Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(CO)CCC=O)=O.ClC1C=CC=CC=1C(=O)CC#N.[S].C(N(CC)CC)C.S1C=CC=C1.[NH2:36][C:37]1[S:38][C:39]([CH2:51][CH:52]([O:55]C=O)[CH2:53][OH:54])=[CH:40][C:41]=1[C:42](=[O:50])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[Cl:49].[OH-].[K+]>CN(C=O)C.CO>[NH2:36][C:37]1[S:38][C:39]([CH2:51][CH:52]([OH:55])[CH2:53][OH:54])=[CH:40][C:41]=1[C:42](=[O:50])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[Cl:49]
Reactant: Nc1sc(CC(CO)OC=O)cc1C(=O)c1ccccc1Cl
Agent: N#CCC(=O)c1ccccc1Cl
Agent: O=CCCC(CO)OC=O
Agent: [K+]
Solvent: c1ccsc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1sc(CC(O)CO)cc1C(=O)c1ccccc1Cl
Yield: 39 %

Procedure:
45.7 g (0.4 mol) of 3,4-dihydro-2H-pyran-2-methanol are subjected to ozonolysis in 100 ml of anhydrous methylene chloride at -40° . Then 104.9 g (0.4 mol) of triphenylphosphine in 70 ml of anhydrous methylene chloride are added dropwise and the reaction mixture is slowly brought to ambient temperature over a period of 3 hours. After 12 hours the solvent is removed and the residue is thoroughly digested with ether and the triphenylphosphine oxide precipitated is suction filtered. Any unreacted triphenylphosphine residues are precipitated in ether with methyl iodide in the form of the phosphonium salt and then suction filtered. The solvent is removed from the filtrate and the residue is fractionated in vacuo. 32 g (55% yield) of the 4-formyloxy-5-hydroxypentanal are obtained, bp0.1 =82°-92° C. 23 g (0.157 mol) of the aldehyde, 28 g (0.137 mol) of 0-chlorocyanoacetophenone, 5 g (0.157 mol) of sulphur and 16 g (0.157 mol) of triethylamine are used for the thiophene cyclisation in 100 ml of DMF in the usual way and the resulting 2-amino-3-(2-chlorobenzoyl)-5-(2-formyloxy-3-hydroxy-n-propyl)thiophene is refluxed for 2 hours, as the crude product, with 15 g (0.16 mol) of potassium hydroxide in 500 ml of methanol. After removal of the solvent, the residue is taken up in ethyl acetate, washed with water and dried and after the removal of the solvent chromatographed on silica gel with ethyl acetate as eluant. 19.9 g (total yield 39%) of 2-amino-3-(2-chlorobenzoyl)-5-(2,3-dihydroxy-n-propyl)-thiophene are obtained, m.p. 136°-137° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.C([Li])CCC.[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=[O:22])[CH:16]=1.[Cl-].[NH4+]>CCCCCC.CCOCC.O>[CH3:9][O:8][C:5]1[CH:4]=[CH:3][C:2]([CH:21]([C:17]2[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=2)[OH:22])=[CH:7][N:6]=1
Reactant: COc1ccc(Br)cn1
Reactant: O=Cc1cccnc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1ccc(C(O)c2cccnc2)cn1
Temperature: -50 °C
Yield: 23.6 %

Procedure:
5-Bromo-2-methoxypyridine (188 g) was added over 30 minutes to a 1.55 molar solution of n-butyllithium in hexane (770 ml) and ether (1200 ml) stirred at -50° C. The suspension was stirred for 1 hour when pyridine-3-carboxaldehyde (112 g) in ether (200 ml) was added over 30 minutes. The solution was stirred for 3.5 hr and then allowed to warm to ambient temperature. Saturated ammonium chloride solution (100 ml) and water (2 L) was added and the solution was concentrated to ca. 2.5 L in vacuo. Chloroform (3 L) was added and the title compound (41.3 g) was collected by filtration. The chloroform layer was separated, dried over magnesium sulphate and the solvent was removed under reduced pressure. The residue was treated with chloroform (200 ml) and filtered to give a second crop of the product (51.01 g). Recrystallisation from isopropanol/ether gave the title compound, m.p. 129°-130° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]12[CH2:16][CH2:15][C:12]([C:17](O)=[O:18])([CH2:13][CH2:14]1)[CH2:11][CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=1[F:31]>>[C:1]([O:5][C:6]([NH:8][C:9]12[CH2:10][CH2:11][C:12]([C:17]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][C:22]=3[F:31])=[O:18])([CH2:15][CH2:16]1)[CH2:13][CH2:14]2)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: Nc1ccc(C(F)(F)F)cc1F
Reactant: CC(C)(C)OC(=O)NC12CCC(C(=O)O)(CC1)CC2
Product: CC(C)(C)OC(=O)NC12CCC(C(=O)Nc3ccc(C(F)(F)F)cc3F)(CC1)CC2

Procedure:
In a similar manner to Example 133, 4-tert-butoxycarbonylaminobicyclo[2.2.2]octane-1-carboxylic acid (100 mg) and 4-amino-3-fluorobenzotrifluoride (106 μL) were used to obtain 4-tert-butoxycarbonylamino-N-(2-fluoro-4-trifluoromethylphenyl)bicyclo[2.2.2]octane-1-carboxamide (58.6 mg).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[C@@:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)([CH3:15])[C@@:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)([CH3:23])[N:12]=[C:11]2[C:31]2[CH:32]=[N:33][C:34]([C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:35][C:36]=2[O:37][CH2:38][CH3:39])=[O:9])[CH2:4][CH2:3]1.[CH2:44]([N:46]=[C:47]=[O:48])[CH3:45]>>[C:40]([C:34]1[N:33]=[CH:32][C:31]([C:11]2[N:10]([C:8]([N:5]3[CH2:4][CH2:3][CH:2]([NH:1][C:47]([NH:46][CH2:44][CH3:45])=[O:48])[CH2:7][CH2:6]3)=[O:9])[C@@:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)([CH3:15])[C@@:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)([CH3:23])[N:12]=2)=[C:36]([O:37][CH2:38][CH3:39])[CH:35]=1)([CH3:42])([CH3:41])[CH3:43]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N)CC1
Reactant: CCN=C=O
Product: CCNC(=O)NC1CCN(C(=O)N2C(c3cnc(C(C)(C)C)cc3OCC)=N[C@@](C)(c3ccc(Cl)cc3)[C@@]2(C)c2ccc(Cl)cc2)CC1

Procedure:
In a manner similar to the method described in example 160, (4-amino-piperidin-1-yl)-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazol-1-yl]-methanone (example 204) was reacted with ethyl isocyanate (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C37H47Cl2N6O3 [(M+H)+] 693.3091, observed 693.3078.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:29])[C@H:11]([CH2:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:12][N:13]([O:16]C2CCCCO2)[CH:14]=[O:15])[C:5]([F:30])=[C:4]([N:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)[N:3]=1.CC(O)=O>O>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:29])[C@H:11]([CH2:23][CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28]2)[CH2:12][N:13]([OH:16])[CH:14]=[O:15])[C:5]([F:30])=[C:4]([N:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)[N:3]=1
Reactant: CN1CCN(c2nc(Cl)nc(NNC(=O)[C@H](CC3CCCC3)CN(C=O)OC3CCCCO3)c2F)CC1
Solvent: CC(=O)O
Solvent: O
Product: CN1CCN(c2nc(Cl)nc(NNC(=O)[C@H](CC3CCCC3)CN(O)C=O)c2F)CC1
Yield: 47.3 %

Procedure:
A solution of [(2R)-3-{2-[2-chloro-5-fluoro-6-(4-methyl-1-piperazinyl)-4-pyrimidinyl]hydrazino}-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (30 mg) in 4:1 AcOH:water (4 mL) was stirred at room temperature overnight. The solvents were removed in vacuo, and the resulting crude product was purified by RP-HPLC to provide [(2R)-3-{2-[2-chloro-5-fluoro-6-(4-methyl-1-piperazinyl)-4-pyrimidinyl]hydrazino}-2-(cyclopentylmethyl)-3-oxopropyl]hydroxyformamide (12 mg, 47%). LCMS: (M+H)+: 458.3.
Reaction SMILES: C[Si](C)(C)[O-].[K+].[Br:7][C:8]1[CH:13]=[C:12](F)[CH:11]=[C:10]([F:15])[CH:9]=1.C[O:17]CCOCCOC.Cl>COC(C)(C)C>[Br:7][C:8]1[CH:13]=[C:12]([OH:17])[CH:11]=[C:10]([F:15])[CH:9]=1
Reactant: COCCOCCOC
Reactant: Fc1cc(F)cc(Br)c1
Agent: C[Si](C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: COC(C)(C)C
Product: Oc1cc(F)cc(Br)c1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
To a N2 flushed, 2 L four necked flask equipped with a mechanical stirrer, a condenser, a temperature controller and a N2 inlet, was added potassium trimethylsilanolate (225.0 g, 1.75 mol, tech. purify 90%), 1-bromo-3,5-difluorobenzene (96.5 g, 0.5 mol) and diglyme (300 mL). The reaction mixture was heated to 120° C. under N2 for 5 h. After cooling to rt, the heating mantle was replaced with an ice bath. The reaction mixture was acidified with a 3 N HCl solution (600 mL) while keeping the reaction temperature below 30° C. Tertiary butyl methyl ether (1 L) was added and the resulting mixture was stirred below 20° C. for 30 min then transferred to a 5 L separatory funnel. The organic layer was separated and washed with water (3×500 mL), sat. NaCl (500 mL), dried over MgSO4, filtered and concentrated in vacuo to give the crude red solid (145.0 g). The crude material was then distillated at 52-55° C./0.1 mm Hg to yield 3-bromo-5-fluorophenol as a slightly yellow oil (88.0 g, 92% yield). 1H NMR (300 MHz, CDCl3) δ 5.34 (s, H), 6.47-6.52 (m, 1H), 6.77-6.83 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:21]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][C:30]([O:32]C)=[O:31])=[CH:25][C:24]=2[O:34][CH3:35])=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[C:16]([C:36]([F:39])([F:38])[F:37])[NH:17]2)(=[O:11])=[O:10].O[Li].O>C1COCC1.CO.O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[C:21]([O:22][C:23]2[CH:28]=[CH:27][C:26]([CH2:29][C:30]([OH:32])=[O:31])=[CH:25][C:24]=2[O:34][CH3:35])=[CH:20][CH:19]=[C:18]2[C:14]=1[CH:15]=[C:16]([C:36]([F:38])([F:39])[F:37])[NH:17]2)(=[O:11])=[O:10]
Reactant: COC(=O)Cc1ccc(Oc2ccc3[nH]c(C(F)(F)F)cc3c2NS(=O)(=O)c2ccc(C)cc2C)c(OC)c1
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(CC(=O)O)ccc1Oc1ccc2[nH]c(C(F)(F)F)cc2c1NS(=O)(=O)c1ccc(C)cc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 14.6 (0.020 g, 0.047 mmol) in a mixture of THF/CH3OH/H2O (0.5 mL, ratio=2/2/1), was added LiOH.H2O (0.010 g, 0.220 mmol). The mixture was stirred at room temperature for 1 h. The solution was chromatographed using HPLC to give 14 as a white solid. MS ESI (pos.) m/z: 549.2 (M+H)+. 1H NMR (400 MHz) (CDCl3) δ 8.32 (s, 1H); 7.57 (d, J=7.2 Hz, 1H); 7.20 (s, 1H); 7.11 (d, J=7.2 Hz, 1H); 6.86 (m, 3H); 6.71 (d, J=9.2 Hz, 1H): 6.64 (d, J=8 Hz, 1H); 6.34 (d, J=8 Hz, 1H); 3.80 (s, 3H); 3.62 (s, 2H); 2.53 (s, 3H); 2.33 (s, 3H).
Reaction SMILES: C(S([C:5]1[N:6]=[CH:7][C:8]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:12]([C:21]3[CH:28]=[CH:27][C:24]([CH:25]=[O:26])=[CH:23][CH:22]=3)=[N:11][C:9]=2[N:10]=1)=O)C.[CH3:29][N:30]([CH3:39])[C:31]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)=[O:32]>O1CCOCC1>[CH:25]([C:24]1[CH:27]=[CH:28][C:21]([C:12]2[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:14][C:8]3[CH:7]=[N:6][C:5]([N:36]4[CH2:35][CH2:34][N:33]([C:31]([N:30]([CH3:39])[CH3:29])=[O:32])[CH2:38][CH2:37]4)=[N:10][C:9]=3[N:11]=2)=[CH:22][CH:23]=1)=[O:26]
Reactant: CN(C)C(=O)N1CCNCC1
Reactant: CCS(=O)c1ncc2cc(-c3ccccc3)c(-c3ccc(C=O)cc3)nc2n1
Solvent: C1COCCO1
Product: CN(C)C(=O)N1CCN(c2ncc3cc(-c4ccccc4)c(-c4ccc(C=O)cc4)nc3n2)CC1
Temperature: 150 °C

Procedure:
To a solution of 4-[2-(ethylsulfinyl)-6-phenylpyrido[2,3-d]pyrimidin-7-yl]benzaldehyde (6-4; 100 mg, 0.258 mmole) in dioxane (1 mL) was added N,N-dimethylpiperazine-1-carboxamide (48 mg, 0.309 mmole) and heated to 150° C. in a microwave reactor for 30 min. The mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography (100% Hex. to 100% EtOAc) to give the title compound. LRMS m/z (M+H) Calcd: 467.2, found 467.1.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C@H:8]2[CH2:12][CH2:11][CH2:10][C@@H:9]2[OH:13])=[CH:6][CH:5]=[N:4]1)[CH3:2]>CCCCCC.C(O)C>[CH2:1]([N:3]1[C:7]([C@@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[OH:13])=[CH:6][CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1nccc1[C@H]1CCC[C@@H]1O
Solvent: CCO
Solvent: CCCCCC
Product: CCn1nccc1[C@@H]1CCC[C@H]1O

Procedure:
The (1S*,2R*)-2-(1-ethyl-1H-pyrazol-5-yl)cyclopentanol prepared in Example 37a was optically resolved with CHIRALPAK AD-H (Daicel Corp.; hexane/ethanol=8:2) to yield the title compound as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([F:10])([F:9])[F:8])=[CH:5][C:4]([NH:11][C:12](=[O:20])OC2C=CC=CC=2)=[N:3]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH2:34][CH2:35][O:36][CH3:37])[N:29]=[CH:28][N:27]=[C:26]2[O:38][C:39]1[CH:40]=[C:41]([CH:43]=[CH:44][CH:45]=1)[NH2:42].C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:21][O:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][C:32]=1[O:33][CH2:34][CH2:35][O:36][CH3:37])[N:29]=[CH:28][N:27]=[C:26]2[O:38][C:39]1[CH:40]=[C:41]([NH:42][C:12]([NH:11][C:4]2[CH:5]=[C:6]([C:7]([F:8])([F:9])[F:10])[N:2]([CH3:1])[N:3]=2)=[O:20])[CH:43]=[CH:44][CH:45]=1
Reactant: Cn1nc(NC(=O)Oc2ccccc2)cc1C(F)(F)F
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(F)(F)F)n(C)n4)c3)c2cc1OC
Yield: 13 %

Procedure:
Using the procedure described in Example 159B, phenyl 1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-ylcarbamate described in Example 165A (0.114 g, 0.4 mmol) was reacted with 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example 117B (0.137 g, 0.4 mmol), and N,N-diisopropylethylamine (0.5 mL) in THF (6 mL) at 50° C. for 3 hours, to afford 1-{3-[6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy]phenyl}-3-[1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]urea as solid (0.028 g, 13%). 1H NMR (300 MHz, CDCl3) δ 9.53 (br, 1H), 8.63 (s, 1H), 7.61 (s, 1H), 7.55 (s, 1H), 7.41 (t, 1H), 7.32 (m, 2H), 7.12 (s, 1H), 7.01 (d, 1H), 6.28 (s, 1H), 4.36 (t, 2H), 4.04 (s, 3H), 3.92 (s and t, 5H), 3.50 (s, 3H); LC-MS (ESI) m/z 533 (M+H)+.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[O:17][C:16]3[C:18]4[CH2:19][CH2:20][CH2:21][C:22]=4[C:23]([CH3:25])=[CH:24][C:15]=3[CH2:14]2)(=O)=O)=CC=1.[N-:26]=[N+:27]=[N-:28].[Na+]>>[CH3:25][C:23]1[C:22]2[CH2:21][CH2:20][CH2:19][C:18]=2[C:16]2[O:17][CH:13]([CH2:12][N:26]=[N+:27]=[N-:28])[CH2:14][C:15]=2[CH:24]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(C)c4c(c3O2)CCC4)cc1
Agent: [Na+]
Product: Cc1cc2c(c3c1CCC3)OC(CN=[N+]=[N-])C2

Procedure:
Treatment of (±)-(5-methyl-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)methyl 4-methylbenzenesulfonate (0.862 g, 2.40 mmol) with sodium azide (0.469 g, 7.21 mmol) generally according to the procedure described for Intermediate 24 gave (±)-(5-methyl-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)methyl azide. Treatment of the azide with palladium on carbon (10 wt. %, 0.055 g) generally according to the procedure described for Example 2 gave 0.460 g (80%) of (±)-1-(5-methyl-3,6,7,8-tetrahydro-2H-indeno[4,5-b]furan-2-yl)methanamine as a white solid, hydrochloride salt. mp>200° C. (dec.); Anal. calcd. for C13H17NOHCl: C, 65.13; H, 7.57; N, 5.84. Found: C, 64.97; H, 7.61; N, 5.67.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH:8]([CH2:17][OH:18])[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:23][C:24]1[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=1[C:26]([O:28][CH3:29])=[O:27].CC(=O)OCC>C1COCC1>[Br:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][CH:8]([NH:7][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:19])[CH2:17][O:18][CH2:23][C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([O:28][CH3:29])=[O:27])=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)NC(CO)Cc1ccc(Br)cc1
Reactant: COC(=O)c1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1COCC(Cc1ccc(Br)cc1)NC(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 33.4 %

Procedure:
To a solution of compound 3f (6.6 g, 20 mmol) in dry THF (100 mL) was added NaH (60%, 960 mg, 24 mmol) in small portions at 0° C. and stirred for 1 hr. Then compound 3b (5 g, 22 mmol) in THF (50 mL) was added dropwise, and the reaction mixture was allowed to stir at rt overnight. The reaction was quenched with water and extracted with EA (2×100 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by CC eluting with PE:EA=9:1 to give 3g as a white solid (3.2 g, 34% yield).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.I[CH2:10][CH2:11][OH:12].C(N(C(C)C)CC)(C)C>C(#N)C>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH2:10][CH2:11][OH:12]
Reactant: CNc1ccccc1
Reactant: OCCI
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCO)c1ccccc1
Yield: 60 %

Procedure:
N-methylaniline (5 mls, 0.05 mol) was reacted with 2-Iodoethanol (3.599 mls, 0.05 mol) and diisopropylethylamine (8.039 mls, 0.05 mol) in ACN at 70° C. for 16 hours. The solvent was evaporated and the residue was purified by silica gel column chromatography with hexane/EtOAc to provide the compound as a yellow orange oil, 2a (4.48 g, 0.03 mol, 64.5% yield). 1H NMR (400 MHz, Chloroform-d) δ 7.27-7.15 (m, 2H), 6.81-6.67 (m, 3H), 3.74 (t, J=5.8 Hz, 2H), 3.42 (t, J=5.8 Hz, 2H), 2.92 (s, 3H).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][C:21]=2[F:22])[N:18]([CH3:23])[C:17](=[O:24])[CH2:16][CH2:15]3)[CH:9]=[N:10][CH:11]=1.[CH2:25]([S:27](Cl)(=[O:29])=[O:28])[CH3:26]>>[F:22][C:21]1[CH:20]=[C:19]2[C:14]([CH2:15][CH2:16][C:17](=[O:24])[N:18]2[CH3:23])=[CH:13][C:12]=1[C:8]1[CH:7]=[C:6]([O:5][CH2:4][CH2:3][NH:2][S:27]([CH2:25][CH3:26])(=[O:29])=[O:28])[CH:11]=[N:10][CH:9]=1
Reactant: CCS(=O)(=O)Cl
Reactant: CN1C(=O)CCc2cc(-c3cncc(OCCN)c3)c(F)cc21
Agent: Cl
Product: CCS(=O)(=O)NCCOc1cncc(-c2cc3c(cc2F)N(C)C(=O)CC3)c1

Procedure:
In analogy to the procedure described for the preparation of example 38, 6-[5-(2-amino-ethoxy)-pyridin-3-yl]-7-fluoro-1-methyl-3,4-dihydro-1H-quinolin-2-one hydrochloride (example 238) and ethanesulfonyl chloride gave the title compound as an orange amorphous solid. MS: 408.4 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([S:6][CH2:7][CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1>CS(O)(=O)=O.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:6][CH2:7][CH2:8][C:9](=[O:11])[C:12]=2[CH:13]=1
Reactant: O=C(O)CCSc1ccc(Br)cc1
Agent: CS(=O)(=O)O
Solvent: O
Product: O=C1CCSc2ccc(Br)cc21
Temperature: 25 °C

Procedure:
A solution of 3.63 g (13.9 mmol) of 3-(4-bromothiophenoxy)propionic acid in 60 ml methanesulfonic acid was heated to 75° C. for 1.5 hours. After cooling to room temperature the solution was diluted with H2O and extracted with EtOAc. The combined organic layers were washed with 2N aqueous NaOH, H2O, and saturated aqueous NaCl and then dried over MgSO4. Removal of the solvent under reduced pressure afforded a yellow solid from which the product was isolated by column chromatography (3% hexanes) as a pale-yellow solid. 1H NMR (CDCl3): δ 8.22 (1H, d, J=2.1 Hz), 7.48 1H, dd, J=2.1, 8.3 Hz), 7.17 (1H, d, J=8.5 Hz), 3.24 (2H, t, J=6.4 Hz), 2.98 (2H, t, J=6.7 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]3[CH2:18][CH2:17][C@H:16]([NH:19][C:20]4[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][C:21]=4[F:30])[C:15]3=[O:31])[CH2:10][CH2:9]2)=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:40]2[CH:41]=[N:42][N:43](C(OC(C)(C)C)=O)[CH:44]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>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>[NH:42]1[CH:41]=[C:40]([C:2]2[CH:3]=[N:4][C:5]([N:8]3[CH2:13][CH2:12][CH:11]([N:14]4[CH2:18][CH2:17][C@H:16]([NH:19][C:20]5[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][C:21]=5[F:30])[C:15]4=[O:31])[CH2:10][CH2:9]3)=[N:6][CH:7]=2)[CH:44]=[N:43]1
Reactant: CS(=O)(=O)c1ccc(N[C@H]2CCN(C3CCN(c4ncc(Br)cn4)CC3)C2=O)c(F)c1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: [Na+]
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(N[C@H]2CCN(C3CCN(c4ncc(-c5cn[nH]c5)cn4)CC3)C2=O)c(F)c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
(S)-1-(1-(5-Bromopyrimidin-2-yl)piperidin-4-yl)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)pyrrolidin-2-one (Example 7; 0.090 g, 0.17 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (0.057 g, 0.19 mmol), Pd(PPh3)4 (0.020 g, 0.018 mmol) and Na2CO3 (0.44 mL, 0.88 mmol) were suspended in dioxane in a sealed tube and stirred at 110° C. overnight. The material was cooled and filtered through silica gel (10% MeOH/EtOAc). The material was purified by reverse phase HPLC purification (5 to 95% acetonitrile in water) to give (S)-1-(1-(5-(1H-pyrazol-4-yl)pyrimidin-2-yl)piperidin-4-yl)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)pyrrolidin-2-one (0.037 g, 42% yield) as a white solid. Mass spectrum (apci) m/z=500.3 (M+H).
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:9]=[N:10][C:11](Cl)=[N:12][CH:13]=1.[CH2:15]([OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C)C=O>[CH2:15]([O:22][C:11]1[N:10]=[CH:9][C:8]([Br:7])=[CH:13][N:12]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Clc1ncc(Br)cn1
Reactant: OCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cnc(OCc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Potassium tert-butoxide (6.96 g) was added to a solution of 5-bromo-2-chloro-pyrimidine (10 g) and benzyl alcohol (6.4 ml) in N,N-dimethylformamide (140 ml) and the mixture was stirred at room temperature for 1.5 hours. Water was added to the mixture and the precipitated solid was collected by filtration, washed with methanol, dried to give the titled compound (10.6 g). MS (m/z): 265/267 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:8]=2)[CH:5]=[N:4][C:3]=1[C:20]#N.CC(C[AlH]CC(C)C)C.[OH2:31].Cl>C1(C)C=CC=CC=1>[CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:8]=2)[CH:5]=[N:4][C:3]=1[CH:20]=[O:31]
Reactant: O
Reactant: Cc1c(C#N)ncn1-c1cccc(Oc2ccccc2)c1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1c(C=O)ncn1-c1cccc(Oc2ccccc2)c1
Temperature: -70 °C
Reaction time: 2 h

Procedure:
4.13 g of 5-methyl-1-(3-phenoxyphenyl)-imidazole-4-carbonitrile is dissolved in 200 ml of toluene. At -60° C. to -70° C., 15 ml of Dibah, 1.2 mol in toluene is instilled. It is stirred for 2 hours at -70° C., 2.5 ml of water is instilled at -70° C. and the mixture is allowed to come to room temperature. It is adjusted to pH 4 with 2N hydrochloric acid solution and the mixture is extracted with toluene and ethyl acetate. The organic phases are combined and dried on MgSO4. After purification by column chromatography, 2.46 g (59% of theory) of the title compound is obtained as oil.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]=1.[Cl:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18]Cl.[I-].[Na+]>C(OCC)(=O)C>[Cl:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][N:5]1[C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[N:8]=[C:4]1[CH3:3]
Reactant: ClCCOCCCl
Reactant: Cc1nc2ccccc2[nH]1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1nc2ccccc2n1CCOCCCl
Temperature: 0 °C

Procedure:
Part A. A mineral oil suspension of sodium hydride (0.91 g, 50%, 37.8 mmol) was washed with hexane and dried under vacuum, then suspended in dimethylsulfoxide (20 mL). The mixture was cooled to 0° C., and a solution of 2-methyl-1H-benzimidazole (5.00 g, 37.8 mmol) was added dropwise with stirring. The mixture was stirred for 5 hours with warming to ambient temperature, then was treated dropwise with a solution of chloroethyl ether (8.90 mL, 75.6 mmol). Sodium iodide (2.83 g, 18.9 mmol) was added, and the mixture was heated to 90° C. for 18 hours. After being cooled to ambient temperature, the reaction mixture was poured into 400 mL ethyl acetate, and washed with water (3×400 mL). The aqueous phases were back-extracted in sequence with ethyl acetate (400 mL). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered and evaporated. The residual oil was separated by flash chromatography to afford the product, 1-[ 2-(2-chloroethoxy)ethyl]-2-methyl-1H-benzimidazole, as a white solid, m.p. 96°-98° C. 1H NMR (CDCl3): 7.74-7.64 (1H, m); 7.31-7.20 (3H, m); 4.31 (2H, t, J=5.4 Hz); 3.81 (2H, t, J=5.4 Hz); 3.59 (2H, t, J=5.1 Hz); 3.51 (2H, t, J=5.1 Hz); 2.64 (3H, s).