Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([C:25]([CH3:28])([CH3:27])[CH3:26])=[C:19]5/[CH:29]=[N:30]\O)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1>C(OC(=O)C)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[C:18]5[C:22](=[CH:23][CH:24]=4)[NH:21][C:20]([C:25]([CH3:26])([CH3:28])[CH3:27])=[C:19]5[C:29]#[N:30])=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(C)(C)c1[nH]c2ccc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)cc2c1/C=N\O
Solvent: CC(=O)OC(C)=O
Product: CC(C)(C)c1[nH]c2ccc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)cc2c1C#N

Procedure:
(Z)-1-(Benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-3-((hydroxyimino)-methyl)-1H-indol-5-yl)cyclopropanecarboxamide (39 mg, 0.090 mmol) was dissolved in acetic anhydride (1 mL) and heated at reflux for 3 h. The mixture was cooled in an ice bath and the precipitate was collected and washed with water. The solid was further dried under high vacuum to yield 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-tert-butyl-3-cyano-1H-indol-5-yl)cyclopropanecarboxamide. ESI-MS m/z calc. 401.5, found 402.5 (M+1)+; retention time 3.70 minutes. 1H NMR (400 MHz, DMSO-d6) δ 11.72 (s, 1H), 8.79 (s, 1H), 7.79 (s, 1H), 7.32 (m, 2H), 7.03-7.02 (m, 1H), 6.95-6.89 (m, 2H), 6.03 (s, 2H), 1.47 (s, 9H), 1.43-1.41 (m, 2H), 1.06-1.04 (m, 2H).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=O.[NH:13]=[C:14]1[CH2:18][CH2:17][CH2:16][NH:15]1>C(Cl)(Cl)Cl>[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:13]=[C:14]3[CH2:18][CH2:17][CH2:16][N:15]3[CH:2]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: N=C1CCCN1
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2cn3c(n2)CCC3)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 6.8 g (29.7 mmoles) of 2-bromo-4'-methoxyacetophenone in 50 ml of CHCl3 was added a solution of 5 g (59.4 mmoles) of 2-iminopyrrolidine in 30 ml of CHCl3 with chilling. After 4 hours of stirring at 25° C., the solvent was removed in vacuo. The residue was dissolved in water, the pH adjusted to 2.5 and the solution heated on a steam bath under argon atmosphere for 8 hours. The cooled solution was adjusted to pH 6. The resulting precipitate was filtered, washed with water and dried in vacuo to afford the titled compound, mp 116°-117° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[H-].[Na+].[CH3:14][O:15][C:16](=[O:29])[CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][OH:28])=[CH:22][CH:21]=1>O1CCCC1.C(OCC)(=O)C>[CH3:14][O:15][C:16](=[O:29])[CH2:17][CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][O:28][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:24][CH:25]=1
Reactant: COC(=O)CCCc1ccc(CCO)cc1
Reactant: Clc1ncnc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)CCCc1ccc(CCOc2ncnc3ccccc23)cc1
Reaction time: 3.5 h
Yield: 42.6 %

Procedure:
A dry 50 mL flask was fitted with an addition funnel. To the flask were added 4-chloroquinazoline (592 mg, 3.6 mmol), anhydrous tetrahydrofuran (10 mL), and 60 wt % sodium hydride (187 mg, 4.7 mmol). A solution of Example 1B (800 mg, 3.6 mmol) in anhydrous tetrahydrofuran (10 mL) was added dropwise using the addition funnel. The reaction was stirred for 3.5 hours. The reaction was diluted with ethyl acetate and quenched by the addition of aqueous 0.1 N hydrochloric acid. The mixture was transferred to a separatory funnel and washed with brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated. Column chromatography [silica gel; eluent hexanes-ethyl acetate (4:1)] provided the desired product (538 mg, 43%). 1H(CDCl3) δ(ppm): 1.92-1.98 (m, 2H); 2.33 (t, 2H); 2.64 (t, 2H); 3.19 (t, 2H); 3.66 (s, 3H); 4.79 (t, 2H); 7.15 (d, 2H); 7.27 (d, 2H); 7.57 (t, 1H); 7.83 (t, 1H); 7.94 (d, 1H); 8.15 (d, 1H); 8.80 (s, 1H). 26.68, 33.59, 34.93, 35.03, 51.67, 67.89, 116.48, 123.72, 127.23, 127.82, 128.87, 129.24, 133.74, 135.76, 139.90, 151.08, 154.56, 166.89, 174.10.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C@@H:11]([OH:16])[C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([Br:9])[C:7]=1[OH:8].Cl[CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23]>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:10][C@@H:11]([OH:16])[C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([Br:9])[C:7]=1[O:8][CH2:18][O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23]
Reactant: COC(=O)[C@H](O)Cc1cc(Br)c(O)c(Br)c1
Reactant: C[Si](C)(C)CCOCCl
Solvent: CC#N
Product: COC(=O)[C@H](O)Cc1cc(Br)c(OCOCC[Si](C)(C)C)c(Br)c1
Temperature: 25 °C

Procedure:
Under a nitrogen atmosphere 11.1 g (76.6 mmol) 40% KF/Al2O3 were added to a solution of 6.78 g (19.2 mmol) methyl(R)-3-(3,5-dibromo-4-hydroxy-phenyl)-2-hydroxy-propionate in 100 mL acetonitrile and the resulting suspension was stirred for a few minutes at RT. Subsequently a solution of 4.07 mL (23.0 mmol) (2-chloromethoxy-ethyl)-trimethyl-silane in 20 mL acetonitrile was added and the reaction mixture was stirred for 20 h at RT. The mixture was filtered through Celite, the solvent was evaporated down i.vac. and the residue was purified by chromatography (silica gel, n-hexane/EtOAc 7:3).
Reaction SMILES: [C:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[OH2:13]>C(#N)C>[C:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]3[C:9]([NH:10]2)=[C:9]2[NH:10][C:11]4[CH:12]=[C:4]([C:1](=[O:13])[CH3:2])[CH:5]=[CH:6][C:7]=4[C:8]2=[C:9]2[NH:10][C:11]4[CH:12]=[C:4]([C:1](=[O:3])[CH3:2])[CH:5]=[CH:6][C:7]=4[C:8]=32)=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2cc[nH]c2c1
Reactant: O
Solvent: CC#N
Product: CC(=O)c1ccc2c(c1)[nH]c1c3[nH]c4cc(C(C)=O)ccc4c3c3c4ccc(C(C)=O)cc4[nH]c3c21
Yield: 70.7 %

Procedure:
15 ml of acetonitrile was poured into a 200 ml three-neck flask, and 1.59 g of 6-acetylindole was dissolved therein. On the other hand, preparation of an oxidant solution was performed by dissolving 16.2 g of ferric chloride anhydrate and 5.4 g of water in 100 ml of acetonitrile and agitating the resultant mixture solution for 15 minutes. Then, the prepared 6-acetyl indole solution was dripped over 60 minutes into the oxidant solution, and the resultant mixture solution was agitated for 5 hours at the temperature of 30° C. Color of the reaction solution changed from yellow to blue-green with slight heat generation. pH of the reaction solution was less than 1. After the end of the reaction, the reaction liquid was suction-filtered with a perforated funnel, and the filtrate was washed with acetonitrile and then methanol, and was dried to obtain 1.11 g of 3,8,13-triacetyl-6,11-dihydro-5H-diindolo [2,3-a:2′,3′-c] carbazole (6-acetyl indole trimer) with a blue-green color (yield: 70%). The resultant trimer was pressure-molded with a tablet molding machine and the mold was cut into a piece with the diameter of 10 mm and thickness of 1 mm. A conductivity thereof was measured by the four terminal method and found to be 0.90 S/cm. The result of elemental analysis was: <C10.00H6.99N0.98O1.98Cl0.10>3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[CH3:43][O:44][C:45]1[C:46]2[N:59]=[C:58]([NH2:60])[S:57][C:47]=2[C:48]([N:51]2[CH2:56][CH2:55][O:54][CH2:53][CH2:52]2)=[N:49][CH:50]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:60][C:58]2[S:57][C:47]3[C:48]([N:51]4[CH2:56][CH2:55][O:54][CH2:53][CH2:52]4)=[N:49][CH:50]=[C:45]([O:44][CH3:43])[C:46]=3[N:59]=2)=[O:9])=[CH:10][CH:11]=1
Reactant: COc1ccc(C(=O)O)cc1
Reactant: COc1cnc(N2CCOCC2)c2sc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: COc1ccc(C(=O)Nc2nc3c(OC)cnc(N4CCOCC4)c3s2)cc1

Procedure:
From 4-methoxybenzoic acid, HATU and N-methylmorpholine in THF, then treatment with 7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-ylamine. ES-MS m/e (%): 401 (M+H+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:18]=[C:17]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)[S:16][C:10]=2[NH:11][C:12](=O)[CH2:13][N:14]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:37])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:18]=[C:17]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)[S:16][C:10]=2[NH:11][C:12](=[S:37])[CH2:13][N:14]=1
Reactant: Cc1ccc(CCc2cc3c(s2)NC(=O)CN=C3c2ccccc2Cl)cc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(CCc2cc3c(s2)NC(=S)CN=C3c2ccccc2Cl)cc1
Yield: 157.5 %

Procedure:
A suspension of 3.9 g of 5-(2-chlorophenyl)-7-[2-(4-methylphenyl)ethyl]-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepin-2-one, melting at 195°-197° C. and 2.5 g of Lawesson reagent in 50 ml of toluene is stirred at 40°-43° C. for an hour. The resultant solution is concentrated under reduced pressure, and the residue is subjected to chromatography on silica gel and then eluted with chloroform-methanol (100:1 to 100:2). The objective fraction is concentrated under reduced pressure to give 4 g of 5-(2-chlorophenyl)-7-[2-(4-methylphenyl)ethyl]-1,3-dihydro-2H-thieno[2,3-e]-1,4-diazepine-2-thione, melting at 190°-191° C. with decomposition.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([CH2:21][C:22]4[CH:27]=[C:26](Cl)[N:25]=[CH:24][N:23]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30].[N-:33]=[N+:34]=[N-:35].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:20]3[C:15](=[CH:16][C:17]([CH2:21][C:22]4[CH:27]=[C:26]([N:33]=[N+:34]=[N-:35])[N:25]=[CH:24][N:23]=4)=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)=[O:10])=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30]
Reactant: O=C(Nc1ccc(F)c(C(F)(F)F)c1)c1cccc2cc(Cc3cc(Cl)ncn3)ccc12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=Nc1cc(Cc2ccc3c(C(=O)Nc4ccc(F)c(C(F)(F)F)c4)cccc3c2)ncn1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A mixture of 200 mg (0.435 mMol) 6-(6-chloro-pyrimidin-4-ylmethyl)-naphthalene-1-carboxylic acid (4-fluoro-3-trifluoromethyl-phenyl)-amide and 50 mg (0.76 mMol) NaN3 in 5 ml DMF is stirred for 2 h at 60° C., giving 6-(6-azido-pyrimidin-4-ylmethyl)-naphthalene-1-carboxylic acid (4-fluoro-3-trifluoromethyl-phenyl)-amide (MS: [M+1]+=467). After cooling to rt, 50 mg Pd/C (10%; Engelhard 4505) are added and the mixture is hydrogenated under a H2-atmosphere for 30 min. Filtration through Celite, concentration and chromatography (Combi Flash; CH2Cl2/MeOH 9:1→1:1) gives the title compound: MS: [M+1]+=441; HPLC: tRet=12.3.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C:8]1[CH:13]=[C:12]([Br:14])[CH:11]=[C:10]([F:15])[C:9]=1[F:16])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:21][C:22]#[N:23]>CN(C=O)C>[C:1]([O:5][C:6](=[O:17])[N:7]([C:8]1[CH:13]=[C:12]([Br:14])[CH:11]=[C:10]([F:15])[C:9]=1[F:16])[CH2:21][C:22]#[N:23])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#CCBr
Reactant: CC(C)(C)OC(=O)Nc1cc(Br)cc(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CC#N)c1cc(Br)cc(F)c1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69 %

Procedure:
A solution (3 mL) of tert-butyl(5-bromo-2,3-difluorophenyl)carbamate (182 mg, 0.591 mmol) in DMF was added to a suspension of 60% sodium hydride-oil dispersion (31.2 mg) in DMF, and stirred at room temperature for 15 minutes. To the reaction solution, bromoacetonitrile (0.041 mL, 0.591 mmol) was added, and stirred at room temperature for 4 hours. After quenched with a saturated aqueous ammonium chloride solution under ice-cooling, extraction was performed with ethyl acetate. The resulting organic phase was dried over anhydrous magnesium sulfate. The solvent was distilled away under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane/ethyl acetate) to thus obtain the title compound.
Reaction SMILES: [C:1]([C:7]1[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=1[C:9](N(C)OC)=[O:10])#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:19]([Mg]Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1COCC1>[C:1]([C:7]1[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=1[C:9](=[O:10])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC#Cc1ccccc1C(=O)N(C)OC
Reactant: Cl[Mg]Cc1ccccc1
Solvent: C1CCOC1
Product: CCCCC#Cc1ccccc1C(=O)Cc1ccccc1
Yield: 78 %

Procedure:
2-(1-Hexyn-1-yl)-N-methyl-N-(methyloxy)benzamide (158) (1.0 g, 4.08 mmol) was treated with benzylmagnesium chloride in THF at 0° C. to give 0.88 g (78%) of compound 171 as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 0.93 (t, J=7.2 Hz, 3H), 1.40-1.53 (m, 2H), 1.56-1.65 (m, 2H), 2.45 (t, J=7.1 Hz, 2H), 4.43 (s, 2H), 7.20-7.26 (m, 4H), 7.27-7.36 (m, 2H), 7.34-7.39 (m, 1H), 7.45-7.52 (m, 2H). LCMS (ESI): m/z 277 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:49])[CH2:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:47][CH3:48])=[C:13]([NH:16][C:17]3[N:30]4[C:21](=[N:22][C:23]5[C:28]([C:29]4=[O:31])=[C:27]([F:32])[C:26]([F:33])=[CH:25][CH:24]=5)[C:20]4[CH:34]=[CH:35][N:36]([S:37]([C:40]5[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=5)(=[O:39])=[O:38])[C:19]=4[N:18]=3)[CH:14]=2)[CH2:9][CH2:8][CH2:7]1)=[O:5].[CH3:50][NH2:51]>C1COCC1.C(OCC)(=O)C>[CH3:1][N:2]([CH3:49])[CH2:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:47][CH3:48])=[C:13]([NH:16][C:17]3[N:30]=[C:21]([NH:22][C:23]4[C:28]([C:29]([NH:51][CH3:50])=[O:31])=[C:27]([F:32])[C:26]([F:33])=[CH:25][CH:24]=4)[C:20]4[CH:34]=[CH:35][N:36]([S:37]([C:40]5[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=5)(=[O:38])=[O:39])[C:19]=4[N:18]=3)[CH:14]=2)[CH2:9][CH2:8][CH2:7]1)=[O:5]
Reactant: CN
Reactant: COc1cc2c(cc1Nc1nc3c(ccn3S(=O)(=O)c3ccc(C)cc3)c3nc4ccc(F)c(F)c4c(=O)n13)N(C(=O)CN(C)C)CCC2
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(Nc2nc(Nc3cc4c(cc3OC)CCCN4C(=O)CN(C)C)nc3c2ccn3S(=O)(=O)c2ccc(C)cc2)ccc(F)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.1 %

Procedure:
To a solution of 5-{[1-(N,N-dimethylglycyl)-6-(methyloxy)-1,2,3,4-tetrahydro-7-quinolinyl]amino}-8,9-difluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one (270 mg, 0.393 mmol) in THF (50 mL) was added methyl amine (2M solution in THF) (1.96 mL, 3.93 mmol). The resulting mixture was let stir at rt for 1 h at which time it was diluted with ethyl acetate and washed with water and a saturated brine solution. Organics were dried over sodium sulfate and solvents removed under reduced pressure. The residue was purified via chromatography on SiO2 and afforded 6-({2-{[1-(N,N-dimethylglycyl)-6-(methyloxy)-1,2,3,4-tetrahydro-7-quinolinyl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-2,3-difluoro-N-methylbenzamide (139 mg, 0.193 mmol) as a yellow solid. (ESIMS (M+H)+=719)
Reaction SMILES: [CH:1]1([C:4]2[NH:5][C:6]3[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=3[N:8]=2)[CH2:3][CH2:2]1.Cl[C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([CH2:24][N:25]3[CH2:30][CH2:29][N:28]([C:31]([CH3:38])([CH3:37])[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:27][CH2:26]3)[N:20]2[CH3:23])=[C:16]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)[N:15]=1>>[CH:1]1([C:4]2[N:5]([C:14]3[N:22]=[C:21]4[C:17]([N:18]=[C:19]([CH2:24][N:25]5[CH2:26][CH2:27][N:28]([C:31]([CH3:37])([CH3:38])[C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:29][CH2:30]5)[N:20]4[CH3:23])=[C:16]([N:39]4[CH2:40][CH2:41][O:42][CH2:43][CH2:44]4)[N:15]=3)[C:6]3[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=3[N:8]=2)[CH2:3][CH2:2]1
Reactant: c1ccc2[nH]c(C3CC3)nc2c1
Reactant: CCOC(=O)C(C)(C)N1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3n2C)CC1
Product: CCOC(=O)C(C)(C)N1CCN(Cc2nc3c(N4CCOCC4)nc(-n4c(C5CC5)nc5ccccc54)nc3n2C)CC1

Procedure:
Following General Procedure I for Buchwald coupling, 2-cyclopropylbenzimidazole and ethyl 2-(4-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperazin-1-yl)-2-methylpropanoate were reacted to give 500. LCMS m/z: 588.4 (MH+)
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:10]1(=[O:16])[O:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C1(C)C=CC=CC=1>[OH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH:1]=[C:11]1[CH2:12][CH2:13][CH2:14][O:15][C:10]1=[O:16]
Reactant: O=C1CCCCO1
Reactant: O=Cc1ccccc1O
Solvent: Cc1ccccc1
Product: O=C1OCCCC1=Cc1ccccc1O
Yield: 27.5 %

Procedure:
Salicylaldehyde (15.2 g) and δ-valerolactone (25 g) were dissolved in toluene (150 ml). By the reaction in the same manner as in Example 307, oily α-(2′-hydroxybenzylidene)-δ-valerolactone (7.0 g) was obtained. Dimethylformamide (70 ml) and potassium carbonate (9.5 g) were added hereto and (S) -glycidyl nosylate (8.9 g) was added. The mixture was stirred at 40° C. for 2 hr. The reaction mixture was concentrated under reduced pressure. Water was added and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the oily title compound (7.8 g). The reaction in the same manner as in Example 307 using this product (1.0 g) and 4-(naphthalen-2-yl)piperidine (1.0 g) in methanol (50 ml) was performed and the obtained oil was recrystallized from ethyl acetate to give the title compound (0.38 g), melting point 142-144° C.
Reaction SMILES: [N:1]#CBr.[CH3:4][N:5]1[C:9]2[CH2:10][CH2:11][C:12]3[C:19]4([CH3:22])[CH:20]([CH3:21])[CH:6]1[CH2:7][C:8]=2[C:13]=3[CH:14]=[CH:15][CH2:16][N:17]=[CH:18]4.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[C:4]([N:5]1[C:9]2[CH2:10][CH2:11][C:12]3[C:19]4([CH3:22])[CH:20]([CH3:21])[CH:6]1[CH2:7][C:8]=2[C:13]=3[CH:14]=[CH:15][CH2:16][N:17]=[CH:18]4)#[N:1]
Reactant: CC1C2CC3=C(CCC4=C3C=CCN=CC41C)N2C
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC1C2CC3=C(CCC4=C3C=CCN=CC41C)N2C#N
Temperature: 25 °C
Yield: 70 %

Procedure:
To a stirred solution of 0.50 g of cyanogen bromide and 20 ml of chloroform was added, at room temperature with stirring, a solution of 1.0 g of 1,2,3,4,5,6-hexahydro-3,6,12-trimethyl-2,6-methano-9H-pyrrolo[3,2-h][3]benzazocine and 40 ml of chloroform. The mixture was heated at reflux for 2.6 hr, under nitrogen, and then cooled to room temperature. Dilute aqueous sodium bicarbonate solution was added and the layers were separated. The organic layer was washed with sodium bicarbonate solution. The combined aqueous layers were back extracted with ether, and the combined organic layers were washed with brine, dried over anhydrous potassium carbonate and filtered. The fitrate was concentrated. The residue was purified by flash chromatography (silica gel, 2% triethylamine/ether) to afford 0.73 g (70%) of 3-cyano-6,12-dimethyl-1,2,3,4,5,6-hexahydro-2,6-methano-9H-pyrrolo[3,2-h][3]benzazocine, which was combined with 0.39 g of the product from a previous reaction.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][O:11][C:10]([NH2:13])=[N:9]2)=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]3[CH2:12][O:11][C:10]([NH2:13])=[N:9]3)=[CH:4][CH:3]=2)=[CH:17][CH:16]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: NC1=NC(c2ccc(Br)cc2)CO1
Product: NC1=NC(c2ccc(-c3ccc(Cl)cc3)cc2)CO1

Procedure:
In analogy to example 30, (RS)-4-(4-bromo-phenyl)-4,5-dihydro-oxazol-2-ylamine was reacted with 4-chlorophenylboronic acid to give (RS)-4-(4′-chloro-biphenyl-4-yl)-4,5-dihydro-oxazol-2-ylamine. Off-white solid. MS (ISP): 273.1 ([M+H]+)
Reaction SMILES: I[CH2:2][C:3]1([CH3:18])[CH2:7][C:6]2[C:8]([CH3:17])=[C:9]([NH2:16])[C:10]([CH3:15])=[C:11]([CH:12]([CH3:14])[CH3:13])[C:5]=2[O:4]1.[C:19]1([CH:25]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C.O>[NH2:16][C:9]1[C:10]([CH3:15])=[C:11]([CH:12]([CH3:14])[CH3:13])[C:5]2[O:4][C:3]([CH2:2][N:30]3[CH2:31][CH2:32][CH:27]([NH:26][CH:25]([C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:28][CH2:29]3)([CH3:18])[CH2:7][C:6]=2[C:8]=1[CH3:17]
Reactant: Cc1c(N)c(C)c(C(C)C)c2c1CC(C)(CI)O2
Reactant: c1ccc(C(NC2CCNCC2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1c(N)c(C)c(C(C)C)c2c1CC(C)(CN1CCC(NC(c3ccccc3)c3ccccc3)CC1)O2
Yield: 91.9 %

Procedure:
A suspension of 2,3-dihydro-2-(iodomethyl)-7-isopropyl-2,4,6-trimethyl-5-benzofuranamine (1.1 g), N-(diphenylmethyl)-4-piperidinamine (1.4 g) and potassium carbonate (0.83 g) in N,N-dimethylacetamide (6 mL) was refluxed for 4.5 hours. The mixture was diluted with water and the product was extracted twice with ethyl acetate. The combined organic layer was washed with water and saturated aqueous sodium chloride, dried over magnesium sulfate, filtrated and evaporated in vacuo. The residue was purified with basic silica gel column chromatography (hexane:ethyl acetate=20:1 to 5:1) and recrystallized from hexane/ethyl acetate to afford 1.4 g of the title compound. Yield 91%.
Reaction SMILES: [C:1]1([C:7]2[C:8]3[CH:16]=[CH:15][S:14][C:9]=3[C:10](=O)[NH:11][N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=P(Cl)(Cl)[Cl:19]>>[Cl:19][C:10]1[C:9]2[S:14][CH:15]=[CH:16][C:8]=2[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:12][N:11]=1
Reactant: O=c1[nH]nc(-c2ccccc2)c2ccsc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nnc(-c2ccccc2)c2ccsc12

Procedure:
To 4-phenylthieno[2,3-d]pyridazin-7(6H)-one (0.714 g, 3.13 mmol) was added POCl3 (2.92 ml, 31.3 mmol). A water condenser was attached to the reaction flask and the mixture was heated to reflux for 15.5 hours. The reaction was concentrated and diluted with CH2Cl2 and ice water. The mixture was basified with solid sodium bicarbonate. The organic layers were separated and dried over sodium sulfate. To the residual crude after concentration, 50% EtOAc was added and the solution was filtered through a pad of silica gel. The product fraction were concentrated to yield 7-chloro-4-phenylthieno[3,2-d]pyridazine as a light yellow solid. MS m/z=247 [M+1]+. Calc'd for C12H7N2S: 246.71.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([NH:16]C(=O)C(O)(C)C)[CH:12]=[C:13]([CH3:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(O)C>O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:12]=[C:13]([CH3:15])[CH:14]=1)[NH2:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(NC(=O)C(C)(C)O)cc(OCc2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(N)cc(OCc2ccccc2)c1
Temperature: 25 °C
Yield: 62.1 %

Procedure:
N-(3-Benzyloxy-5-methylphenyl)-2-hydroxy-2-methylpropanamide (600 mg, 2.0 mmol), as prepared in the preceding step, was mixed with 10N NaOH (25 mL) and ethanol (10 mL), and the mixture was refluxed for 2 days. After cooling to ambient temperature, the mixture was diluted with water (60 mL) and extracted with dichloromethane (3×60 mL). The dichloromethane solution was washed with brine (2×50 mL) and dried over Na2SO4. After evaporating the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane) to give the title compound as a yellow oil (265 mg, 61%). 1H-NMR (300 MHz, CDCl3) δ 7.37 (m, 5 H), 6.24 (s, 1 H), 6.14 (s, 2 H), 5.00 (s, 2 H), 3.59 (br s, 2 H), 2.23 (s, 3 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[C:18]([F:31])[C:19]=1[O:20][C:21]1[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][CH:26]=1)[CH2:5][CH2:6][O:7][C:8]1[NH:9][CH:10]=[C:11]([CH2:15][CH3:16])[C:12](=[O:14])[N:13]=1.[CH3:32]CN(C(C)C)C(C)C.CI>C(Cl)Cl>[F:31][C:18]1[CH:17]=[C:4]([CH:3]=[C:2]([F:1])[C:19]=1[O:20][C:21]1[CH:26]=[N:25][C:24]([C:27]([F:29])([F:30])[F:28])=[N:23][CH:22]=1)[CH2:5][CH2:6][O:7][C:8]1[N:9]([CH3:32])[CH:10]=[C:11]([CH2:15][CH3:16])[C:12](=[O:14])[N:13]=1
Reactant: CCc1c[nH]c(OCCc2cc(F)c(Oc3cnc(C(F)(F)F)nc3)c(F)c2)nc1=O
Reactant: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CI
Product: CCc1cn(C)c(OCCc2cc(F)c(Oc3cnc(C(F)(F)F)nc3)c(F)c2)nc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.2 %

Procedure:
To the solution of 2-(3,5-difluoro-4-((2-(trifluoromethyl)pyrimidin-5-yl)oxy)phenethoxy)-5-ethylpyrimidin-4(1H)-one (30 mg, 0.068 mmol) and DIPEA (0.03 ml, 0.172 mmol) in DCM (1.5 ml) was added MeI (0.025 ml, 0.407 mmol). The solution was stirred at room temperature overnight. Purification via reverse phase flash chromatography then afforded the title compound (12 mg, 0.026 mmol, 38.8% yield). LCMS: rt=3.10 min, [M+H]=457