Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]1COCC1.[F:16][C:17]1[CH:18]=[C:19]([C@@H:24]2[CH2:29][CH2:28][CH2:27][C:26](=[O:30])[N:25]2[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:20]=[C:21]([F:23])[CH:22]=1.IC>COCCOC>[F:16][C:17]1[CH:18]=[C:19]([C@H:24]2[N:25]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:26](=[O:30])[C@H:27]([CH3:11])[CH2:28][CH2:29]2)[CH:20]=[C:21]([F:23])[CH:22]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)CCC[C@H]1c1cc(F)cc(F)c1
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: COCCOC
Solvent: CI
Product: C[C@@H]1CC[C@@H](c2cc(F)cc(F)c2)N(C(=O)OC(C)(C)C)C1=O
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a 1 M solution of sodium bis(trimethylsilyl)amide in THF (0.642 mL, 0.642 mmol) at −78° C. was added dropwise a solution of tert-butyl (2S)-2-(3,5-difluorophenyl)-6-oxopiperidine-1-carboxylate (200 mg, 0.642 mmol, described in Intermediate 26) in DME (10 mL) at −78° C. The resulting mixture was stirred at −78° C. for 10 min then iodomethane (0.040 mL, 0.642 mmol) was added. After stirring at −78° C. for 30 min and at −30° C. for 30 min, the reaction mixture was cooled to −78° C. and quenched with saturated aqueous NH4Cl (10 mL) and extracted with EtOAc (2×10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 90:10. MS: m/z=270 (M−C4H7).
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[CH3:26][S:27]([OH:29])(=[O:1])=[O:28].[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)=[CH:9][CH:10]=1
Reactant: CS(=O)(=O)Cl
Agent: N#Cc1ccc(-c2ccc(OCCO)cc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of example 14A (150 mg, 0.63 mmol) in 6 mL CH2Cl2 at 0° C. was added triethylamine (127 mg, 1.26 mmol, 2 eq.) followed by methanesulfonyl chloride (108 mg, 0.94 mmol, 1.5 eq.). After stirring at ambient temperature for 4 h, the reaction mixture was concentrated and purified on silica gel with 25% EtOAc/hexanes to provide 185 mg (92%) of the desired compound as a white solid.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[C:21]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[C:20]([F:28])[CH:19]=[CH:18][C:17]=1B(O)O>>[F:28][C:20]1[C:21]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[C:16]([F:15])[CH:17]=[CH:18][C:19]=1[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([CH3:13])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1
Reactant: OB(O)c1ccc(F)c(-c2cccnc2)c1F
Reactant: CC(C)(F)c1ccn2c(Br)cnc2n1
Product: CC(C)(F)c1ccn2c(-c3ccc(F)c(-c4cccnc4)c3F)cnc2n1

Procedure:
3-Bromo-7-(1-fluoro-1-methylethyl)imidazo[1,2-α]pyrimidine was coupled to 2,4-difluoro-3-(pyridin-3-yl)phenylboronic acid as described in Example 65 to afford 3-[2,4-difluoro-3-(pyridin-3-yl)phenyl]-7-(1-fluoro-1-methylethyl)imidazo[1,2-α]pyrimidine as a white solid: δH (360 MHz, CDCl3) 1.80 (6H, d, J 22), 7.21-7.29 (2H, m), 7.46 (1H, dd, J 8 and 5), 7.50-7.57 (1H, m), 7.85 (1H, d, J 8), 7.92 (1H, s), 8.31 (1H, dd, J 7 and 3), 8.70 (1H, dd, J 5 and 1), 8.79 (1H, s); m/z (ES+) 369 (M++H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]2[N:19]=[CH:18][N:17]=[C:16]3[C:12]=2[N:13]=[C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:33])[N:15]3[C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[CH2:5][CH2:4]1.[S:34](N)([NH2:37])(=[O:36])=[O:35]>O1CCOCC1>[Cl:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:14]1[N:15]([C:20]2[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=2)[C:16]2[C:12]([N:13]=1)=[C:11]([NH:10][CH2:9][CH:6]1[CH2:7][CH2:8][CH:3]([CH2:2][NH:1][NH:37][SH:34](=[O:36])=[O:35])[CH2:4][CH2:5]1)[N:19]=[CH:18][N:17]=2
Reactant: NS(N)(=O)=O
Reactant: NCC1CCC(CNc2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Solvent: C1COCCO1
Product: O=[SH](=O)NNCC1CCC(CNc2ncnc3c2nc(-c2ccccc2Cl)n3-c2ccc(Cl)cc2)CC1
Temperature: 80 °C
Reaction time: 16 h
Yield: 24.2 %

Procedure:
To a solution of N-{[4-(aminomethyl)cyclohexyl]methyl}-8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-amine (6.6 mg, 0.014 mmol, 1 eq.) in 5 mL of dioxane was added 10 mg of sulfamide. The reaction was heated to 80° C. and stirred 16 h. The reaction was concentrated in vacuo. The crude material was purified by silica gel column chromatography using 0-100% ethyl acetate/hexanes to yield 1.9 mg (25%) of N-{[4-({[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]amino}methyl)cyclohexyl]methyl}aminosulfonamide. 1H NMR (300 MHz, METHANOL-d4) δ ppm 0.80-1.17 (m, 2 H) 1.21-1.79 (m, 6 H) 1.93 (br. s., 2 H) 3.00 (d, J=7.16 Hz, 2 H) 3.59 (br. s., 2 H) 7.19-7.69 (m, 8 H) 8.13-8.35 (m, 1 H), [M+H]+ 562.2.
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[C:5]([O:9][C:10]([NH:12][C@H:13]([C:21]([OH:23])=O)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11])([CH3:8])([CH3:7])[CH3:6].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CCOCC>[C:5]([O:9][C:10]([NH:12][C@@H:13]([CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:21](=[O:23])[CH:1]=[CH2:2])=[O:11])([CH3:6])([CH3:7])[CH3:8]
Reactant: C=C[Mg]Br
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOCC
Product: C=CC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 5 h
Yield: 35 %

Procedure:
Vinylmagnesium bromide (1M in tetrahydrofuran) was cooled under N2 atmosphere to -10° C. and treated in portions with 10 g (37.7 mmol) of N-(t-butyloxycarbonyl)-L-phenylalanine. The resulting solution was stirred at -10° C. for 5 h, and poured into a rapidly stirring mixture of ice, 10% aqueous citric acid and ether. The mixture was separated, and the organic phase was washed sequentially with water, two portions of aqueous NaHCO3, and saturated brine; dried over MgSO4 ; and concentrated in vacuo. Silica gel chromatography of the residue using 4:1 hexane:ethyl acetate provided 3.63 g (35%) of the desired compound (Rf 0.33, 3:1 hexane:ethyl acetate). 1H NMR (CDCl3) δ 1.41 (s, 9 H), 2.98 (dd, J=14, 6 Hz, 1 H), 3.15 (dd, J=14, 6 Hz, 1 H), 4.86 (q, J=8 Hz, 1 H), 5.23 (br d, 1 H), 5.85 (dd, J=9, 2 Hz, 1 H), 6.35 (dd, J=18, 2 Hz, 1 H), 6.45 (dd, J=18, 9 Hz, 1 H), 7.10 (br d, 2 H), 7.25 (m, 3 H). Mass spectrum: (M+H)+ =276.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:12]([NH2:13])=[CH:11][C:10]([C:14]3[CH2:15][CH2:16][O:17][CH2:18][CH:19]=3)=[CH:9][N:8]=2)[CH2:3][CH2:2]1.Cl[C:21]1[C:30]2[C:25](=[CH:26][C:27]([F:32])=[CH:28][C:29]=2[F:31])[N:24]=[C:23]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[C:22]=1[CH3:39].C1(P(C2CCCCC2)C2(C(C)C)CC(C(C)C)=CC(C(C)C)=C2C2C=CC=CC=2)CCCCC1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[O:1]1[CH2:2][CH:3]=[C:4]([C:7]2[C:12]([NH:13][C:21]3[C:30]4[C:25](=[CH:26][C:27]([F:32])=[CH:28][C:29]=4[F:31])[N:24]=[C:23]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=4)[C:22]=3[CH3:39])=[CH:11][C:10]([C:14]3[CH2:15][CH2:16][O:17][CH2:18][CH:19]=3)=[CH:9][N:8]=2)[CH2:5][CH2:6]1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Cl
Reactant: Nc1cc(C2=CCOCC2)cnc1C1=CCOCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)C1=CC(C(C)C)=C(c2ccccc2)C(C(C)C)(P(C2CCCCC2)C2CCCCC2)C1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(C2=CCOCC2)cnc1C1=CCOCC1
Temperature: 90 °C
Reaction time: 21 h

Procedure:
A mixture of 2,5-bis(3,6-dihydro-2H-pyran-4-yl)pyridin-3-amine (47.3 mg, 0.18 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinoline (47.8 mg, 0.16 mmol), 2-dicyclohexylphosphino-2,4,6,-triisopropylbiphenyl, (X-Phos) (12.6 mg, 0.026 mmol), tris(dibenzylideneacetone)dipalladium (0) (7 mg, 7.6 μmol), and sodium tert-butoxide (56.6 mg, 0.59 mmol) in dry toluene (1.5 mL) was degassed by nitrogen. The resulting reaction was heated to 90° C. and monitored with TLC and LC-MS. After 21 h, the reaction was cooled to rt then poured into water. After extracting twice with EtOAc and twice with DCM, the combined organic extractions were dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on basic alumina (10-30% EtOAc in hexanes) to afford a yellow solid as N-(2,5-bis(3,6-dihydro-2H-pyran-4-yl)-pyridin-3-yl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine. 1H NMR (500 MHz, CDCl3) δ ppm 8.71 (1H, dt, J=4.9, 1.2 Hz), 8.27 (1H, d, J=1.7 Hz), 7.96 (2H, m), 7.66 (1H, m), 7.44 (1H, m), 7.32 (1H, d, J=10.3 Hz), 7.03 (2H, ddd, J=13.4, 8.6, 2.4 Hz), 6.37 (1H, m), 6.19 (1H, m), 4.40 (2H, m), 4.30 (2H, q, J=2.7 Hz), 4.04 (2H, t, J=5.4 Hz), 3.90 (2H, t, J=5.5 Hz), 2.72 (2H, m), 2.45 (2H, m), 2.18 (3H, s). Mass Spectrum (pos.) m/e: 513.1 (M+1).
Reaction SMILES: [C:1]([C:6]1(C(OCC)=O)[CH2:15][CH2:14][C:13]2[NH:12][C:11](=[O:16])[NH:10][C:9](=[O:17])[C:8]=2[CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2].Cl>[OH-].[Na+]>[C:1]([CH:6]1[CH2:15][CH2:14][C:13]2[NH:12][C:11](=[O:16])[NH:10][C:9](=[O:17])[C:8]=2[CH2:7]1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)C1(C(=O)OCC)CCc2[nH]c(=O)[nH]c(=O)c2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)C1CCc2[nH]c(=O)[nH]c(=O)c2C1

Procedure:
A solution of 6,6-Dicarboethoxy-5,6,7,8-tetrahydro-2,4(1H,3H)-quinazolinedione (25 g) in 1N NaOH (350 mL) was stirred at 40° C. for 35 min. The solution was cooled in an ice bath and acidified with 35 mL of concentrated HCl. The precipitate that formed was collected and refluxed in 20 ml of dimethylformamide (DMF) for 2 h. The reaction was cooled and the DMF removed in vacuo. To the resulting mixture 40 mL of water was added and the solid collected and dried to yield 6-Carboethoxy-5,6,7,8-tetrahydro-2,4(1H,3H)-quinazolinedione.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][C:9]([CH2:13][C:14]([O:16]C)=[O:15])=[CH:8][CH:7]=2.[C:18]1([CH2:24][CH2:25][C:26]2[C:30]3[CH:31]=[CH:32][C:33](O)=[C:34]([CH2:35][CH2:36][CH3:37])[C:29]=3[O:28][N:27]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([CH2:24][CH2:25][C:26]2[C:30]3[CH:31]=[CH:32][C:33]([O:1][CH2:2][CH2:3][C:4]4[NH:5][C:6]5[C:11]([CH:12]=4)=[CH:10][C:9]([CH2:13][C:14]([OH:16])=[O:15])=[CH:8][CH:7]=5)=[C:34]([CH2:35][CH2:36][CH3:37])[C:29]=3[O:28][N:27]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCCc1c(O)ccc2c(CCc3ccccc3)noc12
Reactant: COC(=O)Cc1ccc2[nH]c(CCO)cc2c1
Product: CCCc1c(OCCc2cc3cc(CC(=O)O)ccc3[nH]2)ccc2c(CCc3ccccc3)noc12

Procedure:
Using the procedures in Example 1, steps F and G, the title compound was prepared from methyl 2-(2-hydroxyethyl)indole-5-acetate and 3-(2-phenyl)ethyl-7-(n-propyl )-6-hydroxybenz[4,5]isoxazole as a slightly tan solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:28](O)=[O:29])=[N:11][C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:13][C:14]=1[OH:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Si:64]([O:71][CH2:72][CH2:73][NH:74][CH:75]1[CH2:77][CH2:76]1)([C:67]([CH3:70])([CH3:69])[CH3:68])([CH3:66])[CH3:65]>CN(C)C=O.CCCCCC.C(OCC)(=O)C>[Si:64]([O:71][CH2:72][CH2:73][N:74]([CH:75]1[CH2:76][CH2:77]1)[C:28]([C:10]1[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:14]([OH:15])[N:13]=[C:12]([CH2:16][C:17]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:11]=1)=[O:29])([C:67]([CH3:70])([CH3:69])[CH3:68])([CH3:66])[CH3:65]
Reactant: O=C(O)c1nc(CC2(c3ccccn3)CCCC2)nc(O)c1OCc1ccccc1
Reactant: CC(C)(C)[Si](C)(C)OCCNC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCCCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCN(C(=O)c1nc(CC2(c3ccccn3)CCCC2)nc(O)c1OCc1ccccc1)C1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.3 %

Procedure:
To a stirred solution of 5-benzyloxy-6-hydroxy-2-(1-pyridin-2-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (437) (150 mg, 0.494 mmol) in dimethylformamide (5 mL), N,N-diisopropylethylamine (0.184 mL, 1.111 mmol), HATU (211.24 mg, 0.556 mmol) and [2-(tert-Butyl-dimethylsilanyloxy)-ethyl]-cyclopropyl-amine (crude) (8d) (239 mg) were added. This reaction mixture was allowed to stir for 16 h at room temperature while silica thin layer chromatography was performed (50% ethyl acetate in hexane; Rf=0.5) The reaction was quenched with ice cold water (25 mL) and extracted with ethyl acetate (2×30 mL). The organic part was dried, then concentrated and the crude product was purified by normal silica gel (100-200 mesh) column chromatography using 30-40% ethyl acetate in hexane as gradient polarity mobile phase to get 5-benzyloxy-6-hydroxy-2-(1-pyridin-2-yl-cyclopentylmethyl)-pyrimidine-4-carboxylicacid[2-(tert-butyl-dimethylsilanyloxy)-ethyl]-cyclopropyl-amide (450) (120 mg, 54%) as a yellow sticky liquid.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([CH2:22][CH:23]([CH3:25])[CH3:24])=[N:15][N:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([N-]C(C)C)(C)C.[Li+].C([Li])CCC.C(NC(C)C)(C)C.[CH3:46][S:47]SC>O1CCCC1.CCOCC.O>[CH:1]1([NH:6][C:7]2[N:12]=[C:11]([C:13]3[C:14]([CH2:22][CH:23]([CH3:25])[CH3:24])=[N:15][N:16]4[C:21]([S:47][CH3:46])=[CH:20][CH:19]=[CH:18][C:17]=34)[CH:10]=[CH:9][N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CSSC
Reactant: CC(C)Cc1nn2ccccc2c1-c1ccnc(NC2CCCC2)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CSc1cccc2c(-c3ccnc(NC4CCCC4)n3)c(CC(C)C)nn12
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a cold (−78° C.) solution of N-cyclopentyl-4(2-isobutylpyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-amine (750 mg, 2.23 mmol) in tetrahydrofuran (25 mL) was added lithium diisopropylamide (LDA) (11.18 mL of a 0.6 M stock solution was prepared from 18.75 mL of 1.6 M butyllithium and 4.20 mL of diisopropylamine in 27 mL of tetrahydrofuran, 6.71 mmol) dropwise. The reusitant solution was stirred at −78° C. for 15 minutes. Dimethyldisulfide (1.0 mL, 11.15 mmol) was added rapidly and the mixture was stirred for 1 hour. Water and ether were added and the layers separated. The organic layer was washed with brine. The aqueous layer was extracted with ether and the combined organics were dried over magnesium sulfate. Filtration and concentration followed flash chromatography on silica gel (2:1 hexane-ether) provided N-cyclopentyl-4-[2-isobutyl-7-(methylthio)pyrazolo[1,5-a]pyridin-3-yl]pyrimidin-2-amine. (712 mg, 84%) as a yellow solid. 1H NMR (CDCl3) δ 8.25 (d, 1H), 8.07 (d, 1H), 7.25 (t, 1H), 6.75 (d, 1H), 6.61 (d, 1H), 5.04 (d, 1H), 4.37 (m, 1H), 3.05 (d, 2H), 2.61 (s, 3H), 2.26–2.05 (m, 3H), 1.79–1.50 (m, 6H), 0.97 (d, 6H); MS m/z 382 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[F:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1.[H-].[Na+].O>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:16][C:15]3[CH:18]=[CH:19][C:12]([F:11])=[CH:13][CH:14]=3)[CH:9]=[CH:10][C:3]=12
Reactant: Clc1ccnc2[nH]ccc12
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(Cn2ccc3c(Cl)ccnc32)cc1
Yield: 76.7 %

Procedure:
To 4-chloro-1H-pyrrolo[2,3-b]pyridine (300 mg, 2.00 mmol) in 5 ml DMF was added 4-Fluorobenzylbromide (0.27 ml, 2.2 mmol) then add NaH (80 mg, 2.0 mmol) and stir at room temperature overnight. Work up by adding water and EtOAc and extract three times with EtOAc. Pool all organics and wash one time with brine then dry over sodium sulfate, filter and concentrate to dryness. The residue was purified by chromatography over silica gel (eluted with Hexanes/EtOAc 99:1 to 50:50) to provide 400 mg (77%) of product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](Cl)=[O:13])[C:10]3[N:15]=[CH:16][CH:17]=[CH:18][C:9]=3[NH:8][C:7](=[O:19])[C:6]=2[CH:20]=1.[CH2:21]([N:23]([CH2:26][CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][N:28]1[CH2:33][CH2:34][NH2:35])[CH2:24][CH3:25])[CH3:22].N>ClCCl.C(OCC)(=O)C.C1CCCCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12]([NH:35][CH2:34][CH2:33][N:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH:27]3[CH2:26][N:23]([CH2:21][CH3:22])[CH2:24][CH3:25])=[O:13])[C:10]3[N:15]=[CH:16][CH:17]=[CH:18][C:9]=3[NH:8][C:7](=[O:19])[C:6]=2[CH:20]=1
Reactant: CCN(CC)CC1CCCCN1CCN
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccc(Br)cc21
Agent: N
Solvent: ClCCl
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: CCN(CC)CC1CCCCN1CCNC(=O)N1c2ccc(Br)cc2C(=O)Nc2cccnc21
Yield: 25 %

Procedure:
Prepared analogously to Example 2 from 8-bromo-11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2-[2-[(diethylamino)methyl]-piperidin-1-yl]ethanamine in a yield of 25% of theory. Colourless crystals, m.p. 117°-119° C., RF 0.3 (Macherey-Nagel, PolygramRSIL G/UV254, pre-coated plastic sheets for TLC, eluant: dichloromethane/ethyl acetate/cyclohexane/methanol/conc. ammonia 58/25/8/8/1 v/v).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:18]2[CH2:22][CH2:21][O:20][CH2:19]2)=[N:9][NH:10]C(OC(C)(C)C)=O)=[C:4](F)[CH:3]=1.N12CCCN=C1CCCCC2>O1CCCC1>[Br:1][C:2]1[CH:7]=[C:6]2[C:5]([C:8]([CH:18]3[CH2:22][CH2:21][O:20][CH2:19]3)=[N:9][NH:10]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)NN=C(c1ccc(Br)cc1F)C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: Brc1ccc2c(C3CCOC3)n[nH]c2c1
Temperature: 150 °C
Yield: 53.4 %

Procedure:
A mixture of 1,1-dimethylethyl 2-[(4-bromo-2-fluorophenyl)(tetrahydro-3-furanyl)methylidene]hydrazinecarboxylate (Intermediate 8, 1.1 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (424 μL) in tetrahydrofuran (12 mL) in a sealed vial was heated in a microwave oven at 150° C. for 30 min. The reaction mixture was partitioned between ethyl acetate (15 mL) and water (15 mL) and the organic layer was dried using a hydrophobic filter tube and concentrated under vacuum. The residue was purified by chromatography on a silica column, eluting with a cyclohexane:ethyl acetate gradient, to give the title compound as a colourless glass (405 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]1[N:8]=[CH:7][N:6]=[C:5]([C:9](OCC)=[O:10])[C:4]=1[CH3:14].[BH4-].[Na+]>CCO>[CH3:1][N:2]([CH3:15])[C:3]1[N:8]=[CH:7][N:6]=[C:5]([CH2:9][OH:10])[C:4]=1[CH3:14]
Reactant: CCOC(=O)c1ncnc(N(C)C)c1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1c(CO)ncnc1N(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of ethyl 6-(dimethylamino)-5-methylpyrimidine-4-carboxylate (45) (60.0 g, 287.0 mmol) in EtOH (600 mL) was added in portionwise NaBH4 (21.82 g, 574.0 mmol) at 0° C. and the mixture was stirred for 16 h at RT. The solvent was evaporated under the reduced pressure and the reaction mixture was poured in to water (200 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layer was washed with water, brine, dried over sodium sulfate and concentrated at reduced pressure to yield (6-(dimethylamino)-5-methylpyrimidin-4-yl)methanol (46); 47 g, (97%).
Reaction SMILES: [Na].[CH3:2][C:3]1[CH:11]=[CH:10][C:9]2[NH:8][C:7]3[CH:12]4[CH2:18][CH2:17][N:15]([CH2:16][C:6]=3[C:5]=2[CH:4]=1)[CH2:14][CH2:13]4.[F:19][C:20]([F:30])([F:29])[C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[CH2:28])=[CH:23][N:22]=1.C1(C=CC(O)=CC=1)O>CS(C)=O>[CH3:2][C:3]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:28][CH2:27][C:24]3[CH:23]=[N:22][C:21]([C:20]([F:30])([F:19])[F:29])=[CH:26][CH:25]=3)[C:7]3[CH:12]4[CH2:13][CH2:14][N:15]([CH2:16][C:6]=3[C:5]=2[CH:4]=1)[CH2:17][CH2:18]4
Reactant: Cc1ccc2[nH]c3c(c2c1)CN1CCC3CC1
Reactant: C=Cc1ccc(C(F)(F)F)nc1
Agent: Oc1ccc(O)cc1
Agent: [Na]
Solvent: CS(C)=O
Product: Cc1ccc2c(c1)c1c(n2CCc2ccc(C(F)(F)F)nc2)C2CCN(CC2)C1
Temperature: 115 °C

Procedure:
Sodium dispersion in paraffin (30%, 46 mg, 0.60 mmol; Aldrich) was combined with 9-methyl-3,4,5,6-tetrahydro-1H-2,5-ethanoazepino[4,3-b]indole (100 mg, 0.442 mmol; Example 2B) in a 20 mL vial with stir bar and septum cap. Dimethyl sulfoxide (2.5 mL) was added, and the vial was evacuated and purged with nitrogen (10 cycles). The mixture was stirred at room temperature for 10 minutes, and a solution of the product of Example 143A (115 mg, 0.663 mmol) and hydroquinone (12 mg, 0.110 mmol) in dimethyl sulfoxide (0.5 mL) was added. The vial was evacuated and purged with nitrogen (5 cycles) and the mixture was stirred with heating at 115° C. for 39 hours. The dark brown mixture was cooled to room temperature, applied directly to a column of silica gel and eluted with chloroform, followed by CHCl3—CH3OH-14.8 M aqueous NH4OH (90:10:1). The product-containing fractions were combined and concentrated under vacuum, and the residue was purified by HPLC [Waters XBridge C18 5 μm OBD column, 30×100 mm, flow rate 40 mL/minute, 20-90% gradient of acetonitrile in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide) over 20 minutes] to provide the title compound: 1H NMR (300 MHz, methanol-d4) δ 1.46-1.64 (m, 2H), 1.79-1.98 (m, 2H), 2.38 (s, 3H), 2.84-3.01 (m, 3H), 3.05-3.22 (m, 4H), 4.16 (s, 2H), 4.42 (t, J=6.27 Hz, 2H), 6.89 (dd, J=8.48, 1.02 Hz, 1H), 7.09 (d, J=7.80 Hz, 1H), 7.10 (d, J=0.68 Hz, 1H), 7.54 (dd, J=8.10, 1.70 Hz, 1H), 7.59 (d, J=8.10 Hz, 1H), 8.12 ppm (s, 1H); MS (ESI) m/z 400 (MH)+.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[C:4]([CH2:9][N:10]2[C:18]3[C:13](=[CH:14][C:15]([CH:19]=O)=[CH:16][CH:17]=3)[CH:12]=[N:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.[OH:23][CH2:24][C@H:25]1[O:30][CH2:29][CH2:28][N:27]([C:31]2[S:32][CH2:33][C:34](=[O:36])[N:35]=2)[CH2:26]1>>[OH:23][CH2:24][C@H:25]1[O:30][CH2:29][CH2:28][N:27]([C:31]2[S:32][C:33](=[CH:19][C:15]3[CH:14]=[C:13]4[C:18](=[CH:17][CH:16]=3)[N:10]([CH2:9][C:4]3[C:3]([C:2]([F:22])([F:1])[F:21])=[CH:8][CH:7]=[CH:6][N:5]=3)[N:11]=[CH:12]4)[C:34](=[O:36])[N:35]=2)[CH2:26]1
Reactant: O=Cc1ccc2c(cnn2Cc2ncccc2C(F)(F)F)c1
Reactant: O=C1CSC(N2CCO[C@H](CO)C2)=N1
Product: O=C1N=C(N2CCO[C@H](CO)C2)SC1=Cc1ccc2c(cnn2Cc2ncccc2C(F)(F)F)c1

Procedure:
2-[(2S)-2-(Hydroxymethyl)morpholin-4-yl]-5-[(1-{[3-(trifluoromethyl)pyridin-2-yl]methyl}-1H-indazol-5-yl)methylidene]-1,3-thiazol-4(5H)-one was prepared from 1-(3-Trifluoromethyl-pyridin-2-ylmethyl)-1H-indazole-5-carbaldehyde and 2(S)-(2-Hydroxymethyl-morpholin-4-yl)-thiazol-4-one following General Procedure D.
Reaction SMILES: [H-].[Na+].I[CH3:4].[Cl:5][C:6]1[N:11]=[C:10]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[C:9]([Cl:21])=[CH:8][N:7]=1>C1COCC1>[Cl:5][C:6]1[N:11]=[C:10]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH3:4])[CH:13]=2)[C:9]([Cl:21])=[CH:8][N:7]=1
Reactant: CI
Reactant: Clc1ncc(Cl)c(-c2c[nH]c3ccccc23)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cn1cc(-c2nc(Cl)ncc2Cl)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.4 %

Procedure:
Sodium hydride (0.136 g, 3.41 mmol) and iodomethane (0.533 ml, 8.52 mmol) were added to a flask charged with 3-(2,5-dichloropyrimidin-4-yl)-1H-indole (INTERMEDIATE 2) (0.750 g, 2.84 mmol) and THF (18.40 ml). The reaction was stirred at RT for 2 h. The reaction was concentrated under reduced pressure and the crude solid obtained was washed with water and 3 mL of THF. The solid was dried under high vacuum to give the title product (0.564 g, 71.4%). m/z 278.