Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCOC(C(C#N)=N[O:8][C:9]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)=[N+](C)C)=O.F[P-](F)(F)(F)(F)F.[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([C:37]2[N:38]=[N:39][N:40]([C:42]3[CH:47]=[CH:46][C:45]([CH2:48]C(O)=O)=[CH:44][CH:43]=3)[CH:41]=2)=[N:29]1.CCN(C(C)C)C(C)C.N1CCOCC1>CN(C=O)C.CCOC(C)=O>[N:13]1([C:9](=[O:8])[CH2:48][C:45]2[CH:46]=[CH:47][C:42]([N:40]3[CH:41]=[C:37]([C:30]4[C:31]5[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=5)[NH:28][N:29]=4)[N:38]=[N:39]3)=[CH:43][CH:44]=2)[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: O=C(O)Cc1ccc(-n2cc(-c3n[nH]c4ccccc34)nn2)cc1
Reactant: CCOC(=O)C(C#N)=NOC(N1CCOCC1)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1COCCN1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Cc1ccc(-n2cc(-c3n[nH]c4ccccc34)nn2)cc1)N1CCOCC1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
COMU (151 mg; 0.41 mmol; 1.3 eq.) was added into a solution of {4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]phenyl}acetic acid (100 mg; 0.31 mmol; 1.0 eq.) and DIEA (69 μl; 0.41 mmol; 1.3 eq.) in DMF (4 mL). After 1-2 min, morpholine (33 μl; 0.38 mmol; 1.2 eq.) was added and the reaction mixture was stirred overnight at RT. EtOAc was added and the reaction mixture was washed twice with an aqueous saturated solution of NaHCO3. The organic layer was dried over magnesium sulfate, filtered and concentrated. Purification by preparative HPLC afforded the tittle compound as a white solid. 1H NMR (300 Mz, DMSO-d6) δ: 13.36 (brs, 1H), 9.29 (s, 1H), 8.36 (d, J=8.1 Hz, 1H), 7.99 (d, J=8.5 Hz, 2H), 7.61 (d, J=8.5 Hz, 1H), 7.49-7.41 (m, 3H), 7.28-7.23 (m, 1H), 3.84 (s, 2H), 3.58-3.55 (m, 6H), 3.49-3.46 (m, 2H). HPLC (Condition A): Rt 2.97 min (purity 98.8%). MS (ESI+): 389.3, MS (ESI−): 387.3.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:9]=[C:10]([C:20]([OH:22])=O)[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].S(Cl)([Cl:25])=O>>[CH2:1]([O:7][C:8]1[CH:9]=[C:10]([C:20]([Cl:25])=[O:22])[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCOc1ccc(-c2ccccc2)c(C(=O)O)c1
Product: CCCCCCOc1ccc(-c2ccccc2)c(C(=O)Cl)c1

Procedure:
4-n-Hexyloxybiphenyl carboxylic acid (3.0 g) and an excessive amount of thionyl chloride were heated under refluxing for 6 hours. Unaltered thionyl chloride was distilled off to obtain 4-n-hexyloxybiphenyl carboxylic acid chloride.
Reaction SMILES: N1(C2C=CC(C(C3C=CC=CC=3)=O)=CC=2)CCNCC1.CO[C:23]1[C:42]([O:43][CH3:44])=[CH:41][C:26]2[C:27]([OH:40])=[CH:28][C:29]3[C:30]([CH3:39])([CH3:38])[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:36]=4[C:37]=3[C:25]=2[CH:24]=1.[NH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1.C([Li])CCC.Cl>CCCCCC.O1CCCC1>[N:45]1([C:23]2[C:42]([O:43][CH3:44])=[CH:41][C:26]3[C:27]([OH:40])=[CH:28][C:29]4[C:30]([CH3:38])([CH3:39])[C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][C:36]=5[C:37]=4[C:25]=3[CH:24]=2)[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1
Reactant: COc1cc2c(O)cc3c(c2cc1OC)-c1ccccc1C3(C)C
Reactant: C1CCNCC1
Agent: Cl
Agent: O=C(c1ccccc1)c1ccc(N2CCNCC2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc2c(O)cc3c(c2cc1N1CCCCC1)-c1ccccc1C3(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To an oven-dried 500 mL one-neck flask was added the product of Step 3, Example 1, of U.S. Pat. No. 6,296,785B1, 2,3-dimethoxy-7,7-dimethyl-7H-benzo[C]fluoren-5-ol (10 g) which is included herein as reference, piperidine (5.2 mL) and anhydrous tetrahydrofuran (150 mL). n-Butyl lithium in hexane solution (2.5M, 35 mL) was dropped to the mixture slowly. The reaction mixture was stirred at room temperature for 3 hours. The mixture was poured into cold aqueous hydrochloric acid (10%, 60 mL). The mixture was extracted with ethyl acetate (200 mL) and the recovered top layer was filtered through a silica gel plug. The desired product 2-piperidino-3-methoxy-7,7-dimethyl-7H-benzo[C]fluoren-5-ol (10 g) was obtained by recrystallization from solution in ethyl acetate/hexanes.
Reaction SMILES: BrC1C=NC2C(C=1)=CC=C1C=2N=CC(Br)=C1.C[O:18][C:19]1[CH:20]=[N:21][C:22]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[C:28]1[C:23]=2[N:24]=[CH:25][C:26]([O:33]C)=[CH:27]1>>[OH:33][C:26]1[CH:25]=[N:24][C:23]2[C:28]([CH:27]=1)=[CH:29][CH:30]=[C:31]1[C:22]=2[N:21]=[CH:20][C:19]([OH:18])=[CH:32]1
Reactant: COc1cnc2c(ccc3cc(OC)cnc32)c1
Agent: Brc1cnc2c(ccc3cc(Br)cnc32)c1
Product: Oc1cnc2c(ccc3cc(O)cnc32)c1

Procedure:
3,8-dihydroxy-1,10-phenanthroline hydrobromate was synthesized using 3,8-dibromo-1,10-phenanthroline obtained in Example 8 through 3,8-dimethoxy-1,10-phenanthroline according to the method described in Synlett., 2001, No. 10, 1629-1631.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.C(O)(=O)[CH2:13][C:14]([OH:16])=[O:15]>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:13][C:14]([OH:16])=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: O=C(O)CC(=O)O
Reactant: COc1ccc(C=O)cc1F
Product: COc1ccc(C=CC(=O)O)cc1F

Procedure:
According to the previously described general procedure (GP1), Knoevenagel condensation (75° C.; 3 h) between 3-fluoro-4-methoxybenzaldehyde (6.080 g; 39.445 mmol) and malonic acid (7.798 g; 74.946 mmol) gave the product 3-(3-fluoro-4-methoxy-phenyl)-acrylic acid as a colorless solid (7.530 g; 97%). LC-MS: tR=0.86 min.; [M+H]+: no ionisation.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])[C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[BrH:19].N([O-])=O.[Na+]>>[Br:19][C:2]1[CH:3]=[C:4]([N:13]2[CH2:17][CH2:16][CH2:15][C:14]2=[O:18])[C:5]([F:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(N)cc(N2CCCC2=O)c1F
Reactant: Br
Agent: O=N[O-]
Agent: [Na+]
Product: COC(=O)c1cc(Br)cc(N2CCCC2=O)c1F
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 18 %

Procedure:
To a solution of methyl 5-amino-2-fluoro-3-(2-oxo-1-pyrrolidinyl)benzoate (D150) (650 mg, 2.6 mmol, 1 equiv) in a 48% aqueous HBr solution at 0° C. was added NaNO2 portionwise and the resulting mixture was stirred at 0° C. for 30 min. CuBr (260 mg, 1.82 mmol, 0.7 equiv) in a 48% aqueous HBr solution (1 ml) was added and the resulting mixture stirred at 90° C. for 1 h then cooled to room temperature and partitioned between H2O and AcOEt. The two layers were separated and the organic phase was dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (iso-hexane/AcOEt: 2/1) gave methyl 5-bromo-2-fluoro-3-(2-oxo-1-pyrrolidinyl)benzoate (D156) (145 mg, 18%) as a white solid. [M+H]+=318.1, RT=2.51 min.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:17])[CH2:4][O:5][C:6]1[C:13]([CH3:14])=[CH:12][C:9]([C:10]#[N:11])=[CH:8][C:7]=1[CH2:15][CH3:16].[C:18](O)(=[O:21])[CH2:19][OH:20].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C([O-])(O)=O.[Na+]>[C:10]([C:9]1[CH:12]=[C:13]([CH3:14])[C:6]([O:5][CH2:4][C@@H:3]([OH:17])[CH2:2][NH:1][C:19](=[O:20])[CH2:18][OH:21])=[C:7]([CH2:15][CH3:16])[CH:8]=1)#[N:11]
Reactant: CCc1cc(C#N)cc(C)c1OC[C@@H](O)CN
Reactant: O=C(O)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Product: CCc1cc(C#N)cc(C)c1OC[C@@H](O)CNC(=O)CO
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.4 %

Procedure:
To a solution of (S)-4-(3-amino-2-hydroxypropoxy)-3-ethyl-5-methylbenzonitrile (6.23 g, 26.59 mmol), glycolic acid (2.43 g, 31.9 mmol), HOBt (4.31 g, 31.9 mmol), and EDC hydrochloride (6.12 g, 31.9 mmol) were added. The mixture was stirred at rt for 18 h before it was diluted with sat. aq. NaHCO3 and extracted twice with EA. The combined org. extracts were dried over MgSO4, filtered and concentrated. The crude product was purified by CC with DCM containing 8% of MeOH to give (S)—N-[3-(4-cyano-2-ethyl-6-methyl-phenoxy)-2-hydroxy-propyl]-2-hydroxy-acetamide as a yellow oil (7.03 g). LC-MS: tR=0.74 min; [M+1]+=293.10; 1H NMR (CDCl3): δ 1.25 (t, J=7.5 Hz, 3H), 2.32 (s, 3H), 2.69 (q, J=7.5 Hz, 2H), 3.48-3.56 (m, 3H), 3.70-3.90 (m, 3H), 4.19 (br s, 3H), 7.06 (m, 1H), 7.36 (s, 1H), 7.38 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:23])[CH:8]=2)[N:3]=1.Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH3:35][S:32]([C:29]1[CH:30]=[CH:31][C:26]([CH2:25][O:23][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[N:3]=[C:2]([CH3:1])[CH:11]=[C:10]3[N:12]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13]2)=[CH:27][CH:28]=1)(=[O:33])=[O:34]
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Reactant: Cc1cc(N2CCC(c3ccccc3)C2)c2cc(O)ccc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(N2CCC(c3ccccc3)C2)c2cc(OCc3ccc(S(C)(=O)=O)cc3)ccc2n1

Procedure:
2-Methyl-4-(3-phenylpyrrolidin-1-yl)quinolin-6-ol (0.05 g; see Example 42 below), 1-bromomethyl-4-methanesulfonylbenzene (0.08 g), caesium carbonate (0.1 g) in DMF (2 mL) was heated in a microwave at 120° C. for 15 minutes. The reaction mixture was diluted with water and extracted with dichloromethane, washed with water, dried (MgSO4), filtered and evaporated to give an oil. The residue was purified by chromatography on silica, eluting with a mixture of dichloromethane, and methanol. Evaporation of the desired fractions gave the title compound as a pale yellow solid.
Reaction SMILES: CO.Cl.Cl.Cl.[S:6]([C:10]1[CH:35]=[CH:34][C:13]([CH2:14][NH:15][C:16]([NH:18][C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[NH:20])=[NH:17])=[CH:12][CH:11]=1)(=[O:9])(=[O:8])[NH2:7].[CH3:36][C:37]([CH3:39])=O>>[CH3:36][C:37]1([CH3:39])[N:17]=[C:16]([NH:15][CH2:14][C:13]2[CH:12]=[CH:11][C:10]([S:6](=[O:8])(=[O:9])[NH2:7])=[CH:35][CH:34]=2)[NH:18][C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[N:20]1
Reactant: CC(C)=O
Reactant: CCCCCCCCCCCCNC(=N)NC(=N)NCc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Solvent: CO
Product: CCCCCCCCCCCCNC1=NC(C)(C)N=C(NCc2ccc(S(N)(=O)=O)cc2)N1

Procedure:
100 ml of methanol, 80 ml of acetone and 0.3 ml of concentrated hydrochloric acid were added to 5.5 g (10.0 mmol) of N1-(4-sulfamoylbenzyl)-N5-dodecyl-biguanide dihydrochloride. The mixture was refluxed for 22 hours, and the solvent was distilled off under reduced pressure. To the residue were added 60 ml of ethanol, 40 ml of water and 6.2 ml of 5N sodium hydroxide, and the mixture was refluxed for 1 hour, concentrated under reduced pressure, and extracted with ethyl acetate. The extract was washed with 10% aqueous sodium acetate, washed with water, and concentrated under reduced pressure to remove the solvent. The residue was recrystallized repeatedly from a mixture of methyl ethyl ketone and ethanol (8:2) and then from ethanol to obtain 1.4 g of colorless crystals having a melting point of 188 to 191° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.Cl.[CH3:13][O:14][C:15](=[O:22])[C@H:16]([CH2:18][CH2:19][S:20][CH3:21])[NH2:17].N1C=CC=CC=1>C(Cl)(Cl)Cl>[Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:17][C@H:16]([C:15]([O:14][CH3:13])=[O:22])[CH2:18][CH2:19][S:20][CH3:21])=[O:8])=[CH:5][CH:4]=1
Reactant: COC(=O)[C@@H](N)CCSC
Reactant: O=C(Cl)c1ccc(CCl)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(CCl)cc1
Reaction time: 12 h
Yield: 63.3 %

Procedure:
A mixture of 4-(chloromethyl)-benzoyl chloride (0.189 g, 1 mmol), methionine methyl ester hydrochloride (0.199 g, 1 mmol), and 0.5 ml of pyridine in 5 ml of chloroform was stirred for 12 hours. The organic solution was washed with 10% HCl, brine, and dried over MgSO4. Flash chromatography of the residue afforded 0.20 g of desired product (64%).
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]12[O:10][C:7]([CH3:11])([CH2:8][CH2:9]1)[CH2:6][CH:5]2[N+]([O-])=O.[O-:15]S([O-])(=O)=O.[Mg+2].[Mn]([O-])(=O)(=O)=O.[K+]>O>[CH3:3][C:4]12[O:10][C:7]([CH3:11])([CH2:8][CH2:9]1)[CH2:6][C:5]2=[O:15]
Reactant: O=S(=O)([O-])[O-]
Reactant: CC12CCC(C)(O1)C([N+](=O)[O-])C2
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Mg+2]
Solvent: O
Product: CC12CCC(C)(O1)C(=O)C2
Reaction time: 1 h

Procedure:
To 900 ml of 0.1N potassium hydroxide was added with stirring 5.0 g of 1,4-dimethyl-2-nitro-7-oxabicyclo[2.2.1]heptane. To this mixture was added 125 ml of 2M MgSO4 solution and sufficient water to bring the total volume to 2.5 liters, followed dropwise at 0°-5° C. by a solution of 4.5 g of potassium permanganate in 125 ml of water. After stirring for 1 hour, the resulting mixture was filtered through celite. The filtrate was decolorized with sodium bisulfite and extracted with methylene chloride. The extract was dried (MgSO4), filtered and stripped to give 3.3 g of a pale yellow oil. This procedure was repeated to yield 3.2 g of a pale yellow oil. These products were combined and distilled to yield 5.8 g of the desired product as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:18]3[C:13]([CH:14]=[CH:15][CH:16]=[CH:17]3)=[CH:12][C:11]=2[C:19]([F:22])([F:21])[F:20])=[CH:6][CH:5]=1)([O-])=O.CCOC(C)=O>CO.[Pd]>[F:22][C:19]([F:20])([F:21])[C:11]1[CH:12]=[C:13]2[N:18]([C:10]=1[C:7]1[CH:8]=[CH:9][C:4]([NH2:1])=[CH:5][CH:6]=1)[CH2:17][CH2:16][CH2:15][CH2:14]2
Reactant: O=[N+]([O-])c1ccc(-c2c(C(F)(F)F)cc3ccccn23)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc(-c2c(C(F)(F)F)cc3n2CCCC3)cc1
Reaction time: 24 h
Yield: 84.6 %

Procedure:
To a solution of 400 mg (1.3 mmol) of 3-(4-Nitro-phenyl)-2-trifluoromethyl-indolizine in 12 mL MeOH was added 200 mg (10%) Pd/C. The solution was allowed to stir under a H2 atmosphere for 24 hrs then filtered through celite and concentrated in vacuo. The resulting oil was purified by silica gel chromatography Hexane:EtOAc (gradient 9:1-1:1) to yield 300 mg (1.1 mmol, 85%) of 4-(2-Trifluoromethyl-5,6,7,8-tetrahydro-indolizin-3-yl)-phenylamine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[C:5]([CH3:11])=[N:4][C:3]=1[CH3:12].CC1(C)C(C)(C)OB([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.CO.O.Cl[Pd]Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[OH:27][C:24]1[CH:25]=[CH:26][C:21]([C:2]2[N:7]=[C:6]([C:8]([NH2:10])=[O:9])[C:5]([CH3:11])=[N:4][C:3]=2[CH3:12])=[CH:22][CH:23]=1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: Cc1nc(C)c(C(N)=O)nc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: COCCOC
Solvent: CO
Solvent: O
Product: Cc1nc(C)c(-c2ccc(O)cc2)nc1C(N)=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
A solution of 6-chloro-3,5-dimethylpyrazine-2-carboxamide (Intermediate A) (20.17 g, 108.67 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (26.3 g, 119.53 mmol) and tripotassium phosphate (34.6 g, 163.00 mmol) in DME (500 mL), MeOH (250 mL) and water (125 mL) was degassed before addition of (1,1′-bis(diphenylphosphino)ferrocene)-dichloropalladium(II) (DCM adduct) (4.47 g, 5.43 mmol). The reaction mixture was heated to 80° C., under nitrogen, and left to stir for 1 hour. The reaction mixture was allowed to cool to room temperature and then evaporated. The residue was partitioned between water (1 L), 2M HCl aq. (1 L) and EtOAc (1 L). The aqueous was re-extracted with EtOAc (2 L) and the combined organics washed with brine (1 L), dried (MgSO4) and evaporated to give crude product. The aqueous was filtered and the solid was washed with water (2 L) to give pure product. The crude product from the organic layer was purified by flash silica chromatography, elution gradient 20 to 80% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford 6-(4-hydroxyphenyl)-3,5-dimethylpyrazine-2-carboxamide (22.00 g, 83%) as a cream solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]O)=[C:4]([O:10][CH3:11])[CH:3]=1.S(Cl)([Cl:14])=O>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][Cl:14])=[C:4]([O:10][CH3:11])[CH:3]=1
Reactant: COc1cc(Cl)ccc1CO
Reactant: O=S(Cl)Cl
Product: COc1cc(Cl)ccc1CCl
Yield: 95 %

Procedure:
Step A In a manner similar to the method described in Example 57 Step A, 4-chloro-2-methoxybenzyl alcohol (Aldrich) (4.9 g, 28 mmol) was reacted with thionyl chloride (20 mL) to give 4-chloro-2-methoxybenzyl chloride as a white solid (5.1 g, 95%).
Reaction SMILES: [N:1]1([C:5]2[N:10]=[CH:9][C:8]([S:11]([N:14]3[CH2:23][CH2:22][C:21]4[C@:16]([CH2:34][OH:35])([CH2:17][C:18]5[CH:26]=[N:25][N:24]([C:27]6[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=6)[C:19]=5[CH:20]=4)[CH2:15]3)(=[O:13])=[O:12])=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1.Cl[CH2:37][C:38]1[O:39][CH:40]=[CH:41][N:42]=1>>[N:1]1([C:5]2[N:10]=[CH:9][C:8]([S:11]([N:14]3[CH2:23][CH2:22][C:21]4[C@:16]([CH2:34][O:35][CH2:37][C:38]5[O:39][CH:40]=[CH:41][N:42]=5)([CH2:17][C:18]5[CH:26]=[N:25][N:24]([C:27]6[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=6)[C:19]=5[CH:20]=4)[CH2:15]3)(=[O:13])=[O:12])=[CH:7][CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: ClCc1ncco1
Reactant: O=S(=O)(c1ccc(N2CCC2)nc1)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(CO)C1
Product: O=S(=O)(c1ccc(N2CCC2)nc1)N1CCC2=Cc3c(cnn3-c3ccc(F)cc3)C[C@]2(COCc2ncco2)C1

Procedure:
The title compound was prepared by the method of Preparation 2b using [(R)-6-(6-azetidin-1-yl-pyridine-3-sulfonyl)-1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triazacyclopenta[b]naphthal-en-4a-yl]methanol and 2-chloromethyloxazole. LCMS (Method C): 577 (M+H)+, Retention time 10.2 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[NH:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])=[CH:10][N:9]=2)[N:6]=[CH:5][C:4]=1C(O)=O.C1C(=O)N([Br:32])C(=O)C1.C(=O)(O)[O-].[Na+]>CN(C=O)C.O>[Br:32][C:4]1[CH:5]=[N:6][N:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:15][CH2:16][CH2:17][CH2:18][O:19][CH3:20])=[O:21])=[CH:10][N:9]=2)[C:3]=1[O:2][CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COCCCNC(=O)c1ccc(-n2ncc(C(=O)O)c2OC)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCCNC(=O)c1ccc(-n2ncc(Br)c2OC)nc1
Yield: 97.1 %

Procedure:
Combined 5-methoxy-1-(5-((3-methoxypropyl)carbamoyl)pyridin-2-yl)-1H-pyrazole-4-carboxylic acid (2.19 g, 6.55 mmol), NBS (1.749 g, 9.83 mmol), and sodium bicarbonate (1.651 g, 19.65 mmol) in DMF (20 mL) and stirred at 20° C. for 1 h. The reaction was diluted with water (100 mL) and extracted with EtOAc (100 mL, then 2×50 mL). The combined organics were washed with brine, dried over magnesium sulfate and concentrated in vacuo to give a residue which was purified on a 120 g silica gel column eluted with 10 to 100% EtOAc in hexanes to give the title compound (2.348 g, 97% yield) as a white solid. MS m/z 369, 371 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.78 (quin, J=6.6 Hz, 2 H) 3.25 (s, 3 H) 3.30-3.37 (m, 2 H) 3.40 (t, J=6.3 Hz, 2 H) 4.05 (s, 3 H) 7.79 (dd, J=8.6, 0.5 Hz, 1 H) 7.85 (s, 1 H) 8.38 (dd, J=8.6, 2.3 Hz, 1 H) 8.74 (t, J=5.6 Hz, 1 H) 8.96 (dd, J=2.4, 0.6 Hz, 1 H).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[O:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=C([CH:19]=[CH:20][CH:21]=2)C(O)=O)[CH2:9][CH2:8]1>C(Cl)Cl.CN(C=O)C>[O:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:14]=[C:1]([CH:19]=[CH:20][CH:21]=2)[C:2]([Cl:4])=[O:3])[CH2:9][CH2:8]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccc(N2CCOCC2)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1cccc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Oxalyl chloride (0.14 ml) was added to a solution of 3-morpholinobenzoic acid (0.28 g) in methylene chloride (10 ml) which contained DMF (2 drops). The reaction mixture was stirred for 18 hours at ambient temperature. The mixture was evaporated and azeotroped with toluene to give 3-morpholinobenzoyl chloride (0.3 g); Mass Spectrum: M+H+ 222.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([CH3:9])[N:3]=1.C(P(C(C)(C)C)C1C=CC2C(=CC=CC=2)C=1C1C2C(=CC=CC=2)C=CC=1)(C)(C)C.C[C:40]([N:42](C)C)=O>FC(F)(F)C([O-])=O.[Pd+2].FC(F)(F)C([O-])=O.[Zn].[C-]#N.[Zn+2].[C-]#N>[Cl:8][C:6]1[N:5]=[C:4]([CH3:9])[N:3]=[C:2]([C:40]#[N:42])[CH:7]=1
Reactant: Cc1nc(Cl)cc(Cl)n1
Reactant: CC(=O)N(C)C
Agent: [Pd+2]
Agent: CC(C)(C)P(c1ccc2ccccc2c1-c1cccc2ccccc12)C(C)(C)C
Agent: O=C([O-])C(F)(F)F
Product: Cc1nc(Cl)cc(C#N)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The 4,6-dichloro-2-methyl-pyrimidine (10 g, 60 mmol), palladium (II) trifluoroacetate (0.86 g, 2.6 mmol), zinc dust (65.3 g, 11.4 mmol), rac-2-(di-t-butylphosphino)-1,1-binaphthyl (2.1 g, 5.3 mmol), zinc cyanide (3.95 g, 33.7 mmol) and dimethyl acetamide (316 ml) were added to a 500 mL, flame-dried flask. The vessel was evacuated and back-filled with N2 (3×). The mixture was stirred under N2 for 30 min. at RT, then heated to 95° C. After 2.5 hours the mixture was diluted with EtOAc (300mL), and washed with water (300 mL×3). The organic fractions were combined, dried over MgSO4, filtered, and the volatiles removed in vacuum. The residue was dissolved in EtOAc (100 mL), washed with water (50 ml), and the layers separated. The aqueous phase was then extracted with EtOAc (50 mL), the organic fractions combined, dried over MgSO4, filtered, and the volatiles removed in vacuum. The crude mixture was purified by chromatography on silica gel (eluting 1:19 ethyl acetate:hexane) to yield the titled compound as a colorless oil. 1H NMR (CD3OD): 8.235 (s, 1H), 2.816 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:19])=[C:7]([CH3:18])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[Br:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25](F)[CH:24]=1>CN(C=O)C.CCOC(C)=O.[Li+].[Cl-]>[Br:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[C:25]([O:19][C:6]2[C:5]3[C:10](=[CH:11][C:2]([F:1])=[CH:3][CH:4]=3)[N:9]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:7]=2[CH3:18])[CH:24]=1
Reactant: N#Cc1ccc(Br)cc1F
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1O
Agent: [Cl-]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1Oc1cc(Br)ccc1C#N
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred solution of 7-fluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-ol (130 mg, 0.51 mmol) in DMF (2.5 mL) was added sodium hydride (18.4 mg, 0.77 mmol). The reaction was stirred at rt for 20 min and then treated with 4-bromo-2-fluorobenzonitrile (102 mg, 0.51 mmol). The reaction was stirred at rt for 20 min and then at 110° C. for 12 h. After this time the reaction was cooled to rt and diluted with EtOAc (100 mL) and LiCl (1M aq. solution, 40 mL). The separated organic layer was dried over magnesium sulfate, filtered and evaporated in vacuo and the residue was purified by flash chromatography (hexanes:EtOAc, 1:0 to 2:1) to give 4-bromo-2-((7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)oxy)benzonitrile. 1H NMR (400 MHz, chloroform-d) δ ppm 8.75 (1H, d, J=5.1 Hz), 7.90-7.98 (2H, m), 7.77-7.89 (2H, m), 7.62 (1H, d, J=8.2 Hz), 7.29-7.45 (3H, m), 6.64 (1H, d, J=2.0 Hz), 2.41 (3H, s). Mass Spectrum (ESI) m/e=434.0 [(M+1) (79Br)] and 435.8 [(M+1) (81Br)].