Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]C(CC)C.[Si:6]([O:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[F:21])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].CN([CH:25]=[O:26])C.Cl>C1COCC1>[Si:6]([O:13][C:14]1[C:15]([F:21])=[C:16]([CH:17]=[C:18]([F:20])[CH:19]=1)[CH:25]=[O:26])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(F)ccc1F
Agent: Cl
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1cc(F)cc(C=O)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.4 %

Procedure:
A 1.0M solution of sec-BuLi (21.5 ml, 21.5 mmol) was added dropwise to a stirred solution of O-tert-butyldimethylsilyl-2,5-difluorophenol (5.0 g, 20 mmol) in THF (20 mL) at -78° C. After 0.5 hr DMF (1.9 ml, 24.6 mmol) was added dropwise while the temperature was kept below -70° C. After 30 min, the mixture was allowed to warm to room temperature over 30 min. To the mixture was added 3N HCl (30 ml) and stirring was continued for 30 min. The mixture was extracted with ether (100 ml) and the extract was washed with water (100 ml), brine (100 ml), dried (sodium sulfate) and evaporated. Column chromatography (silica gel) of the residue eluting with n-hexane gave 3.56 g (64%) of the titled compound as a colorless oil.
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[NH2:21][C:22]1[N:27]=[CH:26][C:25]([Br:28])=[CH:24][N:23]=1>ClCCl.N1C=CC=CC=1>[Br:28][C:25]1[CH:24]=[N:23][C:22]([NH:21][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:21][C:22]2[N:27]=[CH:26][C:25]([Br:28])=[CH:24][N:23]=2)=[O:13])=[N:27][CH:26]=1
Reactant: Nc1ncc(Br)cn1
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ncc(Br)cn1)c1ccccc1SSc1ccccc1C(=O)Nc1ncc(Br)cn1
Yield: 11.1 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (2.00 g, 5.83 mmol) in 50 mL of dichloromethane and 2-amino-5-bromopyrimidine (2.03 g, 11.7 mmol) in 16 mL of pyridine. The crude product was triturated with a hot mixture of ethyl acetate and ethanol, filtered, and recrystallized first from DMF, then from acetonitrile-DMF to yield 0.40 g of the title compound, mp 249-253° C.
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16]Cl)[N:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[P:18]([O:25]CC)([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]>C(OCC)(=O)C>[C:1]([O:9][CH2:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][P:18]([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])=[O:25])[N:15]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1nc(CCl)cs1)c1ccccc1
Reactant: CCOP(OCC)OCC
Solvent: CCOC(C)=O
Product: CCOP(=O)(Cc1csc(COC(=O)c2ccccc2)n1)OCC
Temperature: 150 °C
Reaction time: 17 h
Yield: 90.6 %

Procedure:
A mixture of (4-chloromethyl-1,3-thiazol-2-yl)methyl benzoate (6.4 g), triethyl phosphite (8.7 g) was stirred at 150° C. for 17 hrs. Excess triethyl phosphite was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1:2, v/v)-ethyl acetate to give {4-[(diethoxyphosphoryl)methyl]-1,3-thiazol-2-yl}methyl benzoate as a yellow oil (8.0 g, yield 91%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH:7]1([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([O-])=[O:19])=[CH:16][CH:15]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.O.[OH-].[K+]>C1COCC1>[CH:7]1([O:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:18][OH:19])=[CH:21][CH:22]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=C([O-])c1ccc(OC2CCCCC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc(OC2CCCCC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
Under nitrogen atmosphere, at 0° C., to a stirring mixture of LiAlH4 (2.0 M THF solution, 9.42 mL, 18.84 mmol) in dry THF (6.0 mL), 4-(cyclohexoxy)-benzoate (1.17 g, 4.71 mmol) in dry THF (30 mL) was added dropwise. The mixture was left to react at rt for 4 h, then at 0° C. H2O (0.70 mL), 3.0 M KOH solution (0.70 mL) and H2O (1.6 mL) were very slowly added. The mixture was stirred for 1 h at 0° C., filtered to remove the solid residue, and the organic phase dried over Na2SO4. The organic solution was again filtered and concentrated to dryness, affording the title compound (0.57 g, 59%), which was used in the next step without any further purification. 1H NMR (DMSO-d6): δ 1.21-1.47 (m, 5H), 1.49-1.57 (m, 1H), 1.64-1.77 (m, 2H), 1.87-1.95 (m, 2H), 4.25-4.33 (m, 1H), 4.40 (d, J=5.7 Hz, 2H), 5.00 (t, J=5.7 Hz, 1H), 6.87 (d, J=8.5 Hz, 2H), 7.19 (d, J=8.5 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]#[N:10])=[C:4]([Cl:11])[C:3]=1[CH3:12].O.[SH-].[Na+].[BH4-].[Na+].[OH-].[Na+].[Cl:20][C:21]1N=C(Cl)[CH:24]=[CH:23][N:22]=1>CO.O>[Cl:11][C:4]1[C:3]([CH3:12])=[C:2]([CH:7]=[CH:6][C:5]=1[S:8][C:9]1[CH:24]=[CH:23][N:22]=[C:21]([Cl:20])[N:10]=1)[NH2:1]
Reactant: Cc1c(N)ccc(SC#N)c1Cl
Reactant: Clc1ccnc(Cl)n1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1c(N)ccc(Sc2ccnc(Cl)n2)c1Cl
Temperature: 0 °C
Reaction time: 8 h
Yield: 41.1 %

Procedure:
Crude 4-amino-2-chloro-3-methylphenyl thiocyanate (600 mg, 3.0 mmol) was dissolved in a mixture of methanol:water (2:1, 22 mL) and cooled to 0° C. Sodium hydrosulfide monohydrate (338 mg, 4.6 mmol) and sodium borohydride (447 mg, 11.8 mmol) were added then the mixture was allowed to warm to room temperature and stir overnight. After this time sodium hydroxide (96 mg, 2 4 mmol) was added followed by 2,4-dichloropyrimidine (360 mg, 2 4 mmol) and the mixture allowed to stir for a further 24h. The methanol was removed in vacuo and then the mixture was extracted with ethyl acetate. The extracts were dried (Na2SO4) and evaporated then the residue was purified by flash chromatography to afford 3-chloro-4-[(2-chloropyrimidin-4-yl)thio]-2-methylaniline (353 mg, 41%).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH2:20])=[O:19])=[C:13]3[NH:12][CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.C([SiH](CC)CC)C.[OH-].[K+]>FC(F)(F)C(O)=O>[F:21][C:2]([F:1])([F:22])[C:3]1[CH:4]=[C:5]([CH:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH2:20])=[O:19])=[C:13]3[NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: NC(=O)c1cnn2c1NCC=C2c1cccc(C(F)(F)F)c1
Agent: CC[SiH](CC)CC
Agent: [K+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1cnn2c1NCCC2c1cccc(C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
A solution of 3.44 g of 4,5-dihydro-7-(3-trifluoromethyl)phenyl)pyrazolo(1,5-a)pyrimidine-3-carboxamide (Example 8) in 40 ml of trifluoroacetic acid is stirred under nitrogen and heated to 60° C. in an oil bath. Then 5.0 ml of triethylsilane is added and the mixture is stirred at 60° C. for 24 hours. The reaction mixture is cooled and carefully poured into a beaker containing a 25 percent aqueous solution of potassium hydroxide and cracked ice. The product which precipitates is extracted into chloroform, and the extract is washed with water, dried over anhydrous sodium sulfate and filtered. The filtrate is evaporated in vacuo to give crystals which are then recrystallized from toluene-hexane to give the desired product, mp 152-154° C.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.Cl[C:42]1[C:47](=[O:48])[N:46]([CH3:49])[CH:45]=[C:44]2[C:50](=[O:66])[N:51]([CH2:54][CH2:55][C:56]3[CH:65]=[CH:64][C:63]4[C:58](=[CH:59][CH:60]=[CH:61][CH:62]=4)[N:57]=3)[C:52](=[O:53])[C:43]=12.[NH:67]1[CH2:72][CH2:71][S:70](=[O:74])(=[O:73])[CH2:69][CH2:68]1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:49][N:46]1[C:47](=[O:48])[C:42]([N:67]2[CH2:72][CH2:71][S:70](=[O:74])(=[O:73])[CH2:69][CH2:68]2)=[C:43]2[C:52](=[O:53])[N:51]([CH2:54][CH2:55][C:56]3[CH:65]=[CH:64][C:63]4[C:58](=[CH:59][CH:60]=[CH:61][CH:62]=4)[N:57]=3)[C:50](=[O:66])[C:44]2=[CH:45]1
Reactant: Cn1cc2c(c(Cl)c1=O)C(=O)N(CCc1ccc3ccccc3n1)C2=O
Reactant: O=S1(=O)CCNCC1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cn1cc2c(c(N3CCS(=O)(=O)CC3)c1=O)C(=O)N(CCc1ccc3ccccc3n1)C2=O
Reaction time: 4 h
Yield: 63 %

Procedure:
K2CO3 (1.127 g, 8.16 mmol), Pd2(dba)3 (0.249 g, 0.272 mmol) and dicyclohexyl[2′,4′,6′-tris(1-methylethyl)[1,1′-biphenyl]-2-yl]-phosphine (0.13 g, 0.272 mmol) were subsequently added to a suspension of 7-chloro-5-methyl-2-(2-quinolin-2-yl-ethyl)-5H-pyrrolo[3,4-c]pyridine-1,3,6-trione (1 g, 2.72 mmol, see Example c1)) and thiomorpholine 1,1-dioxide (0.551 g, 4.08 mmol) in toluene (10 ml) and the mixture was stirred for 4 h under reflux. The solvent was removed and the resulting mixture was purified on a silica column (DCM/MeOH=50:1) to afford the title compound (0.8 g, 63% yield).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH:11]([N:13]([CH2:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH2:14][CH3:15])[CH3:12])=[CH:6][CH:5]=1.[O-:23][C:24]#[N:25].[K+]>O>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH:11]([N:13]([CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([C:24]([NH2:25])=[O:23])[CH2:19][CH2:18]2)[CH2:14][CH3:15])[CH3:12])=[CH:8][CH:9]=1
Reactant: CCN(CC1CCNCC1)C(C)Cc1ccc(OC)cc1
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: CCN(CC1CCN(C(N)=O)CC1)C(C)Cc1ccc(OC)cc1
Yield: 77.6 %

Procedure:
A mixture of N-[2-(4-methoxyphenyl)-1-methylethyl]-N-ethyl-(piperidin-4-ylmethyl)amine hydrochloride (0.42 grams, 1.16 mmole) and potassium cyanate (1.5 grams, 18.5 mmole) in water (5 ml) was heated under reflux for about 20 minutes. The white solid which formed upon cooling was collected and recrystallized from chloroform/hexane to give N-[2-(4-methoxyphenyl)-1-methylethyl]-N-ethyl-(1-aminocarbonylpiperidin-4-ylmethyl)amine (0.3 grams, 77%), m.p. 104-10° C.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[NH:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:23][CH2:22]1)(C(C)(C)C)(C)C.[F-].[NH4+].C(=O)(O)[O-].[Na+]>CO>[OH:8][CH2:9][CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[NH:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:23][CH2:22]1
Reactant: CCOC(=O)N1CCC(Nc2nc3ccccc3n2CCO[Si](C)(C)C(C)(C)C)CC1
Agent: O=C([O-])O
Agent: [F-]
Agent: [NH4+]
Solvent: CO
Product: CCOC(=O)N1CCC(Nc2nc3ccccc3n2CCO)CC1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
Combine (1-(2-(t-butyldimethylsilyloxy)ethyl)-1H-benzimidazol-2-yl)(1-(ethoxycarbonyl)piperidin-4-yl)amine (0.53 g, 12 mmol) and ammonium fluoride (2.667 g, 72 mmol) in methanol (60 mL). Heat to about 60° C. After 2.5 hours, cool, evaporate in vacuo and partition the evaporated reaction mixture between dichloromethane and a saturated aqueous sodium bicarbonate solution. Separate the layers and extract the organic layer twice with water and then brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give (1-(2-hydroxyethyl)-1H-benzimidazol-2-yl)(1-(ethoxycarbonyl)piperidin-4-yl)amine.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][N:9]=[C:8]2[I:14])=[O:4].[CH3:15]C([O-])(C)C.[K+].IC>C1COCC1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH3:15])[N:9]=[C:8]2[I:14])=[O:4]
Reactant: COC(=O)c1ccc2[nH]nc(I)c2c1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(=O)c1ccc2c(c1)c(I)nn2C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.8 %

Procedure:
To a solution of 3-iodo-1H-indazole-5-carboxylic acid methyl ester (1.0 g, 3.31 mmol) in THF (12 mL) at 0° C. was added KOt-Bu (520 mg, 4.63 mmol). The reaction mixture was stirred at 0° C. for 30 min then added iodomethane (0.29 mL, 4.63 mmol). Stirred at 0° C. for 30 min then warmed to room temperature and stirred for 2 h. The reaction was quenched with water and extracted with EtOAc (2×) then with CH2Cl2 (2×). The combined organics were dried over MgSO4 and concentrated to afford 950 mg of 3-iodo-1-methyl-1H-indazole-5-carboxylic acid methyl ester a pale yellow solid. NMR analysis revealed an 8:1 mixture of N1:N2 alkylated regioisomers. Major: 1H NMR (CDCl3, 300 MHz): δ (ppm) 8.25 (s, 1H), 8.13 (dd, J=8.7, 1.5 Hz, 1H), 7.39 (d, J=8.7 Hz, 1H), 4.13 (s, 3H), 3.98 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[N:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH2:22])[CH2:10]2)=[N:7][CH:8]=1.Cl[C:26]1[O:27][C:28]([C:31]2[CH:32]=[C:33]([NH:37][C:38](=[O:42])[O:39][CH2:40][CH3:41])[CH:34]=[CH:35][CH:36]=2)=[CH:29][N:30]=1>>[F:24][C:2]([F:1])([F:23])[C:3]1[N:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][C@H:11]([NH:15][C@@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]3[NH:22][C:26]3[O:27][C:28]([C:31]4[CH:32]=[C:33]([NH:37][C:38](=[O:42])[O:39][CH2:40][CH3:41])[CH:34]=[CH:35][CH:36]=4)=[CH:29][N:30]=3)[CH2:10]2)=[N:7][CH:8]=1
Reactant: N[C@@H]1CCCC[C@H]1N[C@H]1CCCN(c2cnc(C(F)(F)F)cn2)C1
Reactant: CCOC(=O)Nc1cccc(-c2cnc(Cl)o2)c1
Product: CCOC(=O)Nc1cccc(-c2cnc(N[C@@H]3CCCC[C@H]3N[C@H]3CCCN(c4cnc(C(F)(F)F)cn4)C3)o2)c1
Reaction time: 0.17 h
Yield: 20.7 %

Procedure:
Ethyl 3-(2-((1R,2R)-2-((S)-1-(5-(trifluoromethyl)pyrazin-2-yl)piperidin-3-ylamino)cyclohexylamino)oxazol-5-yl)phenylcarbamate (7.13 mg, 0.012 mmol, 21% yield) was synthesized as described in General Procedure H using (1R,2R)—N1-((S)-1-(5-(trifluoromethyl)pyrazin-2-yl)piperidin-3-yl)cyclohexane-1,2-diamine (19.86 mg, 0.058 mmol) and Intermediate 44, ethyl 3-(2-chlorooxazol-5-yl)phenylcarbamate (15.42 mg, 0.058 mmol). The product was purified via preparative LC/MS with the following conditions: Column. Waters XBridge C18, 19×100 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 0.1% ammonium hydroxide; Mobile Phase B: 95:5 acetonitrile:water with 0.1% ammonium hydroxide; Gradient: 35-75% B over 10 minutes, then a 7-minute hold at 75% B; Flow rate: 20 mL/min. Anal. Calcd. for C28H34F3N7O3 m/z 573.3, found: 574.3 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ ppm 9.64 (s, 1H), 8.40 (d, J=1.1 Hz, 1H), 8.36 (s, 1H), 7.96 (s, 1H), 7.69 (s, 1H), 7.27-7.18 (m, 3H), 7.15-7.10 (m, 2H), 4.41 (d, J=10.7 Hz, 1H), 4.21 (d, J=12.9 Hz, 1H), 4.13 (q, J=7.2 Hz, 2H), 3.25 (td, J=9.3, 4.0 Hz, 1H), 3.06-2.99 (m, 1H), 2.76-2.69 (m, 1H), 2.66-2.54 (m, 2H), 2.06-1.96 (m, 2H), 1.89-1.82 (m, 1H), 1.75-1.61 (m, 3H), 1.45 (d, J=13.2 Hz, 1H), 1.37-1.28 (m, 2H), 1.28-2.21 (m, 5H), 1.09 (d, J=12.4 Hz, 1H).
Reaction SMILES: [BH4-].[Na+].[C:3]([O:7][C:8]([N:10]1[C:15](=[O:16])[CH:14]2[CH2:17][CH:11]1[CH2:12][CH2:13]2)=[O:9])([CH3:6])([CH3:5])[CH3:4]>C1COCC1.O>[C:3]([O:7][C:8](=[O:9])[NH:10][C@H:11]1[CH2:12][CH2:13][C@@H:14]([CH2:15][OH:16])[CH2:17]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1C(=O)C2CCC1C2
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](CO)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.8 %

Procedure:
In a round-bottomed flask, 3-oxo-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (crude from Step 2, 1.87 g) was dissolved in THF (20 ml) and water (2 ml). The reaction mixture was cooled to 0° C. and sodium borohydride (301 mg, 7.97 mmol) was added. The reaction was stirred at 0° C. for 30 min then a second portion of sodium borohydride (301 mg, 7.97 mmol) was added. The reaction mixture was stirred at 0° C. for 7.5 h then a third portion of sodium borohydride (602 mg, 15.94 mmol) was added. The reaction mixture was stirred at room temperature overnight then a fourth portion of sodium borohydride (602 mg, 15.94 mmol) was added. The reaction mixture was stirred at room temperature overnight then cooled to 0° C. and carefully quenched with 1M HCl. When gas evolution had ceased (pH=˜6) the mixture was extracted with dichloromethane (3×). The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with EtOAc/hexanes (gradient 0-60% EtOAc) to afford 1.73 g (95%, 2 steps) of (cis-3-hydroxymethyl-cyclopentyl)-carbamic acid tert-butyl ester as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:22](Cl)=[O:23]>N1C=CC=CC=1>[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[C:22]([NH:15][C:14]1[CH:16]=[CH:17][C:11]([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]3[CH:8]=2)=[CH:12][CH:13]=1)=[O:23]
Reactant: COc1ccc(C(=O)Cl)cc1F
Reactant: Cc1ccc2nc(-c3ccc(N)cc3)cn2c1
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2ccc(-c3cn4cc(C)ccc4n3)cc2)cc1F
Yield: 71 %

Procedure:
Prepared as described in the Amide Coupling section using 4-(6-methylimidazo[1,2-a]pyridin-2-yl)aniline (0.30 g, 1.34 mmol) and 3-fluoro-4-methoxybenzoyl chloride (0.25 g, 1.34 mmol) in dry pyridine (14 ml) to give the title compound (0.357 g, 71%) as small, colourless needles after work-up, flash chromatography (DCM/MeOH 18:1) and recrystallisation from 1,4-dioxane.
Reaction SMILES: [CH2:1]=[C:2]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10])[CH3:3].[CH2:11]([O:13][N:14]=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])C.Cl[Sn](Cl)(Cl)Cl>ClCCCl>[CH3:11][O:13][N:14]1[CH:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:3][C:2]([CH3:1])=[CH:4][CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10]
Reactant: CCCCCC=NOCC
Reactant: C=C(C)C1CCCCC1=O
Agent: CCCCCC1C/C(C)=C/CCCCC(=O)N1OC
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCCl
Product: CCCCCC1CC(C)=CCCCCC(=O)N1OC

Procedure:
Following the general procedure as described in Example 17, 2-(prop-1-en-2-yl)cyclohexanone (0.88 g, 6.38 mmol), hexanal O-ethyl oxime (0.99 g, 7.65 mmol), and SnCl4 (1.66 g, 6.38 mmol) in 1,2-dichloroethane (65 ml) were reacted to give the title product as a colorless liquid (1.00 g, 59% yield). E isomer>98%.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[C:10]([Cl:12])[C:7]([C:8]#[N:9])=[C:6]([Br:13])[C:5]=1[O:14][CH2:15][CH3:16])(=O)[CH3:2].[NH3:17].[BH4-].[Na+]>C(O)C.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[NH2:17][CH:1]([C:4]1[CH:11]=[C:10]([Cl:12])[C:7]([C:8]#[N:9])=[C:6]([Br:13])[C:5]=1[O:14][CH2:15][CH3:16])[CH3:2]
Reactant: CCOc1c(C(C)=O)cc(Cl)c(C#N)c1Br
Reactant: N
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [BH4-]
Solvent: CCO
Product: CCOc1c(C(C)N)cc(Cl)c(C#N)c1Br
Temperature: 60 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
Titanium tetraisopropoxide (0.82 mL, 2.8 mmol) was added to a mixture of 4-acetyl-2-bromo-6-chloro-3-ethoxybenzonitrile (0.70 g, 2.3 mmol) and 2.0 M ammonia in ethanol (5.78 mL) at 0° C. The reaction was heated and stirred at 60° C. under nitrogen for 3 hours. The reaction was allowed to cool to room temperature, cooled in an ice bath and sodium tetrahydroborate (0.131 g, 3.47 mmol) was added, the solution was stirred at room temperature for another 2 hours. The reaction mixture was quenched with 2 M ammonia in water, and was stirred to allow a precipitate to form. The slurry was filtered and the solid was washed with EtOAc. The organic solvent was removed under vacuum and the residue was dissolved in methylene chloride. The organic layer was then washed with sat'd NaHCO3, water, brine, dried over MgSO4, filtered and concentrated to give 4-(1-aminoethyl)-2-bromo-6-chloro-3-ethoxybenzonitrile as an oil (0.7 g, 100%). The crude was used in the next step without purification. LCMS calculated for C11H13BrClN2O (M+H)+: m/z=302.9, 304.9. found: 302.9, 304.9.
Reaction SMILES: COC1C=CC(C[O:8][CH2:9][C:10]2[CH:11]=[C:12]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=4)[CH2:18][CH2:17]3)[CH:13]=[CH:14][CH:15]=2)=CC=1.C(O)(C(F)(F)F)=O>ClCCl>[N:25]1[CH:24]=[CH:23][C:22]([N:19]2[CH2:20][CH2:21][N:16]([C:12]3[CH:11]=[C:10]([CH2:9][OH:8])[CH:15]=[CH:14][CH:13]=3)[CH2:17][CH2:18]2)=[CH:27][CH:26]=1
Reactant: COc1ccc(COCc2cccc(N3CCN(c4ccncc4)CC3)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OCc1cccc(N2CCN(c3ccncc3)CC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.4 %

Procedure:
1-(3-{[(4-Methoxybenzyl)oxy]methyl}phenyl)-4-(pyridin-4-yl)piperazine (308 mg) was mixed with dichloromethane (2 ml), and TFA (1 ml) was added thereto. The reaction mixture was stirred at room temperature for 1 hour, and then the reaction mixture was concentrated under reduced pressure. To the obtained residue were added a saturated aqueous sodium hydrogen carbonate solution and CHCl3, and the organic layer was dried over MgSO4 and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography to obtain {3-[4-(pyridin-4-yl)piperazin-1-yl]phenyl}methanol (167 mg).
Reaction SMILES: [Br:1]Br.[CH3:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)=[O:5]>C(Cl)Cl.O>[Br:1][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)=[O:5]
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: BrBr
Solvent: O
Solvent: ClCCl
Product: O=C(CBr)c1ccc(Br)cc1
Yield: 86 %

Procedure:
Bromine (1.29 mL, 25.1 mmol) was added dropwise at 15-20° C. to a solution of 4-bromoacetophenone (5 g, 25.1 mmol) in DCM (40 mL) and the mixture was stirred at this temperature until the bromine colour was discharged. The mixture was diluted with water and the organic phase was separated. This was dried over sodium sulfate and concentrated to afford 2-bromo-1-(4-bromo-phenyl)-ethanone (6 g, 86%).
Reaction SMILES: [C:1]1(=[O:25])[N:5]([CH2:6][C:7]2[CH:19]=[CH:18][C:10]([C:11]([O:13]C(C)(C)C)=[O:12])=[CH:9][CH:8]=2)[C:4](=[O:20])[C:3]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:2]12>FC(F)(F)C(O)=O>[C:4]1(=[O:20])[N:5]([CH2:6][C:7]2[CH:19]=[CH:18][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)[C:1](=[O:25])[C:2]2=[CH:24][CH:23]=[CH:22][CH:21]=[C:3]12
Reactant: CC(C)(C)OC(=O)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1

Procedure:
337 mg (1.0 mmol) of tert.butyl 4-phthalimidomethyl-benzoate are stirred in 3 ml of trifluoroacetic acid for 45 minutes at ambient temperature. Then the solvent is eliminated in vacuo.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[N:28]=[C:29]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[O:30][C:31]=3[CH3:32])=[CH:21][CH:20]=2)=[C:8]([CH2:10][CH2:11][C:12]([O:14]CC)=[O:13])[CH:9]=1)[CH3:2].O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[N:28]=[C:29]([C:33]4[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=4)[O:30][C:31]=3[CH3:32])=[CH:21][CH:20]=2)=[C:8]([CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:9]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cc(OCC)ccc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CCOc1ccc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)c(CCC(=O)O)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
To a mixture of ethyl 3-[5-ethoxy-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionate (1.56 g), tetrahydrofuran (5 mL) and ethanol (5 mL) was added a 1N aqueous sodium hydroxide solution (6.0 mL), and the mixture was stirred at 50° C. for 1 hr. 1N Hydrochloric acid and water were added to acidify the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give crystals (1.14 g, 78%) of 3-[5-ethoxy-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionic acid. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 115-116° C.