Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][CH:14]=2)[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.Cl>>[ClH:1].[CH2:19]([C:16]1[CH:17]=[CH:18][C:13]([N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]([CH:11]=[O:12])=[C:2]2[N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:14][CH:15]=1)[CH3:20]
Reactant: C1CNCCN1
Reactant: CCc1ccc(-n2c(Cl)c(C=O)c3ccccc32)cc1
Agent: Cl
Product: CCc1ccc(-n2c(N3CCNCC3)c(C=O)c3ccccc32)cc1
Yield: 39 %

Procedure:
2-Chloro-1-(4-ethylphenyl)-1H-indole-3-carboxaldehyde is reacted with piperazine as described in Step 2 of Example 29 and subsequently treated with hydrochloric acid as described in Example 44 to afford 1-(4-ethylphenyl)-2-(piperazin-1-y)-1H-indole-3-carboxaldehyde hydrochloride (39% yield) as a cream solid. ESI/MS 334 (M+H); RT=2.67 min; NMR 10.13 (1H, s); 8.11 (1H, d, J=6 Hz); 7.50 (4H, s); 7.24 (2H, m); 6.94 (1H, d, J=6 Hz); 3.42 (4H, m); 2.95 (4H, m); 2.76 (2H, q); 1.30 (3H, t).
Reaction SMILES: C1COCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:14][C:15](=O)[CH2:16][CH2:17][C:18]1([CH2:31][CH2:32][C:33](OCC)=[O:34])[C:30]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:24]2[C:19]1=[CH:20][CH:21]=[CH:22][CH:23]=2)C.[OH-].[Na+]>CCOCC.CCOCC.C1COCC1.O>[OH:14][CH2:15][CH2:16][CH2:17][C:18]1([CH2:31][CH2:32][CH2:33][OH:34])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=2[C:25]2[C:30]1=[CH:29][CH:28]=[CH:27][CH:26]=2
Reactant: CCOC(=O)CCC1(CCC(=O)OCC)c2ccccc2-c2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: OCCCC1(CCCO)c2ccccc2-c2ccccc21
Reaction time: 2 h
Yield: 87.7 %

Procedure:
A 2-neck 1-Liter round bottom flask was equipped with a condenser, a magnetic stir bar and an addition funnel. The flask was charged with 15 mL of anhydrous THF and 30 mL of anhydrous ether. Lithium aluminum hydride (4.80 g) was then carefully added to the flask. 3-[9-(2-Ethoxycarbonyl-ethyl)-9H-fluoren-9-yl]-propionic acid ethyl ester (18.2 g) was dissolved in 95 mL of anhydrous ether and 37 mL of anhydrous THF and this mixture was added to the addition funnel. The solution of diester was then added dropwise to the rapidly stirred lithium aluminum hydride suspension over a period of 60 min. After an additional 2 hours, the rapidly stirred reaction mixture was carefully treated by the dropwise addition of water (31 mL), followed by 35% NaOH solution (63 mL), and finally more water (66 mL). Additional diethyl ether was added to keep the slurry stirring. After stirring for 30 min, the ether/THF layer was allowed to separate and was then decanted from the aluminum salts. The salts were rinsed with additional portions of diethyl ether. The combined organic portions were concentrated under reduced pressure to give a white solid. The white solid was dissolved in 200 mL of ether and 100 mL of THF, washed with 1N HCl solution (2×75 mL) and brine. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure. The resulting white solid was crystallized from hot toluene to give the title compound (1-c) (12.3 g) as white flakes. 1H NMR (CDCl3, 500 MHz) δ 7.71 (m, 2H), 7.37-7.27 (m, 6H), 3.32 (t, J=6.4 Hz, 4H), 2.09 (m, 4H), 0.87 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:35])[NH:4][C:5]2[C:10]([N:11]=1)=[C:9]([O:12][C:13]1[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[N:16]=[C:15]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[N:14]=1)[CH:8]=[CH:7][CH:6]=2.[CH:36]1([CH:39]=O)[CH2:38][CH2:37]1>>[NH2:1][C:2]1[C:3](=[O:35])[NH:4][C:5]2[C:10]([N:11]=1)=[C:9]([O:12][C:13]1[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[N:16]=[C:15]([N:29]3[CH2:34][CH2:33][N:32]([CH2:39][CH:36]4[CH2:38][CH2:37]4)[CH2:31][CH2:30]3)[N:14]=1)[CH:8]=[CH:7][CH:6]=2
Reactant: Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)nc(N4CCNCC4)n3)cccc2[nH]c1=O
Reactant: O=CC1CC1
Product: Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)nc(N4CCN(CC5CC5)CC4)n3)cccc2[nH]c1=O

Procedure:
The reaction of 3-amino-5-(2-(piperazin-1-yl)-6-(4-(trifluoromethyl)phenyl)pyrimidin-4-yloxy)quinoxalin-2(1H)-one (27 mg, 0.056 mmol, Example 135) with cyclopropanecarboxaldehyde (59 mg, 0.279 mmol, Aldrich) under the conditions of Example 36 provided the title compound as an amorphous solid. MS (ESI, pos. ion) m/z: 538 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:33])[N:10]([CH2:23][C:24]2[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=2)[C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[CH2:56]([O:58][C:59](=[O:64])[C@H:60]([OH:63])[CH2:61][NH2:62])[CH3:57].C(N(CC)C(C)C)(C)C>CN(C=O)C.C(OCC)(=O)C>[CH2:56]([O:58][C:59](=[O:64])[C@H:60]([OH:63])[CH2:61][NH:62][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][C:24]([CH2:23][N:10]([C:11]2[CH:12]=[CH:13][C:14]([CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)=[CH:15][CH:16]=2)[C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=2)=[O:33])=[CH:25][CH:26]=1)[CH3:57]
Reactant: CCOC(=O)[C@H](O)CN
Reactant: O=C(O)c1ccc(CN(C(=O)Nc2cccc(Br)c2)c2ccc(C3CCCCC3)cc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](O)CNC(=O)c1ccc(CN(C(=O)Nc2cccc(Br)c2)c2ccc(C3CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-[3-(3-Bromophenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoic acid (0.20 g, 0.39 mmol) was dissolved in DMF (2.5 mL) and EDAC (0.12 g, 0.6 mmol) and HOBt (0.089 mg, 0.6 mmol) were added and the mixture was stirred at room temperature for 10 min. (R)-Isoserine ethyl ester hydrochloride (0.10 g, 0.6 mmol) and N,N-diisopropylethylamine (130 μL) dissolved in DMF (2.5 mL) were added and the resulting mixture was stirred at room temperature for 16 hours. The mixture was added ethyl acetate (70 mL) and washed with water (2×100 mL), the organic phase was dried with sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a mixture of ethyl acetate:n-heptane (1:2) containing 10% acetic acid. This afforded 100 mg of (R)-3-{4-[3-(3-bromophenyl)-1-(4-cyclohexylphenyl)ureidomethyl]benzoylamino}-2-hydroxypropionic acid ethyl ester. HPLC-MS (Method B): m/z=624 (M+1); Rt=5.33 min.
Reaction SMILES: Cl.[CH2:2]([C:4]1[N:9]=[N:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1)[CH3:3].[N:12]#[C:13]Br>C(O)C.O>[CH2:2]([C:4]1[CH:5]=[CH:6][C:7]2[N:8]([C:13]([NH2:12])=[N:11][N:10]=2)[N:9]=1)[CH3:3]
Reactant: CCc1ccc(NN)nn1
Reactant: N#CBr
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCc1ccc2nnc(N)n2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(6-Ethylpyridazin-3-yl)hydrazine hydrochloride (2 g) was initially charged in a mixture of ethanol (30 ml) and water (6 ml) while stirring at RT. Thereafter, cyanogen bromide was cautiously added dropwise (2.4 g dissolved in 7.5 ml of ethanol and 1.5 ml of water). After stirring at RT for one hour, the mixture was left to stand overnight and, the next day, stirred for 4 further hours. The solvent was then drawn off and the residue was purified by means of preparative HPLC (met. C). The clean product fractions were combined, freed of the acetonitrile under reduced pressure, alkalized with saturated potassium carbonate solution and extracted repeatedly with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. 830 mg of the title compound were obtained. The aqueous potassium carbonate phase was likewise freeze-dried, then taken up with a little water and extracted five times with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. A further 180 mg of the title compound were obtained.
Reaction SMILES: CS([C:5]1[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][N:6]=1)(=O)=O.[CH3:19][C:20]1([CH3:27])[CH2:25][CH:24]([NH2:26])[CH2:23][CH2:22][O:21]1>>[CH3:19][C:20]1([CH3:27])[CH2:25][CH:24]([NH:26][C:5]2[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][N:6]=2)[CH2:23][CH2:22][O:21]1
Reactant: CS(=O)(=O)c1ncc(C#Cc2ccccc2)cn1
Reactant: CC1(C)CC(N)CCO1
Product: CC1(C)CC(Nc2ncc(C#Cc3ccccc3)cn2)CCO1

Procedure:
The title compound, MS: m/e=308.2 (M+H+), can be prepared in accordance with the general method of example 1, step 3 from 2-methanesulfonyl-5-phenylethynyl-pyrimidine (example 1, step 2) and rac-2,2-dimethyl-tetrahydro-pyran-4-ylamine.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11]CC)=[O:10])=[N+:2]=[N-:3].[OH-].[K+].O>CO>[N:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[N+:2]=[N-:3]
Reactant: CCOC(=O)CCCCCN=[N+]=[N-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: [N-]=[N+]=NCCCCCC(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.2 %

Procedure:
Ethyl 6-azidohexanoate (8.59 g, 44.8 mmol) and KOH (13.0 g, 0.231 mol) were dissolved into a mixture of 120 ml of water and 180 ml of MeOH. The solution was stirred at 0° C. for 2 hrs then MeOH was removed in vacuo. The aqueous layer was extracted by CHCl3 (2×100 ml), acidified to pH=l by 2N aqueous HCl and extracted by Et2O (2×100 ml). The organic layers were combined, washed with water (100 ml) and dried over Na2SO4. After filtration and evaporation of solvent, 6-azidohexanoic acid (6.56 g, 93%) was obtained as a colorless oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=[S:16])[NH2:15])[CH2:10][CH2:9]1)=O)(C)(C)C.Br[CH2:18][C:19](=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(O)C>[CH2:23]([O:22][C:20]([C:19]1[N:15]=[C:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[S:16][CH:18]=1)=[O:21])[CH3:24]
Reactant: CCOC(=O)C(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1
Solvent: CCO
Product: CCOC(=O)c1csc(C2CCNCC2)n1
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
A mixture of 10 g (41 mmol) 4-thiocarbamoyl-piperidine-1-carboxylic acid tert-butyl ester (commercially available) and 7.98 g (41 mmol) ethyl bromopyruvate (commercially available) in 120 ml ethanol was stirred at 70° C. for 90 min. The mixture was evaporated to dryness, Na2CO3 aq. was added and the residue was extracted with ethyl acetate. The organic phases were washed with NaCl aq., dried with MgSO4 and evaporated to dryness. The residue was purified on silica eluting with DCM/MeOH/25% NH3 in water 100/20/1 to yield after evaporation of the product fractions 7.28 g (74%) of the title compound as light brown solid.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C@@H:2]([C@H:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].FC1C=CC(C2(O)ONC(CN3CCC(N4C5C=CC(Cl)=CC=5NC4=O)CC3)=C2O)=CC=1>C(O)C.O>[OH2:3].[C:6]([CH:4]([CH:2]([C:1]([OH:10])=[O:9])[OH:3])[OH:5])([OH:8])=[O:7]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: O=c1[nH]c2cc(Cl)ccc2n1C1CCN(CC2=C(O)C(O)(c3ccc(F)cc3)ON2)CC1
Solvent: O
Solvent: CCO
Product: O=C(O)C(O)C(O)C(=O)O

Procedure:
A 46.5 g-quantity of the above compound (free base) is dissolved in 200 ml of ethanol, and a solution of 15 g of L-tartaric acid in 200 ml of water is added to the ethanol solution. The resulting mixture is allowed to stand at room temperature. The crystals thus precipitated are recrystallized three times from ethanol-water (6:4) to give tartrate monohydrate as colorless prisms. The tartrate monohydrate is treated with an aqueous solution of sodium bicarbonate to give (-)-1-[5-(4-fluorophenyl)-4,5-dihydroisoxazol-3-ylmethyl]-4-(5-chloro-2-oxo-1-benzimidazolinyl)piperidine. Melting point: 143°-145° C. [α]D25 : -108.8 (chloroform).
Reaction SMILES: CN(C)C=O.[H-].[Na+].[NH:8]1[CH:12]=[CH:11][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9]1.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>O>[CH2:32]([N:8]1[CH:12]=[CH:11][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9]1)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH3:19]
Reactant: CCOC(=O)c1cc[nH]c1
Reactant: CCCCCCCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCn1ccc(C(=O)OCC)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.3 %

Procedure:
To dry dimethylformamide (DMF) (15 ml) was added 0.84 g (21 mmol) of sodium hydride (60% oil dispersion), and then 2.78 g (20 mmol) of ethyl pyrrole-3-carboxylate was added portionwise thereto under ice-cooling. After stirring at room temperature for 10 minutes, 6.65 g (24 mmol) of bromotetradecane was added dropwise under ice-cooling. The mixture was stirred for 3.5 hours at room temperature, and then 30 ml of water was added thereto. The resulting mixture was extracted with 70 ml of ethyl acetate, washed with an aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After removing the solvent, the remaining oil was purified by subjecting it to column chromatography over silica gel (eluent: ethyl acetate/hexane=1/20-1/10) to obtain 6.33 g (89.0% yield) of ethyl 1-tetradecylpyrrole-3-carboxylate as white crystals, m.p. 32°-33° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[C:4]1[CH:34]=[CH:33][C:7]([C:8]([NH:10][CH:11]2[CH2:16][CH2:15][CH:14]([O:17][C:18](=[O:20])[CH3:19])[CH2:13][CH:12]2[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH:30]([F:32])[F:31])[CH:22]=2)=O)=[CH:6][CH:5]=1.[OH-].[Na+]>P(Cl)(Cl)(Cl)=O.ClCCl>[CH3:1][O:2][C:3](=[O:35])[C:4]1[CH:34]=[CH:33][C:7]([C:8]2[C:26]3[C:21](=[CH:22][C:23]([O:29][CH:30]([F:32])[F:31])=[C:24]([O:27][CH3:28])[CH:25]=3)[CH:12]3[CH:11]([CH2:16][CH2:15][CH:14]([O:17][C:18](=[O:20])[CH3:19])[CH2:13]3)[N:10]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C(=O)NC2CCC(OC(C)=O)CC2c2ccc(OC)c(OC(F)F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COC(=O)c1ccc(C2=NC3CCC(OC(C)=O)CC3c3cc(OC(F)F)c(OC)cc32)cc1
Temperature: 100 °C
Yield: 64.4 %

Procedure:
500 mg of N-{(1RS,2RS,4RS)-4-acetoxy-2-[3-(1,1-difluoro-methoxy)-4-methoxy-phenyl]-cyclohexyl}-terephthalamic acid methyl ester (compound D2) are dissolved in 2 ml of phosphorus oxychloride and heated for 4.5 h at 100° C. After cooling to room temperature the sample is diluted with 10 ml of dichloromethane and added dropwise to an aqueous sodium hydroxide solution. The water layer is extracted twice with dichloromethane. The solvent is removed and the crude product purified by chromatography on silica gel to give 310 mg of the title compound as a colourless foam.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)O1.Br[C:20]1[CH:21]=[C:22]([F:26])[CH:23]=[CH:24][CH:25]=1.[OH-].[Na+]>C1COCC1.[Pd].C(OCC)(=O)C>[F:26][C:22]1[CH:21]=[C:20]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)[CH:25]=[CH:24][CH:23]=1
Reactant: Fc1cccc(Br)c1
Reactant: CC1(C)OB(c2cccc3[nH]ccc23)OC1(C)C
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Fc1cccc(-c2cccc3[nH]ccc23)c1
Temperature: 70 °C
Reaction time: 15 h
Yield: 89 %

Procedure:
To a mixture of 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole (3, 2.43 g, 10 mmol), and 3-bromofluorobenzene (1.09 mL, 10 mmol) in THF (34 mL)) were added Palladium catalyst Pd(PPh3)4 (347 mg, 0.3 mmol) and the freshly prepared sodium hydroxide solution (1.20 g, 30 mmol in 14 mL water). The system was degassed and then charged with nitrogen. The degas procedure was repeated for three times. The mixture was stirred under nitrogen at 70° C. oil bath for 15 hours. TLC showed the completion of the coupling reaction. The mixture was cooled to room temperature, diluted with ethyl acetate, and separated from water layer. The ethyl acetate solution was washed by brine, dried over Na2SO4, and concentrated. The crude product was purified by a silica gel column eluting with hexanes—EtOAc (9:1) to provide 1.88 g (88%) of the product 4-(3-fluoro-phenyl)-1H-indole as a colorless syrup.
Reaction SMILES: [C:1]1([CH:7]([C:9](=[O:12])[CH2:10][CH3:11])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[CH:18]([N:22]([CH3:24])[CH3:23])N(C)C)(C)(C)C>>[CH3:24][N:22]([CH3:23])[CH:18]=[C:10]([CH3:11])[C:9](=[O:12])[CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:8]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CCC(=O)C(C)c1ccccc1
Product: CC(=CN(C)C)C(=O)C(C)c1ccccc1
Yield: 117.6 %

Procedure:
A mixture of 2-phenyl-3-pentanone (106 mg, 0.54 mmol) and of tert.-butoxy-bis(dimethylamino)methane (146 mg, 0.75 mmol, 90%) was stirred at 110° C. for 16 h. The reaction was evaporated to dryness, treated twice with toluene and the solvent was evaporated under reduced pressure to give the crude title compound (138 mg, 97%) as a dark brown solid which was used directly in the next step without further purification.
Reaction SMILES: [CH2:1]1[C:6]2[NH:7][C:8]3[C:13]([C:14](=[O:15])[C:5]=2[CH2:4][C:3]2[NH:16][C:17]4[C:22]([C:23](=[O:24])[C:2]1=2)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:12][CH:11]=[CH:10][CH:9]=3.CO.[OH-].[Na+].OO>O>[CH:20]1[CH:21]=[C:22]2[C:23]([C:2]3[C:3]([NH:16][C:17]2=[CH:18][CH:19]=1)=[CH:4][C:5]1[C:14]([C:13]2[C:8]([NH:7][C:6]=1[CH:1]=3)=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:15])=[O:24]
Reactant: O=c1c2c([nH]c3ccccc13)Cc1c([nH]c3ccccc3c1=O)C2
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12

Procedure:
A one-liter flask equipped with a thermometer, stirrer and condenser is charged with 50 g 6,13-dihydroquinacridone, 250 ml methanol, 36 ml water, 0.6 g phthalimidomethyl quinacridone as crystal phase director and particle size reducing agent and 75 g 50% aqueous sodium hydroxide. The mixture is stirred under a slow flow of nitrogen at reflux temperature for one hour generating the corresponding 6,13-dihydroquinacridone-di-sodium salt. 1.2 g 2,7-anthraquinone-disulfonic acid sodium salt is added and the resulting mixture is further stirred at reflux for 10 minutes. Subsequently, 91.4 g of an aqueous 17% hydrogen peroxide solution are added at a rate of 0.3 ml/minute maintaining reflux temperature under a slow nitrogen flow. The resulting bright red suspension is diluted with 100 ml cold water, stirred for 5 minutes and then filtered at 50–60° C. The presscake is washed with hot water then dried yielding a high chroma red gamma quinacridone pigment, which shows less than 100 ppm catalyst residues when analyzed by HPLC.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([Cl:24])=[C:8]2[CH:14]=[CH:13][N:12](CC3C=CC(OC)=CC=3)[C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2]>C(O)(C(F)(F)F)=O.OS(O)(=O)=O.C1(OC)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([Cl:24])=[C:8]2[CH:14]=[CH:13][NH:12][C:9]2=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(ccn2Cc2ccc(OC)cc2)c1Cl
Agent: O=S(=O)(O)O
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cnc2[nH]ccc2c1Cl
Reaction time: 3 h
Yield: 46.3 %

Procedure:
To a solution of 4-chloro-1-(4-methoxybenzyl)-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester (prepared as described in J. Heterocycl. Chem. 1972, 235 and Bioorg. Med. Chem. Lett. 2003, 2405) (3.48 g, 10 mmol) in TFA (20 mL), conc. H2SO4 (1.5 mL) and anisole (3 mL) were added at room temperature. The resulting solution was stirred at this temperature for 3 hours and then basified slowly by addition of ice-cold aqueous NaHCO3. The aqueous solution was extracted with ethyl acetate and the combined organic layers were dried (Na2SO4) and concentrated. The residue was filtered and washed with n-hexanes to give a yellow solid (1.04 g, 46%). LC-MS (LCT2) m/z 226 [M+H+], Rt 6.22 min.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:5]=1[C:11](=[O:15])[CH2:12][CH2:13]Cl.S(=O)(=O)(O)O>>[OH:10][C:8]1[CH:7]=[CH:6][C:5]2[C:11](=[O:15])[CH:12]=[CH:13][O:3][C:4]=2[CH:9]=1
Reactant: O=C(CCCl)c1ccc(O)cc1O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=c1ccoc2cc(O)ccc12
Temperature: 25 °C
Yield: 88 %

Procedure:
To a cooled (5° C.) solution of 2N sodium hydroxide (10.0 L) was added the compound of step A (244.1 g) in one portion. The solution was warmed to room temperature over 2 hours using a warm water bath then recooled to 5° C. and the pH adjusted to 2 with 6M sulfuric acid (1.2 L). The mixture was extracted with 3×3.0 L of ethyl acetate, washed with brine (1×2.0 L) dried over sodium sulfate and filtered. Concentration in vacuo gave a tan solid. Trituration with hexanes, and filtration afforded 173.7 g (58% yield) of the title compound. M.P. 136° C.-137° C.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:11]O)[CH:8]=[CH:9][CH:10]=1)[CH:2]=[CH2:3].C(Br)(Br)(Br)[Br:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][Br:14])[CH:6]=1)[CH:2]=[CH2:3]
Reactant: BrC(Br)(Br)Br
Reactant: C=CCOc1cccc(CO)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CCOc1cccc(CBr)c1
Temperature: 5 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
To a solution of (3-allyloxy-phenyl)-methanol (Tetrahedron (2000), 56(13), 1873-1882) (1.07 g, 6.49 mmol) in THF (7 mls) at 3° C. was added carbon tetrabromide (2.69 g, 8.11 mmol) then triphenylphosphine (2.13 g, 8.11 mmol) in THF (2 mls). The reaction mixture was stirred at 5° C. for 1 hour. The reaction mixture was filtered and concentrated in vacuo. The residue was washed with pentane to give a yellow solid which was purified by column chromatography on silica gel, eluting with pentane:ethyl acetate, 100:0, to 95:5 to afford the title compound as a pale yellow oil in 24% yield, 350 mg.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[C:26]([C:27]2[CH:28]=[C:29]([CH:35]=[CH:36][CH:37]=2)[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:25][C:10]2[C:11]([C:21](=[O:24])[NH:22][CH3:23])=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[O:13][C:9]=2[CH:8]=1>N1C=CC=CC=1>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[O:13][C:9]3[CH:8]=[C:7]([NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[C:26]([C:27]4[CH:28]=[C:29]([CH:35]=[CH:36][CH:37]=4)[C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:25][C:10]=3[C:11]=2[C:21](=[O:24])[NH:22][CH3:23])=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1cccc(-c2cc3c(C(=O)NC)c(-c4ccc(F)cc4)oc3cc2N)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)c1cccc(-c2cc3c(C(=O)NC)c(-c4ccc(F)cc4)oc3cc2NS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.1 %

Procedure:
Methanesulfonyl chloride (303 μL, 3.88 mmol) was added to a stirring solution of ethyl 3-(6-amino-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoate (1.40 g, 3.24 mmol) in pyridine (32 mL) at 25° C. It was allowed to stir overnight at rt. The reaction was concentrated and was purified on silica gel (Biotage, EtOAc/hexanes gradient, fraction collection at λ=254 nm) to give the titled compound (1.01 g, 61%). LC-MS retention time: 1.53 min; m/z (MH+): 511. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.