Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([S:24]([CH3:27])(=[O:26])=[O:25])[CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:28][C:29]1[CH:30]=[C:31]2[C:35](=[N:36][CH:37]=1)[NH:34][CH:33]=[CH:32]2.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[NH:34]1[C:35]2[C:31](=[CH:30][C:29]([O:28][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]5[CH2:23][CH2:22][N:21]([S:24]([CH3:27])(=[O:26])=[O:25])[CH2:20][CH2:19]5)=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)=[CH:37][N:36]=2)[CH:32]=[CH:33]1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(S(C)(=O)=O)CC1
Reactant: Oc1cnc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cnc4[nH]ccc4c3)ncnc2cc1OCCCN1CCN(S(C)(=O)=O)CC1
Temperature: 85 °C
Reaction time: 3 h
Yield: 40.8 %

Procedure:
A suspension of 4-chloro-6-methoxy-7-(3-(4-methylsulphonylpiperazin-1-yl)propoxy)quinazoline (0.25 g, 0.66 mmol), 5-hydroxy-7-azaindole (0.089 g, 0.663 mmol), (prepared as described for the starting material in Example 2), and potassium carbonate (0.091 g, 0.66 mmol) in DMF (3 ml) was stirred at 85° C. for 3 hours. The mixture was filtered and the filtrate was purified by preparative LCtMS eluting with acetonitrile/water (containing 1% acetic acid). The fractions containing the expected product were combined and evaporated. The residue was dissolved in methylene chloride and washed with 0.5N aqueous ammonia followed by brine, dried (MgSO4) and evaporated. The residue was triturated under diethyl ether, filtered and dried under vacuum to give 4-(7-azaindol-5-yloxy)-6-methoxy-7-(3-(4-methylsulphonylpiperazin-1-yl)propoxy)quinazoline (0.138 g, 45%).
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]2[CH2:21][CH2:20][O:19][CH:18]([C:22]3[N:23]=[C:24]([NH:27]C(C)=O)[S:25][CH:26]=3)[CH2:17]2)[CH3:15])=[CH:9][CH:8]=1)([O:3]C)=[O:2].[ClH:31].C>>[Cl-:31].[Cl-:31].[C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([N:16]2[CH2:21][CH2:20][O:19][CH:18]([C:22]3[N:23]=[C:24]([NH2:27])[S:25][CH:26]=3)[CH2:17]2)[CH3:15])=[CH:9][CH:8]=1)([OH:3])=[O:2]
Reactant: Cl
Reactant: COC(=O)COc1ccc(CC(C)N2CCOC(c3csc(NC(C)=O)n3)C2)cc1
Product: CC(Cc1ccc(OCC(=O)O)cc1)N1CCOC(c2csc(N)n2)C1
Product: [Cl-]

Procedure:
1.6 g (0.0037 mol) of N-[2-(4-carbomethoxymethoxyphenyl)1-methylethyl]-2-(2-acetamino-thiazol-4-yl)morpholine in 100 ml of 18% strength hydrochloric acid are heated to reflux under nitrogen for 48 hours. 1.5 g of active charcoal are added to the reaction solution which is thoroughly stirred and filtered. The solution is then concentrated, and the product is dried in vacuo over potassium hydroxide.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[CH2:16][CH:17]1[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][C:26]#[N:27])[CH2:19][CH2:18]1.N.[H][H]>[Ni].CO>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[CH2:16][CH:17]1[CH2:18][CH2:19][N:20]([CH2:23][CH2:24][CH2:25][CH2:26][NH2:27])[CH2:21][CH2:22]1
Reactant: [H][H]
Reactant: N#CCCCN1CCC(Cc2nc3ccccc3n2Cc2ccco2)CC1
Agent: [Ni]
Agent: N
Solvent: CO
Product: NCCCCN1CCC(Cc2nc3ccccc3n2Cc2ccco2)CC1
Yield: 99 %

Procedure:
A mixture of 7.4 parts of 4-[[1-(2-furanylmethyl)-1H-benzimidazol-2-yl]methyl]-1-piperidinebutanenitrile and 240 parts of methanol saturated with ammonia was hydrogenated at normal pressure and at room temperature with 3 parts of Raney-nickel catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 7.33 parts (99%) of 4-[[1-(2-furanylmethyl)-1H-benzimidazol-2-yl]methyl]-1-piperidinebutanamine (302).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[C:17]1[N:18]([C:49]2[N:50]=[CH:51][N:52]=[C:53]([NH2:56])[C:54]=2[N:55]=1)[C@@H:19]1[O:48][C@H:38]([CH2:39][O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[C@@H:29]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[C@H:20]1[O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.CCOC(C)=O>[Si:22]([O:21][C@@H:20]1[C@H:29]([O:30][Si:31]([C:34]([CH3:35])([CH3:36])[CH3:37])([CH3:33])[CH3:32])[C@@H:38]([CH2:39][O:40][Si:41]([C:44]([CH3:45])([CH3:46])[CH3:47])([CH3:42])[CH3:43])[O:48][C@H:19]1[N:18]1[C:49]2[N:50]=[CH:51][N:52]=[C:53]([NH2:56])[C:54]=2[N:55]=[C:17]1[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)([C:25]([CH3:27])([CH3:28])[CH3:26])([CH3:23])[CH3:24]
Reactant: OB(O)c1cccnc1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2c(Br)nc3c(N)ncnc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)[Si](C)(C)OC[C@H]1O[C@@H](n2c(-c3cccnc3)nc3c(N)ncnc32)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]1O[Si](C)(C)C(C)(C)C

Procedure:
Pyridine-3-boronic acid (0.59 g, 0.48 mmol) and Cs2CO3 (3.11 g, 9.57 mmol) were added to a solution of 2′,3′,5′-tris-O-(tert-butyldimethylsilyl)-8-bromoadenosine (13) (2.20 g, 3.19 mmol) and Pd(PPh3)4 (0.37 g, 0.32 mmol) in dioxane (50 ml) under argon. Water (10 ml) was added to dissolve all Cs2CO3. The solution was heated under reflux overnight. EtOAc (200 ml) was added to the cold reaction mixture, the resultant solution shaken with water (100 ml), the organic solution dried (MgSO4), evaporated and the residual material subjected to flash chromatography on silica gel using EtOAc:MeOH 99:1; yield 1.76 g (80%). HRESI: M+H 687.3900. Calc. for C33H58N6O4Si3+H, 687.3900. 1H NMR: (300 MHz, CDCl3); δ −0.41/−0.12/0.01/0.02/0.09/0.11 (18H, s, 3×Si(CH3)2), 0.67/0.85/0.86 (27H, s, 3×SiC(CH3)3), 3.71-4.12 (3H, m, H-5′, H-3′ or H-4′), 4.53-4.55 (1H, m, H-4′ or H-3′), 5.61-5.65 (1H, m, H-2′), 5.81 (1H, d, J 6.3 Hz, H-1′), 6.02 (2H, s, NH2), 7.38-7.42 (1H, m, H-5′), 8.09-8.12 (1H, m, H-4″), 8.30 (1H, s, H-2), 8.73-8.75 (1H, m, H-6″), 9.04-9.05 (1H, m, H-2″). 13C NMR: (75 MHz, CDCl3); δ −5.5/−5.4/−5.3/−4.7/−4.6/−4.5 (3×Si(CH3)2), 17.2/18.0/18.3 (3×SiC), 25.6/25.8/25.8 (3×SiC(CH3)3), 62.5 (C-5′), 71.7/72.4 (C-2′, C-3′), 85.5/88.9 (C-4′, C-1′), 120.1/123.1/125.7/136.9/149.9/150.4/151.0/151.1/152.6/155.6 (C-5, C-5″, C-3″, C-4″, C-6, C-8, C-6″, C-2″, C-2, C-4).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][CH3:8])[N:5]=[CH:4][CH:3]=1.[C:9]1([CH2:15][CH2:16][CH:17]([C:23]([CH3:25])=O)[C:18](OCC)=[O:19])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O>[CH2:7]([N:6]1[C:2]2[N:1]=[C:23]([CH3:25])[C:17]([CH2:16][CH2:15][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)=[C:18]([OH:19])[C:3]=2[CH:4]=[N:5]1)[CH3:8]
Reactant: CCOC(=O)C(CCc1ccccc1)C(C)=O
Reactant: CCn1nccc1N
Solvent: O
Product: CCn1ncc2c(O)c(CCc3ccccc3)c(C)nc21
Temperature: 25 °C

Procedure:
33 g. of 5-amino-1-ethylpyrazole (0.3 mol.) in 310 g. of polyphosphoric acid are heated to 80° (bath temperature). While stirring, 70.5 g. of 2-(2-phenylethyl)acetoacetic acid, ethyl ester (0.3 mol.) are added to the mixture. The bath temperature is increased to 100°, the temperature of the solution rising to about 130°. As soon as the reaction temperature begins to drop the bath temperature is elevated to 140° and maintained for 45 minutes. After the mixture has cooled to room temperature, 650 ml. of water are added in portions and stirring is continued until the polyphosphoric acid is dissolved. Then the aqueous phosphoric acid solution is decanted and the undissolved residue is treated with 400 ml. of 5% aqueous ammonia to neutralize the mixture. The mixture is extracted with chloroform and the chloroform extract is washed with water and dried with Na2SO4. Addition of ether precipitates 37 g. (44%) of 1-ethyl-6-methyl-5-(2-phenylethyl)-1H-pyrazolo[3,4-b]pyridin-4-ol; m.p. 251°-256°. Recrystallization from ethanol raises the m.p. to 258°-260°.
Reaction SMILES: [F:1][C:2]1([F:20])[CH2:5][N:4]([C:6]2[CH:7]=[CH:8][C:9]([C:16]([O:18]C)=[O:17])=[N:10][C:11]=2[O:12][CH2:13][CH2:14][F:15])[CH2:3]1.O.[OH-].[Li+]>O1CCCC1.O>[F:20][C:2]1([F:1])[CH2:5][N:4]([C:6]2[CH:7]=[CH:8][C:9]([C:16]([OH:18])=[O:17])=[N:10][C:11]=2[O:12][CH2:13][CH2:14][F:15])[CH2:3]1
Reactant: COC(=O)c1ccc(N2CC(F)(F)C2)c(OCCF)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCCF)n1

Procedure:
A solution of methyl 5-(3,3-difluoroazetidin-1-yl)-6-(2-fluoroethoxyl)pyridine-2-carboxylate (Example 147 b, 73 mg, 252 μmol) and lithium hydroxide hydrate (12.7 mg, 302 μmol) in tetrahydrofuran (500 μL) and water (50.0 μL) was stirred for 12 h at ambient temperature. The reaction mixture was poured onto ice/0.1 N HCl (25 mL) and extracted with EtOAc (2×25 mL). The combined extracts were washed with ice/brine (25 mL), dried over Na2SO4, filtered and evaporated to dryness to give the target compound (69 mg, quant.) as off-white solid, MS (ESI) m/e=277.1 [MH+].
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.CCN(C(C)C)C(C)C>>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[O:13])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:27])([F:28])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: C1CCNC1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)N3CCCC3)ccc21
Yield: 30.8 %

Procedure:
[1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazol-5-yl]-pyrrolidin-1-yl-methanone (34 mg) was prepared by following General Procedure N starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (100 mg), pyrrolidine (17 mg), DPPA (53 uL), and DIEA (43 uL). LC/MS: m/z 462.9. 1H NMR (DMSO-d6, 400 MHz): δ 12.28 (bs, 1H), 7.90 (s, 1H), 7.80-7.56 (m, 2H), 7.42 (s, 2H), 7.33 (d, 1H), 3.63 (s, 3H), 3.55-3.33 (m, 4H), 1.95-1.74 (m, 4H).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[H-].[Na+].[CH3:26][C:27]1[C:28]([C:34]([CH:36]2[CH2:38][CH2:37]2)=O)=[N:29][CH:30]=[CH:31][C:32]=1[Cl:33]>C1COCC1>[CH:36]1([C:34]([C:28]2[C:27]([CH3:26])=[C:32]([Cl:33])[CH:31]=[CH:30][N:29]=2)=[CH:2][O:3][CH3:4])[CH2:38][CH2:37]1
Reactant: Cc1c(Cl)ccnc1C(=O)C1CC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC=C(c1nccc(Cl)c1C)C1CC1
Temperature: 40 °C
Yield: 82.1 %

Procedure:
A solution of methoxymethyl triphenylphosphonium chloride (17.9 g, 52.3 mmol) in dry THF (80 mL) was treated with NaH (2.79 g, 69.8 mmol) at 0° C. for 3 h. To this mixture was added a solution of (3-methyl-4-chloro-pyridin-2-yl)-cyclopropyl-methanone (6.82 g, 34.9 mmol) in dry THF (20 mL). The reaction mixture was heated at 40° C. overnight. The reaction mixture was cooled down to room temperature and filtered. The filtrate was concentrated to dryness. The residue was purified by flash silica column chromatography (hexane:ethyl acetate, 3:1) to afford the title compound (6.41 g, 82%).
Reaction SMILES: [Br:1][CH:2]1[C:7]2=[N:8][CH:9]=[C:10](C(O)=O)[C:11](=[O:12])[N:6]2[CH:5]([CH3:16])[CH2:4][CH2:3]1>N1C=CC=CC=1>[Br-:1].[CH3:16][CH:5]1[N:6]2[C:11](=[O:12])[CH:10]=[CH:9][N:8]=[C:7]2[CH:2]([N+:6]2[CH:7]=[CH:2][CH:3]=[CH:4][CH:5]=2)[CH2:3][CH2:4]1
Reactant: CC1CCC(Br)c2ncc(C(=O)O)c(=O)n21
Solvent: c1ccncc1
Product: CC1CCC([n+]2ccccc2)c2nccc(=O)n21
Product: [Br-]
Reaction time: 72 h
Yield: 66.9 %

Procedure:
1.0 g. (3.48 mmoles) of 9-bromo-6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid is dissolved in 4 ml. of pyridine and the solution is allowed to stand for 3 days at room temperature. The precipitated crystals are filtered and washed with chloroform. 0.75 g. (66.9%) of 1-(6-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-9-yl)-pyridinium bromide is obtained. Melting point: 250°-252° C. After recrystallization twice from methanol the melting point is increased to 270°-272° C.
Reaction SMILES: [CH3:1][CH:2]([CH2:13][CH3:14])[CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4](O)=[O:5].CN(C)C=O.C(Cl)(=O)C([Cl:23])=O>C(Cl)Cl>[CH3:1][CH:2]([CH2:13][CH3:14])[CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([Cl:23])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCC(C)C(C(=O)O)c1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCC(C)C(C(=O)Cl)c1ccccc1
Reaction time: 0.75 h

Procedure:
To a stirred solution of 3-methyl-2-phenylvaleric acid (1.23 g; 6.2 mmol) and a catalytic amount of dry dimethylformamide (ca. 20 μL) in 5 mL of dry methylene chloride under nitrogen at room temperature was added oxalyl chloride (4.8 mL of 2.0 M solution in methylene chloride) dropwise. After 45 minutes, the mixture was concentrated in vacuo and used immediately for Step 2.
Reaction SMILES: CC[C@@H]1[C@@H]2C[C@H]([C@@H](OC3C4C(=CC=CC=4)C(O[C@@H](C4C=CN=C5C=4C=C(OC)C=C5)[C@@H]4N5C[C@H](CC)[C@@H](CC5)C4)=NN=3)C3C=CN=C4C=3C=C([O:22]C)C=C4)N(CC2)C1.[OH2:59].[Cl:60][C:61]1[C:70]2[C:65](=[CH:66][CH:67]=[CH:68][CH:69]=2)[CH:64]=[C:63]([CH3:71])[C:62]=1[CH:72]=[CH2:73]>C(O)(C)(C)C.C(OCC)(=O)C>[Cl:60][C:61]1[C:70]2[C:65](=[CH:66][CH:67]=[CH:68][CH:69]=2)[CH:64]=[C:63]([CH3:71])[C:62]=1[C@@H:72]([OH:22])[CH2:73][OH:59]
Reactant: C=Cc1c(C)cc2ccccc2c1Cl
Reactant: CC[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](Oc1nnc(O[C@@H](c2ccnc3ccc(OC)cc23)[C@H]2C[C@@H]3CCN2C[C@@H]3CC)c2ccccc12)c1ccnc2ccc(OC)cc12
Reactant: O
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Product: Cc1cc2ccccc2c(Cl)c1[C@@H](O)CO
Temperature: 0 °C
Reaction time: 168 h

Procedure:
A biphasic mixture of AD-mix-β (45.7 g, excess) in tert-butanol (147 mL)/H2O (147 mL) was cooled to 0° C. and 1-chloro-3-methyl-2-vinyl-naphthalene (4.46 g, 22.0 mmol) was added. The reaction mixture was stirred for 7 days at 0° C. The mixture was diluted with ethyl acetate, washed with water and brine, dried over Na2SO4, filtered and concentrated and purified by flash column chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) to give (R)-1-(1-chloro-3-methylnaphthalen-2-yl)ethane-1,2-diol. 1H-NMR: 400 MHz, (CDCl3) δ 8.27 (d, J=8.4 Hz, 1H), 7.73 (d, J=7.6 Hz, 1H), 7.57-7.50 (m, 3H), 5.70 (dd, J=10.0, 4.0 Hz, 1H), 4.11 (t, J=10.4 Hz, 1H), 3.79 (dd, J=11.6, 4.0 Hz, 1H), 2.66 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@H:20]([NH2:24])[CH2:19]4)[C:14]([F:25])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:26][N:27]([CH2:35][CH:36]=O)[C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31].C(N(C(C)C)CC)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.CCO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:23][CH2:22][CH2:21][C@@H:20]([NH:24][CH2:36][CH2:35][N:27]([CH3:26])[C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])[CH2:19]4)[C:14]([F:25])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: N[C@@H]1CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Reactant: CN(CC=O)C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCN[C@@H]1CCC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1)C(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 12 h

Procedure:
In a flask containing (1S,3R)—N1-(2-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-yl)cyclohexane-1,3-diamine, 47a, (0.14 g, 0.39 mmol) in THF/EtOH was added tert-butyl N-methyl-N-(2-oxoethyl)carbamate (0.10 g, 0.58 mmol) and diisopropylethylamine (0.13 mL, 0.77 mmol). The solution was heated at 70° C. for 30 min. Sodium triacetoxyborohydride (0.08 g, 0.39 mmol) was added. The solution was stirred at room temperature for 12 hrs. The solution was filtered and the solvent evaporated under reduced pressure. The resulting residue was purified by HPLC using 5-70% MeOH/H2O with 6 mM HCl to provide the desired product.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:37])[CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32]/[CH:33]=[CH:34]\[CH2:35][CH3:36])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[C:38]([O:45][CH3:46])(=[O:44])/[CH:39]=[CH:40]/[C:41]([O-])=[O:42].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(#N)C>[C:15]([NH:14][CH2:13][CH2:12][CH2:11][CH2:10][C@H:2]([NH:1][C:41](=[O:42])/[CH:40]=[CH:39]/[C:38]([O:45][CH3:46])=[O:44])[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])(=[O:37])[CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20]/[CH:21]=[CH:22]\[CH2:23]/[CH:24]=[CH:25]\[CH2:26]/[CH:27]=[CH:28]\[CH2:29]/[CH:30]=[CH:31]\[CH2:32]/[CH:33]=[CH:34]\[CH2:35][CH3:36]
Reactant: COC(=O)/C=C/C(=O)[O-]
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCCCC[C@H](N)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCCCC[C@H](NC(=O)/C=C/C(=O)OC)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 30 %

Procedure:
The crude (S)-tert-butyl 2-amino-6-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)hexanoate, prepared above, was taken up in 40 mL acetonitrile along with monomethyl fumarate (610 mg, 4.69 mmol), DIEA (3.0 mL, 18.8 mmol) and HATU (2.4 g, 6.39 mmol). The resulting reaction mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure. The resulting residue was taken up in 100 mL of EtOAc and washed with water and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. Purification by silica gel chromatography (EtOAc/pentane) afforded (S)-tert-butyl 6-((4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamido)-2-((E)-4-methoxy-4-oxobut-2-enamido)hexanoate (500 mg, 30%).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:16]=[CH:15][C:8]([O:9][CH:10]([CH3:14])[C:11](Cl)=[O:12])=[CH:7][CH:6]=1.C([O-])(=O)CC([O-])=O.C(C(CC)(O[Mg+2])C)C.[C:37]([O:45][CH2:46][CH3:47])(=[O:44])[CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40]>CCOCC>[CH2:42]([O:41][C:39](=[O:40])[CH:38]([C:11](=[O:12])[CH:10]([O:9][C:8]1[CH:15]=[CH:16][C:5]([O:4][C:3]2[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:2]=2[Cl:1])=[CH:6][CH:7]=1)[CH3:14])[C:37]([O:45][CH2:46][CH3:47])=[O:44])[CH3:43]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(Oc1ccc(Oc2ccc(Cl)cc2Cl)cc1)C(=O)Cl
Agent: CCC(C)(CC)O[Mg+2]
Agent: O=C([O-])CC(=O)[O-]
Solvent: CCOCC
Product: CCOC(=O)C(C(=O)OCC)C(=O)C(C)Oc1ccc(Oc2ccc(Cl)cc2Cl)cc1
Temperature: 25 °C
Yield: 73.6 %

Procedure:
A 50% etheral solution of 35 g of 2-[4'-(2",4"-dichloro-phenoxy)-phenoxy]-propionyl-chloride is added under stirring dropwise to a mixture of diethyl-ethoxy-magnesium-malonate prepared from 17.6 g of diethyl malonate and 50 ml of ether. The addition of the acid chloride having been completed the reaction mixture is heated to boiling for an hour, cooled to room temperature and washed successively with 100 ml of 5% sulfuric acid, 100 ml of a 6% sodium bicarbonate solution and 100 ml of water. The etheral phase is evaporated, the excess of the malonic acid ester is distilled off, the residue is admixed with 100 ml of benzene, subjected to chromatography on a silica column and eluted with 50 ml of benzene. The united eluates are evaporated. Thus 35 g of the desired compound are obtained in the form of a slowly solidifying product. Mp.: 46°-50° C. Yield 75%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:10]1[CH2:12][CH2:11]1)[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH:10]1[CH2:11][CH2:12]1)[NH:9][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N(N)C1CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(Nc1ccccc1)C1CC1
Temperature: 50 °C
Yield: 45.3 %

Procedure:
A mixture of N-cyclopropyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 28; 0.111 g, 0.64 mmol), phenylboronic acid (Aldrich; 156 mg, 1.3 mmol), copper(II) acetate (116 mg, 0.64 mmol) and triethylamine (180 μL, 1.3 mmol) in 1,2-dichloroethane (3 mL) was heated in an oil bath at 50° C. for 16 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 40 g column, eluting with 5-40% ethyl acetate/hexanes, to give N-cyclopropyl-N′-phenyl-hydrazinecarboxylic acid tert-butyl ester (72 mg, 45%) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[CH3:19][O:20][C:21](=[O:27])[C@@H:22]1[CH2:26][CH2:25][CH2:24][NH:23]1>CO.C(Cl)Cl>[CH3:19][O:20][C:21](=[O:27])[C@@H:22]1[CH2:26][CH2:25][CH2:24][N:23]1[C:15](=[O:17])[C@H:13]([CH3:14])[NH:12][C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1

Procedure:
Following General Procedure A and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and L-proline methyl ester hydrochloride (Bachem), the title compound was prepared as a viscous solid. The reaction was monitored by tlc(Rf=0.57 in 10% MeOH/DCM) and the product was purified by acid/base washes.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH:12]=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[OH-].[K+].O1CCO[CH2:18][CH2:17]1>>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]3[C:2]=2[N:1]=[CH:18][CH:17]=[CH:12]3)[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1c(C=O)ccc2cccnc12
Reactant: C1COCCO1
Agent: [K+]
Agent: [OH-]
Product: c1cnc2c(c1)ccc1cccnc12

Procedure:
4.0 g of propellane, 3.3 g of aluminium chloride and 2.0 ml of acetyl chloride were added to 200 ml of 1,2-dichloroethane, and reaction carried out for 1.5 hours at room temperature and then for 6 hours at 60° C. By treatment in the normal way, 3.26 g of the triacetyl-propellane was obtained. 1.41 g of this triacetyl derivative was reacted with 1.50 g of 8-amino-7-quinolinecarbaldehyde and 1.5 g of potassium hydroxide in dioxane at 60° C. and, by treatment in the normal way, Phen-5 (1.32 g) shown below was obtained.