Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=O)[CH2:12][C:11]([CH2:15][CH2:16][CH3:17])=[N:10]2)=[CH:5][CH:4]=1.P(Br)(Br)[Br:19]>CC#N>[Br:19][C:13]1[N:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[N:10]=[C:11]([CH2:15][CH2:16][CH3:17])[CH:12]=1
Reactant: BrP(Br)Br
Reactant: CCCC1=NN(c2ccc(OC)cc2)C(=O)C1
Solvent: CC#N
Product: CCCc1cc(Br)n(-c2ccc(OC)cc2)n1
Temperature: 150 °C
Reaction time: 0.67 h
Yield: 45.6 %

Procedure:
1-(4-Methoxyphenyl)-3-propyl-1H-pyrazol-5(4H)-one (495 mg, 2.13 mmol) was put in a microwave tube and closed, MeCN (2.1 mL) and PBr3 (6.4 mL, 68.2 mmol) were added via syringe and the reaction was stirred at 150° C. for 40 min in the microwave. The product poured onto ice and was extracted with EtOAc. The organic phase was separated from the water phase and evaporated. The crude product was purified on silica column (CH2Cl2/Et2O, 1:1) to give 5-bromo-1-(4-methoxyphenyl)-3-propyl-1H-pyrazole (287 mg, 46%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][N:20](C(OCC)=O)[CH2:21][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[K+].O>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18]4[CH2:19][NH:20][CH2:21][C:17]=4[S:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)N1Cc2sc3ncnc(Nc4ccc(F)c(Cl)c4)c3c2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Fc1ccc(Nc2ncnc3sc4c(c23)CNC4)cc1Cl
Temperature: 80 °C
Reaction time: 14 h
Yield: 37.4 %

Procedure:
To a solution of ethyl 4-[(3-chloro-4-fluorophenyl)amino]-5,7-dihydro-6H-pyrrolo[3′,4′:4,5]thieno[2,3-d]pyrimidine-6-carboxylate from Example 22A (413 mg, 1.05 mmol) in ethanol (4 mL) was added a 10 M aqueous potassium hydroxide solution (2 mL), and the mixture was stirred for 14 h at 80° C. Subsequently, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with water, dried over sodium sulfate, and the solvent was removed in vacuo. The residue was triturated with tert-butyl methyl ether, and the precipitate was collected by suction filtration to yield 126 mg (38%) of the title compound. The mother liquor was concentrated in vacuo and purified by preparative HPLC to yield further 35 mg (10%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:18]([C:19](O)=[O:20])=[C:17]2[N:13]([CH2:14][CH2:15][CH2:16]2)[C:12](=[O:22])[C:11]=1[CH3:23].C([O:28][CH2:29][CH2:30][O:31][NH2:32])(C)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:18]([C:19]([NH:32][O:31][CH2:30][CH2:29][OH:28])=[O:20])=[C:17]2[N:13]([CH2:14][CH2:15][CH2:16]2)[C:12](=[O:22])[C:11]=1[CH3:23]
Reactant: Cc1c(Nc2ccc(I)cc2F)c(C(=O)O)c2n(c1=O)CCC2
Reactant: CC(C)(C)OCCON
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: Cc1c(Nc2ccc(I)cc2F)c(C(=O)NOCCO)c2n(c1=O)CCC2
Temperature: 75 °C
Reaction time: 2 h
Yield: 3.6 %

Procedure:
Compound 8e (76 mg, 0.23 mmol) was added to a suspension of O-(2-tert-butoxy-ethyl)-hydroxylamine (see, WO05/110410, 47 mg, 0.36 mmol), HATU (103 mg, 0.27 mmol), and N-methylmorpholine (0.10 mL, 0.90 mmol) in DMF (3 mL). The reaction was heated to 75° C. for 16 h and concentrated in vacuo. The resulting oil was dissolved in 3 mL of TFA and allowed to stir at RT for 2 h. Then MeOH (3 mL) was added and made basic with potassium carbonate. It was allowed to stir for 30 minutes, the solid was filtered off and the filtrate was concentrated in vacuo. The residue was taken up in DMSO (1.5 mL) and methanol (1.5 mL) and purified by preparative HPLC (25/40 water/acetonitrile) to give 4 mg (5%) of Example 8 as a white solid. 1H NMR (400 MHz, MeOD): δ 7.43 (d, 1H, J=8.9 Hz), 7.33 (d, 1H, J=7.6 Hz), 6.43 (t, 1H, J=8.6 Hz), 4.14 (t, 2H, J=7.3 Hz), 3.85 (m, 2H), 3.67 (m, 2H), 3.29 (t. 2H, J=7.6 Hz), 2.09-2.27 (m, 2H), 1.83 (s, 3H). MS (ES) [m+H] calc'd for C18H19FIN3O4, 488. found 488.
Reaction SMILES: [C:1]12([NH:6][C:7]3[N:12]=[C:11]([NH:13][C@@H:14]4[CH2:19][CH2:18][C@@H:17]([CH3:20])[C@H:16]([OH:21])[CH2:15]4)[C:10]([C:22]#[N:23])=[CH:9][N:8]=3)[CH2:5][CH:3]([CH2:4]1)[CH2:2]2.[OH-:24].[Na+].OO>CS(C)=O>[C:1]12([NH:6][C:7]3[N:12]=[C:11]([NH:13][C@@H:14]4[CH2:19][CH2:18][C@@H:17]([CH3:20])[C@H:16]([OH:21])[CH2:15]4)[C:10]([C:22]([NH2:23])=[O:24])=[CH:9][N:8]=3)[CH2:2][CH:3]([CH2:4]1)[CH2:5]2
Reactant: C[C@@H]1CC[C@@H](Nc2nc(NC34CC(C3)C4)ncc2C#N)C[C@H]1O
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Product: C[C@@H]1CC[C@@H](Nc2nc(NC34CC(C3)C4)ncc2C(N)=O)C[C@H]1O
Temperature: 50 °C
Reaction time: 1 h
Yield: 66.9 %

Procedure:
2-(Bicyclo[1.1.1]pentan-1-ylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)pyrimidine-5-carbonitrile (0.38 g, 1.213 mmol) was dissolved in DMSO (26.9 mL) and to this solution was added a 50% aqueous sodium hydroxide solution (0.097 ml, 1.213 mmol) and a 30% aqueous hydrogen peroxide solution 0.137 mL, 1.213 mmol) at room temperature. Then the reaction mixture was stirred at 50° C. for 1 h. The reaction was cooled to room temperature and it was poured into 50 mL of ice water. The white precipitate was collected on filter paper and was washed twice with water. The precipitate was dried to give 2-(bicyclo[1.1.1]pentan-1-ylamino)-4-((1R,3R,4R)-3-hydroxy-4-methylcyclohexylamino)-pyrimidine-5-carboxamide (0.269 g, 0.812 mmol, 67% yield). 1H NMR (DMSO-d6, 400 MHz): δ ppm 0.94 (d, J=6.25 Hz, 3H) 1.10-1.26 (m, 3H) 1.68 (d, J=10.54 Hz, 1H) 1.92 (d, J=10.93 Hz, 1H) 2.06 (s, 6H) 2.17 (d, J=9.76 Hz, 1H) 2.46 (s, 1H) 2.98 (br. s., 1H) 3.82-3.95 (m, 1H) 4.63 (br. s., 1H) 7.16 (br. s., 1H) 7.77 (br. s., 1H) 8.11 (br. s., 1H) 8.33 (s, 1H) 9.24 (br. s., 1H); MS (ESI): m/z 332.3 [M+1]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]([C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=2)[O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.O=[C:32]([CH3:46])[CH2:33][CH2:34][N:35]1C(=O)C2C(=CC=CC=2)C1=O>>[NH2:35][CH2:34][CH2:33][CH:32]([N:8]1[CH2:9][CH2:10][CH:11]([CH:14]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=2)[C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=2)[CH2:12][CH2:13]1)[CH3:46]
Reactant: CC(=O)CCN1C(=O)c2ccccc2C1=O
Reactant: Cc1cccc(OC(c2ccc(C#N)cc2)C2CCN(C(=O)OC(C)(C)C)CC2)n1
Product: Cc1cccc(OC(c2ccc(C#N)cc2)C2CCN(C(C)CCN)CC2)n1
Yield: 44.8 %

Procedure:
Using general procedure C with the above carbamate (1.2 g, 2.95 mmol), then general procedure B with the resulting amine and 2-(3-oxo-butyl)-isoindole-1,3-dione (1.2 g, 5.60 mmol) followed by general procedure D afforded 4-[[1-(3-amino-1-methyl-propyl)-piperidin-4-yl]-(6-methyl-pyridin-2-yloxy)-methyl]-benzonitrile (500 mg, 40% over 4 steps) as a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Cl:18])[C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)=[CH:7][C:6]=2[CH:17]=1.[C:19]1([C:25]2[CH:38]=[CH:37][C:28]([CH:29]=NC3C=CC=CC=3)=[CH:27][CH:26]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CC(C)([O-])C.[K+]>>[Cl:1][C:2]1[CH:3]=[C:4]([Cl:18])[C:5]2[O:9][C:8]([C:10]3[CH:11]=[CH:12][C:13]([CH:16]=[CH:29][C:28]4[CH:37]=[CH:38][C:25]([C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=5)=[CH:26][CH:27]=4)=[CH:14][CH:15]=3)=[CH:7][C:6]=2[CH:17]=1
Reactant: Cc1ccc(-c2cc3cc(Cl)cc(Cl)c3o2)cc1
Reactant: C(=Nc1ccccc1)c1ccc(-c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: Clc1cc(Cl)c2oc(-c3ccc(C=Cc4ccc(-c5ccccc5)cc4)cc3)cc2c1

Procedure:
Following the procedure given in Example 1b equimolar quantities of the above named 5,7-dichloro-2-(p-tolyl)benzofuran and 4-phenylbenzalaniline were interacted in the presence of potassium tert.-butoxide to give 5,7-dichloro2-{4-[2-(4-biphenylyl)vinyl]phenyl}benzofuran which, following recrystallization from chlorobenzene, melted at 258°-260° C. The wavelength of maximum excitation of this compound was 375 nm., and the wavelength of maximum emission was 431 nm.
Reaction SMILES: [CH3:1][CH:2]([CH3:15])[CH2:3][C:4]([C:6]1[C:7]([C:11](OC)=[O:12])=[CH:8][NH:9][CH:10]=1)=O.[CH3:16][NH:17][NH2:18]>>[CH3:16][N:17]1[C:11](=[O:12])[C:7]2=[CH:8][NH:9][CH:10]=[C:6]2[C:4]([CH2:3][CH:2]([CH3:15])[CH3:1])=[N:18]1
Reactant: CNN
Reactant: COC(=O)c1c[nH]cc1C(=O)CC(C)C
Product: CC(C)Cc1nn(C)c(=O)c2c[nH]cc12

Procedure:
Methyl 4-(3-methyl-1-oxobutyl)-1H-pyrrole-3-carboxylate (Example 1, step b, 7.8 g) and methylhydrazine (6 ml) were heated at reflux for 18 hours. The solvent was evaporated and the residue was chromatographed, eluting with dichloromethane-ethanol (19:1), to give the sub-title compound as a sand coloured solid (5.2 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)(O)[C:20]4[N:24]([CH3:25])[CH:23]=[N:22][CH:21]=4)[CH:17]=3)[N:12]([CH3:34])[C:11](=[O:35])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.S(Cl)([Cl:38])=O>>[Cl:2][C:3]1[CH:4]=[C:5]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:19]([Cl:38])([C:27]4[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=4)[C:20]4[N:24]([CH3:25])[CH:23]=[N:22][CH:21]=4)[CH:17]=3)[N:12]([CH3:34])[C:11](=[O:35])[CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Agent: Cl
Product: Cn1cncc1C(Cl)(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc(=O)n2C
Temperature: 22 °C
Reaction time: 0.25 h

Procedure:
A 1 liter reaction vessel was charged with 105.4 g of 4-(3-chlorophenyl)-6-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinone hydrochloric acid salt (compound (III) and 400 ml of N,N-dimethylimidazolidinone added at 22° C. The mixture was stirred vigorously for 15 minutes at 22° C. and became homogeneous. 32.1 ml of thionyl chloride was added over 10 minutes to the reaction mixture, the reaction temperature rising from 22° C. to 40° C. After addition of the thionyl chloride, the reaction mixture was cooled from 40° C. to 22° C. and stirred for three hours at the latter temperature to provide a solution of 4-(3-chlorophenyl)-6-[chloro-(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-1-methyl-2(1H)-quinolinone (compound (IV).
Reaction SMILES: [Br:1][C:2]1[C:12]([Cl:13])=[C:11]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH3:23])=[CH:17][CH:16]=2)[CH:10]=[C:9]([C@H:24]2[C@H:29]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@@H:28]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C@H:27]([O:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C@@H:26]([CH2:54][O:55][CH2:56][C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)[O:25]2)[C:3]=1[O:4][CH2:5][CH2:6]CO.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:82]([Cl:86])(Cl)(Cl)Cl>CC#N>[CH2:47]([O:46][C@H:27]1[C@H:28]([O:38][CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C@@H:29]([O:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C@H:24]([C:9]2[CH:10]=[C:11]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH3:23])=[CH:19][CH:20]=3)[C:12]([Cl:13])=[C:2]([Br:1])[C:3]=2[O:4][CH2:5][CH2:6][CH2:82][Cl:86])[O:25][C@@H:26]1[CH2:54][O:55][CH2:56][C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(OCCCO)c(Br)c2Cl)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: CCOc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(OCCCCl)c(Br)c2Cl)cc1
Temperature: 55 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
To a suspension of bromide 29 (1.47 g, 1.59 mmol) in CH3CN (25 mL) were added triphenylphosphine (1.1 g, 3.98 mmol) and CCl4 (2.5 mL) at r.t. The mixture was stirred at 55° C. for 3 hours. The reaction mixture was cooled to r.t and concentrated in vacuo. The residue was purified using normal phase column chromatography to provide the desired product 29-1 (1.03 g, 70%).
Reaction SMILES: C(C1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#N.BrC1C=C[N:26]2[CH:29]=[N:30][N:31]=C2C=1>>[N:31]1[N:30]=[CH:29][N:26]2[CH:4]=[CH:5][C:6]([CH:9]3[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:13][CH2:14]3)=[CH:7][C:8]=12
Reactant: Brc1ccn2cnnc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C#N)cc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccn3cnnc3c2)CC1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 1.1, except 7-bromo-[1,2,4]triazolo[4,3-a]pyridine (compound 41.2) was used in place of 4-bromobenzonitrile. m/z (ES+) 303 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[F:23])[NH2:19]>COCCOC>[Cl:15][C:16]1[CH:17]=[C:18]([NH:19][C:2]2[C:11]3[C:6](=[CH:7][N:8]=[C:9]([F:12])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:13]#[N:14])[CH:20]=[CH:21][C:22]=1[F:23]
Reactant: N#Cc1cnc2cnc(F)cc2c1Cl
Reactant: Nc1ccc(F)c(Cl)c1
Solvent: COCCOC
Product: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(F)c(Cl)c1
Temperature: 140 °C
Yield: 99 %

Procedure:
In a microwave vial, 4-chloro-6-fluoro-1,7-naphthyridine-3-carbonitrile (1.25 g, 6.02 mmol, prepared as described in Wissner et. al., Bioorg. Med. Chem. Lett., 14, 2004, 1411-1416) and 3-chloro-4-fluoroaniline (0.96 g, 6.6 mmol) were taken up in DME. The vial was crimp-sealed and heated in a microwave reactor at 140° C. for 10 minutes. This was repeated with a second batch of reagents. The contents of the two vials were transferred together to a separatory funnel and partitioned between EtOAc and 5% Na2CO3, and the aqueous layer extracted two additional times with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous MgSO4, filtered and evaporated to give 4-(3-chloro-4-fluorophenylamino)-6-fluoro-1,7-naphthyridine-3-carbonitrile of sufficient purity to be used directly in the next step (3.78 g, 99% yield): 1H NMR (400 MHz, DMSO-D6) δ 7.32-7.49 (m, 1 H) 7.53 (t, J=9.0 Hz, 1 H) 7.72 (dd, J=6.3, 2.3 Hz, 1 H) 8.16 (s, 1 H) 8.69 (s, 1 H) 9.08 (s, 1 H) 10.14 (s, 1 H).
Reaction SMILES: O=[C:2]1[C:10]2([CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11]2)[CH2:9][C:8]2[C:3]1=[CH:4][C:5]([C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[C:23]#[N:24])=[CH:6][CH:7]=2.[C:28](=[N:34][Si](C)(C)C)=[N:29][Si](C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:23]([C:22]1[CH:21]=[C:20]([C:5]2[CH:4]=[C:3]3[C:8](=[CH:7][CH:6]=2)[CH2:9][C:10]2([CH2:19][CH2:18][C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[CH2:11]2)/[C:2]/3=[N:34]/[C:28]#[N:29])[CH:27]=[CH:26][CH:25]=1)#[N:24]
Reactant: N#Cc1cccc(-c2ccc3c(c2)C(=O)C2(CCc4ccccc4C2)C3)c1
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: N#C/N=C1\c2cc(-c3cccc(C#N)c3)ccc2CC12CCc1ccccc1C2
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 133.9 %

Procedure:
To a solution of 3-(1-oxo-1,3,3′,4′-tetrahydro-1′H-spiro[indene-2,2′-naphthalene]-6-yl)benzonitrile (35 mg, 0.1 mmol) in DCM (5 mL) was added TiCl4 (76 mg, 0.4 mmol) dropwise, the mixture was stirred at 50° C. at Ar2 under microwave for 5 minutes, N,N′-methanediylidenebis(1,1,1-trimethylsilanamine) (74 mg, 0.4 mmol) was added dropwise. The mixture was stirred at 60° C. at Ar2 under microwave for 10 minutes and poured into ice-water (10 mL). The aqueous layer was extracted with CH2Cl2, which was combined with the organic layer. The organic layer was dried and concentrated to give crude (Z)—N-(5-(3-cyanophenyl)-3′,4′-dihydro-1′H-spiro[indene-2,2′-naphthalene]-3(1H)-ylidene)cyanamide (50 mg, 93%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.C(N(CC)CC)C.Cl[C:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:6]=1
Reactant: Cc1c[nH]cn1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 3.5 h

Procedure:
4-methyl-1H-imidazole (1) (36.53 mmol, 1 eq) of was dissolved in 120 mL of dimethylformamide, triethylamine (73.06 mmol, 2 eq.) and chlorotriphenylmethane (40.1 mmol, 1.1 eq) where added. The mixture was stirred for 3.5 h. The precipitate filtered off and was washed by means of ice-cooled dimethylformamide (2×50 mL) and water (2×50 mL). After removal of the solvent the remaining product was dried over P4O10.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:16](Cl)[C:17]([F:20])([F:19])[F:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:22]=[N+:23]=[N-:24].[Na+]>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:16]([C:17]([F:20])([F:19])[F:18])=[N:24][N:23]=[N:22]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)(F)C(Cl)=Nc1ccc(OCc2ccccc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(=O)O
Product: FC(F)(F)c1nnnn1-c1ccc(OCc2ccccc2)cc1
Reaction time: 3 h
Yield: 68.6 %

Procedure:
(4-Benzyloxy-phenyl)-(1-chloro-2,2,2-trifluoro-ethylidene)-amine (66 mmol) was added to a stirred flask of glacial acetic acid (250 ml) at 70° under nitrogen. After 4 min sodium azide (210 mmol) was added and heating was continued for 3 h. After cooling the mixture was filtered, the filtrate poured into water (750 ml) then extracted with dichloromethane (500 ml×3). The combined organic extracts were dried (Na2SO4) and evaporated in vacuo. Purification by FCC using hexane-ethyl acetate (19:1) gave the title compound as a white solid (14.5 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][NH:13][C:14](=O)[C:15]2[CH:20]=[CH:19][C:18]([C:21]3[O:25][C:24]([CH3:26])=[N:23][CH:22]=3)=[C:17]([O:27][CH3:28])[CH:16]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].C(Cl)(Cl)(Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[CH2:9][C:10]1[O:11][C:14]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[O:25][C:24]([CH3:26])=[N:23][CH:22]=3)=[C:17]([O:27][CH3:28])[CH:16]=2)=[N:13][N:12]=1
Reactant: COc1cc(C(=O)NNC(=O)Cc2ccc(F)c(F)c2)ccc1-c1cnc(C)o1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cc(-c2nnc(Cc3ccc(F)c(F)c3)o2)ccc1-c1cnc(C)o1
Temperature: 80 °C
Reaction time: 2 h
Yield: 53.8 %

Procedure:
A mixture of N′-[(3,4-difluorophenyl)acetyl]-3-methoxy-4-(2-methyl-1,3-oxazol-5-yl)benzohydrazide (4.69 g), carbon tetrachloride (2.24 mL) and triphenylphosphine (12.3 g) in acetonitrile (117 mL) was stirred at 80° C. for 2 hr. The mixture was allowed to cool to room temperature, the precipitate was filtered off, and the filtrate was concentrated. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate). Ethyl acetate was added to the obtained crude product, the precipitate was filtered off, and the filtrate was concentrated. Acetonitrile was added to the obtained residue, and the resultant precipitate was collected by filtration to give the title compound (2.41 g).
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:7]([NH:8][C:9](=[O:17])[O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[CH2:6][C@H:5]2[C@@H:3]1[CH2:4]2.Cl[C:19]1[N:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:29]3[C:34]([Cl:35])=[C:33]([O:36][CH3:37])[CH:32]=[C:31]([O:38][CH3:39])[C:30]=3[Cl:40])[CH:25]=2)[N:20]=1.C(=O)(O)[O-].[Na+]>CN1CCCC1=O.C(OCC)(=O)C>[Cl:35][C:34]1[C:33]([O:36][CH3:37])=[CH:32][C:31]([O:38][CH3:39])=[C:30]([Cl:40])[C:29]=1[C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[N:20]=[C:19]([NH:1][C@H:2]1[C@@H:7]([NH:8][C:9](=[O:17])[O:10][CH2:11][CH2:12][Si:13]([CH3:14])([CH3:16])[CH3:15])[CH2:6][C@H:5]3[C@@H:3]1[CH2:4]3)[N:28]=[CH:27]2
Reactant: C[Si](C)(C)CCOC(=O)N[C@H]1C[C@@H]2C[C@@H]2[C@H]1N
Reactant: COc1cc(OC)c(Cl)c(-c2ccc3nc(Cl)ncc3c2)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COc1cc(OC)c(Cl)c(-c2ccc3nc(N[C@@H]4[C@H]5C[C@H]5C[C@@H]4NC(=O)OCC[Si](C)(C)C)ncc3c2)c1Cl
Temperature: 25 °C
Yield: 62.5 %

Procedure:
A solution of 2-(trimethylsilyl)ethyl (1S,2R,3S,5S)-2-aminobicyclo[3.1.0]hexan-3-ylcarbamate (250 mg, 0.977 mmol), 2-chloro-6-(2,6-dichloro-3,5-dimethoxyphenyl)quinazoline (300 mg, 0.814 mmol) and sodium bicarbonate (205 mg, 2.442 mmol) in N-methyl-2-pyrrolidone (10 mL) was stirred at 100° C. overnight. The reaction solution was cooled to room temperature, diluted with ethyl acetate (100 mL) and washed with water (eight times) and brine (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated to afford a crude product, which was purified by silica gel column chromatography (ethyl acetate:petroleum ether=4:2) to afford the title compound (300 mg, 52%) as a yellow solid. MS (ES+) C28H34Cl2N4O4Si requires: 588, 590, found: 589, 591 [M+H]+.
Reaction SMILES: [NH2:1][C@H:2]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:3]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])[OH:4].C(Cl)(Cl)Cl>[Cu].CO>[CH:3](=[N:1][C@H:2]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH3:20])[OH:4])[C:5]1[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=1)[OH:11]
Reactant: COc1ccccc1C(O)(c1ccccc1OC)[C@H](N)Cc1ccccc1
Agent: [Cu]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccccc1C(O)(c1ccccc1OC)[C@@H](Cc1ccccc1)N=Cc1ccccc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 0.43 g. (1.4 millimols) of bis (salicylaldehydate) copper in 10 ml. methanol was added dropwise a solution of 1.1 g. (3.0 millimols) of (R)-2-amino-1,1-di(2-methoxyphenyl)-3-phenyl-1-propanol {[α]D +42.3° (c 1.1, chloroform)} in 10 ml. of methanol. The addition was carried out under thorough stirring at room temperature. The period of the addition was one hour and the reaction mixture was stirred for another one hour. The resulting solids were collected by filtration, washed with methanol and dried under reduced pressure to give a mononuclear complex of (R)-N-salicylidene-2-amino-1,1-di(2-methoxyphenyl)-3-phenyl-1-propanol as grayish blue crystals. Yield, 0.75 g. (58%), [α]546, +860° (c 0.065, benzene), melting point: 205° - 206° C. (decomposed).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([OH:21])([C:17]([F:20])([F:19])[F:18])[C:13]([F:16])([F:15])[F:14])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[CH3:22][N:23]([CH3:27])[C:24](Cl)=[S:25]>ClCCl>[CH2:1]([N:5]([C:6]1[CH:11]=[CH:10][C:9]([C:12]([OH:21])([C:17]([F:18])([F:19])[F:20])[C:13]([F:15])([F:14])[F:16])=[CH:8][CH:7]=1)[C:24]([N:23]([CH3:27])[CH3:22])=[S:25])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Reactant: CN(C)C(=S)Cl
Solvent: ClCCl
Product: CCCCN(C(=S)N(C)C)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 150 °C

Procedure:
2-(4-Butylamino-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol and dimethylthio-carbamoyl chloride are mixed together in a sealed vial and heated at 150° C. for 10 min in a microwave. The reaction mixture is dissolved in dichloromethane and purified over preparative TLC (Acetonitrile: CH2Cl2=2:98) to give the title compound. 1HNMR (CD3OD) δ 0.95(t, 3H), 1.38(m, 2H), 1.65(m, 2H), 2.99 (s, 6H), 4.05(t, 2H), 4.90(s, 1H), 7.04(d, 2H), and 7.68(d, 2H); ESIMS m/z 401(M−H).