Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S([N:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([N:17]3[CH2:22][CH2:21][CH2:20][C@@H:19]4[C:23]5[CH:24]=[C:25](OS(C(F)(F)F)(=O)=O)[CH:26]=[CH:27][C:28]=5[CH2:29][C@H:18]34)=[O:16])=[CH:14][C:9]=2[N:8]=[CH:7]1)(=O)=O.N1[C:44]2C=CC=C[C:43]=2NC=1>CN(C)C=O>[NH:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([N:17]3[CH2:22][CH2:21][CH2:20][C@@H:19]4[C:23]5[CH:24]=[C:25]([C:43]#[CH:44])[CH:26]=[CH:27][C:28]=5[CH2:29][C@H:18]34)=[O:16])=[CH:14][C:9]=2[N:8]=[CH:7]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: O=C(c1ccc2c(c1)ncn2S(=O)(=O)C(F)(F)F)N1CCC[C@@H]2c3cc(OS(=O)(=O)C(F)(F)F)ccc3C[C@@H]21
Solvent: CN(C)C=O
Product: C#Cc1ccc2c(c1)[C@H]1CCCN(C(=O)c3ccc4[nH]cnc4c3)[C@H]1C2
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A flask charged with a stir bar, trifluoromethanesulfonic acid cis-1-(1-trifluoromethane-sulfonyl-1H-benzoimidazole-5-carbonyl)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridin-6-yl ester (mixture of isomers regarding sulfonyl group attachment to N-1 or N-3 of the benzimidazole, 0.20 g) and N,N-dimethylformamide (2 mL) is sparged with argon for 5 min. Copper(I) iodide (13 mg), Pd(PPh3)2Cl2 (25 mg), triethylamine (0.31 mL), and trimethylsilylacetylene (0.14 mL) are added in the given order, the vessel is sealed, and the resulting mixture is heated to 60° C. After stirring the mixture at 60° C. overnight, it is cooled to room temperature and aqueous K2CO3 solution is added. The resulting mixture is extracted with ethyl acetate, the combined extract is dried (Na2SO4), and the solvent is evaporated. The residue is chromatographed on silica gel (dichloromethane/methanol 1:0→9:1) to afford the trimethylsilylated title compound which is taken up in methanol (3 mL) and treated with saturated aqueous K2CO3 solution at room temperature for 2 h. The mixture is then concentrated, water is added to the residue, and the resulting mixture is extracted with ethyl acetate. The combined extract is dried (Na2SO4) and concentrated. The residue is chromatographed on silica gel (dichloromethane/methanol 1:0→9:1) to afford the title compound. Yield: 0.03 g (26% of theory); LC (method 1): tR=2.65 min; Mass spectrum (ESI+): m/z=342 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:8])([CH:5]([F:7])[F:6])[CH2:3][OH:4].C(N(CC)CC)C.[F:16][C:17]([F:23])([F:22])[S:18](F)(=[O:20])=[O:19]>C(Cl)(Cl)Cl>[F:16][C:17]([F:23])([F:22])[S:18]([O:4][CH2:3][C:2]([F:8])([F:1])[CH:5]([F:7])[F:6])(=[O:20])=[O:19]
Reactant: OCC(F)(F)C(F)F
Reactant: O=S(=O)(F)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=S(=O)(OCC(F)(F)C(F)F)C(F)(F)F
Reaction time: 0.75 h

Procedure:
2,2,3,3-tetrafluoropropan-1-ol (244.3 g, 1.85 mol, obtained from Sinochem Corp.), triethylamine (187.2 g, 1.85 mol, obtained from Aldrich Chemical Co.) and 500 mL of chloroform were combined in a 2-liter Parr pressure reactor and sealed. The reactor temperature was set to −10° C. Trifluoromethanesulfonyl fluoride (281.33 g, 1.85 mol, obtained from 3M Company) was added at such a rate that the temperature did not exceed −5° C. Once the addition was complete, the mix was held at −10° C. for 45 minutes. The reaction mix was then emptied and washed with 2×500 mL portions of water and 1×250 mL portion of 1N HCl. GC analysis of the reaction mixture indicated a 97 percent conversion to the product. The chloroform solvent was removed by rotary evaporation. The product was dried over anhydrous magnesium sulfate which was then filtered from the product.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)#N.C(O)=[O:17]>[Ni]>[CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)=[O:17]
Reactant: O=CO
Reactant: Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Ni]
Product: Cc1ccc(-c2ccccc2C=O)cc1
Temperature: 85 °C
Reaction time: 8 h
Yield: 71.2 %

Procedure:
To a solution of 10 g (0.051 mol) of 4-(2-cyanophenyl)toluene in 300 ml of formic acid 30 g of Raney Ni is added. Reaction mixture is stirred at the 85° C. overnight and filtered. Filter cake is washed with 50 ml of dichloromethane. 150 ml of water are added to the filtrate, mixture is stirred for 10 minutes and layers separated. Organic layer is dried over MgSO4 and evaporated under reduced pressure giving 7.13 g of oily residue, which is purified on chromatographic column (silica gel, petroleum ether:ether 4:1) to produce 5.23 g of pure product in a form of a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[CH:16][C:17]([CH:18]=O)=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[S:20]1[CH2:26][C:24](=[O:25])[NH:23][C:21]1=[S:22].N1CCCCC1>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][N:12]3[N:15]=[CH:16][C:17]([CH:18]=[C:26]4[S:20][C:21](=[S:22])[NH:23][C:24]4=[O:25])=[C:11]3[N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cnn2ccc(Nc3cccc(Cl)c3)nc12
Reactant: O=C1CSC(=S)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1NC(=S)SC1=Cc1cnn2ccc(Nc3cccc(Cl)c3)nc12
Temperature: 80 °C

Procedure:
To 5-(3-chlorophenylamino)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (50 mg, 0.184 mmol) in 1 mL EtOH was added rhodanine (24 mg, 0.184 mmol) and piperidine (18 μL, 0.184 mmol). The mixture was heated in microwave (200 W) for 10 minutes at 80° C. The solid formed was isolated by filtration and air dried to give 5-((5-(3-chlorophenylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)-2-thioxothiazolidin-4-one. LCMS (M+1=388)
Reaction SMILES: [CH3:1][C@@H:2]([OH:5])[C:3]#[CH:4].[F:6][C:7]1[C:8](I)=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:19][CH:20]=[CH:21][C:22]=1[O:23][CH3:24]>CN(C=O)C.CCN(CC)CC.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:6][C:7]1[C:8]([C:4]#[C:3][C@H:2]([OH:5])[CH3:1])=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])/[C:10]/2=[CH:17]\[C:18]1[NH:19][CH:20]=[CH:21][C:22]=1[O:23][CH3:24]
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#C[C@@H](C)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#C[C@@H](C)O)c21

Procedure:
Using Method C above, (R)-but-3-yn-2-ol (37 mg, 0.53 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (50 mg, 0.13 mmol) (Starting Material 6) using (Ph3P)4Pd (15 mg, 0.01 mmol) and Cul (2 mg) in a mixture of DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 6 hrs. Upon completion, the reaction mixture was diluted with EtOAc and extracted with H2O. The organic layer was dried over Na2SO4 and concentrated. (R)-(Z)-1,3-Dihydro-5-fluoro-4-(3-hydroxy-1-butynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one was obtained after a silica gel column with a 0-70% EtOAc in hexanes gradient and trituration with petroleum ether. (Yield 21 mg, 48%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([SH:9])[S:8][C:4]=2[CH:3]=1.[CH:12](=O)[CH3:13].C(O)(=O)C.[BH3-]C#N.[Na+]>C1COCC1.O>[CH2:12]([NH:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([SH:9])[S:8][C:4]=2[CH:3]=1)[CH3:13]
Reactant: Nc1ccc2nc(S)sc2c1
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: CCNc1ccc2nc(S)sc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
Into a 100 mL two-necked flask are added 6-amino-1,3-benzothiazole-2-thiol (1.92 g, 10.5 mmol) and THF (20 mL), followed by acetaldehyde (0.591 mL, 10.5 mmol), glacial acetic acid (1 mL) and water (1 mL) at 0° C. The suspension is stirred for 1.5 hrs before a solution of NaCNBH3 (0.723 g, 10.5 mmol) in THF (20 mL) is introduced slowly through a dropping funnel. The reaction mixture is stirred at room temperature for 2 hrs after the addition. The precipitates are collected by filtration, washed with water and ether, and dried under reduced pressure to give the intermediate of 6-ethylamino-benzothiazole-2-thiol as light yellow solid (1.8 g, 82%). 1H NMR (CD3OD) δ 1.21 (t, 3H), 3.08 (q, 2H), 6.68-6.72 (m, 2H), 7.04 (d, 2H); ESIMS: m/z 211.0(M+H).
Reaction SMILES: [CH2:1]([Si:3]([CH2:15][CH3:16])([CH2:13][CH3:14])[O:4][C@@H:5]([CH2:10][CH2:11][CH3:12])[C@H:6]([CH3:9])[CH:7]=[O:8])[CH3:2].[BH4-].[Na+].C([Si](CC)(CC)O[C@H](CCC)[C@@H](C)CO)C>CCOC(C)=O>[CH2:15]([Si:3]([CH2:1][CH3:2])([CH2:13][CH3:14])[O:4][C@@H:5]([CH2:10][CH2:11][CH3:12])[C@@H:6]([CH3:9])[CH2:7][OH:8])[CH3:16]
Reactant: CCC[C@H](O[Si](CC)(CC)CC)[C@H](C)C=O
Agent: CCC[C@@H](O[Si](CC)(CC)CC)[C@@H](C)CO
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCC[C@H](O[Si](CC)(CC)CC)[C@@H](C)CO
Yield: 47 %

Procedure:
Aldehyde 22 and 2.5 eq sodium borohydride were reacted as in the preparation of 24 to give 47% alcohol 25 after chromatography (35 g SiO2, 2% EtOAc/1% TEA/97% CH2Cl2, Rf=0.34). 1H NMR (CDCl3, 360.134 MHZ δ:3.70 (1H, br d, J=11.02 Hz), 3.65 (1H,q,J=5.45 Hz), 3.46 (1H, br d), 2.85 (1H, br), 1.68 (1H,m), 1.46 (2H,m), 1.27 (2H,m), 092 (3H,d,J=5.45 Hz), 3.46 (1H, br d), 2.85 (1H, br), 1.68 (1H,m), 1.46 (2H,m), 1.27 (2H,m), 0.92 (3H,d,J=7.07 Hz), 0.90 (9H,t,J=7.90 Hz), 0.85 (3H,t,J=7.30 Hz), and 0.56 (6H,q,J=7.90 Hz). 13C NMR (CDCl3, 90.55 MHz) δ:77.6, 65.7, 38.0, 37.3, 18.0, 14.6, 14.3, 6.8, and 5.0. IR (thin film): 3400 (br) 2958(s), 2913(s), 2876(s), 1458(m), 1415(w), 1379(w), 1239(m), 1119(w), 1079(sJ), 1007 (s), 784 (w), 739 (s), and 727 (s) cm-1. High resolution MS (m/z): 217.1624, calcd for C11H25O2Si 217.1621 (M-C2H5).
Reaction SMILES: [I:1][CH2:2][CH:3]([CH2:8][I:9])[CH2:4][C:5]([OH:7])=[O:6].Cl.[CH2:11](O)[CH3:12]>>[CH2:11]([O:6][C:5](=[O:7])[CH2:4][CH:3]([CH2:8][I:9])[CH2:2][I:1])[CH3:12]
Reactant: O=C(O)CC(CI)CI
Reactant: CCO
Agent: Cl
Product: CCOC(=O)CC(CI)CI
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 2.831 g (8 mmole) 3-iodomethyl-4-iodobutyric acid in 80 mL ethanol is saturated with HCl gas at 0° C. After stirring the solution at room temperature for two days, the solvent is removed under vacuum, and the residue is dissolved in dichloromethane. The dichloromethane layer is washed with 10% aqueous sodium bicarbonate (3×100 mL), water (1×100 mL) and brine. The separated dichloromethane layer is dried over with magnesium sulfate, filtered and evaporated to give ethyl-3-iodomethyl-4-iodobutyrate.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[OH:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[CH2:14][CH2:13]2>CCOC(C)=O>[Cl:8][C:4]1[CH:5]=[N:6][CH:7]=[C:2]([O:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13]3)[N:3]=1
Reactant: Clc1cncc(Cl)n1
Reactant: O=C1CCc2cc(O)ccc21
Solvent: CCOC(C)=O
Product: O=C1CCc2cc(Oc3cncc(Cl)n3)ccc21
Yield: 100 %

Procedure:
Using Method DD with 2,6-dichloropyrazine (200 mg, 1.34 mmol) and 5-hydroxyindanone (219 mg, 1.49 mmol), and crystallisation in AcOEt, the title compound was obtained (350 mg). Yield: 100%. 1H NMR (250 MHz, DMSO-d6) δ 2.67 (t, 2H, H3, J=5.9 Hz), 3.13 (t, 2H, H2, J=5.5 Hz), 7.31 (dd, 1H, Harom 6, Jm=1.9 Hz, Jo=8.3 Hz), 7.47 (d, 1H, Harom 4, J=1.3 Hz), 7.73 (d, 1H, Harom 7, J=8.3 Hz), 8.59 (s, 1H, HPz 5), 8.64 (s, 1H, HPz 3). m/z: 261.0 [(M+H)+, calcd for C13H9ClN2O2 260.0].
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([CH:15]=1)[O:7][CH:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1.C(=[NH:30])(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>C1COCC1.Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH3:16][C:5]1[CH:4]=[CH:3][C:2]([NH2:30])=[CH:15][C:6]=1[O:7][CH:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1
Reactant: Cc1ccc(Br)cc1OC1CCN(C)CC1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1ccc(N)cc1OC1CCN(C)CC1
Reaction time: 9 h
Yield: 92.8 %

Procedure:
Combine 4-(5-bromo-2-methyl-phenoxy)-1-methyl-piperidine (preparation 20, 3.90 g, 13.7 mmol), benzophenone imine (2.98 g, 16.44 mmol), Pd2(dba)3 (251 mg, 0.27 mmol), BINAP (512 mg, 0.82 mmol), sodium f-butoxide (1.843 g, 19.18 mmol) and toluene (40 mL) and heat at 85° C. After 9 hr., quench the reaction with saturated NaHCO3 solution, extract with ethylacetate three times, combine the organic layers, dry over Na2SO4, filter and concentrate to give a residue. Dissolve the residue in THF (55 mL) and add 5N HCl (5.5 mL) and stir. After 1 hr., dilute the mixture with 0.1N HCl, extract with ethylacetate/hexanes (1:2) twice, keep aqueous layer, adjust pH>11 with 5N NaOH, extract with methylene dichloride three time. Combine methylene dichloride layers, dry over Na2SO4, filter and concentrate to give a residue. Purify by silica gel chromatography, eluting with 6.5% 2M NH3-methanol in methylene dichloride to give the title compound as a yellow oil (2.80 g, 93%). Mass spectrum (ion spray): m/z=221.1 (M+1); 1H NMR (CDCl3, ppm): 6.79 (d, 1H), 6.09 (m, 2H), 4.16 (m, 1H), 3.41 (s, br, 1H), 2.53 (m, 2H), 2.24 (m, 2H), 2.19 (s, 3H), 2.00 (s, 3H), 1.93-1.68 (m, 4H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([CH:30]2[O:35][CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31]2)[CH:12]=[CH:13][C:14]=1[NH:15][C:16]([C:18]1[CH:19]=[N:20][N:21]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH:22]=1)=[O:17].[OH-].[Na+]>O.C(#N)C>[Cl:8][C:9]1[CH:10]=[C:11]([CH:30]2[O:35][CH2:34][CH2:33][NH:32][CH2:31]2)[CH:12]=[CH:13][C:14]=1[NH:15][C:16]([C:18]1[CH:19]=[N:20][N:21]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[CH:22]=1)=[O:17]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(NC(=O)c3cnn(-c4ccc(F)cc4)c3)c(Cl)c2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(Nc1ccc(C2CNCCO2)cc1Cl)c1cnn(-c2ccc(F)cc2)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 96.2 %

Procedure:
To a stirred solution of trifluoroacetic acid (200 μl) in water (4.5 ml) was added a solution of tert-butyl (RS)-2-(3-chloro-4-(1-(4-fluorophenyl)-1H-pyrazole-4-carboxamido)phenyl)morpholine-4-carboxylate (100 mg) in acetonitrile (3 ml). The reaction mixture was then capped and the mixture was shaken at 80° C. for 5 h. The reaction mixture was then cooled to room temperature and poured into 1 M aq. NaOH and the resulting mixture was extracted twice with EtOAc. The organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash column chromatography (Isolute® Flash-NH2 from Separtis); gradient: MeOH/EtOAc/heptane) to afford (RS)—N-(2-chloro-4-(morpholin-2-yl)phenyl)-1-(4-fluorophenyl)-1H-pyrazole-4-carboxamide (77 mg, 96%) as a white solid. MS (ISP): 403.1 ([{37Cl}M+H]+), 401.0 ([{35Cl}M+H]+).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.[Cl:43][C:44]1C=[CH:48][N:47]=[CH:46][C:45]=1CCl>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[CH:48]=[N:47][CH:46]=[CH:45][C:44]=3[Cl:43])[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: ClCc1cnccc1Cl
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3cnccc3Cl)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 4-chloro-3-(chloromethyl)pyridine and isolated as light yellow gum. MS (m/e): 408.3 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH2:11])[N:7]([CH2:12][CH2:13][CH3:14])[C:6](=[O:15])[C:5]2([CH3:17])[CH3:16].Br[C:19]#[N:20].C(Cl)Cl.CO>O.C1COCC1>[NH2:20][C:19]1[NH:1][C:2]2=[CH:3][C:4]3[C:5]([CH3:16])([CH3:17])[C:6](=[O:15])[N:7]([CH2:12][CH2:13][CH3:14])[C:8]=3[CH:9]=[C:10]2[N:11]=1
Reactant: N#CBr
Reactant: CCCN1C(=O)C(C)(C)c2cc(N)c(N)cc21
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: CCCN1C(=O)C(C)(C)c2cc3[nH]c(N)nc3cc21
Yield: 92.7 %

Procedure:
Analogously to general procedure (III) 5,6-diamino-3,3-dimethyl-1-propyl-1,3-dihydro-indol-2-one (1.52 g) is cyclized using BrCN (3 M; 2.4 ml; 7.2 mmol) at RT in water (5 ml) and THF (13 ml). After aqueous work-up and flash chromatography on silica gel eluting with CH2Cl2/MeOH (15:1) the desired compound (1.56 g) is obtained.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[S:10][C:9]([C:12]3[N:17]=[C:16]([C:18]([NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27]C(=O)OC(C)(C)C)=[O:19])[CH:15]=[CH:14][CH:13]=3)=[N:8][C:7](=[O:35])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[ClH:36]>O1CCOCC1>[ClH:36].[NH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][NH:20][C:18]([C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([C:9]2[S:10][C:11]3[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=3[C:7](=[O:35])[N:8]=2)[N:17]=1)=[O:19]
Reactant: Cc1cccc2c(=O)nc(-c3cccc(C(=O)NCCCCCCNC(=O)OC(C)(C)C)n3)sc12
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cccc2c(=O)nc(-c3cccc(C(=O)NCCCCCCN)n3)sc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 20 %

Procedure:
tert-Butyl 6-[[[6-(8-methyl-4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridyl]carbonyl]amino]hexylcarbamate (0.30 g, 0.60 mmol) was dissolved in dioxane (10 ml), and 4 N hydrochloric acid in dioxane (1.0 ml. 4.00 mol) was added thereto. The reaction mixture was stirred at room temperature for 24 hrs. The precipitates were collected by filtration and recrystallized from diisopropyl ether-methanol to give the titled compound (0.05 g, 20%) as pale yellow crystals.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.O>N1C=CC=CC=1>[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16]([O:8][CH2:7][CH:5]2[CH2:4][O:3][C:2]([CH3:9])([CH3:1])[O:6]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(C)OCC(CO)O1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC2COC(C)(C)O2)cc1
Reaction time: 48 h

Procedure:
To a solution of 7.2 g of 2,2-dimethyl-1,3-dioxolan-4-ylmethanol in 40 ml of pyridine at 0° C. was added 11.3 g of p-toluenesulfonyl chloride in portions. The solution was kept at 25° C. for 48 hours, then poured into water and extracted with diethyl ether. The organic solution was washed twice with water, once with dilute hydrochloric acid and once with dilute sodium carbonate solution. The organic solution was dried with magnesium sulfate and evaporated under vacuum to yield (±)-2,2-dimethyl-1,3-dioxolan-4-ylmethyl p-toluenesulfonate.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH:7]1[CH2:10][NH:9][CH2:8]1.[CH2:16]([N:18]=[C:19]=[O:20])[CH3:17]>C1C=CC=CC=1.C(Cl)Cl>[CH2:16]([NH:18][C:19]([N:9]1[CH2:10][CH:7]([O:6][C:5]2[CH:11]=[CH:12][CH:13]=[C:3]([C:2]([F:1])([F:14])[F:15])[CH:4]=2)[CH2:8]1)=[O:20])[CH3:17]
Reactant: CCN=C=O
Reactant: FC(F)(F)c1cccc(OC2CNC2)c1
Solvent: c1ccccc1
Solvent: ClCCl
Product: CCNC(=O)N1CC(Oc2cccc(C(F)(F)F)c2)C1

Procedure:
To a stirred and chilled (15°-20° C.) solution of 0.024 mole of 3-[3-(trifluoromethyl)phenoxy]azetidine in 50 ml of dry benzene was added dropwise 1.99 g (0.028 mole) of ethyl isocyanate. The reaction mixture was stirred at room temperature overnight and was diluted with 50 ml of methylene chloride. The solution was washed with 5% sodium hydroxide (2×50 ml), water (50 ml), saturated sodium chloride (25 ml), dried over sodium hydroxide, and concentrated in vacuo. The residue (9.6 g) was twice recrystallized from ethyl acetate-isopropyl ether to give 5.4 g or a white solid, m.p. 125°-126° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)O)=[CH:5][CH:4]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:13]1([CH:9]2[C:10]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:11]=3)[CH:7]=[CH:8]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1ccc2c(c1)C(O)(c1ccccc1)CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc2c(c1)C(c1ccccc1)C=C2
Yield: 59.1 %

Procedure:
To 1.5 L of toluene was added 32 g (0.133 mol) of 6-methoxy-1-phenyl-indan-1-ol and 100 mg of p-toluenesulfonic acid monohydrate and the mixture was placed on a Rotovap and the solvent was distilled in vacuo (40 mm) until a brown oil residue was obtained. The brown oil was chromatographed (silica, 1:1 hexane/methylene chloride) to afford 17.47 g (60.2%) of 1-phenyl-6-methoxy-indene as a pale yellow oil.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=2[N:5]([C:14]([C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)=[O:15])[CH2:4][CH:3]1[NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].Br[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[CH3:39])=[O:32].[OH-].[Na+].Cl>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:34]1([CH3:39])[C:33]([C:31]([CH2:30][N:8]2[C:7]3[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:6]=3[N:5]([C:14]([C:16]3[O:17][CH:18]=[CH:19][CH:20]=3)=[O:15])[CH2:4][CH:3]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:2]2=[O:1])=[O:32])=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)c1ccco1
Reactant: Cc1ccccc1C(=O)CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)c1ccco1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.9 %

Procedure:
2-Oxo-3-tert-butoxycarbonylamino-5-(furan-2-ylcarbonyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (1.50 g) was suspended in toluene (20 ml), 2-bromo-2′-methylacetophenone (995 mg), 1N aqueous sodium hydroxide (10 ml) and tetra n-butylammonium bromide (20 mg) were added, and the mixture was stirred for 2 hours at room temperature. The reaction mixture was weakly acidified with 1N hydrochloric acid, and extracted with methylene chloride. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography(chloroform:ethyl acetate=20:1), to thereby obtain 1.55 g of the titled compound (Yield: 76.9%).
Reaction SMILES: [C:1]1([CH3:22])[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:15]3[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=3)[CH:9]=2)[CH:2]=1.I[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[CH3:30].C(=O)([O-])[O-].[K+].[K+]>[N+](C1C=CC=CC=1)([O-])=O.[Cu]>[C:1]1([CH3:22])[CH:6]=[CH:5][CH:4]=[C:3]([N:7]([C:3]2[CH:2]=[C:1]([CH3:22])[CH:6]=[CH:5][CH:4]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([N:14]([C:29]3[CH:24]=[C:25]([CH3:30])[CH:26]=[CH:27][CH:28]=3)[C:15]3[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=3)[CH:9]=2)[CH:2]=1
Reactant: Cc1cccc(Nc2cccc(Nc3cccc(C)c3)c2)c1
Reactant: Cc1ccccc1I
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1cccc(N(c2cccc(C)c2)c2cccc(N(c3cccc(C)c3)c3cccc(C)c3)c2)c1

Procedure:
More specifically, resorcinol of formula (A) is reacted with m-toluidine of formula (B) in the presence of iodine in a nitrogen current to obtain N,N'-di(3-tolyl)-1,3-phenylenediamine of formula (C). Then, N,N'-di(3-tolyl)-1,3-phenylenediamine is reacted with iodotoluene of formula (D) in the presence of potassium carbonate and powdery copper under reflux in nitrobenzene to obtain N,N,N',N'-tetra(3-tolyl)-1,3-phenylenediamine of formula (E).