Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:10][C:11]([OH:13])=[O:12])[O:2][CH:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.Cl.[CH3:15]O>>[C:1]1([CH2:10][C:11]([O:13][CH3:15])=[O:12])[O:2][CH:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CO
Reactant: O=C(O)Cc1occ2ccccc12
Agent: Cl
Product: COC(=O)Cc1occ2ccccc12

Procedure:
Compound 7 (72 g) was dissolved in methanol (200 ml) and the solution saturated with dry HCl. The solution was refluxed for 2 hours and the solvent evaporated. The residue was dissolved in methylene chloride (200 ml) and the solution washed with 5% sodium bicarbonate, and then with water (100 ml). The residue was dried over magnesium sulfate and the solvent was evaporated. The product was distilled in vacuo. The yield was approximately 67.3 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH:9][C:10](=[O:29])[C@@H:11]([NH:19][C:20]2([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH2:22][CH2:21]2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][C:6](C2C=CN=CC=2)=[CH:5][N:4]=1.COC1C(N)=CC([C:45]2[N:49]([CH:50]3[CH2:55][CH2:54][CH2:53][CH2:52][O:51]3)[N:48]=[CH:47][CH:46]=2)=CN=1>>[CH3:1][O:2][C:3]1[C:8]([NH:9][C:10](=[O:29])[C@@H:11]([NH:19][C:20]2([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH2:22][CH2:21]2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][C:6]([C:45]2[N:49]([CH:50]3[CH2:55][CH2:54][CH2:53][CH2:52][O:51]3)[N:48]=[CH:47][CH:46]=2)=[CH:5][N:4]=1
Reactant: COc1ncc(-c2ccncc2)cc1NC(=O)[C@H](Cc1ccccc1)NC1(c2ccccn2)CC1
Reactant: COc1ncc(-c2ccnn2C2CCCCO2)cc1N
Product: COc1ncc(-c2ccnn2C2CCCCO2)cc1NC(=O)[C@H](Cc1ccccc1)NC1(c2ccccn2)CC1

Procedure:
This example was made using the same general procedure as the synthesis of 11.1 starting with 2-methoxy-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-3-amine 14.1.C instead of 2-Methoxy-5-(pyridine-4-yl)pyridine-3-amine 11.1.B to give (2S)—N-(2-methoxy-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)pyridin-3-yl)-3-phenyl-2-(1-(pyridin-2-yl)cyclopropylamino)propanamide 14.1.D.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[CH:20][CH:19]=1>CO>[CH:1]1([NH:7][C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:17][C:18]3[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=[CH:20][CH:19]=3)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1ccnc2ccccc12
Reactant: O=C(O)c1cc(NC2CCCCC2)ncn1
Solvent: CO
Product: O=C(Nc1ccnc2ccccc12)c1cc(NC2CCCCC2)ncn1

Procedure:
Following the general method as outlined in Example 1, starting from 6-(cyclohexylamino)pyrimidine-4-carboxylic acid (Intermediate 4) and 4-aminoquinoline (Tyger), the title compound was obtained as a red solid after trituration in methanol.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[OH-].[Na+].[CH2:14]1[CH2:18][O:17][CH2:16][CH2:15]1.C(Cl)(=O)CCC>C(OCC)(=O)C>[C:16]([NH:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5])(=[O:17])[CH2:15][CH2:14][CH3:18]
Reactant: NC(=O)c1cc(Cl)ccc1N
Reactant: C1CCOC1
Agent: CCCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1ccc(Cl)cc1C(N)=O
Temperature: 0 °C
Reaction time: 96 h

Procedure:
2-Amino-5-chlorobenzamide (1.10 g, 6.5 mmol, 1 eq.), 1.000 N NaOH (6.50 mL, 6.5 mmol, 1 eq.) and THF (20 mL) were mixed and stirred at 0° C. To this mixture was added butyryl chloride dropwise (0.68 mL, 6.50 mmol, 1 eq.). More acid chloride and base were added to drive reaction to completion. The reaction was allowed to warm to rt. After 4 days the reaction was worked up by adding ethyl acetate, washing with 1 N HCl (3×), saturated sodium bicarbonate (1×), and brine (1×). The organic layer was dried and stripped to yield 1.44 g of a white powder as product. LCMS detects (M+H)+=241.0.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[O:8][N:9]=[C:10]([OH:11])[C:5]2=[CH:4][CH:3]=1.[N:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[C:13]=[O:14]>C1COCC1>[CH2:15]([NH:12][C:13]([N:9]1[C:10](=[O:11])[C:5]2[C:6](=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[O:8]1)=[O:14])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCN=C=O
Reactant: Cc1ccc2c(O)noc2n1
Solvent: C1CCOC1
Product: CCCCCCNC(=O)n1oc2nc(C)ccc2c1=O

Procedure:
In analogy to example 1c, 50 mg (0.33 mmol) of 6-methylisoxazolo[5,4-b]pyridin-3-ol were reacted with 50.8 mg (0.4 mmol) of 1-isocyanatohexane in THF. Yield: 30 mg (32%), M+H+: 278.1.
Reaction SMILES: [F:1][C:2]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]2[C:3]=1[S:4][CH:5]([C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][N:35]3[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]3)=[CH:28][CH:27]=1)[C:6]1[C:15]2=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][C:10]([O:21]S(C)(=O)=O)=[CH:11]2.[OH-].[K+].[Cl-:43].[NH4+].Cl.CCOCC>CO.C(Cl)Cl>[ClH:43].[F:1][C:2]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]2[C:3]=1[S:4][CH:5]([C:26]1[CH:27]=[CH:28][C:29]([O:32][CH2:33][CH2:34][N:35]3[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]3)=[CH:30][CH:31]=1)[C:6]1[C:15]2=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][C:10]([OH:21])=[CH:11]2
Reactant: [Cl-]
Reactant: CS(=O)(=O)Oc1ccc2c3c(ccc2c1)-c1cc(F)cc(F)c1SC3c1ccc(OCCN2CCCCC2)cc1
Agent: Cl
Agent: [K+]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CO
Solvent: ClCCl
Product: Oc1ccc2c3c(ccc2c1)-c1cc(F)cc(F)c1SC3c1ccc(OCCN2CCCCC2)cc1
Yield: 99 %

Procedure:
Dissolve methanesulfonic acid 7,9-difluoro-5-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-5H-6-thia-chrysen-2-yl ester (5.2 g, 9.0 mmol) in methanol (150 mL). Add potassium hydroxide (5.0 g, 90 mmol) and stir at room temperature. After 4 hours pour into saturated aqueous ammonium chloride and extract with methylene chloride. Dry over sodium sulfate, filter and concentrate. Dissolve residue in methylene chloride (90 mL) and add 2M HCl in ether (9 mL, 18 mmol). Concentrate in vacuo to yield 4.8 g (99%) of the title compound. LCMS Rt (0.01% heptafluorobutyric acid:1.0% isopropylalcohol:water is mobile phase A and 0.01% heptafluorobutyric acid:1.0% isopropylalcohol:acetonitrile is mobile phase B; gradient method 15 to 95% B, Purity@254 nm)=3.21 min (100%); mass spectrum (ion spray): m/z=504.3 (M+H). Chiral HPLC: 87%.
Reaction SMILES: [C@@H:1]1([N:10]2[CH:17]=[CH:16][C:14](=[O:15])[NH:13][C:11]2=[O:12])[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3].[I:18]I.CO>C(Cl)(Cl)Cl.[N+]([O-])(O)=O>[I:18][C:16]1[C:14](=[O:15])[NH:13][C:11](=[O:12])[N:10]([CH:17]=1)[C@@H:1]1[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4]([OH:5])[C@H:2]1[OH:3]
Reactant: O=c1ccn([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: II
Solvent: ClC(Cl)Cl
Solvent: O=[N+]([O-])O
Solvent: CO
Product: O=c1[nH]c(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)cc1I
Temperature: 80 °C

Procedure:
In a round bottom flask, uridine (1 g, 4.1 mmol) and iodine powder (1.15 g, 4.5 mmol) were dissolved in a mixture of CHCl3 (55 ml) and 1M HNO3 (10 ml). The reaction was heated at reflux (80° C.) for 5 h. Reaction progress was monitored by TLC (30% methanol in chloroform, Rf: 0.60; RfSM: 0.45). Upon cooling of the reaction mixture to 4° C., crystals of the title compound formed as colourless needles. The precipitate was collected by filtration and dried under vacuum overnight to provide 1.39 g (92%) of 5-iodouridine 1; δH (DMSO-d6, 300 MHz) 3.49-3.71 (2H, m, H-5′), 3.84-3.88 (1H, m, H-4′), 3.98 (1H, t, J=5.0 Hz, H-3′), 4.02 (1H, t, J=5.0 Hz, H-2′), 5.08 (1H, d, J=5.3 Hz, OH-3′), 5.27 (1H, t, J=4.7 Hz, OH-5′), 5.43 (1H, d, J=5.4 Hz, OH-2′), 5.71 (1H, d, J=4.6 Hz, H-1′), 8.48 (1H, s, H-6) 11.69 (1H, s, NH); δC (DMSO-d6, 300 MHz) 61.2 (C-5′), 70.3 (C-3′), 70.9 (C-5), 75.0 (C-2′), 85.7 (C-4′), 89.5 (C-1′), 146.0 (C-6), 152.5 (C-2), 162.9 (C-4). m/z (ESI) 388.0000 [M+NH4]+, C9H15IN3O6 requires 388.0000.
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH3:10])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[CH2:11]([O:13][C:14]1[O:15][C:16](=[O:28])[C:17]2[CH:27]=[C:26]3[C:21]([CH:22]=[CH:23][CH:24]=[CH:25]3)=[CH:20][C:18]=2[N:19]=1)[CH3:12]>C1C=CC=CC=1>[C:5](/[C:4](=[C:16](\[C:17]1[C:18]([NH:19][C:14]([O:13][CH2:11][CH3:12])=[O:15])=[CH:20][C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=1)/[OH:28])/[C:3]([O:9][CH3:10])=[O:8])(=[O:6])[CH3:7]
Reactant: COC(=O)CC(C)=O
Reactant: CCOc1nc2cc3ccccc3cc2c(=O)o1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CCOC(=O)Nc1cc2ccccc2cc1/C(O)=C(\C(C)=O)C(=O)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a dispersion of sodium hydride (95%) (1.00 g, 41.7 mmol, 2.1 equiv) in anhydrous benzene (250 ml) under nitrogen was added dropwise methyl acetoacetate (6.5 ml, 7.00 g, 60.3 mmol, 3.1 equiv) and the mixture was stirred at room temp for 1 hour. 2-ethoxy-4H-naphtho[2,3-d][1,3]oxazin-4-one (1-2) (4.72 g, 19.5 mmol, 1.0 equiv) was added and the reaction continued stirring at room temperature for 20 hours. The reaction was quenched with water and the organic layer was separated, and extracted three times with water. The emulsion and combined aqueous layers were made acidic with conc. HCl and stirred for 20 hours. The solid precipitate was filtered and dried to yield methyl (2Z)-2-acetyl-3-{3-[(ethoxycarbonyl)amino]-2-naphthyl}-3-hydroxyprop-2-enoate (1-3) as a yellow solid. LRMS m/z (M+H) 358.3 found, 358.1 required.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]1[C:13]([CH3:15])([CH3:14])[S:12][CH2:11][CH2:10][N:9]1[S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25]C(=O)C)=[CH:21][CH:20]=1)(=[O:18])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O.CCCCCC>CO.O>[C:1]([O:5][C:6]([C@H:8]1[C:13]([CH3:15])([CH3:14])[S:12][CH2:11][CH2:10][N:9]1[S:16]([C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)(=[O:18])=[O:17])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=O)Oc1ccc(S(=O)(=O)N2CCSC(C)(C)[C@@H]2C(=O)OC(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)[C@@H]1N(S(=O)(=O)c2ccc(O)cc2)CCSC1(C)C
Temperature: 28 °C
Reaction time: 3.5 h
Yield: 97.4 %

Procedure:
A suspension of 4-(4-Acetoxy-benzenesulfonyl)-2,2-dimethyl-thiomorpholine-3(S)-carboxylic acid tert-butyl ester (1 kg, 2.33 mol) and potassium carbonate (354 g, 2.56 mol) in methanol (5 L) and water (500 mL) was stirred at ambient temperature (internal temp=28° C.) for 3.5 hours. The reaction was determined to be complete by TLC (1:1 EtOAc/hexane). The solvent was removed under vacuum. The residue was diluted with water (5 L) and the pH adjusted to 2 with 12 M hydrochloric acid (˜400 mL). The resulting solid was collected by filtration, washed with water, and dried in a vacuum oven at 60° C. to give 879 g of 4-(4hydroxy-benzenesulfonyl)-2,2-dimethyl-thiomorpholine-3(S)-carboxylic acid tert-butyl ester (97% yield). This compound had the following properties: m.p. 171.3° C.; [α]D25=−1.97° (c 0.61, MeOH); IR (KBr): 3376, 2978, 2936, 1734, 1601, 1587, 1369, 1325 cm−1; 1H NMR (300 MHz, CDCl3): δ 7.61 (d, J=8.8 Hz, 2H, ArH), 6.86 (d, J=8.8 Hz, 2H, ArH), 4.30 (s, 1H, CαH), 4.04 (m, 1H), 3.85 (dt, J=12.7 and 2.6 Hz, 1H), 3.11 (dt, J=13.6 and 4.1 Hz, 1H), 2.43 (br d, J=13.6 Hz, 1H), 1.60 (s, 3H, CH3), 1.33 (s, 3H, CH3), 1.31 (s, 9H, But); 13C NMR (75 MHz, CDCl3): δ168.1 (C═O), 160.3, 131.8, 129.7 (×2), 116.2 (×2), 82.8, 63.9, 41.5, 40.6, 29.1, 28.3 (×3), 27.8, 25.0; Anal. Calculated for C17H25NO5S2+0.5% water (Karl Fisher analysis): C, 52.69; H, 6.50; N, 3.61; S, 16.55. Found: C, 52.73; H, 6.54; N, 3.64; S, 16.45.
Reaction SMILES: [N+]([C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=1)[C:8]#[N:9])([O-])=O.[C:14]1([CH3:21])[C:19]([OH:20])=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:14]1([CH3:21])[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=1[O:20][C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=[CH:10][CH:11]=1)[C:8]#[N:9]
Reactant: Cc1ccccc1O
Reactant: N#Cc1ccc([N+](=O)[O-])cc1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccccc1Oc1ccc(C#N)c(C#N)c1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
A mixture of 4-nitrophthalonitrile (10.6 g, 60.0 mmol), o-cresol (7.9 g, 72.0 mmol) and K2CO3 (16.6 g, 120.0 mmol) in DMF (70 mL) was heated to 60° C. under a nitrogen atmosphere for 3 hours. The crude reaction was then poured into H2O (300 mL). The resulting mixture was extracted twice with EtOAc. The combined organic layers were washed with sat'd NaHCO3 solution, dried over MgSO4 and concentrated in vacuo. The residue was then dissolved in EtOH (60 mL). After storing for 5 hours at room temperature, the precipitate was collected by filtration and the filter cake was washed with cold EtOH to give the title compound in 8.9 g. MS: (+) m/z 235.46 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH:8]([NH:13][C:14](=[O:34])[CH:15]([NH:20][C:21](=[O:33])[C:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:24])[CH3:23])[CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:7]2.Br.Br[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1.[H-].[Na+]>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][N:39]=1)[C:9](=[O:12])[CH:8]([NH:13][C:14](=[O:34])[C@H:15]([NH:20][C:21](=[O:33])[C:22]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:23])[CH3:24])[CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:7]2
Reactant: CC(C)CC(NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C(=O)NC1Cc2cccc(N)c2NC1=O
Reactant: BrCc1ccccn1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C(=O)NC1Cc2cccc(N)c2N(Cc2ccccn2)C1=O
Reaction time: 2 h

Procedure:
tert-Butyl 1-(1-(8-amino-2-oxo-1,2,3,4-tetrahydroquinolin-3-ylamino)-4-methyl-1-oxopentan-2-ylamino)-2-methyl-1-oxopropan-2-ylcarbamate (1.04 g) and 2-(bromomethyl)pyridine hydrobromide (553 mg) were sequentially added to N,N-dimethylformaldehyde (7.5 mL), and sodium hydride (174 mg) was added in two portions to the mixture under cooling on ice, followed by stirring for two hours. The resultant mixture was extracted with ethyl acetate and water, and the aqueous layer was further extracted with ethyl acetate. The organic layers were combined, and the combined organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the thus-recovered residue was purified through silica gel column chromatography (hexane:ethyl acetate=1:2), whereby the title compound (393 mg) was yielded.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[CH3:8][N:9]1[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:11]2[C:18](=[O:29])[N:19]([CH2:22][C:23]3[N:24]=[CH:25][NH:26][C:27]=3[CH3:28])[CH2:20][CH2:21][C:10]1=2.C(N(CC)CC)C>ClCCl>[CH3:1][N:2]([CH3:7])[S:3]([N:26]1[C:27]([CH3:28])=[C:23]([CH2:22][N:19]2[CH2:20][CH2:21][C:10]3[N:9]([CH3:8])[C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:11]=3[C:18]2=[O:29])[N:24]=[CH:25]1)(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Cc1[nH]cnc1CN1CCc2c(c3ccccc3n2C)C1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(CN2CCc3c(c4ccccc4n3C)C2=O)ncn1S(=O)(=O)N(C)C

Procedure:
A solution of dimethylsulphamoyl chloride (0.107 ml) in dry dichloromethane was added to a stirred solution of 2,3,4,5-tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1H-pyrido[4,3-b]indol-1-one (0.294 g) and triethylamine (0.2 ml) in dry dichloromethane (30 ml) under nitrogen, and the mixture was heated at reflux for ca. 24 h. After cooling the solution was concentrated onto FCC silica and purified by FCC eluting with System A (150:8:1) to give an oil. This oil was triturated with ether to give a solid which was further purified by slow evaporation from a solution in ethyl acetate to give the title compound (122 mg), m.p. 194°-196°, t.l.c. (System A, 100:8:1) Rf 0.43.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].Br[C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C:26](=[O:28])[CH3:27]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[C:26](=[O:28])[CH3:27]
Reactant: OB(O)c1ccc(F)cc1F
Reactant: CC(=O)c1ccc(F)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Product: CC(=O)c1ccc(F)cc1-c1ccc(F)cc1F
Yield: 29.5 %

Procedure:
The title compound was prepared from 2,4-difluorophenylboronic acid (2.0 g, 12.7 mmol), tetrabutylammonium bromide (3.71 g, 11.5 mmol), potassium carbonate (4.78 g, 34.6 mmol), 2′-bromo-4′-fluoroacetophenone (2.5 g, 11.5 mmol), and palladium acetate (259 mg, 1.15 mmol) according to the procedure and in the same manner as described in Example 105, step a. The product was purified by preparative liquid chromatography on a Biotage® 40 Mi column of prepacked silica gel (90 g), eluting with a gradient of 10%-30% methyl tert-butyl ether in hexane, to afford the desired compound (850 mg, 30%) as a clear yellow oil;
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:8][C:9]([OH:11])=[O:10])[CH2:5][CH2:6][OH:7].[OH-].[Na+:13]>O>[OH:1][CH2:2][CH2:3][N:4]([CH2:8][C:9]([O-:11])=[O:10])[CH2:5][CH2:6][OH:7].[Na+:13]
Reactant: O=C(O)CN(CCO)CCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C([O-])CN(CCO)CCO

Procedure:
N,N-Bis-(2-hydroxyethyl)aminoacetic acid (364,933 grams, 2.2144 moles) (this material is 99% pure; it contains 1% or 3.613 grams of H2O) is added with stirring to a cooled solution of pure sodium hydroxide (88.57 grams, 2.2144 moles) in pyrogen-free distilled water (400 ml.). The mixture is stirred until solution is effected. After reaching room temperature, the solution is stirred while enough pyrogen-free distilled water is added to make the total volume 1.000 ml. The solution is sterilized by filtration. This solution is 41% or 2.2144 molar in sodium N,N-bis-(2-hydroxyethyl)aminoacetate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17](O)[C:18]4[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH2:28]([O:35]/[C:36](/[O:39][Si](C)(C)C)=[CH:37]/[CH3:38])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH2:28]([O:35][C:36](=[O:39])[CH:37]([CH3:38])[CH:17]([C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][CH:19]=1)[C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[N:9]=[CH:10]2)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: C/C=C(/OCc1ccccc1)O[Si](C)(C)C
Reactant: O=C(O)c1ccc(C(O)c2ccc3c(cnn3-c3ccc(F)cc3)c2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C(=O)OCc1ccccc1)C(c1ccc(C(=O)O)cc1)c1ccc2c(cnn2-c2ccc(F)cc2)c1
Reaction time: 3 h
Yield: 55.1 %

Procedure:
To a solution of 4-((1-(4-fluorophenyl)-1H-indazol-5-yl)(hydroxy)methyl)benzoic acid (180 mg, 0.5 mmol) and (Z)-(1-(benzyloxy)prop-1-enyloxy)trimethylsilane (10.0 mmol, prepared using General Silyl Ketene Acetal Method A) in 10 mL of dry DCM was added TiCl4 (1.0 mL of 1.0 M DCM solution, 1.0 mmol) and then stirred 3 h. The reaction was quenched with MeOH, poured into aqueous sodium bicarbonate and extracted 2×EtOAc. The organic layers were dried over MgSO4, filtered, and concentrated. MPLC purification on SiO2 using a 0-100% EtOAc/hexane gradient gave 140 mg (55% yield) of 4-(3-(benzyloxy)-1-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2-methyl-3-oxopropyl)benzoic acid. MS found: (M+H)+=509.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:6][C:7]=1I.[CH3:16][N:17](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[C:16]([C:7]1[CH:6]=[CH:5][C:4]([CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:3][C:2]=1[F:1])#[N:17]
Reactant: CCOC(=O)C(C)c1ccc(I)c(F)c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CCOC(=O)C(C)c1ccc(C#N)c(F)c1
Temperature: 25 °C
Yield: 66 %

Procedure:
To a solution of ethyl 2-(3-fluoro-4-iodophenyl)propanoate (1.15 g, 3.570 mmol) in DMF was added Zn(CN)2 (629 mg, 5.355 mmol) and Pd(PPh3)4 (825 mg, 0.714 mmol). The reaction mixture was refluxed for 8 hours and then cooled to room temperature. The mixture was filtered through a plug of Celite and concentrated. The residue was diluted with EtOAc and washed with 10% HCl solution. The organic layer was dried over MgSO4 and concentrated. The residue was purified by column chromatography to afford the pure compound ethyl 2-(4-cyano-3-fluorophenyl)propanoate (520 mg, 66%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[NH:16][C:15]4[N:23]=[CH:24][CH:25]=[CH:26][C:14]=4[N:13]3[C:27]=2[C:28]2[CH:33]=[CH:32][C:31]([C:34]3([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])[CH2:37][CH2:36][CH2:35]3)=[CH:30][CH:29]=2)=[CH:6][CH:5]=1)([O-])=O.[BH4-].[Na+]>C1COCC1.CO.Cl[Ni]Cl>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[NH:16][C:15]4[N:23]=[CH:24][CH:25]=[CH:26][C:14]=4[N:13]3[C:27]=2[C:28]2[CH:33]=[CH:32][C:31]([C:34]3([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:43])([CH3:42])[CH3:44])[CH2:35][CH2:36][CH2:37]3)=[CH:30][CH:29]=2)=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc([N+](=O)[O-])cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc(N)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
To a solution of tert-butyl (1-{4-[2-(4-nitrophenyl)-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl]phenyl}cyclobutyl)carbamate (317 mg, 0.49 mmol) in THF (10 mL) and MeOH (5 mL) cooled to 0° C. was added NiCl2 (245 mg, 1.03 mmol) and NaBH4 (84 mg, 2.04 mmol). The reaction was slowly allowed to warm to room temperature and stirred 30 min. The reaction was diluted with sat.NaHCO3aq and extracted with ethyl acetate (3×20 mL). The organic layers were combined, washed with brine. The organic phase was dried over sodium sulfate, filtered and concentrated gave the title compound as a yellow solid (214 mg, 76%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C@@H:8]([C:22](=[O:27])NCOC)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[C:1]([O:5][C:6](=[O:28])[NH:7][C@@H:8]([CH:22]=[O:27])[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][CH:15]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: COCNC(=O)[C@@H](Cc1ccc(-c2ccccc2)cc1)NC(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](C=O)Cc1ccc(-c2ccccc2)cc1
Temperature: -2.5 °C
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
[(R)-2-Biphenyl-4-yl-1-(methoxymethylcarbamoyl)ethyl]carbamic acid t-butyl ester (7.5 g, 19.5 mmol, 1.0 eq.) was combined with THF (distilled) (100 mL) under nitrogen. Lithium aluminum hydride (750 mg, 19.8 mmol, 1.0 eq.) was added to the resulting stirred solution in several batches at −5-0° C. over a period of 30 minutes. The resulting solution was stirred for 30 minutes at −5-0° C. The reaction was then quenched by the addition of a solution of KHSO4 (6.6 g) in water (35 mL). The resulting solution was combined with a 1N HCl (75 mL) solution, and stirred for five minutes. EtOAc (100 mL) was added and the resulting solution was extracted with EtOAc (3×100 mL) and the organic layers were combined to yield the title compound (6.3 g) as a yellow oil.