Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH:7]1[CH2:11][CH2:10][O:9][C:8]1=[O:12])(=O)C.CO>O>[O:4]1[CH2:1][CH2:11][CH:7]([C:8]([O:9][CH3:10])=[O:12])[CH2:6][CH2:5]1
Reactant: CC(=O)OCCC1CCOC1=O
Solvent: CO
Solvent: O
Product: COC(=O)C1CCOCC1
Reaction time: 12 h

Procedure:
A solution consisting of 53 wt % of 3-(2'-acetoxyethyl)-dihydro-2(3H)furanone, 39 wt % of methanol, and 8 wt % of water was evaporated at a rate 25 g per hour and the vapors were passed at a temperature of 250° C. over 90 g of aluminum oxide catalyst (diameter 1.5 mm) in a tubular reactor. The gaseous effluent was condensed in cold traps and analyzed by gas chromatography. The experiment was carried out for a period of 12 h and the total amount of starting material used was 600 g. 62 mol % of methyl tetrahydropyran-4-carboxylate was formed, plus 20 mol % of 3-(2'-methoxyethyl)-dihydro-2(3H)furanone and 3 mol % of 5-oxaspiro-[2.4]heptan-4-one. The conversion of 3-(2'-acetoxyethyl)-dihydro-2(3H)furanone was better than 99%.
Reaction SMILES: [O:1]=[C:2]1[NH:7][N:6]=[C:5]([C:8]([OH:10])=[O:9])[CH:4]=[CH:3]1.C(O[CH2:15][CH2:16][CH2:17][CH3:18])(=O)C.OS(O)(=O)=O>C(O)CCC>[O:1]=[C:2]1[NH:7][N:6]=[C:5]([C:8]([O:10][CH2:15][CH2:16][CH2:17][CH3:18])=[O:9])[CH:4]=[CH:3]1
Reactant: O=C(O)c1ccc(=O)[nH]n1
Reactant: CCCCOC(C)=O
Agent: O=S(=O)(O)O
Solvent: CCCCO
Product: CCCCOC(=O)c1ccc(=O)[nH]n1
Yield: 79.6 %

Procedure:
A mixture of 6-oxo-1,6-dihydropyridazine-3-carboxylic acid (117.24 g) [Ref: British Patent 856, 409], n-butyl acetate (293 ml), n-butanol (410 ml) and conc. H2SO4 (5.9 ml) was heated at reflux for 1 hour. The solvent was evaporated and the residue washed with n-butyl acetate to give n-butyl 6-oxo-1,6-dihydropyridazine-3-carboxylate (130.6 g, 79.6% yield), mpt 79°-8° C.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]([CH3:13])[C:4](=[O:14])[C:3]1=[O:15].[Br:16]Br.O.[OH-].[Na+]>C(O)(=O)C>[Br:16][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[CH3:12])[N:5]([CH3:13])[C:4](=[O:14])[C:3](=[O:15])[N:2]2[CH3:1]
Reactant: BrBr
Reactant: Cc1ccc2c(c1)n(C)c(=O)c(=O)n2C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc2c(cc1Br)n(C)c(=O)c(=O)n2C
Temperature: 50 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
To a solution of 1,4,6-trimethyl-1,4-dihydro-quinoxaline-2,3-dione (0.66 g, 3.2 mmol) in acetic acid (40 mL) was added bromine (0.52 g, 3.2 mmol) and the solution stirred at 50° C. overnight. The reaction mixture was cooled to room temperature and poured into water. The solution was neutralized with aqueous NaOH to Ph=7, extracted with dichloromethane and washed with brine, dried (Mg2SO4), filtered and evaporated to give 0.9 g of 6-bromo-1,4,7-trimethyl-1,4-dihydro-quinoxaline-2,3-dione used without further purification in the Suzuki coupling (step a). 1H NMR (300 MHz; CDCl3): 2.47 (s, 3 H), 3.64 (s, 6 H), 7.09 (s, 1 H), 7.40 (s, 1 H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:16][CH2:15]2)=[CH:10][C:9]=1[NH2:17])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:25][C:24]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([C:32]#[N:33])[CH:27]=2)=[CH:23][C:22](=O)[O:21]1>>[C:1]([O:5][C:6](=[O:18])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:16][CH2:15]2)=[CH:10][C:9]=1[NH:17][C:22](=[O:21])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][N:29]=[C:28]([C:32]#[N:33])[CH:27]=1)=[O:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2ccnc(C#N)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C2CC2)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(C2CC2)cc1NC(=O)CC(=O)c1ccnc(C#N)c1

Procedure:
Prepared from (2-amino-4-cyclopropyl-phenyl)-carbamic acid tert.-butyl ester (Example G48) and 4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-pyridine-2-carbonitrile (Example J16) according to the general procedure K. Obtained as a light brown solid (148 mg).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH2:14]([N:16](CC)[CH2:17][CH3:18])[CH3:15].N1CCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C(C)=CC=CC=1>[N+:11]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[N:16]1[CH2:17][CH2:18][CH2:15][CH2:14]1)[C:6]([OH:8])=[O:7])([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCN(CC)CC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCNC1
Solvent: Cc1ccccc1C
Product: O=C(O)c1ccc(N2CCCC2)c([N+](=O)[O-])c1
Yield: 96 %

Procedure:
4-Chloro-3-nitrobenzoic acid (5.0 g) is suspended in xylene (50 ml), and thereto are added triethylamine (2.5 g) and pyrrolidine (2.0 g), and the mixture is refluxed for 2 hours. To the reaction mixture is added 10% aqueous citric acid solution, and the precipitated crystals are separated by filtration, washed with water and dried to give 3-nitro-4-(1-pyrrolidinyl)benzoic acid (5.6 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH:5]=[C:6]1[CH2:10][C@@H:9]([CH3:11])[C@H:8]([CH3:12])[CH2:7]1)[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].[N+:32]([CH3:35])([O-:34])=[O:33]>C1COCC1.C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1([CH2:35][N+:32]([O-:34])=[O:33])[CH2:7][C@@H:8]([CH3:12])[C@H:9]([CH3:11])[CH2:10]1)[CH3:2]
Reactant: CCOC(=O)C=C1C[C@@H](C)[C@H](C)C1
Reactant: C[N+](=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CC1(C[N+](=O)[O-])C[C@@H](C)[C@H](C)C1
Temperature: 60 °C

Procedure:
To a solution of (2) (4.24 g, 23.3 mmol) in THF (15 mL) was added TBAF (32 mL of a 1 M solution in THF, 32 mmol) followed by nitromethane (3 mL) and the reaction heated at 60° C. for 8 hours. After cooling, the reaction mixture was diluted with ethyl acetate (150 mL) and washed with 2N HCl (40 mL) then saturated brine (50 mL). Column chromatography (10:1 heptane/ethyl acetate) gave the product as an oil, 2.24 g, 40%.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH2:16])[CH:10]=1>C1(C)C(C)=CC=CC=1>[Cl:8][C:4]1[N:3]=[C:2]([NH:16][CH2:15][C:11]2[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=2)[CH:7]=[N:6][CH:5]=1
Reactant: NCc1cccnc1
Reactant: Clc1cncc(Cl)n1
Solvent: Cc1ccccc1C
Product: Clc1cncc(NCc2cccnc2)n1
Yield: 93 %

Procedure:
A mixture 2,6-dichloropyrazine (0.671 mmol) and 3-picolylamine (2.014 mmol) in xylene (25 ml) was refluxed overnight. The residue obtained after evaporation of the solvent was suspended between CH2Cl2 (100 ml) and water (100 ml). The organic layer was separated and the aqueous layer was extracted with CH2Cl3 (3×50 ml). The combined organic extracts were washed with brine (1×100 ml), dried (Na2SO4) and the solvent removed in vacuo. The residue was then purified by column chromatography eluting with a hexane:ethyl acetate gradient mixture to afford the desired product (93%).
Reaction SMILES: CO.C([O:6][C@H:7]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C:9](=[CH:10][C@H:11]([OH:27])[C@@H:12]3[C@@H:21]2[CH2:20][CH2:19][C@@:17]2([CH3:18])[C@H:13]3[CH2:14][CH2:15][C:16]2=[O:26])[CH2:8]1)(=O)C.C([O-])([O-])=O.[Na+].[Na+]>O>[CH3:18][C@:17]12[CH2:19][CH2:20][C@H:21]3[C@@H:12]([C@@H:11]([OH:27])[CH:10]=[C:9]4[C@:22]3([CH3:25])[CH2:23][CH2:24][C@H:7]([OH:6])[CH2:8]4)[C@@H:13]1[CH2:14][CH2:15][C:16]2=[O:26]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=C[C@H](O)[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C[C@]12CC[C@H](O)CC1=C[C@H](O)[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 67.9 %

Procedure:
A 500 L reactor was charged 230 kg methanol, 33 kg (wet) 3β-acetoxy-7β-hydroxy-5-androsten-17-one, 108 kg water and 15 kg Na2CO3. The mixture was heated to reflux for 3 hours. Methanol was removed under vacuum whereupon 250 kg of water was added to the residue. The mixture was put in refrigerator overnight to give a precipitate. The solids were collected by filtration, then washed with water and dried at 40-50° C. to yield 9.5-10.5 kg (67.9-75.0%) of the title compound as a white solid.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15](C(O)=O)[CH:16]=3)[CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.C1(P([N:36]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CC(O)(C)C>[NH2:36][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[CH2:11][C:10]1([C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[NH:3][C:2]1=[O:1])[CH2:18]2
Reactant: O=C(O)c1ccc2c(c1)CC1(C2)C(=O)Nc2ccccc21
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(C)(C)O
Product: Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ccccc21

Procedure:
A solution of (±)-2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-indole]-5-carboxylic acid from Step B (65.0 mg, 0.233 mmol), diphenylphosphoryl azide (0.060 mL, 0.279 mmol), and triethylamine (0.039 mL, 0.279 mmol) in t-BuOH (5 mL) was heated to reflux for 3 h. The reaction mixture was concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexane:EtOAc—100:0 to 50:50, to give the title compound. MS: m/z=295 (M-C4H7).
Reaction SMILES: [C:1]([Si:5]([CH3:20])([CH3:19])[O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17]O)([CH3:4])([CH3:3])[CH3:2].C(Br)(Br)(Br)[Br:22].N1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:22][CH2:17][CH2:16][O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)OCCOCCOCCOCCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OCCOCCOCCOCCBr
Temperature: 0 °C
Reaction time: 2 h
Yield: 83.2 %

Procedure:
Compound 5c (680 mg, 2.20 mmol) and carbon tetrabromide (947 mg, 2.86 mg) were dissolved in dichloromethane (20 ml). The solution was cooled down to 0° C. with an ice bath and pyridine (2.0 ml) was added followed by triphenylphosphine (749 mg, 0.286 mmol). The solution was stirred at 0° C. for half an hour and at room temperature for 2 hours. After standard workup with dichloromethane, the residue was purified by silica gel column chromatography (20% ethyl acetate in hexane) to afford compound 6c (680 mg, 79.6%): 1H NMR δ 3.79 (m, 4H), 3.66 (m, 8H), 3.56 (t, 2H), 3.47 (t, 2H), 0.89 (s, 9H), 0.07 (s, 6H).
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.[Br:9][CH2:10][C:11](Cl)=[O:12].[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClCCCl>[Br:9][CH2:10][C:11]([C:2]1[CH:3]=[C:4]([CH3:7])[CH:5]=[CH:6][C:1]=1[CH3:8])=[O:12]
Reactant: Cc1ccc(C)cc1
Reactant: O=C(Cl)CBr
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cc1ccc(C)c(C(=O)CBr)c1
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 105.1 %

Procedure:
A mixture of 10.60 g (0.10 mol) of para-xylene and 16.53 g (0.105 mol) of α-bromoacetyl chloride in 300 mL of 1,2-dichloroethane was cooled in an ice bath under an atmosphere of dry N2 and treated portionwise with 14.15 g (0.106 mol) of aluminum chloride. The reaction mixture was stirred for 30 minutes at 0-5° C. and then for 2.5 hours at room temperature. The mixture was then poured onto ice and the aqueous layer was acidified with concentrated HCl. The organic layer was separated and the aqueous layer was extracted twice with methylene dichloride. The combined organic extracts were dried with brine solution and with magnesium sulfate. The solvent was evaporated to give 23.87 g of an amber oil which was for use in the next reaction without further purification.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].Cl[C:6]1C=C2C(C=CC(COC3C=C(C=CCC4C=CC=CC=4C(OC)=O)C=CC=3)=N2)=C[CH:7]=1.[SH:37][CH2:38][CH:39]([CH3:43])[C:40]([OH:42])=[O:41]>>[SH:37][CH2:38][CH:39]([CH3:43])[C:40]([O:42][CH2:6][CH3:7])=[O:41]
Reactant: CC(CS)C(=O)O
Reactant: COC(=O)c1ccccc1CC=Cc1cccc(OCc2ccc3ccc(Cl)cc3n2)c1
Agent: [Al+3]
Agent: [Cl-]
Product: CCOC(=O)C(C)CS

Procedure:
At -10° C., AlCl3 (2.437 g, 18.3 mmol) was added to a solution of the styrene of Step 7 (1.013 g, 2.28 mmol) and 3-mercapto-2-methylpropanoic acid (356 mg, 2.96 mmol, obtained from the hydrolysis of ethyl 3-mercapto-2-methylpropanoate (Example 1, Method B, Step 6) as in Example 7, Step 4, or alternatively from the NaOH hydrolysis of ethyl 3-(acetylthio)-2-methylpropanoate) in 25 mL of CH2Cl2 and the mixture was stirred at 0° C. in the dark for 2 h. Cold aq NH4OAc, EtOAc and THF were then added and the mixture was stirred until complete dissolution of the oil. The product was extracted with EtOAc:THF 1:1, dried over Na2SO4 and concentrated. The sodium salt of the acid was formed in EtOH with 500 μl of 10N NaOH. It was purified on an Amberlite ion exchange resin XAD-8: elution with water separate the sodium 3-mercapto-2-methyl-propanoate and elution with methanol afforded the title acid as an impure sodium salt. The compound was dissolved in saturated aq NH4Cl, extracted with EtOAc:THF 1:1, dried over Na2SO4 and purified by flash chromatography on silica using acetone:toluene:acetic acid 5:95:1 to yield 766 mg (60%) of the title acid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([N+:20]([O-])=O)=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1.[H][H]>CO.CC(O)=O.[Pt]>[NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]([NH2:20])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1
Reactant: [H][H]
Reactant: Nc1cc(COc2ccc([N+](=O)[O-])c3ccccc23)ccn1
Agent: [Pt]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1cc(COc2ccc(N)c3ccccc23)ccn1
Yield: 94.5 %

Procedure:
2-Amino-4-((4-nitronaphthalen-1-yloxy)methyl)pyridine (2) (4.50 g, 15.24 mmol) in MeOH (200 mL) and AcOH (200 mL) was passed through a Thales H-cube (2.0 mL·min−1, 40° C., 55 mm 10% Pt/C Cat-Cart, full hydrogen mode) and the volatiles were removed in vacuo. The crude product was subjected to SCX capture and release eluting with 1% NH3 in MeOH solution and the solvent was removed in vacuo to give 2-amino-4-((4-aminonaphthalen-1-yloxy)methyl)pyridine (3) (3.82 g, 94%) as a purple solid: m/z 266 (M+H)+ (ES+).
Reaction SMILES: [CH:1]12[CH2:16][CH:12]([CH2:13][NH:14][CH2:15]1)[C:11]1[C:10]([C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])=[C:9]3[C:4]([NH:5][C:6](=O)[CH:7]=[CH:8]3)=[CH:3][C:2]2=1.O=P(Cl)(Cl)[Cl:26]>>[Cl:26][C:6]1[CH:7]=[CH:8][C:9]2[C:4](=[CH:3][C:2]3[CH:1]4[CH2:16][CH:12]([C:11]=3[C:10]=2[C:17](=[O:22])[C:18]([F:20])([F:19])[F:21])[CH2:13][NH:14][CH2:15]4)[N:5]=1
Reactant: O=C(c1c2c(cc3[nH]c(=O)ccc13)C1CNCC2C1)C(F)(F)F
Reactant: O=P(Cl)(Cl)Cl
Product: O=C(c1c2c(cc3nc(Cl)ccc13)C1CNCC2C1)C(F)(F)F
Temperature: 100 °C
Reaction time: 3 h

Procedure:
1-(5,14-diazatetracyclo[10.3.1.02,11.04,9]hexadeca-2(11),3,7,9-tetraen-6-one-10-yl)-2,2,2-trifluoro-ethanone (156 mg, 0.49 mmol) was treated with POCl3 (5 mL) and warmed to 100° C. with stirring for 3 hours. After concentration in vacuo, the residue was diluted with CH2Cl2 (15 mL) and carefully treated with saturated NaHCO3 solution (10 mL) with stirring. Once CO2 evolution slowed the mixture was separated and the aqueous layer extracted CH2Cl2 (3 times). The organic layer was washed with H2O and saturated NaCl solution, filtered through cotton and concentrated to a brown oil (217 mg, 93%). (TLC ethyl acetate, Rf 0.3) 1H NMR (400 MHz, 2HCCl3) δ 8.03 (d, J=8.5 Hz, 1H), 7.83 (s, 1H), 7.62 (s, 1H), 7.35 (d, J=8.5 Hz, 1H), 4.43 (m, 1H), 4.01 (m, 1H), 3.62 (m, 1H), 3.29 (m, 2H), 3.23 (m, 1H), 2.45 (m, 1H), 2.10 (d, J=11.6 Hz, 1H). APCI MS m/e 341.1 [(M+1)+].
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[OH:12].[Cl:13][C:14]1[CH:15]=[C:16]([CH:20](O)[CH2:21][CH2:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([C:31]3[CH:32]=[C:33]([NH:37][C:38](=[O:42])[CH:39]([CH3:41])[CH3:40])[CH:34]=[CH:35][CH:36]=3)[CH2:27][CH2:26]2)[CH:17]=[CH:18][CH:19]=1.Cl>>[Cl:13][C:14]1[CH:15]=[C:16]([CH:20]([O:12][C:3]2[CH:4]=[C:5]([C:8]([F:10])([F:11])[F:9])[CH:6]=[CH:7][C:2]=2[F:1])[CH2:21][CH2:22][CH2:23][CH2:24][N:25]2[CH2:26][CH2:27][CH:28]([C:31]3[CH:32]=[C:33]([NH:37][C:38](=[O:42])[CH:39]([CH3:40])[CH3:41])[CH:34]=[CH:35][CH:36]=3)[CH2:29][CH2:30]2)[CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(O)c3cccc(Cl)c3)CC2)c1
Reactant: Oc1cc(C(F)(F)F)ccc1F
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(Oc3cc(C(F)(F)F)ccc3F)c3cccc(Cl)c3)CC2)c1

Procedure:
Prepared by Procedure A and Scheme AN using 2-fluoro-5-(trifluoromethyl)phenol and N-(3-{1-[5-(3-chlorophenyl)-5-hydroxypentyl]-4-piperidinyl}phenyl)-2-methylpropanamide: 1H NMR (400 MHz, CDCl3), HCl salt δ 8.17 (s, br, 1H), 7.75–6.88 (m, 11H), 5.26–5.14 (m, 1H), 3.68–3.56 (m, br, 2H), 3.05–2.90 (br, 2H), 2.90–2.60 (m, br, 4H), 2.56–2.36 (m, br, 2H), 2.18–1.84 (m, br, 6H), 1.70–1.44 (m, br, 2H), 1.25 (d, 6H, J=7.2 Hz). Anal. Calc. for C33H38Cl2F4N2O2.0.9EtOAc: C, 60.98; H, 6.32; N, 3.89; Found: C, 60.99; H, 6.17; N, 3.81. ESMS m/e: 605.2 (M+H)+.
Reaction SMILES: [Br:1]CCCC1CCCCN1C(OCC1C=CC=CC=1)=O.O[CH2:22][CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[CH2:27]1>>[Br:1][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[CH2:27]1
Reactant: O=C(OCc1ccccc1)N1CCCC(CCCCO)C1
Reactant: O=C(OCc1ccccc1)N1CCCCC1CCCBr
Product: O=C(OCc1ccccc1)N1CCCC(CCCCBr)C1

Procedure:
Prepared similarly to Intermediate 30 from phenylmethyl 3-(4-hydroxybutyl)-1-piperidinecarboxylate.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([N-]C(C)C)(C)C.[Li+].[CH:32]([C:34]1[CH:35]=[C:36]([C:39]([O:41][CH3:42])=[O:40])[NH:37][CH:38]=1)=O.O>O1CCCC1>[CH3:2][O:3][CH:4]=[CH:32][C:34]1[CH:35]=[C:36]([C:39]([O:41][CH3:42])=[O:40])[NH:37][CH:38]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)c1cc(C=O)c[nH]1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COC=Cc1c[nH]c(C(=O)OC)c1
Reaction time: 1 h
Yield: 50 %

Procedure:
Into a solution of 200 g (0.58 mol) of methoxymethyltriphenylphosphonium chloride in 1.5 liter of tetrahydrofuran, was added dropwise 220 ml of a tetrahydrofuran solution (2.01 mol concentration) containing 0.44 mol of lithium diisopropylamide under stirring and cooling with ice. After one-hour stirring at room temperature, 400 ml of a tetrahydrofuran solution of 57.6 g (0.38 mol) of methyl 4-formylpyrrole-2-carboxylate was added to the mixture at 5° to 8° C. under cooling with ice. The reaction was carried out for one hour at room temperature, and the reaction mixture was added with water and extracted with ethyl acetate. The organic layer was collected, washed with a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate and evaporated to obtain a residue. The residue was purified by a silica-gel column chromatography (eluent:ethyl acetate/hexane=1/4) to obtain 34.4 g of methyl 4-methoxyvinylpyrrole-2-carboxylate as a mixture of E-isomer and Z-isomer. The yield was 50%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[CH:5]2.[Cl:20]N1C(=O)CCC1=O>ClCCl.CCOCC>[Cl:20][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=2)[NH:7][C:6]=1[C:11]([N:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12]
Reactant: CN1CCN(C(=O)c2cc3cc(Cl)ccc3[nH]2)CC1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CN1CCN(C(=O)c2[nH]c3ccc(Cl)cc3c2Cl)CC1
Reaction time: 18 h
Yield: 50.3 %

Procedure:
(5-Chloro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone (Example 1, 0.23 g) in dichloromethane (3 mL) at ambient temperature was treated with N-chlorosuccinimide (0.123 g) and stirred for 18 h. The reaction mixture was diluted with ether, washed with water, saturated sodium hydrogencarbonate solution and then brine, dried over sodium sulfate, filtered, and concentrated to give crude product. Purification via silica gel chromatography, eluting with 1-8% methanol/dichloromethane afforded the title compound (0.13 g). 1H NMR (400 MHz, CDCl3): δ 2.36 (3H), 2.53 (4H), 3.79 (4H), 7.22 (1H), 7.29 (1H), 7.58 (1H), 10.39 (1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:22][CH3:23])[C@H:14]2[CH2:19][CH2:18][C@H:17]([NH:20][CH3:21])[CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].Br[CH2:25][CH2:26][O:27][CH3:28].C([O-])([O-])=O.[K+].[K+]>C(#N)C.O>[Br:1][C:2]1[CH:3]=[C:4]([N:13]([CH2:22][CH3:23])[C@H:14]2[CH2:19][CH2:18][C@H:17]([N:20]([CH2:25][CH2:26][O:27][CH3:28])[CH3:21])[CH2:16][CH2:15]2)[C:5]([CH3:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COCCBr
Reactant: CCN(c1cc(Br)cc(C(=O)OC)c1C)[C@H]1CC[C@H](NC)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCN(c1cc(Br)cc(C(=O)OC)c1C)[C@H]1CC[C@H](N(C)CCOC)CC1
Temperature: 65 °C
Reaction time: 16 h

Procedure:
To a stirred solution of crude methyl 5-bromo-3-(ethyl((trans)-4-(methylamino)cyclohexyl)amino)-2-methylbenzoate (25 g, 65.44 mmol), 1-bromo-2-methoxyethane (18.19 g, 130.8 mmol) in acetonitrile (250 mL), K2CO3 (18.06 g, 130.8 mmol) and KI (6.51 g, 39.21 mmol) were added. The resulting reaction mass was stirred at 65° C. for 16 h. On completion, reaction mixture was diluted with water (300 mL) and extracted with DCM (500 mL×3). The combined organic layers were washed with water, dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by silica gel column chromatography to afford the title compound (20 g, 69.3% yield).
Reaction SMILES: [CH:1]([C:13]([O:15]CC)=O)([C:8](OCC)=[O:9])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C(O)(=O)C.[CH:22]([NH2:24])=[NH:23].Cl>C[O-].[Na+].CO>[OH:15][C:13]1[C:1]([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:8]([OH:9])[N:24]=[CH:22][N:23]=1
Reactant: CCOC(=O)CC(C(=O)OCC)C(=O)OCC
Reactant: N=CN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)Cc1c(O)ncnc1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.2 %

Procedure:
Charge 394.5 L methanol into the reactor at room temperature. Charge 0.3682 Kg of sodium methoxide into the reactor at RT followed by triethyl ethane-1,1,2-tricarboxylate (93.31 Kg). Stir at RT for 3 hours. Heat the reaction to 40-50° C. and distill out methanol completely under vacuum. Charge 263 L of methanol into the reactor at 40-50° C. and distill out methanol completely under vacuum at 40-50° C. Charge 263 L of methanol into the reactor at 40-50° C. cool slowly to 10-15° C. to promote crystallization. Charge 54.54 Kg of sodium methoxide maintaining the temperature at 10-15° C. Heat the reaction slowly to RT and stir for 1 hour. Charge 26.3 Kg of Formamidine acetate into the reactor at RT and slowly raise the temperature of the reaction mass to reflux (65-68° C.). Stir for 2-9 hours by maintaining the temperature at 65-68° C. Slowly decrease the reaction temperature to 10-15° C. and adjust the pH of reaction to 1.5-2.0 by slowly adding the Methanolic HCl (15-18%) maintaining the temperature at 10-15° C. Cool the reaction to 0-5° C. and maintain for 1 hour. Filter the resulting solids via centrifuge at 0-5° C. and spin dry the wet cake for 30 minutes. Wash the wet cake with 26.3 L of chilled methanol (0-5° C.) and spin-dry the wet cake for 30 min. Dry the material under vacuum at 40-45° C. to afford ethyl 2-(4,6-dihydroxypyrimidin-5-yl)acetate (35.65 Kg, 76.6%) as a solid.