Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:24]=[C:5]2[C:6]([NH:10][CH2:11][C:12]3[C:13]([N:18]([CH3:23])[S:19]([CH3:22])(=[O:21])=[O:20])=[N:14][CH:15]=[CH:16][CH:17]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[NH2:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([CH3:35])[C:30](=[O:36])[CH2:29]2.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[CH3:23][N:18]([C:13]1[C:12]([CH2:11][NH:10][C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:25][C:26]4[CH:27]=[C:28]5[C:32](=[CH:33][CH:34]=4)[N:31]([CH3:35])[C:30](=[O:36])[CH2:29]5)[N:24]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:17][CH:16]=[CH:15][N:14]=1)[S:19]([CH3:22])(=[O:21])=[O:20]
Reactant: CN1C(=O)Cc2cc(N)ccc21
Reactant: CN(c1ncccc1CNc1cccn2nc(Cl)nc12)S(C)(=O)=O
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CN1C(=O)Cc2cc(Nc3nc4c(NCc5cccnc5N(C)S(C)(=O)=O)cccn4n3)ccc21

Procedure:
N-Methyl-N-(3-{[2-(1-methyl-2-oxo-2,3-dihydro-1H-indol-5-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino]-methyl}-pyridin-2-yl)-methanesulfonamide was prepared from N-{3-[(2-chloro-[1,2,4]triazolo[1,5-a]pyridin-8-ylamino)-methyl]-pyridin-2-yl}-N-methyl-methanesulfonamide (75.0 mg, 0.204 mmol) and 5-amino-1-methyl-1,3-dihydro-indol-2-one (37.0 mg, 0.228 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (23.0 mg, 0.0421 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a green-brown foam (0.017 g, 17%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.41 (d, J=4.8 Hz, 1H), 7.85 (d, J=7.7 Hz, 1H), 7.81 (d, J=6.6 Hz, 1H), 7.65 (s, 1H), 7.38 (d, J=8.5 Hz, 1H), 7.30-7.25 (m, 1H), 6.78 (d, J=8.4 Hz, 1H), 6.66 (t, J=7.3 Hz, 1H), 6.62 (s, 1H), 6.31 (d, J=7.8 Hz, 1H), 5.31 (t, J=6.2 Hz, 1H), 4.76 (d, J=6.2 Hz, 2H), 3.57 (s, 2H), 3.32 (s, 3H), 3.21 (s, 3H), 3.09 (s, 3H). MS=493 (MH)+.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@:18]([CH3:26])([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[F:27][C:28]([F:45])([F:44])[C@H:29]([O:31][C:32](=O)[O:33]C1C=CC([N+]([O-])=O)=CC=1)[CH3:30]>>[F:27][C:28]([F:45])([F:44])[C@H:29]([O:31][C:32]([N:23]1[CH2:24][CH2:25][CH:20]([C@:18]2([CH3:26])[O:17][C:14]3=[CH:15][N:16]=[C:11]([C:8]4[CH2:9][CH2:10][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:6][CH:7]=4)[CH:12]=[C:13]3[CH2:19]2)[CH2:21][CH2:22]1)=[O:33])[CH3:30]
Reactant: C[C@@H](OC(=O)Oc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Reactant: C[C@]1(C2CCNCC2)Cc2cc(C3=CCN(S(C)(=O)=O)CC3)ncc2O1
Product: C[C@@H](OC(=O)N1CCC([C@@]2(C)Cc3cc(C4=CCN(S(C)(=O)=O)CC4)ncc3O2)CC1)C(F)(F)F

Procedure:
The title compound is prepared from (R)-5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-methyl-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine and carbonic acid 4-nitro-phenyl ester (R)-2,2,2-trifluoro-1-methyl-ethyl ester following a procedure analogous to that described for Example 1. LC (method 4): tR=0.92 min; Mass spectrum (ESI+): m/z=518 [M+H]+.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:7]2[CH2:12][CH2:11][CH:10]([NH:13][CH2:14][CH2:15][OH:16])[CH2:9][CH2:8]2)[S:5][CH:6]=1.[CH3:17][C:18]1([CH3:38])[C:27]2[C:22](=[CH:23][C:24](B3OC(C)(C)C(C)(C)O3)=[CH:25][CH:26]=2)[C:21](=[O:37])[CH2:20][CH2:19]1>>[OH:16][CH2:15][CH2:14][NH:13][CH:10]1[CH2:11][CH2:12][N:7]([C:4]2[S:5][CH:6]=[C:2]([C:24]3[CH:23]=[C:22]4[C:27]([C:18]([CH3:38])([CH3:17])[CH2:19][CH2:20][C:21]4=[O:37])=[CH:26][CH:25]=3)[N:3]=2)[CH2:8][CH2:9]1
Reactant: OCCNC1CCN(c2nc(Br)cs2)CC1
Reactant: CC1(C)CCC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Product: CC1(C)CCC(=O)c2cc(-c3csc(N4CCC(NCCO)CC4)n3)ccc21

Procedure:
The preparation is carried out as already described above starting from 100 mg (0.27 mmol) of 2-[1-(4-bromothiazol-2-yl)piperidin-4-ylamino]ethanol (preparation already described above) and 88 mg (0.29 mmol) of 4,4-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-naphthalen-1-one. The product was purified by means of flash chromatography on silica gel.
Reaction SMILES: [C:1]([C:4]1[CH:17]=[CH:16][C:15]2[O:14][C:13]3[C:8](=[CH:9][C:10]([C:18](=[O:20])[CH3:19])=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:22].[Na+].[Na+].O>C(O)(=O)C>[C:1]([C:4]1[CH:17]=[CH:16][C:15]2[O:14][C:13]3[C:8](=[CH:9][C:10]([C:18](=[O:20])[CH3:19])=[CH:11][CH:12]=3)[C:7](=[O:22])[C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)Cc1cc(C(C)=O)ccc1O2
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)c1ccc2oc3ccc(C(C)=O)cc3c(=O)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 133.1 g (0.5 mole) of 2,7-diacetylxanthene in three liters of glacial acetic acid was added slowly over 11/2 hours 149.0 g (0.5 mole) of sodium dichromate. The resulting mixture was stirred for 2 hours at room temperature and then heated on a steam bath for 4 hours, then cooled, after which the reaction mixture was poured into 9 liters of water. The solid was filtered off and recrystallized from benzene to give the desired product. M.P. 226°-228°C.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[S:8][C:9]3[CH:15]=[C:14]([O:16][S:17]([C:20]4[CH:25]=[CH:24][C:23](F)=[CH:22][CH:21]=4)(=[O:19])=[O:18])[CH:13]=[CH:12][C:10]=3[N:11]=2)=[O:5])[CH2:3][CH2:2]1.[N:27]1([CH2:32][CH2:33][CH2:34][NH2:35])[CH:31]=[CH:30][N:29]=[CH:28]1>CN1C(=O)CCC1>[CH:1]1([C:4]([NH:6][C:7]2[S:8][C:9]3[CH:15]=[C:14]([O:16][S:17]([C:20]4[CH:25]=[CH:24][C:23]([NH:35][CH2:34][CH2:33][CH2:32][N:27]5[CH:31]=[CH:30][N:29]=[CH:28]5)=[CH:22][CH:21]=4)(=[O:19])=[O:18])[CH:13]=[CH:12][C:10]=3[N:11]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1)C1CC1
Reactant: NCCCn1ccnc1
Solvent: CN1CCCC1=O
Product: O=C(Nc1nc2ccc(OS(=O)(=O)c3ccc(NCCCn4ccnc4)cc3)cc2s1)C1CC1

Procedure:
A solution of 4-fluorobenzenesulfonic 2-(cyclopropanecarbonylamino)benzo-thiazol-6-yl ester (example 7) (100 mg, 0.255 mmol) and 3-imidazol-1-yl-propylamine (123 μl, 1.019 mmol) in 2 ml of NMP is heated at 150° C. by microwave for 5 minutes. The crude reaction product is purified by preparative LC/MS (basic medium (pH 9)) to give after freeze-drying 63 mg of 4-(3-imidazol-1-ylpropylamino)benzenesulfonic 2-(cyclopropanecarbonylamino)benzothiazol-6-yl ester (white solid).
Reaction SMILES: CCCCCC.C([Li])CCC.[CH3:12][C:13]1[CH:17]=[C:16]([CH3:18])[O:15][N:14]=1.Cl.C1C[O:23][CH2:22][CH2:21]1>CC(N(C)C)=O>[CH2:18]([C:16]1[O:15][N:14]=[C:13]([CH3:12])[CH:17]=1)[C:22]([CH3:21])=[O:23]
Reactant: C1CCOC1
Reactant: Cc1cc(C)on1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CC(=O)N(C)C
Product: CC(=O)Cc1cc(C)no1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Into a 2 L flask filled with nitrogen were placed 1000 ml of anhydrous THF and 500 ml of a 1.6M n-hexane solution of n-butyl lithium. The flask was placed in a dry ice-acetone bath to set the inside temperature to −70° C., and 68.0 g of 3,5-dimethylisoxazole was slowly dropped in the flask. After the resulting solution was stirred for 30 minutes at the same temperature, a solution of 120.0 g of dimethylacetamide in 300 ml of THF was slowly dropped. After the completion of the dropping, the solution was further stirred for an hour at −60° C. to −65° C. The reaction solution was poured into 1 L of ice water acidified with hydrochloric acid. The organic layer was separated. The aqueous layer was further extracted with ethyl acetate. The obtained organic layers were combined and concentrated under reduced pressure. The obtained concentrate was dissolved in 500 ml of ethyl acetate, washed with water and then with saturated salt water, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation. The residue was purified by distillation under reduced pressure to give 68.5 g of the title compound as a colorless liquid. Boiling point: 85° C./1.0 mmHg.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][OH:16])([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][O:16][S:24]([CH3:23])(=[O:26])=[O:25])([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC1(CO)CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(COS(C)(=O)=O)CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 3 h
Yield: 95.5 %

Procedure:
To 4-hydroxymethyl-4-methylpiperidine-1-carboxylic acid tert-butyl ester (1.25 g, 5.45 mmol) and pyridine (0.661 mL, 8.18 mmol) in dichloromethane (10 mL) at 0° C. is added methanesulfonyl chloride (0.593 mL, 7.63 mmol). After 3 hours, one additional equivalent of methanesulfonylchloride and pyridine are added. After 1 hour the reaction mixture is concentrated, then EtOAc and water are added. The organic layer is concentrated and chromatographed on silica gel eluting with MeOH in dichloromethane 0-3% to give the title compound as a yellow oil (1.60 g, 95% yield).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16].C([N-]C(C)C)(C)C.[Li+].CON(C)[C:28](=[O:44])[CH:29]([O:42][CH3:43])[C:30]1[CH:35]=[CH:34][C:33]([N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)=[CH:32][CH:31]=1>C1COCC1>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][C:12]([C:28](=[O:44])[CH:29]([O:42][CH3:43])[C:30]3[CH:31]=[CH:32][C:33]([N:36]4[CH2:37][CH2:38][O:39][CH2:40][CH2:41]4)=[CH:34][CH:35]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: COC(C(=O)N(C)OC)c1ccc(N2CCOCC2)cc1
Reactant: COc1cc(-c2ccco2)cc(OC)c1Br
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(-c2ccc(C(=O)C(OC)c3ccc(N4CCOCC4)cc3)o2)cc(OC)c1Br
Temperature: -78 °C
Reaction time: 0.58 h
Yield: 59 %

Procedure:
To a solution of 2-(4-bromo-3,5-dimethoxyphenyl)furan (0.203 g, 0.72 mmol) in anhydrous THF (2 mL) under argon in an oven-dried flask cooled to −78° C. was added a solution of lithium diisopropylamide (2.0 M in THF/heptane/ethylbenzene; 0.4 mL, 0.8 mmol) dropwise. After stirring for 35 min at −78° C., a solution of N,2-dimethoxy-N-methyl-2-(4-morpholinophenyl)acetamide (0.315 g, 1.1 mmol) in THF (2 mL) was added dropwise. After stirring for 25 min, the mixture was allowed to warm to room temp while stirring for 2 hrs. The reaction was quenched with the addition of saturated aqueous NH4C1 then brine and EtOAc were added. The layers were separated and the organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. Purification by column chromatography (35-65% EtOAc-hexanes) provided an oil that was triturated with MeOH-Et2O (1:1) with sonication. The solid was collected on a Büchner, rinsed with MeOH-Et2O (1:1) and dried in vacuo to give 1-(5-(4-bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-methoxy-2-(4-morpholinophenyl)ethanone as a yellow solid. A second batch was collected from MeOH-Et2O (˜10%) to give additional product (0.220 g total, 59% yield). MS: m/z 516.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([N:8]2[C:16]([Cl:17])=[C:15]3[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]3)=[N:9]2)[CH:7]=1.[S-:19][C:20]#[N:21].[NH4+].BrBr.O>C(O)(=O)C>[NH2:21][C:20]1[S:19][C:3]2[CH:4]=[C:5]([F:18])[C:6]([N:8]3[C:16]([Cl:17])=[C:15]4[C:10]([CH2:11][CH2:12][CH2:13][CH2:14]4)=[N:9]3)=[CH:7][C:2]=2[N:1]=1
Reactant: N#C[S-]
Reactant: Nc1ccc(F)c(-n2nc3c(c2Cl)CCCC3)c1
Agent: BrBr
Agent: [NH4+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1nc2cc(-n3nc4c(c3Cl)CCCC4)c(F)cc2s1
Temperature: 100 °C
Reaction time: 8 h
Yield: 31.4 %

Procedure:
2-(5-Amino-2-fluorophenyl)-3-chloro-4,5,6,7-tetrahydro-2H-indazole (22.97 g) was dissolved in 95% aqueous acetic acid (79.53 g), and ammonium thiocyanate (15.92 g) was added thereto at room temperature (ca. 20° C.). To the resultant mixture, a solution of bromine (15.89 g) in acetic acid (23.77 g) was dropwise added in 105 minutes. After being allowed to stand overnight, the mixture was heated to 100° C., and hot water (173 ml) was added thereto, followed by filtration. The filtrate was cooled and neutralized with sodium carbonate. The precipitated crystals were collected by filtration and dried to give 2-(2-amino-6-fluorobenzothiazol-5-yl)-3-chloro-4,5,6,7-tetrahydro-2H-indazole (8.77 g). m.p., 212.4° C.
Reaction SMILES: [N:1]1[C:2]([CH2:10][CH2:11][O:12][C:13]2[CH:45]=[CH:44][C:16]([CH2:17][CH:18]3[S:22][C:21](=[O:23])[N:20](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:19]3=[O:43])=[CH:15][CH:14]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.FC(F)(F)C(O)=O>C(Cl)Cl>[N:1]1[C:2]([CH2:10][CH2:11][O:12][C:13]2[CH:45]=[CH:44][C:16]([CH2:17][CH:18]3[S:22][C:21](=[O:23])[NH:20][C:19]3=[O:43])=[CH:15][CH:14]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: O=C1SC(Cc2ccc(OCCc3cn4ccccc4n3)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NC(=O)C(Cc2ccc(OCCc3cn4ccccc4n3)cc2)S1

Procedure:
A procedure similar to that described in Example 2 was repeated, except that 0.94 g of 5-[4-{2-(imidazo-[1,2-a]pyridin-2-yl)ethoxy}benzyl]-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 27), 4 ml of methylene chloride and 1 ml of trifluoroacetic acid were used, to give the title compound as a crude product. This product was purified by column chromatography through silica gel, using a 2:1 by volume mixture of hexane and ethyl acetate and subsequently a 1:2 by volume mixture of ethyl acetate and tetrahydrofuran, as the eluents, to give 287 mg of the title compound, melting at 205.9-207.0° C. (with decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:21](N1C=CN=C1)([N:23]1C=CN=C1)=O.CN.O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:23][CH3:21])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: CN
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)Cn1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 47.5 %

Procedure:
Under a nitrogen atmosphere, a suspension of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid, 6.0 g (0.021 mole) and 1,1'-carbonyldiimidazole (3.39 g, 0.021 mole) in tetrahydrofuran (150 ml) was refluxed, with stirring, for 2.5 hrs. The mixture was cooled to room temperature and a solution of 3.6 g (0.116 mole) of monomethylamine in tetrahydrofuran (60 ml) was added dropwise and the reaction mixture was stirred at room temperature overnight. The tetrahydrofuran was evaporated and the residue was triturated in water (150 ml). The solid was filtered and rinsed with water. The solid was dissolved in hot isopropyl alcohol, treated with charcoal, filtered, and allowed to cool. Solid formed, and water was added to precipitate more. The solid was filtered and dried under vacuum to give 3.0 g (47.5%) of title compound, mp 238°-238.5° C.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)O)=O)=[CH:5][CH:4]=1.[NH2:25][C:26]([NH2:28])=[S:27].O>CN(C)C=O>[F:1][C:2]([F:24])([F:23])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:25][C:26](=[S:27])[NH:28][C:11]=2[C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1
Reactant: O=C(c1ccc(C(F)(F)F)cc1)C(O)c1ccc(C(F)(F)F)cc1
Reactant: NC(N)=S
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)c1ccc(-c2[nH]c(=S)[nH]c2-c2ccc(C(F)(F)F)cc2)cc1

Procedure:
A mixture of 4,4'-di(trifluoromethyl)benzoin (50 g, 0.15 mol) and thiourea (15.2 g, 0.2 mol) in dimethylformamide (350 ml) was refluxed under argon for three hours. The cooled solution was poured into 1 liter of water and the resulting solid was collected, washed with water, air-dried and recrystallized from ethanol to give 4,5-bis-(4-trifluoromethylphenyl)-1H-imidazole-2-thione, m.p. 312°-315°.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15](C)=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=3)[CH:5]=[CH:4][C:3]1=2.[CH3:33]C1(C)CC=C(OS(C(F)(F)F)(=O)=O)C2C=C(C#CC3C=CC(C(OCC)=O)=CC=3)C=CC1=2>>[CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=2[CH3:33])[C:8]2[CH:7]=[C:6]([C:19]#[C:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:30][CH:31]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(OS(=O)(=O)C(F)(F)F)=CCC3(C)C)cc1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C)cc2)=CCC3(C)C)cc1
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccccc2C)=CCC3(C)C)cc1

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl)ethynyl]benzoate (Compound 1), 200.0 mg (0.418 mmol) of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(trifluoromethylsulfonyl)oxy-2-naphthalenyl)ethynyl]benzoate (Compound G) was converted into the title compound (colorless solid) using 199.4 mg (1.463 mmol) of zinc chloride, 24 mg (0.02 mmol) of tetrakis(triphenylphosphine)palladium(0) in 4.0 ml of THF, and 2-methylphenyl lithium (prepared by adding 133.9 mg (1.23 ml, 2.09 mmol) of tert-butyllithium (1.7M solution in pentane) to a cold solution (−78° C.) of 178.7 mg (1.045 mmol) of 2-methylbromobenzene in 2.0 ml of THF). 1H NMR (CDCl3): δ 7.97 (2H, d, J=8.4 Hz), 7.50 (2H, d, J=8.4 Hz), 7.49—7.19 (6H, m), 6.81 (1H, d, J=1.6 Hz), 5.89 (1H, t, J=4.5 Hz), 4.36 (2H, q, J=7.1 Hz), 2.43-2.14 (2H, dq, J=3.7, 5.4 Hz), 2.15 (3H, s), 1.39-1.34 (9H, m).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[O:13]=[C:14]1[C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:17][CH2:16][N:15]1[CH2:31][C:32](O)=[O:33].[Cl:35][C:36]1[CH:48]=[C:47]([Cl:49])[CH:46]=[CH:45][C:37]=1[CH2:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>ClCCl>[Cl:35][C:36]1[CH:48]=[C:47]([Cl:49])[CH:46]=[CH:45][C:37]=1[CH2:38][N:39]1[CH2:40][CH2:41][N:42]([C:32](=[O:33])[CH2:31][N:15]2[CH2:16][CH2:17][C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:14]2=[O:13])[CH2:43][CH2:44]1
Reactant: Clc1ccc(CN2CCNCC2)c(Cl)c1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)N1CCN(Cc2ccc(Cl)cc2Cl)CC1
Temperature: 25 °C

Procedure:
A mixture of N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.049 g, 0.254 mmol), 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.050 g, 0.169 mmol) and 1-(2,4-dichlorobenzyl)piperazine (0.046 g, 0.186 mmol) in dichloromethane (0.5 mL) was stirred at room temperature. After stirring overnight, the reaction was loaded directly onto a SF15-12 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 5% to 100% ethyl acetate/hexanes over 20 minutes (flow=30 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 7.20-7.39 (m, 13H), 4.19 (s, 2H), 3.59 (t, J=4.8 Hz, 2H), 3.53 (s, 2H), 3.52 (t, J=6.4 Hz, 2H), 3.42 (t, J=4.9 Hz, 2H), 2.81 (t, J=6.5 Hz, 2H), 2.43 (t, J=4.9 Hz, 2H), 2.32 (t, J=4.9 Hz, 2H); MS (ESI+) m/z 522 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:9][C:10]=2[N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:5]=[CH:4][N:3]=1.[Cl:26][C:27]1[C:32]([NH2:33])=[C:31]2[O:34][CH2:35][O:36][C:30]2=[CH:29][CH:28]=1>C(O)(C)C>[Cl:26][C:27]1[C:32]([NH:33][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:18][CH2:19][CH2:20][N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:9][C:10]=3[N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:5]=[CH:4][N:3]=2)=[C:31]2[O:34][CH2:35][O:36][C:30]2=[CH:29][CH:28]=1
Reactant: Nc1c(Cl)ccc2c1OCO2
Reactant: Clc1ncnc2cc(OCCN3CCCC3)cc(N3CCOCC3)c12
Solvent: CC(C)O
Product: Clc1ccc2c(c1Nc1ncnc3cc(OCCN4CCCC4)cc(N4CCOCC4)c13)OCO2
Temperature: 80 °C
Yield: 9.4 %

Procedure:
A mixture of 4-chloro-5-morpholino-7-(2-pyrrolidin-1-ylethoxy)quinazoline (0.27 g), 6-chloro-2,3-methylenedioxyaniline (0.14 g) and isopropanol (4 ml) was stirred and heated to 80° C. for 1 hour. The mixture was evaporated and the residue was dissolved in a 49:1 mixture of methylene chloride and a saturated methanolic ammonia solution. The mixture was filtered and the filtrate was poured onto a column of silica and eluted with a 97:3 mixture of methylene chloride and a saturated methanolic ammonia solution. The material so obtained was triturated under diethyl ether. The resultant solid was isolated, washed with diethyl ether and dried under vacuum. There was thus obtained the title compound (0.035 g); NMR Spectrum: (CDCl3) 1.85 (br s, 4H), 2.65 (br s, 4H), 3.0 (m, 2H), 3.08 (m, 2H), 3.18 (d, 2H), 3.82 (m, 2H), 4.05 (m, 2H), 4.25 (m, 2H), 6.05 (s, 2H), 6.75 (d, 1H), 6.95–7.1 (m, 3H), 8.52 (s, 1H); Mass Spectrum: M+H+ 498 and 500.
Reaction SMILES: [OH:1][C:2]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14](O)=[O:15])=[CH:11][CH:12]=2)[N:7]([C:17]2[CH:21]=[CH:20][S:19][CH:18]=2)[N:6]=1)([CH3:4])[CH3:3].Cl.Cl.[CH3:24][C:25]1[N:29]=[C:28]([C@H:30]([NH2:32])[CH3:31])[O:27][N:26]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[OH:1][C:2]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH:32][C@@H:30]([C:28]3[O:27][N:26]=[C:25]([CH3:24])[N:29]=3)[CH3:31])=[O:15])=[CH:11][CH:12]=2)[N:7]([C:17]2[CH:21]=[CH:20][S:19][CH:18]=2)[N:6]=1)([CH3:4])[CH3:3]
Reactant: Cc1noc([C@@H](C)N)n1
Reactant: CC(C)(O)c1nn(-c2ccsc2)c2cc(C(=O)O)ccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1noc([C@@H](C)NC(=O)c2ccc3c(C(C)(C)O)nn(-c4ccsc4)c3c2)n1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 89.8 %

Procedure:
3-(2-Hydroxypropan-2-yl)-1-(thiophen-3-yl)-1H-indazole-6-carboxylic acid (457.8 mg, 1.514 mmol), (1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethanamine bis-hydrochloride (374.3 mg, 1.871 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (600.2 mg, 3.13 mmol), 1-hydroxy-7-azabenzotriazole (105.3 mg, 0.774 mmol), and N-methylmorpholine (670 μl, 6.09 mmol) were dissolved in N,N-dimethylformamide (15 mL) at 25° C. The reaction mixture was heated to 50° C. and allowed to stir for 10 min. The reaction was stopped, quenched by addition of water (ca 1 mL) and trifluoroacetic acid (ca 1 mL). The reaction mixture was purified directly by preparative HPLC (reverse phase (C-18)), eluting with acetonitrile/water 0.1% trifluoracetic acid, to give the title compound (559.5 mg, 1.360 mmol, 90% yield) as a white solid. FIRMS: [M+1]=412.1452. 1H NMR (400 MHz, CDCl3): δ 8.22 (s, 1H); 8.06 (d, J=8.5 Hz, 1H); 7.54 (dd, J=8.5, 1.4 Hz, 1H); 7.52-7.46 (m, 2H); 6.89 (d, J=7.7 Hz, 1H); 5.65-5.56 (m, 1H); 2.83 (s, 1H); 2.40 (s, 3H); 1.81 (s, 6H); 1.73 (d, J=7.1 Hz, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4]1.O1CCCC1.[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[CH2:16]([O:1][CH2:2][C:3]1([CH2:7][OH:8])[CH2:6][CH2:5][CH2:4]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OCC1(CO)CCC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: OCC1(COCc2ccccc2)CCC1
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
To a solution of 8.0 g (69 mmol) of [1-(hydroxymethyl)cyclobutyl]methanol in 120 ml of a 1:1 mixture of tetrahydrofuran:N,N-dimethylformamide was added 3.30 g (69 mmol) of a 60% dispersion of sodium hydride in oil and the contents stirred for 30 min. 8.6 mL (72.4 mmol) of benzyl bromide was then added and the contents stirred for 2 h. The reaction was quenched with aqueous ammonium chloride followed by the addition of diethyl ether. The organic phase was isolated, dried using magnesium sulfate, and concentrated under vacuum to afford the crude product which was purified by silica gel chromatography using ethyl acetate:hexane (3:7) as the eluent to afford 12.0 g (86%) of {1-[(benzyloxy)methyl]cyclobutyl}methanol as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.33-7.25 (m, 5H), 4.49 (s, 2H), 3.66 (d, J=6 Hz, 2H), 3.52 (s, 2H), 2.53 (t, J=6 Hz, 1H), 1.91-1.73 (m, 6H). GC-MS m/z 207 (M+H).