Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[CH2:4][C:5]1[C:6](=[O:18])[O:7][C:8]2[C:13]([C:14]=1[CH3:15])=[CH:12][C:11]([Cl:16])=[C:10]([OH:17])[CH:9]=2.[I-].[N:25]1([C:35](N2C=C[N+](C)=C2)=[O:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[CH2:4][C:5]1[C:6](=[O:18])[O:7][C:8]2[C:13]([C:14]=1[CH3:15])=[CH:12][C:11]([Cl:16])=[C:10]([O:17][C:35]([N:25]1[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28][CH2:27][CH2:26]1)=[O:36])[CH:9]=2
Reactant: C[n+]1ccn(C(=O)N2CCCc3ccccc32)c1
Reactant: Cc1c(Cc2c(Cl)cccc2Cl)c(=O)oc2cc(O)c(Cl)cc12
Agent: [I-]
Product: Cc1c(Cc2c(Cl)cccc2Cl)c(=O)oc2cc(OC(=O)N3CCCc4ccccc43)c(Cl)cc12

Procedure:
The title compound was prepared from 3-(2,6-dichloro-benzyl)-6-chloro-7-hydroxy-4-methyl-2H-chromen-2-one and 3-(3,4-dihydro-2H-quinoline-1-carbonyl)-1-methyl-3H-imidazol-1-ium iodide. HPLC-MS m/z=530 (M+1), Rt: 6.09 min.
Reaction SMILES: [K].C([CH2:7][N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]([O:16]CC)=O)[CH2:9]1)(OCC)=O.Cl.CCCCCC(=O)CC>C1(C)C=CC=CC=1.CCCCCC.C(O)C>[N:8]12[CH2:9][CH:10]([C:14](=[O:16])[CH2:7]1)[CH2:11][CH2:12][CH2:13]2
Reactant: CCOC(=O)CN1CCCC(C(=O)OCC)C1
Agent: CCCCCC(=O)CC
Agent: Cl
Agent: [K]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCCCCC
Product: O=C1CN2CCCC1C2
Temperature: 120 °C
Reaction time: 1 h

Procedure:
A mixture of ethanol (9 ml) and toluene (10 ml) was added dropwise to a rapidly stirred suspension of potassium (6 g) in toluene (30 ml). at 120° C. After all the ethanol had been added the reaction mixture was stirred at 120° C. for 1 hr before adding a solution of 1-carboethoxymethyl-3-carboethoxy piperidine (15 g, 61.7 mmol) in toluene (40 ml) dropwise at 140° C. The reaction mixture was heated for 3 hr at 140° C. before adding concentrated hydrochloric acid (3×50 ml), and refluxing the aqueous phase for 16 hr. The solvent was removed in vacuo, water (100 ml) added and the solution neutralised with potassium carbonate. The solution was extracted with dichloromethane (3×150 ml, the combined extracts washed with saturated sodium chloride solution, dried (Na2SO4) and evaporated. The crude product was chromatographed through slicia-gel, eluting with dichloromethane/methanol (90:10) to give 1-azabicyclo[3:2:1]octan-6-one as a crystalline solid (1.1 g): mp. 83°-87° (hexane): m/e 125 (M+): δ(360 MHz, CDCl3) 1.30-2.40 (5H, m, 2×CH2, and CH): 3.12 (2H, s, CH2 --N); 2.60-3.60 (4H, m, 2×CH2 --N).
Reaction SMILES: [CH:1]([C:3]1[CH:17]=[CH:16][C:6]([O:7][C:8]([CH3:15])([CH2:13][CH3:14])[C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=1)=O.[CH2:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[CH:23][CH:22]=1)[CH3:19].[Na]>C(O)C>[CH2:18]([O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([CH:28]=[CH:1][C:3]2[CH:17]=[CH:16][C:6]([O:7][C:8]([CH3:15])([CH2:13][CH3:14])[C:9]([O:11][CH3:12])=[O:10])=[CH:5][CH:4]=2)=[O:29])=[CH:23][CH:22]=1)[CH3:19]
Reactant: CCC(C)(Oc1ccc(C=O)cc1)C(=O)OC
Reactant: CCOc1ccc(C(C)=O)cc1
Agent: [Na]
Solvent: CCO
Product: CCOc1ccc(C(=O)C=Cc2ccc(OC(C)(CC)C(=O)OC)cc2)cc1

Procedure:
Following the procedure in Example 1 using 7.1 parts of methyl 2-(4-formylphenoxy)-2-methyl-2-ethylacetate and 4.9 parts of p-ethoxyacetophenone in 10 parts by volume of ethanol containing 0.1 part of sodium metal provides methyl 2-[4-(2-p-ethoxybenzoylethenyl)phenoxy]-2-methyl-2 ethylacetate. This compound has the following structural formula. ##SPC11##
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]([C:8]2[N:9]=[C:10]([C:24]([F:27])([F:26])[F:25])[N:11]3[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][C:12]=23)=[O:7])[CH2:3][CH2:2]1.[ClH:28]>O1CCOCC1>[ClH:28].[CH:1]1([CH2:4][NH:5][C:6]([C:8]2[N:9]=[C:10]([C:24]([F:25])([F:26])[F:27])[N:11]3[CH2:16][CH2:15][NH:14][CH2:13][C:12]=23)=[O:7])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)NCC3CC3)c2C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(NCC1CC1)c1nc(C(F)(F)F)n2c1CNCC2
Reaction time: 12 h

Procedure:
Crude tert-butyl 1-(cyclopropylmethylcarbamoyl)-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo[1,5-a]pyrazine-7-carboxylate 24a (300 mg, 0.77 mmol) was dissolved in 20 mL of a 2 M solution of hydrogen chloride in 1,4-dioxane. After stirring for 12 hours, the reaction mixture was concentrated under reduced pressure to obtain crude N-(cyclopropylmethyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro imidazo[1,5-a]pyrazine-1-carboxamide hydrochloride 24b (250 mg) as a light yellow oil. The product was used directly in the next reaction without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][C:7]=1[F:8].[Si:11]([O:18][CH2:19][C:20](N(OC)C)=[O:21])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]>C1COCC1.CCCCCC>[Si:11]([O:18][CH2:19][C:20]([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=1)=[O:21])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: CON(C)C(=O)CO[Si](C)(C)C(C)(C)C
Reactant: Fc1ccc([Mg]Br)cc1Cl
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCC(=O)c1ccc(F)c(Cl)c1
Reaction time: 2 h
Yield: 87.9 %

Procedure:
0.5M (3-Chloro-4-fluorophenyl)magnesium bromide in THF (27.4 mL, 13.7 mmol) was added dropwise to 2-(tert-butyldimethylsilyloxy)-N-methoxy-N-methylacetamide (2.00 g, 8.57 mmol) in THF (20 mL) cooled in ice. The mixture became turbid after about half of the Grignard reagent was added. This was stirred in an ice bath for 2 hours, quenched with saturated aqueous NH4Cl, and concentrated to remove the THF. The aqueous residue was extracted with 2 portions DCM. The combined DCM layers were dried over MgSO4, filtered, and evaporated to yield a crude product (3.62 g) as an oil. This was taken up in hexane and purified on a silica gel plug with hexane until product started eluting, then 15:1 hexane/EtOAc. Product-containing fractions yielded 2-(tert-butyldimethylsilyloxy)-1-(3-chloro-4-fluorophenyl)ethanone (2.28 g, 7.53 mmol, 87.9% yield) as an oil.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=3)[CH:10]=[N:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[S:28][CH2:29][CH2:30][C:31](O)=[O:32]>>[CH:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][C:19]=1[S:28][CH2:29][CH2:30][C:31]([NH:17][C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[N:9][N:8]2[CH2:7][CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:12][CH:13]=1)=[O:32]
Reactant: Nc1ccc2cnn(CCN3CCCC3)c2c1
Reactant: O=C(O)CCSc1ccc2ccccc2c1
Product: O=C(CCSc1ccc2ccccc2c1)Nc1ccc2cnn(CCN3CCCC3)c2c1

Procedure:
According to the procedure for Example 49, 1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-6-ylamine and 3-(naphthalen-2-ylsulfanyl)-propionic acid were processed to provide the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.84 (m, 2 H), 1.99 (m, 2 H), 2.79 (t, J=7.02 Hz, 2 H), 3.04 (m, 2 H), 3.40 (t, J=7.02 Hz, 2 H), 3.53 (m, 2 H), 3.71 (q, J=6.10 Hz, 2 H), 4.68 (t, J=6.26 Hz, 2 H), 7.06 (m, 1 H), 7.50 (m, 3 H), 7.70 (m, 1 H), 7.88 (m, 4 H), 8.09 (s, 1 H), 8.30 (s, 1 H), 9.62 (br s, N H); MS (DCI/NH3) m/z 445 (M+H)+.
Reaction SMILES: Cl.[F:2][C:3]([F:34])([F:33])[CH2:4][C:5]1[S:32][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][CH:14]3[CH2:19][CH2:18][N:17]([CH2:20][C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[NH:26][C:25]([C:30]#[N:31])=[CH:24]5)[CH2:16][CH2:15]3)[C:7]=2[CH:6]=1.Br[CH2:36][C:37]([NH2:39])=[O:38].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:30]([C:25]1[N:26]([CH2:36][C:37]([NH2:39])=[O:38])[C:27]2[C:23]([CH:24]=1)=[CH:22][C:21]([CH2:20][N:17]1[CH2:16][CH2:15][CH:14]([NH:13][C:12]3[C:7]4[CH:6]=[C:5]([CH2:4][C:3]([F:33])([F:2])[F:34])[S:32][C:8]=4[N:9]=[CH:10][N:11]=3)[CH2:19][CH2:18]1)=[CH:29][CH:28]=2)#[N:31]
Reactant: N#Cc1cc2cc(CN3CCC(Nc4ncnc5sc(CC(F)(F)F)cc45)CC3)ccc2[nH]1
Reactant: NC(=O)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: N#Cc1cc2cc(CN3CCC(Nc4ncnc5sc(CC(F)(F)F)cc45)CC3)ccc2n1CC(N)=O
Yield: 40.3 %

Procedure:
760 mg of 5-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H-indole-2-carbonitrile hydrochloride (1.5 mmol) and 207 mg of bromoacetamide (1.5 mmol) were dissolved in 3.6 mL of dry DMF. 1.96 g of cesium carbonate (6 mmol) was added and reaction mixture was stirred for 4 hs. Then it was quenched with 50 mL of water and extracted with DCM-MeOH 10:1. Combined organic extracts were evaporated with silica gel and loaded on column. The product was eluted with DCM-MeOH 10:1 mixture. After evaporation of product containing fractions it was recrystallized from MeOH to produce 319 mg of 2-(2-cyano-5-((4-((6-(2,2,2-trifluoroethyl)thieno[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)methyl)-1H-indol-1-yl)acetamide, which was converted to hydrochloride salt by dissolving in 5 mL of MeOH, adding of 1 eq of 1M HCl in water. Hydrochloride salt can be recrystallized further from MeOH. Monohydrochloride salt exists as a mixture of rotomers in approximate ratio 10:1, NMR is described for the major one: 1H NMR (600 MHz, MeOD-d4): 8.44 (s, 1H), 7.91 (s, 1H), 7.57 (m, 2H), 7.41 (s, 1H), 5.10 (s, 2H), 4.53 (m, 1H), 4.47 (s, 1H), 3.89 (q, 2H, J=10.3 Hz), 3.62 (m, 2H), 3.24 (m, 2H), 2.35 (m, 2H), 1.93 (m, 2H). 13C NMR (150 MHz, MeOD-d4): δC 171.07, 157.66, 153.62, 140.17, 130.77, 129.55, 127.95, 127.10, 125.64, 123.46, 121.90, 118.31, 114.76, 113.69, 113.52, 112.60, 61.96, 52.67, 49.60, 47.98, 47.40, 35.52 (q, J=33 Hz), 29.96. ESI MS [MH+]: 528.1783.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].[OH-].[K+].[C:14](=S)=[S:15]>C(O)C>[SH:15][C:14]1[O:11][C:3]2[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=[N+]([O-])c1ccc2nc(S)oc2c1

Procedure:
A 500 mg portion of 2-amino-5-nitrophenol dissolved in 35 ml of ethanol was mixed with 180 mg of potassium hydroxide. After 10 minutes of reaction, the resulting solution was mixed with 35 ml of carbon disulfide and refluxed under heating for 48 hours. The reaction mixture was concentrated under a reduced pressure, and the resulting residue was dissolved in 300 ml of ethyl acetate and washed with an aqueous acidic solution of hydrochloric acid (pH 4) and water in that order. The resulting ethyl acetate layers were combined, dehydrated with sodium sulfate and then concentrated under a reduced pressure. Thereafter, the resulting residue was purified by a silica gel column chromatography (chloroform) to obtain 629 mg of 2-mercapto-6-nitrobenzoxazole.
Reaction SMILES: [C:1]([O:5][C:6](=[O:52])[C@@H:7]([NH:31][C:32](=[O:51])[NH:33][C@@H:34]([CH2:42][CH2:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:30])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20](ON1C(=O)CCC1=O)=[O:21])([CH3:4])([CH3:3])[CH3:2].[NH2:53][C@@H:54]([CH2:58][CH2:59][CH2:60][CH2:61][N:62]([CH2:70][C:71]([O:73][C:74]([CH3:77])([CH3:76])[CH3:75])=[O:72])[CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][N:65]=1)[C:55]([OH:57])=[O:56].CCN(C(C)C)C(C)C>CN(C=O)C>[C:74]([O:73][C:71](=[O:72])[CH2:70][N:62]([CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][N:65]=1)[CH2:61][CH2:60][CH2:59][CH2:58][C@@H:54]([C:55]([OH:57])=[O:56])[NH:53][C:20](=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:13](=[O:30])[NH:12][CH2:11][CH2:10][CH2:9][CH2:8][C@@H:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:52])[NH:31][C:32](=[O:51])[NH:33][C@H:34]([C:35]([O:37][C:38]([CH3:39])([CH3:40])[CH3:41])=[O:36])[CH2:42][CH2:43][C:44](=[O:45])[O:46][C:47]([CH3:49])([CH3:50])[CH3:48])([CH3:77])([CH3:76])[CH3:75]
Reactant: CC(C)(C)OC(=O)CN(CCCC[C@H](N)C(=O)O)Cc1ccccn1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCNC(=O)CCCCCCC(=O)ON1C(=O)CCC1=O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)N[C@@H](CCCCNC(=O)CCCCCCC(=O)N[C@@H](CCCCN(CC(=O)OC(C)(C)C)Cc1ccccn1)C(=O)O)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Yield: 32.5 %

Procedure:
A solution of (S)-di-tert-butyl 2-(3-((S)-1-tert-butoxy-6-(8-(2,5-dioxopyrrolidin-1-yloxy)-8-oxooctanamido)-1-oxohexan-2-yl)ureido)pentanedioate (0.528 g, 0.712 mmol), (S)-2-amino-6-((2-tert-butoxy-2-oxoethyl)(pyridin-2-ylmethyl)amino)hexanoic acid (0.25 g, 0.712 mmol) and DIPEA (1.0 mL) in DMF (5.0 mL) was stirred at room temperature for overnight. The solvent was evaporated to give a residue, which was purified by Biotage eluting with DCM/MeOH to give (7S,11S,26S)-26-(4-((2-tert-butoxy-2-oxoethyl)(pyridin-2-ylmethyl)amino)butyl)-7,11-bis(tert-butoxycarbonyl)-2,2-dimethyl-4,9,17,24-tetraoxo-3-oxa-8,10,16,25-tetraazaheptacosan-27-oic acid (0.226 g, 32%). MS (ESI), 489.5 (M/2+H)+.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:19]4[CH2:20][C:21]5[S:22][CH:23]=[CH:24][C:25]=5[C:18]=4[N:17](COCC[Si](C)(C)C)[N:16]=3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.Cl>CO>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[C:19]4[CH2:20][C:21]5[S:22][CH:23]=[CH:24][C:25]=5[C:18]=4[NH:17][N:16]=3)=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: C[Si](C)(C)CCOCn1nc(-c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)c2c1-c1ccsc1C2
Agent: Cl
Solvent: CO
Product: FC(F)(F)c1ccc(-c2ccc(-c3n[nH]c4c3Cc3sccc3-4)cc2)cc1
Temperature: 100 °C
Yield: 37 %

Procedure:
6-(4′-Trifluoromethyl-biphenyl-4-yl)-4-(2-trimethylsilanyl-ethoxymeth yl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.14 g, 0.27 mmol) was dissolved in MeOH and treated with concentrated HCl (0.1 mL, 27 mmol). The reaction mixture was heated at 100° C. for 4 hr. The solution was cooled to room temperature and the resultant precipitate was filtered, washed with MeOH and concentrated under reduced pressure to provide the corresponding 6-(4′-Trifluoromethyl-biphenyl-4-yl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.04 g, 0.1 mmol) as brown solid in 38% yield.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[CH:14]=[CH:13][N:12]=[C:11]2[CH3:15])[N:6]=[N:7][CH:8]=1.[OH-].[Na+]>O1CCOCC1>[CH3:15][C:11]1[N:10]([CH2:9][C:5]2[NH:6][N:7]=[CH:8][C:3](=[O:2])[CH:4]=2)[CH:14]=[CH:13][N:12]=1
Reactant: COc1cnnc(Cn2ccnc2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1nccn1Cc1cc(=O)cn[nH]1
Temperature: 25 °C
Yield: 102.6 %

Procedure:
5-Methoxy-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine (4.25 g, 21 mmol) was dissolved in dioxane (65 ml) and 2N NaOH (42 ml) was added. The mixture was refluxed for 7 hours, cooled to room temperature and quenched with 2N HCl (65 ml). The pH was adjusted to 8 with saturated solution of NaHCO3. The solvent was removed in vacuo and the residue was taken in MeOH (100 ml). After filtration, the solvent was removed in vacuo and diluted with MeOH (50 ml). Silicagel (10 g) was added and the solvent was evaporated. The residue was chromatographed over silica gel (CH2Cl2—MeOH 9:1, 4:1, 2:1) to provide 6-(2-methyl-imidazol-1-yl-methyl)-1H-pyridazin-4-one (4.1 g, 100%) as a pale yellow solid, MS: m/e=191.3 (M+H+).
Reaction SMILES: Cl[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([Cl:11])[S:10][C:5]=2[S:4](=[O:13])(=[O:12])[N:3]=1.[NH2:14][C@H:15]([CH2:17][OH:18])[CH3:16]>O>[Cl:11][C:9]1[S:10][C:5]2[S:4](=[O:13])(=[O:12])[N:3]=[C:2]([NH:14][C@@H:15]([CH3:16])[CH2:17][OH:18])[NH:7][C:6]=2[CH:8]=1
Reactant: C[C@H](N)CO
Reactant: O=S1(=O)N=C(Cl)Nc2cc(Cl)sc21
Solvent: O
Product: C[C@@H](CO)NC1=NS(=O)(=O)c2sc(Cl)cc2N1

Procedure:
The title compound was prepared from 3,6dichloro-4H-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxide and L-alaninol by a procedure analogous to the procedure described in example 1Bb; mp 204°-206° C. (water), 1H-NMR (DMSO-d6): δ 1.11 (d, 3H), 3.4 (d, 2H), 3.78 (m, 1H), 4.95 (br. s, 1H), 7.05 (br. s, 1H), 7.09 (s, 1H), 10.8 (br. s, 1H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:9]([C:11]([OH:13])=[O:12])=[CH:8][O:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.O.[C:15]1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[O:1]=[C:2]1[C:10]2[C:9]([C:11]([O:13][CH3:15])=[O:12])=[CH:8][O:7][C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)c1coc2c1C(=O)CCC2
Solvent: CO
Solvent: O
Product: COC(=O)c1coc2c1C(=O)CCC2
Temperature: 25 °C
Yield: 848.6 %

Procedure:
To a solution of 2.11 g of 4-oxo-4,5,6,7-tetrahydrobenzo[b]furan-3-carboxylic acid in 100 ml of methanol is added 202 mg of p-toluenesulfonic acid hydrate and the mixture heated at reflux for 24 hours. The reaction mixture is cooled to room temperature and the methanol concentrated in vacuo to a residue. The residue is dissolved in 100 ml of ethyl acetate and washed with 30 ml of saturated sodium bicarbonate and 30 ml of brine. The organic layer is dried with Na2SO4, filtered and the filtrate concentrated in vacuo to a residue which is crystallized from ethyl acetate-hexane to give 1.75 g of the desired product as a white crystalline solid, m.p. 100°-102° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].Cl[C:13](OC(Cl)(Cl)Cl)=[O:14]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[N:4]=[C:13]=[O:14]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc([N+](=O)[O-])cc1F
Solvent: Cc1ccccc1
Product: O=C=Nc1ccc([N+](=O)[O-])cc1F
Reaction time: 18 h
Yield: 199.5 %

Procedure:
A solution of 9.4 grams (0.06 mole) of 2-fluoro-4-nitroaniline in 200 mL of toluene was stirred, and 5.9 grams (0.03 mole) of trichloromethyl chloroformate was added dropwise. Upon completion of addition, the reaction mixture was warmed to reflux, where it stirred for about 18 hours. After this time the reaction mixture was cooled and concentrated under reduced pressure, yielding about 10.9 grams of 2-fluoro-4-nitrophenyl isocyanate. The reaction product was used immediately in the next step.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:7][N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[S:5][CH:6]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.CC([O-])=O.[K+].[NH2:37][C:38]1C2C=C(Br)SC=2[C:41]([C:48]([NH2:50])=[O:49])=[CH:40][N:39]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.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>[NH2:37][C:38]1[C:2]2[CH:3]=[C:4]([CH2:7][N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[S:5][C:6]=2[C:41]([C:48]([NH2:50])=[O:49])=[CH:40][N:39]=1
Reactant: Brc1csc(CN2CCOCC2)c1
Reactant: NC(=O)c1cnc(N)c2cc(Br)sc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1cnc(N)c2cc(CN3CCOCC3)sc12
Temperature: 120 °C
Yield: 83.3 %

Procedure:
To a mixture of 4-(4-bromo-thiophen-2-ylmethyl)-morpholine 64 (173 mg, 0.66 mmol), bis(pinacolato)diboron (352 mg, 1.39 mmol.), Pd(PPh3)4 (76 mg, 0.07 mmol) and KOAc (194 mg, 2.0 mmol) was added degassed DMF (5 mL). The reaction mixture was heated at 120° C. under N2 for 2 h and then cooled down to room temperature. A solution of 4-amino-2-bromo-thieno[3,2-c]pyridine-7-carboxylic acid amide 17 (150 mg, 0.55 mmol), Pd(PPh3)4 (69 mg, 0.06 mmol) and Na2CO3 (1.0 mL of a 2M aqueous solution, 3.3 mmol) in DMF (2.0 mL) was added. The resulting mixture was heated at 90 0 C for 1.5 h. The solvent was then removed via vacuum, the residue was dissolved in DMSO (4.0 mL) and the mixture purified by reverse phase preparative HPLC to give 66 (134 mg). 1H NMR (400 MHz, CDCl3) δ, 3.12 (m, 2H), 3.32 (m, 2H), 3.82 (m, 2H), 3.95 (m, 2H), 4.62 (s, 2H), 7.75 (s, 1H), 7.81 (br, 1H), 8.09 (s, 1H), 8.34 (s, 1H), 8.38 (br, 1H), 8.56 (s, 1H), 9.19 (br, 1H), 11.73 (br, 1H). MS (EI) m/z (M+H+) 375.
Reaction SMILES: C(O[C:6]([NH:8][CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[N:30]=[CH:29][C:28]4[N:27]=[CH:26][C:25](=[O:31])[N:24]([CH:32]5[CH2:36][CH2:35][CH2:34][CH2:33]5)[C:23]=4[N:22]=3)=[CH:16][CH:15]=2)[CH2:10]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:32]1([N:24]2[C:23]3[N:22]=[C:21]([NH:20][C:17]4[CH:18]=[CH:19][C:14]([N:11]5[CH2:10][CH2:9][N:8]([CH3:6])[CH2:13][CH2:12]5)=[CH:15][CH:16]=4)[N:30]=[CH:29][C:28]=3[N:27]=[CH:26][C:25]2=[O:31])[CH2:33][CH2:34][CH2:35][CH2:36]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(Nc3ncc4ncc(=O)n(C5CCCC5)c4n3)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCN(c2ccc(Nc3ncc4ncc(=O)n(C5CCCC5)c4n3)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.9 %

Procedure:
A solution of 0.14 g (0.28 mmol) of 2-[[4-[3-(tert-butoxycarbonyl amino)pyrrolidin-1-yl]phenyl]amino]-8-cyclopentyl-8H-pteridin-7-one (from example 23) in 10 mL CH2Cl2 is treated with 1 mL of trifluoroacetic acid, and the resulting mixture is stirred at room temperature for 3 hours. After removal of the solvent, the residue is triturated with aqueous ammonia to give 0.11 g (100%) of the title compound (Compound 17): mp (MeOH(aq)) 197–200° C.
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:38]=[CH:37][C:6]([CH2:7][NH:8][C:9]2[N:14]=[CH:13][C:12]([C:15]([C:18]3[C:26]4[C:21](=[N:22][CH:23]=[CH:24][CH:25]=4)[N:20]([Si](C(C)C)(C(C)C)C(C)C)[CH:19]=3)(O)[CH3:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(#N)C>[NH:20]1[C:21]2=[N:22][CH:23]=[CH:24][CH:25]=[C:26]2[C:18]([C:15]([C:12]2[CH:11]=[CH:10][C:9]([NH:8][CH2:7][C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:40])[F:39])=[CH:38][CH:37]=3)=[N:14][CH:13]=2)=[CH2:16])=[CH:19]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(C)(O)c2ccc(NCc3ccc(C(F)(F)F)cc3)nc2)c2cccnc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: C=C(c1ccc(NCc2ccc(C(F)(F)F)cc2)nc1)c1c[nH]c2ncccc12
Yield: 49.6 %

Procedure:
1-[6-(4-Trifluoromethyl-benzylamino)-pyridin-3-yl]-1-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-ethanol (622, 125.0 mg, 0.22 mmol) was dissolved in acetonitrile (11.7 mL) and trifluoroacetic acid (0.175 mL, 2.3 mmol) and triethylsilane (0.292 mL, 1.8 mmol) were added. The reaction was heated to reflux overnight. The reaction was concentrated, then washed with ethyl acetate and saturated sodium bicarbonate. The organic portions were dried with anhydrous sodium sulfate, filtered and the filtrate was adsorbed onto silica. The mixture was purified by silica gel chromatography (0-60% ethyl acetate:hexanes) to provide the desired compound (623, 43 mg, 50%), consistent with the compound structure by 1H-NMR.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[O:24])=[CH:19][CH:18]=1>>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([C:23]([C:20]2[CH:21]=[CH:22][C:17]([O:16][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][CH:3]=3)=[CH:18][CH:19]=2)=[O:24])=[CH:26][CH:27]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: O=C(c1ccc(O)cc1)c1ccc(Cl)cc1
Product: COc1cc2nccc(Oc3ccc(C(=O)c4ccc(Cl)cc4)cc3)c2cc1OC
Temperature: 180 °C
Reaction time: 0.33 h
Yield: 12.4 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (112 mg) and commercially available 4-chlorophenyl 4-hydroxyphenyl ketone (349 mg) were mixed and stirred at 180° C. for 20 minutes. The reaction mixture was purified by thin layer chromatography on silica gel eluting with chloroform/ethyl acetate (5/1) to obtain 26 mg of the title compound (yield: 12%).
Reaction SMILES: [SiH4].[OH:2][C:3]1[CH:4]=[CH:5][C:6]([N+:11]([O-:13])=[O:12])=[C:7]([CH:10]=1)[CH2:8][OH:9].[OH-].[Na+].[C:16](Br)(=O)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH2:26]>[Br-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1>[N+:11]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH:17]=[CH2:16])=[CH:10][C:7]=1[CH2:8][OH:9])([O-:13])=[O:12]
Reactant: C=CCCCCCCCCC(=O)Br
Reactant: O=[N+]([O-])c1ccc(O)cc1CO
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: [Br-]
Agent: [Na+]
Product: C=CCCCCCCCCCOc1ccc([N+](=O)[O-])c(CO)c1

Procedure:
Synthesis of a o-nitrobenzyl PEG-silane of the above formula wherein R3 is H and m=11 was achieved in three steps. First, 5-hydroxy-2-nitrobenzyl alcohol I in 0.3 NaOH was refluxed for four days with undecylenic bromide II (dissolved in CH2Cl2) in the presence of benzyltributylammonium bromide to form 2-nitro-5-(10-undecenyloxy)phenylmethanol III according to the following reaction scheme: ##STR6##