Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]([CH2:23][CH2:24][CH3:25])[C:5](=O)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:9]([NH2:21])[CH:8]=1)[CH2:2][CH3:3].B.[ClH:27].O>O1CCCC1>[ClH:27].[ClH:27].[CH2:14]([O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[CH2:23][CH2:24][CH3:25])=[CH:8][C:9]=1[NH2:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCCN(CCC)C(=O)Cc1ccc(OCc2ccccc2)c(N)c1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CCCN(CCC)CCc1ccc(OCc2ccccc2)c(N)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 13.9 g of 2-(3-amino-4-benzyloxyphenyl)acetic acid dipropylamide in 65 ml of tetrahydrofuran is added dropwise under a nitrogen atmosphere into 12 ml of a one-molar solution of borane in tetrahydrofuran, cooled to +5° C., during a period of 20 minutes. Subsequently, the mixture is agitated for 4 hours at room temperature and refluxed for 22 hours. The mixture is combined with semiconcentrated hydrochloric acid and water and the tetrahydrofuran is distilled off. The aqueous solution is then adjusted to a pH value of 10 with sodium hydroxide and extracted by shaking with ether. The ether solution yields, after evaporation and chromatography on silica gel with methylene chloride/acetone (1:1), 8.93 g of pure 2-benzyloxy-5-(2-dipropylaminoethyl)-aniline as an oil. Treatment of this product with 2N HCl in methanol and evaporation yield 2-benzyloxy-5-(2-dipropylaminoethyl)aniline, dihydrochloride, mp 111°-112° C.
Reaction SMILES: [C:1]1([C:7]2([CH2:16][CH2:17][C:18]#[N:19])[CH2:12][CH2:11][CH2:10][C:9](=[N+:13]=[N-:14])[C:8]2=[O:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C2(CCC#N)CCCC([CH:32]=[O:33])C2=O)C=CC=CC=1>>[CH3:32][O:33][C:5]1[CH:6]=[C:1]([C:7]2([CH2:16][CH2:17][C:18]#[N:19])[CH2:12][CH2:11][CH2:10][C:9](=[N+:13]=[N-:14])[C:8]2=[O:15])[CH:2]=[CH:3][CH:4]=1
Reactant: N#CCCC1(c2ccccc2)CCCC(C=O)C1=O
Reactant: N#CCCC1(c2ccccc2)CCCC(=[N+]=[N-])C1=O
Product: COc1cccc(C2(CCC#N)CCCC(=[N+]=[N-])C2=O)c1

Procedure:
Similarly prepared was 2-phenyl-2-(2-cyanoethyl)-6-diazocyclohexanone from 2-phenyl-2-(2-cyanoethyl)-6-formylcyclohexanone.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH3:6][C:7]([CH3:37])([CH2:35][CH3:36])[CH2:8][C:9](=O)[CH2:10][NH:11][C:12]([C:14]1([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][N:28]=3)=[CH:23][CH:22]=2)[CH2:18][CH2:17][C:16](=[O:19])[NH:15]1)=O>>[CH3:6][C:7]([CH3:37])([CH2:35][CH3:36])[CH2:8][C:9]1[N:5]=[C:12]([C:14]2([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][N:28]=4)=[CH:23][CH:22]=3)[NH:15][C:16](=[O:19])[CH2:17][CH2:18]2)[NH:11][CH:10]=1
Reactant: CCC(C)(C)CC(=O)CNC(=O)C1(Cc2ccc(-c3ccc(F)cn3)cc2)CCC(=O)N1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Product: CCC(C)(C)Cc1c[nH]c(C2(Cc3ccc(-c4ccc(F)cn4)cc3)CCC(=O)N2)n1
Temperature: 160 °C
Reaction time: 1 h

Procedure:
Ammonium acetate (1.18 g, 15.4 mmol) was added to an ambient temperature solution of N-(4,4-dimethyl-2-oxohexyl)-2-[4-(5-fluoropyridin-2-yl)benzyl]-5-oxopyrrolidine-2-carboxamide in xylenes (minimal volume). After stirring in a sealed tube at 160° C. for 1 hr, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The aqueous phase was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (sodium sulfate) and concentrated in vacuo. High pressure liquid chromatography (KR100-5C18 100×21.2 mm column) eluting with 10-100% acetonitrile/water containing 0.05% trifluoroacetic acid afforded the title compound. (M+H) found: 421.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=[O:7])=[C:4]([I:12])[CH:3]=1.[C:13]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH3:13][O:7][C:6](=[O:8])[C:5]1[C:9]([CH3:11])=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=1[I:12]
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(Cl)cc(I)c1C(=O)O
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1c(C)cc(Cl)cc1I
Temperature: 70 °C
Reaction time: 2 h
Yield: 46.9 %

Procedure:
A solution of 4-chloro-2-iodo-6-methyl-benzoic acid (5.9 g, 20.0 mmol) in acetone (50 mL) was treated with anhydrous K2CO3 (4.14 g, 30 mmol) followed by methyl iodide (1.5 g, 24 mmol). The reaction mixture was stirred at 70° C. for 2 h. GC-MS and TLC indicated that the reaction was completed. The solids were removed by filtration and the filtrate was evaporated under reduced pressure. Silica gel column chromatography of the resulting material using 10% ethyl acetate in hexanes afforded 4-chloro-2-iodo-6-methyl-benzoic acid methyl ester (2.91 g, 47%). GC-MS: m/z 310 (M)+, 279 (M−31)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[F:13][CH2:14][C:15](Cl)=[O:16]>C(Cl)Cl>[F:13][CH2:14][C:15]([C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[F:8])=[O:16]
Reactant: Fc1cccc(F)c1
Reactant: O=C(Cl)CF
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CF)c1ccc(F)cc1F
Yield: 36 %

Procedure:
1,3-Difluorobenzene (2.02 g; 17.7 mM) and anhydrous aluminium chloride (2.60 g; 19.47 mM) were stirred together under dry nitrogen at room temperature. A solution of fluoroacetyl chloride (1,71 g; 17.7 mM) in anhydrous methylene chloride (2 ml) was added over 30 minutes. The mixture was then warmed at about 50° for 3 hours. On cooling methylene chloride (40 ml) was added and the mixture was poured onto ice. The methylene chloride layer was separated, dried over magnesium sulphate and evaporated to give a white solid. This material was chromatographed on a column of silica eluting with a mixture of hexane/methylene chloride (65:35 by volume). The product-containing fractions were collected. The title compound crystallised on evaporation of these fractions and was dried in a vacuum desiccator to a colourless crystalline solid (1.12 g; 36% yield), melting point 57°-8°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([F:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:11]([O-:13])=[O:12])=[C:6]([CH:10]=1)[C:7]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([S:21]([F:24])(=[O:23])=[O:22])=[CH:17][CH:16]=1)=[O:8]
Reactant: Nc1ccc(S(=O)(=O)F)cc1
Reactant: O=C(Cl)c1cc(Cl)ccc1[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(S(=O)(=O)F)cc1)c1cc(Cl)ccc1[N+](=O)[O-]

Procedure:
86.00 g (0.39 mol) of 5-chloro-2-nitro-benzoyl chloride was dissolved in 300 ml of toluene, a solution of 62.00 g (0.35 mol) of 4-aminobenzenesulfonyl fluoride was added dropwise, and the mixture was heated under reflux for 4 h. Subsequently it was cooled, concentrated in vacuo to half of its volume, cooled, and the precipitated solid was filtered off with suction. 121.60 g (86%) of the title compound having a melting point of 182-184° C. were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][N:3]=1.[CH3:9][C:10]([OH:14])([C:12]#[CH:13])[CH3:11].CCN(CC)CC>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:13]#[C:12][C:10]([CH3:11])([OH:14])[CH3:9])=[CH:6][CH:7]=1
Reactant: Nc1ccc(Br)cn1
Reactant: C#CC(C)(C)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(O)C#Cc1ccc(N)nc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 94.6 %

Procedure:
A mixture of commercially available 2-amino-5-bromopyridine (25 g, 144 mmol), 2-methyl-3-butyn-2-ol (21.2 mL, 217 mmol), Et3N (30.2 mL, 217 mmol), PdCl2(PPh3)2 (507 mg, 0.5 mol %) and PPh3 (95 mg, 0.25 mol %) in DMF (140 mL) was purged for 10 min with argon. Then CuI (83 mg, 0.3 mol %) was added and the reaction mixture was heated up to 90° C., stirring was continued at 90° C. for 16 h. Cooled to 23° C., the reaction mixture was concentrated in vacuum to remove all volatiles left a dark brown residue which was purified by flash chromatography with n-heptane and ethyl acetate to give the title compound as a brown solid (24 g, 94%, contains residual DMF). MS (ISP) 177.2 [(M+H)+].
Reaction SMILES: [C:1]1([C:7]2[NH:11][N:10]=[C:9]([C:12]3[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O1CCCC1.Cl>CO>[C:1]1([C:7]2[NH:11][N:10]=[C:9]([C:12]3[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=3)[N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(-c2n[nH]c(-c3ccccc3)n2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2n[nH]c(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
A mixture of methyl 4-(5-phenyl-1H-1,2,4-triazol-3-yl)benzoate (0.500 g), 1 M aqueous sodium hydroxide solution (5.4 ml), tetrahydrofuran (6 ml) and methanol (3 ml) was stirred at room temperature for 2 hrs. and heated under reflux for 2 hrs. After cooling, 1 M hydrochloric acid was added to acidify the reaction mixture. The crystals were collected by filtration to give 4-(5-phenyl-1H-1,2,4-triazol-3-yl)benzoic acid (0.380 g, yield 79%). Recrystallization from hexane-tetrahydrofuran gave colorless prism crystals. melting point: >300° C.
Reaction SMILES: [C:1](/[CH:3]=[CH:4]/[C@H:5]([NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][C:24]([F:27])([F:26])[F:25])(=[O:16])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)#[N:2].Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:1](/[CH:3]=[CH:4]/[C@H:5]([N:13]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][C:24]([F:25])([F:26])[F:27])(=[O:15])=[O:16])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)#[N:2]
Reactant: CCOC(=O)CBr
Reactant: N#C/C=C/[C@@H](Cc1ccccc1)NS(=O)(=O)c1ccccc1OC(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CN([C@@H](/C=C/C#N)Cc1ccccc1)S(=O)(=O)c1ccccc1OC(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.3 %

Procedure:
To a solution of compound 31g (4.2 g, 10.6 mmol) in DMF (100 mL) was added ethyl bromoacetate (2.1 g, 12.7 mmol) and K2CO3 (3.5 g, 25.4 mmol). The mixture was stirred at rt for 12 h, then water (100 mL) was added to the mixture. The mixture was extracted with EA three times and the combined organic layer was washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was evaporated and the residue was purified by CC (hexane/EA=5:1) to give compound 31h (3.7 g, 73% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C@H:8]([CH2:11]OS(C)(=O)=O)[O:7][C:6]=2[CH:17]=1.Br.[NH:19]1[CH2:24][CH2:23][CH2:22][C@H:21]([C:25]2[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=2)[CH2:20]1.C([O-])(O)=O.[Na+].O>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C@H:8]([CH2:11][N:19]3[CH2:24][CH2:23][CH2:22][C@H:21]([C:25]4[CH:26]=[C:27]([OH:31])[CH:28]=[CH:29][CH:30]=4)[CH2:20]3)[O:7][C:6]=2[CH:17]=1
Reactant: Oc1cccc([C@H]2CCCNC2)c1
Reactant: CS(=O)(=O)OC[C@H]1COc2ccc(F)cc2O1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Oc1cccc([C@H]2CCCN(C[C@H]3COc4ccc(F)cc4O3)C2)c1
Temperature: 120 °C
Yield: 36.8 %

Procedure:
A mixture of methanesulfonic acid (R)-(7-fluoro-2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl ester (51 mg, 0.19 mmol), (R*)-3-(piperidin-3-yl)phenol HBr (50 mg, 0.19 mmol) and NaHCO3 (33 mg, 0.39 mmol) in DMF (3.5 ml) was heated at 120° C. for 1.5 h. Water (10 ml) was added to the cooled mixture, which was then extracted with EtOAc (3×10 ml). The combined organic layers were washed several times with water and finally twice with brine. Drying (Na2SO4), filtering and evaporation of the solvent gave the crude product, which was recrystallised from EtOH to afford 24 mg of the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1)[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:69][NH:70][CH:71]1[CH2:76][CH2:75][CH2:74][CH2:73][CH2:72]1>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:15](=[O:17])[N:70]([CH:71]2[CH2:76][CH2:75][CH2:74][CH2:73][CH2:72]2)[CH3:69])[CH:18]=[C:19]([Cl:21])[CH:20]=1)[C:22]1[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Reactant: CNC1CCCCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)C1CCCCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.039 g), TBTU (0.064 g) and HOBt (0.027 g) in DMF (1 ml) was added DIPEA (0.036 ml) followed by N-methylcyclohexylamine (0.027 ml) after 15 min. The reaction mixture was stirred at room temperature for 18 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.036 g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[CH:13][CH:14]=[C:7]1[CH:6]([CH2:15][CH3:16])[NH:5]2.[CH3:17][O:18][C:19]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]1[CH:12]=[CH:13][CH:14]=[C:7]1[CH:6]([CH2:15][CH3:16])[N:5]2[C:21](=[O:22])[C:20]1[CH:24]=[CH:25][C:26]([O:28][CH3:29])=[CH:27][C:19]=1[O:18][CH3:17]
Reactant: CCC1Nc2cc(Br)ccc2-n2cccc21
Reactant: COc1ccc(C(=O)Cl)c(OC)c1
Product: CCC1c2cccn2-c2ccc(Br)cc2N1C(=O)c1ccc(OC)cc1OC

Procedure:
7-Bromo-5-(2,4-dimethoxybenzoyl)-4-ethyl-4,5-dihydropyrrolo[1,2-a]quinoxaline was prepared from 7-bromo-4-ethyl-4,5-dihydropyrrolo[1,2-a]quinoxaline (see Example 42) and 2,4-dimethoxybenzoyl chloride according to the procedure of Example 106, Step 2. The product was purified via Biotage Horizon® (25S, silica gradient from 5% EtOAc/Hexane to 40% EtOAc/hexane) and isolated as a white foam. MS (ESI) m/z 441/443 ([M+H]+); HRMS: calcd for C22H21BrN2O3, 440.0736; found (ESI+), 441.08006.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:13])[CH2:9][CH2:10][CH2:11][OH:12])[C:5]([CH3:14])=[CH:4][N:3]=1.O[C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH:20]=[CH:19]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>ClCCl.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH2:9][CH2:10][CH2:11][O:12][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[NH:21][CH:20]=[CH:19]3)[CH3:13])[C:5]([CH3:14])=[CH:4][N:3]=1
Reactant: Cc1cnc(Cl)nc1N(C)CCCO
Reactant: Oc1ccc2[nH]ccc2c1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cnc(Cl)nc1N(C)CCCOc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 24.1 %

Procedure:
To a solution of 3-[(2-chloro-5-methyl-4-pyrimidinyl)(methyl)amino]-1-propanol (0.316 g, 1.47 mmol) (prepared in similar fashion as Example 83) and 5-hydroxyindole (0.195 g, 1.47 mmol) in dichloromethane (7 mL) was added triphenylphosphine (1.15 g, 4.40 mmol) and 1,1′-(azodicarbonyl)-dipiperidine (1.11 g, 4.40 mmol) under argon. The golden yellow mixture was stirred at rt for 24 h. The desired product (0.117 g, 24%) was obtained after column chromatography (50% hexanes in EtOAc). LC/MS m/z 331.3 (M+H)+, RT 2.76 min.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.Br.Br.[C:24]12[CH2:31][NH:30][CH2:29][C:28]=1[CH2:27][NH:26][CH2:25]2.N12CCCN=C1CCCCC2>C(#N)C>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11]([N:26]4[CH2:27][C:28]5[CH2:29][NH:30][CH2:31][C:24]=5[CH2:25]4)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)c(F)c2c1=O
Reactant: C1NCC2=C1CNC2
Agent: Br
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CC4=C(CNC4)C3)c(F)c(F)c2c1=O
Reaction time: 8 h
Yield: 74.4 %

Procedure:
0.6 g of 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 1.2 g of 3,7-diazabicyclo[3.3.0]oct-1(5)-ene dihydrobromide and 1.3 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) were suspended in 20 ml of acetonitrile, and then the reaction mixture was refluxed for 10 hours. This reaction mixture was kept overnight at the room temperature, and the produced precipitate was filtered and then the residue was washed with ethanol to obtain 0.58 g the title compound (yield 74%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:5]([CH2:11][CH:12]1[CH2:17][CH2:16][N:15](CC3C=CC=CC=3)[CH2:14][CH2:13]1)=[N:6]2.[C:33](Cl)(=[O:37])[O:34][CH2:35][CH3:36].[OH-].[NH4+]>CC1C=CC=CC=1>[Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]([CH2:25][C:26]1[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=1)[C:5]([CH2:11][CH:12]1[CH2:13][CH2:14][N:15]([C:33]([O:34][CH2:35][CH3:36])=[O:37])[CH2:16][CH2:17]1)=[N:6]2
Reactant: CCOC(=O)Cl
Reactant: Fc1ccc(Cn2c(CC3CCN(Cc4ccccc4)CC3)nc3ncnc(Cl)c32)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC(Cc2nc3ncnc(Cl)c3n2Cc2ccc(F)cc2)CC1
Reaction time: 2 h
Yield: 100 %

Procedure:
A mixture of 16 parts of 6-chloro-7-[(4-fluorophenyl)methyl]-8-[[1-(phenylmethyl)-4-piperidinyl]methyl]-7H-purine, 4.65 parts of ethyl carbonochloridate and 180 parts of methylbenzene was stirred for 2 hours at reflux temperature. After cooling, the reaction mixture was treated with ammonium hydroxide and the product was extracted with methylbenzene. The extract was washed with water, dried, filtered and evaporated, yielding 18.7 parts (100%) of ethyl 4-[[6-chloro-7-[(4-fluorophenyl)methyl]-7H-purin-8-yl]methyl]-1-piperidinecarboxylate as a residue (compound 28).
Reaction SMILES: [CH3:1][N:2]([CH3:45])[C:3](=O)[CH2:4][NH:5][C@:6]12[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:7]1[C@@H:8]1[C@@:21]([CH3:24])([CH2:22][CH2:23]2)[C@@:20]2([CH3:25])[C@@H:11]([C@:12]3([CH3:37])[C@@H:17]([CH2:18][CH2:19]2)[C:16]([CH3:27])([CH3:26])[C:15]([C:28]2[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=2)=[CH:14][CH2:13]3)[CH2:10][CH2:9]1.Cl.ClCCN1C[CH2:54][O:53][CH2:52]C1>>[CH3:24][C@:21]12[C@@:20]3([CH3:25])[C@@H:11]([C@:12]4([CH3:37])[C@@H:17]([CH2:18][CH2:19]3)[C:16]([CH3:27])([CH3:26])[C:15]([C:28]3[CH:29]=[CH:30][C:31]([C:32]([OH:34])=[O:33])=[CH:35][CH:36]=3)=[CH:14][CH2:13]4)[CH2:10][CH2:9][C@@H:8]1[C@H:7]1[C@H:38]([C:41]([CH3:43])=[CH2:42])[CH2:39][CH2:40][C@:6]1([NH:5][CH2:4][CH2:3][N:2]1[CH2:45][CH2:54][O:53][CH2:52][CH2:1]1)[CH2:23][CH2:22]2
Reactant: C=C(C)[C@@H]1CC[C@]2(NCC(=O)N(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: ClCCN1CCOCC1
Agent: Cl
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCOCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for the synthesis of 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(2-(dimethylamino)-2-oxoethylamino)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoic acid using 4-(2-chloroethyl)morpholine hydrochloride as the alkylating agent in Step 1. The product was isolated as a white solid (65 mg, 49.4%). LCMS: m/e 643.6 (MH+), 2.35 min (method 13). 1H NMR (400 MHz, MeOD) δ ppm 7.95 (m, J=8.3 Hz, 2H), 7.24 (m, J=8.3 Hz, 2H), 5.31 (d, J=4.8 Hz, 1H), 4.86 (s, 1H), 4.74 (s, 1H), 3.82-3.99 (m, 4H), 3.37-3.58 (m, 4H), 3.21 (d, J=4.5 Hz, 2H), 3.19 (br. s., 2H), 2.67-2.86 (m, 1H), 2.02-2.26 (m, 5H), 1.83-1.90 (m, 1H), 1.64-1.81 (m, 8H), 1.45-1.64 (m, 7H), 1.34-1.45 (m, 2H), 1.27-1.34 (m, 1H), 1.15-1.27 (m, 4H), 1.12 (s, 3H), 1.04 (s, 3H), 0.99 (s, 3H), 0.93 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH2:32][CH2:31][C:30]([CH3:34])([CH3:33])[CH2:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].C(N(C(C)C)C(C)C)C.[CH3:44][O:45][CH2:46]Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH2:32][CH2:31][C:30]([CH3:33])([CH3:34])[CH2:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([O:26][CH2:44][O:45][CH3:46])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4]
Reactant: COC(=O)c1sc(C2=CCC(C)(C)CC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](O)CC1
Reactant: COCCl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCO[C@H]1CC[C@H](N(c2cc(C3=CCC(C)(C)CC3)sc2C(=O)OC)C(=O)[C@H]2CC[C@H](C)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(4,4-dimethyl-cyclohex-1-enyl)-3-[(trans-4-hydroxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (406 mg, 0.83 mmol), i-Pr2EtN (218 μL, 1.25 mmol) and DMAP (15 mg, 0.12 mmol) in dry CH2Cl2 (20 mL) was added chloromethyl methyl ether (95 μL, 1.25 mmol), and the mixture was stirred at room temperature overnight. Then the mixture was diluted with CH2Cl2, washed with brine, organic fraction was dried over Na2SO4, concentrated under reduced pressure and purified by column chromatography on silica gel eluting with 0-30% EtOAc in hexanes to give 286 mg (65%) of 5-(4,4-dimethyl-cyclohex-1-enyl)-3-[(trans-4-methoxymethoxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester.
Reaction SMILES: [NH3:1].[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]1[C:8]2[S:20][CH:19]=[CH:18][C:9]=2[N:10]=[C:11]([C:13](OCC)=[O:14])[N:12]=1>C(O)C>[O:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]1[C:8]2[S:20][CH:19]=[CH:18][C:9]=2[N:10]=[C:11]([C:13]([NH2:1])=[O:14])[N:12]=1
Reactant: CCOC(=O)c1nc(-c2ccco2)c2sccc2n1
Reactant: N
Solvent: CCO
Product: NC(=O)c1nc(-c2ccco2)c2sccc2n1
Yield: 67 %

Procedure:
Ammonia gas was bubbled through a hot solution of ethyl 4-(2-furyl)thieno[3,2-d]pyrimidine-2-carboxylate (0.156 g, 0.57 mmol) in ethanol (20 mL) for 3 h then the mixture cooled and the resulting white solid filtered to give the title compound (94 mg, 67%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:15])[N:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[N:5]=[CH:6][C:7]=1Cl.C(=O)([O-])[O-].[K+].[K+].[OH:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[C:25]#[N:26]>C(#N)C>[Cl:1][C:2]1[C:3](=[O:15])[N:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[N:5]=[CH:6][C:7]=1[O:22][C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[C:25]#[N:26]
Reactant: N#Cc1ccccc1O
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#Cc1ccccc1Oc1cnn(C2CCCCO2)c(=O)c1Cl
Temperature: 25 °C
Yield: 99.2 %

Procedure:
A solution of 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (Intermediate 20, 60 g, 0.24 mol) in acetonitrile (500 mL) was treated with potassium carbonate (35.2 g, 0.26 mol) and 2-hydroxy-benzonitrile (29 g, 0.24 mol). The resulting reaction mixture was heated at reflux for 2 h and then allowed to cool to 25° C. The reaction mixture was then partitioned between water and methylene chloride. The organics were washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, rinsed, and concentrated in vacuo to afford 2-[5-chloro-6-oxo-1-(tetrahydro-pyran-2-yl)-1,6-dihydro-pyridazin-4-yloxy]-benzonitrile (79 g, 99%); ESI-MS 332 [M+H+]; HPLC: >99% (purity). 1H-NMR (300 MHz, CDCl3) δ 7.74-7.76 (m, 1H), 7.58-7.64 (m, 2H), 7.31-7.34 (m, 1H), 6.07-6.10 (d, 1H), 4.12-4.16 (d, 1H), 3.73-3.80 (t, 1H), 2.15-1.60 (m, 6H).