Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][N:3]1[C:8]([CH3:10])([CH3:9])[CH2:7][C:6](=O)[CH2:5][C:4]1([CH3:13])[CH3:12].[CH2:14]([NH2:18])[CH2:15][CH2:16][CH3:17]>[Pt].CO>[CH3:1][O:2][N:3]1[C:8]([CH3:10])([CH3:9])[CH2:7][CH:6]([NH:18][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:5][C:4]1([CH3:13])[CH3:12]
Reactant: CON1C(C)(C)CC(=O)CC1(C)C
Reactant: CCCCN
Agent: [Pt]
Solvent: CO
Product: CCCCNC1CC(C)(C)N(OC)C(C)(C)C1
Yield: 80.2 %

Procedure:
A mixture of 10.1 g (54.5 mmol) of 1-methoxy-2,2,6,6-tetramethylpiperidin-4-one, 27.9 g (382 mmol) of n-butyl amine, 100 ml of methanol, and 1.0 g of 5% platinum on carbon is hydrogenated (50 psi, 25° C.) for 5 hours. The catalyst is removed by filtration. Evaporation of the filtrate gives an oil which is purified by fractional distillation to afford 10.6 g (80% yield) of the title compound, a colorless oil, b.p. 93°-100° C. (0.25 mm).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C([Sn](CCCC)(CCCC)[C:43]1[O:44][C:45]2[CH:51]=[CH:50][CH:49]=[CH:48][C:46]=2[N:47]=1)CCC.[F-].[Cs+]>O1CCOCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[O:44]1[C:45]2[CH:51]=[CH:50][CH:49]=[CH:48][C:46]=2[N:47]=[C:43]1[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc2ccccc2o1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(Br)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4nc5ccccc5o4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 130 °C
Yield: 21.2 %

Procedure:
A mixture of tert-butyl {1-[4-(2-bromo-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (50.0 mg, 0.0895 mmol), 2-(tributylstannyl)-1,3-benzoxazole (81.2 mg, 0.179 mmol), bis (tri-tert-butylphosphine)palladium(0) (9.15 mg, 0.0179 mmol) and cesium fluoride (88.4 mg, 0.582 mmol) in 1,4-dioxane (1.00 mL) was heated at 130° C. under microwave irradiation for 2 hours under nitrogen. After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc (×3). The combined organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by PTLC (EtOAc/hexane=1:1, DCM/EtOAc=1:1) to afford desired product (11.3 mg, 21.2%) as white solid. 1HNMR (CDCl3) 500 MHz δ: 8.27 (dd, J=7.7, 1.7 Hz, 1H), 8.08-8.02 (m, 1H), 7.75-7.68 (m, 1H), 7.52-7.38 (m, 5H), 7.37-7.25 (m, 3H), 7.20-7.14 (m, 1H), 6.98 (d, J=8.0 Hz, 1H), 6.92-6.81 (m, 1H), 6.63 (dd, J=8.0, 4.6 Hz, 1H), 6.45 (s, 1H), 5.20 (s, 1H), 2.68-2.25 (m, 4H), 2.22-2.09 (m, 1H), 1.97-1.86 (m, 1H), 1.54-1.11 (m, 9H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[CH3:14].[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[CH2:14][Br:16]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(C(=O)OC)c(C)c1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(C(=O)OC)c(CBr)c1

Procedure:
88 G. of dimethyl-2-methylterephthalate in 1000 ml. of carbon tetrachloride containing 89 g. (1 eq. ) of N-bromosuccinimide is refluxed for 3 hours using a heat lamp. The solution is cooled, filtered and evaporated to dryness to give dimethyl-2-bromomethylterephthalate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:25]=[C:24]([O:26][C@H:27]3[C@H:31]4[O:32][CH2:33][C@@H:34]([OH:35])[C@H:30]4[O:29][CH2:28]3)[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=1.Br[C:45]1[CH:50]=[CH:49][C:48]([NH:51][S:52]([CH3:58])(=[N:54][CH:55]2[CH2:57][CH2:56]2)=[O:53])=[CH:47][CH:46]=1>>[OH:35][C@H:34]1[C@H:30]2[O:29][CH2:28][C@@H:27]([O:26][C:24]3[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:5]4=[N:6][C:7]([C:8]5[CH:13]=[CH:12][C:11]([C:45]6[CH:50]=[CH:49][C:48]([NH:51][S:52]([CH3:58])(=[N:54][CH:55]7[CH2:57][CH2:56]7)=[O:53])=[CH:47][CH:46]=6)=[CH:10][CH:9]=5)=[C:2]([Cl:1])[CH:3]=[C:4]4[N:25]=3)[C@H:31]2[O:32][CH2:33]1
Reactant: CS(=O)(=NC1CC1)Nc1ccc(Br)cc1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)OC1(C)C
Product: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2cc(Cl)c(-c3ccc(-c4ccc(NS(C)(=O)=NC5CC5)cc4)cc3)nc21

Procedure:
The title compound is prepared from (3R,3aR,6R,6aR)-6-(6-chloro-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridin-2-yloxy)hexahydrofuro[3,2-b]furan-3-ol and N-(4-bromophenyl)-N′-cyclopropyl-methanesulfonimidamide following a procedure analogous to that described for Intermediate 3 (Step 3). LC (method 1): tR=1.11 min; Mass spectrum (ESI+): m/z=712 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:28]([OH:30])=[O:29])=[C:16]([C:17](=O)[NH:18][C:19]([C:24](=[O:26])[NH2:25])([CH3:23])[CH:20]([CH3:22])[CH3:21])[C:11]=2[N:10]=[C:9]1[CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl>O>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:28]([OH:30])=[O:29])=[C:16]([C:17]3[NH:25][C:24](=[O:26])[C:19]([CH:20]([CH3:22])[CH3:21])([CH3:23])[N:18]=3)[C:11]=2[N:10]=[C:9]1[CH3:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc2c(C(=O)NC(C)(C(N)=O)C(C)C)c(C(=O)O)ccc2n1Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1nc2c(C3=NC(C)(C(C)C)C(=O)N3)c(C(=O)O)ccc2n1Cc1ccccc1
Reaction time: 4 h
Yield: 30.9 %

Procedure:
A mixture of 1-benzyl-4-[(1-carbamoyl-1,2-dimethylpropyl)carbamoyl]-2-methyl-5-benzimidazolecarboxylic acid (3.58 g, 8.47 mmol), 10N sodium hydroxide (5.08 mL, 50.8 mmol) and water is stirred for 4 hours at reflux temperature, cooled, acidified to pH 4 with hydrochloric acid and filtered. The filter cake is recrystallized from acetonitrile to give the title product as an off-white powder (1.06 g, 31.0%), mp 198°-208° C. (dec).
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]([CH:17]=[O:18])[C:6]=2[CH:5]=1)([OH:3])=[O:2].[BH4-].[Na+].Cl>O>[C:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]([CH2:17][OH:18])[C:6]=2[CH:5]=1)([OH:3])=[O:2]
Reactant: O=CC1c2ccccc2-c2ccc(C(=O)O)cc21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc2c(c1)C(CO)c1ccccc1-2
Reaction time: 16 h

Procedure:
2-Carboxy-9-formylfluorene (2.77 g, 0.012 mole) and distilled water (110 mL) were added to a round bottom flask. Sodium borohydride (8.65 g, 0.228 mole) was added slowly to the reaction solution. After approximately twenty minutes additional sodium borohydride (8.65 g, 0.228 mol) was added. After approximately 16 hours at room temperature, 1 M hydrochloric acid was added until the pH of the solution was approximately 2. The product was filtered and rinsed with distilled water. The 2-carboxy-9-hydroxymethylfluorene was dried under reduced pressure with either phosphorus pentoxide or drierite present. NMR confirmed the structure by the disappearance of the aldehyde proton and the appearance of a multiplet (three protons) centered at δ4.05 ppm, which is consistent with the proton at C-9 and the methylene of the hydroxymethyl group.
Reaction SMILES: [N:1]([C@H:4]1[C@H:9]([OH:10])[CH2:8][CH:7]=[CH:6][CH2:5]1)=[N+:2]=[N-:3].C(=O)(O)[O-:12].[Na+].ClC1C=CC=C(C(OO)=O)C=1>ClCCl>[N:1]([C@@H:4]1[CH2:5][CH:6]2[C@@H:7]([O:12]2)[CH2:8][C@H:9]1[OH:10])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=N[C@@H]1CC=CC[C@H]1O
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: [N-]=[N+]=N[C@@H]1CC2O[C@H]2C[C@H]1O
Reaction time: 12 h
Yield: 64.5 %

Procedure:
(1R,6R)-6-Azidocyclohex-3-en-1-ol 3c (500 mg, 3.60 mmol) was dissolved in 150 mL of dichloromethane followed by the addition of sodium bicarbonate (600 mg, 7.20 mmol) and m-Chloroperbenzoic acid (2.40 g, 9.60 mmol), the reaction solution was stirred for 12 hours. The resulting solution was washed with saturated sodium bicarbonate solution (50 mL), saturated sodium thiosulfate solution (50 mL) and saturated sodium chloride solution (50 mL×3) successively, then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure, the residue was purified by HPLC to obtain the title compound (1S,3R,4R)-4-azido-7-oxabicyclo[4.1.0]heptan-3-ol 3d (360 mg, yield: 64.6%) as a white solid.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:35])[C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[C:14]([CH:16]3[CH2:20][CH2:19][CH2:18][N:17]3C(OC(C)(C)C)=O)[CH:15]=1)[O:12][C:11]([N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)=[CH:10][C:9]2=[O:34])=[O:5]>C(Cl)Cl>[CH3:2][N:3]([CH3:35])[C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[C:14]([CH:16]3[CH2:20][CH2:19][CH2:18][NH:17]3)[CH:15]=1)[O:12][C:11]([N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)=[CH:10][C:9]2=[O:34])=[O:5]
Reactant: CN(C)C(=O)c1cc(C2CCCN2C(=O)OC(C)(C)C)c2oc(N3CCOCC3)cc(=O)c2c1
Agent: Cl
Solvent: ClCCl
Product: CN(C)C(=O)c1cc(C2CCCN2)c2oc(N3CCOCC3)cc(=O)c2c1
Reaction time: 8 h
Yield: 101 %

Procedure:
HCl (4.50 mL, 18 mmol, 4M solution) was added to a stirred solution of tert-butyl 2-(6-(dimethylcarbamoyl)-2-morpholino-4-oxo-4H-chromen-8-yl)pyrrolidine-1-carboxylate (850 mg, 1.80 mmol) dissolved in DCM (10 mL) at room temperature and stirred for 8 h. After evaporation of the volatile, DCM (5 mL) and MeOH (5 mL) were added followed by 10% methanolic ammonia (7 N, 5 mL) in DCM. The solid was filtered, washed with a 1:1 mixture of DCM and MeOH. The solvent was evaporated to dryness to afford after trituration with diethyl diethyl ether, N,N-dimethyl-2-morpholino-4-oxo-8-(pyrrolidin-2-yl)-4H-chromene-6-carboxamide (675 mg, 101%) as a pale beige solid. Mass Spectrum: m/z [M+H]+=372.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)[C:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:40]2[CH:45]=[CH:44][C:43]([S:7]([CH3:1])(=[O:9])=[O:8])=[CH:42][CH:41]=2)=[CH:20][CH:21]2[CH2:22][CH2:23][O:24][CH2:25][CH2:26]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCOCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(C(=CC2CCOCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Yield: 94.6 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-(tetrahydro-pyran-4-yl)-vinyl ester (prepared as in Example 67, 0.5 g, 0.93 mmol), 4-(trifluoromethyl)phenylboronic acid (0.56 g, 2.8 mmol) and dichlorobis(triphenylphosphine)palladium (II) (63 mg, 0.09 mmol) in dioxane (8 mL) was added an aqueous sodium carbonate solution (2 M, 1.4 mL). The resulting mixture was subjected to microwave irradiation for 4 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 50% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-[1-(4-methanesulfonyl-phenyl)-2-(tetrahydro-pyran-4-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (0.23 g, 47%) as a white solid.
Reaction SMILES: [CH3:1][N:2]([C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]1[S:20][CH:21]=[CH:22][N:23]=1)=[CH:15]2)[C:3]([C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)=O.B.O1CCCC1.CO>O1CCCC1>[CH3:1][N:2]([CH2:3][C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]1[S:20][CH:21]=[CH:22][N:23]=1)=[CH:15]2
Reactant: CN(C(=O)c1cccs1)c1cccc2cc(-c3nccs3)[nH]c12
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: CN(Cc1cccs1)c1cccc2cc(-c3nccs3)[nH]c12
Temperature: 25 °C
Yield: 38.2 %

Procedure:
To a solution of N-methyl-N-[2-(1,3-thiazol-2-yl)-1H-indol-7-yl]thiophene-2-carboxamide (150 mg) in tetrahydrofuran (10 mL) was added borane-tetrahydrofuran complex (1.0 M tetrahydrofuran solution, 10 mL). The reaction mixture was stirred with heating under reflux for 1 hr. The reaction mixture was cooled to room temperature, and methanol (5 mL) was added. The reaction mixture was stirred with heating under reflux for 1 hr, and the reaction mixture was concentrated. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=1:3) to give the title compound (55 mg, yield 38%) as a yellow oil. M+1=326.
Reaction SMILES: [CH3:1][CH:2]([CH:8]([N+:11]([O-])=O)[CH2:9][CH3:10])[CH2:3][C:4](OC)=[O:5]>CCO.O=[Pt]=O>[CH2:9]([CH:8]1[NH:11][C:4](=[O:5])[CH2:3][CH:2]1[CH3:1])[CH3:10]
Reactant: CCC(C(C)CC(=O)OC)[N+](=O)[O-]
Agent: O=[Pt]=O
Solvent: CCO
Product: CCC1NC(=O)CC1C
Yield: 59.9 %

Procedure:
A solution of 4.0 g (21 mmol) of methyl 3-methyl-4-nitrohexanoate (from step A) in 20 mL of EtOH containing 0.4 g of PtO2 was hydrogenated on a Parr apparatus for 3 days. The catalyst was filtered and washed with EtOH and the filtrate was concentrated. Vacuum distillation of the residue furnished 1.6 g (61%) of the title compound: bp 102°-107° C./2 mm.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:11][CH3:12])=[C:5]([O:9][CH3:10])[CH:6]=[CH:7][CH:8]=1.[N+:13]([O-])([OH:15])=[O:14]>CC(O)=O>[CH3:10][O:9][C:5]1[CH:6]=[C:7]([N+:13]([O-:15])=[O:14])[CH:8]=[C:3]([O:2][CH3:1])[C:4]=1[O:11][CH3:12]
Reactant: O=[N+]([O-])O
Reactant: COc1cccc(OC)c1OC
Solvent: CC(=O)O
Product: COc1cc([N+](=O)[O-])cc(OC)c1OC

Procedure:
Trimethoxybenzene (100 g, 0.594 mol) was dissolved in AcOH (220 mL) and stirred while adding 70% HNO3 (69 mL, 1.088 mol) over 20 min. The temperature was kept at 70° C. by cooling as necessary in a water bath. The cooling bath was removed after addition and the mixture remained at 65° C. for several min before cooling. Ice/water was added to precipitate a solid product which was washed well with water. 1M NaOH (500 mL) was added and stirred with the solid for 5 min. The solid was collected, washed with water until the washings were colorless and dried in air, giving 3,4,5-trimethoxynitrobenzene as pale yellow needles.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:16]=[C:17]([CH:25]=[CH:26][CH:27]=3)[C:18]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10][CH2:9]2)=[O:7])=[CH:4][C:3]=1[CH3:30].C1C([N+]([O-])=O)=CC=C([Cl-][C:41]([O-])=[O:42])C=1.[CH3:44][C:45]([CH3:49])([CH3:48])[CH2:46][NH2:47]>ClCCl>[C:21]([NH:20][C:18](=[O:19])[C:17]1[CH:25]=[CH:26][CH:27]=[C:15]([CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:5]3[CH:28]=[CH:29][C:2]([NH:1][C:41]([NH:47][CH2:46][C:45]([CH3:49])([CH3:48])[CH3:44])=[O:42])=[C:3]([CH3:30])[CH:4]=3)[CH2:9][CH2:10]2)[CH:16]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: Cc1cc(C(=O)N2CCN(Cc3cccc(C(=O)NC(C)(C)C)c3)CC2)ccc1N
Reactant: CC(C)(C)CN
Solvent: ClCCl
Product: Cc1cc(C(=O)N2CCN(Cc3cccc(C(=O)NC(C)(C)C)c3)CC2)ccc1NC(=O)NCC(C)(C)C
Reaction time: 1 h
Yield: 14.4 %

Procedure:
To a stirred solution of 3-((4-(4-amino-3-methylbenzoyl)piperazin-1-yl)methyl)-N-tert-butylbenzamide (0.153 mmols 62.5 mg) in dichloromethane (2 mL) was added 4-nitrophenylchloroformate (0,153 mmol, 30.8 mg). After 1 hour stirring, 2,2-dimethylpropan-1-amine (0.306 mmol, 26.7 mg) was added and stirring continued for 1 hour. The reaction was concentrated under vacuum and the residue dissolved in methanol (1 mL). Purification by basic reverse phase HPLC gave the title compound (11.5 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[C:9]1(=O)[O:14][C:12](=[O:13])[C:11]2=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]12>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([N:5]2[C:12](=[O:13])[C:11]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]3[C:9]2=[O:14])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: Nc1cccc(Br)c1
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A stirring slurry of 3-bromoaniline (3.00 g, 17.44 mmol), phthalic anhydride (2.58 g, 17.44 mmol), and toluene (45 ml) was heated under reflux, using a Dean-Stark apparatus, at 140° C. (oil bath temperature) for 24 h. After cooling to ambient temperature, the solution was concentrated by rotary evaporation. The resulting off-white solid was purified by column chromatography on silica gel (150 g, Merck 70-230 mesh) eluting with CHCl3-acetone (9:1, v/v) to collect unreacted 3-bromoaniline (Rf 0.61) and phthalic anhydride (Rf 0.43). Elution with CHCl3-methanol (9:1, v/v) gave the product (Rf 0.38). Selected fractions containing the product were combined and concentrated by rotary evaporation to give 1.53 g of an off-white to light-beige solid. Impure fractions were combined and concentrated by rotary evaporation. The resulting white solid was dissolved in a mixture of CHCl3, acetone, and methanol and re-chromatographed on silica gel (150 g). Elution with CHCl3 removed impurities; the product was then eluted with CHCl3-acetone (4:1, v/v). Selected fractions were combined, concentrated by rotary evaporation, and vacuum dried for 16 h to give 1.41 g of an off-white to light-beige solid, mp 176-179° C., bringing the total yield to 2.94 g (55.8%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1(O)[C:12]2[C:7](=[C:8]([O:15][CH3:16])[C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH2:6][CH2:5][CH2:4]1.[Cl:18][C:19]1[CH:29]=[C:28]([O:30][CH3:31])[C:22]([O:23][CH2:24][C:25](O)=O)=[C:21]([O:32][CH3:33])[CH:20]=1.B#B.Cl>>[ClH:18].[Cl:18][C:19]1[CH:29]=[C:28]([O:30][CH3:31])[C:22]([O:23][CH2:24][CH2:25][NH:1][CH2:2][C:3]2[C:12]3[C:7](=[C:8]([O:15][CH3:16])[C:9]([O:13][CH3:14])=[CH:10][CH:11]=3)[CH2:6][CH2:5][CH:4]=2)=[C:21]([O:32][CH3:33])[CH:20]=1
Reactant: COc1ccc2c(c1OC)CCCC2(O)CN
Reactant: COc1cc(Cl)cc(OC)c1OCC(=O)O
Agent: B#B
Agent: Cl
Product: COc1cc(Cl)cc(OC)c1OCCNCC1=CCCc2c1ccc(OC)c2OC

Procedure:
1-aminomethyl-5,6-dimethoxy-1-hydroxy-1,2,3,4-tetrahydronaphthalene is reacted with the acid chloride of 4-chloro-2,6-dimethoxyphenoxy acetic acid. The resulting amide is reduced with diborane and dehydrated with HCl as described in Example 30 to obtain 1-[2(4-chloro-2,6-dimethoxyphenoxy)ethylaminomethyl]-5,6dimethoxy-3,4-dihydronaphthalene HCl.
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[C:16]4[N:17]([CH:31]=[CH:32][N:33]=4)[N:18]=[C:19]([C:21]4[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=4)[C:24]([O:26]C)=[O:25])[CH:20]=3)[CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[OH-].[Na+]>O1CCOCC1.O>[CH3:1][C:2]1([CH3:34])[CH2:7][CH2:6][N:5]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[C:16]4[N:17]([CH:31]=[CH:32][N:33]=4)[N:18]=[C:19]([C:21]4[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=4)[C:24]([OH:26])=[O:25])[CH:20]=3)[CH:11]=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: COC(=O)c1cccc(-c2cc(Nc3cccc(N4CCC(C)(C)CC4)n3)c3nccn3n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)CCN(c2cccc(Nc3cc(-c4cccc(C(=O)O)c4)nn4ccnc34)n2)CC1
Temperature: 40 °C
Reaction time: 2 h
Yield: 9.2 %

Procedure:
A mixture of methyl 3-(8-(6-(4,4-dimethylpiperidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoate (200 mg, 0.44 mmol) and NaOH (200 mg, 5 mmol) in 1,4-dioxane (5 mL) and water (5 mL) was stirred for 2 h at 40° C. Then the mixture was concentrated to 5 mL and adjusted to pH=2 with 2M HCl. The precipitate was filtered and purified by prep-HPLC to give 3-(8-(6-(4,4-dimethylpiperidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (18 mg, 9%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 10.53 (s, 1H), 8.94 (s, 1H), 8.52 (s, 2H), 8.18-8.12 (m, 3H), 7.72 (t, 1H, J=7.8 Hz), 7.57 (t, 1H, J=7.8 Hz), 6.76 (d, 1H, J=7.8 Hz), 6.54 (d, 1H, J=8.1 Hz), 3.59-3.57 (m, 4 h), 1.38-1.36 (m, 4 h), 0.98 (s, 6H). LC-MS: [M+H]+, 443, tR=1.788 min, HPLC: 100% at 214 nm, 100% at 254 nm, tR=6.762 min.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[O:5][N:4]=1.C[O:19][C:20](=[O:31])[CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([SH:29])=[CH:25][C:24]=1[CH3:30]>>[CH3:30][C:24]1[CH:25]=[C:26]([S:29][CH2:2][C:3]2[CH:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=3)[O:5][N:4]=2)[CH:27]=[CH:28][C:23]=1[O:22][CH2:21][C:20]([OH:31])=[O:19]
Reactant: COC(=O)COc1ccc(S)cc1C
Reactant: FC(F)(F)c1ccc(-c2cc(CCl)no2)cc1
Product: Cc1cc(SCc2cc(-c3ccc(C(F)(F)F)cc3)on2)ccc1OCC(=O)O

Procedure:
The title compound was prepared in a manner analogous to Example 1F using 42C and 2C. MS m/z 438 (M+1).
Reaction SMILES: Cl.C[O:3][C:4](=[O:16])[CH:5]([NH2:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1.[N:17]1[S:21][N:20]=[C:19]2[C:22]([S:26]([NH:29][C:30]3[CH:38]=[C:37]([Cl:39])[C:36]([Cl:40])=[CH:35][C:31]=3[C:32](O)=[O:33])(=[O:28])=[O:27])=[CH:23][CH:24]=[CH:25][C:18]=12>>[N:17]1[S:21][N:20]=[C:19]2[C:22]([S:26]([NH:29][C:30]3[CH:38]=[C:37]([Cl:39])[C:36]([Cl:40])=[CH:35][C:31]=3[C:32]([NH:15][C@@H:5]([CH2:6][C:7]3[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=3)[C:4]([OH:3])=[O:16])=[O:33])(=[O:28])=[O:27])=[CH:23][CH:24]=[CH:25][C:18]=12
Reactant: COC(=O)C(N)Cc1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1cc(Cl)c(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Agent: Cl
Product: O=C(N[C@@H](Cc1ccc(Cl)c(Cl)c1)C(=O)O)c1cc(Cl)c(Cl)cc1NS(=O)(=O)c1cccc2nsnc12

Procedure:
The title compound was prepared as in EXAMPLE 1, substituting 2-amino-3-(3,4-dichloro-phenyl)-propionic acid methyl ester hydrochloride (prepared as in Example 2, Part A) and 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoic acid in Part C. HPLC: RT=10.48 min. MS (ESI−): mass calcd. for C22H14Cl4N4O5S2, 620.31; m/z found, 617/619/621 [M−H]−. 1H NMR (400 MHz, acetone-d6): 11.64 (s, 1H), 8.53 (s, 2H), 8.46 (d, J=7.0, 1H), 8.29 (d, J=8.7, 1H), 7.89 (dd, J=8.8, 7.1, 1H), 7.83 (s, 1H), 7.75 (s, 1H), 7.56 (d, J=1.8, 1H), 7.49 (d, J=8.2, 1H), 7.34 (dd, J=8.2, 1.8, 1H), 5.00-4.94 (m, 1H), 3.40-3.36 (m, 1H), 3.25-3.17 (m, 1H).
Reaction SMILES: O[CH2:2][C:3]([NH:6][C:7]([C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=1)=[O:8])([CH3:5])[CH3:4].S(Cl)(Cl)=O>>[CH3:2][C:3]1([CH3:5])[CH2:4][O:8][C:7]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:10]=2)=[N:6]1
Reactant: COC(=O)c1ccc(C(=O)NC(C)(C)CO)cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(C2=NC(C)(C)CO2)cc1
Temperature: 60 °C
Yield: 83.6 %

Procedure:
To a solution of methyl 4-[(2-hydroxy-1,1-dimethylethyl)carbamoyl]benzoate (100 mg, 0.40 mmol) in CDCl3 (2 mL) was added thionyl chloride (57 mg, 0.48 mmol). The mixture was heated to 60° C. in a sealed tube for 4 h. After cooling, the reaction was quenched by pouring onto saturated aqueous NaHCO3 (20 mL). After extraction with dichloromethane (3×20 mL), the combined organic extracts were washed with brine (20 mL), dried (MgSO4), filtered and concentrated at reduced pressure. Purification by silica FCC (eluting with 20:80 heptane/EtOAc) gave the title compound (78 mg, 84% yield) as colourless oil.