Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[N:11]=[C:10]([CH2:12][C:13]#[N:14])[C:9]([CH2:15][CH3:16])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:19][C:20]([C:22]1[N:26]([CH3:27])[N:25]=[C:24]([CH3:28])[C:23]=1[CH3:29])=O)C.C(OCCOCCO)C.[Na].Cl>O.COCCOCCOC.CCCCCCC>[O:19]=[C:20]([C:22]1[N:26]([CH3:27])[N:25]=[C:24]([CH3:28])[C:23]=1[CH3:29])[CH:12]([C:10]1[C:9]([CH2:15][CH3:16])=[N:8][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:11]=1)[C:13]#[N:14]
Reactant: CCc1nn(-c2ccccc2)nc1CC#N
Reactant: CCOC(=O)c1c(C)c(C)nn1C
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCCCCCC
Solvent: COCCOCCOC
Product: CCc1nn(-c2ccccc2)nc1C(C#N)C(=O)c1c(C)c(C)nn1C
Temperature: 92.5 °C
Yield: 90 %

Procedure:
In a 2 L-reaction flask equipped with a rectification column, 116.7 g (0.55 mol) of 2-phenyl-4-cyanomethyl-5-ethyl-1,2,3-triazole, 91 g (0.5 mol) of 1,3,4-trimethylpyrazol-5-carboxylic acid ethyl ester, 900 g of heptane, 60 g of diethylene glycol dimethyl ether, and 30 g of diethylene glycol monoethyl ether were added, then azeotropic dehydration was carried out by heating at 90 to 95° C., thereafter 115.5 g (0.6 mol) of 28% sodium was added dropwise over 10 hours, and the resulting mixture was reacted for 7 hours. After cooling to 30° C. or less, 3000 g of water was added to separate out heptane phase, and further the aqueous phase was washed with 600 g of heptane, the heptane phase was separated out, 900 g of xylene was added, then 62.5 g (0.6 mol) of 35% hydrochloric acid was added dropwise to be neutralized. The aqueous phase was separated out, washed with 600 g of water two times, the aqueous phase was separated out to obtain a xylene solution containing 156.8 g (yield 90%) of 3-oxo-2-(2-phenyl-5-ethyl-1,2,3-triazol-4-yl)-3-(1,3,4-trimethylpyrazol-5-yl) propionitrile.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][N:8]=1)(=O)=O.[CH3:21][Sn:22](Cl)([CH3:24])[CH3:23]>>[C:13]1([C:10]2[CH:11]=[CH:12][C:7]([Sn:22]([CH3:24])([CH3:23])[CH3:21])=[N:8][CH:9]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=S(=O)(Oc1ccc(-c2ccccc2)cn1)C(F)(F)F
Reactant: C[Sn](C)(C)Cl
Product: C[Sn](C)(C)c1ccc(-c2ccccc2)cn1

Procedure:
5-phenylpyridin-2-yl trifluoromethanesulfonate (1.5 mmol) was used in Procedure J with trimethyltin chloride to yield 5-phenyl-2-(trimethylstannyl)pyridine. The crude material (˜1.25 mmol) was used in Procedure K with N-(4-chloro-3-iodophenyl)-2-methyl-6-(trifluoromethyl)nicotinamide (1 mmol). Purified by silica gel chromatography (1% acetone/methylene chloride) to yield N-(4-chloro-3-(5-phenylpyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamideas a tan solid: TLC Rf=0.15 (1% acetone/methylene chloride); MS (Q1) 467 (M)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[NH:15][C:14]3[CH:16]=[C:17]([Cl:27])[C:18]([O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[CH:19][C:13]=3[N:12]=2)[CH:10]=1)=[O:5])C.Cl.O>C(O)(=O)C>[Cl:27][C:17]1[C:18]([O:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:19][C:13]2[N:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]3)[NH:15][C:14]=2[CH:16]=1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Oc4ccccc4)c(Cl)cc3[nH]2)c1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1cnn(-c2nc3cc(Oc4ccccc4)c(Cl)cc3[nH]2)c1
Yield: 34.4 %

Procedure:
1-(6-Chloro-5-phenoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (0.361 g) was dissolved in glacial acetic acid (9 mL) and 6N HCl (9 mL) and heated in a sealed tube at 100° C. for 6 h. After cooling in ice, water (5 mL) was added and the solids were collected via filtration, washed with water, and dried under vacuum (60° C., 10 mmHg). The resulting tan powder was recrystallized from MeOH:water (10 mL, 10:1), collected via filtration and dried under reduced pressure to afford the title compound as a tan solid (115 mg, 90%). Mp=134-138° C. (dec.). MS (ESI/CI): mass calcd. for C17H11ClN4O3, 354; m/z found, 355 [M+H]+, 396 [MH+MeCN]+. 1H NMR (mixture of tautomers) (500 MHz, DMSO-d6): 13.60 (s, 0.5H), 13.50 (s, 0.5H), 12.93 (s, 1H), 8.89 (s, 1H), 8.30 (s, 1H), 7.90 (s, 0.5H), 7.65 (s, 0.5H), 7.42 (m, 2.5H), 7.15 (m, 1.5H), 7.02-6.75 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([CH:11]=[CH2:12])[C:8]([CH:13]=[C:14]([CH3:16])[CH3:15])=[N:7][CH:6]=1)[CH3:2].CCO>C1COCC1.[Pd]>[CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([CH2:11][CH3:12])[C:8]([CH2:13][CH:14]([CH3:15])[CH3:16])=[N:7][CH:6]=1)[CH3:2]
Reactant: C=Cc1cc(C(=O)OCC)cnc1C=C(C)C
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)c1cnc(CC(C)C)c(CC)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 61.2 %

Procedure:
To solution of 6-(2-methyl-propenyl)-5-vinyl-nicotinic acid ethyl ester (1.37 g, 6.74 mmol) in THF (20 mL), Pd/C (100 mg, 10% Pd) followed by EtOH (20 mL) is added. The mixture is stirred under 1 atm of H2 at rt for 24 h. The catalyst is removed by filtration and the filtrate is concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give 5-ethyl-6-isobutyl-nicotinic acid ethyl ester (970 mg) as a colourless oil, LC-MS: tR=0.79 min, [M+1]+=236.20; 1H NMR (CDCl3): δ0.97 (d, J=6.8 Hz, 6H), 1.27 (t, J=7.5 Hz, 3H), 1.42 (t, J=7.0 Hz, 3H), 2.17-2.28 (m, 1H), 2.69-2.78 (m, 4H), 4.42 (q, J=7.0 Hz, 2H), 8.07 (s, 1H), 9.00 (s, 1H).
Reaction SMILES: [OH-].[Na+].[CH:3]1([CH:12]([CH2:16][C:17](=[O:28])[N:18]2[CH2:27][CH2:26][C:21]3([CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:20][CH2:19]2)[C:13]([O-:15])=[O:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1>O.O1CCCC1.CO>[CH:3]1([CH:12]([CH2:16][C:17](=[O:28])[N:18]2[CH2:19][CH2:20][C:21]3([CH2:22][CH2:23][CH2:24][CH2:25]3)[CH2:26][CH2:27]2)[C:13]([OH:15])=[O:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1
Reactant: O=C([O-])C(CC(=O)N1CCC2(CCCC2)CC1)C1CCc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C(CC(=O)N1CCC2(CCCC2)CC1)C1CCc2ccccc21
Temperature: 60 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
A solution of 6.8 g (0.17 mol) of sodium hydroxide in 60 ml of water is added to a solution of 20 g (0.0522 mol) of ethyl [R-(R*,S*)]-α-(2,3-dihydro-1H-inden-1-yl)-γ-oxo-8-azaspiro[4.5]decane-8-butanoate in a mixture of 150 ml of tetrahydrofuran and 150 ml of methanol, and the mixture is stirred for 3 h at 60° C. The mixture is concentrated, 200 ml of water are added, the solution obtained is washed with twice 150 ml of diethyl ether and then acidified at 0° C. with 6 M hydrochloric acid to pH 2 and it is extracted with twice 250 ml of dichloromethane; the organic phases are washed with brine, dried with sodium sulphate and evaporated to dryness. 16 g of [R-(R*,S*)]-α-(2,3-dihydro-1H-inden-1-yl)-γ-oxo-8-azaspiro[4.5]decane-8-butanoic acid are obtained in the form of a colourless oil; the (R*,S*) diastereoisomeric ratio=6/4. Yield 86%; 14 g (0.0295 mol) of this acid are dissolved in 320 ml of ethyl acetate, the solution is cooled to 0° C. and then a solution of 3.57 g (0.0295 mol) of (R) (+)-α-methylbenzylamine in 25 ml of ethyl acetate is added; the mixture is stirred at room temperature for 16 h, the precipitate formed is filtered, it is stirred in 30 ml of ethyl acetate, it is filtered and then it is dried; 7 g of a white solid of melting point 155-156° C. are obtained; 75 ml of water are added to a suspension of 7 g of the preceding solid, the solution is cooled to 0° C. and acidified with 6 M hydrochloric acid to pH 2; the mixture is stirred for 15 min with 170 ml of diisopropyl ether, the organic phase is decanted off and the aqueous phase is extracted with 170 ml of diisopropyl ether; the organic phases are washed with brine, dried over sodium sulphate and then evaporated to dryness. 4.9 g of [R-(R*,S*)]-α-(2,3-dihydro-1H-inden-1-yl)-γ-oxo-8-azaspiro[4.5]decane-8-butanoic acid are obtained in the form of a white solid; (R*,S*) diastereomeric ratio >99%. The product melts at 137° C. with decomposition. [α]D=−26° (c=5%, ethanol)
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[C:13](Cl)(=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17].O>N1C=CC=CC=1>[C:13]([NH:6][C:5]1[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Reactant: CCCCC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCCC(=O)Nc1ccc(OC)cc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
4.2 g (0.025 mol) of 2-nitro-4-methoxy-aniline are dissolved in 30 ml of pyridine, cooled to 0° C. and treated with 3.3 g (0.0275 mol) of valeryl chloride with stirring. After stirring for 1 hour at ambient temperature, the mixture is poured into iced water, the crystals are filtered off under suction and dried.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[N:11]3[N:12]=[C:13]([CH3:21])[CH:14]=[C:15]([CH:16]([CH2:19][CH3:20])[CH2:17][CH3:18])[C:10]3=[N:9][C:8]=2[CH3:22])=[C:4]([CH3:23])[CH:3]=1.[I-].[F:25][C:26]1[CH:27]=[C:28]([Zn+])[CH:29]=[CH:30][CH:31]=1.C1COCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:17]([CH:16]([C:15]1[C:10]2[N:11]([C:7]([C:5]3[S:6][C:2]([C:30]4[CH:29]=[CH:28][CH:27]=[C:26]([F:25])[CH:31]=4)=[CH:3][C:4]=3[CH3:23])=[C:8]([CH3:22])[N:9]=2)[N:12]=[C:13]([CH3:21])[CH:14]=1)[CH2:19][CH3:20])[CH3:18]
Reactant: Fc1cccc([Zn+])c1
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(Br)cc3C)c(C)nc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [I-]
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3sc(-c4cccc(F)c4)cc3C)c(C)nc12
Yield: 46 %

Procedure:
Using a procedure similar to Example 32, 3-(5-bromo-3-methyl-thiophen-2-yl)-8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.50 g, 1.27 mmol) and PdCl2(dppf) (0.047 g, 0.063 mmol) and 0.5 M solution of 3-fluorophenylzinc iodide in THF (5.1 mL, 2.55 mmol) furnish the title compound (0.24 g, 0.59 mmol, 46%). 1H NMR (CDCl3), δ 0.90 (t, J=7.5 Hz, 6H), 1.76-1.94 (m, 4H), 2.17 (s, 3H), 2.51 (s, 3H), 2.53 (s, 3H), 3.31-3.39 (m, 1H), 6.69 (s, 1H), 6.94-7.01 (m, 1H), 7.26 (s, 1H), 7.30-7.42 (m, 3H). LC/MS (m/z): calcd. for C24H26FN3S (M+H)+: 408.7; found: 408.2.
Reaction SMILES: C([O:8][C:9]([C@@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[NH:16][C:17](=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1)=[O:10])C1C=CC=CC=1.O.[OH-].[Li+]>C1COCC1.O.C(OCC)(=O)C>[CH3:25][O:24][C:20]1[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=1)[C:17]([NH:16][N:12]1[CH2:13][CH2:14][CH2:15][C@H:11]1[C:9]([OH:10])=[O:8])=[O:26]
Reactant: COc1cccc(C(=O)NN2CCC[C@H]2C(=O)OCc2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cccc(C(=O)NN2CCC[C@H]2C(=O)O)c1
Yield: 97.9 %

Procedure:
(2S)-1-(3-Methoxybenzoylamino)pyrrolidine-2-carboxylic acid benzyl ester (654 mg, 1.93 mmol) was dissolved in THF/H2O (9:1, 10 ml). Lithium hydroxide monohydrate (243 mg, 5.79 mmol) was added. After 18 h at room temperature the reaction mixture was diluted with ethyl acetate (50 ml). This solution was washed with 1M KHSO4, water and brine, dried (Na2SO4) and evaporated in vacuo to give a colourless oil identified as the title compound (470 mg, 1.89 mmol, 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:16][CH2:15][CH2:14][C@@H:13]3[C@H:8]([O:9][CH2:10][CH2:11][NH:12]3)[C:6]=2[CH:7]=1.[C:17]([OH:24])(=[O:23])/[CH:18]=[CH:19]\[C:20]([OH:22])=[O:21].[CH3:25]N1CCO[C@@H]2C3C=CC=CC=3OCC[C@@H]12>>[C:17]([OH:24])(=[O:23])/[CH:18]=[CH:19]\[C:20]([OH:22])=[O:21].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:16][CH2:15][CH2:14][C@@H:13]3[C@H:8]([O:9][CH2:10][CH2:11][N:12]3[CH3:25])[C:6]=2[CH:7]=1
Reactant: Clc1ccc2c(c1)[C@H]1OCCN[C@@H]1CCO2
Reactant: CN1CCO[C@@H]2c3ccccc3OCC[C@H]21
Agent: O=C(O)/C=C\C(=O)O
Product: CN1CCO[C@@H]2c3cc(Cl)ccc3OCC[C@H]21

Procedure:
Following essentially the same procedure but substituting trans-10-chloro-3,4,4a,5,6,11b-hexahydro-2H-[1]benzoxepino[5,4-b]-1,4-oxazine for the trans-3,4,4a,5,6,11b-hexahydro-2H-[1]benzoxepino[5,4-b]-1,4-oxazine above, results in the formation of trans-10-chloro-3,4,4a,5,6,11b-hexahydro-4-methyl-2H-[1]benzoxepino[5,4-b]-1,4-oxazine maleate having a mp. 142°-143° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH:17]([OH:19])[CH3:18])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[C:4]([CH3:20])[C:3]=1[C:21]([NH2:23])=[O:22].[CH2:24]1[O:32][C:31]2[CH:30]=[CH:29][C:28]([CH2:33][C:34](OC)=O)=[CH:27][C:26]=2[O:25]1.CC(C)([O-])C.[K+].C(=O)([O-])O.[Na+]>ClCCl>[CH2:24]1[O:32][C:31]2[CH:30]=[CH:29][C:28]([CH2:33][C:34]3[NH:23][C:21](=[O:22])[C:3]4[C:4]([CH3:20])=[N:5][N:6]([CH:7]([CH:17]([OH:19])[CH3:18])[CH2:8][CH2:9][CH2:10][C:11]5[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=5)[C:2]=4[N:1]=3)=[CH:27][C:26]=2[O:25]1
Reactant: COC(=O)Cc1ccc2c(c1)OCO2
Reactant: Cc1nn(C(CCCc2ccccc2)C(C)O)c(N)c1C(N)=O
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: ClCCl
Product: Cc1nn(C(CCCc2ccccc2)C(C)O)c2nc(Cc3ccc4c(c3)OCO4)[nH]c(=O)c12
Yield: 29.3 %

Procedure:
10 mg (0.037 mmol) of 5-amino-1-[1-(1-hydroxy-ethyl)-4-phenyl-butyl]-3-methyl-1H-pyrazole-4-carboxamide and 30 mg (0.129 mmol) of methyl 3,4-methylenedioxyphenylacetate are refluxed for 6 hours in 0.3 ml of a 0.5M ethanolic potassium tert-butoxide solution. After dichloromethane and saturated aqueous sodium hydrogen carbonate solution have been added, the phases are separated. Purification by chromatography gives 5 mg (31%) of a solid, Rf=0.44 (dichloromethane/methanol=15:1).
Reaction SMILES: C(O)CCCCCCCO.FC1C=CC(F)=CC=1CBr.[F:21][C:22]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:23]=1[CH2:24][O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][OH:34].FC1C=CC(F)=CC=1COCCCCCCCC(O)=O.Cl.Cl.[CH2:62]([O:69][C:70](=[O:78])[CH2:71][C@@H:72]([NH2:77])[CH2:73][N:74]([CH3:76])[CH3:75])[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1>>[CH2:62]([O:69][C:70](=[O:78])[CH2:71][C@@H:72]([NH:77][C:33](=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][O:25][CH2:24][C:23]1[CH:35]=[C:36]([F:39])[CH:37]=[CH:38][C:22]=1[F:21])[CH2:73][N:74]([CH3:75])[CH3:76])[C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1
Reactant: OCCCCCCCCOCc1cc(F)ccc1F
Reactant: CN(C)C[C@H](N)CC(=O)OCc1ccccc1
Agent: Cl
Agent: Fc1ccc(F)c(CBr)c1
Agent: O=C(O)CCCCCCCOCc1cc(F)ccc1F
Product: CN(C)C[C@@H](CC(=O)OCc1ccccc1)NC(=O)CCCCCCCOCc1cc(F)ccc1F

Procedure:
The title compound, m/e=413.3 ([M−H]−), was produced in analogy with intermediate 1, steps 1 to 4. Thus, 1,8-octanediol was alkylated in step 1 with 2,5-difluorobenzyl bromide, leading to 8-(2,5-difluoro-benzyloxy)-octan-1-ol, which was oxidized in step 2 to 8-(2,5-difluoro-benzyloxy)-octanoic acid. This was coupled in step 3 with (R)-3-amino-4-dimethylamino-butyric acid benzyl ester dihydrochloride to produce (R)-3-[8-(2,5-difluoro-benzyloxy)-octanoylamino]-4-dimethylamino-butyric acid benzyl ester, which was hydrogenated in step 4.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[N:14]1([C:20]2[CH:21]=[CH:22][CH:23]=[C:24]3[C:29]=2[CH2:28][NH:27][CH2:26][CH2:25]3)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:27]3[CH2:26][CH2:25][C:24]4[C:29](=[C:20]([N:14]5[CH2:19][CH2:18][O:17][CH2:16][CH2:15]5)[CH:21]=[CH:22][CH:23]=4)[CH2:28]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: c1cc2c(c(N3CCOCC3)c1)CNCC2
Product: O=C(c1cc2ncc(Br)cn2n1)N1CCc2cccc(N3CCOCC3)c2C1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 8-morpholin-4-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7].Cl[C:14]1[C:23]2[CH:22]=[CH:21][C:20]([CH3:24])=[C:19]([NH:25][C:26]3[C:31]([C:32]4[CH:37]=[C:36]([NH:38][CH3:39])[N:35]=[CH:34][N:33]=4)=[CH:30][CH:29]=[CH:28][N:27]=3)[C:18]=2[CH:17]=[CH:16][N:15]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1.CN(C=O)C.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]>[CH3:24][C:20]1[CH:21]=[CH:22][C:23]2[C:14]([NH:7][C:6]3[CH:8]=[CH:9][CH:10]=[C:4]([O:3][C:2]([F:11])([F:12])[F:1])[CH:5]=3)=[N:15][CH:16]=[CH:17][C:18]=2[C:19]=1[NH:25][C:26]1[C:31]([C:32]2[CH:37]=[C:36]([NH:38][CH3:39])[N:35]=[CH:34][N:33]=2)=[CH:30][CH:29]=[CH:28][N:27]=1
Reactant: Nc1cccc(OC(F)(F)F)c1
Reactant: CNc1cc(-c2cccnc2Nc2c(C)ccc3c(Cl)nccc23)ncn1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CNc1cc(-c2cccnc2Nc2c(C)ccc3c(Nc4cccc(OC(F)(F)F)c4)nccc23)ncn1
Temperature: 150 °C

Procedure:
3-(Trifluoromethoxy)aniline (13 μL, 96 μmol), 1-chloro-6-methyl-N-(3-(6-(methylamino)pyrimidin-4-yl)pyridin-2-yl)isoquinolin-5-amine (33 mg, 88 μmol), tris (dibenzylideneacetone)dipalladium (0) (3 mg, 4 μmol), and 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (3 mg, 7 μmol) were added to a microwave tube and suspended in THF-DMF (1:1, 1 mL). The tube was flushed with nitrogen and a solution of lithium bis(trimethylsilyl)amide, 1.0 M in hexanes (385 μL, 385 μmol) was added. The tube was heated in a microwave reactor at 150° C. for 15 min. The reaction mixture was partitioned between DCM and saturated aqueous sodium bicarbonate. The DCM layer was washed with brine, dried over sodium sulfate and concentrated. The residue was purified via preparative TLC on silica (DCM:EtOAc:EtOH:TEA=5:5:10:10) to give the desired product as a yellow solid. MS (M+H)+ 518.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:14])[CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH2:12][OH:13])[CH:8]=[CH:7]2.CS(C)=O.S([O-])([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([F:14])[CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH:12]=[O:13])[CH:8]=[CH:7]2
Reactant: OCc1ccc2cc(F)cc(Br)c2n1
Agent: O=S(=O)([O-])[O-]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=Cc1ccc2cc(F)cc(Br)c2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.1 %

Procedure:
(8-bromo-6-fluoroquinolin-2-yl)methanol (2 g, 7.8 mmol), DMSO (8.9 mL, 125.0 mmol), and TEA (4.9 mL, 35 mmol) were weighed into a flask and dissolved in a 10 mL of DCM, followed by cooling to 0° C. Pyridinium sulfate (4.351 g, 27.3 mmol) was added and the reaction stirred 0° C. for 1 hour. The reaction was poured onto 50 mL water and extracted with ethyl acetate. The combined organics were then dried over MgSO4, then concentrated in vacuo affording a yellow/white semi-solid, which was further purified by triturating with 20% ethyl acetate/Hexanes, affording the desired product as a tan solid (1.35 g, 68% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([I:10])=[C:6]([OH:11])[CH:5]=1.Br[CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([I:10])=[C:6]([O:11][CH2:14][CH2:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[CH:5]=1
Reactant: Cc1cccc(CCBr)c1
Reactant: COC(=O)c1ccc(I)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(I)c(OCCc2cccc(C)c2)c1
Yield: 32.7 %

Procedure:
10.0 g of 3-hydroxy-4-iodo-benzoic acid methyl ester, 7.2 g of 1-(2-bromo-ethyl)-3-methyl-benzene and 10.0 g of potassium carbonate were stirred in 100 ml of anhydrous DMF for 28 h at 80° C. The solvent was evaporated and the residue dissolved in 200 ml of water and 400 ml of EA. The organic layer was separated, washed with 200 ml of water, dried with magnesium sulfate and evaporated. Silica gel chromatography (EA/HEP gradient) of the residue yielded 4.66 g of the title compound.
Reaction SMILES: [N+:1]([C:4]1[S:5][C:6]([Cl:10])=[C:7]([Cl:9])[CH:8]=1)([O-])=O.[C:11](O)(=[O:13])[CH3:12].C(OC(=O)C)(=O)C.Cl>[Fe].O>[Cl:9][C:7]1[CH:8]=[C:4]([NH:1][C:11](=[O:13])[CH3:12])[S:5][C:6]=1[Cl:10]
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)s1
Reactant: CC(=O)O
Agent: [Fe]
Agent: Cl
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1cc(Cl)c(Cl)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled solution of the above 4,5-dichlorothiophene (13.0 g, 66.0 mmol) are added acetic acid (78 ml) and acetic anhydride (78 ml), followed by iron powder (13.0 g) in portions over 30 min. at such rate that the mixture is kept at 5°-10°. The suspension is stirred at RT overnight, after which it is poured into water, acidified with conc. HCl and cooled in an ice bath for 6 hours. It is then filtered, and the solid is washed with water and dried, dissolved in ether and filtered. Charcoal is added to the filtrate, which is then filterded and stripped of solvent to give N-(4,5-dichloro-2-thienyl)acetamide, a solid.
Reaction SMILES: C([O:5][C:6]([N:8]1[C:19]2[C:11](=[C:12]3[C:16](=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:15][C:14]([C:23]([O:25][CH3:26])=[O:24])=[CH:13]3)[CH:10]([CH2:27][OH:28])[CH2:9]1)=O)(C)(C)C.CCN=C=NCCCN(C)C.Cl.[CH3:41][O:42][C:43]1[CH:44]=[C:45]2[C:49](=[C:50]([O:54][CH3:55])[C:51]=1[O:52][CH3:53])[NH:48][C:47](C(O)=O)=[CH:46]2.C([O-])(O)=O.[Na+]>Cl.CC(N(C)C)=O>[OH:28][CH2:27][CH:10]1[C:11]2=[C:12]3[C:16](=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[C:19]2[N:8]([C:6]([C:47]2[NH:48][C:49]4[C:45]([CH:46]=2)=[CH:44][C:43]([O:42][CH3:41])=[C:51]([O:52][CH3:53])[C:50]=4[O:54][CH3:55])=[O:5])[CH2:9]1)[NH:15][C:14]([C:23]([O:25][CH3:26])=[O:24])=[CH:13]3
Reactant: COC(=O)c1cc2c3c(cc([N+](=O)[O-])c2[nH]1)N(C(=O)OC(C)(C)C)CC3CO
Reactant: COc1cc2cc(C(=O)O)[nH]c2c(OC)c1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cc2c3c(cc([N+](=O)[O-])c2[nH]1)N(C(=O)c1cc2cc(OC)c(OC)c(OC)c2[nH]1)CC3CO
Temperature: 20 °C
Reaction time: 16 h
Yield: 71.4 %

Procedure:
A solution of 29 (1.52 g, 3.87 mmol) in HCl-saturated dioxane (120 mL) was stirred for 100 min (until TLC indicated complete reaction) and the suspension was evaporated. EDCI.HCl (1.48 g, 7.74 mmol) and 5,6,7-trimethoxyindole-2-carboxylic acid (0.97 g, 3.87 mmol) in DMA (12 mL) were added, and the mixture stirred at 20° C. for 16 h. Dilute aq NaHCO3 (100 mL) was added, and the precipitated solid was filtered off, washed with H2O, and dried. Trituration with hot MeOH gave methyl 1-hydroxymethyl-5-nitro-3-[(5,6,7-trimethoxyindol-2-yl)carbonyl]-1,2-dihydro-3H-pyrrolo[3,2-e]indole-7-carboxylate (56) as an orange powder (1.45 g, 71%), mp 239-240.5° C. (dec.). 1H NMR [(CD3)2SO] δ 11.46 (d, J=32 1.6 Hz, 1 H, NH), 11.30 (s, 1 H, NH), 9.19 (s, 1 H, H-4), 7.54 (s, 1 H, H-8), 7.09 (s, 1 H, H-3'), 6.95 (s, 1 H, H-4'), 5.11 (t, J=5.3 Hz, 1 H, OH), 4.71 (t, J=10.1 Hz, 1 H, H-2), 4.47 (dd, J=10.6, 4.1 Hz, 1 H, H-2), 4.02-3.95 (m, 1 H), 3.94 (s, 3 H, OMe), 3.93 (s, 3 H, OMe), 3.82 (s, 3 H, OMe), 3.80 (s, 3 H, OMe), 3.81-3.75 (m, 2 H). Anal. Calculated for C25H24N4O9.1/2H2O: C, 56.3; H, 4.7; N, 10.5. Found: C, 56.4; H, 4.4; N, 10.3%.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]([CH3:18])[CH3:17])N)=[CH:5][CH:4]=1.CC[O:23][C:24]([CH2:26][CH:27]1[C:32](=O)[CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:25]>>[Cl:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:28]3[CH:27]([CH2:26][C:24]([OH:25])=[O:23])[CH2:32][CH2:31][CH2:30][C:29]=3[C:15]3[C:10]2=[C:11]([CH:16]([CH3:18])[CH3:17])[CH:12]=[CH:13][CH:14]=3)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CC1CCCCC1=O
Reactant: CC(C)c1ccccc1N(N)Cc1ccc(Cl)cc1
Agent: Cl
Product: CC(C)c1cccc2c3c(n(Cc4ccc(Cl)cc4)c12)C(CC(=O)O)CCC3

Procedure:
Following the procedure of Example 1, but using 1-(4-chlorobenzyl)-1-(2-isopropylphenyl)hydrazine hydrochloride and ethyl 2-cyclohexanone acetate as starting materials, the title compound was prepared.