Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[F:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:35][CH2:34][CH2:33][CH:32]2[C:36]2[CH:37]=[C:38]([C:54](O)=[O:55])[CH:39]=[C:40]3[C:45]=2[O:44][C:43]([N:46]2[CH2:51][CH2:50][O:49][C@H:48]([CH3:52])[CH2:47]2)=[CH:42][C:41]3=[O:53])[CH:27]=[C:28]([F:30])[CH:29]=1.CCN(C(C)C)C(C)C.[NH:66]1[CH2:71][CH2:70][O:69][CH2:68][CH2:67]1>CC(N(C)C)=O>[F:30][C:28]1[CH:27]=[C:26]([N:31]2[CH2:35][CH2:34][CH2:33][CH:32]2[C:36]2[CH:37]=[C:38]([C:54]([N:66]3[CH2:71][CH2:70][O:69][CH2:68][CH2:67]3)=[O:55])[CH:39]=[C:40]3[C:45]=2[O:44][C:43]([N:46]2[CH2:51][CH2:50][O:49][C@H:48]([CH3:52])[CH2:47]2)=[CH:42][C:41]3=[O:53])[CH:25]=[C:24]([F:23])[CH:29]=1
Reactant: C1COCCN1
Reactant: C[C@@H]1CN(c2cc(=O)c3cc(C(=O)O)cc(C4CCCN4c4cc(F)cc(F)c4)c3o2)CCO1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1CN(c2cc(=O)c3cc(C(=O)N4CCOCC4)cc(C4CCCN4c4cc(F)cc(F)c4)c3o2)CCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
TBTU (154 mg, 0.48 mmol) was added to a stirred solution of 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-((R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxylic acid (90 mg, 0.19 mmol), DIPEA (0.083 mL, 0.48 mmol) dissolved in DMA (2 mL) under nitrogen. The resulting solution was stirred at room temperature for 30 min. Morpholine (0.050 mL, 0.57 mmol) was added and the mixture was stirred at room temperature for 1 h. The reaction mixture was purified by preparative HPLC. The fractions containing the desired compound were evaporated to dryness to afford 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-((R)-2-methylmorpholino)-6-(morpholine-4-carbonyl)-4H-chromen-4-one (68 mg, 66%) as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][S:11]([NH:14][CH2:15][B:16]([OH:18])[OH:17])(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[OH:19][C:20]([C:23]([OH:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21].[ClH:27]>C(OCC)(=O)C.[Pd]>[ClH:27].[NH2:1][C:4]1[CH:5]=[C:6]([CH2:10][S:11]([NH:14][CH2:15][B:16]([OH:18])[OH:17])(=[O:13])=[O:12])[CH:7]=[CH:8][CH:9]=1.[OH:19][C:20]([C:23]([OH:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: O=[N+]([O-])c1cccc(CS(=O)(=O)NCB(O)O)c1
Agent: [Pd]
Agent: CC(C)(O)C(C)(C)O
Agent: Cl
Solvent: CCOC(C)=O
Product: Nc1cccc(CS(=O)(=O)NCB(O)O)c1
Yield: 82.2 %

Procedure:
Palladium 10 wt. % on activated carbon (51 mg, 40% w/w) was added to a solution of 6 (128 mg, 0.36 mmol) in ethyl acetate (4 mL), and allowed to react under hydrogen atmosphere for 16 h. The catalyst was filtered off and the solvent was evaporated in vacuo. The crude residue was dissolved in HCl (0.1 M soln in MeOH, 3.6 mL, 0.36 mmol). After 45 min the mixture was concentrated under reduced pressure and the residue repeatedly washed with diethyl ether, affording 7 as a yellowish solid (118 mg, 90% yield). Mp 193-196° C. 1H-NMR (400 MHz, DMSO): δ 1.23 (12H, s, pinacol protons), 2.59 (2H, d, J 3.82, BCH2), 4.37 (2H, s, PhCH2), 6.76 (1H, br, SO2NH), 7.30-7.36 (3H, m, HArom), 7.46 (1H, t, J 7.60, HArom), 9.60-10.60 (3H, br, NH3+). 13C-NMR (100 MHz, DMSO): δ 25.0, 27.5 (CB), 55.9, 84.2, 122.8, 125.3, 130.1, 130.5, 132.7, 133.0. EI-MS, m/z: 326 (M+, 5%), 156 (8), 107 (64), 106 (100), 104 (15), 77 (11), 59 (11), 41 (8). Anal. Calcd. for C14H24BClN2O4S: C, 46.36; H, 6.67; N, 7.72; S, 8.84. Found: C, 46.41; H, 6.50; N, 7.55; S, 8.68.
Reaction SMILES: [Li].N.[CH2:3]([OH:6])[C:4]#[CH:5].[CH2:7](Br)[CH2:8][CH2:9][CH2:10][CH3:11]>O>[CH2:3]([OH:6])[C:4]#[C:5][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: C#CCO
Reactant: CCCCCBr
Agent: N
Agent: [Li]
Solvent: O
Product: CCCCCC#CCO
Reaction time: 1 h
Yield: 57.5 %

Procedure:
Under argon atmosphere, a piece of lithium was added to a liquid ammonia (250 ml) in a three neck distillation flask. After the reaction mixture had became dark blue, a catalytic amount of ferric nitrate nonahydrate was added thereto under argon atmosphere. A piece of lithium (2.75 g, 396 mmol) was successively added over 30 min. and the mixture was stirred for one hour. Propargyl alcohol (8.16 g, 146 mmol) was then added and the mixture was stirred for 30 min. Further, n-pentyl bromide (20 g, 132 mmol) was added and the mixture was stirred for 10 min. and allowed to stand overnight at room temperature. To the resulting mixture were added hydrated ether (50 ml) and water (200 ml), and the mixture was then extracted with ether (200 ml, 100 ml, 50 ml×3). The combined ether layers were washed with water (400 ml) and with brine (400 ml), dried over anhydrous sodium sulfate (50 g), and concentrated. Distillation of the residue gave a colorless oily product of 2-octyne-1-ol (9.5758 g, 52%, B.p.: 58°-61° C./0.3 mmHg). The product was assigned the structure by the following data.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]([C:14]3[C:15]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:30]([O:32]CC)=[O:31].[OH-].[Na+:36]>C(O)C>[OH2:13].[Na+:36].[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]([C:14]3[C:15]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:28])([F:29])[F:27])=[CH:22][CH:21]=4)=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:8][CH:9]=2)[CH:4]=[C:3]1[C:30]([O-:32])=[O:31]
Reactant: CCOC(=O)c1cc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2n1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1c(C(=O)[O-])cc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc21
Product: O
Reaction time: 8 h
Yield: 151.6 %

Procedure:
Ethyl 1-methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxylate (46.7 g) from the previous step and aqueous sodium hydroxide (8.0 g in 140 ml) were combined in refluxing ethanol (280 mL) for 1 hour. The solution was cooled, granulating overnight and the resulting slurry was filtered. The product solids were washed with an ethanol-water mixture and dried, yielding the title compound, 1-methyl-5-[4′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxamido]-1H-indole-2-carboxylic acid sodium salt hydrate (36.3 g, 79% as-is). Anhydrous Mol wt of parent acid (calc) 438.41, MS: 439.2 (MH+), 437.0 (M−). 1H NMR (DMSO-d6): δ 4.00 (s, 3H), 6.55 (s, 1H), 7.12-7.75 (complex, 11H), 10.04 (s, 1H).; HPLC retention time 9.30 minutes.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.Br[CH2:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH:23]1([CH2:22][N:15]2[CH2:16][C:17](=[O:18])[N:13]([C:11]3[CH:10]=[N:9][N:8]([CH2:7][C:6]4[C:2]([CH3:1])=[N:3][O:4][C:5]=4[CH3:20])[CH:12]=3)[C:14]2=[O:19])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: BrCC1CCCCC1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(CC3CCCCC3)C2=O)cn1
Yield: 20 %

Procedure:
Prepared as in example 10-52 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and bromomethylcyclohexane. Yield: 20%. 1H NMR (DMSO-d6, 400 MHz): δ0.88 (q, J=10.4 Hz, 2H), 1.09-1.19 (m, 3H), 1.58-1.65 (m, 6H), 2.12 (s, 3H), 2.38 (s, 3H), 3.13 (d, J=7.2 Hz, 2H), 4.06 (s, 2H), 5.17 (s, 2H), 7.75 (s, 1H), 8.14 (s, 1H). MS M+H calculated 372.2; found 372.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.28 μM.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][C:18]([Cl:22])=[C:19](Br)[CH:20]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[C:1]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[N:17][C:18]([Cl:22])=[C:19]([C:27]2[CH:28]=[CH:29][C:24]([Cl:23])=[CH:25][CH:26]=2)[CH:20]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cnc(Cl)c(Br)c1
Reactant: OB(O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cnc(Cl)c(-c2ccc(Cl)cc2)c1
Yield: 26 %

Procedure:
To a solution of 3-(1-BOC-2-(S)-pyrrolidinylmethoxy)-5-bromo-6-chloropyridine (1.64 g, 4.20 mmol) and 4-chlorophenylboronic acid (620 mg, 3.9 mmol.) in toluene (20 mL) was added Pd(0) (97 mg) and Na2CO3 (5 mL of a 2 M solution), and the mixture was heated at reflux for 16 h. The reaction mixture was quenched with saturated NaHCO3 solution and extracted with Et2O. The solvent was removed under vacuum, and the residue was chromatographed (silica gel; EtOAc/hexane, 1:4) to afford the title compound (430 mg, 24% yield): 1H NMR (CDCl3, 300 MHz) δ1.45 (s, 9H), 1.83-2.00 (m, 4H), 3.30-3.45 (m, 2H), 4.00 (m, 1H), 4.06-4.25 (m, 2H), 7.36-7.46 (m, 5H), 8.10 (s, 1H); MS (CI/NH3) m/z 423 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=2)=[CH:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[N:15]=2)[CH:10]=1)=[O:4].[CH3:33][N:34]([CH3:39])[CH2:35][CH2:36][CH2:37][NH2:38].C1COCC1.O.[OH-].[Li+]>CO.O>[Cl:23][C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:4])=[O:2])[C:6]([C:24]4[CH:29]=[CH:28][C:27]([C:30](=[O:31])[NH:38][CH2:37][CH2:36][CH2:35][N:34]([CH3:39])[CH3:33])=[CH:26][CH:25]=4)=[CH:7][CH:8]=3)[S:12][CH:13]=2)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Reactant: CN(C)CCCN
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CN(C)CCCNC(=O)c1ccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
Using the conditions of General Procedure D for Amide Coupling in Parallel Mode, 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (which may be prepared as described for Intermediate 8; 100 mg, 0.21 mmol) was reacted with N,N-dimethyl-1,3-propanediamine (available from Aldrich Chemical Company, Inc.; 42 mg, 0.41 mmol) to give the crude amide product. The crude amide was hydrolyzed by adding THF (2 mL), water (0.05 mL), MeOH (1 mL), and lithium hydroxide monohydrate (12.3 mg, 0.29 mmol) and stirring the mixture overnight at room temperature. Lithium hydroxide monohydrate (22 mg, 0.52 mmol) was added. The reaction mixture was stirred overnight, and then another portion of lithium hydroxide monohydrate (22 mg, 0.52 mmol) was added. The reaction mixture was stirred overnight. The reaction mixture was concentrated to dryness under vacuum at 40° C. 1 M HCl (3 mL) was added, and the mixture was stirred, concentrated to dryness, and purified and purified using HPLC Purification Conditions A to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-(3-dimethylamino-propylcarbamoyl)-biphenyl-2-carboxylic acid (102 mg, 89%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.16 (br s, 1H), 8.68 (t, J=5.6 Hz, 1H), 8.48 (s, 1H), 8.40 (d, J=1.8 Hz, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.25 (dd, J=8.0, 1.8 Hz, 1H), 8.09 (dd, J=8.5, 2.0 Hz, 1H), 7.92 (d, J=8.3 Hz, 2H), 7.77 (d, J=8.3 Hz, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.50 (d, J=8.3 Hz, 2H), 3.34-3.40 (m, 2H), 3.08-3.16 (m, 2H), 2.79-2.82 (m, 6H), 1.86-1.95 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:39])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([Se:14][C:15]#[C:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[CH:19][CH:18]=3)[CH:5]=[C:4]([O:27][CH2:28][C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]=[CH:31][CH:30]=3)[C:3]1=2.[OH-].[Na+]>>[CH3:1][C:2]1([CH3:39])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([Se:14][C:15]#[C:16][C:17]3[CH:26]=[CH:25][C:20]([C:21]([OH:23])=[O:22])=[CH:19][CH:18]=3)[CH:5]=[C:4]([O:27][CH2:28][C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]=[CH:31][CH:30]=3)[C:3]1=2
Reactant: COC(=O)c1ccc(C#C[Se]c2cc(OCc3cccc4ccccc34)c3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC1(C)CCC(C)(C)c2c(OCc3cccc4ccccc34)cc([Se]C#Cc3ccc(C(=O)O)cc3)cc21

Procedure:
In a manner similar to that of Example 1g, by reacting 400 mg (0.7 mmol) of methyl 4-[5,5,8,8-tetramethyl-4-(naphthylmethoxy)-5,6,7,8-tetrahydro-2-naphthylselanylethynyl]benzoate with 140 mg of sodium hydroxide. A white crystallized solid is obtained (m=258 mg; yield=65%; m.p.=254° C.).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]3[N:12]=[C:13]([NH2:15])[S:14][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[N:18]([CH3:20])[CH3:19].[O:21]([CH2:28][C:29](Cl)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>N1C=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]3[N:12]=[C:13]([NH:15][C:29](=[O:30])[CH2:28][O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[S:14][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[N:18]([CH3:20])[CH3:19]
Reactant: O=C(Cl)COc1ccccc1
Reactant: CN(C)c1cc(-c2ccc3nc(N)sc3c2)cnc1Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C)c1cc(-c2ccc3nc(NC(=O)COc4ccccc4)sc3c2)cnc1Cl

Procedure:
To a mixture of 6-(6-chloro-5-(dimethylamino)pyridin-3-yl)benzo[d]thiazol-2-amine (100 mg, 328 μmol) in pyridine (0.3 mL) and DCM (2 mL) was added 2-phenoxyacetyl chloride (150 μl, 1086 μmol). A clear solution formed. More 2-phenoxyacetyl chloride (150 μl, 1086 μmol) was added until the reaction was complete. The DCM was evaporated and the mixture was diluted with EtOAc (10 mL). The mixture was filtered, washed with EtOAc, H2O (3×5 mL) and dried in air to give a gray powder. MS (ESI, POS. ION) M/Z: calc'd for C22H19ClN4O2S: 438.1. found: 439.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.85 (s, 6H) 4.95 (s, 2H) 6.90-7.08 (m, 3H) 7.33 (t, J=7.78 Hz, 2H) 7.75-7.92 (m, 3H) 8.36 (s, 1H) 8.44 (s, 1H) 12.70 (s, 1H).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9](/[CH:12]=[CH:13]/[C:14](=O)[CH2:15][CH2:16][C:17]([OH:19])=O)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.O.[NH2:22][NH2:23]>C(O)C>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]3[CH2:15][CH2:16][C:17](=[O:19])[NH:22][N:23]=3)=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: NN
Reactant: O=C(O)CCC(=O)/C=C/c1ccc(-n2ccnc2)cc1
Solvent: O
Solvent: CCO
Product: O=C1CCC(C=Cc2ccc(-n3ccnc3)cc2)=NN1

Procedure:
A solution of 2 g of (E)-6-[4-(1H-imidazol-1-yl)phenyl]-4-oxo-5-hexenoic acid in 60 ml of ethanol containing 0.5 g of 80% hydrazine hydrate is heated to reflux for three hours. The solution is concentrated to a small volume (ca 10 ml) and filtered. The residue is crystallized from THF/methanol to give 0.6 g of the 4,5-dihydro-pyridazinone, mp 230°-231° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:13]2[CH2:12][CH2:11][CH2:10][CH:9]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[CH2:8][C:7]=2[C:6]([NH2:20])=[CH:5][CH:4]=1.Cl[C:22]1[N:27]=[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[S:35]([N:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])[C:25]([Cl:41])=[CH:24][N:23]=1>>[Cl:41][C:25]1[C:26]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[S:35]([N:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])=[N:27][C:22]([NH:20][C:6]2[C:7]3[CH2:8][CH:9]([N:14]4[CH2:15][CH2:16][O:17][CH2:18][CH2:19]4)[CH2:10][CH2:11][CH2:12][C:13]=3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:23][CH:24]=1
Reactant: COc1ccc(N)c2c1CCCC(N1CCOCC1)C2
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: COc1ccc(Nc2ncc(Cl)c(Nc3ccccc3S(=O)(=O)N(C)C)n2)c2c1CCCC(N1CCOCC1)C2

Procedure:
The title compound was prepared from 4-methoxy-8-morpholin-4-yl-6,7,8,9-tetrahydro-5H-benzocyclohepten-1-ylamine (50 mg, 0.2 mmol) and 2-(2,5-dichloropyrimidin-4-ylamino)-N,N-dimethylbenzenesulfonamide (70 mg, 0.2 mmol) in an analogous manner to Example 944 to afford a white foam (49 mg, 50%). Mp: 196-8° C. LCMS (m/e) 587 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 9.60 (s, 1H), 8.07 (m, 1H), 7.80 (d, J=8 Hz, 1H), 7.25 (m, 1H), 7.19 (d, J=9 Hz, 1H), 7.11 (m, 1H), 6.81 (d, J=9 Hz, 1H), 6.70 (br s, 1H), 3.86 (s, 3H), 3.60 (m, 4H), 3.42 (m, 1H), 3.22 (m, 1H), 2.75 (s, 6H), 2.59 (m, 3H), 2.33 (m, 4H), 2.00 (m, 3H), 1.72 (m, 1H).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][N:3]=1.Br[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1.C(N=C(N(C)C)N(C)C)(C)(C)C>CC#N>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:17]=2)[N:3]=1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(I)c12
Reactant: FC(F)(F)c1cccc(CBr)c1
Agent: CN(C)C(=NC(C)(C)C)N(C)C
Solvent: CC#N
Product: O=[N+]([O-])c1cccc2c1c(I)nn2Cc1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85.4 %

Procedure:
To a slurry of 3-iodo-4-nitro-1H-indazole (0.410 g, 1.42 mmol) and CH3CN (7.0 mL) was added 1-(bromomethyl)-3-(trifluoromethyl)benzene (0.261 mL, 1.70 mmol) and the solution was cooled to 0° C. 2-tert-Butyl-1,1,3,3-tetramethylguanidine (0.372 mL, 1.84 mmol) was added and the mixture was gradually warmed to ambient temperature where it stirred for 2 hours. The mixture was concentrated and diluted with saturated aqueous NH4Cl (20 mL) and EtOAc (75 mL). The layers were mixed and separated and the organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was passed through a silica gel plug eluting with 20% EtOAc/hexane to provide 0.542 g (85%) of the product as dark yellow/orange oil.
Reaction SMILES: Cl[C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3.[CH3:19][O:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24]>>[CH3:19][O:20][C:21]1[CH:22]=[C:23]([NH:24][C:2]2[CH:17]=[C:6]3[C:7]4[C:12]([CH2:13][CH2:14][N:5]3[C:4](=[O:18])[N:3]=2)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=4)[CH:25]=[CH:26][CH:27]=1
Reactant: COc1ccc2c(c1)CCn1c-2cc(Cl)nc1=O
Reactant: COc1cccc(N)c1
Product: COc1cccc(Nc2cc3n(c(=O)n2)CCc2cc(OC)ccc2-3)c1

Procedure:
The title compound was prepared from 2-chloro-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (4) and 3-methoxyaniline as in Example 1 d. 1H-NMR (400 MHz, d6-DMSO) δ 9.59 (s, 1H), 7.68 (d, 1H), 7.52 (br, 1H), 7.30 (d, 1H), 7.23 (t, 1H), 7.05-6.95 (2H), 6.63 (dd, 1H), 6.35 (s, 1H), 3.98 (t, 2H), 3.84 (s, 3H), 3.75 (s, 3H) and 2.96 (t, 2H); MS (ESI) (M+H)+ 350.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]4[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=4)[C:19]([O:21]C)=[O:20])=[N:11][N:10]3[CH:26]=2)=[O:5])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>O1CCCC1>[CH:1]1([C:4]([NH:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]4[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=4)[C:19]([OH:21])=[O:20])=[N:11][N:10]3[CH:26]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: COC(=O)c1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.3 %

Procedure:
To a solution of methyl 3-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}oxy)benzoate (225 mg, 0.64 mmol) in tetrahydrofuran (5.0 mL) was added 1N sodium hydroxide (2.5 mL), and the mixture was stirred at room temperature for 24 hr. 1N Hydrochloric acid was added to the mixture (pH=3), and the aqueous layer was extracted three times with ethyl acetate/tetrahydrofuran. Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The solvent was evaporated under reduced pressure, and the residue was filtrated, and washed with ethyl acetate/hexane to give the title compound (150 mg, 69%) as a white powder.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][C:3]=1[F:11].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[F:11][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH:8][CH:7]=[CH:6]2
Reactant: Fc1cc2cc[nH]c2cc1Br
Reactant: OB(O)c1ccccc1
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: O
Solvent: COCCOC
Product: Fc1cc2cc[nH]c2cc1-c1ccccc1
Temperature: 85 °C
Reaction time: 18 h
Yield: 95.6 %

Procedure:
A mixture of 6-bromo-5-fluoro-1H-indole (0.214 g, 1 mmol), phenylboronic acid (0.171 g, 1.4 mmol), sodium carbonate (1.06 g, 10 mmol), Pd(PPh3)4 (0.116 g, 0.1 mmol), 1,2-dimethoxyethane (5 mL) and water (5 mL) was stirred under nitrogen at 85° C. for 18 h. The mixture was partitioned between water (20 mL) and DCM (2×30 mL) and the combined extracts were dried (Na2SO4) and evaporated in vacuo to give an oil. Chromatography (SiO2; gradient elution with 0-50% Et2O in petrol) gave 5-fluoro-6-phenyl-1H-indole (0.202 g, 95%) as a pale green solid. MS: [M+H]+=212. A solution of borane in THF (1 M, 1.42 mL) was added to 5-fluoro-6-phenyl-1H-indole (0.20 g, 0.95 mmol) under nitrogen with external cooling using an ice-MeOH bath. The resulting mixture was stirred at 0° C. for 0.5 h, then TFA was added dropwise over 0.1 h. The mixture was stirred at 0° C. for 1 h then a solution of sodium hydroxide (0.8 g, 20 mmol) and water (5 mL) was added dropwise over 0.1 h. The resulting mixture was partitioned between water (20 mL) and DCM (2×30 mL) and the combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give an oil. Chromatography (SiO2; gradient elution with 0-100% Et2O in petrol) gave the title compound (0.17 g, 85%) as an oil. MS: [M+H]+=214.
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[CH:3](O)[OH:4].[Cl:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][CH:10]=1>>[Cl:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH:15][CH:3]([OH:4])[C:2]([Cl:7])([Cl:6])[Cl:1])=[O:14])=[CH:11][CH:10]=1
Reactant: NC(=O)c1ccc(Cl)cc1
Reactant: OC(O)C(Cl)(Cl)Cl
Product: O=C(NC(O)C(Cl)(Cl)Cl)c1ccc(Cl)cc1

Procedure:
2,2,2-Trichloro-1,1-ethanediol and 4-chlorobenzamide were processed as described in Example 37C to provide the desired product.
Reaction SMILES: C(OC(N1CCN(C2C(=O)N(CC(C)C)N=C(C3C=CC(C(F)(F)F)=CC=3)C=2C)CC1)=O)(C)(C)C.[C:36]1([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=2)[CH:41]=[CH:40][C:39]([C:42]2[CH:43]=[C:44]([C:53](O)=[O:54])[C:45](=[O:52])[N:46]([CH2:48][CH:49]([CH3:51])[CH3:50])[N:47]=2)=[CH:38][CH:37]=1>>[C:36]1([C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)[CH:37]=[CH:38][C:39]([C:42]2[CH:43]=[C:44]([CH2:53][OH:54])[C:45](=[O:52])[N:46]([CH2:48][CH:49]([CH3:50])[CH3:51])[N:47]=2)=[CH:40][CH:41]=1
Reactant: CC(C)Cn1nc(-c2ccc(-c3ccccc3)cc2)cc(C(=O)O)c1=O
Agent: Cc1c(-c2ccc(C(F)(F)F)cc2)nn(CC(C)C)c(=O)c1N1CCN(C(=O)OC(C)(C)C)CC1
Product: CC(C)Cn1nc(-c2ccc(-c3ccccc3)cc2)cc(CO)c1=O

Procedure:
Following the procedure of Example 1 (8), 6-(4-biphenylyl)-4-carboxy-2-isobutyl-2H-pyridazin-3-one was reacted to yield the title compound as a while solid (yield: 15.6%).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:8][CH3:9])[CH2:4][CH2:5][CH2:6]O.CN(C)C=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:35]>O>[CH3:1][O:2][CH:3]([O:8][CH3:9])[CH2:4][CH2:5][CH2:6][Br:35]
Reactant: COC(CCCO)OC
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: COC(CCCBr)OC

Procedure:
A solution of 0.1 moles of 4,4-dimethoxybutanol in 50 ml. of dimethylformamide containing 0.1 moles of triphenylphosphine is allowed to react for 18 hours with 0.1 moles of carbon tetrabromide. The mixture is diluted with water and extracted with ether. The ether extracts are combined, washed with water, dried and evaporated to a crude product which is purified by distillation to yield 4,4-dimethoxybutylbromide. This bromide is then converted into the diethyl phosphonate using the procedure described in Example 2.