Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][NH:6]2.[O:12]=[CH:13][C@@H:14]([C@H:16]([C@@H:18]([C@@H:20]([CH2:22][OH:23])[OH:21])[OH:19])[OH:17])O.C(O)C>O>[Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[C@@H:22]1[O:23][C@H:14]([CH2:13][OH:12])[C@@H:16]([OH:17])[C@H:18]([OH:19])[C@H:20]1[OH:21]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: Clc1cc(Cl)c2c(c1)NCC2
Solvent: CCO
Solvent: O
Product: OC[C@H]1O[C@@H](N2CCc3c(Cl)cc(Cl)cc32)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
A mixture of 4,6-dichloroindoline (6.57 g) and D-glucose (10.70 g) in H2O (25 ml)-ethyl alcohol (160 ml) was refluxed for 3 days. The organic solvent was evaporated under reduced pressure, and thereto were added brine and ammonium sulfate. The mixture was extracted with ethyl acetate 5 times, and the combined organic layer was dried over sodium sulfate. The insoluble materials were filtered off, and the filtrate was evaporated under reduced pressure to give crude 4,6-dichloro-1-(β-D-gluco-pyranosyl)indoline, which was used in the subsequent step without further purification.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]=1.[I:24]I>C1COCC1>[F:13][C:14]1[C:19]([I:24])=[CH:18][CH:17]=[C:16]([C:20]([F:21])([F:22])[F:23])[N:15]=1
Reactant: II
Reactant: Fc1cccc(C(F)(F)F)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: Fc1nc(C(F)(F)F)ccc1I
Temperature: -78 °C
Reaction time: 2 h
Yield: 46.7 %

Procedure:
A solution of N,N-diisopropylamine (1.4 mL, 10.0 mmol) in anhydrous THF (15 mL) is cooled under N2 to −78° C. and nBuLi (2.5 M in hexanes, 4.0 mL, 10.0 mmol) is added dropwise at a rate to maintain the temperature below −65° C. A solution of 2-fluoro-6-(trifluoromethyl)pyridine (1.65 g, 10.0 mmol) in anhydrous THF (15 mL) is added dropwise over 10 min and the resulting orange solution is stirred for 2 h at −78° C. Iodine (2.54 g, 10.0 mmol) in anhydrous THF (12.5 mL) is then added dropwise over 15 min (keeping the temperature under −65° C.), causing the colour of the solution to change to red-brown and a precipitate to form. After 30 min the mixture is allowed to warm to 10° C. and the solvent is evaporated under reduced pressure. The residue is diluted with diethyl ether (25 mL) and washed with Na2S2O3 (2 M aq., 10 mL), HCl (2 M aq., 2×12.5 mL), NaHCO3 (sat. aq., 12.5 mL) and brine (12.5 mL). The organic solvents are dried over Na2SO4 and evaporated under reduced pressure to afford a yellow oil. The product is purified by silica chromatography, eluting with cyclohexane, to afford the title compound as a white solid (1.36 g). Alternatively, this compound may be used directly in the next step without further purification.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([F:15])([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[C:4]([F:7])([F:6])[F:5].C(O)(=O)C.S(=O)(=O)(O)O.[N+:27]([O-])([OH:29])=[O:28]>O>[F:1][C:2]([F:16])([F:17])[C:3]([F:15])([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([N+:27]([O-:29])=[O:28])[CH:9]=1)[C:4]([F:7])([F:6])[F:5]
Reactant: Oc1ccc(C(F)(C(F)(F)F)C(F)(F)F)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(C(F)(C(F)(F)F)C(F)(F)F)ccc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 3.60 g of mixture containing 4-(heptafluoroisopropyl)phenol, 8 ml of acetic acid, and 2.5 g of concentrated sulfuric acid, a mixture of 1.05 g of 69% nitric acid and 1 ml of acetic acid was added dropwise while ice-cooling, and then stirred at room temperature for two hours. The reaction mixture was poured into water, and extracted with ethyl acetate three times. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 2.96 g of 4-(heptafluoroisopropyl)-2-nitrophenol.
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])=[CH:6][CH:5]=1>C(OCC)C>[Br:1][CH:11]([CH2:12][CH2:13][CH2:14][CH3:15])[C:10]([C:7]1[CH:6]=[CH:5][C:4]([Cl:3])=[CH:9][CH:8]=1)=[O:16]
Reactant: BrBr
Reactant: CCCCCC(=O)c1ccc(Cl)cc1
Solvent: CCOCC
Product: CCCCC(Br)C(=O)c1ccc(Cl)cc1

Procedure:
Bromine (0.02 mol) was added dropwise to a stirred solution of 4'-chlorohexanophenone (0.02 mol) in dry diethyl ether (20 ml) at 10°-20° over one hour. The ether was then removed in vacuo from the reaction mixture to leave a pale-yellow liquid which on distillation gave 2-bromo-4'-chlorohexanophenone, b.p. 124°-126°/0.04 mm Hg.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28]([C:29]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:27]=[N:26][N:25]=3)=[CH:14][CH:13]=2)[C:7](=[O:10])[NH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].Cl[CH2:49][O:50][C:51]1[CH:56]=[CH:55][C:54]([Cl:57])=[CH:53][CH:52]=1>>[CH2:1]([C:5]1[N:6]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28]([C:29]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=4)([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[N:27]=[N:26][N:25]=3)=[CH:16][CH:17]=2)[C:7](=[O:10])[N:8]([CH2:49][O:50][C:51]2[CH:56]=[CH:55][C:54]([Cl:57])=[CH:53][CH:52]=2)[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1n[nH]c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: ClCOc1ccc(Cl)cc1
Product: CCCCc1nn(COc2ccc(Cl)cc2)c(=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Yield: 55 %

Procedure:
The alkylation of 5-n-butyl-2,4-dihydro-4-[[2'-(N-trityltetrazol-5-yl)biphenyl-4-yl]methyl]-3H-1,2,4-triazol-3-one (from Example 2, Step D) with α,4-dichloroanisole was carried out as described in Example 3, Step A, except that only 5 equivalents of the alkylating agent was used. After work-up, the residue was flash chromatographed over silica gel (25 mL for 0.162 mmole, gradient elution using 0.25-1.0% MeOH/CH2Cl2) to give the desired material as a colorless oil in 55% yield, homogeneous by TLC in 2% MeOH/CH2Cl2, mass spectrum (FAB) 758 (M+1)+.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[C:4]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)[N:3]=1.[C:23]([C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1)([CH3:26])([CH3:25])[CH3:24]>CS(C)=O>[C:23]([C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH:36][C:2]2[C:7]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[O:15][CH3:16])=[C:6]([Cl:17])[N:5]=[C:4]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)[N:3]=2)(=[O:34])=[O:35])=[CH:29][CH:28]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2cccs2)nc1Cl
Reactant: CC(C)(C)c1ccc(S(N)(=O)=O)cc1
Solvent: CS(C)=O
Product: COc1ccccc1Oc1c(Cl)nc(-c2cccs2)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
A solution of 0.353 g of 4,6-dichloro-5-(2-methoxyphenoxy)-2-(thiophen-2-yl)-pyrimidine in 5 ml of DMSO was heated to 150° C. with 0.376 g of p-tert-butylbenzenesulphonamide for 30 minutes. The solution was concentrated in a high vacuum and the oily residue was poured on to ice, made acid (pH=3) and the suspension was extracted with ethyl acetate. The organic extracts were combined, washed with water, dried over sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica gel with toluene-ethyl acetate 9:1 and yielded 4-tert-butyl-N-[6-chloro-5-(2-methoxyphenoxy)-2-(thiophen-2-yl)-pyrimidin-4-yl]-benzenesulphonamide as a white foam.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.Cl.Cl[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]Cl.C(=O)([O-])[O-].[K+].[K+].Cl>C(O)CCC>[N:1]1([C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:10]=2[NH:9][CH:8]=[CH:7]3)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: ClCCNCCCl
Reactant: Nc1cccc2cc[nH]c12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCO
Product: c1cc(N2CCNCC2)c2[nH]ccc2c1
Yield: 32.3 %

Procedure:
A suspension of 7-aminoindole (4.10 g, 0.031 moles), bischloroethylamine hydrochloride (6.23 g, 0.035 moles) and potassium carbonate (9.66 g, 0.035 moles) in butanol (100 ml) was heated at reflux under argon for 6h. Further bischloroethylamine hydrochloride (3.0 g, 0.016 moles) and potassium carbonate (4.5 g, 0.016 moles) was added, then the suspension was heated at reflux under argon for 18 h. The solvent was evaporated in vacuo to give a deep purple residue which was taken up into dilute hydrochloric acid (300 ml), washed with ethyl acetate (2×100 ml), made basic with sodium hydroxide, extracted into dichloromethane, filtered, dried (MgSO4) then evaporated in vacuo to a yellow oil. This was crystallised twice from ether to give 7-(1-piperazinyl)indole (2.07 g, 0.010 moles) as a grey/white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[N:16][C:15]3[C:14]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[N:13][C:12]([C:24]4[CH:25]=[N:26][C:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[N:28][CH:29]=4)=[N:11][C:10]=3[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:38][CH2:39][C:40](Cl)=[O:41].C(N(CC)CC)C>C(Cl)Cl>[Cl:38][CH2:39][C:40]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[N:16][C:15]3[C:14]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[N:13][C:12]([C:24]4[CH:25]=[N:26][C:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:34])([CH3:36])[CH3:35])=[N:28][CH:29]=4)=[N:11][C:10]=3[CH:9]=2)[CH:5]=[CH:6][CH:7]=1)=[O:41]
Reactant: CC(C)(C)OC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3ncc(-c4cccc(N)c4)cc3n2)cn1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3ncc(-c4cccc(NC(=O)CCl)c4)cc3n2)cn1
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 86.6 %

Procedure:
To a 25 mL round bottom flask, tert-butyl (5-(7-(3-aminophenyl)-4-morpholinopyrido[3,2-d]pyrimidin-2-yl)pyrimidin-2-yl)carbamate (Example 7, Step 2) (0.15 g, 0.0003 mol), chloroacetyl chloride (0.051 g, 0.00045 mol) and DCM (10 mL) were added and then cooled to 10° C. To the same reaction flask, triethylamine (0.12 mL, 0.0009 mol) was added. The reaction mass was stirred at room temperature for 30 minutes. The reaction mixture was diluted with DCM, washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated to provide the crude product. The crude product was purified by column chromatography (60-120 silica-gel and 0-2% methanol in chloroform) to afford the title compound (0.15 g, 87%). 1H NMR (300 MHz, DMSO-d6): δ 10.52 (s, 1H), 10.42 (s, 1H), 9.48 (s, 1H), 9.08 (d, J=1.8 Hz, 1H), 8.33 (d, J=2.1 Hz, 1H), 8.18 (s, 1H), 7.68 (t, J=4.8 Hz, 2H), 7.57 (t, J=7.8 Hz, 1H), 4.65-4.52 (br s, 4H), 4.33 (s, 2H), 3.84 (s, 4H), 1.49 (s, 9H): LC-MS (ESI): Calculated mass. 576.2, Observed mass [M+H]+: 577.2 (RT=1.53 min).
Reaction SMILES: [CH3:1][SiH:2]([Cl:4])[Cl:3].[CH2:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH2:5]([CH2:1][SiH:2]([Cl:4])[Cl:3])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: C[SiH](Cl)Cl
Reactant: C=Cc1ccccc1
Product: Cl[SiH](Cl)CCCc1ccccc1

Procedure:
The intermediate isomeric phenethylmethyldichlorosilane was prepared from methyldichorosilane and styrene using the method described by J. L. Speier at pages 435ff of ADVANCES IN ORGANOMETALLIC CHEMISTRY, Academic Press, Edited by F. G. A. Stone and R. West, 17 (1979). It contained approximately 65% of the 2-phenethyl isomer and 35% of the 1-phenethyl isomer.
Reaction SMILES: [ClH:1].Cl.[CH2:3]([N:5]([CH2:20][CH3:21])[CH2:6][CH2:7][CH2:8][NH:9][CH2:10][C:11]1[CH:16]=[C:15]([I:17])[CH:14]=[C:13]([CH3:18])[C:12]=1[OH:19])[CH3:4].C=O.[C:24]([BH3-])#N.[Na+]>CO>[ClH:1].[ClH:1].[CH2:20]([N:5]([CH2:3][CH3:4])[CH2:6][CH2:7][CH2:8][N:9]([CH2:10][C:11]1[CH:16]=[C:15]([I:17])[CH:14]=[C:13]([CH3:18])[C:12]=1[OH:19])[CH3:24])[CH3:21]
Reactant: [BH3-]C#N
Reactant: CCN(CC)CCCNCc1cc(I)cc(C)c1O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCN(CC)CCCN(C)Cc1cc(I)cc(C)c1O

Procedure:
Reductive methylation of N[3(Diethylamino)propyl]-2-hydroxy-3-methyl-5-iodo-benzylamine dihydrochloride (5 mmol, from last step) formaldehyde (5 mL, 37% solution) and sodium cyanoborohydride (0.63 g, 10 mmol) in methanol (25 mL), work-up, conversion to the dihydrochloride (conc. hydrochloric acid, 5 mL), evaporation to dryness in vacuo and crystallization of the resulting material from methanol-acetone as described for Example 1 gave the title compound as colorless crystals. Yield(overall): 1,945 g (84%); mp. 166°-168° C. NMR (CDCl3, free base): δ0.97 (t, 6H, J-6 Hz, --CH2 --CH3); 1.5-1.9 (m, 2H, --CH2 --); 2.13 (s, 3H, --CH3); 2.23 (s, 3H, --CH3); 2.3-2.7 (m, 8H, N--CH2); 3.6 (s, 2H benzylic CH2), 7.1 (d, 1H, J=1 Hz, aromatic H); 7.35 (d, 1H, J=1 Hz, aromatic H); IR (KBr): 3420, 2940, 2640, 1625, 1470, 1390, 1210 cm-1. Analysis found: C, 41.47; H, 6.24; N, 5.93. C16H29Cl2IN2O requires: C, 41.49; H, 6.31; N, 6.05.
Reaction SMILES: [P:1](Cl)([O:5][CH3:6])([O:3][CH3:4])=[S:2].[OH:8][C:9]1[N:13]=[C:12]([S:14][CH2:15][CH3:16])[S:11][N:10]=1>>[CH3:4][O:3][P:1]([O:8][C:9]1[N:13]=[C:12]([S:14][CH2:15][CH3:16])[S:11][N:10]=1)([O:5][CH3:6])=[S:2]
Reactant: CCSc1nc(O)ns1
Reactant: COP(=S)(Cl)OC
Product: CCSc1nc(OP(=S)(OC)OC)ns1

Procedure:
Using the procedure of Example 3, dimethyl chlorothiophosphate and 3-hydroxy-5-ethylthio-1,2,4-thiadiazole were reacted to obtain 3-(dimethoxythiophosphoryloxy)-5-ethylthio-1,2,4-thiadiazole with a refractive index of nD20 = 1.559 and Rf=0.5.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3([C:17]4[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=4)[CH2:16][CH2:15]3)=[O:13])[CH2:8]2)[CH:2]=1.[CH:24]1(O)[CH2:28][CH2:27][CH2:26][CH2:25]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH:24]1([O:23][C:20]2[CH:19]=[CH:18][C:17]([C:14]3([C:12]([N:9]4[CH2:10][CH2:11][CH:7]([C:3]5[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=5)[CH2:8]4)=[O:13])[CH2:16][CH2:15]3)=[CH:22][CH:21]=2)[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: OC1CCCC1
Reactant: O=C(N1CCC(c2cccnc2)C1)C1(c2ccc(O)cc2)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(N1CCC(c2cccnc2)C1)C1(c2ccc(OC3CCCC3)cc2)CC1
Reaction time: 8 h

Procedure:
To a solution of 4-{1-[(3-pyridin-3-ylpyrrolidin-1-yl)carbonyl]cyclopropyl}phenol (40.0 mg, 0.000130 mol) in tetrahydrofuran were added cyclopentanol (29.4 μL, 0.000324 mol) diethyl azodicarboxylate (0.0511 mL, 0.000324 mol), and triphenylphosphine (85.0 mg, 0.000324 mol) at room temperature, and the reaction mixture was stirred overnight. The crude product was purified by prep-HPLC. LCMS: m/z 377.1 (M+H)+
Reaction SMILES: Br[C:2]1[C:3]([CH3:8])=[N:4][NH:5][C:6]=1[Br:7].[N+:9]([O-])([OH:11])=[O:10].O>S(=O)(=O)(O)O>[Br:7][C:6]1[NH:5][N:4]=[C:3]([CH3:8])[C:2]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1n[nH]c(Br)c1Br
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1n[nH]c(Br)c1[N+](=O)[O-]
Temperature: 9 °C
Reaction time: 0.5 h

Procedure:
6.5 g (0.027 mole) of 4,5-dibromo-3-methylpyrazole was dissolved in 20 ml of concentrated sulfuric acid. The solution was cooled to 9° C. and 10 ml of 90% nitric acid was added dropwise. The solution was stirred 30 minutes and then slowly heated to 60° C. and kept at that temperature for 30 minutes. The solution was cooled and poured into water. The mixture was extracted with ether and the ether was washed with water. The ether solution, after drying over magnesium sulfate was concentrated in vacuo and gave a white solid (1.5 g). One recrystallization from ethyl acetate gave a solid product.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[CH3:12][N:13]([CH3:20])[CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C.O>O>[CH3:12][N:13]([CH3:20])[CH:14]1[CH2:19][CH2:18][N:17]([C:2]2[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=2)[CH2:16][CH2:15]1
Reactant: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reactant: CN(C)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C1CCN(c2ccc([N+](=O)[O-])c(N)n2)CC1
Yield: 88 %

Procedure:
A solution of 6-chloro-3-nitro-pyridine-2-yl-amine (7 g, 40.6 mmol), dimethylpiperidine-4-yl-amine (5.7 g, 44.5 mmol), K2CO3 (6.39 g, 60.9 mmol) and DMF/water (4:1, 100 mL) was heated at 100° C. for 10 minutes in microwave reactor. After cooling, water was added and the resulting precipitate was collected by filtration and dried to give 6-(4-dimethylamino-piperidin-1-yl)-3-nitro-pyridin-2-yl-amine (9.48 g, 88%) as a yellow solid. 1H NMR (400 MHz, CD2Cl2) δ: 1.48 (m, 2H), 1.72 (m, 2H), 2.28 (s, 6H), 2.42 (m, 1H), 3.01 (m, 2H), 4.50 (m, 2H), 6.16 (d, J=9.54 Hz, 1H), 8.14 (d, J=9.54 Hz, 1H). HRMS: m/z 266.1628 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][C:9]1[N:10]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=1)=[CH:16][C:15]([OH:26])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH2:36][C:37]([NH2:39])=[O:38].O>CN(C)C=O>[C:1]([O:5][C:6](=[O:32])[NH:7][CH2:8][C:9]1[N:10]([CH2:28][CH:29]([CH3:30])[CH3:31])[C:11](=[O:27])[C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=1)=[CH:16][C:15]([O:26][CH2:36][C:37]([NH2:39])=[O:38])=[CH:14][CH:13]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccc(Cl)cc2)c2cc(O)ccc2c1=O
Reactant: NC(=O)CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccc(Cl)cc2)c2cc(OCC(N)=O)ccc2c1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 52.5 %

Procedure:
To a solution of tert-butyl[4-(4-chlorophenyl)-6-hydroxy-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.45 g, 1 mmol) in N,N-dimethylformamide (10 ml) was added sodium hydride (48 mg, 1.2 mmol) (60% in oil) at 0° C., and the mixture was stirred at 0° C. for 10 min. To the obtained mixture was added 2-iodoacetamide (0.22 g, 1.2 mmol) and the mixture was stirred at 0° C. for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with water, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give tert-butyl[6-(2-amino-2-oxoethoxy)-4-(4-chlorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.27 g, 52.9%) as crystals.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([O:10][CH3:11])=[N:4][CH:3]=1.Cl[CH2:13][C:14]1[C:15]2[N:16]([CH:20]=[CH:21][N:22]=2)[CH:17]=[CH:18][CH:19]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:22]1[CH:21]=[CH:20][N:16]2[CH:17]=[CH:18][CH:19]=[C:14]([CH2:13][O:1][C:2]3[C:7]([CH:8]=[O:9])=[CH:6][C:5]([O:10][CH3:11])=[N:4][CH:3]=3)[C:15]=12
Reactant: ClCc1cccn2ccnc12
Reactant: COc1cc(C=O)c(O)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)c(OCc2cccn3ccnc23)cn1
Temperature: 125 °C
Yield: 37.6 %

Procedure:
A mixture of 5-hydroxy-2-methoxyisonicotinaldehyde (723.6 mg, 4.7 mmol), 8-(chloromethyl)-imidazol[1,2-a]pyridine (785 mg, 4.7 mmol), and K2CO3 (1.9 g, 14.1 mmol) in DMF (20 mL) was heated at microwave reactor at 125° C. for 15 min. The mixture was filtered and concentrated. The residue was purified on silica gel (50-100% EtOAc in hexanes) to give 5-(imidazo[1,2-a]pyridin-8-ylmethoxy)-2-methoxyisonicotinaldehyde (500 mg, 38%) as an off-white solid. 1H NMR (400 MHz; DMSO) δ=10.37 (s, 1H), 8.58 (d, 1H), 8.39 (s, 1H), 8.02 (s, 1H), 7.61 (s, 1H), 7.44 (d, 1H), 6.98 (s, 1H), 6.93 (t, 1H), 5.61 (s, 2H), 3.84 (s, 3H). LRMS (M+H+) m/z 284.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][NH:12][CH2:11][CH:10]2[N:14]([CH3:25])[C:15](=[O:24])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:26][O:27][CH:28]1[CH2:33][CH2:32][CH:31]([C:34](O)=[O:35])[CH2:30][CH2:29]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:13][N:12]([C:34]([CH:31]3[CH2:32][CH2:33][CH:28]([O:27][CH3:26])[CH2:29][CH2:30]3)=[O:35])[CH2:11][CH:10]2[N:14]([CH3:25])[C:15](=[O:24])[CH2:16][C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(C(=O)Cc1ccc(F)cc1)C1CNCC1c1ccc(Cl)c(Cl)c1
Reactant: COC1CCC(C(=O)O)CC1
Product: COC1CCC(C(=O)N2CC(c3ccc(Cl)c(Cl)c3)C(N(C)C(=O)Cc3ccc(F)cc3)C2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 87 (step c), the title compound N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-(4-methoxy-cyclohexanecarbonyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide was prepared from N-[(3RS,4SR)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-2-(4-fluoro-phenyl)-N-methyl-acetamide using 4-methoxycylcohexanecarboxylic acid instead of 1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carboxylic acid and was obtained as a colorless oil. MS m/e: 521.3 [M]+.
Reaction SMILES: [C:1]1([N:7]=[N:8][C:9]2[CH:21]=[CH:20][C:12]([O:13][CH2:14][C:15]([O:17]CC)=[O:16])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>CN(C)C=O.O>[C:1]1([N:7]=[N:8][C:9]2[CH:10]=[CH:11][C:12]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:20][CH:21]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)COc1ccc(N=Nc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(O)COc1ccc(N=Nc2ccccc2)cc1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 81 %

Procedure:
3.66 g (0.013 mol) of ethyl 2-[4-(phenylazo)phenoxy]-ethanoate was dissolved in a mixture of 160 mL of dimethylformamide and 40 mL of water in a 250 mL one-neck round flask fitted with a magnetic stirring bar and a reflux condenser by heating to 90° C. while stirring on an oil bath. 3.6 g (0.090 mol) of NaOH was added in once through the condenser. Stirring and heating were continued for 1.5 h after which the reaction mixture was left for cooling finally on an ice-bath. The reaction mixture was then added 38 mL of 5.5 N HCl. A yellow precipitate was recovered and 40 mL of water was added. After filtration and vacuum drying 14 h at 50° C. 2.70 g (yield 82%) of 2-[4-(phenylazo)phenoxy]-ethanoic acid was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]([NH:8][CH2:9][CH:10]=[O:11])=O)=[C:4]([Cl:14])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:13]=[CH:12][C:5]([C:6]2[O:11][CH:10]=[CH:9][N:8]=2)=[C:4]([Cl:14])[CH:3]=1
Reactant: O=CCNC(=O)c1ccc(Br)cc1Cl
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Clc1cc(Br)ccc1-c1ncco1
Reaction time: 24 h
Yield: 19.8 %

Procedure:
To a stirred solution of 4-bromo-2-chloro-N-(2-oxoethyl)benzamide (1.00 g, 3.617 mmol) in CH2Cl2 (30 mL) were added triphenylphosphine (1.90 g, 7.234 mmol), iodine (1.84 g, 7.234 mmol) and triethylamine (2.0 mL, 14.47 mmol) at room temperature. After 24 hour, the mixture was washed with water (20 mL), dried over MgSO4. Removal of the solvent, gave an oily recidue, which was purified by flash chromatography eluting with ethyl acetate/hexane (1/5) to give title compound (0.185 g, 20% yield).