures analogous to those described in EXAMPLE 1, Steps J and K to provide the title compound: ESI-MS 543 (M+H); HPLC (YMC ODS-A 4.6×50 mm column, gradient elution using 10:90 v/v CH3CN/H2O+0.1% TFA to 100% CH3CN +0.1% TFA over 2.0 min, hold 1 min, 5.0 mL/min, 220 nm): Retention Time: 1.34 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[CH:5][CH:6]=[CH:7][CH:8]=1.Br[CH2:11][CH2:12][CH2:13][CH3:14].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:11]([NH:9][C:4]1[C:3](=[CH:8][CH:7]=[CH:6][CH:5]=1)[O:2][CH3:1])[CH2:12][CH2:13][CH3:14]
Reactant: COc1ccccc1N
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCNc1ccccc1OC
Yield: 53.6 %

Procedure:
A suspension of 6.2 g (50 mmol) o-anisidine M10, 7.5 g (55 mmiol) 1-bromobutane M17, 7.6 g (55 mmol) K2CO3 and 0.91 g (5.5 mmol) KI in 25 ml DMF was heated at 95° C. for 24 hours. DMF was evaporated and the residue was dissolved in 100 ml CHCl3 and 100 ml saturated NaCl. The organic layer was dried over Na2SO4. The solvent was evaporated to give 9.4 g crude oil. This oil was purified by a plug packed with 45 g silica gel 100 using cyclohexane as eluant, wherein 4.8 g pure product were obtained (yield: 55%).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1([C:13]([OH:15])=[O:14])[C:10]([OH:12])=[O:11].F[C:17](F)(F)[C:18](O)=O>C(Cl)Cl>[CH2:17]([O:11][C:10]([C:2]1([C:13]([OH:15])=[O:14])[CH2:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:1]1)=[O:12])[CH3:18]
Reactant: O=C(O)C1(C(=O)O)Cc2ccccc2C1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1(C(=O)O)Cc2ccccc2C1
Reaction time: 20 h

Procedure:
A 200 mL round bottom flask is charged with indan-2,2-dicarboxylic acid tent-butyl ester ethyl ester (8.69 g, 29.93 mmol). DCM (40 mL) and a stirring bar are added. Stirring is initiated. Trifluoroacetic acid (20.0 mL, 269 mmol) is added. After 20 h, tlc analysis (silica, 1:1 ethyl actetate:heptanes), indicates complete consumption of starting material. The reaction mixture is diluted with DCM (50 mL) and evaporated under reduced pressure. The resultant oil is diluted with DCM (55 mL) and evaporated under reduced pressure. The resultant oil is diluted with toluene (50 mL) and evaporated under reduced pressure by pumping to constant weight to give 6.78 g of white solid material.
Reaction SMILES: N[C:2]1[C:10]2[NH:9][C:8](=[O:11])[NH:7][C:6]=2[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[I-:16].[Cs+].N(OCCC(C)C)=O>C(Cl)Cl.[Cu]I>[I:16][C:2]1[C:10]2[NH:9][C:8](=[O:11])[NH:7][C:6]=2[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1
Reactant: [I-]
Reactant: Nc1cc(C(F)(F)F)cc2[nH]c(=O)[nH]c12
Agent: [Cu]I
Agent: CC(C)CCON=O
Agent: [Cs+]
Solvent: ClCCl
Product: O=c1[nH]c2cc(C(F)(F)F)cc(I)c2[nH]1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
(Analogous to the procedure described in Heterocycles, 2001, 55, 461-464). To a solution of 4-amino-6-(trifluoromethyl)-1,3-dihydro-2H-benzimidazol-2-one from step (a) above (0.76 g, 3.5 mmol) in 20 mL of DCM was added CsI (0.91 g, 3.5 mmol), 12 (0.44 g, 1.75 mmol), and CuI (0.2 g, 1.06 mmol). To the mixture was added isoamyl nitrite (2.8 mL, Aldrich) and the reaction mixture was heated at 60° C. with stirring for 3 h. The reaction mixture was cooled to room temperature, filtered, and the filtrate was diluted with EcOAc (60 mL). The solution was washed with 25% NH4OH (2×30 mL), 5% Na2S2O3 (20 mL) and brine, dried over MgSO4 and filtered. The filtrate was evaporated and the residue was purified by silica gel column chromatography, eluting with 30% EtOAc/hexane to give the title compound as a brown solid. MS (ESI, pos. ion) m/z: 329(M+1)