Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.Br[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([C:20]3[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][CH:21]=3)[N:18]=[C:17]([C:30]([F:33])([F:32])[F:31])[CH:16]=2)=[CH:11][CH:10]=1.O>CN(C=O)C.[Cu]>[N:3]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:19]([C:20]4[CH:21]=[CH:22][C:23]([S:26]([CH3:29])(=[O:27])=[O:28])=[CH:24][CH:25]=4)[N:18]=[C:17]([C:30]([F:32])([F:31])[F:33])[CH:16]=3)=[CH:11][CH:10]=2)[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(Br)cc2)cc1
Reactant: c1c[nH]cn1
Agent: [Cu]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(-n3ccnc3)cc2)cc1
Temperature: 150 °C
Reaction time: 0.5 h
Yield: 16.2 %

Procedure:
To a suspention of sodium hydride (0.04 g:1 mmol) (60% mineral oil dispersion; washed with dry hexane (3 mL)) in DMF(2 mL) was added imidazol (0.068 g) at room temperature and the mixture was stirred 30 minutes. Then, 4-[5-[4-Bromophenyl]-3-trifluoromethyl-1-[4-(methylsulfonyl)phenyl]-1H-pyrazole (0.445 g) and copper powder (0.0063 g) were added and the whole was heated at 150° C. for 3 hours. After cooling, water (30 mL) was added to the reaction mixture and the whole was extracted with CH2Cl2 (30 mL×2), the extract was washed with water and brine, dried over MgSO4,and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate/methanol (1/0.03). The resulting solid was recrystallized with dichloroethane-diisopropyl ether to give the title compound (0.07 g).
Reaction SMILES: [H-].[Na+].[CH:3]1[C:8]([OH:9])=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:10].Cl[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[C:15]([C:22]3[NH:30][C:29]4[CH2:28][CH2:27][NH:26][C:25](=[O:31])[C:24]=4[CH:23]=3)[CH:16]=[CH:17][CH:18]=2)[N:13]=1>CN(C=O)C>[CH3:10][C:4]1[CH:3]=[C:8]([CH:7]=[CH:6][CH:5]=1)[O:9][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[C:15]([C:22]3[NH:30][C:29]4[CH2:28][CH2:27][NH:26][C:25](=[O:31])[C:24]=4[CH:23]=3)[CH:16]=[CH:17][CH:18]=2)[N:13]=1
Reactant: Cc1cccc(O)c1
Reactant: O=C1NCCc2[nH]c(-c3cccc4ccc(Cl)nc34)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(Oc2ccc3cccc(-c4cc5c([nH]4)CCNC5=O)c3n2)c1
Yield: 9.3 %

Procedure:
Prepared according to Example 103, using NaH as a 60% dispersion in mineral oil (47.0 mg, 1.176 mmol, Sigma Aldrich) in DMF (1679 μl), m-cresol (123 μl, 1.176 mmol, Sigma Aldrich), and 2-(2-chloroquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 1; 50 mg, 0.168 mmol) and heating to 85° C. for 16 h. Purification by reverse phase HPLC (Phenomenex Gemini column, 10 micron, C18, 100 Å, 150×30 mm, 0.1% TFA in ACN/H2O, gradient 5% to 90%) provided 2-(2-(3-methylphenoxy)-8-quinolinyl)-1,5,6,7-tetrahydro-4H-pyrrolo[3,2-c]pyridin-4-one (5.8 mg, 9.4%) as the free base following filtration through a Si-carbonate cartridge (Silicyle) with MeOH. 1H NMR (400 MHz, MeOH-d4) δ ppm 8.37-8.41 (1H, m) 8.10-8.14 (1H, m) 7.73-7.76 (1H, m) 7.46-7.56 (1H, m) 7.28-7.37 (2H, m) 7.14-7.22 (1H, m) 7.04 (3H, s) 3.48-3.55 (2H, m) 3.14-3.19 (2H, m) 2.47 (3H, s). m/z (ESI, +ve) 370.2 (M+H)+.
Reaction SMILES: [CH2:1]=[CH:2]C=C.C([CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(C)(C)C>>[CH:1]([C:16]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH:10]=[CH2:9])=[CH2:2]
Reactant: C=CC=C
Reactant: CC(C)(C)C=Cc1ccccc1
Product: C=Cc1ccccc1C=C

Procedure:
A second reactor (7.6 L, purchased from Chemineer, Inc.) was used to make poly(t-butyl styrene) (“PtBuSt”). The second reactor was first charged with 0.51 lbs of t-butyl styrene, followed by 3 lbs of hexane. Polymerization was initiated at 57° C. by adding 3 ml of 1.6 M oligomeric oxolanyl propanes in hexane and 4 ml of 1.54 M n-butyllithium in hexane. The polymerization was then allowed to continue for approximately two hours. The GPC analysis indicated that the PtBuSt in the solution had an Mn of 48,880 and an Mw/Mn of 1.12. Then, the PtBuSt/hexane solution was charged into the polybutadiene solution prepared in the first reactor as described above. After thoroughly mixing, 450 ml of the mixed solution, which was still chemically alive, was placed into a clean, dry, nitrogen purged closed bottle. Polymerization was then extended by charging 24 ml of a styrene/hexane blend (containing 33 weight percent styrene) to form a polystyrene (“PS”) block on the PBd and PtBuSt blocks. After approximately half an hour, the resulting diblock copolymers (i.e., PBd-PS and PtBuSt-PS) formed spherical micelles in the hexane solution (about 14 weight percent solid aggregated) with the styrene blocks directed toward the center of the micelle structures and the butadiene and t-butylstyrene blocks as tails extending therefrom. After forming the micelles, 1 ml of divinyl benzene (“DVB”) was added to the bottle in order to polymerize and crosslink the polystyrene core.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]2[N:18]3[N:19]=[CH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH:28]([CH3:32])[C:29]([OH:31])=O)[CH:27]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6].Cl.[CH3:36][O:37][CH:38]1[CH2:42][CH2:41][NH:40][CH2:39]1>>[CH3:36][O:37][CH:38]1[CH2:42][CH2:41][N:40]([C:29](=[O:31])[CH:28]([N:26]2[CH:27]=[C:23]([C:21]3[CH:20]=[N:19][N:18]4[C:14]([C:10]5[CH:9]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:33])([F:1])[F:34])=[O:6])[CH:13]=[CH:12][CH:11]=5)=[CH:15][N:16]=[C:17]4[CH:22]=3)[CH:24]=[N:25]2)[CH3:32])[CH2:39]1
Reactant: CC(C(=O)O)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1
Reactant: COC1CCNC1
Agent: Cl
Product: COC1CCN(C(=O)C(C)n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)C1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 54, Step 3 starting from 2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)propanoic acid and 3-methoxypyrrolidine hydrochloride (Matrix and Cat. No. 023344). LCMS (M+H)+: m/z=557.2.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].Cl[CH2:6][Si:7]([CH3:10])([CH3:9])[CH3:8].[OH-].[Na+]>O>[CH2:1]([NH:4][CH2:6][Si:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=[CH2:3]
Reactant: C[Si](C)(C)CCl
Reactant: C=CCN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=CCNC[Si](C)(C)C
Temperature: 70 °C
Reaction time: 24 h
Yield: 72.7 %

Procedure:
To 118 mL (1.57 mol) of allylamine warmed at 40° C. in an inert atmosphere was very slowly added 100 mL (0.72 mol) of chloromethyl trimethylsilane (approximate rate of 1 mL/min). The reaction mixture was slowly warmed to 70° C. and stirred for 24 h. The reaction mixture was cooled to 0° C. and to it was added water to break up the gel and then 300 mL of 2N NaOH solution. The reaction mixture was extracted with ether. The combined organic fractions were washed with 500 mL of sat'd NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by distillation (bp 80-84° C. @ 100 torr) to give 75 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([SH:11])[CH:3]=1.[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)#[N:13]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]2[C:6](=[O:8])[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[S:11][C:4]=2[CH:3]=1
Reactant: O=C(O)c1ccc(Cl)cc1S
Reactant: N#Cc1ccccn1
Solvent: c1ccncc1
Product: O=c1nc(-c2ccccn2)sc2cc(Cl)ccc12
Yield: 47.3 %

Procedure:
A mixture of 4-chloro-2-mercaptobenzoic acid (6.00 g, 31.8 mmol), 2-cyanopyridine (1.90 g, 17.7 mmol) and pyridine (50.0 ml) was refluxed for 9 hrs as described in Example 9. After cooling, the precipitated crystals were collected by filtration and recrystallized from hexane-chlorobenzene to give the titled compound (2.30 g, 48%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[OH:37])[C:5]([CH2:7][NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]1[CH2:26][CH2:25][C:24]2[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=2[CH2:18]1)=O.Cl[CH2:39][C:40]([N:42]1[CH2:47][CH2:46][CH:45]([CH3:48])[CH2:44][CH2:43]1)=O>>[F:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][C:36]=1[O:37][CH2:39][CH2:40][N:42]1[CH2:47][CH2:46][CH:45]([CH3:48])[CH2:44][CH2:43]1)[CH2:5][CH2:7][NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]1[CH2:26][CH2:25][C:24]2[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:19]=2[CH2:18]1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCC(=O)c2ccc(O)c(F)c2)c1
Reactant: CC1CCN(C(=O)CCl)CC1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCc2ccc(OCCN3CCC(C)CC3)c(F)c2)c1
Yield: 17.6 %

Procedure:
Synthesized from pivalic acid 6-{2-[(3-fluoro-4-hydroxybenzoyl)methylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 2-chloro-1-(4-methylpiperidin-1-yl)ethanone (14 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (3.7 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:14][CH3:15])[C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([NH:9][NH2:10])=[O:8].[CH:16]([O-])([O-])OC>>[CH3:15][O:14][CH:3]([O:2][CH3:1])[C:4]1[CH:5]=[C:6]([C:7]2[O:8][CH:16]=[N:10][N:9]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: COC(OC)c1cccc(C(=O)NN)c1
Reactant: COC([O-])[O-]
Product: COC(OC)c1cccc(-c2nnco2)c1
Yield: 61.4 %

Procedure:
2.1 g of 3-dimethoxymethylbenzhydrazide and 12.7 g of methyl orthoformate were reacted at atmospheric pressure for 24 hours while distilling off the methanol formed. Excessive methyl orthoformate was removed by distillation under reduced pressure. The residue was purified by a column chromatography (eluant: n-hexane/ethyl acetate=3/1) to obtain 1.35 g of colorless oily 2-(3-dimethoxymethylphenyl)-1,3,4-oxadiazole.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[C:11]2[CH:20]=[CH:19][S:18][C:12]=2[NH:13][C:14](=S)[CH2:15][N:16]=1)([O-:3])=[O:2].[C:21]([NH:24][NH2:25])(=O)[CH3:22]>C(O)CCC>[CH3:22][C:21]1[N:13]2[C:12]3[S:18][CH:19]=[CH:20][C:11]=3[C:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N+:1]([O-:3])=[O:2])=[N:16][CH2:15][C:14]2=[N:25][N:24]=1
Reactant: O=[N+]([O-])c1ccccc1C1=NCC(=S)Nc2sccc21
Reactant: CC(=O)NN
Solvent: CCCCO
Product: Cc1nnc2n1-c1sccc1C(c1ccccc1[N+](=O)[O-])=NC2
Reaction time: 2 h

Procedure:
9.1 g (0.03 mol) of 1,3-dihydro-5-(o-nitrophenyl)-2H-thieno[2,3-e]-1,4-diazepine-2-thione are refluxed with 500 ml of absolute butanol and 9 g of acetic hydrazide, a stream of nitrogen being conducted through the solution. After 2 hours, the solvent is evaporated and the residue taken up in 300 ml of methylene chloride and washed three times with 100 ml of water each time. After drying and evaporation of the organic phase and trituration with ethyl acetate, there is obtained crystalline 9-methyl-4-(o-nitrophenyl)-6H-thieno[3,2-f]-s-triazolo[4,3-a][1,4]diazepine which, after recrystallization from ethanol and treatment with active carbon, melts at 260°-262° C.
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[C:3]=1[O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7].C([O-])([O-])=O.[Na+].[Na+].[F:33][C:34]([F:46])([F:45])[O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O>COCCOC>[F:26][C:21]1[C:3]([O:4][CH2:5][C:6]([N:8]([CH:18]([CH3:20])[CH3:19])[NH:9][C:10](=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])=[C:2]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=2[O:35][C:34]([F:33])([F:46])[F:45])[CH:24]=[C:23]([F:25])[CH:22]=1
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1c(F)cc(F)cc1Br
Reactant: OB(O)c1ccccc1OC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)COc1c(F)cc(F)cc1-c1ccccc1OC(F)(F)F
Yield: 58.8 %

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-4,6-difluoro-phenoxy)-acetyl]-N′-isopropyl-hydrazide (100 mg, 0.234 mmol) in DME (3 ml)/2M Na2CO3 (0.410 ml, 0.819 mmol) was treated with 2-trifluoromethoxybenzeneboronic acid (72 mg, 0.351 mmol) and Pd[PPh3]4 (54 mg, 0.046 mmol) in a microwave oven at 150° C. for 10 min. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-40% ethyl acetate/hexanes gradient to afford the product as a white crystalline solid (70 mg, 59%). MS m/e 509.24 (M+H+)
Reaction SMILES: [Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([CH:13]=O)[CH:3]=1.C1(P(=[CH:34][C:35]#[N:36])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:11]([Cl:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4](/[CH:13]=[CH:34]/[C:35]#[N:36])[CH:3]=1
Reactant: N#CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1cc(Cl)c(Cl)cc1C=O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(Cl)c(Cl)cc1/C=C/C#N
Temperature: 25 °C

Procedure:
A mixture of the product from Example 56C (2.0 g, 8.6 mmol) and (triphenylphosphoranylidene)acetonitrile (2.87 g, 9.5 mmol) in toluene (30 mL) was refluxed for 24 hours. The reaction was cooled to room temperature and filtered through a short plug of silica gel eluting with diethyl ether to remove the triphenyl phosphine oxide. The filtrate was concentrated and the residue was purified via flash chromatography on a silica gel column (5:95 ethyl acetate:hexane) to afford the title compound and the corresponding Z isomer. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.88 (s, 3H) 6.55 (d, J=16.27 Hz, 1H) 8.05 (d, J=16.95 Hz, 1H) 8.09 (s, 1H) 8.13 (s, 1H); MS (DCI+) m/z 273.0 [M+H]+.
Reaction SMILES: [C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][C:13]2[NH:14][C:15]3[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[CH:18][C:16]=3[N:17]=2)=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:39])C=1>ClCCl.CO>[C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12]([C:13]2[NH:14][C:15]3[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[CH:18][C:16]=3[N:17]=2)=[O:39])=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCc1c(OCCCSc2nc3ccc(C(=O)O)cc3[nH]2)ccc(C(C)=O)c1O
Solvent: CO
Solvent: ClCCl
Product: CCCc1c(OCCCS(=O)c2nc3ccc(C(=O)O)cc3[nH]2)ccc(C(C)=O)c1O
Reaction time: 0.25 h
Yield: 52.1 %

Procedure:
To a mixture of 2-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)-propylthio]benzimidazole-5-carboxylic acid (1.00 g) in dichloromethane (30 ml) and methanol (3 ml) stirring in ice-salt-water bath, was added m-chloroperbenzoic acid (80%, 503 mg) in a small portions below 0° C. Further stirring for an additional 15 minutes, the mixture was evaporated, and the residue was purified by silica gel chromatography, eluting with dichloromethane-ethyl acetate-methanol (10:2:1), and recrystallized from ethanol-water to give the title compound (540 mg, 52.1%) as colorless crystals, mp 173-175° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32][O:33]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1.O[C:49]1[C:54]([CH3:55])=[CH:53][CH:52]=[CH:51][C:50]=1[CH2:56][CH2:57][NH:58][C:59](=[O:61])[CH3:60]>>[C:59]([NH:58][CH2:57][CH2:56][C:50]1[CH:49]=[C:54]([CH3:55])[CH:53]=[CH:52][C:51]=1[O:33][CH2:32][CH2:31][O:30][CH:18]1[CH:17]([C:14]2[CH:15]=[CH:16][C:11]([O:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C:4]3[CH:44]=[CH:45][CH:46]=[CH:47][C:3]=3[O:2][CH3:1])=[CH:12][CH:13]=2)[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19]1)(=[O:61])[CH3:60]
Reactant: CC(=O)NCCc1cccc(C)c1O
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccc(C)cc2CCNC(C)=O)cc1

Procedure:
Analogously to Method G, 0.45 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-[2-(toluene-4-sulphonyloxy)ethoxy]piperidine-1-carboxylate (Example 14b) and 0.26 g of N-[2-(2-hydroxy-3-methylphenyl)ethyl]acetamide are reacted. The title compound is obtained as a yellow oil. Rf=0.60 (EtOAc); Rt=5.78.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[NH2:16][C:17](N)=[O:18]>O>[C:12]([C:11]1[CH:14]=[CH:15][C:8]([CH2:7][CH2:6][CH2:5][N:4]([CH2:3][CH2:2][OH:1])[C:17]([NH2:16])=[O:18])=[CH:9][CH:10]=1)#[N:13]
Reactant: NC(N)=O
Reactant: N#Cc1ccc(CCCNCCO)cc1
Solvent: O
Product: N#Cc1ccc(CCCN(CCO)C(N)=O)cc1
Temperature: 130 °C
Yield: 72.7 %

Procedure:
4-[3-(2-Hydroxyethylamino)propyl]benzonitrile (6.7 g, 0.0328 mol; see Preparation A(v) above) and urea (2 g, 0.0328 mol) were mixed and heated at 130° C. for 2 h. The reaction mixture was cooled to room temperature and water was added. The resulting solid was filtered and dried to give 5.9 g (72%) of the sub-title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:21]=[CH:20][C:19]2[N:18]3[CH2:22][CH2:23][CH2:24][C:17]3=[CH:16][C:15]=2[C:14]=1[C:25]([O:27][CH3:28])=[O:26])(=[O:11])=[O:10].[CH2:29]([N:31]([CH2:48][CH3:49])[CH2:32]/[CH:33]=[CH:34]\[Sn](CCCC)(CCCC)CCCC)[CH3:30]>O1CCOCC1.CS(C)=O>[CH2:29]([N:31]([CH2:48][CH3:49])[CH2:32]/[CH:33]=[CH:34]\[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:12][C:13]1[CH:21]=[CH:20][C:19]2[N:18]3[CH2:22][CH2:23][CH2:24][C:17]3=[CH:16][C:15]=2[C:14]=1[C:25]([O:27][CH3:28])=[O:26])(=[O:11])=[O:10])[CH3:30]
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2Br)ccc2c1cc1n2CCC1
Reactant: CCCC[Sn](/C=C\CN(CC)CC)(CCCC)CCCC
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: CCN(CC)C/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(cc3n2CCC3)c1C(=O)OC
Temperature: 95 °C
Yield: 90.7 %

Procedure:
A mixture of methyl 7-(2-bromo-4-fluorobenzenesulfonylamino]-2,3-dihydro-1H-pyrrolo[1,2-a]indole-8-carboxylate (Intermediate 17, 0.100 g) and N,N-diethyl-N—((Z)- 1-tributylstannanylprop-1-en-3-yl)-amine (Intermediate 3, 0.172 g) in dioxane (2 mL) and DMSO (0.2 mL) was de-gassed and purged with nitrogen. Tris-(dibenzylideneacetone)-dipalladium (0.009 g) and tri-tert-butylphosphonium tetrafluoroborate (0.006 g) were added and the reaction mixture was heated at 95° C., under an atmosphere of nitrogen for 45 minutes. After cooling, the mixture was partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried (MgSO4), filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-7.5% to give methyl 7-[2-((Z)-3-diethylaminoprop-1-enyl)-4-fluorobenzenesulfonylamino]-2,3-dihydro-1H-pyrrolo[1,2-a]indole-8-carboxylate (0.097 g) as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[N:9]([C:10]=1[CH2:11][N:12]1[CH2:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[CH:7][N:6]=[C:5]2[NH2:19].[Br:20]N1C(C)(C)C(=O)N(Br)C1=O>C(Cl)(Cl)Cl>[Br:20][C:3]1[C:2]([CH3:1])=[C:10]([CH2:11][N:12]2[CH2:18][CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:9]2[C:4]=1[C:5]([NH2:19])=[N:6][CH:7]=[N:8]2
Reactant: Cc1cc2c(N)ncnn2c1CN1CCCOCC1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: ClC(Cl)Cl
Product: Cc1c(Br)c2c(N)ncnn2c1CN1CCCOCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 118.5 %

Procedure:
To a stirring solution of chloroform (20 mL) and 6-methyl-7-(1,4-oxazepan-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (650 mg, 2.49 mmol), at −40° C., was added 1,3-dibromo-5,5-dimethylhydantoin (356 mg, 1.24 mmol). The mixture was allowed to stir for 10 minutes while warming to rt. The mixture was partitioned between ethyl acetate (200 mL) and saturated aqueous Na2CO3 solution (150 mL). The layers were separated and the organic phase was washed with brine, dried (Na2SO4), and concentrated to dryness. Trituration with acetonitrile afforded 500 mg (59%) of the desired product. 1H-NMR (DMSO-d6) δ 7.82 (s, 1H), 3.91 (s, 2H), 3.62 (t, J=5.4 Hz, 2H), 3.55-3.53 (m, 2H), 2.61-2.56 (m, 4H), 2.15 (s, 3H), 1.77-1.72 (m, 2H); MS [M+H]+=339.9, 341.9; LCMS RT=1.09.
Reaction SMILES: [H-].[Na+].Br.Cl[C:5]1[CH:6]=[CH:7][C:8]2[N:9]([C:11]([NH2:14])=[N:12][N:13]=2)[N:10]=1.O.[CH:16]1([OH:20])[CH2:19][CH2:18][CH2:17]1>>[CH:16]1([O:20][C:5]2[CH:6]=[CH:7][C:8]3[N:9]([C:11]([NH2:14])=[N:12][N:13]=3)[N:10]=2)[CH2:19][CH2:18][CH2:17]1
Reactant: OC1CCC1
Reactant: Nc1nnc2ccc(Cl)nn12
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Nc1nnc2ccc(OC3CCC3)nn12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Cyclobutanol (2.43 ml) was initially charged at RT with stirring and cooled almost to 0° C. with an ice bath. Subsequently, the mixture was admixed with portions of sodium hydride (146 mg). The suspension formed was heated to 55° C. for 30 min and admixed with portions of 6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine hydrobromide (W2.001, 200 mg), suspended in cyclobutanol (5 ml). After stirring at 55° C. for 1.5 h, the mixture was left to stand at RT overnight and then admixed with water and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. 136 mg of the title compound were obtained in solid form. LC-MS rt: 0.82 min [M+1-1]+: 206.2 (met. a)
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.[H-].[Na+].[CH3:14]I>CN(C=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:14])=[C:4]([Cl:11])[N:3]=1
Reactant: CI
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1cnc2c(Cl)nc(Cl)nc21
Reaction time: 0.17 h

Procedure:
To a cold solution of 2,6-Dichloro-7H-purine (1 g, 5.29 mmol) in DMF (5 mL) was added 60% NaH (233 mg, 5.8 mmol) under N2. After stirring for 10 min, MeI (910 μL) was added, the reaction mixture was stirred for 30 min at this temperature and then overnight at room temperature, concentrated and co-evaporated with H2O to dryness. The residue was suspended in 2 mL cold water and filtered to the give crude mixture of 7A and 8A in about 1:1 ratio.
Reaction SMILES: COC(=O)C[S:5][C:6](=S)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:15][NH2:16]>C(O)C>[C:6]([NH:15][NH2:16])(=[S:5])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NN
Reactant: COC(=O)CSC(=S)c1ccccc1
Solvent: CCO
Product: NNC(=S)c1ccccc1
Reaction time: 2 h
Yield: 94 %

Procedure:
Add a solution of thiobenzoylsulfanylacetic acid methyl ester (1.9 g, 8.4 mmol) in ethanol (30 mL) to a solution of anhydrous hydrazine (1 mL) at room temperature under nitrogen and stir for 2 hours. Then add water (20 mL) and remove the solvent under reduced pressure. Dissolve the residue in ethyl acetate (300 mL), wash with water (200 mL) and brine (200 mL), and dry over magnesium sulfate. Remove the solvent under reduced pressure to provide thiobenzoic acid hydrazide (1.2 g, 94%).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.Cl.[CH3:15][N:16]([CH3:20])[CH2:17][CH2:18]Cl.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:15][N:16]([CH3:20])[CH2:17][CH2:18][NH:1][C:2]1[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: Nc1cc([N+](=O)[O-])cc2c1OCC2
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CN(C)CCNc1cc([N+](=O)[O-])cc2c1OCC2
Yield: 14.9 %

Procedure:
A solution of 7-amino-5-nitro-2,3-dihydrobenzofuran (D4) (2 g) in ethanol (60 ml) was treated with 2-dimethylaminoethyl chloride hydrochloride (3.36 g) and excess sodium carbonate (6 g), and heated at reflux for 4 days under argon. The solvent was evaporated under reduced pressure, and the residue partitioned between water and chloroform. The organic phase was dried (Na2SO4) and evaporated under reduced pressure to leave an oil which was chromatographed on silica, eluting with methanol and chloroform to give the title compound as a viscous red oil (416 mg, 15%)