Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1)[CH2:9][C:10]([C:12]1[CH:13]=[CH:14][C:15](=[O:18])[NH:16][CH:17]=1)=[O:11].IC.[C:31](=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([C:19]1[CH:20]=[CH:21][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][CH:24]=1)[CH2:9][C:10]([C:12]1[CH:13]=[CH:14][C:15](=[O:18])[N:16]([CH3:31])[CH:17]=1)=[O:11]
Reactant: CS(=O)(=O)c1ccc(C(CC(=O)c2ccc(=O)[nH]c2)c2ccccc2Cl)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: Cn1cc(C(=O)CC(c2ccc(S(C)(=O)=O)cc2)c2ccccc2Cl)ccc1=O

Procedure:
In analogy to example 161, step 1, 5-[3-(2-chloro-phenyl)-3-(4-methanesulfonyl-phenyl)-propionyl]-1H-pyridin-2-one was reacted with iodomethane in the presence of potassium carbonate to give the title compound as a colorless solid, MS (ESI+): m/z=430.1 [M+H]+.
Reaction SMILES: [BH4-].[Na+].[C:3]([N:22]1[CH:26]=[C:25]([CH2:27][O:28][CH2:29][C:30]([C:32]2[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[CH:34][CH:33]=2)=[O:31])[N:24]=[CH:23]1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(O)(=O)C>C(O)C>[OH:31][CH:30]([C:32]1[CH:33]=[CH:34][C:35]([C:36]#[N:37])=[CH:38][CH:39]=1)[CH2:29][O:28][CH2:27][C:25]1[N:24]=[CH:23][N:22]([C:3]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:26]=1
Reactant: N#Cc1ccc(C(=O)COCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: N#Cc1ccc(C(O)COCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Sodium borohydride is added in portions to a solution of 1 mmol of 4-[2-(1-trityl-1H-imidazol-4-ylmethoxy)acetyl]benzonitrile in 12 ml of ethanol at 0° C. The reaction solution is stirred at room temperature for 12 hours, then poured into ice-water and stirred for 15 minutes. The mixture is adjusted to pH 5 by adding glacial acetic acid and extracted with tert-butyl methyl ether (2×). The combined organic phases are washed with water and brine, dried over sodium sulphate and evaporated. The title compound is identified from the residue on the basis of the Rf by flash chromatography (SiO2 60 F).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5](=[O:11])[N:6]([CH2:8][CH2:9][OH:10])[CH:7]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[OH:10][CH2:9][CH2:8][N:6]1[CH:7]=[C:2]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=[N:4][C:5]1=[O:11]
Reactant: O=c1ncc(Br)cn1CCO
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=c1ncc(-c2ccccc2)cn1CCO
Temperature: 75 °C
Yield: 70.5 %

Procedure:
To a 10 mL round bottomed flask was added 5-bromo-1-(2-hydroxyethyl)pyrimidin-2(1H)-one (0.088 g, 0.40 mmol), phenylboronic acid (0.098 g, 0.80 mmol), 1,2-dimethoxyethane (2.5 mL) and 2 M sodium carbonate (0.40 mL, 0.80 mmol). The mixture was carefully evacuated and backfilled with N2. This was repeated twice. To the mixture was added dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct (0.029 g, 0.040 mmol). The mixture was again carefully evacuated and backfilled with N2. This was repeated once. The mixture was then heated at 75° C. for 1.5 hours. After cooling to room temperature, the mixture was poured into water (50 mL) and then extracted with EtOAc (2×) and then with 25% iPrOH/CHCl3 (3×). The combined extracts were washed with brine (1×), dried (Na2SO4) and concentrated onto silica. Purification by silica gel chromatography (0 to 2% MeOH (2M NH3)/CH2Cl2) afforded 1-(2-hydroxyethyl)-5-phenylpyrimidin-2(1H)-one (0.061 g, 70% yield) as an off-white solid. MS (ESI, pos. ion.) m/z: 217 (MH+). Calc'd exact mass for C12H12N2O2: 216. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.71 (q, J=5.3 Hz, 2 H), 4.00 (t, J=5.3 Hz, 2 H), 4.95 (t, J=5.6 Hz, 1 H), 7.35 (t, J=7.3 Hz, 1 H), 7.46 (t, J=7.6 Hz, 2 H), 7.61 (d, J=7.4 Hz, 2 H), 8.44 (d, J=3.3 Hz, 1 H), 8.95 (d, J=3.3 Hz, 1 H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1Br.[CH3:12][C:13]1([CH3:28])[CH2:18][CH2:17][C:16](B2OC(C)(C)C(C)(C)O2)=[CH:15][CH2:14]1>CO.C(Cl)Cl>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[C:16]1[CH2:17][CH2:18][C:13]([CH3:28])([CH3:12])[CH2:14][CH:15]=1
Reactant: NC(=O)c1ccc(N)c(Br)c1
Reactant: CC1(C)CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Solvent: CO
Solvent: ClCCl
Product: CC1(C)CC=C(c2cc(C(N)=O)ccc2N)CC1
Yield: 77.9 %

Procedure:
The title compound was prepared by the Suzuki coupling procedure of Example 11, step (e) using 4-amino-3-bromo-benzamide (as prepared in Example 16, step (a), 62.4 mg, 0.289 mmol), and 2-(4,4-dimethyl-cyclohex-1-enyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (75.0 mg, 0.318 mmol). Silica gel chromatography (0-2% MeOH/DCM) afforded the title compound (55 mg, 78%) as a faint yellow solid. Mass spectrum (ESI, m/z): Calcd. for C15H20N2O, 245.2 (M+H), found 245.2.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[CH2:24]([NH2:26])[CH3:25]>>[CH2:24]([NH:26][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][N:10]=[CH:9][N:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1)[CH3:25]
Reactant: Cc1onc(-c2ccncn2)c1COc1ccc(C(=O)O)cn1
Reactant: CCN
Product: CCNC(=O)c1ccc(OCc2c(-c3ccncn3)noc2C)nc1
Yield: 78 %

Procedure:
As described for example 313b, 6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-nicotinic acid (53 mg, 0.17 mmol) was converted, using ethylamine (2 M solution in THF) instead of isopropylamine, to the title compound (45 mg, 78%) which was obtained as a white solid. MS: m/e=340.0 [M+H]+.
Reaction SMILES: CC1[N:3]([C:7]2[CH:8]=[C:9]([C:13]3[CH:22]=[N:21][CH:20]=[CH:19][C:14]=3[C:15]([O:17]C)=[O:16])[CH:10]=[CH:11][CH:12]=2)[CH2:4][CH2:5][N:6]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C@H:27]1[O:29][CH2:28]1.[OH-].[Na+].Cl>C1(C)C=CC=CC=1.CO>[Cl:23][C:24]1[CH:25]=[C:26]([C@@H:27]([OH:29])[CH2:28][NH:6][CH2:5][CH2:4][NH:3][C:7]2[CH:8]=[C:9]([C:13]3[CH:22]=[N:21][CH:20]=[CH:19][C:14]=3[C:15]([OH:17])=[O:16])[CH:10]=[CH:11][CH:12]=2)[CH:30]=[CH:31][CH:32]=1
Reactant: Clc1cccc([C@@H]2CO2)c1
Reactant: COC(=O)c1ccncc1-c1cccc(N2CCN=C2C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Product: O=C(O)c1ccncc1-c1cccc(NCCNC[C@H](O)c2cccc(Cl)c2)c1
Temperature: 110 °C
Yield: 57.7 %

Procedure:
A solution of methyl 3-[3-(2-methyl-4,5-dihydro-1H-imidazol-1-yl)phenyl]isonicotinate (0.25 g) and (R)-3-chlorostyrene oxide (0.13 g) in anhydrous toluene (2 ml) was heated at reflux (ca. 110° C.) for 18 h. The mixture was cooled to ca. 50° C., 1M sodium hydroxide solution (4.8 ml) and methanol (3 ml) were added over 5-10 min. The apparatus was configured to distill out 4 ml of solvents under atmospheric pressure. The homogeneous mixture obtained was heated at reflux for 2 h. The mixture was cooled to <50° C., and concentrated hydrochloric acid (36%, 0.3 ml) was added dropwise to adjust pH to 7. The aqueous solution was loaded on to silica gel column and eluted with a mixture of dichloromethane and methanol (8/2, v/v). The product was isolated as 0.2 g (57%) of hygroscopic brown solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:9]=[CH:8][N:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:6]=1)=[O:4].[OH-].[Na+]>C1COCC1.CO>[CH2:10]([N:7]1[CH:8]=[N:9][C:5]([C:3]([OH:4])=[O:2])=[N:6]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COC(=O)c1ncn(Cc2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ncn(Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 1-benzyl-1H-[1,2,4]triazole-3-carboxylic acid methyl ester (4.11 g) in THF (30 mL) in methanol (30 mL), was added sodium hydroxide solution (1.0 N, 28 mL, 28 mmol). The solution was stirred at room temperature for 3 hours. The organic solvents were removed by evaporation. The aqueous phase washed with diethyl ether one time. The aqueous solution was acidified by adding 2 N HCl and then filtered to yield 1-benzyl-1H-[1,2,4]triazole-3-carboxylic acid as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:28][C:29]1([CH2:32][O:33][CH3:34])[CH2:31][CH2:30]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:28][C:29]2([CH2:32][O:33][CH3:34])[CH2:31][CH2:30]2)=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Reactant: COCC1(CBr)CC1
Product: COCC1(Cn2cc(C(=O)N3CCC4(CC3)OCc3ccccc34)c3ccc(Cl)cc32)CC1

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine] (prepared according to example 69) with 1-bromomethyl-1-methoxymethyl-cyclopropane (described in WO 2001032633) gave the title compound. ES-MS m/e (%): 465.5 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].C(O[CH:18](OCC)[N:19]([CH3:21])[CH3:20])C>>[C:1]([C:3]1[CH:4]=[C:5]([C:9](=[CH:18][N:19]([CH3:21])[CH3:20])[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CCOC(OCC)N(C)C
Reactant: CCOC(=O)Cc1cccc(C#N)c1
Product: CCOC(=O)C(=CN(C)C)c1cccc(C#N)c1

Procedure:
The title compound was prepared in a manner similar to Example Preparation 10 using ethyl 2-(3-cyanophenyl)acetate and 1,1-diethoxy-N,N-dimethylmethanamine to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12 (t, J=7.1 Hz, 3H) 2.67 (s, 6H) 4.00 (q, J=7.1 Hz, 2H) 7.42-7.45 (m, 1H) 7.45-7.50 (m, 1H) 7.53-7.55 (m, 1H) 7.57 (s, 1H) 7.64 (dt, J=7.1, 1.7 Hz, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[O:8].C1(C)C(S([CH2:18][N+:19]#[C-:20])(=O)=O)=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO>[O:8]1[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:20][N:19]=[CH:18]1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccccc1C
Reactant: O=Cc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: c1ccc(-c2cnco2)nc1

Procedure:
Picolinaldehyde (2.5 g, 23 mmol) and toluenesulfonylmethyl isocyanide (5.3 g, 27 mmol) were dissolved in methanol (30 ml), and potassium carbonate (3.5 g, 25 mmol) was added thereto. The mixture was refluxed for 30 minutes. The solvent was evaporated, and ethyl acetate and water were added to the residue. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated. The residue was subjected to a silica gel column chromatography. The fractions eluted with hexane-ethyl acetate (2:3, v/v) were collected and concentrated to give the titled compound.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][CH2:11][C:10](=[O:13])[N:9]([CH3:14])[C:8]3[CH:15]=[N:16][C:17]([NH:19][C:20]4[CH:34]=[CH:33][C:23]([C:24]([NH:26][CH:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)=[O:25])=[CH:22][C:21]=4[O:35][CH3:36])=[N:18][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[O:51]1[CH2:56][CH2:55][C:54](=O)[CH2:53][CH2:52]1.C(O)(=O)C>C(Cl)Cl>[CH:1]1([N:6]2[CH2:12][CH2:11][C:10](=[O:13])[N:9]([CH3:14])[C:8]3[CH:15]=[N:16][C:17]([NH:19][C:20]4[CH:34]=[CH:33][C:23]([C:24]([NH:26][CH:27]5[CH2:32][CH2:31][N:30]([CH:54]6[CH2:55][CH2:56][O:51][CH2:52][CH2:53]6)[CH2:29][CH2:28]5)=[O:25])=[CH:22][C:21]=4[O:35][CH3:36])=[N:18][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C1CCOCC1
Reactant: COc1cc(C(=O)NC2CCNCC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CCC(=O)N2C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1cc(C(=O)NC2CCN(C3CCOCC3)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CCC(=O)N2C
Yield: 24.7 %

Procedure:
4-(9-Cyclopentyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(piperidin-4-yl)benzamide (Intermediate 12) (35 mg, 0.07 mmol, 1 eq) and sodium triacetoxyborohydride (18 mg, 0.084 mmol, 1.2 eq) in DCM (0.5 mL) were reacted with tetrahydropyran-4-one (6.5 μL, 0.07 mmol, 1 eq) at rt for 2 days. Further and sodium triacetoxyborohydride (18 mg, 1.2 eq), tetrahydropyran-4-one (6.5 μL, 1 eq) were added and acetic acid (4 μL, 1 eq). After two days the RM was diluted with DCM, washed with water and the organic layer concentrated in vacuo. The resulting residue was purified by preparative RP-HPLC-MS (Preparative—1) to provide 4-(9-cyclopentyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-[1-(tetrahydro-pyran-4-yl)-piperidin-4-yl]-benzamide (10 mg, 25%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:13][C@H:12]1[CH2:42][CH2:43]OS(C)(=O)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C-:49]#[N:50].[Na+]>CS(C)=O.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][C@H:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]3[O:27][CH2:26][CH2:25][N:24]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[C:23]=3[CH:33]=2)[C@@H:14]([C:34]2[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=2)[CH2:13][C@H:12]1[CH2:42][CH2:43][C:49]#[N:50])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](CCOS(C)(=O)=O)C[C@@H]3c3ccc(OC)cc3)cc21
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(C(=O)OCc4ccccc4)[C@H](CCC#N)C[C@@H]3c3ccc(OC)cc3)cc21
Temperature: 50 °C

Procedure:
To a stirred solution of 0.90 g of (2S,4R,5R)-2-(2-methanesulfonyloxy-ethyl)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid benzyl ester (from example 18b) in 10 ml of dimethylsulfoxide are added 0.25 g of sodium cyanide and the mixture is heated to 50° C. for 4 hours. The reaction mixture is diluted with water, extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by flash chromatography (SiO2 60 F) to afford the title compound as a colourless oil. Rf=0.30 (EtOAc-heptane 1:1); Rt=5.20.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].C([O-])([O-])=O.[K+].[K+].[Cl:20][C:21]1[CH:41]=[CH:40][C:24]([CH2:25][CH2:26][NH:27][C:28](=[O:39])[C:29]2[CH:34]=[CH:33][C:32](Cl)=[C:31]([N+:36]([O-:38])=[O:37])[CH:30]=2)=[CH:23][CH:22]=1>CS(C)=O.C(Cl)Cl>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:25][CH2:26][NH:27][C:28]([C:29]2[CH:34]=[CH:33][C:32]([O:8][C:7]3[CH:6]=[CH:5][C:4]([CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:3][C:2]=3[F:1])=[C:31]([N+:36]([O-:38])=[O:37])[CH:30]=2)=[O:39])=[CH:40][CH:41]=1
Reactant: O=C(NCCc1ccc(Cl)cc1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: COC(=O)Cc1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: COC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2[N+](=O)[O-])c(F)c1
Temperature: 80 °C
Reaction time: 12 h
Yield: 46.4 %

Procedure:
Methyl 2-(3-fluoro-4-hydroxyphenyl)acetate (prepared in Step A; 163 mg, 0.885 mmol) was diluted with DMSO (3 mL) followed by the addition of K2CO3 (122 mg, 0.885 mmol) and N-(4-chlorophenethyl)-4-chloro-3-nitrobenzamide (prepared in Step B; 300 mg, 0.885 mmol). The reaction was stirred at 80° C. for 12 hours. The reaction was cooled, diluted with DCM and washed with 10% aq. sodium carbonate, water and brine. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated. The material was purified by silica gel chromatography, eluting with hexane:acetone (2:1) to yield methyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)-2-nitrophenoxy)-3-fluorophenyl)acetate (200 mg, 46.4% yield).
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].CN(C)C=O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.Cl.[CH2:44]([NH:46][C:47]([NH:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]2[N:57]=[C:58]([N:66]3[CH2:71][CH2:70][O:69][CH2:68][C@@H:67]3[CH3:72])[C:59]3[CH2:65][NH:64][CH2:63][CH2:62][C:60]=3[N:61]=2)=[CH:52][CH:51]=1)=[O:48])[CH3:45]>>[C:1]([CH2:3][C:4]([N:64]1[CH2:63][CH2:62][C:60]2[N:61]=[C:56]([C:53]3[CH:52]=[CH:51][C:50]([NH:49][C:47]([NH:46][CH2:44][CH3:45])=[O:48])=[CH:55][CH:54]=3)[N:57]=[C:58]([N:66]3[CH2:71][CH2:70][O:69][CH2:68][C@@H:67]3[CH3:72])[C:59]=2[CH2:65]1)=[O:6])#[N:2]
Reactant: N#CCC(=O)O
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CNCC3)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4C)n2)CN(C(=O)CC#N)CC3)cc1
Temperature: 40 °C
Reaction time: 96 h

Procedure:
Cyanoacetic acid (0.0300 g, 0.000353 mol) in dry N,N-Dimethylformamide (1.60 mL, 0.0207 mol) was added 1-Hydroxybenzotriazole (0.0488 g, 0.000361 mol) followed by N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.0721 g, 0.000376 mol) then followed by N,N-Diisopropylethylamine (0.161 mL, 0.000924 mol) and then (S)-1-ethyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)phenyl)urea hydrochloride (0.1000 g, 0.0002310 mol). The reaction mixture heated at 40° C. and was stirred for 4 days. The reaction mixture was concentrated, chromatographed through silica gel again (12 g, 0-10% MeOH in dichloromethane), and purified by HPLC. 1H NMR (500 MHz, DMSO) δ 8.69 (s, 1H), 8.18 (d, J=8.8, 2H), 7.48 (d, J=8.8, 2H), 6.18 (t, J=5.6, 1H), 4.65 (d, J=15.7, 1H), 4.51-4.38 (m, 1H), 4.26-4.14 (m, 2H), 3.96-3.84 (m, 2H), 3.80-3.56 (m, 5H), 3.44 (dd, J=19.8, 12.6, 2H), 3.15-3.07 (m, 2H), 3.02-2.94 (m, 1H), 2.84 (s, 1H), 1.25 (t, J=5.4, 3H), 1.06 (t, J=7.2, 3H). LC/MS-m/z+464.2 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[N:10]([O-])=O.[Na+].Cl[Sn]Cl.Cl>Cl>[Br:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH:4][NH2:10]
Reactant: O=N[O-]
Reactant: Nc1ccc(F)cc1Br
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Product: NNc1ccc(F)cc1Br
Temperature: -5 °C
Reaction time: 0.17 h
Yield: 83 %

Procedure:
Commercially available 2-bromo-4-fluoroaniline 1 (2.36 ml, 20.75 mmol) was added to a stirring solution of concentrated hydrochloric acid (40 ml) that was cooled to −5° C. This solution was allowed to age while stirring for 10 minutes. An aqueous solution of NaNO2 was added over 15 minutes. SnCl2/HCl (10.40 g, 46.1 mmol, 10 ml HCl) was added over 15 minutes and aged for an additional 30 minutes to 1 hour. The mixture was filtered and washed with dichloromethane. The resulting solid was dissolved in 1.0M HCl and extracted 3 times with dichloromethane. The organic layer was vacuum dried overnight to give 3.53 g (83% yield). 1H NMR (400 MHz, CDCl3): δ7.169 (dd, J=8 Hz, J=2.8 Hz 1H), δ7.076 (dd, J=5.2 Hz, J=9.2 Hz, 1H), δ6982 (td, J=8.4 Hz, J=2 Hz 1H), δ5.540 (bs, 1H), δ3.590 (bs, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([C:24](=O)[C:25]([N:27]([CH3:29])[CH3:28])=[O:26])[CH:19]=3)[CH:16]=2)[N:11]([S:31]([C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=2)(=[O:33])=[O:32])[CH:10]=1.COC1C=CC=CC=1C1C2C(=NC=C(B3OC(C)(C)C(C)(C)O3)C=2)[N:51](S(C2C=CC(C)=CC=2)(=O)=O)[CH:50]=1.BrC1C=CN=C(C(C#N)C(N(C)C)=O)C=1.C(=O)(O)[O-].[Na+]>C(#N)C.C1(C)C=CC=CC=1>[C:50]([CH:24]([C:20]1[CH:19]=[C:18]([C:15]2[CH:16]=[C:17]3[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[CH:10][N:11]([S:31]([C:34]4[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=4)(=[O:32])=[O:33])[C:12]3=[N:13][CH:14]=2)[CH:23]=[CH:22][N:21]=1)[C:25]([N:27]([CH3:28])[CH3:29])=[O:26])#[N:51]
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3ccnc(C(=O)C(=O)N(C)C)c3)cc12
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Agent: CN(C)C(=O)C(C#N)c1cc(Br)ccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: Cc1ccccc1
Product: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3ccnc(C(C#N)C(=O)N(C)C)c3)cc12
Temperature: 80 °C

Procedure:
2-{4-[3-(2-Methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyridin-2-yl}-N,N-dimethyl-2-oxo-acetamide was 3-(2-methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine (493 mg, 0.977 mmol), 2-(4-bromo-pyridin-2-yl)-2-cyano-N,N-dimethyl-acetamide (80%, 391 mg, 1.46 mmol) and 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)-dichloride dichloromethane adduct (39.8 mg, 0.048 mmol) were combined in a vial under nitrogen and dissolved in acetonitrile (2.5 mL) and toluene (2.5 mL). Saturated sodium bicarbonate (5 mL) was added and the system was purged with nitrogen gas. The reaction mixture was capped and heated for 15 h at 80° C. The cooled mixture was diluted with ethyl acetate and washed with brine. The combined organic layers were dried over sodium sulfate and purified by flash chromatography on silica gel using a gradient of ethyl acetate in hexanes to afford 2-cyano-2-{4-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-pyridin-2-yl}-N,N-dimethyl-acetamide.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22]([OH:24])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:25][C:26]1[CH:31]=[C:30]([N:32]2[CH:36]=[N:35][C:34]([CH3:37])=[N:33]2)[CH:29]=[CH:28][C:27]=1[CH2:38][NH2:39]>>[F:25][C:26]1[CH:31]=[C:30]([N:32]2[CH:36]=[N:35][C:34]([CH3:37])=[N:33]2)[CH:29]=[CH:28][C:27]=1[CH2:38][NH:39][C:22]([C:10]1[N:11]=[C:12]2[N:17]([C:18](=[O:19])[C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:16][CH2:15][O:14][C:13]2([CH3:20])[CH3:21])=[O:24]
Reactant: Cc1ncn(-c2ccc(CN)c(F)c2)n1
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Product: Cc1ncn(-c2ccc(CNC(=O)c3nc4n(c(=O)c3OCc3ccccc3)CCOC4(C)C)c(F)c2)n1

Procedure:
The title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid and intermediate 87, (2-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)methanamine. White crystals; mp 183–185° C. (ethyl acetate). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.65 (6H, s, 2×CH3), 2.52 (3H, s, CH3), 4.05 (4H, m, 2×CH2), 4.64 (2H, d, J=6.1 Hz, NCH2), 5.33 (2H, s, OCH2), 7.29–7.55 (8H, m, aromatics), 7.84 (1H, broad t, NH), 8.45 (1H, s, CH). Anal. Calcd for C27H27FN6O4: C, 62.54; H, 5.25; N, 16.21. Found: C, 62.41; H, 5.40; N, 16.23.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][S:7][C:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([OH:5])=[O:4].CCN(C(C)C)C(C)C.[F:36][C:37]([F:55])([F:54])[C@H:38](OS(C(F)(F)F)(=O)=O)[C:39]1[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=1>C(Cl)Cl>[F:55][C:37]([F:36])([F:54])[C@@H:38]([NH:1][C@@H:2]([CH2:6][S:7][C:8]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:3]([OH:5])=[O:4])[C:39]1[CH:40]=[CH:41][C:42]([F:45])=[CH:43][CH:44]=1
Reactant: N[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Reactant: O=S(=O)(O[C@H](c1ccc(F)cc1)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)N[C@@H](c1ccc(F)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77.7 %

Procedure:
2(R)-Amino-3-tritylsulfanylpropionic acid (78 g, 214.6 mmol) was dissolved in CH2Cl2 and DIPEA (112 mL, 643.8 mmol) was added and the reaction mixture was stirred for 10 min at room temperature. Trifluoromethanesulfonic acid 2,2,2-trifluoro-1(R)-(4-fluorophenyl)ethyl ester (70 g, 214.6 mmol) in CH2Cl2 was added and the reaction mixture was stirred overnight at room temperature. Solvent was removed under the reduced pressure and the residue was dissolved in Et2O and washed with 1N HCl, brine and dried over MgSO4. Solvent was removed give 2(R)-[2,2,2-trifluoro-1(S)-(4-fluorophenyl)ethylamino]-3-tritylsulfanylpropionic acid (90 g) as a yellow solid.