Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.[Br:11]Br.N>C(Cl)(Cl)Cl>[Br:11][C:6]1[NH:7][C:8]2[C:4](=[N:3][CH:2]=[N:1][C:9]=2[NH2:10])[N:5]=1
Reactant: Nc1ncnc2nc[nH]c12
Reactant: BrBr
Agent: N
Solvent: ClC(Cl)Cl
Product: Nc1ncnc2nc(Br)[nH]c12
Temperature: 25 °C
Reaction time: 72 h
Yield: 60.1 %

Procedure:
Adenine (47 g, 0.35 mole) was suspended in 200 ml of CHCl3 before adding bromine (180 ml, 3.5 mole) in one portion. The suspension was left stirring at room temperature for 72 hours in a closed system that was vented by a 20 G needle. The reaction was worked up by adding shaved ice into the suspension before slowly neutralizing with aqueous ammonia to pH 8-9, followed by precipitation of the desired product with acetic acid. The crude product was dried under reduced pressure for 2 days to give 8-Bromoadenine as a light brown powder (45 g, 60% yield). 1H NMR (DMSO-d6) δ 8.12 (s, 1H), 7.22 (s, 2H). Rf(75% EtOAc/Hex)=0.4.
Reaction SMILES: [OH:1][C:2]1C=CC2[C:4](=CC=C([N+]([O-])=O)C=2)[C:3]=1C=O.C[N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](C)(C)[C:19]1=[CH2:29]>C(O)C>[O:1]1[CH:2]=[CH:3][CH:4]=[CH:29][C:19]21[CH2:20][C:21]1[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=1)[NH:18]2
Reactant: O=Cc1c(O)ccc2cc([N+](=O)[O-])ccc12
Reactant: C=C1N(C)c2ccccc2C1(C)C
Solvent: CCO
Product: C1=COC2(C=C1)Cc1ccccc1N2
Temperature: 0 °C

Procedure:
A solution is prepared of 2.17 g. (0.0295 mole) of 2-hydroxy-6-nitro-1-naphthaldehyde in 80 cm3 of hot ethanol, to this is added 1.73 g. (0.0295 mole) of 1,3,3-trimethyl-2-methyleneindoline and the mixture is heated for two hours at boiling temperature under reflux. The mixture is then cooled to 0° C. and a precipitate of indolinespiropyran is obtained. This is filtered and dried. The composition has a melting point of 234° C. The product is recrystallized twice from benzene and the melting point is increased to 240°-241° C. The purified product weight is 1.34 g. which represents a recovery of 36%.
Reaction SMILES: C[O-].[Na+].CO.[CH3:6][NH:7][C:8]1[C:13]([CH:14]=[CH:15][C:16](OCCCC)=[O:17])=[CH:12][C:11]([N+:23]([O-:25])=[O:24])=[CH:10][N:9]=1>O>[CH3:6][N:7]1[C:8]2[C:13](=[CH:12][C:11]([N+:23]([O-:25])=[O:24])=[CH:10][N:9]=2)[CH:14]=[CH:15][C:16]1=[O:17]
Reactant: CCCCOC(=O)C=Cc1cc([N+](=O)[O-])cnc1NC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cn1c(=O)ccc2cc([N+](=O)[O-])cnc21
Yield: 76 %

Procedure:
5M sodium methoxide (methanol solution) (0.5 ml) was added to a methanol solution (2 ml) containing n-butyl 3-(2-(methylamino)-5-nitropyridin-3-yl)acrylate (43 mg) obtained in the 1st step, followed by reflux for 3.5 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resultant was washed with saturated saline and dried over anhydrous sodium sulfate. Subsequently, the solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=4:1 to 2:1), and a white solid of 1-methyl-6-nitro-1,8-naphthyridin-2(1H)-one (24 mg) was thus obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4](=[N:11][OH:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CCOCC.[Cl:23][CH:24]([F:28])[C:25](Cl)=[O:26]>O>[Cl:23][CH:24]([F:28])[C:25]([NH:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4](=[N:11][OH:12])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:26]
Reactant: Nc1ccc(Cl)cc1C(=NO)c1ccccc1
Reactant: O=C(Cl)C(F)Cl
Solvent: CCOCC
Solvent: O
Product: O=C(Nc1ccc(Cl)cc1C(=NO)c1ccccc1)C(F)Cl
Reaction time: 0.5 h
Yield: 88 %

Procedure:
Water, 250 ml, was added to a solution of 50 g (0.203 mole) of 2-amino-5-chlorobenzophenone oxime (mixture of isomers) in 1 l. of ether, and the mixture was stirred rapidly and cooled to 5°. Solutions of (A) 100 ml of 10% sodium hydroxide in water and (B) 33.5 g (0.228 mole) of chlorofluoroacetyl chloride made up to 100 ml with ether were simultaneously added at the same rate over 30 min., keeping the temperature of the reaction mixture at about 10° with cooling. The reaction mixture was stirred for 30 min. after the addition, and the ether layer was separated, washed with water, dried (MgSO4), and evaporated to dryness under reduced pressure. The residue was recrystallized from benzene to give 61.2 g (88%) of 2-(chlorofluoroacetamido)-5-chlorobenzophenone oxime (mixture of isomers) as light yellow crystals, mp 110°-129°. The 19F nmr (acetone-d6) indicates a mixture of two isomers in a 70:30 ratio: δ -143.2 ppm (d, d, J=50, 2.5 Hz, 30%) and δ -144.3 ppm (d, d, J=50, 2.5 Hz, 70%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[OH:30][C:31]1[CH:36]=[C:35]([C:37]([F:40])([F:39])[F:38])[CH:34]=[CH:33][C:32]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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.O>[OH:30][C:31]1[CH:36]=[C:35]([C:37]([F:38])([F:39])[F:40])[CH:34]=[CH:33][C:32]=1[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([N:15]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:16]3[S:17][CH:18]=[CH:19][N:20]=3)(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1O
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(Cl)nccc3c2)cc1
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: O
Solvent: C1COCCO1
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4O)nccc3c2)cc1

Procedure:
To a microwave vial charged with 1-chloro-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Intermediate JJJ) (87 mg, 0.194 mmol), (2-hydroxy-4-(trifluoromethyl)phenyl)boronic acid (40 mg, 0.194 mmol), potassium carbonate (134 mg, 0.971 mmol) and Pd(Ph3P)4 (22.45 mg, 0.019 mmol) was added Dioxane (971 μl) and Water (324 μl) and irradiated at 100° C. for 30 min affording conversion to desired product as the primary species. The organic layer was decanted, the aqueous rinsed with EtOAc and the combined organics dried under reduced pressure. The crude material was used without further purification. m/z (ESI) 572.3 (M+H)+
Reaction SMILES: Br[C:2]1[CH:21]=[N:20][C:5]2[NH:6][CH2:7][CH2:8][N:9]([CH2:10][C:11]3[C:16]([F:17])=[CH:15][CH:14]=[C:13]([F:18])[C:12]=3[Cl:19])[C:4]=2[C:3]=1[CH3:22].[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][O:32][C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:26][CH2:25]1>>[Cl:19][C:12]1[C:13]([F:18])=[CH:14][CH:15]=[C:16]([F:17])[C:11]=1[CH2:10][N:9]1[CH2:8][CH2:7][NH:6][C:5]2[N:20]=[CH:21][C:2]([C:36]3[CH:37]=[CH:38][C:33]([O:32][CH2:31][CH2:30][N:27]4[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]4)=[CH:34][CH:35]=3)=[C:3]([CH3:22])[C:4]1=2
Reactant: Cc1c(Br)cnc2c1N(Cc1c(F)ccc(F)c1Cl)CCN2
Reactant: CN1CCN(CCOc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: Cc1c(-c2ccc(OCCN3CCN(C)CC3)cc2)cnc2c1N(Cc1c(F)ccc(F)c1Cl)CCN2

Procedure:
The entitled compound can be prepared from 7-bromo-1-(2-chloro-3,6-difluorobenzyl)-8-methyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazine and 1-methyl-4-{2-[4-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)-phenoxy]-ethyl}-piperazine as described in example 25.
Reaction SMILES: [C:1]([NH:9][C:10]([N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][C:13]1=[O:21])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23].Cl>CN(C)C=O.CN(C1C=CN=CC=1)C>[C:1]([NH:9][C:10]([N:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]([C:22](=[O:24])[CH3:23])[C:13]1=[O:21])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(NC(=O)N1C(=O)Cc2ccccc21)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(=O)C1C(=O)N(C(=O)NC(=O)c2ccccc2)c2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 39.8 %

Procedure:
To a stirred slurry of 841 mg (3.0 mmole) of N-benzoyl-2-oxindole-1-carboxamide in 5 ml of N,N-dimethylformamide was added 806 mg (6.6 mmole) of 4-(N,N-dimethylamino)pyridine. Stirring was continued for a few minutes, and then the slurry was cooled in an ice-bath and a solution of 337 mg (3.3 mmole) of acetic anhydride in 2 ml of N,N-dimethylformamide was added dropwise. Stirring was continued for 1 hour, and then the reaction mixture was poured onto a mixture of 65-70 ml. of ice-water and 2.2 ml of 3N hydrochloric acid. The solid which precipitated was recovered by filtration. It was recrystallized from ethanol to give 385 mg of the title compound as tan crystals, mp 198° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[N:6][CH:7]=1.[CH3:16][CH:17]1[C:21](=O)[CH2:20][CH2:19][O:18]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>C1(C)C=CC=CC=1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:14]#[N:15])[CH2:9][CH2:10][N:11]([C@H:21]3[CH2:20][CH2:19][O:18][C@H:17]3[CH3:16])[CH2:12][CH2:13]2)=[N:6][CH:7]=1
Reactant: N#CC1(c2ccc(Br)cn2)CCNCC1
Reactant: CC1OCCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@@H]1OCC[C@@H]1N1CCC(C#N)(c2ccc(Br)cn2)CC1
Yield: 69.4 %

Procedure:
To a solution of 4-(5-bromopyridin-2-yl)piperidine-4-carbonitrile (1.15 g) in toluene (14.4 ml), was added 2-methyltetrahydrofuran-3-one (526 mg), and then, sodium triacetoxyborohydride (1.37 g), and the mixture was stirred at room temperature for five hours. Water and 1N aqueous solution of sodium hydroxide were added to the reaction solution at 0° C., and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified with NH silica gel chromatography (n-hexane/ethyl acetate) to give cis-4-(5-bromopyridin-2-yl)-1-(2-methyltetrahydrofuran-3-yl)piperidine-4-carbonitrile (1.05 g) as a yellow solid.
Reaction SMILES: [OH:1][C:2]([CH3:7])([CH3:6])[C:3](O)=[O:4].[CH2:8]([C:10]1[N:14]([C:15]2[N:23]=[C:22]3[C:18]([N:19]=[C:20]([C:25]4([O:31][CH3:32])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]4)[N:21]3[CH3:24])=[C:17]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[N:16]=2)[C:13]2[CH:39]=[CH:40][CH:41]=[CH:42][C:12]=2[N:11]=1)[CH3:9].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C>C1COCC1>[CH2:8]([C:10]1[N:14]([C:15]2[N:23]=[C:22]3[C:18]([N:19]=[C:20]([C:25]4([O:31][CH3:32])[CH2:30][CH2:29][N:28]([C:3](=[O:4])[C:2]([OH:1])([CH3:7])[CH3:6])[CH2:27][CH2:26]4)[N:21]3[CH3:24])=[C:17]([N:33]3[CH2:34][CH2:35][O:36][CH2:37][CH2:38]3)[N:16]=2)[C:13]2[CH:39]=[CH:40][CH:41]=[CH:42][C:12]=2[N:11]=1)[CH3:9]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CCNCC3)n(C)c2n1
Reactant: CC(C)(O)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C3(OC)CCN(C(=O)C(C)(C)O)CC3)n(C)c2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61.6 %

Procedure:
To a solution of 2-hydroxyisobutyric acid (49 mg, 0.47 mmol) in THF (3 mL) was added 2-(2-ethylbenzoimidazol-1-yl)-8-(4-methoxypiperidin-4-yl)-9-methyl-6-morpholin-4-yl-9H-purine (150 mg, 0.32 mmol), HOBt (47 mg, 0.35 mmol), NMM (77 μL, 0.69 mmol) and EDCI (91 mg, 0.47 mmol). The resulting mixture was allowed to stir at r.t. for 4 h then quenched with sat. aq. NH4Cl and extracted with DCM. The organic phase was washed with brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-20%) then triturated with MeOH/H2O. The resulting solid was collected by filtration and dried in vacuo affording 800 (111 mg, 63%). LCMS (method G): RT 7.36 min, [M+H]+ 563.4. 1H NMR (DMSO, 400 MHz): δ 8.05-8.04 (1 H, m), 7.66-7.62 (1 H, m), 7.25-7.24 (2 H, m), 5.44 (1 H, s), 4.26 (6 H, brd s), 3.92 (3 H, s), 3.78 (4 H, t, J=4.52 Hz), 3.30-3.23 (4 H, m), 3.09 (3 H, s), 2.26-2.16 (2 H, m), 2.19-2.02 (2 H, m), 1.35-1.33 (9 H, m)
Reaction SMILES: [Cl:1][CH2:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:12][S:13](Cl)(=[O:15])=[O:14].C(N(CC)CC)C>C(Cl)Cl>[Cl:1][CH2:2][C:3]1[N:4]([S:13]([CH3:12])(=[O:15])=[O:14])[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: ClCc1nc2ccccc2[nH]1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)n1c(CCl)nc2ccccc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 63.8 %

Procedure:
To a solution of 2-(chloromethyl)benzimidazole (80 g, 0.48 mol) and methanesulfonyl chloride (58.3 mL, 0.75 mol) in 0.5 L of methylene chloride, triethylamine (136 mL, 0.97 mol) was added dropwise under nitrogen. The resulting mixture was stirred at room temperature for 6 hours. The mixture was filtered and the filtrate was evaporated. The residue was triturated in methanol and filtered to afford 74.9 g of the title compound as a brown solid.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:17])[C:4]1[CH:9]=[CH:8][C:7]([S:10](=[O:16])(=[O:15])[NH:11][CH2:12][CH2:13][OH:14])=[CH:6][CH:5]=1.[CH2:18]([N:20]([CH2:23][C:24]1[S:28][C:27]([C:29](O)=O)=[CH:26][C:25]=1[CH3:32])[CH2:21][CH3:22])[CH3:19]>>[CH2:18]([N:20]([CH2:23][C:24]1[S:28][C:27]([C:29]2[O:1][N:2]=[C:3]([C:4]3[CH:9]=[CH:8][C:7]([S:10]([NH:11][CH2:12][CH2:13][OH:14])(=[O:16])=[O:15])=[CH:6][CH:5]=3)[N:17]=2)=[CH:26][C:25]=1[CH3:32])[CH2:21][CH3:22])[CH3:19]
Reactant: CCN(CC)Cc1sc(C(=O)O)cc1C
Reactant: N=C(NO)c1ccc(S(=O)(=O)NCCO)cc1
Product: CCN(CC)Cc1sc(-c2nc(-c3ccc(S(=O)(=O)NCCO)cc3)no2)cc1C
Yield: 9.1 %

Procedure:
Starting from N-hydroxy-4-(2-hydroxy-ethylsulfamoyl)-benzamidine (201 mg, 0.774 mmol) and 5-diethylaminomethyl-4-methyl-thiophene-2-carboxylic acid (160 mg, 0.704 mmol), the title compound (29 mg) is obtained as a yellow oil according to Method A; LC-MS: tR=0.49 min; [M+1]+=451.02; 1H NMR (CDCl3): δ1.27 (t, J=7.3 Hz, 6H), 2.34 (s, 3H), 2.91 (q, J=7.3 Hz, 4H), 3.17-3.22 (m, 2H), 3.73-3.77 (m, 2H), 4.11 (s, 2H), 7.74 (s, 1H), 8.01-8.04 (m, 2H), 8.24 (s br, 1H), 8.30-8.33 (m, 2H).
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[Cl:16][C:17]1[CH:22]=[C:21](Cl)[N:20]=[C:19]([NH2:24])[N:18]=1>CN(C=O)C>[NH2:24][C:19]1[N:20]=[C:21]([N:8]2[C:9]3[C:5](=[CH:4][CH:3]=[C:2]([I:1])[CH:10]=3)[C:6]([C:11]([OH:13])=[O:12])=[N:7]2)[CH:22]=[C:17]([Cl:16])[N:18]=1
Reactant: O=C(O)c1n[nH]c2cc(I)ccc12
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Nc1nc(Cl)cc(-n2nc(C(=O)O)c3ccc(I)cc32)n1
Temperature: 25 °C

Procedure:
To a solution of 6-iodo-1H-indazole-3-carboxylic acid (3.00 g, 10.42 mmol) in dry DMF (50 mL) at 0° C. under an atmosphere of nitrogen was introduced sodium hydride (1.25 g of a 60% dispersion in mineral oil, 31.25 mmol). The reaction mixture was warmed to RT for 15 mins. 4,6-Dichloropyrimidin-2-amine (2.56 g, 15.62 mmol) was then added, and the solution warmed to 60° C. for 18 hr. After cooling to 0° C., the reaction was carefully quenched with water (50 mL) and acidified by addition of 0.5M aqueous citric acid. The resulting precipitate was collected by filtration, washed on the filter with 1:1 methanol/EtOAc and dried under vacuum to furnish the title compound as a beige solid: LC-MS: m/z=+415.85/417.90 (M+H)+. This compound, with LC-MS purity=70% UV, was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:24]2[CH2:28][CH2:27][CH:26]([CH2:29][O:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=3)[CH2:25]2)=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)=[O:8].O1CCOCC1.O.[OH-].[Li+]>O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:24]2[CH2:28][CH2:27][CH:26]([CH2:29][O:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=3)[CH2:25]2)=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1([C:13]2[CH:22]=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)[CH2:12][CH2:11]1)=[O:8]
Reactant: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CCC(COc4cccc(F)c4)C3)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CCC(COc4cccc(F)c4)C3)CC2)cc1
Reaction time: 0.08 h
Yield: 51 %

Procedure:
To a solution of methyl 4-(1-(5-chloro-2-(3-((3-fluorophenoxy)methyl)pyrrolidin-1-yl)nicotinamido)cyclopropyl)benzoate (D200) (37 mg, 0.070 mmol) in a mixture 1,4-dioxane and water (3:1) (2 ml) lithium hydroxide monohydrate (10 mg, 0.238 mmol) was added and the mixture was stirred 20 min (4 cycles of 5 min each) under microwaves irradiation. After solvent evaporation the residue was diluted with water (5 ml) and 1M HCl (5 ml) and extracted with ethylacetate (3×10 ml). Collected organics after solvent evaporation afforded a residue that was purified by ISOLUTE Spe-Si (1 g) eluting with a mixture dichloromethane/methanol 98:2. Collected fractions after solvent evaporation afforded the title compound (E76) (18.2 mg)
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClCCl.[CH:28]([C:30]1[CH:31]=[CH:32][C:33]2[N:34]([CH3:44])[C:35]3[C:40]([S:41][C:42]=2[CH:43]=1)=[CH:39][CH:38]=[CH:37][CH:36]=3)=O>CCCCCC.[Zn]>[Br:2][C:1]([Br:5])=[CH:28][C:30]1[CH:31]=[CH:32][C:33]2[N:34]([CH3:44])[C:35]3[C:40]([S:41][C:42]=2[CH:43]=1)=[CH:39][CH:38]=[CH:37][CH:36]=3
Reactant: BrC(Br)(Br)Br
Reactant: CN1c2ccccc2Sc2cc(C=O)ccc21
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: ClCCl
Product: CN1c2ccccc2Sc2cc(C=C(Br)Br)ccc21
Temperature: 25 °C
Reaction time: 23 h
Yield: 63.4 %

Procedure:
In an atmosphere of argon, carbon tetrabromide (8.29 g, 25 mmol) and zinc powder (1.63 g, 25 mmol) were added in that order to a mixture of triphenylphosphine (6.56 g, 25 mmol) and dichloromethane (75 ml), and the mixture was stirred at room temperature for 23 hours. A dichloromethane (25 ml) solution of 3-formyl-10-methylphenothiazine (3.02 g, 12.5 mmol) was added and the mixture was again stirred for 7 hours. The reaction mixture was diluted with hexane and the insoluble matter was removed by filtration. The reaction product was extracted from the insoluble matter three times with hexane (about 60° C.), and the thus collected organic layers were combined and concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; ethyl acetate:dichloromethane:hexane=10:10:80) to give the title compound (3.15 g, 7.93 mmol, 63%) as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])=[CH:11][C:10]([C:21](O)=[O:22])=[C:9]2[CH2:24][CH2:25][CH2:26][OH:27])=[CH:4][CH:3]=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2([C:41]([NH2:43])=[O:42])[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[CH:31][CH:30]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2([C:41]([NH2:43])=[O:42])[CH2:36][CH2:37][N:38]([C:21]([C:10]3[CH:11]=[C:12]([C:13]4[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=4[Cl:20])[N:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)[C:9]=3[CH2:24][CH2:25][CH2:26][OH:27])=[O:22])[CH2:39][CH2:40]2)=[CH:31][CH:30]=1
Reactant: NC(=O)C1(c2ccc(Cl)cc2)CCNCC1
Reactant: O=C(O)c1cc(-c2ccc(Cl)cc2Cl)n(-c2ccc(Cl)cc2)c1CCCO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)C1(c2ccc(Cl)cc2)CCN(C(=O)c2cc(-c3ccc(Cl)cc3Cl)n(-c3ccc(Cl)cc3)c2CCCO)CC1

Procedure:
Into a round-bottomed flask under nitrogen are introduced 300 mg of the acid obtained in step 3a) in 30 ml of DMF, 246 mg of 4-(4-chlorophenyl)piperidine-4-carboxamide (prepared according to the procedure described in patent application US 2005/0070549, in particular in Example 460, paragraphs 1394 to 1397), 0.62 ml of DIPEA and 250 mg of TBTU.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([NH2:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:15]1(=O)[O:21][C:19](=[O:20])[CH:18]=[C:16]1[CH3:17].C([O-])([O-])=O.[K+].[K+]>C(O)(=O)C>[CH3:17][C:16]1[C:15](=[O:21])[N:14]([C:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[C:19](=[O:20])[CH:18]=1
Reactant: Nc1ccc([N+](=O)[O-])c2ccccc12
Reactant: CC1=CC(=O)OC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: CC1=CC(=O)N(c2ccc([N+](=O)[O-])c3ccccc23)C1=O
Temperature: 115 °C
Reaction time: 0.25 h
Yield: 121 %

Procedure:
4-nitro-1-naphthalamine (2.00 g, 10.63 mmol) and citraconic anhydride (1.05 mL, 11.69 mmol) were dissolved in acetic acid (10 mL) and heated to 115° C. for 14 h. The reaction was then cooled to 25° C. and transferred to cold sat K2CO3 with vigorous stirring. After 15 min, the solution was filtered, rinsed with water and dried under vacuum to yield 3.63 g of compound 16A as a yellow solid. This material was taken on to the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][N:8]2[CH2:21][C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[CH:4][C:3]=1[O:34][CH3:35].[CH2:36](Br)[CH2:37][CH2:38][CH3:39]>>[CH2:36]([O:1][C:2]1[CH:33]=[CH:32][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=3)[CH2:10][CH2:9][N:8]2[CH2:21][C:22]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])=[CH:4][C:3]=1[O:34][CH3:35])[CH2:37][CH2:38][CH3:39]
Reactant: COc1cc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)ccc1O
Reactant: CCCCBr
Product: CCCCOc1ccc(CC2c3cc(OC)c(OC)cc3CCN2CC(=O)NCc2ccccc2)cc1OC

Procedure:
prepared by reaction of 2-[1-(4-hydroxy-3-methoxy-benzyl)-6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-benzyl-acetamide with butyl bromide
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][O:8][C:4]=2[C:3]=1[CH:12]=[O:13].[C:14]([O-])([O-])=O.[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:14][O:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6]([CH3:9])=[N:7][O:8][C:4]=2[C:3]=1[CH:12]=[O:13]
Reactant: O=C([O-])[O-]
Reactant: Cc1noc2c(C=O)c(O)ccc12
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: COc1ccc2c(C)noc2c1C=O
Temperature: 60 °C

Procedure:
A mixture of 6-hydroxy-3-methylbenzo[d]isoxazole-7-carbaldehyde (437 mg; 2.46 mmol) and K2CO3 (409 mg; 2.96 mmol) in anh. acetone (21 ml) was treated with dimethyl sulfate (373 mg; 2.96 mmol), and the resulting mixture was heated to 60° C., under nitrogen, for 1.5 h. After cooling to rt, the resulting reaction mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. DCM was added, and the mixture was washed successively with 1 M aq. NH4OH, water, and brine. The organic layer was dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure to give 6-methoxy-3-methylbenzo[d]isoxazole-7-carbaldehyde as an orange solid. LC-MS (conditions A): tR=0.53 min.; [M+H]+: 192.12 g/mol.