Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([CH:19]=[CH2:20])=[CH:15][C:10]=1[C:11]([O:13]C)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CO>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([CH:19]=[CH2:20])=[CH:15][C:10]=1[C:11]([OH:13])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=Cc1ccc(OCc2ccccc2)c(C(=O)OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=Cc1ccc(OCc2ccccc2)c(C(=O)O)c1
Yield: 80.6 %

Procedure:
To a stirred solution of methyl 2-benzyloxy-5-vinylbenzoate (1.95 g) in methanol (10 ml) was added 2N aqueous sodium hydroxide solution (7.6 ml) at room temperature, and the mixture was heated under reflux for 1 hour with stirring. The reaction mixture was acidified with 2N hydrochloric acid, and the resulting mixture was extracted with dichloromethane. The extract was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Crystallization of the residue from a mixed solution of hexane and diethyl ether (2/1) gave 2-benzyloxy-5-vinylbenzoic acid (1.49 g)
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=O.N1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.C(OCC)(=O)C.O>CN(C=O)C>[Cl:1][C:2]1[C:10]([CH3:11])=[C:9]([F:12])[CH:8]=[CH:7][C:3]=1[C:4]#[N:6]
Reactant: Cc1c(F)ccc(C(N)=O)c1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1c(F)ccc(C#N)c1Cl
Yield: 70.8 %

Procedure:
To a solution (50 ml) of 2-chloro-4-fluoro-3-methylbenzamide (4.69 g) and pyridine (2.97 g) in DMF was added dropwise oxalyl chloride (3.80 g) with stirring under ice-cooling at not more than 10° C. After stirring at the same temperature for 1 hr, the mixture was poured into ethyl acetate/water and partitioned. The organic layer was washed with water, aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the precipitated crystals were collected by filtration, washed with cold hexane and dried to give the title compound (3.00 g) as crystals.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C@H:9]([CH2:19][CH3:20])[CH2:10][C@:11]([OH:18])([C:14]([F:17])([F:16])[F:15])[CH:12]=O)[CH:5]=[CH:6][C:7]=1[F:8].[NH2:23][C:24]1[CH:33]=[C:32]([F:34])[CH:31]=[C:30]2[C:25]=1[CH:26]=[N:27][C:28]([CH3:35])=[N:29]2>CC(C)([O-])C.[Ti+4].CC(C)([O-])C.CC(C)([O-])C.CC(C)([O-])C>[Cl:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C@H:9]([CH2:19][CH3:20])[CH2:10][C@@:11]([C:14]([F:16])([F:15])[F:17])([OH:18])[CH:12]=[N:23][C:24]2[CH:33]=[C:32]([F:34])[CH:31]=[C:30]3[C:25]=2[CH:26]=[N:27][C:28]([CH3:35])=[N:29]3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC[C@H](C[C@@](O)(C=O)C(F)(F)F)c1ccc(F)c(Cl)c1OC
Reactant: Cc1ncc2c(N)cc(F)cc2n1
Agent: [Ti+4]
Agent: CC(C)(C)[O-]
Product: CC[C@H](C[C@@](O)(C=Nc1cc(F)cc2nc(C)ncc12)C(F)(F)F)c1ccc(F)c(Cl)c1OC

Procedure:
In the same way as in Example 148, 300 mg (0.88 mmol) of (2R,4R)-4-(3-chloro-4-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexanal, 172 mg (0.97 mmol) of 5-amino-7-fluoro-2-methylquinazoline and 0.55 ml of titanium tert-butoxide are reacted to give 5-{[(2R,4R)-4-(3-chloro-4-fluoro-2-methoxyphenyl)-1-[(7-fluoro-2-methylquinazolin-5-yl)imino]-2-(trifluoromethyl)hexan-2-ol. 450 mg of crude imine are cyclized in the same way as in Example 148 at −30° C. with 2.5 ml (2.5 mmol) of 1 M boron tribromide solution to give the desired product. Column chromatography on silica gel (hexane/ethyl acetate 0-50%) yields 56 mg of desired product.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH2:12]([C:14]([OH:21])([CH2:19][CH3:20])[C:15]#[C:16][CH2:17][OH:18])[CH3:13].[OH-].[K+].O>CCOCC>[CH2:12]([C:14]([OH:21])([C:15]#[C:16][CH2:17][O:18][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8])[CH2:19][CH3:20])[CH3:13]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCC(O)(C#CCO)CC
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: CCC(O)(C#CCOS(=O)(=O)c1ccc(C)cc1)CC
Temperature: 0 °C
Yield: 78 %

Procedure:
An ice-cold solution of 4-toluenesulfonyl chloride (6.4 g) and 4-ethylhex-2-yn-1,4-diol (McLamore, W. M. et al., J. Org. Chem., 19, 570-574 (1954) and Gouge, M., Ann. Chim., 6, 648-702 (1951)) (4.0 g) in ether (40 ml) was stirred with powdered potassium hydroxide (15 g) for 2 h. Water was added and the mixture was extracted with ether (2×250 ml). Work-up with chromatography using ether/pentane 1:1 (v/v) gave the title compound (6.5 g). 1H NMR: 0.91 (t, 6H), 1.55 (q, 4H), 1.83 (s, 1H), 2.45 (s, 2H), 4.76 (s, 2H), 7.36 (d, 2H), 7.82 (d, 2H).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:13][CH3:14])=[C:4]([CH:10]([NH2:12])[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].[NH2:15][C:16]1[C:21]([C:22]#[N:23])=[C:20](Cl)[N:19]=[CH:18][N:17]=1.C(N(CC)C(C)C)(C)C.C(O)C>>[NH2:15][C:16]1[C:21]([C:22]#[N:23])=[C:20]([NH:12][CH:10]([C:4]2[CH:5]=[C:6]([Cl:9])[C:7]([F:8])=[C:2]([Br:1])[C:3]=2[O:13][CH3:14])[CH3:11])[N:19]=[CH:18][N:17]=1
Reactant: COc1c(C(C)N)cc(Cl)c(F)c1Br
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COc1c(C(C)Nc2ncnc(N)c2C#N)cc(Cl)c(F)c1Br
Temperature: 100 °C
Yield: 54 %

Procedure:
A mixture of 1-(3-bromo-5-chloro-4-fluoro-2-methoxyphenyl)ethanamine (40 mg, 0.14 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (J & W PharmLab, #70-0156 33 mg, 0.21 mmol) and N,N-diisopropylethylamine (74 μL, 0.43 mmol) in ethanol (1.6 mL, 27 mmol) was heated at 100° C. overnight. Purification by preparative LC/MS (pH10) gave the desired compound (54% yield). LCMS calculated for C14H13BrClFN5O (M+H)+: m/z=400.0, 402.0. found: 400.0, 402.0. 1H NMR (300 MHz, DMSO-d6): δ 7.95 (s, 1H), 7.77 (m, 1H), 7.28 (br s, 2H), 5.56 (m, 1H), 3.92 (s, 1H), 1.40 (m, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].Br[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+]>N1C=CC=CC=1.[Cu]>[F:17][C:14]1[CH:15]=[CH:16][C:11]([O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])=[CH:12][CH:13]=1
Reactant: Fc1ccc(Br)cc1
Reactant: O=Cc1cccc(O)c1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: O=Cc1cccc(Oc2ccc(F)cc2)c1
Temperature: 25 °C
Yield: 73 %

Procedure:
A heterogeneous mixture of 3-hydroxybenzaldehyde (9.16 g, 75 mmol), 4-bromofluorobenzene (27.30 g, 156 mmol), K2CO3 (16.07 g, 116.3 mmol) and copper powder (2.38 g, 37.5 mmol) in pyridine (75 mL) was refluxed for 40 hrs. It was then cooled to room temperature and filtered through Celite. The filtrate was diluted with ethylacetate (500 mL) and washed with water (3×300 mL). The organic was then dried with MgSO4 and concentrated. The resulting residue was chromatographed (silica gel, hexane:ether, 85:15) to afford 11.83 g (73%) of 3-(4-fluorophenoxy)benzaldehyde as a yellow oil.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1.C([O:38][C@@H:39]([CH3:43])[C:40](Cl)=[O:41])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[CH:9][C:8]=2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]3[C:22]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:40](=[O:41])[C@@H:39]([OH:38])[CH3:43])[CH2:33][CH2:34]4)=[O:27])=[C:23]([CH3:25])[NH:24][C:17]=23)[CH2:4][CH2:3]1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: COc1cc(OCC2CC2)c(-c2ccnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)cc1F
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2ccnc3c(C(=O)NC4CCN(C(=O)[C@H](C)O)CC4)c(C)[nH]c23)cc1F

Procedure:
Starting from 7-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-2-methyl-N-piperidin-4-yl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f26) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[N:7]([CH2:13][C:14]1[CH:22]=[CH:21][C:17]2[O:18][CH2:19][O:20][C:16]=2[CH:15]=1)[CH2:8][CH2:9][CH2:10][NH:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]1[N:29]=[C:28](Cl)[S:27][N:26]=1.CS(C)=O>O>[C:1]([O:5][C:6](=[O:23])[N:7]([CH2:13][C:14]1[CH:22]=[CH:21][C:17]2[O:18][CH2:19][O:20][C:16]=2[CH:15]=1)[CH2:8][CH2:9][CH2:10][N:11]([C:28]1[S:27][N:26]=[C:25]([Cl:24])[N:29]=1)[CH3:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: Clc1nsc(Cl)n1
Reactant: CNCCCN(Cc1ccc2c(c1)OCO2)C(=O)OC(C)(C)C
Solvent: O
Solvent: CS(C)=O
Product: CN(CCCN(Cc1ccc2c(c1)OCO2)C(=O)OC(C)(C)C)c1nc(Cl)ns1
Yield: 69 %

Procedure:
A solution of benzo[1,3]dioxol-5-ylmethyl-(3-methylamino-propyl)-carbamic acid tert-butyl ester (10 g, 46 mmol), 3,5-dichloro-1,2,4-thiadiazole (7.1 g, 46 mmol), DMSO (20 mL) and TEA (20 mL) was stirred at r.t. for 20 min. Water (150 mL) was added and the solution was extracted with ethyl acetate (2×150 mL), washed with brine and dried over Na2SO4. Evaporation of the solvent gave 14 g (69%) of benzo[1,3]dioxol-5-ylmethyl-{3-[(3-chloro-[1,2,4]thiadiazol-5-yl)-methyl-amino]-propyl}-carbamic acid tert-butyl ester as a clear gum. The product was used directly in the next step. 1H-NMR (400 MHz, CD3OD) δ 6.77 (m, 3H), 5.96 (s, 2H), 4.35 (s, 2H), 3.4-3.0 (m, 6H), 1.84 (br s, 3H), 1.50 (s, 9H).
Reaction SMILES: C([BH3-])#N.[Na+].C(O)(=O)C.[CH3:9][O:10][N:11]=[CH:12][CH2:13][CH2:14][CH2:15][N:16]1[C:28]2[C:27]3[N:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]=[C:20]([NH2:29])[C:19]=2[N:18]=[C:17]1[CH2:30][CH2:31][CH3:32]>CO>[CH3:9][O:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[C:28]2[C:27]3[N:26]=[CH:25][CH:24]=[CH:23][C:22]=3[N:21]=[C:20]([NH2:29])[C:19]=2[N:18]=[C:17]1[CH2:30][CH2:31][CH3:32]
Reactant: CCCc1nc2c(N)nc3cccnc3c2n1CCCC=NOC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCc1nc2c(N)nc3cccnc3c2n1CCCCNOC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 106.8 %

Procedure:
Sodium cyanoborohydride (0.54 g, 8.64 mmol, 3 eq) and acetic acid (7 mL) were added to a solution of 4-(4-amino-2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyraldehyde O-methyloxime (0.94 g, 2.88 mmol, 1 eq) in methanol (7 mL) and stirred at ambient temperature for 20 minutes. The reaction mixture was concentrated under reduced pressure and diluted with dichloromethane (60 mL) and saturated aqueous sodium bicarbonate (40 mL). The phases were separated and the aqueous phase was adjusted to pH ˜8 with solid sodium bicarbonate and extracted with dichloromethane (2×20 mL). The combined organics were dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to provide 1.01 g of 1-[4-(methoxyamino)butyl]-2-propyl-1H-imidazo[4,5-c]-1,5-naphthyridin-4-amine as a yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[CH2:15][CH2:14][NH:13][CH2:12][C:11]=2[C:10]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:24](O)(=O)[CH3:25].C(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[CH2:1]([N:8]1[C:16]2[CH2:15][CH2:14][N:13]([CH2:24][CH3:25])[CH2:12][C:11]=2[C:10]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ccc(-c2cn(Cc3ccccc3)c3c2CNCC3)cc1
Reactant: CC(=O)O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CCN1CCc2c(c(-c3ccc(Cl)cc3)cn2Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 1-benzyl-3-(4-chloro-phenyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine (Example 25; 0.11 g) in 1,2-dichloroethane (5 mL) was added 18 μL of acetic acid, 26 μL of acetaldehyde, and 0.10 g of NaBH(OAc)3. The mixture was stirred at RT for 15 h. The mixture was diluted with CH2Cl2 and washed with satd. aq. NaHCO3 (2×). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. Chromatography on SiO2 (1% 2 M NH3 in MeOH/CH2Cl2) afforded 0.02 g of the title compound. The product was dissolved in Et2O and treated with excess 1.0 M HCl in Et2O to afford 0.02 g of the corresponding HCl salt. MS (ESI): exact mass calculated for C22H23ClN2, 350.15. found, m/z 351.2 [M+H]+, 353.2 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.37-7.27 (m, 7H), 7.19-7.17 (m, 3H), 5.17-5.13 (m, 2H), 4.48-4.37 (m, 2H), 3.85-3.76 (m, 2H), 3.45-3.23 (m, 2H), 3.00-2.84 (m, 2H), 1.38 (t, J=7.1 Hz, 3H).
Reaction SMILES: [N:1]#[N:2].C(OC([NH:13][C@@H:14]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C@H:15]([OH:29])[CH2:16][C@@:17]1([C:26]([NH2:28])=[O:27])[CH2:21][CH2:20][CH2:19][N:18]1[C:22]([CH3:25])([CH3:24])[CH3:23])=O)C1C=CC=CC=1>C(O)C.[Pd]>[N:1]#[N:2].[NH2:13][C@@H:14]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C@H:15]([OH:29])[CH2:16][C@@:17]1([C:26]([NH2:28])=[O:27])[CH2:21][CH2:20][CH2:19][N:18]1[C:22]([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)N1CCC[C@@]1(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(N)=O
Agent: [Pd]
Agent: N#N
Solvent: CCO
Product: CC(C)(C)N1CCC[C@@]1(C[C@@H](O)[C@@H](N)Cc1ccccc1)C(N)=O
Yield: 98.4 %

Procedure:
A solution of 0.46 g of N2 -[3(S)-(benzyloxyformamido)-2(R)-hydroxy-4-phenylbutyl]-N1 -tert.butyl-L-prolinamide in 40 ml of ethanol was hydrogenated over 40 mg of 10% palladium-on-carbon at room temperature and under atmospheric pressure for 1.5 hours to give 0.33 g of N2 -[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N1 -tert.butyl-L-prolinamide as a gum which crystallized on standing.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3](=[O:20])[C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:5]([OH:14])[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13].C(N(CC)CC)C.[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CCOCC>[CH3:21][N:2]([CH3:1])[C:3](=[O:20])[C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:5]([O:14][C:29](=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)C(C(=O)N(C)C)=C(O)c1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)C(C(=O)N(C)C)=C(OC(=O)c1ccccc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C

Procedure:
To a well stirred mixture of 12.4 g of N,N-dimethylalphaethoxycarbonyl-beta-hydroxy-2,4-dichlorocinnamamide, 4.0 g of triethylamine and 150 ml of dry ether at 4° C. was added dropwise benzoyl chloride at such a rate that the temperature did not exceed 5° C. The reaction was allowed to warm up to room temperature, stirred at this temperature for 2 hours, the cooled again to 4° C. The solids were filtered off and the filtrate concentrated under reduced pressure to yield 12.0 g of a white solid. The solid was crystallized from ether/hexane to yield 8.0 g of the desired product, m.p. 106° C.
Reaction SMILES: [F:1][CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:11][O:12]CCO>>[F:1][CH2:2][C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH2:9][O:12][CH3:11])=[O:6]
Reactant: COCCO
Reactant: CCOC(=O)CC(=O)CF
Product: COCCOC(=O)CC(=O)CF

Procedure:
Ethyl 4-fluoro-3-oxobutanoate (2.1 g) was heated at reflux in 2-methoxyethanol (10 ml) for 3 hours. The solvent was removed in vacuo and the residue distilled to give the title compound as a colourless oil (1.75 g). Nmr (CDCl3)δ4.9 (d,2H,J-48 Hz), 3.4 (s,3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8](C3C=CC4C(C=3)=NN(CC3C=CC=CC=3)C=4)[CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.FC(F)(F)C(O)=O.C([O-])(O)=O.[Na+]>ClCCl>[NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([C:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]=3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc3c(N)ncnn23)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 152.9 %

Procedure:
To a solution of tert-butyl 4-[4-amino-5-(2-benzyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]piperidine-1-carboxylate (325 mg, 0.62 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL). The reaction was stirred (rt) for 17 h. The mixture was made basic (pH 9) with the addition of saturated aqueous NaHCO3 and the layers were separated. The aqueous phase was back extracted with dichloromethane (2×10 mL) and the combined organics were washed with brine, dried (Na2SO4), and evaporated to afford 299 mg (100%) of the desired product, which contained trace impurities. 1H NMR (300 MHz, DMSO-d6) δ 8.53 (s, 1 H), 7.87 (s, 1 H), 7.78 (d, 1 H), 7.57 (s, 1 H), 7.36-7.30 (m, 5 H), 7.13 (d, 1 H), 6.55 (s, 1 H), 5.64 (s, 2 H), 3.41 (br s, 1 H), 3.30-3.18 (m, 1 H), 3.07 (d, 2 H), 2.75-2.64 (m, 2H), 1.97 (d, 2 H), 1.68-1.53 (m, 2 H); ES-MS m/z 424.3 [M+H]+, HPLC RT (min) 0.78.
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15]Br)=[CH:9][CH:8]=1)C.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[OH:26].CO[C@@H](CC1C=CC(OCCCOC2C=CC=CC=2)=CC=1)C(O)=O>>[CH3:18][O:17][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][O:26][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:19]
Reactant: CCOC(=O)[C@H](Cc1ccc(OCCBr)cc1)OC
Reactant: Oc1ccccn1
Agent: CO[C@@H](Cc1ccc(OCCCOc2ccccc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCCOc2ccccn2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(2-bromo-ethoxy)-phenyl]-2-methoxy-propionic acid ethyl ester (Example 283, Step 2) and pyridin-2-ol via the same procedure used for the preparation of (2S)-2-Methoxy-3-[4-(3-phenoxy-propoxy)-phenyl]-propionic acid (Example 285, Step 1); to produce a colorless oil. MS (ES) for C17H19NO5 [M+H]+: 318.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][O:10]C)=[CH:4][CH:3]=1.[N+:12]([C:15]1[S:19][C:18]([CH:20]=O)=[CH:17][CH:16]=1)([O-:14])=[O:13]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH:20][C:18]2[S:19][C:15]([N+:12]([O-:14])=[O:13])=[CH:16][CH:17]=2)[CH:9]=[O:10])=[CH:4][CH:3]=1
Reactant: COC=Cc1ccc(Cl)cc1
Reactant: O=Cc1ccc([N+](=O)[O-])s1
Product: O=CC(=Cc1ccc([N+](=O)[O-])s1)c1ccc(Cl)cc1

Procedure:
1-(4-chlorophenyl)-2-methoxyethylene is reacted in analogous manner with 5-nitrothiophene-2-aldehyde, and the title compound is obtained in the form of brown crystals having a M.P. of 135°-136°, after purification by column chromatography over silica gel with toluene.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[NH:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]2[CH:25]=[CH:24][C:23]([C@@H:26]([NH:28][C:29](=[O:31])[CH3:30])[CH3:27])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)=[NH:13].C(N(CC)CC)C>C1COCC1>[C:2]1([C:1]2[O:8][N:13]=[C:12]([N:14]3[CH2:19][CH2:18][CH:17]([C:20]4[CH:21]=[CH:22][C:23]([C@@H:26]([NH:28][C:29](=[O:31])[CH3:30])[CH3:27])=[CH:24][CH:25]=4)[CH2:16][CH2:15]3)[N:11]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(=O)N[C@@H](C)c1ccc(C2CCN(C(=N)NO)CC2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N[C@@H](C)c1ccc(C2CCN(c3noc(-c4ccccc4)n3)CC2)cc1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
0.019 mL (0.16 mmol) Benzoyl chloride are added to a mixture of 45.7 mg (0.15 mmol) (S)—N-(1-{4-[1-(N-hydroxycarbamimidoyl)-piperidin-4-yl]-phenyl}-ethyl)-acetamide (XXVII.2) and 0.063 mL (0.45 mmol) triethylamine in 4 mL THF. The mixture is stirred for 12 h at 80° C. and is subsequently purified by HPLC (RP C18 Sunfire; water (+0.1% TFA)/MeOH) to yield the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([N:16]3[C:20]([CH2:21][CH3:22])=[C:19]([C:23](O)=[O:24])[C:18]([CH2:26][CH3:27])=[N:17]3)[CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1.[CH2:28]([N:30]([CH2:36][CH3:37])[CH:31]1[CH2:35][CH2:34][NH:33][CH2:32]1)[CH3:29]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]([N:16]3[C:20]([CH2:21][CH3:22])=[C:19]([C:23]([N:33]4[CH2:34][CH2:35][CH:31]([N:30]([CH2:36][CH3:37])[CH2:28][CH3:29])[CH2:32]4)=[O:24])[C:18]([CH2:26][CH3:27])=[N:17]3)[CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1
Reactant: CCN(CC)C1CCNC1
Reactant: CCc1nn(-c2cccc(/C=C/c3ccc(Cl)cc3)c2)c(CC)c1C(=O)O
Product: CCc1nn(-c2cccc(/C=C/c3ccc(Cl)cc3)c2)c(CC)c1C(=O)N1CCC(N(CC)CC)C1

Procedure:
In analogy to the procedure described for example 2, 1-{3-[(E)-2-(4-chloro-phenyl)-vinyl]-phenyl}-3,5-diethyl-1H-pyrazole-4-carboxylic acid (intermediate 1) and [rac]-diethyl-pyrrolidin-3-yl-amine gave the title compound as colorless oil. MS: 505.3 (MH+, 1 Cl).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9]>[Cu].CN(C=O)C>[F:9][C:8]([F:11])([F:10])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([F:11])([F:10])[F:9]
Reactant: FC(F)(F)c1ccccc1I
Agent: [Cu]
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccccc1-c1ccccc1C(F)(F)F
Yield: 78.5 %

Procedure:
To a 2-L three-necked, round-bottom flask fitted with a mechanical stirrer and a condenser was added 507.5 g of 2-iodotrifluoromethylbenzene (1.86 mol), 282.0 g of copper powder and 400 ml of DMF. The reaction mixture was stirred and heated at reflux for 24 hours and filtered. The filtrate was distilled under reduced pressure to yield 211.8 g (78%) of a light yellow oil.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[CH:5][S:6][C:7]=1/[CH:8]=[CH:9]\[S:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C-:30]#[N:31].[Na+]>CN(C=O)C.[Cl-].[Na+].O>[C:30]([CH2:2][C:3]1[N:4]=[CH:5][S:6][C:7]=1/[CH:8]=[CH:9]\[S:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)#[N:31]
Reactant: [C-]#N
Reactant: ClCc1ncsc1/C=C\SC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CCc1ncsc1/C=C\SC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 38.6 %

Procedure:
A suspension of 350 mg of 4-chloromethyl-5-((Z)-2-tritylthioethen-1-yl)thiazole, prepared in step a) in Example 2, in 7 ml of DMF was cooled in ice, and 94 mg of sodium cyanide was added to the cooled suspension under an argon atmosphere. The mixture was stirred at room temperature for 2.5 hr, and brine was then added to the reaction solution. The mixture was extracted twice with ethyl acetate, and the organic layers were combined, followed by washing with brine. The washed organic layer was dried over anhydrous magnesium sulfate, was filtered, and was concentrated under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1) to give 132 mg of the title compound.
Reaction SMILES: C([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10](Cl)=[N:9][CH:8]=1)(C)(C)C.[CH3:15][CH:16]([CH3:21])[CH2:17][CH2:18][Mg]Br.C(O)(=O)C1C=CC=NC=1>>[CH3:15][CH:16]([CH3:21])[CH2:17][CH2:18][C:10]1[CH:11]=[CH:12][C:7]([C:6]([OH:5])=[O:14])=[CH:8][N:9]=1
Reactant: CC(C)CC[Mg]Br
Reactant: CC(C)(C)OC(=O)c1ccc(Cl)nc1
Agent: O=C(O)c1cccnc1
Product: CC(C)CCc1ccc(C(=O)O)cn1

Procedure:
6-(3-Methyl-butyl)-nicotinic acid is prepared by reacting 6-chloro-nicotinic acid tert-butly ester with 3-methyl-butylmagnesium bromide under Fürstner conditions as described for Nicotinic acid 2; LC-MS: tR=0.58 min, [M+1]+=194.30.