Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:17]([CH3:19])[CH3:18])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([OH:16])=O)=[O:8])=[O:4].[C:20]([C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C@H:34]([C:35]3[CH:41]=[CH:40][C:38]([NH2:39])=[CH:37][CH:36]=3)[CH2:33][CH2:32][C@H:31]2[C:42]2[CH:48]=[CH:47][C:45]([NH2:46])=[CH:44][CH:43]=2)=[CH:26][CH:25]=1)([CH3:23])([CH3:22])[CH3:21].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CS(C)=O>[CH3:1][O:2][C:3]([NH:5][C@H:6]([C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([NH:39][C:38]1[CH:37]=[CH:36][C:35]([C@@H:34]2[CH2:33][CH2:32][C@@H:31]([C:42]3[CH:48]=[CH:47][C:45]([NH2:46])=[CH:44][CH:43]=3)[N:30]2[C:27]2[CH:26]=[CH:25][C:24]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:29][CH:28]=2)=[CH:41][CH:40]=1)=[O:16])=[O:8])[CH:17]([CH3:19])[CH3:18])=[O:4]
Reactant: CC(C)(C)c1ccc(N2[C@H](c3ccc(N)cc3)CC[C@H]2c2ccc(N)cc2)cc1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)Nc1ccc([C@@H]2CC[C@@H](c3ccc(N)cc3)N2c2ccc(C(C)(C)C)cc2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.1 %

Procedure:
To a solution of the product from Example 37B (17.7 mg, 0.065 mmol) and the product from Example 37E (50 mg, 0.130 mmol) in anhydrous DMSO (1.3 mL) was added HATU (27.1 mg, 0.071 mmol) and Hunig's Base (0.015 mL, 0.084 mmol). The resulting mixture was stirred at rt for 30 min, and was then partitioned between H2O (5 mL) and EtOAc (3×5 mL). The combined organic layers were dried over Na2SO4. The drying agent was filtered off, and solvent was removed in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-5% MeOH in CH2Cl2 to give the title compound (20 mg, 24%). 1H NMR (400 MHz, DMSO-D6) δ ppm 0.88 (d, J=6.72 Hz, 3 H), 0.93 (d, J=6.72 Hz, 3 H), 1.11 (s, 9 H), 1.52-1.66 (m, 2 H), 1.79-2.06 (m, 4 H), 2.06-2.20 (m, 1 H), 2.34-2.47 (m, 2 H), 3.52 (s, 3 H), 3.56-3.67 (m, 1 H), 3.74-3.87 (m, 1 H), 4.02 (t, J=8.51 Hz, 1 H), 4.42 (dd, J=8.08, 4.83 Hz, 1 H), 4.83-4.94 (m, 2 H), 5.02 (d, J=7.16 Hz, 0.5 H), 5.08 (d, J=7.59 Hz, 0.5 H), 6.18 (d, J=8.78 Hz, 2 H), 6.48 (d, J=8.35 Hz, 2 H), 6.84 (d, J=8.35 Hz, 2 H), 6.93 (d, J=8.89 Hz, 2 H), 7.11 (d, J=8.57 Hz, 2 H), 7.31 (d, J=8.35 Hz, 1 H), 7.48 (d, J=8.57 Hz, 2 H), 9.97 (s, 1 H); MS (ESI) m/z 640.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26]O.C(C=P(CCCC)(CCCC)CCCC)#N.CCCCCC>C1(C)C=CC=CC=1.C(OCC)(=O)C.CCCCCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[F:19])[CH2:26][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: OCc1ccccn1
Reactant: O=S(=O)(Cc1cc(F)ccc1F)c1ccc(Cl)cc1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccc(Cl)cc1)C(Cc1ccccn1)c1cc(F)ccc1F
Yield: 49.5 %

Procedure:
Under an argon atmosphere, the 2-[(4-chlorophenyl)sulfonylmethyl]-1,4-difluorobenzene (150 mg, 0.495 mmol) obtained in Example 5 and 2-pyridylmethanol (95.5 μl, 0.990 mmol) were dissolved in toluene (5 ml), followed by the addition of cyanomethylenetri-n-butylphosphorane (239 mg, 0.990 mmol). The resulting mixture was heated under reflux for 18 hours under an argon atmosphere. The reaction mixture was then concentrated. The residue thus obtained was subjected to flash chromatography on a silica gel column, and the fraction obtained from the hexane:ethyl acetate=1:1 eluate was concentrated. The solid thus obtained was recrystallized from ethyl acetate-hexane, whereby the title compound (96.6 mg, 0.245 mmol, 49%) was obtained as colorless needle crystals.
Reaction SMILES: CN(C)CCN(C)C.[Li]CCCC.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([SH:21])=[CH:17][CH:16]=1.CN([CH:25]=[O:26])C.Cl>C1CCCCC1>[Cl:14][C:15]1[CH:20]=[C:19]([CH:25]=[O:26])[C:18]([SH:21])=[CH:17][CH:16]=1
Reactant: Sc1ccc(Cl)cc1
Reactant: CN(C)C=O
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCCCC1
Product: O=Cc1cc(Cl)ccc1S
Temperature: 0 °C
Reaction time: 1 h
Yield: 14.4 %

Procedure:
Tetramethylethylenediamine (TMEDA)(10.44 mL, 8.035 g, 69.15 mmol) was added via syringe to n-BuLi (43.22 mL of 1.6 M in hexanes, 69.15 mmol) and the solution was chilled to 0° C. A solution of 4-chlorothiophenol (5.00 g, 34.57 mmol) in cyclohexane (25 mL) was added with stirring over 1 hour. The resulting tan slurry was stirred overnight at room temperature, chilled to 0° C., and DMF (2.94 mL, 2.78 g, 38.03 mmol) was added via syringe over 2 minutes. The resulting gummy slurry was stirred at room temperature for 30 hours and became a powdery suspension. A mixture of 2 N HCl and ice was added to the reaction mixture until the pH became acidic (pH=1). During this addition, the mixture warmed and became first red and then pale yellow. This mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo yielding a clear red-brown oil. This oil was triturated with hexanes yielding a red-brown semisolid. This semisolid was purified by plug flash chromatography over silica gel, eluting with 1:1, hexanes:dichloromethane to afford 5-chloro-thiosalicylaldehyde (0.858 g, 14%) as an intensely yellow solid suitable for use without further purification.
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:12][C:11]2[N:10]=[CH:9][N:8]=[C:7]([N:13]3[CH2:19][C:18]4[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:17]=4[O:16][CH2:15][CH2:14]3)[C:6]=2[CH2:5][CH2:4]1)[CH3:2].[NH2:27][C:28]1[C:33]([S:34]([N:37]2[CH2:41][CH2:40][C@@H:39]([NH:42]C(=O)OC(C)(C)C)[CH2:38]2)(=[O:36])=[O:35])=[CH:32][C:31](Br)=[CH:30][N:29]=1>>[NH2:42][C@@H:39]1[CH2:40][CH2:41][N:37]([S:34]([C:33]2[C:28]([NH2:27])=[N:29][CH:30]=[C:31]([C:21]3[CH:22]=[CH:23][C:17]4[O:16][CH2:15][CH2:14][N:13]([C:7]5[C:6]6[CH2:5][CH2:4][C@H:3]([CH2:1][CH3:2])[CH2:12][C:11]=6[N:10]=[CH:9][N:8]=5)[CH2:19][C:18]=4[CH:20]=3)[CH:32]=2)(=[O:35])=[O:36])[CH2:38]1
Reactant: CC[C@H]1CCc2c(ncnc2N2CCOc3ccc(B(O)O)cc3C2)C1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(S(=O)(=O)c2cc(Br)cnc2N)C1
Product: CC[C@H]1CCc2c(ncnc2N2CCOc3ccc(-c4cnc(N)c(S(=O)(=O)N5CC[C@@H](N)C5)c4)cc3C2)C1

Procedure:
Prepared according to the method of example 5 by using {4-[(7S)-7-ethyl-5,6,7,8-tetrahydroquinazolin-4-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl}boronic acid (reagent preparation 23) and 1,1-dimethylethyl {(3R)-1-[(2-amino-5-bromopyridin-3-yl)sulfonyl]pyrrolidin-3-yl}carbamate (reagent preparation 25) in step 1. 1H NMR (400 MHz, d6-DMSO): 8.53 (d, 1H), 8.33 (s, 1H), 7.99 (d, 1H), 7.57 (d, 1H), 7.44 (dd, 1H), 7.01 (d, 1H), 6.75 (brs, 2H), 4.70 (dd, 2H), 4.36 (m, 1H), 4.24 (m, 1H), 3.86 (m, 2H), 3.36 (m, 2H), 3.26 (m, 2H), 2.87, 2.83 (m, dd, 3H), 2.27 (dd, 1H), 1.89 (m, 3H), 1.68 (m, 1H), 1.52 (m, 1H), 1.37 (m, 2H), 1.11 (m, 1H), 0.94 (t, 3H); MS (EI) for C28H35N7O3S: 550 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:8]([F:13])(F)[C:9](O)=O>ClCCl>[F:13][C:8]1[CH:5]=[CH:4][C:3]([C:5]2[CH:4]=[C:3]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][NH:1]3)[CH:2]=[N:1][CH:6]=2)=[CH:2][CH:9]=1
Reactant: c1ccncc1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1ccc(-c2cncc(C3CCCCN3)c2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The above-described pyridine derivative (1.25 g, 3.5 mmol) was dissolved in a mixture of dichloromethane (10 mL) and trifluoroacetic acid (10 mL) and this was stirred at 25° C. for 18 h. The solvents were removed in vacuo and the crude material dissolved in ethyl acetate (50 mL). Saturated sodium carbonate solution (30 mL) was added and the organic layer separated. The aqueous phase was extracted with two further portions of ethyl acetate (2×30 mL), the combined organic extracts washed with brine (20 mL), dried (Na2SO4) and concentrated in vacuo. The residue was chromatographed on silica gel with ethyl acetate, then methanol:ethyl acetate (1:9) as eluant to afford 5-(4-fluorophenyl)-3-(2-piperidinyl)pyridine, 940 mg, 100%. 1H NMR (CDCl3, 300 MHz): δ 8.69 (d, J=2 Hz, 1 H), 8.55 (d, J=2 Hz, 1 H), 7.93 (t, J=2 Hz, 1 H), 7.56 (m, 2 H), 7.16 (app. tm, J=9 Hz, 2 H), 3.18 (d, J=12 Hz, 1 H), 2.83 (td, J=12, 3 Hz, 1 H), 2.61 (bs exch., 1 H), 1.92 (m, 2 H), 1.45-1.75 (m, 6 H).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][CH:5]=[C:6]2[CH:10]=[CH:9][O:8][C:7]=12.C(=O)([O-])O.[Na+].[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>C(O)CO>[N:16]1([C:2]2[N:3]=[CH:4][CH:5]=[C:6]3[CH:10]=[CH:9][O:8][C:7]=23)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1
Reactant: Clc1nccc2ccoc12
Reactant: C1CNCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: OCCO
Product: c1cc2ccoc2c(N2CCNCC2)n1
Temperature: 140 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
In 100 ml of ethylene glycol 8.6 g of anhydrous piperazine was dissolved, and to which 7-chlorofuro[2,3-c]pyridine was added, followed by an overnight's stirring at 140° C. After cooling, saturated aqueous sodium hydrogencarbonate solution was added to the solution, which was then extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified on silica gel column chromatography to provide 1.52 g (75%) of 7-piperazin-1-ylfuro[2,3-c]pyridine.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:6][NH:5][NH:4][C:3]1=[O:7].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])(O)=O.[Na+]>C(O)C.C(OCC)C>[CH2:9]([N:5]1[CH2:6][C:2]([CH3:8])([CH3:1])[C:3](=[O:7])[NH:4]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC1(C)CNNC1=O
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: CC1(C)CN(Cc2ccccc2)NC1=O
Temperature: 25 °C
Yield: 52 %

Procedure:
4,4-dimethyl-3-pyrazolidinone [1.42 g] and benzyl bromide [1.78 mL] and NaHCO3 [1.26 g] were combined in 5 mL ethanol. The mixture was heated at reflux for 30 minutes. The reaction mixture was cooled to room temperature, diluted with diethyl ether (50 mL), dried with MgSO4, filtered and evaporated. The resulting oil was chromatographed on silica gel to yield 1.22 g (52%) of 1-Benzyl-4,4-dimethyl-3-pyrazolidinone as a light oil. 1H NMR: 7.6-7.2 (5H, m), 3.8-3.4 (4H, m), 1.2 (6H, s).
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16](Cl)=[N:17][OH:18])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]([C:22]1[C:23]([NH2:29])=[N:24][C:25]([NH2:28])=[CH:26][CH:27]=1)#[CH:21].C(N(CC)CC)C>O1CCCC1>[C:1]1([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]3[CH:21]=[C:20]([C:22]4[C:23]([NH2:29])=[N:24][C:25]([NH2:28])=[CH:26][CH:27]=4)[O:18][N:17]=3)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ON=C(Cl)Cc1ccc(CNc2ccccc2)cc1
Reactant: C#Cc1ccc(N)nc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Nc1ccc(-c2cc(Cc3ccc(CNc4ccccc4)cc3)no2)c(N)n1
Temperature: 25 °C
Reaction time: 7 h
Yield: 20.1 %

Procedure:
To a tetrahydrofuran (3 mL) solution of (4-phenylaminomethyl-phenyl)-acetohydroximoyl chloride (150 mg, 0.546 mmol) described in Manufacturing Example 73-1-6 and 3-ethynyl-pyridin-2,6-diamine (46.4 mg, 0.348 mmol) described in Manufacturing Example 13-1-3 was added triethylamine (104 μL, 0.748 mmol). This mixture was stirred for 7 hours at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1 to 1:2˜ethyl acetate) to obtain the title compound (26 mg, 13%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].O.[CH2:8]([C:17]1[C:26]([CH3:27])=[C:25]([O:28]C(=O)C)[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([F:32])[CH:23]=2)[N:18]=1)/[CH:9]=[CH:10]/[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].Cl>CO>[CH2:8]([C:17]1[CH:26]([CH3:27])[C:25](=[O:28])[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([F:32])[CH:23]=2)[N:18]=1)/[CH:9]=[CH:10]/[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCC/C=C/Cc1nc2ccc(F)cc2c(OC(C)=O)c1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCCCCC/C=C/CC1=Nc2ccc(F)cc2C(=O)C1C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89.8 %

Procedure:
A solution of 24 mg (0.17 mmols) of potassium carbonate and 1 ml of water was added to a solution of 60 mg (0.17 mmols) of 2-(trans-2-nonenyl)-3-methyl-4-acetoxy-6-fluoroquinoline in 8 ml of methanol and stirred at room temperature for 10 minutes. This solution was neutralized with 1N hydrochloric acid, after which the solvent was distilled off under reduced pressure, followed by addition of 10 ml of chloroform, washing with water and drying with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the resultant residue was purified by silica gel column chromatography (solvent: n-hexane : ethyl acetate=1:1) to obtain 46 mg (yield 87 %) of 2-(trans-2-nonenyl)-3-methyl-6-fluoro-4-quinolone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][NH:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:21][Si:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][O:25][CH2:26]Cl>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[N:11][N:12]([CH2:26][O:25][CH2:24][CH2:23][Si:22]([CH3:29])([CH3:28])[CH3:21])[C:13]=2[CH3:14])=[CH:7][CH:8]=1.[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:13]([CH3:14])=[N:12][N:11]([CH2:26][O:25][CH2:24][CH2:23][Si:22]([CH3:29])([CH3:28])[CH3:21])[CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2cn[nH]c2C)cc1
Reactant: C[Si](C)(C)CCOCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cn(COCC[Si](C)(C)C)nc2C)cc1
Product: COc1ccc(-c2cnn(COCC[Si](C)(C)C)c2C)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
4-(4-Methoxy-phenyl)-5-methyl-1H-pyrazole (1 eq) was taken up in DMF and under N2 was cooled to 0° C. Caesium carbonate (1 eq) was added and the solution was stirred for five minutes. 2-(Trimethylsilyl)ethoxy methyl chloride (0.95 eq) was added dropwise and all was stirred for 2 hours. The reaction mixture was partitioned between water and EtOAc. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to give a gum. This was purified by flash chromatography (8:1 hexane: EtOAc) to give 4-(4-methoxy-phenyl)-5-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazole and 4-(4-methoxy-phenyl)-3-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazole as a mixture of isomers.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[N:13]2[CH2:16][CH2:17][N:18]([CH:19]([CH3:21])[CH3:20])[C:12]2=[N:11][C:10]=1[C:22](O)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[NH2:32][CH2:33][C:34]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][C:35]=1[C:36]([NH:38][CH3:39])=[O:37]>>[F:44][C:41]1[CH:42]=[CH:43][C:34]([CH2:33][NH:32][C:22]([C:10]2[N:11]=[C:12]3[N:18]([CH:19]([CH3:20])[CH3:21])[CH2:17][CH2:16][N:13]3[C:14](=[O:15])[C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:23])=[C:35]([C:36](=[O:37])[NH:38][CH3:39])[CH:40]=1
Reactant: CC(C)N1CCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Reactant: CNC(=O)c1cc(F)ccc1CN
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCN2C(C)C
Yield: 73 %

Procedure:
Coupling of 6-(benzyloxy)-1-isopropyl-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylic acid (0.300 g, 0.91 mmol) and 2-(aminomethyl)-5-fluoro-N-methylbenzamide trifluoroacetate salt (0.210 g, 0.96 mmol) as described for the synthesis of intermediate 3 gave 0.328 g (72% yield) of the title amide as white crystals; mp 197-198° C. (ethyl acetate). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.23 (6H, d, J=6.8 Hz, 2×CH3), 2.98 (3H, d, J=5 Hz, NCH3), 3.66 (2H, t, J=9 Hz, CH2), 4.12 (2H, t, J=9 Hz, CH2), 4.43 (1H, m, CH), 4.48 (2H, d, J=6.3 Hz, NCH2), 5.09 (2H, s, OCH2), 7.05 (1H, m, aromatic), 7.13-7.17 (2H, m, aromatics), 7.3-7.35 (4H, m, NH and aromatics), 7.43-7.46 (2H, m, aromatics), 8.35 (1H, broad t, NH). Anal. Calcd for C26H28FN5O4: C, 63.27; H, 5.71; N, 14.19. Found: C, 63.06; H, 5.65; N, 14.02.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([O:20][CH3:21])[CH2:9][C@H:10]([CH2:15][CH2:16][CH2:17][CH:18]=O)[C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][C:24]=1[CH3:31].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl>[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH:28][CH2:18][CH2:17][CH2:16][CH2:15][C@@H:10]([CH2:9][C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[O:20][CH3:21])[C:11]([O:13][CH3:14])=[O:12])=[CH:25][C:24]=1[CH3:31]
Reactant: Cc1cc(CN)ccc1F
Reactant: COC(=O)[C@@H](CCCC=O)C[C@@H](OC)c1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COC(=O)[C@@H](CCCCNCc1ccc(F)c(C)c1)C[C@@H](OC)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-methyl 2-((R)-2-(4-fluorophenyl)-2-methoxyethyl)-6-oxohexanoate (40 mg, 0.13 mmol) in 2 mL DCE was added 4-Fluoro-3-methyl-benzylamine (21 mg, 0.15 mmol) followed by NaBH(OAc)3 (39.9 mg, 1.4 mmol) and AcOH (9.3 mg, 9 μL, 0.15 mmol) at room temperature. The mixture was stirred for 8 h at the room temperature. The reaction was quenched by pouring into 10 mL 5% aqueous NaOH and diluted with ethyl acetate. The mixture was extracted with more ethyl acetate (3×20 mL) and the combined organic layers washed with brine (2×10 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the crude product used directly in the next step without further purification.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=[O:12])[CH2:2]1.Cl.[CH3:15]O>>[CH3:15][O:12][C:11]([C:3]1[CH2:2][O:1][C:10]2[C:5]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)=[O:13]
Reactant: CO
Reactant: O=C(O)C1=Cc2ccccc2OC1
Agent: Cl
Product: COC(=O)C1=Cc2ccccc2OC1

Procedure:
Compound 16B (5 g) and concentrated HCl (2 mL) in MeOH (200 mL) were heated to reflux for 30 h. The reaction mixture was quenched with water (200 mL) and ether (200 mL). Separated the organic layer, washed with water, brine, dried (MgSO4), concentrated to give an off-white solid, compound 16C (4.2 g). mp 56-57° C.; MS: 191 (M+1)+. Preparation of 6-Chlorosulfonyl-2H-chromene-3-carboxylic acid methyl ester (Compound 16D)
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:12]=[C:11]2[C:6]([C:7](=O)[NH:8][C:9](=O)[NH:10]2)=[CH:5][CH:4]=1.C[N:18](C)[C:19]1[CH:24]=CC=CC=1.P(Cl)(Cl)([Cl:28])=O>>[Cl:28][C:9]1[N:8]=[C:7]([CH2:24][CH2:19][NH2:18])[C:6]2[C:11](=[CH:12][C:3]([C:2]([F:16])([F:15])[F:1])=[CH:4][CH:5]=2)[N:10]=1
Reactant: CN(C)c1ccccc1
Reactant: O=c1[nH]c(=O)c2ccc(C(F)(F)F)cc2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: NCCc1nc(Cl)nc2cc(C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred suspension of 7-trifluoromethyl-1H-quinazoline-2,4-dione (25 g, 0.11 mol) and N,N-dimethylaniline (13.1 g, 0.11 mol) at 0° C. was added phosphorus oxychloride (101 mL, 1.1 mol) and the reaction mixture was heated at reflux for 6 h. The reaction mixture was allowed to cool to room temperature then concentrated under reduced pressure. The resultant solid was dissolved in THF (50 mL) then cooled to 0° C. and a solution of ethylamine (10 mL, 2 molar in THF) was added dropwise with stirring. After 2 h, the reaction mixture was concentrated under reduced pressure, diluted with water (250 mL) and extracted with ethyl acetate (2×150 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. Yield=14 g, 47%; LC-MS: 3.1 min, 276 (M+); 1H NMR (DMSO-d6): δ 1.26 (apparent t, 3 H, J=7 Hz), 3.57 (ddd, 2H, J=12.7, 7.3, 5.6 Hz), 7.84 (dd, 1 H, J=8.7, 1.6 Hz), 7.93 (s, 1 H), 8.49 (d, 1 H, J=8.7 Hz), 9.05 (apparent t, 1 H, J=5 Hz).
Reaction SMILES: Cl.[CH3:2][NH:3][C:4]1[NH:8][C:7]2[CH:9]=[CH:10][C:11]([C:13]([O:15]C)=[O:14])=[CH:12][C:6]=2[N:5]=1>>[CH3:2][NH:3][C:4]1[NH:8][C:7]2[CH:9]=[CH:10][C:11]([C:13]([OH:15])=[O:14])=[CH:12][C:6]=2[N:5]=1
Reactant: CNc1nc2cc(C(=O)OC)ccc2[nH]1
Agent: Cl
Product: CNc1nc2cc(C(=O)O)ccc2[nH]1
Yield: 89.7 %

Procedure:
3 N Aqueous hydrochloric acid (14 mL, 42 mmol) was added to methyl 2-(methylamino)-1H-benzo[d]imidazole-5-carboxylate (2.9 g, 14 mmol) and the reaction was stirred at reflux overnight. The reaction was concentrated to give the title compound (2.4 g, 90%) as a yellow solid. 1H NMR (400 MHz, CD3OD, δ): 7.96-8.00 (m, 2 H), 7.40 (d, J=8.4 Hz, 1 H), 3.10 (s, 3 H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[CH3:24][O:23][C:13]1[C:11]2[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([N:38]4[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]4)[CH:3]=3)[S:9][C:10]=2[C:16]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:15][CH:14]=1
Reactant: CN1CCNCC1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(N4CCN(C)CC4)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and 1-methylpiperazine. ES-MS m/e (%): 469 (M+H+, 100).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.[C-:9]#[N:10].[Na+]>CS(C)=O.CCOC(C)=O>[F:8][C:4]1[N:3]=[C:2]([C:9]#[N:10])[CH:7]=[CH:6][CH:5]=1
Reactant: Fc1cccc(F)n1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1cccc(F)n1
Temperature: 100 °C

Procedure:
2,6 Difluoropyridine (12 g, 100 mmol) was dissolved in DMSO (3 mL) and sodium cyanide (1.3 g, 26 mmol) in DMSO (100 mL) was added dropwise via syringe pump over 16 h. The reaction was then heated at 100° C. for 16 h. The crude mixture was then diluted with EtOAc (500 mL) and washed with a mixture of brine (200 mL) and H2O (500 mL). The organic phase was dried (MgSO4), filtered, and concentrated in vacito. The residue was chromatographed on silica gel eluting with hexanes:EtOAc (4:1) to afford 6-fluoropyridine-2-carbonitrile. MS (ESI) 122.0 (M++H).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](Cl)=[O:15].[Cl-].[Al+3].[Cl-].[Cl-]>>[Br:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([C:4]1[CH:5]=[CH:6][C:1]([OH:7])=[CH:2][CH:3]=1)=[O:15]
Reactant: O=C(Cl)CCCCCBr
Reactant: Oc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(CCCCCBr)c1ccc(O)cc1
Yield: 20.1 %

Procedure:
Phenol (0.88 g), 6-bromohexanoyl chloride (2.0 g) and aluminum chloride (1.4 g) were reacted and treated in the same manner as in Preparation Example 105 to give 0.51 g of 6-bromo-1-(4-hydroxyphenyl)-1-hexanone.