Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:32]([C:33]([F:36])([F:35])[F:34])=[CH:31][CH:30]=[CH:29][C:3]=1[CH2:4][N:5]([CH2:20][C@H:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:22])[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[C:12]([CH2:16][C:17]([OH:19])=[O:18])[CH:13]=[CH:14][CH:15]=1.Cl.[CH3:38]O>>[CH3:38][O:18][C:17](=[O:19])[CH2:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH2:8][CH2:7][CH2:6][N:5]([CH2:4][C:3]2[CH:29]=[CH:30][CH:31]=[C:32]([C:33]([F:34])([F:35])[F:36])[C:2]=2[Cl:1])[CH2:20][C@H:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH3:22])[CH:11]=1
Reactant: C[C@H](CN(CCCOc1cccc(CC(=O)O)c1)Cc1cccc(C(F)(F)F)c1Cl)c1ccccc1
Reactant: CO
Agent: Cl
Product: COC(=O)Cc1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)C[C@@H](C)c2ccccc2)c1
Yield: 90 %

Procedure:
To a solution of (3-{3-[(2-Chloro-3-trifluoromethyl-benzyl)-((S)-2-phenyl-propyl)-amino]-propoxy}-phenyl)-acetic acid (Example 10, 0.5 g, 3.7 mmol) in methanol (300 ml) was added concentrated hydrochloric acid (10 ml). After the resulting mixture was heated to reflux for 2 h solvent was removed under vacuum. The residue was dissolved in water and neutralized to pH=7. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate, brine, dried over sodium sulfate, and concentrated in vacco to give the title compound as colorless oil (0.5 g, 90%). MS m/e 534.6 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:15]2[O:14][CH2:13][CH2:12][CH2:11][O:10][C:9]=2[C:8]([N+:16]([O-])=O)=[CH:7][CH:6]=1)=[O:4].C1COCC1.CO>C(OCC)C.[Pd]>[CH3:1][O:2][C:3]([C:5]1[C:15]2[O:14][CH2:13][CH2:12][CH2:11][O:10][C:9]=2[C:8]([NH2:16])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc([N+](=O)[O-])c2c1OCCCO2
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)c1ccc(N)c2c1OCCCO2
Temperature: 70 °C

Procedure:
To a mixture of 9-nitro-3,4-dihydro-2H-benzo[b][1,4]dioxepine-6-carboxylic acid methyl ester (C-5; 2.53 g) and Pd/C (450 mg) suspended in 90 mL of a 1/1 mixture of THF/CH3OH was added HCO2HN4 (3.153 g) and the resulting reaciton heated to 70° C. for 30 minutes. The reaction was diluted with 900 mL of diethyl ether. The resulting solution was filtered through celite and the organic solvent removed in vacuo to yield 2.152 g of white crystalline soldid. AP+ 192 (—OCH3).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@@H:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:9]#[C:10][CH:11]=[O:12]>O1CCOCC1.[Pd]>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][C@@H:8]([CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:9][CH2:10][CH:11]=[O:12]
Reactant: CCCCC[C@@H](C#CC=O)OC1CCCCO1
Agent: [Pd]
Solvent: C1COCCO1
Product: CCCCC[C@@H](CCC=O)OC1CCCCO1

Procedure:
(4S)-4-(2-Tetrahydropyranyloxy)-2-nonynal (54.6 g., 0.23 mole) in dioxane (200 ml.) is hydrogenated at room temperature and a pressure of 2-3 atmospheres over a 5% palladium on charcoal catalyst to yield (4S)-4-(2-tetrahydropyranyloxy)nonanal purified by distillation at reduced pressure.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=[O:28])[CH2:10][CH:11]([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.Cl.[NH2:30][C:31]1([CH2:34][OH:35])[CH2:33][CH2:32]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>O1CCCC1>[OH:35][CH2:34][C:31]1([NH:30][C:23](=[O:24])[C:22]2[CH:21]=[CH:20][C:19]([CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[CH2:10][C:9]([C:4]3[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=3)=[O:28])=[CH:27][CH:26]=2)[CH2:33][CH2:32]1
Reactant: NC1(CO)CC1
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(C(=O)NC2(CO)CC2)cc1

Procedure:
In analogy to example 207, step 2, 4-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-benzoic acid (example 207, step 1) was coupled with (1-aminocyclopropyl)methanol hydrochloride using benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate in tetrahydrofuran to give the title compound as an off-white solid, MS (ESI+): m/z=445.4 [M+H]+.
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=1)#[N:2].S(Cl)([Cl:15])=O>>[C:1]([CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([Cl:15])=[O:9])=[CH:6][CH:5]=1)#[N:2]
Reactant: O=S(Cl)Cl
Reactant: N#CCc1ccc(C(=O)O)cc1
Product: N#CCc1ccc(C(=O)Cl)cc1

Procedure:
Ten grams of 4-(cyanomethyl)benzoic acid is refluxed in 70 mls. of thionyl chloride for four hours. The solvents are removed leaving a residue of 4-cyanomethylbenzoyl chloride. To a solution of 5.5 g. of 3-amino-2-hydroxy pyridine in cold pyridine there is added slowly, with cooling, 8 g. of 4-cyanomethyl benzoyl chloride. The mixture is allowed to come to room temperature and stirred overnight. The mixture is added to 300 ml. of ice and the solid amide separated by filtration and recrystallized from methanol. A mixture of 3 g. of the above amide in 50 mls. of phsophorus oxychloride is heated under reflux for 5 hours. The solvents are removed in vacuo and the residue is crystallized from ethyl acetate to give 2-(4-cyanomethylphenyl)oxazolo[5,4-b]pyridine.
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)[CH2:12][CH2:13][C@@H:14]2[CH2:16][C:15]2([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=CC=1)([O-])=O.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][CH2:37][CH2:38][CH2:39][NH2:40])[CH:31]=1>O1CCCC1>[C:23]1([C:15]2([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:16][C@H:14]2[CH2:13][CH2:12][C:11]([NH:40][CH2:39][CH2:38][CH2:37][CH2:36][C:32]2[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=2)=[O:10])[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: NCCCCc1cccnc1
Reactant: O=C(CC[C@@H]1CC1(c1ccccc1)c1ccccc1)Oc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Product: O=C(CC[C@@H]1CC1(c1ccccc1)c1ccccc1)NCCCCc1cccnc1
Yield: 87.1 %

Procedure:
As in Example 141, (R)-2,2-diphenylcyclopropanepropanoic acid 4-nitrophenyl ester (4.8 g) was treated with 3-pyridinebutanamine (1.88 g) in tetrahydrofuran (110 mL) at 25° C. for 2 hours. The crude product, isolated in the normal manner, was purified by HPLC (ethyl acetate-hexane; 9:1) and lyophilized from benzene to give 4.3 g of (R)-2,2-diphenyl-N-[4-(3-pyridinyl)butyl]cyclopropanepropanamide as an oil, [α]D25 +86.4° (c, 1.0, MeOH).
Reaction SMILES: [CH:1]([C:3]1[C:16]([O:17]CC2C=CC=CC=2)=[CH:15][CH:14]=[CH:13][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:2]>C(O)C>[CH:1]([C:3]1[C:16]([OH:17])=[CH:15][CH:14]=[CH:13][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:2]
Reactant: O=Cc1c(OCCCCC(=O)O)cccc1OCc1ccccc1
Solvent: CCO
Product: O=Cc1c(O)cccc1OCCCCC(=O)O
Reaction time: 0.33 h

Procedure:
A solution of 5-(2-formyl-3-benzyloxyphenoxy) pentanoic acid (1.0 g, 0.003 M) in ethanol containing 5% palladium on charcoal catalyst (0.61 g) was hydrogenated at atmospheric pressure. After 20 minutes the reaction was complete and the catalyst was filtered off and the ethanol removed in vacuo to give 5-(2-formyl-3-hydroxyphenoxy)pentanoic acid, m.p. 94° C.
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[C:5]([O:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:6](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]3[N:18]([C:19]=2[C:20](O)=[O:21])[CH:17]=[CH:16][S:15]3)[CH:7]=[CH:8][CH:9]=1.[Cl:30][C:31]1[C:32]([NH2:41])=[N:33][CH:34]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:36]=1.CCN=C=NCCCN(C)C.Cl.C1COCC1>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:30][C:31]1[C:32]([NH:41][C:20]([C:19]2[N:18]3[C:14]([S:15][CH:16]=[CH:17]3)=[N:13][C:12]=2/[CH:11]=[CH:10]/[C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([O:3][CH:2]([F:29])[F:1])[C:5]=2[O:23][CH2:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:21])=[N:33][CH:34]=[C:35]([C:37]([F:40])([F:38])[F:39])[CH:36]=1
Reactant: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)O)cccc1OC(F)F
Reactant: Nc1ncc(C(F)(F)F)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)(C)COc1c(/C=C/c2nc3sccn3c2C(=O)Nc2ncc(C(F)(F)F)cc2Cl)cccc1OC(F)F

Procedure:
The title compound was prepared according to the general procedure (Method B) by coupling Intermediate 7A (100 mg, 0.236 mmol) with 3-chloro-5-(trifluoromethyl)pyridin-2-amine (51 mg, 0.260 mmol) in the presence of EDCI hydrochloride (90 mg, 0.472 mmol) and DMAP (27 mg, 0.236 mmol) in the mixture of THF and DMF (1:1, 6 mL) to give 25 mg of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.07 (s, 9H), 3.57 (s, 2H), 7.16 (t, J=73.5 Hz, 1H), 7.20-7.46 (m, 3H), 7.53-7.62 (m, 2H), 7.88 (d, J=15.9 Hz, 1H), 8.09 (s, 1H), 8.57 (s, 1H), 8.86 (s, 1H), 11.12 (br s, 1H); APCI-MS (m/z) 601.30 (MH)+.
Reaction SMILES: [CH2:1]([C@@H:7]1[CH2:16][CH2:15][C:14]2[CH:13]=[C:12]([C@H:17]3[CH2:26][CH2:25][C@@:19]4([NH:23]C(=O)[O:21][CH2:20]4)[CH2:18]3)[CH:11]=[CH:10][C:9]=2[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-].[Na+]>O1CCOCC1.C(OCC)(=O)C>[NH2:23][C@:19]1([CH2:20][OH:21])[CH2:25][CH2:26][C@H:17]([C:12]2[CH:11]=[CH:10][C:9]3[CH2:8][C@H:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:16][CH2:15][C:14]=3[CH:13]=2)[CH2:18]1
Reactant: CCCCCC[C@@H]1CCc2cc([C@H]3CC[C@]4(COC(=O)N4)C3)ccc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCCCCC[C@@H]1CCc2cc([C@H]3CC[C@](N)(CO)C3)ccc2C1
Temperature: 100 °C
Yield: 78.2 %

Procedure:
To a mixture of (5R,7S)-7-((R)-6-hexyl-5,6,7,8-tetrahydronaphthalen-2-yl)-3-oxa-1-azaspiro[4.4]nonan-2-one (400 mg, 1.125 mmol) in dioxane (30 mL) was added aqueous NaOH (1N, 20 mL). The reaction mixture was heated at 100° C. for 3 days, cooled to room temperature, diluted with ethyl acetate and washed with water. The organic layer was dried with MgSO4, filtered and concentrated. The crude material was purified on a silica gel cartridge (24 g) using an 20% (2N NH3/MeOH) in DCM/DCM gradient (0-75% of 20% (2N NH3/MeOH) in DCM over 13 CV) to afford 290 mg of ((1R,3S)-1-amino-3-((R)-6-hexyl-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopentyl)methanol. HPLC retention time=10.09 min (Condition H); LC/MS M+1=330; 1H NMR (400 MHz, methanol-d4) δ 7.03-6.91 (m, 3H), 3.54-3.41 (m, 2H), 3.01 (tt, J=11.1, 7.2 Hz, 1H), 2.87-2.69 (m, 3H), 2.34 (dd, J=16.2, 10.5 Hz, 1H), 2.20 (dd, J=13.0, 7.5 Hz, 1H), 2.07-1.84 (m, 3H), 1.83-1.60 (m, 3H), 1.60-1.48 (m, 1H), 1.47-1.25 (m, 1H), 1.00-0.88 (m, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([N+:15]([O-])=O)=[C:12]([NH2:14])[CH:13]=2)[CH2:4][CH2:3]1>C(O)C.[Pd]>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[C:12]([NH2:14])[C:11]([NH2:15])=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(N)c2)CC1
Agent: [Pd]
Solvent: CCO
Product: CN1CCN(c2ccc(N)c(N)c2)CC1
Yield: 83.5 %

Procedure:
A solution of 5-fluoro-2-nitrobenzenamine (3.0 g, 18.1 mmol), triethylamine (5.0 mL, 36.3 mmol), and 1-methylpiperazine (2.0 mL, 18.1 mmol) in dioxane (25 mL) was heated at reflux for 18 hr. After cooling to room temperature, the mixture was concentrated under reduced pressure and the residue dissolved in DCM (100 mL). This solution was washed with saturated aqueous sodium bicarbonate followed by brine, then dried over magnesium sulfate and concentrated under reduced pressure to give 5-(4-methylpiperazin-1-yl)-2-nitrobenzenamine (3.25 g) as a dark brown solid. A solution of 5-(4-methylpiperazin-1-yl)-2-nitrobenzenamine (3.25 g; 13.7 mmol) in absolute ethanol (40 mL) was hydrogenated at atmospheric pressure with 10% palladium on carbon (0.30 g; 2.7 mmol) at room temperature for 17 hr. The mixture was filtered through diatomaceous earth and concentrated under reduced pressure to give 4-(4-methylpiperazin-1-yl)benzene-1,2-diamine (2.36 g).
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13]C)=[O:12])=[CH:4][CH:3]=1>C(OCC)(=O)C>[F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][O:7][C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(OCc2ccc(F)cc2)c1
Solvent: CCOC(C)=O
Product: O=C(O)c1cccc(OCc2ccc(F)cc2)c1

Procedure:
Saponification of methyl 3-(4-fluorobenzyloxy)-benzoate as described in the preparation of Intermediate 1B gave the title acid as white needles: mp 145-146° C. (ethyl acetate). 1HNMR 400 MHz (CDCl3) δ (ppm): 5.11 (2H, s, OCH2), 7.12 (2H, m, aromatics), 7.24 (1 H, m, aromatics), 7.45 (3 H, m, aromatics), 7.75 (2H, m, aromatics). Anal. Calcd for C14H11FO3: C, 68.29; H, 4.50. Found: C, 68.39; H, 4.43.
Reaction SMILES: I(Cl)(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1.[C:20]([C:24]1[C:29]2[O:30][CH2:31][C:32]([CH3:34])([CH3:33])[C:28]=2[CH:27]=[C:26]([C:35](=[O:37])[CH3:36])[CH:25]=1)([CH3:23])([CH3:22])[CH3:21].[Cl:38]CCCl>CO>[C:20]([C:24]1[C:29]2[O:30][CH2:31][C:32]([CH3:34])([CH3:33])[C:28]=2[CH:27]=[C:26]([C:35](=[O:37])[CH2:36][Cl:38])[CH:25]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(=O)c1cc(C(C)(C)C)c2c(c1)C(C)(C)CO2
Reactant: ClCCCl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=I(=O)Cl
Solvent: CO
Product: CC(C)(C)c1cc(C(=O)CCl)cc2c1OCC2(C)C
Temperature: 25 °C

Procedure:
A mixture of benzyltrimethylammonium dichloroiodate (18.18 g, 52.2 mmol), 1-(7-tert-butyl-3,3-dimethyl-2,3-dihydrobenzo[b]furan-5-yl)-ethan-1-one (6.65 g, 27.0 mmol), 325 mL of 1,2-dichloroethane, and 130 mL of methanol is heated at reflux for 1.5 h. The reaction mixture is cooled to room temperature and concentrated in vacuo; 5% aqueous sodium bisulfite solution (126 mL) is added to the residue obtained. This mixture is extracted with ether and the extract is dried over anhydrous magnesium sulfate and concentrated to afford 8.38 g of the title compound as a reddish solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([NH:17][CH3:18])=[O:16])=[CH:13][CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:6]=2[N:7]=1.[O:30]1[CH2:35][CH2:34][CH:33]([OH:36])[CH2:32][CH2:31]1.CC(C)([O-])C.[Na+]>O1CCOCC1.C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([O:36][CH:33]2[CH2:34][CH2:35][O:30][CH2:31][CH2:32]2)[C:5]2[C:10]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([NH:17][CH3:18])=[O:16])=[CH:13][CH:12]=3)=[CH:9][N:8]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:28])[CH3:27])[C:6]=2[N:7]=1
Reactant: OC1CCOCC1
Reactant: CNC(=O)c1ccc(-c2cn(COCC[Si](C)(C)C)c3nc(Cl)nc(Cl)c23)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: CNC(=O)c1ccc(-c2cn(COCC[Si](C)(C)C)c3nc(Cl)nc(OC4CCOCC4)c23)cc1
Temperature: 70 °C
Reaction time: 16 h
Yield: 89 %

Procedure:
A solution of 4-(2,4-dichloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-N-methylbenzamide (1 equiv), tetrahydro-2H-pyran-4-ol (1.1 equiv), and sodium tert-butoxide (1.2 equiv) in 1,4-dioxane (0.22 M) were combined in a sealable flask. The reaction mixture was put under a nitrogen atmosphere, the sealable flask was sealed, and the mixture was stirred at 70° C. for 16 h. The mixture was cooled to room temperature and concentrated to afford an oil, which was suspended in DCM and purified using flash chromatography (0-50% ethyl acetate in hexane) to afford the desired product (89% yield) as a clear oil. MS (ESI) m/z 517.5 [M+1]+.
Reaction SMILES: [OH:1][CH:2]1[O:8][C@@H:7]([CH2:9][OH:10])[C@H:5]([OH:6])[C@@H:3]1[OH:4].[C:11]([O-])(=O)C.[Na+]>CO.S(=O)(=O)(O)O>[CH3:11][O:1][CH:2]1[O:8][C@@H:7]([CH2:9][OH:10])[C@H:5]([OH:6])[C@@H:3]1[OH:4]
Reactant: CC(=O)[O-]
Reactant: OC[C@@H]1OC(O)[C@@H](O)[C@H]1O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC1O[C@@H](CO)[C@H](O)[C@@H]1O
Yield: 649.2 %

Procedure:
L-ribofuranose (20.0 g; 132 mmol) and methanol (226 g) were added to a 1,000-mL flask. Thereafter, concentrated sulfuric acid (1.49 g; 0.11 equivalents) dissolved in methanol (21.2 g) was slowly added dropwise thereto. The obtained mixture was reacted at room temperature for 5 hours. Thereafter, sodium acetate (2.40 g) was added to the reaction product for neutralization, and it was then concentrated under reduced pressure, so as to obtain 31.18 g of crude 1-O-methyl-L-ribofuranose as a whitish oily substance.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:19][C@H:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH3:21])=[N:5][C:6]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][N:12]=2)=[C:7]([F:9])[CH:8]=1.[O:29]=[C:30]1[NH:34][CH:33]([C:35](O)=[O:36])[CH2:32][CH2:31]1>C1COCC1.C(Cl)Cl>[CH:16]1([C:14]2[NH:13][N:12]=[C:11]([NH:10][C:6]3[N:5]=[C:4]([NH:19][C@H:20]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[CH3:21])[C:3]([CH2:2][N:1]4[C:35](=[O:36])[CH2:33][CH2:32][CH:31]4[C:30]([NH2:34])=[O:29])=[CH:8][C:7]=3[F:9])[CH:15]=2)[CH2:18][CH2:17]1
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CN)c1ccc(F)cc1
Reactant: O=C1CCC(C(=O)O)N1
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CN1C(=O)CCC1C(N)=O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 10 %

Procedure:
A round bottom flask was charged with (S)-3-(aminomethyl)-N-(5-cyclopropyl-1H-pyrazol -3-yl)-5-fluoro-N2-(1-(4-fluorophenyl)ethyl)pyridine-2,6-diamine (Example 3; 0.08 g, 0.2 mmol), 5-oxopyrrolidine-2-carboxylic acid loaded TFP resin (1.4 mmol/g loading, 0.2 mmol), and a THF-DCM solution (3 ml) at 0° C. The resulting solution was shaken vigorously at 0° C. for 45 min and filtered. The resulting resin was washed with a THF-DCM solution (1:1, 3×5 ml for 30 min. each). The resulting organic layers were combined and concentrated. The resulting solid was purified by reverse-phase column chromatography (5-50% CH3CN in H2O over 400 ml) to give the title compound (0.013 g, 10%). 1H NMR (400 MHz, CD3OD) δ 7.41-7.32 (m, 2H), 7.21-7.13 (m, 1H), 7.05-6.97 (m, 2H), 6.05 (s, 1H), 5.21-5.02 (m, 1H), 4.34-4.19 (m, 3H), 2.44-2.28 (m, 3H), 2.11-1.98 (m, 1H), 1.88-1.81 (m, 1H), 1.51 (d, J=5.2 Hz, 3H), 0.99-0.86 (m, 2H), 0.69-0.61 (m, 2H). MS: Calcd.: 495 Found: [M+H]+ 496.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][OH:10].[H-].[Na+].F[C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][N:15]=1>C1COCC1>[F:20][C:18]1[CH:17]=[CH:16][N:15]=[C:14]([O:10][CH2:9][CH2:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH:19]=1
Reactant: OCCOC1CCCCO1
Reactant: Fc1ccnc(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Fc1ccnc(OCCOC2CCCCO2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52.5 %

Procedure:
2-(Tetrahydro-2H-pyran-2-yl-oxy)ethanol (731 mg, 679 μL, 5.00 mmol) was suspended in anhydrous THF and NaH (60% dispersion in mineral oil, 240 mg, 6.0 mmol) was added portionwise, resulting in evolution of gas and the reaction stirred at room temp. After 15 min, a solution of 2,4-difluoropyridine (690 mg, 6.00 mmol) in anhydrous THF (2 mL) was slowly added. After stirring for 2 h, the reaction was partitioned between H2O and EtOAc. The organic layer was separated, and the aqueous extracted again with EtOAc. The combined organics were dried over MgSO4, concentrated in vacuo and subjected to FCC, eluting with 0-30% EtOAc/cyclohexane, to afford the title compound as a colourless oil (633 mg, 43%). LCMS (Method 3) Rt 3.57 min, m/z 264.2 [M+Na].
Reaction SMILES: F[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])[C:3]=1[C:15]([F:18])([F:17])[F:16].[C-:19]#[N:20].[Na+].O.C(OCC)C>C(#N)C>[C:19]([C:2]1[N:6]([CH3:7])[N:5]=[C:4]([C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10])[C:3]=1[C:15]([F:18])([F:17])[F:16])#[N:20]
Reactant: Cn1nc(C(F)(F)C(F)(F)F)c(C(F)(F)F)c1F
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCOCC
Product: Cn1nc(C(F)(F)C(F)(F)F)c(C(F)(F)F)c1C#N

Procedure:
42.0 g (147 mmol) of 5-fluoro-1-methyl-3-pentafluoroethyl-4-trifluoromethylpyrazole [synthesis see Izvestiya Akademii Nauk SSSR, Seriya Khimicheskaya 1990, (11), 2583-9] and 11.5 g (235 mmol) of sodium cyanide are suspended in 150 ml of acetonitrile and then heated at reflux temperature under a protective gas atmosphere. After cooling, the reaction mixture is poured onto a mixture of 300 ml of distilled water and 300 ml of diethyl ether. The aqueous phase is extracted three times with diethyl ether. The combined organic phases are washed twice with water and once with saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulphate and then filtered. The solvent is removed under reduced pressure on a rotary evaporator and the residue obtained in this way is subjected to fractional distillation in vacuo. This gives 37.0 g of 5-cyano-1-methyl-3-pentafluoroethyl-4-trifluoromethylpyrazole (82%) as a colourless liquid (b.p. 74° C./10 mbar).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH2:21][N:22]([CH3:24])[CH3:23])=[N:8][C:9]2[C:14]([C:15]=1[CH3:16])=[CH:13][CH:12]=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:10]=2)=O)C.C[Al](C)C.[F:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH2:33][NH2:34].CCOC(C)=O.CCCCCC>C1(C)C=CC=CC=1.CCOC(C)=O.CO>[CH3:24][N:22]([CH2:21][C:7]1[C:6]([C:4]([NH:34][CH2:33][C:32]2[CH:35]=[CH:36][CH:37]=[C:30]([F:29])[CH:31]=2)=[O:3])=[C:15]([CH3:16])[C:14]2[C:9](=[CH:10][C:11]([C:17]([F:19])([F:20])[F:18])=[CH:12][CH:13]=2)[N:8]=1)[CH3:23]
Reactant: NCc1cccc(F)c1
Reactant: CCOC(=O)c1c(CN(C)C)nc2cc(C(F)(F)F)ccc2c1C
Agent: C[Al](C)C
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1c(C(=O)NCc2cccc(F)c2)c(CN(C)C)nc2cc(C(F)(F)F)ccc12
Temperature: 120 °C
Yield: 9 %

Procedure:
To a stirred solution of 530 mg (1.56 mmol) 2-((dimethylamino)methyl)-4-methyl-7-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester in toluene (33 ml) were added 5.5 ml (2M solution in toluene, 10.9 mmol) Me3Al at RT followed by the addition of 1.77 g (15.6 mmol) 3-fluorobenzylamine. The reaction mixture was heated at 120° C. for 2 d. Then the reaction was quenched with water and acidified to pH ˜2 with conc. aq. HCl. After washing with EtoAc the aqueous layer was basified with NaOH to pH ˜11. The solution was then extracted twice with EtOAc. The combined organic layers were washed with water and brine, dried over MgSO4 and concentrated in vacuum. After CC (EtOAc/hexane 1:1->EtOAc/MeOH 9:1) of the residue, 60 mg (0.14 mmol, 9%) 2-(Dimethylaminomethyl)-N-[(3-fluorophenyl)-methyl]-4-methyl-7-(trifluoromethyl)-quinoline-3-carboxylic acid amide (example 31) were obtained. MS: m/z 420.2 [M+H]+.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[C:17](=[O:18])[C:12]3[N:13]=[C:14]([CH3:16])[S:15][C:11]=3[CH:10]=[CH:9][C:8]=2[CH:19]=1>CO.ClCCl>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]2[CH:17]([OH:18])[C:12]3[N:13]=[C:14]([CH3:16])[S:15][C:11]=3[CH:10]=[CH:9][C:8]=2[CH:19]=1
Reactant: Cc1nc2c(=O)c3ccc(Cl)cc3ccc2s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1nc2c(s1)C=Cc1cc(Cl)ccc1C2O

Procedure:
Sodium borohydride (0.3 g) was added portionwaise to a suspension of the product from step (ii) (1 g) in a mixture of methanol (40 ml) and dichloromethane (30 ml) at room temperature. After 1 hour the reaction mixture was partitioned between dichloromethane and brine. The organic phase was collected, dried (MgSO4) and evaporated under reduced pressure to leave a beige foam. Yield: 1 g. Used directly in the next step.