Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:15])([O:4][C:5]([NH:7][C:8]1([C:12](O)=O)[CH2:11][CH2:10][CH2:9]1)=[O:6])[CH3:3].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(CC)CC.[CH3:45][O:46][C:47](=[O:58])[C:48]1[CH:53]=[C:52]([NH:54][CH3:55])[C:51]([NH2:56])=[CH:50][C:49]=1[CH3:57]>C(Cl)Cl>[CH3:45][O:46][C:47]([C:48]1[C:49]([CH3:57])=[CH:50][C:51]2[N:56]=[C:12]([C:8]3([NH:7][C:5]([O:4][C:2]([CH3:15])([CH3:3])[CH3:1])=[O:6])[CH2:11][CH2:10][CH2:9]3)[N:54]([CH3:55])[C:52]=2[CH:53]=1)=[O:58]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCC1
Reactant: CNc1cc(C(=O)OC)c(C)cc1N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc2c(cc1C)nc(C1(NC(=O)OC(C)(C)C)CCC1)n2C
Reaction time: 20 h
Yield: 58.1 %

Procedure:
1-((1,1-Dimethylethoxycarbonyl)amino)cyclobutanecarboxylic acid (1.40 g, 6.5 mmol) was dissolved in CH2Cl2 (45 mL) and reacted with TBTU in the presence of Et3N for a period of 30 min to pre-activate the acid. A solution of 4-amino-2-methyl-5-(methylamino)benzoic acid methyl ester 6-8 from Example 6 (1.33 g, 6.85 mmol) in CH2Cl2 (10 mL) was added slowly over a period of 30 min and stirring of the reaction mixture was continued for 20 h. The reaction mixture was concentrated to dryness, and the residue was re-dissolved in AcOH (10.0 mL) and stirred at 70° C. for 2 h to achieve cyclization of the benzimidazole ring. The reaction mixture was concentrated to dryness and the residue was dissolved in EtOAc (˜250 mL), extracted with aqueous saturated NaHCO3 (2×100 mL) and brine (100 mL). The organic layer was dried over anhydrous MgSO4 and evaporated to dryness. The residue was purified by flash column chromatography (using a solvent gradient from 40% to 50% EtOAc in hexane) to obtain the pure 2-(1-tert-butoxycarbonylaminocyclobutyl)-3,6-dimethyl-3H-benzoimidazole-5-carboxylic acid methyl ester 7-1 as a beige solid (1.41 g, 55% yield) and recover some of the unreacted diamino starting material.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>Cl.CO>[N:11]1([C:14]2[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:21][CH:22]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)O)cc2)CC1
Agent: Cl
Solvent: CO
Product: O=C(O)c1ccc(N2CCNCC2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.6 %

Procedure:
A mixture of 4-(4-(tert-butoxycarbonyl)piperazin-1-yl)benzoic acid (28 g, 91 mmol) in hydrochloric acid in methanol (300 mL) was stirred at room temperature for 4 h. The resulting precipitate was collected by filtration and concentrated to dryness to provide the title compound (17 g, 61% yield) as a white solid.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2)(=[O:5])=[O:4])[CH3:2]>C(O)(=O)C.[Pt]=O>[CH2:1]([S:3]([CH:6]1[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH2:7]1)(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)c1cnc2ccccc2c1
Agent: O=[Pt]
Solvent: CC(=O)O
Product: CCS(=O)(=O)C1CNc2ccccc2C1

Procedure:
A solution of 0.3 g of 3-ethylsulfonylquinoline in 15 ml of glacial acetic acid is hydrogenated in the presence of 30 mg of platinum oxide at 50° C. for 22 h. After working up analogously to Example 52c) and FC over 30 g of silica gel (mobile phase I), the pure title compound is obtained: mp 88°-90° C., Rf (K)=0.51; IR(KBr): 3380(s), 1590, 1500(m), 1270(s), 1130(s), 750(s); anal. calc. for C11H15NO2S: C58.64%, H6.71%, N6.22%; found C58.95,6.75, N6.21.
Reaction SMILES: N[C:2]1C(C)=CC=CC=1C(OC)=O.[CH:13]([O:16][C:17]([N:19]1[CH2:25][CH2:24][CH2:23][CH:22]([N:26]([C:42](=[O:44])[CH3:43])[CH2:27][C:28]2[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=2)[C:21]2[CH:45]=[CH:46][CH:47]=[CH:48][C:20]1=2)=[O:18])([CH3:15])[CH3:14]>>[C:42]([N:26]([CH2:27][C:28]1[CH:33]=[C:32]([C:34]([F:35])([F:36])[F:37])[CH:31]=[C:30]([C:38]([F:39])([F:40])[F:41])[CH:29]=1)[CH:22]1[CH2:23][CH2:24][CH2:25][N:19]([C:17]([O:16][CH:13]([CH3:15])[CH3:14])=[O:18])[C:20]2[C:48]([CH3:2])=[CH:47][CH:46]=[CH:45][C:21]1=2)(=[O:44])[CH3:43]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2ccccc21
Reactant: COC(=O)c1cccc(C)c1N
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2c(C)cccc21

Procedure:
This compound was prepared utilizing the same methodology described in Example 1 wherein replacement of 2-amino-benzoic acid methyl ester with methyl 2-amino-3-methylbenzoate following the procedure of Example 1, Steps 1-8 for the synthesis of 5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylic acid isopropyl ester. CI MS 531 (M+H).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C([Li])CCC.F[C:11]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]>C1COCC1>[CH:1]([NH:4][C:11]1[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:23])[F:22])=[CH:16][C:12]=1[C:13]([OH:15])=[O:14])([CH3:3])[CH3:2]
Reactant: O=C(O)c1cc(C(F)(F)F)ccc1F
Reactant: CC(C)N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)Nc1ccc(C(F)(F)F)cc1C(=O)O
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Isopropylamine (4.0 mL) was dissolved in THF (20 mL). This solution was cooled to 0° C. and n-butyllithium (2.5 M, 20 mL) was added. The reaction was stirred for 90 min and then transferred to a solution of 2-fluoro-5-(trifluoromethyl)benzoic acid (4.2 g) in THF (40 mL) at-78° C. This mixture was stirred for 15 min and then quenched with aqueous NH4Cl. The mixture was extracted with EtOAc (3×), and the organic layer was dried, filtered, and concentrated in vacuo. Flash chromatography of the resulting residue provided 2-isopropylamino-5-(trifluoromethyl)benzoic acid (2.4 g). MS found: (M+H)+=248.2.
Reaction SMILES: [CH2:1]([C:8](Cl)=[S:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:11]1[CH:15]=[C:14]([C:16]2[NH:17][C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3[N:20]=2)[N:13]=[CH:12]1>N1C=CC=CC=1>[CH2:1]([C:8]([N:20]1[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[N:17]=[C:16]1[C:14]1[N:13]=[CH:12][S:11][CH:15]=1)=[S:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: S=C(Cl)Cc1ccccc1
Reactant: c1ccc2[nH]c(-c3cscn3)nc2c1
Solvent: c1ccncc1
Product: S=C(Cc1ccccc1)n1c(-c2cscn2)nc2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
17.0 G. (0.091 moles) of benzylthiocarbonyl chloride is added dropwise under anhydrous conditions over a period of 25 minutes to a stirred suspension of 18.3 g. (0.091 moles) of 2-(4-thiazolyl)-benzimidazole in 140 ml. of pyridine. All of the solid material dissolved before the completion of the addition. When the addition is complete, precipitation of pyridine hydrochloride commences. The reaction mixture is stirred at room temperature for 18 hours, filtered and the pyridine solution evaporated to dryness in vacuo. The residue is dissolved in 250 ml. of methylene chloride filtered and the filtrate washed twice with 250 ml. of 0.25 normal hydrochloric acid and 200 ml. of saturated sodium bicarbonate solution. The methylene chloride is dried, treated with charcoal, filtered and evaporated to dryness in vacuo affording a solid material which is recrystallized from toluene affording 14.3 g. (45%) of 1-benzylthiocarbonyl-2-(4-thiazolyl)-benzimidazole, melting point 122° to 123° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([NH2:11])=[N:6]2.Br[C:23]1[CH:36]=[CH:35][C:26]([O:27][CH2:28][CH2:29][N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[CH:25][CH:24]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC([O-])(C)C.[Na+]>O1CCOCC1.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]>[CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([NH:11][C:23]1[CH:24]=[CH:25][C:26]([O:27][CH2:28][CH2:29][N:30]3[CH2:31][CH2:32][CH2:33][CH2:34]3)=[CH:35][CH:36]=1)=[N:6]2
Reactant: Cc1nc(-c2cccc(C(F)(F)F)c2)n2nc(N)ncc12
Reactant: Brc1ccc(OCCN2CCCC2)cc1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: Cc1nc(-c2cccc(C(F)(F)F)c2)n2nc(Nc3ccc(OCCN4CCCC4)cc3)ncc12
Yield: 71.4 %

Procedure:
In a similar manner as described for Example 41, 5-methyl-7-[3-(trifluoromethyl)phenyl]imidazo[5,1-f][1,2,4]triazin-2-amine (Intermediate 45) (0.025 g, 0.09 mmol), 1-[2-(4-bromophenoxy)ethyl]pyrrolidine (0.016 mL, 0.09 mmol), Pd2(dba)3 (0.008 g, 0.01 mmol), 2-(Di-t-butylphosphino)biphenyl (0.008 g, 0.03 mmol), and NaOtBu (0.011 g, 0.11 mmol) in 1,4-dioxane (1 mL) gave 5-methyl-N-[4-(2-pyrrolidin-1-ylethoxy)phenyl]-7-[3-(trifluoromethyl)phenyl]imidazo[5,1-f][1,2,4]triazin-2-amine (0.031 g) as a yellow solid. 1H NMR (CD3OD): δ9.04 (s, 1H), 8.84 (s, 1H), 8.53 (d, J=7.3 Hz, 1H), 8.34 (bs, 2H), 7.75-7.64 (m, 4H), 7.02 (d, J=8.8 Hz, 2H), 4.33 (t, J=4.8 Hz, 2H), 3.66 (t, J=4.8 Hz, 2H), 3.48 (bs, 4H), 2.58 (s, 3H), 2.13 (bs, 4H). MS m/z 483 (M+1).
Reaction SMILES: [C:1]([C:3]1[C:4]([O:27][CH3:28])=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]([CH2:13][N:14]1[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]1)[O:8][CH2:7][CH2:6]2)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:28][O:27][C:4]1[C:3]([C:1]#[N:2])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][O:8][CH:9]2[CH2:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1
Reactant: COc1c(C#N)ccc2c1CCOC2CN1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1c(C#N)ccc2c1CCOC2CN1CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-[(6-cyano-5-methoxy-3,4-dihydro-1H-isochromen-1-yl)methyl]piperazine-1-carboxylate (30 mg, 0.08 mmol) in 5 mL of DCM was added 5 mL of TFA was stirred at room temperature for 1 hours, and the reaction was concentrated to afford 5-methoxy-1-(piperazin-1-ylmethyl)-3,4-dihydro-1H-isochromene-6-carbonitrile.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:8]Br)=[N:4][CH:5]=[CH:6][CH:7]=1.[F:10][C:11]1[CH:19]=[CH:18][C:14]([C:15]([NH2:17])=[O:16])=[CH:13][CH:12]=1.[H-].[Na+]>C1COCC1.[Cl-].[NH4+]>[Br:1][C:2]1[C:3]([CH2:8][NH:17][C:15](=[O:16])[C:14]2[CH:18]=[CH:19][C:11]([F:10])=[CH:12][CH:13]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1ccc(F)cc1
Reactant: BrCc1ncccc1Br
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C(NCc1ncccc1Br)c1ccc(F)cc1
Reaction time: 24 h

Procedure:
To a mixture of 3-bromo-2-bromomethyl-pyridine (1.30 g, 5.18 mmol) and 4-fluoro-benzamide (725 mg, 5.21 mmol) in THF (20 mL) is added 60% sodium hydride in mineral oil (210 mg, 5.3 mmol) and the mixture is warmed at reflux. After 24 hours, the mixture is diluted with saturated aqueous ammonium chloride (25 mL) and extracted with ethyl acetate (2×25 mL). The combined organic layers are washed with brine (2×25 mL), dried over magnesium sulfate, filtered and concentrated. The residue is purified by silica gel chromatography eluting using a gradient of 5-25% EtOAc in hexanes to afford N-(3-bromopyridin-2-ylmethyl)-4-fluoro-benzamide.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[N:7][CH:8]=1.[I-].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]([CH3:36])[C:28](N2C=C[N+](C)=C2)=[O:29])=[CH:23][CH:22]=1>C(OCC)(=O)C.CCCCCCC>[F:18][C:2]([F:1])([F:17])[C:3]1[CH:4]=[CH:5][C:6]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:28](=[O:29])[N:27]([C:24]3[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=3)[CH3:36])=[CH:14][CH:15]=2)=[N:7][CH:8]=1
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Reactant: CN(C(=O)n1cc[n+](C)c1)c1ccc(Cl)cc1
Agent: [I-]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CN(C(=O)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared from 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenol and 3[(4-chlorophenyl)-methyl-carbamoyl]-1-methyl-3H-imidazol-1-ium iodide. The crude product was subjected to flash chromatography (ethyl acetate/heptan, 1:5) (77%, white crystals). HPLC-MS m/z=423.1 (M+1), Rt: 5.3 min.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:12]([C:13]([O:15]CC)=[O:14])=[CH:11][N:10]=[C:9]3[N:18]([CH2:21][CH3:22])[N:19]=[CH:20][C:8]=23)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C(O)C.O>[CH:1]1([NH:6][C:7]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][N:10]=[C:9]3[N:18]([CH2:21][CH3:22])[N:19]=[CH:20][C:8]=23)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1NC1CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCn1ncc2c(NC3CCCC3)c(C(=O)O)cnc21
Temperature: 50 °C
Yield: 95.2 %

Procedure:
A solution of Intermediate 2 (2.2 g) in ethanol: water (95:5, 16.85 ml) was treated with sodium hydroxide (1.2 g) and heated at 50° C. for 16 h. The mixture was concentrated in vacuo and the residue re-dissolved in water (0.85 ml). The solution was acidified to pH4 using acetic acid and the resultant white precipitate was collected by filtration and dried under vacuum to afford Intermediate 3 (1.9 g). LCMS showed MH+=275; TRET=2.65 min
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:26](O)=[O:27])[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.O[N:30]=[C:31]([NH2:39])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:32]([C:31]1[N:39]=[C:26]([CH:12]2[CH2:13][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:15][N:10]([C:8]([N:5]3[CH2:4][CH2:3][CH:2]([OH:1])[CH2:7][CH2:6]3)=[O:9])[CH2:11]2)[O:27][N:30]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Reactant: NC(Cc1ccccc1)=NO
Product: O=C(N1CCC(O)CC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(Cc3ccccc3)no2)C1

Procedure:
100 mg (0.250 mmol) of 1-[(4-hydroxypiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 99A) and 41.3 mg (0.275 mmol) of N′-hydroxy-2-phenylethanimidamide were reacted according to the General Method 1. Yield: 61.5 mg (47% of theory).
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([C:6]([S:20][C:21]3[C:22]([F:32])=[C:23]([CH:29]=[CH:30][CH:31]=3)[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:7][N:8]2[C:12]2[CH:13]=[N:14][N:15]([CH2:17][CH2:18][CH3:19])[CH:16]=2)=[CH:4][CH:3]=1.C1C(=O)N([Cl:40])C(=O)C1>C(Cl)Cl.O>[Cl:40][C:7]1[N:8]([C:12]2[CH:13]=[N:14][N:15]([CH2:17][CH2:18][CH3:19])[CH:16]=2)[C:9]2[C:5]([C:6]=1[S:20][C:21]1[C:22]([F:32])=[C:23]([CH:29]=[CH:30][CH:31]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:4][CH:3]=[C:2]([Cl:1])[C:10]=2[F:11]
Reactant: CCCn1cc(-n2cc(Sc3cccc(C(=O)OCC)c3F)c3ccc(Cl)c(F)c32)cn1
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: ClCCl
Product: CCCn1cc(-n2c(Cl)c(Sc3cccc(C(=O)OCC)c3F)c3ccc(Cl)c(F)c32)cn1
Reaction time: 8 h
Yield: 46.7 %

Procedure:
To a stirred solution of ethyl 3-((6-chloro-7-fluoro-1-(1-propyl-1H-pyrazol-4-yl)-1H-indol-3-yl)thio)-2-fluorobenzoate 1 (Example 7, Step 1; 100 mg, 0.21 mmol) in CH2Cl2 (3 mL) was added NCS (33.7 mg, 0.25 mmol) at RT under inert atmosphere. After 8 h stirring, additional NCS (33.7 mg, 0.25 mmol) was added at RT and stirred again for 24 h. The reaction was monitored by TLC; after completion of the reaction, the reaction mixture was diluted with water (20 mL) and extracted with CH2Cl2 (2×20 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. This was purified by silica gel column chromatography using 9-11% EtOAc/Hexanes to afford compound 2 (50 mg, 47%) as an off-white solid. 1H NMR (400 MHz, CDCl3): δ 7.71-7.67 (m, 1H), 7.66 (s, 1H), 7.64 (s, 1H), 7.30 (d, J=8.8 Hz, 1H), 7.18 (dd, J=8.4, 6.0 Hz, 1H), 7.04-6.97 (m, 2H), 4.40 (q, J=7.2 Hz, 2H), 4.18 (t, J=7.2 Hz, 2H), 2.04-1.93 (m, 2H), 1.40 (t, J=7.2 Hz, 3H), 0.97 (t, J=7.2 Hz, 3H); LC-MS (ESI): 98.8%; m/z 510.4 (M+H+); (column: X Select CSH C-18, 50×3.0 mm, 3.5 μm); RT 4.94 min; 5 mM NH4OAc: ACN; 0.8 mL/min).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].P(Cl)(Cl)(Cl)(Cl)[Cl:12]>ClC(Cl)C>[Cl:12][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnccc1O
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Product: O=[N+]([O-])c1cnccc1Cl
Yield: 76 %

Procedure:
5 g of 4-hydroxy-3-nitropyridine and 15.5 g of phosphorous pentachloride were added to 100 ml of dichloroethane and reacted under reflux for 90 minutes. When it was poured onto ice to separate an organic phase and allowed to stand at room temperature for a while, crystals were precipitated. They were collected by filtration and washed with hexane, to give 4.3 g of the title compound.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:16][CH3:17])=[C:11]([CH2:13][CH2:14][Cl:15])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].Cl.[F:19][C:20]1[CH:21]=[CH:22][C:23]2[C:27]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:26][O:25][C:24]=2[CH:34]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.C1(C)C=CC=CC=1.O>[ClH:15].[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:16][CH3:17])=[C:11]([CH2:13][CH2:14][N:31]3[CH2:32][CH2:33][CH:28]([C:27]4[C:23]5[CH:22]=[CH:21][C:20]([F:19])=[CH:34][C:24]=5[O:25][CH:26]=4)[CH2:29][CH2:30]3)[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: Fc1ccc2c(C3CCNCC3)coc2c1
Reactant: CCc1c(CCCl)sc2c1CCN(C(C)=O)C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: CCc1c(CCN2CCC(c3coc4cc(F)ccc34)CC2)sc2c1CCN(C(C)=O)C2
Temperature: 70 °C
Reaction time: 7 h
Yield: 27.7 %

Procedure:
A mixture of 1.0 g of 6-acetyl-2-(2-chloroethyl)-3-ethyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridine, 0.95 g of 4-(6-fluorobenzo(b)furan-3-yl)piperidine hydrochloride, 3.0 g of potassium carbonate and 1.0 g of potassium iodide in 25 ml of dimethylformamide and 25 ml of toluene was stirred at 70° C. for 7 hours and poured into water. The toluene layer was washed with water, dried over magnesium sulfate and concentrated. The residue was purified by column chromatography on a silica gel and dissolved in ethanol to convert hydrochloride thereof, and then recrystallized from isopropyl alcohol to give 0.5 g of 6-acetyl-3-ethyl-2-(2-(4-(6-fluorobenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine hydrochloride, m.p. 205° C. (decomposition).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:25]1[NH:26][C:27](I)=[C:28](I)[N:29]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36]2[C:41](=[CH:42][CH:43]=1)[CH:40]=[C:39](B(O)O)[CH:38]=[CH:37]2.C([O-])([O-])=O.[K+].[K+].COCCOC.O>CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:25]1[NH:26][C:27]([C:39]2[CH:38]=[CH:37][C:36]3[C:41](=[CH:42][CH:43]=[C:34]([O:33][CH3:32])[CH:35]=3)[CH:40]=2)=[CH:28][N:29]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CCCCC[C@H](NC(=O)OCc1ccccc1)c1nc(I)c(I)[nH]1
Reactant: COc1ccc2cc(B(O)O)ccc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: COc1ccc2cc(-c3cnc([C@H](CCCCCC(=O)OC(C)(C)C)NC(=O)OCc4ccccc4)[nH]3)ccc2c1
Temperature: 110 °C

Procedure:
A degassed microwave vial was charged with D4, (6-methoxy-2-naphthyl)boronic acid (2 eq.), PdCl2(dppf)2 (0.2 eq.) and K2CO3 (3 eq.). A degassed solution of DME/H2O (1:1, 0.05 M) was added and the suspension was degassed for further 10 minutes and then heated at 110° C. for 30 min. After cooling, reaction mixture was diluted with EtOAc and filtered through a pad of Solka-Floc®. The filtrate was washed with sat. aq. NaHCO3 sol., brine, dried over Na2SO4, filtered and concentrated to give a dark red residue. The resulting crude was purified by column chromatography (eluent: petroleum ether/EtOAc from 95:5 to 1:1) to give the title compound as a pale yellow solid. MS (ES+) C33H39N3O5: 558 (M+H)+.
Reaction SMILES: O.Cl.[CH3:3][CH:4]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[O:14]COC)[O:6][CH2:5]1>CO.ClCCl>[CH3:3][CH:4]1[CH2:13][C:12]2[C:11]([OH:14])=[CH:10][CH:9]=[CH:8][C:7]=2[O:6][CH2:5]1
Reactant: COCOc1cccc2c1CC(C)CO2
Agent: Cl
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CC1COc2cccc(O)c2C1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 64.9 %

Procedure:
In a 8 ml vial 3-methyl-5-{[(methyloxy)methyl]oxy}-3,4-dihydro-2H-chromene (Intermediate 116, 103.6 mg) was dissolved in methanol (3 ml) to give a colourless solution. A 2M/H2O solution of HCl (0.224 ml, 0.448 mmol) was added. The reaction mixture was shaken at 60° C. After 2 h 30 min, the reaction mixture was diluted with 10 ml of dichloromethane. The phases were separated through a phase separator cartridge. The organic phase was evaporated under vacuum to afford the crude product which was purified via Biotage SP1 (with Cyclohexane/EtOAc as eluents from 1:0 to 5:1 in 10 CV; then 5:1 for 5 CV; then from 5:1 to 3:1 in 5 CV; (10 g SNAP Silica column). The collected fractions afforded the title compound as a white solid (53.0 mg).
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30](O)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[C:70]1([C@H:76]([NH2:78])[CH3:77])[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1>CN(C=O)C>[CH2:37]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([NH:78][C@@H:76]([C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)[CH3:77])=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:38]
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: C[C@@H](N)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)N[C@H](C)c3ccccc3)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.8 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (26 mg, 0.05 mmol) in DMF (0.5 mL) were added HBTU (28 mg, 0.075 mmol), triethylamine (21.1 uL, 0.15 mmol) and [(1R)-1-phenylethyl]amine (12.9 uL, 0.1 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (14 mg, 45%). LC-MS m/z 625 (M+H)+.
Reaction SMILES: [O:1]=[C:2]([C@@H:6]1[CH2:20][C@H:19]2[C@@H:9]([CH2:10][C:11]3[C:21]4[C:14](=[CH:15][CH:16]=[CH:17][C:18]2=4)[NH:13][CH:12]=3)[N:8]([CH3:22])[CH2:7]1)[CH2:3][CH:4]=O.Cl.[NH2:24]O>C(O)(=O)C>[CH3:22][N:8]1[C@H:9]2[C@@H:19]([C:18]3[CH:17]=[CH:16][CH:15]=[C:14]4[C:21]=3[C:11]([CH2:10]2)=[CH:12][NH:13]4)[CH2:20][C@@H:6]([C:2]2[O:1][N:24]=[CH:4][CH:3]=2)[CH2:7]1
Reactant: CN1C[C@H](C(=O)CC=O)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Reactant: NO
Agent: Cl
Solvent: CC(=O)O
Product: CN1C[C@H](c2ccno2)C[C@@H]2c3cccc4[nH]cc(c34)C[C@H]21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 5 g (0.017 mole) of 3-oxo-3-(6-methylergolin-8β-yl)-propionaldehyde in 100 ml of glacial acetic acid and 5 g of hydroxylamine hydrochloride was stirred for 20 hours at room temperature and then poured in ice-cold water. After basification with ammonium hydroxide, the solid which separated was filtered and dissolved in ethyl acetate. The organic solution was washed with brine, dried and the solvent was removed, and the residue was crystallized twice from acetone affording the title compound, 1.8 g; m.p. 132°-134° C.