Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[C:12]([N:19]1[CH2:24][C@@H:23]([CH3:25])[NH:22][CH2:21][C@@H:20]1[CH3:26])([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C=O)C.O>[C:15]([O:14][C:12]([N:19]1[CH2:24][C@@H:23]([CH3:25])[N:22]([C:2]2[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=2)[CH2:21][C@@H:20]1[CH3:26])=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])cnc1N1C[C@H](C)N(C(=O)OC(C)(C)C)C[C@H]1C
Temperature: 80 °C
Reaction time: 20 h

Procedure:
Dissolve 2-chloro-3-methyl-5-nitropyridine (310 mg, 1.82 mmol, 1.0 equiv) and N—BOC-trans-2,5-dimethylpiperazine (397 mg, 2.0 mmol, 1.1 equiv) in 5 mL of anhydrous DMF, add potassium carbonate (251 mg, 1.82 mmol, 1.0 equiv) and stir the mixture for 20 hours at 80° C. Pour the solution in a 1:1 v/v mixture of EtOAc and iced water. Extract the aqueous phase with EtOAc (2×20 mL) and wash the combined organic layers with water (3×20 mL) and saturated aq. sodium chloride (30 mL). Dry the organic solution over sodium sulfate and concentrate under reduced pressure to obtained a crude rac-(trans)-2,5-dimethyl-4-(3-methyl-5-nitro-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester. MS(ES+): m/z=251.2 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9]([OH:11])=O)=[CH:3]1.C(Cl)(=O)C(Cl)=O.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25]Br)=[C:21]([Cl:27])[CH:20]=1>C(Cl)Cl.CN(C)C=O.COCCOC.[Zn].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>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C:9]([C:4]2[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=2)=[O:11])=[C:21]([Cl:27])[CH:20]=1
Reactant: Clc1cc(Br)ccc1CBr
Reactant: Cn1cc(C(=O)O)ccc1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C(Cl)C(=O)Cl
Agent: [Zn]
Solvent: ClCCl
Solvent: COCCOC
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)Cc2ccc(Br)cc2Cl)ccc1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid (606 mg) in CH2Cl2 (5 ml) were added one drop of N,N-dimethylformamide and oxalylchloride (803 mg). The mixture was stirred at room temperature for 1.5 h and was then concentrated to dryness. 1,2-Dimethoxyethane was added and the solvent was evaporated again to give the crude acid chloride. To a suspension of zinc powder (517 mg) in 1,2-dimethoxyethane (5 ml) was added tetrakis(triphenylphosphine)palladium(0) (55 mg). A suspension of the acid chloride in 1,2-dimethoxyethane (5 ml) was added. The mixture was cooled in an ice bath and a solution of 4-bromo-1-bromomethyl-2-chloro-benzene (1.125 g) in 1,2-dimethoxyethane (5 ml) was slowly added over 30 min. The mixture was stirred for 30 min at 0° C. and for 1.5 h at room temperature. The mixture was filtered and the filtrate was concentrated. The product was purified by chromatography (SiO2, cyclohexane/EtOAc 7:3=>0:1) to give the title compound (603 mg, not completely pure) as a colorless solid. MS (m/e, ISP neg. ion)=338.0 [M−H+].
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:73])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:59]=[C:58]4[C:54]([CH:55]=[CH:56][N:57]4[CH2:60][CH2:61][CH2:62][O:63][Si](C(C)(C)C)(C)C)=[CH:53][CH:52]=3)[CH:46]([O:71][CH3:72])[CH2:45]2)[CH:7]([CH3:74])[CH:6]([OH:75])[CH2:5][C:4]1=[O:76])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.CO>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:73])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][C:51]3[CH:59]=[C:58]4[C:54]([CH:55]=[CH:56][N:57]4[CH2:60][CH2:61][CH2:62][OH:63])=[CH:53][CH:52]=3)[CH:46]([O:71][CH3:72])[CH2:45]2)[CH:7]([CH3:74])[CH:6]([OH:75])[CH2:5][C:4]1=[O:76])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc5ccn(CCCO[Si](C)(C)C(C)(C)C)c5c4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: ClCCl
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(Oc4ccc5ccn(CCCO)c5c4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reaction time: 3 h
Yield: 66.8 %

Procedure:
To a solution of 17-Ethyl-1,14-dihydroxy -12-[2'-(4"-(1-(3-t-butyldimethylsilyloxypropyl)indol -6-yl)oxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetra -one (318 mg) in CH2Cl2 (5 mL) at rt was added a solution of p-toluene sulfonic acid (25 mg) in CH3OH (5 mL). The reaction mixture was stirred for 3 hours quenched with saturated NaHCO3, then extracted with CH2Cl2. The extracts were combined, dried over Na2SO4, filtered and concentrated in vacuo. The product was purified by preparative TLC on silica gel (2:1,hexane/acetone) to give 190 mg of the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:13]=[CH:12][N:11]([C:14]3[S:15][C:16]([C:26]([NH2:28])=[O:27])=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[N:18]=3)[C:10]=2[CH:29]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[OH:38][CH2:39][CH2:40][NH:41][CH2:42][CH2:43][OH:44]>CN(C)C=O>[OH:38][CH2:39][CH2:40][N:41]([CH2:42][CH2:43][OH:44])[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:13]=[CH:12][N:11]([C:14]3[S:15][C:16]([C:26]([NH2:28])=[O:27])=[C:17]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[N:18]=3)[C:10]=2[CH:29]=1
Reactant: OCCNCCO
Reactant: NC(=O)c1sc(-n2cnc3ccc(OCCCCl)cc32)nc1-c1cccc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1sc(-n2cnc3ccc(OCCCN(CCO)CCO)cc32)nc1-c1cccc(Cl)c1
Reaction time: 3 h
Yield: 56.2 %

Procedure:
A mixture of 0.043 g (0.1 mmole) of 2-[6-(3-chloro-propoxy)-benzoimidazol-1-yl]-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid amide (I.34a), 1 mL of dimethylformamide, 0.069 g (0.5 mmole) of potassium carbonate, 0.001 g of potassium iodide and 0.029 mL (0.3 mmole) of 2-(2-hydroxy-ethylamino)-ethanol was stirred at 100 degrees for 3 hours. The mixture was concentrated under reduced pressure, and diluted with 20 mL of water. The precipitate was collected by filtration and the solid triturated with diethyl ether to give 0.029 g of 2-(6-{3-[bis-(2-hydroxy-ethyl)-amino]-propoxy}-benzoimidazol-1-yl)-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid amide (I.35) as a white powder. MH+/Z=516
Reaction SMILES: ClC(OCC(C)C)=O.C(N(CC)CC)C.C([O-])(=O)C.[NH2:20][CH2:21][C:22]([NH:24][C@H:25]([C:33]([NH-:35])=[O:34])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:23]>C(OCC)(=O)C.CN(C)C=O>[NH2:20][CH2:21][C:22]([NH:24][C@H:25]([C:33]([NH2:35])=[O:34])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:23]
Reactant: [NH-]C(=O)[C@H](Cc1ccccc1)NC(=O)CN
Agent: CC(=O)[O-]
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: NCC(=O)N[C@@H](Cc1ccccc1)C(N)=O
Temperature: -15 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
In 12.5 ml. of dimethylformamide (DMF) there was dissolved 131 mg. (250 μmoles) of a labelling cyanine dye shown by formula III below: ##STR22## and the solution was cooled to -15° C. To the solution was added 33 μliters (250 μmoles) of isobutyl chloroformate, and after further adding thereto 35 μliters (250 μmoles) of triethylamine, the reaction was performed for 5 minutes at a temperature of -15° C. to -10° C. Then, after further adding 70 mg (250 μmoles) of the acetate of glycylphenylalanylamide and 35 μliters (250 μmoles) of triethylamine to the reaction mixture, reaction was further performed for one hour at 0° C. and then for one further hour at room temperature. To the reaction mixture obtained was added 25 ml of ethyl acetate and the precipitates formed were recovered by filtration and washed with ethyl acetate. The powder thus obtained was repeatedly purified by a silica gel column chromatography (eluate: a 3:1 mixture of chloroform and methanol) and then recrystallized from a 1:1 mixture of chloroform and methanol to provide 128 mg (yield of 71%) of glycylphenylalaninamide the N-terminal of which has been modified or labelled by the dye of formula III.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[CH:8]2)[CH3:2].[Cl-].[CH3:13][O:14][C:15]1[CH:27]=[CH:26][CH:25]=[CH:24][C:16]=1[CH:17]=[N+:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>>[CH2:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[C:8]2[CH:17]([C:16]1[CH:24]=[CH:25][CH:26]=[CH:27][C:15]=1[O:14][CH3:13])[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH3:2]
Reactant: COc1ccccc1C=[N+]1CCOCC1
Reactant: CCc1cccc2cc[nH]c12
Agent: [Cl-]
Product: CCc1cccc2c(C(c3ccccc3OC)N3CCOCC3)c[nH]c12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 7-ethyl-1H-indole and 4-(2-methoxy-benzylidene)-morpholin-4-ium chloride.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:18](=[O:28])[C:19]([CH2:21][C:22]5[CH:23]=[N:24][CH:25]=C[CH:27]=5)=[CH:20][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:16][CH3:17])[CH:10]=3.[N:29]1C=C(C=O)C=NC=1>>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:18](=[O:28])[C:19]([CH2:21][C:22]5[CH:23]=[N:24][CH:25]=[N:29][CH:27]=5)=[CH:20][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:16][CH3:17])[CH:10]=3
Reactant: O=Cc1cncnc1
Reactant: COc1cc2c3c(c1)c(=O)c(Cc1cccnc1)cn3-c1cc(Br)ccc1S2
Product: COc1cc2c3c(c1)c(=O)c(Cc1cncnc1)cn3-c1cc(Br)ccc1S2
Yield: 89.8 %

Procedure:
According to Example 1 <step 4>, the compound (2 g) produced in Example 36 <step 2> was reacted with pyrimidine-5-aldehyde (3.11 g) to obtain the title compound (1.8 g; 72%).
Reaction SMILES: [CH2:1]([NH:3][CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]2[C:21]([CH:22]3[CH2:32][CH:23]3[CH2:24][O:25]2)=[CH:20][CH:19]=1)(=[O:16])=[O:15])[CH3:2].[CH3:33]OC(N(C1C(C(OC)=O)=C2C(C3CC3CO2)=CC=1)S(C1C=CC(F)=CC=1/C=C\CO)(=O)=O)=O.NC(C)C>>[CH3:2][CH:1]([NH:3][CH2:4]/[CH:5]=[CH:6]\[C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[S:14]([NH:17][C:18]1[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]2[C:21]([CH:22]3[CH2:32][CH:23]3[CH2:24][O:25]2)=[CH:20][CH:19]=1)(=[O:16])=[O:15])[CH3:33]
Reactant: CCNC/C=C\c1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OCC1CC21
Reactant: COC(=O)c1c(N(C(=O)OC)S(=O)(=O)c2ccc(F)cc2/C=C\CO)ccc2c1OCC1CC21
Solvent: CC(C)N
Product: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2/C=C\CNC(C)C)ccc2c1OCC1CC21

Procedure:
Prepared by proceeding in a similar manner to Intermediate 63, starting from methyl (1aRS,7bSR)-5-{N-[methoxycarbonyl]-N-[2-((Z)-3-hydroxyprop-1-enyl)-4-fluorobenzene-sulfonyl]amino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 64) and 2-aminopropane.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[CH2:11]([O:25][C:26]1[O:30][C:29]([C:31]([OH:33])=[O:32])=[CH:28][CH:27]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(=O)([O-])[O-].[Cs+].[Cs+].Cl>>[CH2:11]([O:25][C:26]1[O:30][C:29]([C:31]([O:33][CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][O:8][CH2:7][CH2:6]2)=[O:32])=[CH:28][CH:27]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: ClCCN1CCOCC1
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)o1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)OCCN2CCOCC2)o1

Procedure:
The title compound was prepared as in Example 30 starting with 0.224 g (1.2 mmol) of 4-(2-chloroethyl)morpholine hydrochloride and 0.162 g (0.5 mmol) of 5-(tetradecyloxy)furan-2-carboxylic acid with the exception that a total of 0.730 g of cesium carbonate was added to neutralize the hydrochloride. 1H NMR (300 MHz, CDCl3) δ: 7.15 (d, 1H), 5.30 (d, 1H), 4.40 (t, 2H), 4.10 (t, 2H), 3.70 (app t, 4H), 2.70 (t, 2H), 2.55 (app t, 4H), 1.80 (p, 2H), 1.18-1.55 (m, 22H), 0.89 (t, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]([CH3:11])[CH3:10])[C:4]=1[OH:12])[CH3:2].[OH2:13]>>[CH2:1]([C:3]1[CH:8]=[C:7]([OH:13])[CH:6]=[C:5]([CH:9]([CH3:11])[CH3:10])[C:4]=1[OH:12])[CH3:2]
Reactant: O
Reactant: CCc1cccc(C(C)C)c1O
Product: CCc1cc(O)cc(C(C)C)c1O
Reaction time: 3 h

Procedure:
To a solution of K2S2O8 (8.2 g) in 80 mL of water, was added at once a solution of the above 2-ethyl-6-isopropylphenol (2 g, 12.2 mmol in 25 mL 5% NaOH solution). The mixture was stirred for 3 h and extracted with hexane (3×60 mL). The organic extract was stirred with Na2S2SO4 solution (8.5 g, in 100 mL water) for one hour and the layers were separated. The organic layer was dried over Na2S2O4 and concentrated and dried under high vacuum to give 2-ethyl-6-isopropylbenzene-1,4-diol. To a solution of the crude 2-ethyl-6-isopropylbenzene-1,4-diol in dichloromethane (50 mL) was added acetyl chloride (2.9 g, 36 mmol) and then triethylamine (6 g, 60 mmol) slowly at 0° C. The mixture was stirred at room temperature for 2 h and diluted with hexane/EtOAc (4:1). The mixture was filtered and the filtrate was washed with water (3×80 mL) and dried over Na2SO4 and concentrated. The crude product was purified to afford 2-ethyl-6-isopropyl-1,4-phenylene diacetate as a yellow oil (750 mg).
Reaction SMILES: [OH-].[Na+].[NH2:3][C:4]1[N:5]=[CH:6][C:7]2[CH:12]([C:13]([O:15]C)=[O:14])[CH2:11][CH2:10][C:8]=2[N:9]=1.Cl>CO>[NH2:3][C:4]1[N:5]=[CH:6][C:7]2[CH:12]([C:13]([OH:15])=[O:14])[CH2:11][CH2:10][C:8]=2[N:9]=1
Reactant: COC(=O)C1CCc2nc(N)ncc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1ncc2c(n1)CCC2C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Sodium hydroxide (13.0 mL, 13.0 mmol) was added to a solution of methyl 2-amino-6,7-dihydro-5H-cyclopenta[d]pyrimidine-5-carboxylate (1.10 g, 5.69 mmol) in methanol (21 mL). The resulting mixture was stirred at RT for 1.5 hours. Hydrochloric acid (13 mL, 13.00 mmol) was added. The solvent was evaporated. The residue was purified by chromatography on silica (24 g cartridge) eluting with CH2Cl2:MeOH 95:5 (150 mL) and CH2Cl2:MeOH:AcOH 90:10:1 to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[C:15]([NH:17][CH3:18])[C:14]([N+:19]([O-:21])=[O:20])=[CH:13][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH2:12])[CH:7]=1.[C:22](Cl)(=[O:24])[CH3:23].O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:16]=[C:15]([NH:17][CH3:18])[C:14]([N+:19]([O-:21])=[O:20])=[CH:13][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([NH:12][C:22](=[O:24])[CH3:23])[CH:7]=1
Reactant: CC(=O)Cl
Reactant: CNc1cc(OC)c(Oc2ccnc(N)c2)cc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: O
Product: CNc1cc(OC)c(Oc2ccnc(NC(C)=O)c2)cc1[N+](=O)[O-]
Reaction time: 0.08 h

Procedure:
Under a nitrogen atmosphere, 4-(2-methoxy-4-(methylamino)-5-nitrophenoxy)pyridin-2-amine (1 eq) and disopropylethylamine (4 eq) in methylene chloride was brought to 0° C. Acetyl chloride (1.1 eq) was added dropwise and mixture stirred for 5 minutes. Reaction brought to room temperature and water added. Organic layer washed with brine, dried over sodium sulfate and concentrated to yield N-(4-(2-methoxy-4-(methylamino)-5-nitrophenoxy)pyridin-2-yl)acetamide. HPLC=3.21 min; MS: MH+=333.
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[CH2:11][C:10]2[C:5](=[CH:6][C:7]([NH:12][C:13](=[O:26])[C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=3)=[CH:8][CH:9]=2)[CH2:4][N:3]1C(=O)C(F)(F)F.C(=O)([O-])[O-].[K+].[K+]>CO.O>[CH3:1][C:2]1([CH3:33])[CH2:11][C:10]2[C:5](=[CH:6][C:7]([NH:12][C:13](=[O:26])[C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([C:22]([F:24])([F:23])[F:25])[CH:15]=3)=[CH:8][CH:9]=2)[CH2:4][NH:3]1
Reactant: COc1ccc(C(=O)Nc2ccc3c(c2)CN(C(=O)C(F)(F)F)C(C)(C)C3)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1ccc(C(=O)Nc2ccc3c(c2)CNC(C)(C)C3)cc1C(F)(F)F
Yield: 86.1 %

Procedure:
To a stirred solution of N-(3,3-dimethyl-1,2,3,4-tetrahydro-2-trifluoroacetylisoquinolin-7-yl)-4-methoxy-3-trifluoromethyl benzamide (442 mg; 0.93 mmol) in methanol (50 ml) and water (25 ml) was added potassium carbonate (642 mg; 4.65 mmol) and the resultant mixture heated under reflux for I h. Evaporation in vacuo gave a residue which was partitioned between dichloromethane and water. The organic phase was dried over sodium sulfate, and evaporation in vacuo gave the title compound (303 mg).
Reaction SMILES: CO[C:3]1[CH:14]=[CH:13][C:6]2[CH:7]=[CH:8][CH2:9][C:10](=[O:12])[NH:11][C:5]=2[CH:4]=1.[C:15](O)(=[O:17])C>[Pd]>[CH3:15][O:17][C:6]1[CH:13]=[CH:14][C:3]2[CH2:4][CH2:5][NH:11][C:10](=[O:12])[CH2:9][C:8]=2[CH:7]=1
Reactant: CC(=O)O
Reactant: COc1ccc2c(c1)NC(=O)CC=C2
Agent: [Pd]
Product: COc1ccc2c(c1)CC(=O)NCC2

Procedure:
Here, 8-methoxy-1,3-dihydro-2H-benzazepin-2-one (melting point: 190°-191° C.) (56.8 g, 0.3 mol), dissolved in glacial acetic acid (600 ml), is hydrogenated for 12 hours in the presence of 10% palladium/charcoal (5 g) at 80° C. and at 5 bar. The catalyst is removed by suction filtering and the acetic acid is distilled off in vacuo. The residue is mixed with water, neutralized with potassium carbonate, the precipitate obtained is suction filtered, washed with water and dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:18]=[C:17]([C:19](O)=[O:20])[C:16]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)=[CH:15][C:11]=2[C:12]([OH:14])=O)=[CH:5][CH:4]=1>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]2[NH:9][C:10]3[C:11]([C:12](=[O:14])[C:5]=2[CH:4]=1)=[CH:15][C:16]1[NH:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=2[C:19](=[O:20])[C:17]=1[CH:18]=3
Reactant: COc1ccc(Nc2cc(C(=O)O)c(Nc3ccc(OC)cc3)cc2C(=O)O)cc1
Solvent: O
Product: COc1ccc2[nH]c3cc4c(=O)c5cc(OC)ccc5[nH]c4cc3c(=O)c2c1
Yield: 101.8 %

Procedure:
2,5-Bis{(4-methoxyphenyl)amino}terephthalic acid (1.02 gm; 2.5 mmol) and polyphosphoric acid (10 gm) were heated at 160° C. for 15 minutes under a nitrogen atmosphere. The mixture was allowed to cool and then poured into iced water (200 ml) when a purple solid precipitated out. This was filtered off, washed with water and methanol, then dried under vacuum over phosphorous pentoxide to give 948 mg (100%) of 2,9-dimethoxyquinacridone.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[F:23])[CH:3]=1.[C:24]([CH2:26][C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)#[N:25].C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.O.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>[F:23][C:14]1[CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=[CH:18][C:13]=1[CH2:12][CH2:11][NH:10][C:4]1[N:5]=[C:6]([O:8][CH3:9])[N:7]=[C:2]([C:31]2[CH:32]=[C:27]([CH2:26][C:24]#[N:25])[CH:28]=[CH:29][CH:30]=2)[CH:3]=1
Reactant: COc1nc(Cl)cc(NCCc2ccc(C(F)(F)F)cc2F)n1
Reactant: N#CCc1cccc(B(O)O)c1
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: [Cs+]
Solvent: O
Solvent: COCCOC
Product: COc1nc(NCCc2ccc(C(F)(F)F)cc2F)cc(-c2cccc(CC#N)c2)n1
Reaction time: 1 h

Procedure:
A mixture of (6-chloro-2-methoxy-pyrimidin-4-yl)-[2-(2-fluoro-4-trifluoromethyl-phenyl)-ethyl]-amine [800 mg, 2.29 mmol, see Example 52, step 1], (3-cyanomethyl-phenyl)-boronic acid, pinacol ester (563 mg, 3.43 mmol), and Cs2CO3 (1.86 g, 5.72 mmol) in ethylene glycol dimethyl ether (15 mL) and water (4 mL) is degassed by bubbling with Argon gas for 5 minutes, and treated with tetrakis(triphenylphosphine)palladium(0) (132 mg, 0.11 mmol) at room temperature. After 1 h at 85° C., the mixture is diluted with water (50 mL), and extracted with EtOAc (2×50 mL). The extracts are dried (MgSO4), filtered through a pad of SiO2, and concentrated to afford (3-{6-[2-(2-fluoro-4-trifluoromethyl-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-acetonitrile (1.2 g). LCMS: RT=2.47 minutes, 92% purity. MS: 431 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH2:6]Br)([O-:3])=[O:2].Cl.[CH3:13][O:14][C:15](=[O:18])[CH2:16][NH2:17].CCN(C(C)C)C(C)C.O>CN(C=O)C>[CH3:13][O:14][C:15](=[O:18])[CH2:16][NH:17][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1CBr
Reactant: COC(=O)CN
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CNCc1ccccc1[N+](=O)[O-]
Yield: 73.7 %

Procedure:
To a solution of 2-nitrobenzyl bromide (1.0 g, 4.63 mmol) and glycine methyl ester hydrochloride (868 mg, 6.94 mmol) in dry DMF (10 mL), was added DIPEA (2.42 mL, 13.89 mmol) under nitrogen atmosphere. The reaction mixture was stirred at. r.t. overnight. After completion of the reaction as confirmed by TLC, water (50 mL) was added to the reaction mixture. The crude product was extracted with ethyl acetate (20 mL). The aqueous layer was washed with ethyl acetate (2×10 mL), The combined organic extract was dried over Na2SO4 and the solvents were removed in vacuo to afford the crude compound, which was purified by column chromatography (silica gel, 1:9 EtOAc:Pet Ether) to afford pure (2-nitro-benzylamino)-acetic acid methyl ester (765 mg 73%) as a viscous oil.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[S:8][C:9]3[CH:15]=[C:14]([O:16][S:17]([C:20]4[CH:25]=[CH:24][C:23](F)=[CH:22][CH:21]=4)(=[O:19])=[O:18])[CH:13]=[CH:12][C:10]=3[N:11]=2)=[O:5])[CH2:3][CH2:2]1.[NH2:27][CH2:28][C:29]([CH3:32])([OH:31])[CH3:30]>CN1C(=O)CCC1>[CH:1]1([C:4]([NH:6][C:7]2[S:8][C:9]3[CH:15]=[C:14]([O:16][S:17]([C:20]4[CH:25]=[CH:24][C:23]([NH:27][CH2:28][C:29]([OH:31])([CH3:32])[CH3:30])=[CH:22][CH:21]=4)(=[O:19])=[O:18])[CH:13]=[CH:12][C:10]=3[N:11]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(Nc1nc2ccc(OS(=O)(=O)c3ccc(F)cc3)cc2s1)C1CC1
Reactant: CC(C)(O)CN
Solvent: CN1CCCC1=O
Product: CC(C)(O)CNc1ccc(S(=O)(=O)Oc2ccc3nc(NC(=O)C4CC4)sc3c2)cc1

Procedure:
A solution of 4-fluorobenzenesulfonic 2-(cyclopropanecarbonylamino)benzo-thiazol-6-yl ester (example 7) (100 mg, 255 μmol) and 1-amino-2-methyl-propan-2-ol (91 mg, 1.02 mmol) in 2 ml of NMP is heated at 150° C. by microwave for 5 minutes. The crude reaction product is purified by preparative LC/MS (basic medium (pH 9)) to give after freeze-drying 61 mg of 4-(2-hydroxy-2-methylpropylamino)benzenesulfonic 2-(cyclopropanecarbonyl-amino)benzothiazol-6-yl ester (beige-colored solid).