Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]1[C:8]([C:9]2[CH:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([S:22](=[O:25])(=[O:24])[NH2:23])=[CH:18][CH:17]=3)[N:10]=2)=[CH:7][N:6]=[CH:5]1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[Br:1][C:14]1[C:9]([C:8]2[N:4]([CH3:3])[CH:5]=[N:6][CH:7]=2)=[N:10][C:11]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([S:22](=[O:25])(=[O:24])[NH2:23])=[CH:20][CH:21]=2)=[N:12][CH:13]=1
Reactant: BrBr
Reactant: Cn1cncc1-c1ccnc(Nc2ccc(S(N)(=O)=O)cc2)n1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cn1cncc1-c1nc(Nc2ccc(S(N)(=O)=O)cc2)ncc1Br
Reaction time: 1 h
Yield: 52.9 %

Procedure:
Bromine (75.5 mg, 0.47 mmol) was added to a solution of 4-(1-methylimidazol-5-yl)-2-(4-sulphamoylanilino)pyrimidine (Example 15; 0.14 g, 0.42 mmol) and sodium acetate (41.7 mg, 0.51 mmol) in acetic acid (4 ml) and the mixture stirred for 1 hour. The volatiles were evaporated and the residue partitioned between EtOAc and saturated aqueous potassium hydrogen carbonate solution. The organic phase was separated and dried. The residue was pre-absorbed on to silica gel and purified by column chromatography on silica gel eluting with DCM/2% methanolic ammonia (9:1) to give the title compound (91 mg, 52%). NMR 10.14 (s, 1H), 8.75 (s, 1H), 7.90-7.69 (m, 4H), 7.17 (s, 2H), 3.84 (s, 3H); m/z 409.
Reaction SMILES: [C:1]([OH:26])(=O)[CH2:2][CH2:3][C@H:4]([C@@H:6]1[C@:23]2([CH3:24])[C@H:9]([C@H:10]3[C@H:20]([CH2:21][CH2:22]2)[C@:18]2([CH3:19])[C@@H:13]([CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:12][CH2:11]3)[CH2:8][CH2:7]1)[CH3:5].C(Cl)(=O)C([Cl:30])=O>C(Cl)Cl>[C:1]([Cl:30])(=[O:26])[CH2:2][CH2:3][C@H:4]([C@@H:6]1[C@:23]2([CH3:24])[C@H:9]([C@H:10]3[C@H:20]([CH2:21][CH2:22]2)[C@:18]2([CH3:19])[C@@H:13]([CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:12][CH2:11]3)[CH2:8][CH2:7]1)[CH3:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4CCCC[C@]4(C)[C@H]3CC[C@]12C
Solvent: ClCCl
Product: C[C@H](CCC(=O)Cl)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4CCCC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 60 °C

Procedure:
A mixture of 0.5 g (1.39 mmol) of 5β-cholanic acid (Aldrich), 0.4 mL (4.6 mmol) of oxalyl chloride, and 10 mL of methylene chloride was heated in a sealed reaction vessel at 60° C. for 15 minutes. The volatiles were distilled off to give 5β-cholanoyl chloride as a colorless solid in quantitative yield. m.p. 104-106° C. 1H NMR (CDCl3, 500 MHz): δ 2.94 (m, 1H), 2.83 (m, 1H), 2.00-0.67 (m, 37H).
Reaction SMILES: [CH:1]1([CH2:8][CH2:9][C:10]#[N:11])[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[O:7].ClC1C=CC=C(C(OO)=[O:20])C=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([OH:29])=[O:28]>CCCCCC>[C:10]([CH2:9][CH2:8][CH:1]1[O:20][C:2](=[O:7])[CH2:3][CH2:4][CH2:5][CH2:6]1)#[N:11].[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([OH:29])=[O:28]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: N#CCCC1CCCCC1=O
Agent: O=C(O)c1cccc(Cl)c1
Solvent: CCCCCC
Product: N#CCCC1CCCCC(=O)O1
Temperature: 55 °C

Procedure:
A reactor is loaded with 151 g of 3-(2-cyclohexanonyl)propionitrile in 500 ml of n-hexane and 260 g of m-chloroperbenzoic acid (70% titer) dissolved at 50° C. in 2000 ml of n-hexane in 30 minutes. The solution is heated to 55° C. for 15 hours. Cooling separates from the solution, in crystalline form, part of the m-chlorobenzoic acid, which is scarcely soluble in the system, together with a heavy liquid phase which is formed by 7-cyanoethyl-2-oxepanone and by m-chlorobenzoic acid. 71.5 g of 7-cyanoethyl-2-oxepanone, impure with m-chlorobenzoic acid, are recovered from the lower phase. 24 g of 7-cyanoethyl-2-oxepanone are recovered from the upper phase by concentration and by several crystallizations. Conversion with respect to the initial ketone is 85%. Yield on the converted substance is 57%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3=[N:13][C:14]4[CH2:15][CH2:16][CH2:17][C:18](=[CH2:21])[C:19]=4[CH:20]=[C:11]3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.O.[OH:23]I(C1C=CC=CC=1)OS(C1C=CC(C)=CC=1)(=O)=O.FC1C=CC(N2C3=NC4CCCC(=C)C=4C=C3C(=O)N2)=CC=1>CO.OI(C1C=CC=CC=1)OS(C1C=CC(C)=CC=1)(=O)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]3[N:13]=[C:14]4[CH2:15][CH2:16][CH2:17][C:18](=[O:23])[CH2:21][C:19]4=[CH:20][C:11]=3[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OI(O)c2ccccc2)cc1
Reactant: C=C1CCCc2nc3c(cnn3-c3ccc(F)cc3)cc21
Agent: C=C1CCCc2nc3c(cc21)c(=O)[nH]n3-c1ccc(F)cc1
Solvent: CO
Solvent: O
Product: O=C1CCCc2nc3c(cnn3-c3ccc(F)cc3)cc2C1
Temperature: 19 °C
Reaction time: 1 h
Yield: 78.8 %

Procedure:
A flask was charged with 1-(4-fluorophenyl)-5-methylene-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-b]quinoline (113, R1=4-Fluorophenyl) (44.0 g, 158 mmol), MeOH (1050 mL) and water (105 mL). [Hydroxy(tosyloxy)iodo]benzene (61.8 g, 158 mmol) was dissolved in MeOH (160 mL) then the solution was added dropwise to the stirred 1-(4-fluorophenyl)-5-methylene-5,6,7,8-tetrahydro-1H-pyrazolo[3,4-b]quinolone slurry. The internal temperature of the reaction mixture was maintained at about 18 to 20° C. during the addition. The addition was carried out over about 1 h. After about 90 min [hydroxy(tosyloxy)iodo]benzene (3.09 g, 7.88 mmol) was added and the mixture was stirred for about 1 h. A third portion of [hydroxy(tosyloxy)iodo]benzene (2.5 g, 6.37 mmol) was added then after about 15 min the reaction mixture was concentrated under reduced pressure to remove about 1 L solvent (˜70 torr, bath temp ˜40° C.). Water (1.5 L) was added to the mixture and the resulting slurry was stirred for about 4 h at rt. The solids were collected by filtration then the pad was washed with about 150 mL water. The material was air dried then dissolved in DCM (500 mL) then washed with a mixture of water (100 mL) with sat. aq. NaHCO3 (100 mL). The organic solution was dried over MgSO4, filtered and the filtrate concentrated to dryness under reduced pressure. The material was treated with DCM (100 mL) then the slurry was poured onto a filter funnel containing 500 gram silica gel pre-gelled with DCM. The pad was washed with DCM (500 mL) then 9:1 DCM/EtOAc (2 L). Filtrate containing desired product was concentrated under reduced pressure then the material was treated with DCM (50 mL) and heptane (250 mL). The solids were collected by filtration and washed with heptane (100 mL). The material was dried under vacuum at about 70° C. to yield 1-(4-fluorophenyl)-5,7,8,9-tetrahydrocyclohepta[b]pyrazolo[4,3-e]pyridin-6(1H)-one (114, R1=4-Fluorophenyl) (36.78 g, 79%). LC/MS, method 3, Rt=2.31 min, MS m/z 296 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.36 (s, 1H), 8.34-8.28 (m, 2H), 8.16 (s, 1H), 7.46-7.38 (m, 2H), 3.92 (s, 2H), 3.36-3.28 (m, 2H), 2.57 (t, J=6.9 Hz, 2H), 2.05-1.94 (m, 2H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH:7]2[C:13]3=[CH:14][CH:15]=[CH:16][N:12]3[CH2:11][C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=3[O:8]2)[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[F:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30]Cl>>[F:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30][N:1]1[CH2:2][CH2:3][CH:4]([CH:7]2[C:13]3=[CH:14][CH:15]=[CH:16][N:12]3[CH2:11][C:10]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=3[O:8]2)[CH2:5][CH2:6]1
Reactant: c1ccc2c(c1)Cn1cccc1C(C1CCNCC1)O2
Reactant: Fc1ccccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1ccccc1CN1CCC(C2Oc3ccccc3Cn3cccc32)CC1
Temperature: 85 °C
Reaction time: 1.5 h

Procedure:
To a solution of 11-(piperidin-4-yl)-5H,11H-pyrrolo[2,1-c][1,4]benzoxazepine (5.0 g; 0.010 mole in 75 ml DMF) and 10 g milled K2CO3 was added 2-fluorobenzyl chloride (3.18 g; 0.022 mole in 15 ml DMF). This was stirred at 85° C. for 1.5 hours.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[N+:23]([C:26]1[CH:27]=[C:28]([N:35]=[C:36]=[O:37])[CH:29]=[C:30]([N+:32]([O-:34])=[O:33])[CH:31]=1)([O-:25])=[O:24]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:36]([NH:35][C:28]2[CH:27]=[C:26]([N+:23]([O-:25])=[O:24])[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[CH:29]=2)=[O:37])=[CH:20][CH:21]=1
Reactant: O=C=Nc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4cc([N+](=O)[O-])cc([N+](=O)[O-])c4)cc3)c2cc1OC
Yield: 57.5 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (54 mg) was dissolved in toluene (5 ml) with heat, 3,5-dinitrophenyl isocyanate (81 mg) was added, and the admixture was refluxed with heat for 20 minutes. The reaction solution was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 53 mg of the title compound (yield: 57%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][C:3]=1[C:9]([O:11]C)=O.[NH2:13][C:14]1[NH:18][N:17]=[C:16]([CH3:19])[CH:15]=1>C(O)CCC>[Cl:8][C:6]1[N:5]=[CH:4][C:3]2[C:9](=[O:11])[N:18]3[N:17]=[C:16]([CH3:19])[CH:15]=[C:14]3[NH:13][C:2]=2[CH:7]=1
Reactant: Cc1cc(N)[nH]n1
Reactant: COC(=O)c1cnc(Cl)cc1Cl
Solvent: CCCCO
Product: Cc1cc2[nH]c3cc(Cl)ncc3c(=O)n2n1

Procedure:
205 g. of 4,6-dichloropyridine-3-carboxylic acid, methyl ester and 194 g. of 5-amino-3-methylpyrazole are refluxed together in 500 ml. of butyl alcohol with stirring for 24 hours. After this time, 6-chloro-2-methylpyrazolo[1,5-a]pyrido[4,3-d]pyrimidin-9(4H)-one is filtered off, washed with water and recrystallized from dimethylformamide, yield: 195 g. (83%); m.p. >300°.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.B([O-])([O-])O[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][CH3:44])=[C:37]([O:45][CH2:46][CH3:47])[CH:36]=1.C(=O)([O-])[O-].[K+].[K+].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.C1(C)C=CC=CC=1>[CH2:46]([O:45][C:37]1[CH:36]=[C:35]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:26][CH2:27][O:28][CH2:29][CH2:30]5)=[CH:21][CH:22]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)[CH:40]=[CH:39][C:38]=1[O:41][CH2:42][CH2:43][CH3:44])[CH3:47]
Reactant: CCCOc1ccc(OB([O-])[O-])cc1OCC
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.8 %

Procedure:
A mixture of 7-bromo-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (0.3 g), 3-ethoxy-4-propoxyphenyl borate (0.16 g), 1M potassium carbonate solution (1.3 ml), ethanol (1.3 ml) and toluene (25 ml) was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (0.03 g), and the mixture was refluxed under argon atmosphere for 6 hours and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried with anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified with silica gel column chromatography (ethyl acetate/methanol/triethylamine) to give crude crystals, which were recrystallized from ethanol to give 7-(3-ethoxy-4-propoxyphenyl)-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 125) (0.16 g) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[N:19]=[C:18]([NH:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[C:17]([OH:27])=[CH:16][N:15]=2)=[N:6]1.Br[CH2:33][CH:34]([OH:37])[CH2:35][OH:36].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[N:19]=[C:18]([NH:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[C:17]([O:27][CH2:33][CH:34]([OH:37])[CH2:35][OH:36])=[CH:16][N:15]=2)=[N:6]1
Reactant: Oc1cnc(-c2nn(Cc3ccccc3F)c3ccccc23)nc1Nc1ccncc1
Reactant: OCC(O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCC(O)COc1cnc(-c2nn(Cc3ccccc3F)c3ccccc23)nc1Nc1ccncc1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
25.0 mg of 2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-4-(pyridin-4-ylamino)pyrimidin-5-ol (3-3, 0.06 mmol, 1 eq.), 28.2 mg of 3-bromo-propane-1,2-diol (0.18 mmol, 3 eq.) and 41.9 mg of potassium carbonate (0.30 mmol, 5 eq.) were suspended in 466 μl of dry DMF. The reaction mixture was stirred at 100° C. oil bath temperature for 18 hours. Then the mixture was partitioned between half saturated aq. sodium chloride solution and ethyl acetate. The phases were separated and the aqueous layer was extracted once more with ethyl acetate and once with dichloromethane/isopropanol 4:1. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative thin layer chromatography to yield 2.60 mg (5.34 μmol, 9%) of the analytically pure target compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[CH:17]=[N:18][C:19]([CH2:22]Br)=[CH:20][CH:21]=1)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[P:24]([O:31]CC)([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27]>C1(C)C(C)=CC=CC=1>[CH2:26]([O:25][P:24]([CH2:22][C:19]1[CH:20]=[CH:21][C:16]([N:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:17][N:18]=1)(=[O:31])[O:28][CH2:29][CH3:30])[CH3:27]
Reactant: CCOP(OCC)OCC
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ccc(CBr)nc1
Solvent: Cc1ccccc1C
Product: CCOP(=O)(Cc1ccc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cn1)OCC
Temperature: 140 °C
Reaction time: 4 h
Yield: 73 %

Procedure:
To a solution of di-tert-butyl[6-(bromomethyl)pyridin-3-yl]imidodicarbonate (Compound 260C, 3.0 g, 7.7 mmol) in dry xylene (100 mL) was added a triethyl phosphite (6.0 g, 36 mmol). The reaction mixture was stirred at 140° C. for 4 h, then concentrated. The residue was purified by column chromatography to give the desired compound (2.5 g, yield: 92%) as a liquid. 1H NMR (CDCl3, 400 MHz): δ=1.34 (t, J=7.6 Hz, 6H), 1.39 (s, 18H), 3.43 (d, J=22.0 Hz 2H), 4.09-4.18 (m, 4H), 7.43 (dd, J=2.0, 8.0 Hz, 1H), 7.67 (s, 1H), 8.33 (d, J=8.0 Hz, 1H).
Reaction SMILES: [C:1]([NH:5][C:6](=[O:8])[OH:7])([CH3:4])([CH3:3])[CH3:2].CO[CH2:11][C:12]1([S:15]([NH2:18])(=[O:17])=[O:16])[CH2:14][CH2:13]1.[CH:19]1(CBr)[CH2:21][CH2:20]1>>[C:1]([NH:5][C:6](=[O:7])[OH:8])([CH3:4])([CH3:3])[CH3:2].[CH:19]1([CH2:11][C:12]2([S:15]([NH2:18])(=[O:17])=[O:16])[CH2:14][CH2:13]2)[CH2:21][CH2:20]1
Reactant: BrCC1CC1
Reactant: COCC1(S(N)(=O)=O)CC1
Agent: CC(C)(C)NC(=O)O
Product: NS(=O)(=O)C1(CC2CC2)CC1

Procedure:
Step 16IId) This compound, 1-cyclopropyl-methylcyclopropylsulfonylamine tert-butylcarbamate, was obtained in 92% yield according to the procedure described in the synthesis of 1-methoxymethylcyclo-propylsulfonylamine tert-butylcarbamate (Step 15IId) except 1.10 equivalents of cyclopropylmethyl bromide were used as electrophile. The compound was taken directly into the next reaction without purification: 1H NMR (CDCl3) δ 0.10 (m, 2H), 0.51 (m, 2H), 0.67 (m, 1H), 1.10 (m, 2H), 1.49 (s, 9H), 1.62 (m, 2H), 1.87 (d, J=7.0 Hz, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[OH:12].Cl.[CH3:14][N:15]([CH3:20])[CH2:16][CH2:17][CH2:18]Cl.CC1C=C(C2OC(C)=NN=2)C=CC=1C1C=CC(C(O)=O)=CC=1>>[CH3:14][N:15]([CH3:20])[CH2:16][CH2:17][CH2:18][O:12][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[NH2:9]
Reactant: CN(C)CCCCl
Reactant: COc1ccc([N+](=O)[O-])cc1O
Agent: Cc1nnc(-c2ccc(-c3ccc(C(=O)O)cc3)c(C)c2)o1
Agent: Cl
Product: COc1ccc(N)cc1OCCCN(C)C

Procedure:
The title compound was prepared from 2-methoxy-5-nitrophenol and 3-dimethyaminopropyl chloride hydrochloride using a similar procedure to Descriptions 1 and 2 (58%).
Reaction SMILES: Br[CH:2]([CH3:31])[C:3]([NH:5][C:6]1[S:21][C:9]2[CH2:10][N:11]([C:14]([O:16][CH2:17][CH2:18][C:19]#[CH:20])=[O:15])[CH2:12][CH2:13][C:8]=2[C:7]=1[C:22](=[O:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:29])=[O:4].[NH3:32]>C(OCC)(=O)C>[NH2:32][CH:2]([CH3:31])[C:3]([NH:5][C:6]1[S:21][C:9]2[CH2:10][N:11]([C:14]([O:16][CH2:17][CH2:18][C:19]#[CH:20])=[O:15])[CH2:12][CH2:13][C:8]=2[C:7]=1[C:22](=[O:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[Cl:29])=[O:4]
Reactant: N
Reactant: C#CCCOC(=O)N1CCc2c(sc(NC(=O)C(C)Br)c2C(=O)c2ccccc2Cl)C1
Solvent: CCOC(C)=O
Product: C#CCCOC(=O)N1CCc2c(sc(NC(=O)C(C)N)c2C(=O)c2ccccc2Cl)C1
Temperature: 100 °C

Procedure:
1.16 g of 2-(2-bromopropionylamino)-3-(2-chlorobenzoyl)-6-(3-butynyloxycarbonyl)-4,5,6,7-tetrahydro-thieno[2,3-C]pyridine was dissolved in 36 ml of ethyl acetate, into which ammonia gas was introduced under cooling conditions, followed by heating in a sealed tube at 100° C. After completion of the reaction, the mixture was cooled, to which 50 ml of ethyl acetate was added. The mixture was washed with 1N hydrochloric acid, after which the aqueous phase was neutralized with a sodium carbonate aqueous solution and extracted with chloroform. The resultant organic phase was dried with anhydrous magnesium sulfate. The solvent was distilled off under reduced conditions and the resultant residue was purified by the use of silica gel column chromatography (elution solvent: dichloromethane), thereby obtaining 0.36 g of the intended compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[O:12])[N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:15][CH:14]=3)[C:9](=[S:25])[NH:8][C:7]=2[N:26]=1.C(=O)([O-])O.[Na+].I[CH2:33][CH3:34].C(#N)C>C(OCC)(=O)C>[CH2:33]([S:25][C:9]1[N:10]([C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:17][CH:18]=2)[C:11](=[O:12])[C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[N:26][C:7]=2[N:8]=1)[CH3:34]
Reactant: COc1ccc2c(=O)n(-c3ccc(OCC(F)(F)F)cc3)c(=S)[nH]c2n1
Reactant: CCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCSc1nc2nc(OC)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of 7-methoxy-2-thioxo-3-[4-(2,2,2-trifluoroethoxy)phenyl]-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one (383 mg), 1M aqueous sodium hydrogen carbonate solution (1.0 ml), iodoethane (0.4 ml) and acetonitrile (10 ml) was stirred at 100° C. for 1 hr. The reaction mixture was allowed to be cooled, diluted with ethyl acetate (80 ml), washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (375 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[CH:9]=[C:10](I)[C:3]=12.[Li][C:23](C)(C)[CH3:24].C(I)C.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[CH:9]=[C:10]([CH2:23][CH3:24])[C:3]=12
Reactant: [Li]C(C)(C)C
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2c(Cl)ccnc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCI
Solvent: C1CCOC1
Product: CCc1cn([Si](C(C)C)(C(C)C)C(C)C)c2nccc(Cl)c12
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
The 4-chloro-3-iodo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (27.0 g, 62.1 mmol) in THF (300 mL) was cooled to about −75° C. then t-BuLi (1.7 M in pentane, 73.1 mL, 124 mmol) was added over about 30 min keeping the internal temperature below about −70° C. After complete addition, EtI (15.0 mL, 186 mmol) was added. The mixture was warmed slowly to about −40° C. then the mixture was allowed to warm to rt. Saturated aqueous NaHCO3 (50 mL) was added and the mixture was stirred for about 30 min. The mixture was filtered and the solids washed with EtOAc (3×50 mL). The solvents were removed under reduced pressure then the material was partitioned between EtOAc (200 mL) and water (50 mL). The layers were separated then the organic layer was washed with saturated aqueous NaCl (50 mL), dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The resulting material was treated with MeOH (80 mL) then warmed to about 60° C. The mixture was cooled to rt and the resulting slurry stirred overnight at rt. The solids were collected by filtration then washed with MeOH (10 mL). The filtrate was concentrated under reduced pressure then purified by silica gel chromatography using a 120 g silica gel column and eluting with heptane. The material was stirred with MeOH (15 mL) overnight then the solid was collected by filtration and washed with MeOH (2 mL). The solid material was combined with the first crop of solids and dried under reduced pressure to give 4-chloro-3-ethyl-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (17.4 g, 83%): LC/MS (Table 2, Method g) Rt=3.21 min; MS m/z 337 (M+H)+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([NH:10][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][CH:7]=[CH:6][N:5]=1.Br[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>O1CCCC1>[Cl:3][C:4]1[C:9]([N:10]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:11](=[O:18])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: O=C(Nc1cccnc1Cl)c1ccccc1
Reactant: CCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCN(C(=O)c1ccccc1)c1cccnc1Cl
Temperature: 25 °C
Yield: 58 %

Procedure:
0.63 g sodium hydride (NaH) (26 mmol) and 50 mL tetrahydrofuran (THF) were added in an ice bath with stirring. 3.01 g N-(2-chloro-pyridin-3-yl)-benzamide (13 mmol) and 40 mL THF were then added and reacted for 30 min. Next, 3.28 g 1-bromo-hexane (20 mmol) was added and reacted for 24 hr. After cooling to room temperature, the reaction was quenched by water. After extraction three times by ethyl acetate, removal of water by magnesium sulphate (MgSO4), concentration, and purification by column, 2.39 g white solid was obtained, with a yield of 58%.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].CC(C)([O-])C.[K+].[CH:18]([Si:21]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[O:22][CH2:23][CH:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1)([CH3:20])[CH3:19].O>O1CCCC1>[CH:34]([Si:21]([CH:18]([CH3:20])[CH3:19])([CH:31]([CH3:33])[CH3:32])[O:22][CH2:23][CH:24]1[CH2:29][CH2:28][C:27](=[CH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:26][CH2:25]1)([CH3:35])[CH3:36]
Reactant: CC(C)[Si](OCC1CCC(=O)CC1)(C(C)C)C(C)C
Reactant: COC(=O)CP(=O)(OC)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C=C1CCC(CO[Si](C(C)C)(C(C)C)C(C)C)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97 %

Procedure:
To a solution of 6.37 g (35 mmol) of tri methyl phosphonoacetate in 200 mL of tetrahydrofuran (THF) was added 4.28 g (35 mmol) of potassium tert-butoxide. The reaction mixture was stirred at room temperature for 10 minutes. To the resultant slurry was added a solution of 9.3 g (32.7 mmol) of ketone from step C in 20 mL of THF. The mixture was stirred at room temperature under nitrogen overnight, then poured into water and extracted with three 100 mL portions of ether. The combined organic phases were washed sequentially with water, aqueous saturated sodium bicarbonate, and brine, dried over magnesium sulfate, and concentrated to give 10.8 g (97%) of the title compound as a clear oil which was used without further purification. 1H NMR (500 MHz, CDCl3) δ 5.63 (s, 1H), 3.78 (m, 1H), 3.69 (s, 1H), 3.53 (m, 2H), 2.32 (m, 1H), 2.21(m, 1H), 1.97 (m, 2H), 1.76 (m, 1H), 1.10–1.03 (m 23H).