Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8](B3OC(C)(C)C(C)(C)O3)[CH:9]=[CH:10][C:5]=2[O:4][C:3]1=[O:20].Br[C:22]1[CH:23]=[N:24][CH:25]=[CH:26][C:27]=1[CH:28]([O:30][CH3:31])[CH3:29].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:31][O:30][CH:28]([C:27]1[CH:26]=[CH:25][N:24]=[CH:23][C:22]=1[C:8]1[CH:9]=[CH:10][C:5]2[O:4][C:3](=[O:20])[N:2]([CH3:1])[C:6]=2[CH:7]=1)[CH3:29]
Reactant: Cn1c(=O)oc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Reactant: COC(C)c1ccncc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(C)c1ccncc1-c1ccc2oc(=O)n(C)c2c1
Yield: 68.8 %

Procedure:
A mixture of 3-Methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3H-benzooxazol-2-one (255 mg, 0.93 mmol), 3-Bromo-4-(1-methoxy-ethyl)-pyridine (200 mg, 0.93 mmol), Na2CO3 (2 M in water, 1.6 mL, 0.8 mmol) and PdCl2(PPh3)2 (52 mg, 0.07 mmol) in DMF (3 was heated at 100″C for overnight. After concentration, the residue was diluted in DCM and saturated NH4Cl solution. After filtration and extraction, the combined extracts were dried over anhydrous Na2SO4. After filtration and concentration, the residue was purified by flash column (MeOH—CH2Cl2, v/v, 0-1.5%) to give the title compound (182 mg, 69%). The racemate was resolved by chiral HPLC (ChiralPak, IA-H column, 40% EtOH/Heptane) to the first peak (enantiomer 1, retention time=10.90 min) and the second peak (enantiomer 2, retention time 14.25 min). ESI-MS m/z: 285 [M+1]+, Retention time 1.13 min; 1HNMR (MeOD, 400 MHz) δ 1.38 (d, J=6.8 Hz, 3H), 3.30 (s, 3H), 3.48 (s, 3H), 4.69 (q, J=6.8 Hz, 1H), 7.27 (dd, J=8.0, 1.6 Hz, 1H), 7.32 (d, J=1.6 Hz, 1H), 7.45 (d, J=8.0 Hz, 1H), 8.25 (d, J=6.0 Hz, 1H), 8.78 (s, 1H), 8.89 (id, J=6.0 z, 1H).
Reaction SMILES: [Br:1][C:2]([Br:29])=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][C@H:13]([CH2:15][N:16]3C(=O)C4[C:18](=CC=CC=4)[C:17]3=[O:26])[O:12][C:11]2=[O:27])=[CH:6][C:5]=1[F:28].C1COCC1.C(O)C.O.NN>C1COCC1.ClCCl>[Br:29][C:2]([Br:1])=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][C@H:13]([CH2:15][NH:16][C:17](=[O:26])[CH3:18])[O:12][C:11]2=[O:27])=[CH:6][C:5]=1[F:28]
Reactant: O=C1c2ccccc2C(=O)N1C[C@H]1CN(c2ccc(C=C(Br)Br)c(F)c2)C(=O)O1
Agent: NN
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(C=C(Br)Br)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A suspension of Example 1D (2.45 g) in 1:1 THF/ethanol (36 mL) was heated to 70 ° C., and treated with hydrazine monohydrate (3×227 μL) at 1 hour intervals. One hour after the final addition, the mixture was cooled to 25° C., and filtered. The filtrate was concentrated, dissolved in a mixture of pyridine (10 mL) and dichloromethane (25 mL), cooled to −5° C., treated with acetic anhydride (880 μL), warmed to room temperature, stirred for 5 minutes, and concentrated to provide crude product. The crude product was dissolved in 4:1 THF/dichloromethane (75 mL) and washed with 1:1 brine/water. The aqueous wash was extracted with dichloromethane (25 mL), and the combined extracts were dried over MgSO4. Next the mixture was filtered and concentrated. The residue was dissolved in acetone (20 mL) and filtered. The filtrate was concentrated and the residue triturated with hexanes to provide the desired product. mp 177-179° C.; MS (ESI(+)) m/e 437 (M+H)+; 1H NMR (300 MHz, CDCl3) δ 7.81 (t, 1H), 7.50 (s, 1H), 7.47 (dd, 1H), 7.20 (dd, 1H), 5.92 (br t, 1H), 4.80 (m, 1H), 4.06 (t, 1H), 3.77 (dd, 1H), 3.75-3.55 (m, 2H), 2.02 (s, 3H).
Reaction SMILES: ClCC(N(CC)C1C=C(OC)C=CC=1C1CCC2C(=CC=C(OC)C=2)C1)=O.N1CCCC1.[CH2:33]([N:35]([C:44]1[CH:49]=[C:48]([O:50][CH3:51])[CH:47]=[CH:46][C:45]=1[CH:52]1[CH2:61][CH2:60][C:59]2[C:54](=[CH:55][CH:56]=[C:57]([O:62][CH3:63])[CH:58]=2)[CH2:53]1)[C:36](=O)[CH2:37][N:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1)[CH3:34]>>[CH2:33]([N:35]([C:44]1[CH:49]=[C:48]([O:50][CH3:51])[CH:47]=[CH:46][C:45]=1[CH:52]1[CH2:61][CH2:60][C:59]2[C:54](=[CH:55][CH:56]=[C:57]([O:62][CH3:63])[CH:58]=2)[CH2:53]1)[CH2:36][CH2:37][N:38]1[CH2:39][CH2:40][CH2:41][CH2:42]1)[CH3:34]
Reactant: CCN(C(=O)CN1CCCC1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Agent: CCN(C(=O)CCl)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Solvent: C1CCNC1
Product: CCN(CCN1CCCC1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1
Yield: 83.4 %

Procedure:
Synthesized from 2-chloro-N-ethyl-N-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]acetamide and pyrrolidine according to an analogous synthetic method to Preparation Example 89, N-ethyl-N-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]-2-pyrrolidin-1-ylacetamide (119 mg) was used according to an analogous synthetic method to Example 337 described below to provide ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl](2-pyrrolidin-1-ylethyl)amine (96 mg). This compound (95 mg) was used according to an analogous synthetic method to Example 111 described below to provide the title compound (92 mg).
Reaction SMILES: [NH2:1][C:2]([CH3:25])([CH3:24])[C:3]([NH:5][C:6]1[S:7][C:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:10]=1)=[O:4].[F:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.C(N(CC)CC)C>CN(C=O)C>[CH2:17]([C:8]1[S:7][C:6]([NH:5][C:3](=[O:4])[C:2]([NH:1][S:33]([C:30]2[CH:31]=[CH:32][C:27]([F:26])=[CH:28][CH:29]=2)(=[O:35])=[O:34])([CH3:25])[CH3:24])=[N:10][C:9]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: CC(C)(N)C(=O)Nc1nc(-c2ccccc2)c(Cc2ccccc2)s1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(NS(=O)(=O)c1ccc(F)cc1)C(=O)Nc1nc(-c2ccccc2)c(Cc2ccccc2)s1

Procedure:
2-Amino-N-(benzyl-4-phenyl-thiazol-2-yl)-2-methyl-propionamide (100 mg, 0.3 mmol), 4-Fluoro-benzensulfonyl chloride (80 mg, 0.4 mmol) and triethyl amine (85 μL, 1 mmol) were stirred a solution in DMF (5 mL). Purification via HPLC afforded the title compound. 1H NMR (400 MHz, DMSO-D6) δ 1.31 (s, 6H) 4.21 (s, 2H) 7.20-7.26 (m, 3H) 7.28-7.39 (m, 5H) 7.45 (s, 2H) 7.62 (d, J=7.07 Hz, 2H) 7.85 (s, 2H) 7.95 (s, 1H) 11.80 (s, 1H). m/z 510.1 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:37]([CH3:38])=[CH:36][C:5]2[NH:6][C:7]([CH2:9][N:10]([CH:26]3[C:35]4[N:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH2:29][CH2:28][CH2:27]3)[CH2:11][CH2:12][CH2:13][CH2:14][N:15]3C(=O)C4C(=CC=CC=4)C3=O)=[N:8][C:4]=2[CH:3]=1.O.NN>C(O)C.C(OCC)C>[CH3:38][C:37]1[C:2]([CH3:1])=[CH:3][C:4]2[NH:8][C:7]([CH2:9][N:10]([CH:26]3[C:35]4[N:34]=[CH:33][CH:32]=[CH:31][C:30]=4[CH2:29][CH2:28][CH2:27]3)[CH2:11][CH2:12][CH2:13][CH2:14][NH2:15])=[N:6][C:5]=2[CH:36]=1
Reactant: Cc1cc2nc(CN(CCCCN3C(=O)c4ccccc4C3=O)C3CCCc4cccnc43)[nH]c2cc1C
Agent: NN
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: Cc1cc2nc(CN(CCCCN)C3CCCc4cccnc43)[nH]c2cc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.4 %

Procedure:
To a stirred solution of 2-{4-[(5,6-dimethyl-1H-benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-isoindole-1,3-dione (60 mg, 0.118 mmol) in ethanol (2.5 mL) was added hydrazine hydrate (0.05 mL, 1.03 mmol) and the mixture stirred at room temperature for 16 hours. The mixture was then diluted with diethyl ether, dried (MgSO4), filtered and concentrated under reduced pressure to give a crude yellow oil. The oil was purified by flash chromatography (1.75 cm ID, 12 g silica, 10:1:1 CH2Cl2: MeOH: NH4OH) to give pure N1-(5,6-dimethyl-1H-benzimidazol-2-ylmethyl)-N1-(5,6,7,8-tetrahydro-quinolin-8-yl)-butane-1,4-diamine (18 mg, 38%). 1H NMR (CDCl3) δ 1.30-1.46 (m, 4H), 1.60-1.75 (m, 1H), 1.82-1.96 (m, 1H), 1.98-2.08 (m, 1H), 2.14-2.24 (m, 1H), 2.35 (s, 6H), 2.47-2.59 (m, 3H), 2.65-2.90 (m, 3H), 3.92-4.06 (m, 3H), 7.13 (dd, 1H, J=7.9, 4.8 Hz), 7.34 (s, 2H), 7.40 (d, 1H, J=7.1 Hz), 8.58 (s, 1H, J=3.5 Hz).
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=O.[CH3:16][CH2:17][O:18][C:19](/[C:21](/P(OCC)(OCC)=O)=[CH:22]\[CH3:23])=[O:20].O[Li].O>C1COCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH2:17]([O:18][C:19](=[O:20])/[CH:21]=[CH:22]/[CH:23]=[CH:1]/[CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)[CH3:16]
Reactant: C/C=C(\C(=O)OCC)P(=O)(OCC)OCC
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C/C=C/C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 95.3 %

Procedure:
A mixture of the above aldehyde (21) (2.10 g, 10 mmol), triethyl trans-4-phosphono-2-butenoate (3.0 g, 12 mmol), LiOH—H2O (510 mg, 12 mmol) and 4A molecular sieve (5 g) in THF (100 mL) was heated at reflux 1.5 hours. The molecular sieve was filtered through a short pad of Celite and washed with EtOAc (100 mL) and the filtrate concentrated to give sticky brown oil. The oily residue was diluted with 5% citric acid and extracted thrice with 100 mL of EtOAc. The combined extracts were washed with NaHCO3, brine, then dried over Na2SO4 and concentrated. Purification by flash chromatography (EtOAc:Hexanes=1:5) gave a white solid (22) (2.95 g, 95%) of the desired compound. 1H NMR (500 MHz, CDCL3) δ 7.24 (dd, J=15.5, 10.5 Hz, 1H), 6.16 (dd, J=15.5, 10.5 Hz, 1H), 6.04 (dd, J=15.5, 7.0 Hz, 1H), 5.82 (d, J=15.5 Hz, 1H), 4.20 (q, J=7.0 Hz, 2H), 4.10 (m, 2H), 2.75 (m, 2H), 2.25 (m, 1H), 1.71 (m, 2H), 1.46 (s, 9H), 1.34 (m, 2H), 1.29 (t, J=7.0 Hz, 3H); MS (ESI+) m/z 210.75 (M+H+-boc).
Reaction SMILES: [S:1](C1OC2C=CN=C(OC)C=2C=1)(=[O:4])(=[O:3])[NH2:2].[CH3:16][O:17][C:18]1[N:19]=[CH:20][CH:21]=[C:22]2[CH:26]=[CH:25][O:24][C:23]=12.COC1C2C=COC=2C=CN=1>>[S:1]([C:25]1[O:24][C:23]2=[C:18]([O:17][CH3:16])[N:19]=[CH:20][CH:21]=[C:22]2[CH:26]=1)(=[O:4])(=[O:3])[NH2:2]
Reactant: COc1nccc2ccoc12
Reactant: COc1nccc2oc(S(N)(=O)=O)cc12
Agent: COc1nccc2occc12
Product: COc1nccc2cc(S(N)(=O)=O)oc12
Yield: 64 %

Procedure:
The title compound was prepared according to the procedure described for the preparation of 2-sulfamoyl-4-methoxyfuro[3,2-c]pyridine (Example 6) except that 7-methoxyfuro[2,3-c]pyridine was substituted for 4-methoxyfuro[3,2-c]pyridine. This compound was obtained in 64% yield after recrystallization from ethyl acetate, m.p. 204°-206° C.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][CH2:19][CH2:20][O:21][C:22]1[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=1)[C:13]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:12]2[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[CH:43]([CH3:45])[CH3:44])C1C=CC=CC=1>O1CCCC1.O[Pd]O>[OH:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH2:18][CH2:19][CH2:20][O:21][C:22]1[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=1)[C:13]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:12]2[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1[CH:43]([CH3:44])[CH3:45]
Reactant: CCOC(=O)c1c(-c2ccccc2C(C)C)c2cc(OCc3ccccc3)ccc2n1CCCOc1cccc2ccccc12
Agent: O[Pd]O
Solvent: C1CCOC1
Product: CCOC(=O)c1c(-c2ccccc2C(C)C)c2cc(O)ccc2n1CCCOc1cccc2ccccc12

Procedure:
A mixture of EXAMPLE 149A (250 mg) and dihydroxypalladium (on carbon) (20 mg) in tetrahydrofuran was stirred a room temperature under a hydrogen atmosphere (30 psi) for 29 hours. The insoluble material was filtered off and the filtrate was concentrated. The residue was purified by flash chromatography, eluting with dichloromethane to provide the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15](#[N:18])[CH:16]=[CH2:17]>ClCCl.[H-].[Na+]>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][CH2:17][CH2:16][C:15]#[N:18])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC#N
Reactant: OC1CCN(Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: N#CCCOC1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 60.3 %

Procedure:
Sodium hydride [50% w/w in mineral oil] (2.0 g) was added to a slurry of 1-benzyl-4-piperidinol (400 g) and acrylonitrile (530 g) at 0° C. over 1 hour. The reaction mixture was warmed slowly to room temperature and stirred for 18 hours after which time the acrylonitrile was removed under reduced pressure and the residue taken up in isopropanol (1 L). The resulting yellow precipitate was filtered off. The filtrate was evaporated under reduced pressure to afford an orange oil which was dissolved in dichloromethane and washed with water. The organic layer was separated, dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by distillation to afford 2-[(1-benzyl-4-piperidyl)oxy]ethyl cyanide (308 g), b.p. 150-160° C. @ 0.2 mmHg.
Reaction SMILES: [H-].[Na+].[CH2:3]1[C:6]2([CH2:9][CH2:8][CH2:7]2)[CH2:5][CH:4]1[C:10]([OH:12])=[O:11].[CH:13]([N-]C(C)C)(C)C.[Li+].CI>C1COCC1>[CH3:13][C:4]1([C:10]([OH:12])=[O:11])[CH2:5][C:6]2([CH2:9][CH2:8][CH2:7]2)[CH2:3]1
Reactant: O=C(O)C1CC2(CCC2)C1
Reactant: CC(C)[N-]C(C)C
Agent: [H-]
Agent: [Li+]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CC1(C(=O)O)CC2(CCC2)C1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 82.5 %

Procedure:
A slurry of 2.15 g (44.2 mmol) of sodium hydride (50% in oil) in 45.0 ml of dry THF was stirred under argon at -20° C. A solution of 5.52 g (40.0 mmol) of spiro[3.3]heptane-2-carboxylic acid in 5.0 ml of dry THF was added dropwise. The reaction mixture was stirred for 0.5 hr at -20° C. A solution of 44.5 mmol of freshly-prepared, -20° C lithium diisopropylamide in 31.0 ml of THF was added to the reaction mixture. The reaction mixture was stirred for 0.3 hr at 0° C. Methyl iodide (2.80 ml, 44.5 mmol) was added, and the reaction mixture stirred an additional 2.0 hr at 25° C. The reaction mixture was cooled to -20° C and the reaction quenched by careful addition of cold 10% aqueous HCl. The mixture was extracted with 1:1 ethylacetate-ether. The extracts were washed with brine, then dried (MgSO4), filtered, and solvents evaporated in vacuo. The residue was dissolved in 1 N NaOH and extacted three times with ether. The aqueous layer was acidified with 6 N HCl and extracted with 1:1 ethyl-acetate-ether. These extracts were washed with brine, dried (MgSO4), filtered and evaporated in vacuo to yield 5.1 g of 2-methylspiro[3.3]heptane-2-carboxylic acid as a light yellow oil (82.5%).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[F:9].Cl.[OH:11][CH2:12][C:13]1[N:14]=[CH:15][NH:16][CH:17]=1.OC1C=CC=C2C=1N=CC=C2.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.[Cu]I.CCOC(C)=O.O>[F:9][C:3]1[CH:4]=[C:5]([N:16]2[CH:17]=[C:13]([CH2:12][OH:11])[N:14]=[CH:15]2)[CH:6]=[CH:7][C:2]=1[I:1]
Reactant: OCc1c[nH]cn1
Reactant: Fc1cc(I)ccc1I
Agent: [Cu]I
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: OCc1cn(-c2ccc(I)c(F)c2)cn1
Temperature: 130 °C

Procedure:
A mixture of 2,5-diiodofluorobenzene II-4 (2.50 g, 7.18 mmol), 4-hydroxymethylimidazole hydrochloride (0.967 g, 7.18 mmol), 8-hydroxyquinoline (0.104 g, 0.717 mmol) and K2CO3 (2.00 g, 14.5 mmol) in DMSO (12 mL) was degassed with Ar before being charged with CuI (0.136 g, 0.716 mmol). The mixture in a sealed tube was heated at 130° C. overnight. After being cooled to room temperature, H2O and EtOAc were added. It was filtered through celite. The organic phase was separated, dried over Na2SO4, concentrated in vacuo. The residue was purified by a silica gel column, eluted with MeOH in CH2Cl2 (0-5% MeOH) to give (1-(3-fluoro-4-iodophenyl)-1H-imidazol-4-yl)methanol (0.39 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH:11]([NH:13][C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=2)[C:10]2=[N:23][C:24]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][N:29]=3)=[CH:25][C:26](=[O:27])[N:9]2[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:34][N:35]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[N:36]1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.CCO>[CH2:1]([O:3][C:4]([N:6]1[CH2:12][CH:11]([NH:13][C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([C:38]3[CH:37]=[N:36][N:35]([CH3:34])[CH:39]=3)=[CH:17][CH:16]=2)[C:10]2=[N:23][C:24]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][N:29]=3)=[CH:25][C:26](=[O:27])[N:9]2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCn2c(nc(-c3ccncn3)cc2=O)C(NC(=O)c2ccc(Br)cc2)C1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCn2c(nc(-c3ccncn3)cc2=O)C(NC(=O)c2ccc(-c3cnn(C)c3)cc2)C1
Temperature: 90 °C
Reaction time: 15 h
Yield: 61.1 %

Procedure:
A mixture containing 0.145 g (0.28 mmol) of 9-(4-bromo-benzoylamino)-4-oxo-2-pyrimidin-4-yl-5,6,8,9-tetrahydro-4H-1,4a,7-triaza-benzocycloheptene-7-carboxylic acid ethyl ester (example 10), 0.082 g (0.40 mmol) of 1-methyl-1H-pyrazole-4-boronic acid pinacol ester, 0.35 mL (0.71 mmol) of sodium carbonate (solution 2M), 0.065 g (0.06 mmol) of tetrakis(tri-phenylphosphine)palladium in 5.60 mL of toluene/EtOH (10/1) under argon atmosphere was stirred at 90° C. for 15 hours. The reaction mixture was cooled, aqueous saturated solution of sodium carbonate was added and the resulting solution extracted with dichloromethane. The combined extracts were washed with saturated aqueous sodium chloride, dried over sodium sulfate and evaporated. The crude product was purified by chromatography on silica gel eluting with a mixture of dichloromethane/methanol/aqueous ammonia solution (29%) in the proportions 98/2/0.2 to 97/3/0.3 to afford 0.088 g (76%) of the pure product as a white powder.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:9](O)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.P(Br)(Br)([Br:20])=O.C(=O)(O)[O-].[Na+]>ClCCCl>[Br:20][C:9]1[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]2[C:8]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=P(Br)(Br)Br
Reactant: Cc1cccc2nc(O)c(-c3ccccc3)n12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: Cc1cccc2nc(Br)c(-c3ccccc3)n12
Temperature: 25 °C
Yield: 53.4 %

Procedure:
5-Methyl-3-phenylimidazo[1,2-a]pyridin-2-ol from step 2 (1.30 g, 5.22 mmol) were dissolved in 41 mL 1,2-dichloroethane under argon atmosphere. 5 Equivalents of phosphoryl bromide (7.48 g, 26.1 mmol) were added and the reaction mixture was stirred at reflux temperature overnight. LC/MS analysis showed incomplete conversion, therefore another 5 equivalents phosphoryl bromide were added. After stirring for 4 h at reflux temperature LC/MS analysis again showed incomplete conversion, so 5 equivalents were added again. After stirring at reflux temperature overnight the reaction mixture was allowed to cool to room temperature. The reaction mixture was neutralized with aqueous sodium bicarbonate-solution followed by extraction with dichloromethane. The organic phase was washed with brine and filtered through a Whatman-filter. Drying under high vacuum gave 801 mg (44%) of the title compound in 83% purity (LC/MS, area-%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.C([O-])(O)=O.[Na+].[NH2:14][CH2:15][C@@H:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[OH:17]>CC#N>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:14][CH2:15][C@@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[OH:17])[CH:7]=1
Reactant: NC[C@H](O)c1ccccc1
Reactant: Clc1cc(Cl)ncn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: O[C@@H](CNc1cc(Cl)ncn1)c1ccccc1
Temperature: 25 °C

Procedure:
To a solution of 4,6-dichloropyrimidine (50 g, 0.34 mol, 1.0 equiv) in CH3CN (1.2 L), was added NaHCO3 (34 g, 0.40 mol, 1.2 equiv) and (R)-(−)-2-amino-1-phenyl-ethanol (48.3 g, 0.35 mol, 1.05 equiv) sequentially. The reaction mixture was stirred at reflux temperature under N2 for 3 hours then cooled to rt. HPLC analysis of the crude reaction mixture indicated that the reaction was complete, to afford the intermediate (1R)-2-[(6-chloropyrimidin-4-yl)amino]-1-phenylethanol. In the same flask, without purification or work-up, was added a solution of K3PO4 (85 g, 0.40 mol, 1.2 equiv) in H2O (750 mL), 3-chloro-4-(trifluoromethyl)phenylboronic acid (79.4 g, 0.35 mol, 1.05 equiv), Pd(dppf)Cl2. CH2Cl2 (2.4 g, 2.9 mmol, 0.009 equiv) and Pd(OAc)2 (68 mg, 0.29 mmol, 0.0009 equiv) sequentially under N2 at rt. The reaction solution was degassed with N2 (3×) and was stirred at reflux temperature for 16 hours then cooled to rt. The layers were separated and the CH3CN phase was dried (MgSO4) and filtered. The filtrate solution was stirred with Si-Thiol (8.8 g, 1.5 mmol/g loading, 4 equiv of Pd added) at rt for 1 hour. Si-Thiol is commercially available through SiliCycle (230-400 mesh, 40-63 μm). The Si-Thiol was removed by filtration and washed with EtOAc. The organics were combined and concentrated under reduced pressure. The crude residue was recrystallized from hot EtOH (−250 mL) with stirring to afford the title compound (83 g). Further concentration of the mother liquor followed by a second recrystallization from hot EtOH with stirring provided an additional crop of the title compound (23 g). The combined recrystallized yield of the title compound was 80% (106 g, >99% ee). MS (ESI): mass calcd. for C19H15ClF3N3O, 393.1; m/z found, 394.1 [M+H]+. 1H NMR (CDCl3, 500 MHz): 8.69 (s, 1H), 8.12 (s, 1H), 7.93 (d, J=8.2 Hz, 1H), 7.79 (d, J=8.2 Hz, 1H), 7.52-7.28 (m, 5H), 6.74 (s, 1H), 5.42 (brs, 1H), 5.10-4.98 (m, 1H), 3.92 (brs, 1H), 3.70-3.58 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[N+:12]([O-:14])=[O:13])[NH:8][CH2:7][CH2:6]2.[Br:15][CH2:16][C:17](Cl)=[O:18].C([O-])([O-])=O.[K+].[K+].O>C(Cl)Cl>[Br:15][CH2:16][C:17]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:11]([N+:12]([O-:14])=[O:13])[CH:10]=2)[CH2:6][CH2:7]1)=[O:18]
Reactant: COc1cc2c(cc1[N+](=O)[O-])NCC2
Reactant: O=C(Cl)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)CBr)CC2
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
A solution of 5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole (33.6 g, 173 mmol) in CH.2Cl2 (150 mL) was added dropwise to a mixture of bromoacetylchloride (54.5 g, 346 mmol) and K2CO3 (53.0 g, 381 mmol) in CH2Cl2 (150 mL). The resulting solution was stirred at 0° C. for 1 hour, then warmed up RT for 4 hours. Water (150 mL) was added and the mixture was extracted with CH2Cl2 (2×100 mL). The organic phase was dried over Na2SO4, the solvent was removed to yield the 1-(bromoacetyl)-5-(methyloxy)-6-nitro-2,3-dihydro-1H-indole (54.2 g, 99%). 1HNMR (400 MHz, DMSO) δ ppm 2.47(s, 2H), 3.25 (m, 2 H), 3.87 (s, 3 H), 4.21 (m, 2 H), 7.34 (s, 1 H), 8.42 (s, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([C:29]2([OH:35])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:15][N:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)[CH:9]=1.C(=O)([O-])[O-].[K+].[K+].[C:42]([OH:49])(=[O:48])/[CH:43]=[CH:44]\[C:45]([OH:47])=[O:46]>CO>[C:42]([OH:49])(=[O:48])/[CH:43]=[CH:44]\[C:45]([OH:47])=[O:46].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([C:29]2([OH:35])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]2)[CH2:15][N:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]2)[CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CC(c2cccc(-c3ccccc3F)c2)C2(O)CCCCC2)CC1
Agent: O=C(O)/C=C\C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: OC1(C(CN2CCNCC2)c2cccc(-c3ccccc3F)c2)CCCCC1

Procedure:
In an analogous manner to Example 135, step 4 1-[1-(2′-fluoro-11′-biphenyl-3-yl)-2-piperazin-1-ylethyl]cyclohexanol dihydrochloride was prepared from tert-butyl 4-[2-(2′-fluoro-biphenyl-3-yl)-2-(1-hydroxycyclohexyl)ethyl]piperazine-1-carboxylate. The compound was neutralized with 10% aqueous potassium carbonate, and the residue dissolved in methanol. One equivalent of maleic acid was then added and the solution was concentrated. The product was triturated with diethyl ether to yield 1-[1-(2′-fluoro-1,1′-biphenyl-3-yl)-2-piperazin-1-ylethyl]cyclohexanol maleate as a colorless solid. MS (ESI) m/z 383 ([M+H]+); Anal. Calcd for C24H31FN2O. C4H4O4. 0.50H2O: C, 66.25; H, 7.15; N, 5.52. Found: C, 66.03; H, 7.38; N, 5.31.