Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:28]=[CH:27][CH:26]=[CH:25][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[C:9]([O:17][CH2:18][CH2:19][N:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:8]=1)=[O:5].CCN(C(C)C)C(C)C.[F:38][C:39]1[CH:46]=[CH:45][C:42]([CH2:43][NH2:44])=[CH:41][CH:40]=1>CCOCC>[F:38][C:39]1[CH:46]=[CH:45][C:42]([CH2:43][NH:44][C:2]2[N:28]=[CH:27][CH:26]=[CH:25][C:3]=2[C:4]([NH:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[C:9]([O:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:8]=2)=[O:5])=[CH:41][CH:40]=1
Reactant: NCc1ccc(F)cc1
Reactant: O=C(Nc1ccc(C(F)(F)F)c(OCCN2CCCC2)c1)c1cccnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: O=C(Nc1ccc(C(F)(F)F)c(OCCN2CCCC2)c1)c1cccnc1NCc1ccc(F)cc1
Temperature: 130 °C

Procedure:
2-Chloro-N-[3-(2-pyrrolidin-1-yl-ethoxy)-4-trifluoromethyl-phenyl]-nicotinamide (199.1 mg), DIEA (252 μL) and 4-fluorobenzylamine (193 μL) were combined in a sealed tube and heated to 130° C. for 2 h. The mixture was purified on silica gel chromatography (2-3.5% MeOH/CH2Cl2). The desired fractions were concentrated in vacuo, and the residue was dissolved in Et2O and hexanes were added until the solution became cloudy. The solids were filtered, and dried. Additional material was obtained from the filtrate upon additional rounds of concentration, dissolving in Et2O and treatment with hexanes. M+H 503.4, Calc'd for C26H26N4O2F4-502.2.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH:17]1[CH2:20][CH2:19][CH2:18]1)=[O:15].[CH3:21][O:22][C:23]1[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:24]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:26]3[CH:25]=[CH:24][C:23]([O:22][CH3:21])=[CH:28][C:27]=3[O:29][CH3:30])[C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:14]([NH:16][CH:17]1[CH2:20][CH2:19][CH2:18]1)=[O:15]
Reactant: Nc1c(C(=O)NC2CCC2)nnc2c(Br)c(F)ccc12
Reactant: COc1ccc(B(O)O)c(OC)c1
Product: COc1ccc(-c2c(F)ccc3c(N)c(C(=O)NC4CCC4)nnc23)c(OC)c1
Yield: 65 %

Procedure:
Using Method A, 4-amino-8-bromo-7-fluoro-N-cyclobutyl-cinnoline-3-carboxamide (175 mg) and 2,4-dimethoxy-phenyl boronic acid (205 mg) were reacted to afford the title compound (133 mg) as white solid. 1H NMR (500 MHz, DMSO-d6) δ 9.20 (d, 1H), 8.47 (m, 1H), 7.70 (m, 1H), 7.18 (m, 1H), 6.70 (m, 1H), 6.64 (m, 1H), 4.49 (m, 1H), 3.85 (s, 3H), 3.65 (s, 3H), 2.26-2.10(m, 4H), 1.72-1.62 (m, 2H). MS APCI, m/z=397 (M+H).
Reaction SMILES: Br[C:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[N:5]=[CH:4][C:3]=1[C:11]1[S:12][CH:13]=[C:14]([CH2:16][C:17]([NH:19][CH2:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[O:18])[N:15]=1.[O:27]1[CH2:32][CH2:31][O:30][C:29]2[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][C:28]1=2>>[C:7]([N:6]1[C:2]([C:34]2[CH:35]=[CH:36][C:28]3[O:27][CH2:32][CH2:31][O:30][C:29]=3[CH:33]=2)=[C:3]([C:11]2[S:12][CH:13]=[C:14]([CH2:16][C:17]([NH:19][CH2:20][CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:18])[N:15]=2)[CH:4]=[N:5]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: OB(O)c1ccc2c(c1)OCCO2
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)NCC3CCOCC3)cs2)c1Br
Product: CC(C)(C)n1ncc(-c2nc(CC(=O)NCC3CCOCC3)cs2)c1-c1ccc2c(c1)OCCO2

Procedure:
Using 2-(2-(5-bromo-1-tert-butyl-1H-pyrazol-4-yl)thiazol-4-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)acetamide and (2,3-dihydrobenzo[b][1,4]dioxin-6-yl)boronic acid and by reaction and purification in the same manner as in the method described in Example 43, the title compound was obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][C@@H:9]([OH:12])[C@H:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7]1)=[O:5])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1O.N(C(OCC)=O)=NC(OCC)=O>C1C=CC=CC=1>[Cl:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[O:12][C@H:9]1[CH2:10][CH2:11][N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][C@H:8]1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Oc1ccccc1Cl
Reactant: CCOC(=O)N1CC[C@@H](O)[C@H](c2ccccc2)C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CCOC(=O)N1CC[C@H](Oc2ccccc2Cl)[C@H](c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of 6.23 g of trans-1-ethoxycarbonyl-3-phenyl-4-piperidinol, 7.21 g of triphenylphosphine, 2.85 g of 2-chlorophenol and 250 ml of benzene is added dropwise at 5° C. under nitrogen, a solution of 4.79 g of diethyl azodicarboxylate in 250 ml of benzene. After the addition is complete, the mixture is stirred overnight at room temperature. The reaction mixture is processed according to the procedure of Example 75 to give product as a gum.
Reaction SMILES: [H][H].[NH:3]1[C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:6]=2[N:5]=[C:4]1[C:12]1[C:24]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[N:25]O)[C:16]=2[CH:15]=[CH:14][CH:13]=1>C(O)C.O1CCCC1.[Ni]>[NH:3]1[C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:6]=2[N:5]=[C:4]1[C:12]1[C:24]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]([NH2:25])[C:16]=2[CH:15]=[CH:14][CH:13]=1
Reactant: ON=C1c2ccccc2-c2c1cccc2-c1nc2c([nH]1)CCCC2
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Solvent: CCO
Product: NC1c2ccccc2-c2c(-c3nc4c([nH]3)CCCC4)cccc21
Yield: 97.3 %

Procedure:
The procedure used in Example 6 is followed. In a 25 ml autoclave, dissolve 43 mg of 4-(4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)-9H-fluoren-9-one oxime (Z,E), obtained in the previous stage, in a mixture of 4 ml of ethanol and 4 ml of tetrahydrofuran, add a spatula of Raney activated nickel and then subject to a hydrogen pressure of 1 bar and heat the autoclave at 600 for 12 hours. After cooling, the volume of hydrogen absorbed is 12 ml. After filtration of the catalyst, concentration to dryness under reduced pressure and purification by formation of a paste with diisopropyl ether, in this way we obtain 40 mg of 4-(4,5,6,7-tetrahydro-1H-benzimidazol-2-yl)-9H-fluoren-9(R,S)-ylamine, in the form of a beige powder, which is used as it is in the following stage, with the following characteristics:
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[N:15]=[CH:16][N:17]([C:19]3[N:24]=[C:23]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[CH:26]=4)[CH:22]=[C:21]([C:32]([F:35])([F:34])[F:33])[N:20]=3)[CH:18]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:31][C:27]1[CH:26]=[C:25]([C:23]2[CH:22]=[C:21]([C:32]([F:34])([F:33])[F:35])[N:20]=[C:19]([N:17]3[CH:18]=[C:14]([C:11]4[S:10][C:9]([S:6]([NH2:5])(=[O:8])=[O:7])=[CH:13][CH:12]=4)[N:15]=[CH:16]3)[N:24]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: CC(C)(C)NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4cccc(Cl)c4)cc(C(F)(F)F)n3)cn2)s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(-c2cn(-c3nc(-c4cccc(Cl)c4)cc(C(F)(F)F)n3)cn2)s1
Temperature: 25 °C
Reaction time: 15 h
Yield: 10 %

Procedure:
To a cooled and stirred solution of 5-{1-[4-(3-chloro-phenyl)-6-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-thiophene-2-sulfonic acid tert-butyl amide (0.4 g) in dichloromethane (6 mL) was added TFA (6 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and purified by flash chromatography (heptane/ethyl acetate) and crystallization (dichloromethane/MeOH/hexane) to yield the title compound as a white solid (0.036 g, 5%). MS (ISP) 486.2 [(M+H)+]; mp 280° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]4[C:23](=[O:35])[N:24]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[N:25]([CH3:28])[C:26]=4[CH3:27])=[O:21])=[CH:15][CH:14]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:36][CH3:37].[CH3:38][C@H:39]1[CH2:41][O:40]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[OH:40][C@@H:39]([CH3:41])[CH2:38][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[CH:15][C:16]([NH:19][C:20]([C:22]4[C:23](=[O:35])[N:24]([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:25]([CH3:28])[C:26]=4[CH3:27])=[O:21])=[CH:17][CH:18]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:36][CH3:37]
Reactant: C[C@H]1CO1
Reactant: COc1cc2c(Oc3ccc(NC(=O)c4c(C)n(C)n(-c5ccccc5)c4=O)cc3)ccnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccc(NC(=O)c4c(C)n(C)n(-c5ccccc5)c4=O)cc3)ccnc2cc1OC[C@H](C)O

Procedure:
The title compound was prepared according to the procedure described in Example 15 by using N-(4-((7-hydroxy-6-methoxyquinolin-4-yl)oxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (4.93 g, 9.93 mmol), (S)-2-methyloxirane (8.8 mL, 150 mmol) and K2CO3 (2.74 g, 19.8 mmol) in DMF/H2O (21 mL/4 mL). The title compound was purified by a silica gel column chromatography (DCM/MeOH=50/1 to 20/1) and was obtained as a pale solid (2.1 g, 38.3%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C@@H:15]2[C@@H:10]([CH2:11][CH2:12][CH2:13][NH:14]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC([O-])=O)([O:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=O)=O>CO>[CH2:1]([N:8]1[CH2:16][C@@H:15]2[C@@H:10]([CH2:11][CH2:12][CH2:13][N:14]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:19])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(=O)[O-]
Reactant: c1ccc(CN2C[C@@H]3CCCN[C@@H]3C2)cc1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC[C@H]2CN(Cc3ccccc3)C[C@H]21
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
The preparation comprises stirring [1S,6S]-8-benzyl-2,8-diazabicyclo[4,3,0]nonane (5.0 g, 23.1 mmol) in methanol (50 mL) at room temperature, adding batchwise tertbutyloxycarbonyl dicarbonate (5.1 g, 23.4 mmol), stirring for 0.5 h, vacuum distilling to remove solvent, and column chromatographing with petroleum ether and ethyl, acetate at the ratio of 10:1 to give [1S,6S]-8-benzyl-2-tertbutyloxycarbonyl-2,8-diazabicyclo[4,3,0]nonane (7.1 g, 97.2%), [α]20D=−72.4° (CHCl3, C=5).
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.[H-].[Na+].[CH3:12][O:13][CH2:14][CH2:15][O:16][CH2:17]Cl.O>O1CCCC1>[CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][O:8][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])[CH2:4][O:3]1
Reactant: COCCOCCl
Reactant: CC1(C)OCC(CO)O1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COCCOCOCC1COC(C)(C)O1
Reaction time: 3 h
Yield: 83 %

Procedure:
7(a) A solution of 9.25 g of (4RS)-2,2-dimethyl 1.3-dioxolane-4-methanol in 100 ml of tetrahydrofuran was added dropwise to a suspension of 3.36 g of sodium hydride (as a 55% w/w dispersion in mineral oil) in 300 ml of tetrahydrofuran at 20° to 24° C. over a period of 30 minutes. At the end of this time. 10.46 g of 2-methoxyethoxymethyl chloride in 50 ml of tetrahydrofuran were added dropwise to the mixture cooled on an ice bath. The reaction mixture was stirred at 0° to 2° C. for 3 hours, and then poured into water. It was then extracted twice with ethyl acetate. The combined extracts were washed with water, dried and concentrated by evaporation under reduced pressure. The residue was subjected to column chromatography through 200 g of silica gel. 12.80 g of (4RS)-2,2-dimethyl-4-(2-methoxyethoxy)methoxymethyl-1,3-dioxolane were obtained as a colorless oil from the fractions eluted with mixtures of ethyl acetate and hexane ranging from 1:5 to 1:4 by volume.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[CH3:24][O:25][CH2:26][C:27](O)=[O:28]>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][C:27](=[O:28])[CH2:26][O:25][CH3:24])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COCC(=O)O
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: COCC(=O)O[C@@]1(C#Cc2cccc(C)c2)CCC[C@@H]2[C@H]1CCN2C(=O)OC

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and methoxy-acetic acid to yield (3aR,4S,7aR)-4-(2-methoxy-acetoxy)-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. MS [M+H] 296 (ester elimination ion); RT=7.930 min; HPLC Method I
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:31][CH:30]=2)[N:4]=[C:5]2[C:14]3[C:13]([O:15]C)=[CH:12][C:11]([O:17][CH3:18])=[CH:10][C:9]=3[N:8]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C:7](=[O:28])[C:6]=12.[Br-].[Mg+2].[Br-].N1C=CC=CC=1>O>[NH2:1][C:2]1[N:3]([C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:31][CH:30]=2)[N:4]=[C:5]2[C:14]3[C:13]([OH:15])=[CH:12][C:11]([O:17][CH3:18])=[CH:10][C:9]=3[N:8]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=3)[C:7](=[O:28])[C:6]=12
Reactant: COc1ccc(Cn2c(=O)c3c(N)n(-c4ccc(Oc5ccccc5)cc4)nc3c3c(OC)cc(OC)cc32)cc1
Agent: [Br-]
Agent: [Mg+2]
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(Cn2c(=O)c3c(N)n(-c4ccc(Oc5ccccc5)cc4)nc3c3c(O)cc(OC)cc32)cc1
Yield: 73.9 %

Procedure:
A mixture of 3-amino-7,9-dimethoxy-5-(4-methoxybenzyl)-2-(4-phenoxyphenyl)-2,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one (500 mg), magnesium bromide (168 mg) and pyridine (10 ml) was heated under reflux for 2 days, added water thereto after cooling. The precipitated solid was collected by filtration, washed with water, and purified with silica gel column chromatography to obtain the target compound (360 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([NH2:20])=[C:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15](Br)[CH:14]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4].[CH:21]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)=[O:22].C([O-])([O-])=O.[Na+].[Na+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([NH2:20])=[C:8]([S:10]([C:13]2[CH:14]=[C:15]([C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([CH:21]=[O:22])[CH:28]=3)[CH:16]=[CH:17][CH:18]=2)(=[O:12])=[O:11])[CH:9]=1)=[O:4]
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: COC(=O)c1cc(S(=O)(=O)c2cccc(Br)c2)c(N)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1cc(S(=O)(=O)c2cccc(-c3cccc(C=O)c3)c2)c(N)s1
Yield: 39.5 %

Procedure:
The procedure as in Example 1: step c was followed using 5-amino-4-(3-bromo-benzenesulfonyl)-thiophene-2-carboxylic acid methyl ester (754.2 mg, 2 mmol, Example 20: step e), 3-formyl phenyl boronic acid (599.7 mg, 4 mmol), Pd(PPh3)4 (462.2 mg, 0.4 mmol), aqueous Na2CO3 (2M, 8 mL, 16 mmol), ethanol (8 mL) and toluene (16 mL). Purification by flash column chromatography (Biotage Flash™ System—40 M SiO2 column) (25% EtOAc in hexanes) of the residue yielded the title compound (317 mg, 40%) as a brown solid. 1H-NMR (CDCl3): δ 10.10 (s, 1H), 8.10–8.17 (m, 2H), 7.92–7.95 (m, 2H), 7.82–7.89 (t, 2H, J=8.1 Hz), 7.58–7.70 (m, 3H), 6.05 (br s, 2H), 3.80 (s, 3H).
Reaction SMILES: C([S:9][CH2:10][CH2:11][C:12]([NH:14][C:15]([CH3:20])([CH3:19])[C:16]([OH:18])=[O:17])=[O:13])(=O)C1C=CC=CC=1.[OH-].[NH4+]>O>[SH:9][CH2:10][CH2:11][C:12]([NH:14][C:15]([CH3:20])([CH3:19])[C:16]([OH:18])=[O:17])=[O:13]
Reactant: CC(C)(NC(=O)CCSC(=O)c1ccccc1)C(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CC(C)(NC(=O)CCS)C(=O)O

Procedure:
2.8 g. of the product of Example 45 is treated with a mixture of 20 ml. water and 20 ml. of concentrated ammonium hydroxide solution under an argon blanket for one hours. The benzamide precipitate is filtered and the filtrate is extracted twice with ethyl acetate. The aqueous phase is concentrated in vacuo, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic layer is dried and concentrated to dryness in vacuo and the residual product 2-[(3-mercaptopropanoyl)amino]-2-methylpropanoic acid, is crystallized from acetonitrile, yield 1.2 g., m.p. 169°-170°.
Reaction SMILES: [Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=O)=[CH:7][C:6]=1[F:20].ClC1N=C[C:25]([C:28]([C:30]2[CH:35]=[CH:34][C:33](OC3CCCCO3)=[CH:32][CH:31]=2)=O)=[CH:24]C=1>>[Br:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)=[C:28]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:25][CH3:24])=[CH:7][C:6]=1[F:20]
Reactant: O=C(c1ccc(O)cc1)c1ccc(OCCBr)c(F)c1
Reactant: O=C(c1ccc(OC2CCCCO2)cc1)c1ccc(Cl)nc1
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCBr)c(F)c1)c1ccccc1
Yield: 74.3 %

Procedure:
According to general procedure of McMurry reaction as example 1, step D described, (4-(2-bromoethoxy)-3-fluorophenyl)(4-hydroxyphenyl)methanone (150 mg, 0.442 mmol) was reacted with 1-(2,3-dihydrobenzofuran-5-yl)propan-1-one (94 mg, 0.533 mmol, made by example 1, step A) to give 145 mg desired product (68%, Z/E=1/1) as a gray solid.
Reaction SMILES: CCN(C(C)C)C(C)C.[OH:10][C:11]1[C:12]2[CH:13]=[CH:14][CH:15]=[N:16][C:17]=2[C:18]([CH3:28])([CH3:27])[C:19](=[O:26])[C:20]=1[C:21]([O:23]CC)=O.Cl.[C:30]([O:34][C:35](=[O:38])[CH2:36][NH2:37])([CH3:33])([CH3:32])[CH3:31]>O1CCOCC1>[OH:10][C:11]1[C:12]2[CH:13]=[CH:14][CH:15]=[N:16][C:17]=2[C:18]([CH3:27])([CH3:28])[C:19](=[O:26])[C:20]=1[C:21]([NH:37][CH2:36][C:35]([O:34][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:38])=[O:23]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CCOC(=O)C1=C(O)c2cccnc2C(C)(C)C1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2cccnc2C(C)(C)C1=O
Temperature: 75 °C
Reaction time: 1.5 h
Yield: 47.1 %

Procedure:
DIPEA (0.05 mL, 276 μmol) was added to a stirred mixture of ethyl 5-hydroxy-8,8-dimethyl-7-oxo-7,8-dihydroquinoline-6-carboxylate (24 mg, 92 μmol) and glycine tert-butyl ester hydrochloride (38 mg, 230 μmol) in 1,4-dioxane (3 mL). The reaction mixture was then stirred at 75° C. for 1.5 hours. The reaction mixture was concentrated, and the residue was purified by silica flash chromatography (0-75% EtOAc/hexane) to give the title compound as a crystalline white solid (15 mg, 47%). MS (m/z)=347 (M+H)+. Calculated for C18H22N2O5 346.4.
Reaction SMILES: [C:1]1([C:7]2[NH:15][C:14]3[C:9](=[N:10][CH:11]=[CH:12][C:13]=3[N:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1>CO.[Pd]>[CH:1]1([C:7]2[NH:15][C:14]3[C:9](=[N:10][CH:11]=[CH:12][C:13]=3[N:16]3[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]3)[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C1=C(c2cc3nccc(N4CCCCC4)c3[nH]2)CCCC1
Agent: [Pd]
Solvent: CO
Product: c1cc(N2CCCCC2)c2[nH]c(C3CCCCC3)cc2n1
Reaction time: 16 h
Yield: 98.8 %

Procedure:
2-Cyclohex-1-enyl-7-piperidylpyrrolo[3,2-b]pyridine (Example 43(b)) (280 mg, 1 mmol) was dissolved in MeOH (5 mL), and 10% palladium on charcoal (28 mg) was added. The flask was purged with H2 and a doubled-walled balloon filled with H2 was attached to the flask (˜30 psi H2). After 16 h, the mixture was filtered through celite, and the filtrate was concentrated in vacuo. The crude material was purified by flash chromatography 1:9 MeOH:EtOAc to afford 0.28 g (99%) of the title compound as an off-white solid. 1H NMR (DMSO-d6; 500 MHz): δ 2.0-1.2 (m, 16), 2.72 (m, 1), 3.18 (t, 4, J=5.2), 6.22 (s, 1), 6.55 (d, 1, J=5.3), 8.04 (d, 1, J=5.3), 10.61 (s, 1). MS m/z: 284 (M+1). Anal. Calcd for C18H25N3O.0.2H20: C, 75.33; H, 8.92; N, 14.64. Found: C, 75.39; H, 8.64; N, 14.64.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].C([O:13][CH:14]=[C:15]([C:21](OCC)=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C.C1(OC2C=CC=CC=2)C=CC=CC=1>C(O)C>[OH:22][C:21]1[C:7]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=[CH:9][CH:8]=2)[NH:6][C:14](=[O:13])[C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: Nc1ccccc1[N+](=O)[O-]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCO
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c(O)c2cccc([N+](=O)[O-])c2[nH]c1=O
Temperature: 80 °C
Yield: 24.8 %

Procedure:
A mixture of 2-nitroaniline (6.907 g) and diethyl ethoxymethylenemalonate (10.812 g) is heated to 130° C. for 2 h with removal of ethanol by a Dean-Stark trap. The mixture is cooled to 80° C. Diphenyl ether (60 mL) is added and the mixture is heated to 250° C. for 2 h. The solution is cooled to room temperature. The resulting solid is collected, washed with hexanes and dried to yield 3.447 g of ethyl 4-hydroxy-8-nitroquinolone-3-carboxylate as a gold solid. To a mixture of this ester (1.2 g) in 66 mL of 1:1 MeOH:THF is added 18 mL of 1M LiOH. The reaction is maintained at 40° C. overnight. The reaction mixture is cooled to room temperature, then diluted with 35 mL glacial acetic acid. The resulting precipitate is collected, washed with H2 0 and hot isopropanol, and dried to yield 0.639 g of 4-hydroxy-8-nitroquinoline-3-carboxylic acid as a yellow solid. A mixture of this acid (0.20 g) and p-chlorobenzylamine (0.10 mL) are dissolved in 25 mL xylenes and heated to reflux. PCl3 (0.037 mL) is added dropwise and the mixture is refluxed for 4 hours. The reaction mixture is cooled to room temperature and H2O is added to quench excess PCl3. An orange solid precipitates, which is collected, washed with ether, and dried. The crude product is recrystallized with hot MeOH to yield 0.0367 g of the desired product as a yellow solid.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].F[C:8]1[CH:9]=[CH:10][C:11]2[N:12]([C:14]([C:17]3[S:21][C:20]([C:22](=[O:24])[CH3:23])=[CH:19][CH:18]=3)=[CH:15][N:16]=2)[N:13]=1.[CH2:25]([CH2:27][NH2:28])[OH:26]>CN(C)C=O>[OH:26][CH2:25][CH2:27][NH:28][C:8]1[CH:9]=[CH:10][C:11]2[N:12]([C:14]([C:17]3[S:21][C:20]([C:22](=[O:24])[CH3:23])=[CH:19][CH:18]=3)=[CH:15][N:16]=2)[N:13]=1
Reactant: CC(=O)c1ccc(-c2cnc3ccc(F)nn23)s1
Reactant: NCCO
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(-c2cnc3ccc(NCCO)nn23)s1
Temperature: 40 °C
Reaction time: 1 h
Yield: 36.4 %

Procedure:
Cesium carbonate [534-17-8] (150 mg, 0.5 mmol) was added to a solution of 1-[5-(6-fluoro-imidazo[1,2-b]pyridazin-3-yl)-thiophen-2-yl]-ethanone (60 mg, 0.2 mmol) and ethanolamine [141-43-5] (29 mg, 0.5 mmol) in N,N-dimethylformamide (3 mL). The mixture was stirred at 40° C. for 1 h then partitioned between ethyl acetate and water. Analysis of the organic extract revealed preparation ratio of the desired arylamine product to the ether to be approximately 2:1. Preparative RP-HPLC isolated 22 mg of 1-{5-[6-(2-hydroxy-ethylamino)-imidazo[1,2-b]pyridazin-3-yl]-thiophen-2-yl}-ethanone as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.83 (s, 3H) 2.57 (s, 2H) 3.04 (t, J=5.68 Hz, 1H) 4.43 (t, J=5.68 Hz, 1H) 7.04 (d, J=9.60 Hz, 1H) 7.91 (d, J=4.04 Hz, 1H) 8.03 (d, J=4.04 Hz, 1H) 8.16 (d, J=9.60 Hz, 1H) 8.36 (s, 1H). LRMS (ESI) m/z 303.1 [(M+H)]+, calc'd for C14H14N4O2S: 302.36.