Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=O)=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1.[S:37]1[CH2:41][C:40](=[O:42])[NH:39][C:38]1=[O:43].N1CCCCC1>C(O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[C:41]4/[C:40](=[O:42])[NH:39][C:38](=[O:43])[S:37]/4)=[CH:22][N:21]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: O=C1CSC(=O)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C2\SC(=O)NC2=O)ccc1OCc1nc(-c2ccco2)oc1C
Yield: 85.3 %

Procedure:
A mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (1.10 g), 1,3-thiazolidine-2,4-dione (0.27 g), piperidine (0.04 g) and ethanol (30 mL) was heated under reflux for 3 hrs. The reaction mixture was concentrated, and the obtained crystals were washed with ethanol to give (5Z)-5-({3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}methylene)-1,3-thiazolidine-2,4-dione as yellow crystals (1.13 g, yield 84%). Recrystallization from tetrahydrofuran-hexane gave yellow prism crystals. melting point: 252-253° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([NH:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:25]([O:27][CH2:28]C)=[O:26])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:32]I>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]([N:18]([CH3:32])[CH:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:25]([O:27][CH3:28])=[O:26])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CI
Reactant: CCOC(=O)c1ccc2nc(-c3ccc(F)cc3)c(NC3CCOCC3)nc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N(C)C3CCOCC3)nc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of ethyl 2-(4-fluorophenyl)-3-(tetrahydro-2H-pyran-4-ylamino)quinoxaline-6-carboxylate (180.0 mg, 0.47 mmol) in tetrahydrofuran (20 mL) was added sodium hydride (22.7 mg, 0.95 mmol) at 0° C. and stirred for 1 h at room temperature. Then CH3I (134.0 mg, 0.94 mmol) was added at 0° C. and stirred overnight at room temperature. The reaction mixture was quenched by the addition of NH4Cl solution (100 ml) and adjusted to pH 6 with hydrochloric acid (1N), extracted with dichloromethane (3×30 mL), dried over anhydrous magnesium sulfate and concentrated under vacuum to afford methyl 2-(4-fluorophenyl)-3-(methyl(tetrahydro-2H-pyran-4-yl)amino)quinoxaline-6-carboxylate as yellow oil (100 mg, crude).
Reaction SMILES: [CH2:1]([CH:3]([C:24]([OH:26])=[O:25])[N:4]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]#[N:12])[CH:6]=1)[CH3:2].[N+]([O-])(O)=O.C[C:32]1C=C(C)[N:34](C(N)=N)[N:33]=1>N1C=CC=CC=1>[CH2:1]([CH:3]([C:24]([OH:26])=[O:25])[N:4]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([NH:23][CH:32]=[N:33][NH2:34])=[CH:21][CH:22]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]#[N:12])[CH:6]=1)[CH3:2]
Reactant: Cc1cc(C)n(C(=N)N)n1
Reactant: CCC(C(=O)O)N(CCCCc1ccc(N)cc1)c1cccc(C#N)c1
Solvent: O=[N+]([O-])O
Solvent: c1ccncc1
Product: CCC(C(=O)O)N(CCCCc1ccc(NC=NN)cc1)c1cccc(C#N)c1
Yield: 58.3 %

Procedure:
Part E. A solution of ethyl N-[4-[4-aminophenyl]butyl]-N-[3-cyanophenyl]glycine (0.12 gm, 0.34 mmol) and 3,5-dimethylpyrazole-1-carboxamidine nitrate (0.103 gm, 0.51 mmol) in 10 mL pyridine was heated to 100° C. under a nitrogen atmosphere for 3 hrs. The reaction mixture was allowed to cool and was partitioned between ethyl acetate and water. The combined organic layer was washed with water, brine, dried over magnesium sulfate and concentrated to give the crude product. The product was purified by flash chromatography on silica gel eluting chloroform:methanol (v:v, 80:20) to give ethyl N-[4-[4-[(aminoiminomethyl)amino]phenyl]butyl]-N-[3-cyanophenyl]glycine 0.078 gm (58%) MS 394(M+H)+ 1 H NMR (CDCl3): 7.0(m, 10H), 6.8(m, 2H), 4.2(q, 2H), 4.0(s, 2H), 3.4(m, 2H), 2.7(m, 2H), 1.2(t, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[NH:10]1[CH:14]=[CH:13][N:12]=[CH:11]1.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)=[CH:3][CH:4]=1
Reactant: c1c[nH]cn1
Reactant: COc1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: COc1ccc(-n2ccnc2)cc1
Yield: 49.9 %

Procedure:
A mixture of 37.4 g (0.2 mole) of 4-bromoanisole, 170 g (0.25 mole) of imidazole, 26 g (0.2 mole) of potassium carbonate, and 1.2 g of cuprous bromide in 150 ml of N-methylpyrrolidinone was heated at reflux under a blanket of nitrogen for 4 hr. The mixture was filtered and concentrated to remove the solvent. The residue was partitioned between dilute sodium hydroxide solution and methylene chloride. After filtration, the organic fraction was chromatographed. The desired fractions were concentrated and the crystalline residue was recrystallized from toluene/cyclohexane to give 17.4 g (50%) of the title compound as white plates, mp 63.0°-64.0° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][C:10]([C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)([CH2:15][N+:16]([O-])=O)[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:4][C:3]=1[CH2:28][N:29]1[C:33](=[O:34])[C:32]2=[CH:35][CH:36]=[CH:37][CH:38]=[C:31]2[C:30]1=[O:39].C([O-])=O.[NH4+].C(OCC)(=O)C.O>O1CCCC1.[Zn]>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2[CH2:9][C:10]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=3)([C:11]([F:13])([F:12])[F:14])[CH2:15][N:16]=2)[CH:5]=[CH:4][C:3]=1[CH2:28][N:29]1[C:30](=[O:39])[C:31]2=[CH:38][CH:37]=[CH:36][CH:35]=[C:32]2[C:33]1=[O:34]
Reactant: O=C(CC(C[N+](=O)[O-])(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccc(CN2C(=O)c3ccccc3C2=O)c(Br)c1
Agent: O=C[O-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(C2=NCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1Br
Temperature: 25 °C

Procedure:
To a solution of 0.70 g of N-[2-bromo-4-[3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-(nitromethyl) butanoyl]phenylmethyl]phthalimide and 1.03 g of ammonium formate in 20 mL of tetrahydrofuran, 1.07 g of zinc powder was added and the resultant reaction mixture was stirred while heating the mixture to reflux for 1 hour. After the completion of the reaction, the reaction mixture was left to be cooled down to room temperature, and 100 mL of ethyl acetate and 50 mL of water were added to the reaction mixture, followed by filtering the reaction mixture with Celite. Subsequently, the organic phase was separated off and was dehydrated and dried over a saturated brine and anhydrous magnesium sulfate in this order, and the solvent was distilled off under reduced pressure. The resultant residue was purified by silica gel column chromatography eluting with chloroform to obtain 0.18 g of the objective substance as a white crystal.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]([O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[CH:17]1OCC[O:18]1)([CH2:7][CH3:8])[CH2:5][CH3:6]>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3](=[O:22])[C:4]([O:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=1[CH:17]=[O:18])([CH2:5][CH3:6])[CH2:7][CH3:8]
Reactant: CCC(CC)(Oc1ccc(Cl)cc1C1OCCO1)C(=O)OC
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)(Oc1ccc(Cl)cc1C=O)C(=O)OC
Yield: 93.6 %

Procedure:
A solution of 2-(4-chloro-2-[1,3]dioxolan-2-yl-phenoxy)-2-ethyl-butyric acid methyl ester (16 g, 48.8 mmol) in trifluoroacetic acid (20 mL) was stirred at room temperature for 3 h. Then the mixture was concentrated and the residue was partitioned between EtOAc and water. The organic layer was washed with 1N NaOH solution, water, dried over anhydrous Na2SO4 and concentrated to give the title compound (13 g).
Reaction SMILES: [CH2:1]([C:3]1[S:21][C:6]2[N:7]=[CH:8][N:9]=[C:10]([NH:11][CH:12]3[CH2:17][CH2:16][CH:15]([N:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)[C:5]=2[CH:4]=1)[CH3:2].[Br:22]Br>CC(O)=O>[Br:22][C:4]1[C:5]2[C:10]([NH:11][CH:12]3[CH2:17][CH2:16][CH:15]([N:18]([CH3:19])[CH3:20])[CH2:14][CH2:13]3)=[N:9][CH:8]=[N:7][C:6]=2[S:21][C:3]=1[CH2:1][CH3:2]
Reactant: CCc1cc2c(NC3CCC(N(C)C)CC3)ncnc2s1
Reactant: BrBr
Solvent: CC(=O)O
Product: CCc1sc2ncnc(NC3CCC(N(C)C)CC3)c2c1Br
Temperature: 70 °C
Reaction time: 8 h
Yield: 35.7 %

Procedure:
Into a 250-mL round-bottom flask containing a solution of 4-N-[6-ethylthieno[2,3-d]pyrimidin-4-yl]-1-N,1-N-dimethylcyclohexane-1,4-diamine (2 g, 6.57 mmol, 1.00 equiv) in AcOH (40 mL) was added Br2 (2.1 g, 13.14 mmol, 2.00 equiv) at room temperature. The resulting solution was stirred overnight at 70° C. The resulting mixture was concentrated under vacuum. The pH value of the solution was adjusted to 9 with sodium carbonate (sat.) and extracted with 3×200 mL of ethyl acetate. The combined.organic layers were washed with 300 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give the resulted 4-N-[5-bromo-6-ethylthieno[2,3-d]pyrimidin-4-yl]-1-N,1-N-dimethylcyclohexane-1,4-diamine (0.9 g, crude) as a brown solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[N:11]1([C:17]([C:19]2[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=2)=[O:18])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(=O)(O)[O-].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:8]1[C:5]2=[N:6][CH:7]=[C:2]([C:23]3[CH:24]=[C:19]([C:17]([N:11]4[CH2:16][CH2:15][O:14][CH2:13][CH2:12]4)=[O:18])[CH:20]=[CH:21][CH:22]=3)[CH:3]=[C:4]2[CH:10]=[CH:9]1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: O=C(c1cccc(B(O)O)c1)N1CCOCC1
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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(c1cccc(-c2cnc3[nH]ccc3c2)c1)N1CCOCC1
Temperature: 110 °C
Reaction time: 15 h
Yield: 83.7 %

Procedure:
A mixture of 5-bromo-1H-pyrrolo[2,3-b]pyridine (3 g, 15 mmol), 3-(morpholine-4-carbonyl)phenylboronic acid (4 g, 18 mmol), sodium bicarbonate (4 g, 46 mmol), and tetrakis(triphenylphosphine)palladium(0) in dioxane/water (100 mL/20 mL) was stirred at 110° C. for 15 hours. The mixture was then poured into ice water and extracted with ethyl acetate (3×). The organic layers were combined, dried over sodium, sulfate, filtered and concentrated to dryness. Silica gel chromatography of the crude product afforded (3-(1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)(morpholino)methanone (3.86 g, 84% yield) as yellow solids. MS: m/z 308.1 (M+H+).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21]5[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=5)=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:63]1([CH2:69][CH2:70][NH2:71])[CH2:68][CH2:67][CH2:66][CH2:65][CH2:64]1>CN(C=O)C.O>[N:63]1([CH2:69][CH2:70][NH:71][C:25](=[O:26])[C:24]2[CH:23]=[CH:22][C:21]([C:18]3[N:17]=[C:16]4[N:12]([CH2:11][C:7]5[CH:6]=[C:5]6[C:10](=[CH:9][CH:8]=5)[N:1]=[CH:2][CH:3]=[CH:4]6)[N:13]=[N:14][C:15]4=[CH:20][CH:19]=3)=[CH:29][CH:28]=2)[CH2:68][CH2:67][CH2:66][CH2:65][CH2:64]1
Reactant: O=C(O)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1
Reactant: NCCN1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCCN1CCCCC1)c1ccc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1
Reaction time: 12 h
Yield: 51.8 %

Procedure:
To a solution of example 8 (0.120 g, 0.314 mmol) in DMF (0.7 ml), N-ethyldiisopropylamine (0.041 g, 0.314 mmol) and HATU (0.119 g, 0.314 mmol) were added and stirred for 5 min. (2-(piperidin-1-yl)ethanamine (0.040 g, 0.314 mmol) was added at RT and the reaction mixture was stirred for 12 h. To the reaction mixture water was added and extracted with ethyl acetate, dried over sodium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as a yellow solid (0.080 g, 52%). M.P.: 104-107° C., 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 8.88 (dd, J=4.1, 1.6 Hz, 1H), 8.70 (d, J=8.7 Hz, 1H), 8.62 (bs, 1H), 8.38 (m, 3H), 8.21 (d, J=8.8 Hz, 1H), 8.03-7.98 (m, 4H), 7.84 (dd, J=8.7, 1.9 Hz, 1H), 7.53 (dd, J=8.3, 4.2 Hz, 1H), 6.22 (s, 2H), 3.48 (bs, 2H), 2.48 (m, 6H), 1.54 (m, 6H).
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@@H:27]4[CH2:31][CH2:30][NH:29][CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1.C([O:35][CH2:36][C:37](Cl)=[O:38])(=O)C>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][C:8]=2[C:14]2[C:15]3[NH:22][C:21]([CH3:23])=[C:20]([C:24]([NH:26][C@@H:27]4[CH2:31][CH2:30][N:29]([C:36](=[O:35])[CH2:37][OH:38])[CH2:28]4)=[O:25])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:4][CH2:3]1
Reactant: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1CCNC1
Reactant: CC(=O)OCC(=O)Cl
Agent: Cl
Product: Cc1[nH]c2c(-c3cc(F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@@H]1CCN(C(=O)CO)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-fluorophenyl]-6-methyl-N-[(3R)-pyrrolidin-3-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f15) and commercially available 2-chloro-2-oxoethyl acetate the title compound is obtained as colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]#[C:10][CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][C@H:14]2[CH3:18])=[C:6]([NH2:8])[CH:7]=1.Cl.[N:20]([O-])=O.[Na+].[OH2:24]>>[Br:1][C:2]1[CH:7]=[C:6]2[C:5]([C:9]([OH:24])=[C:10]([CH2:11][CH2:12][N:13]3[CH2:17][CH2:16][CH2:15][C@H:14]3[CH3:18])[N:20]=[N:8]2)=[CH:4][CH:3]=1
Reactant: O
Reactant: O=N[O-]
Reactant: C[C@@H]1CCCN1CCC#Cc1ccc(Br)cc1N
Agent: Cl
Agent: [Na+]
Product: C[C@@H]1CCCN1CCc1nnc2cc(Br)ccc2c1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
To a mixture of Example 168C (0.10 g, 0.325 mmol) in 2 mL of water was added 1.5 mL 6 M HCl. The resulting solution was cooled to 0° C. and NaNO2 (0.034 g, 0.488 mmol), dissolved in 1 mL water, was added dropwise. The resulting mixture was stirred for 30 minutes at 0° C. and subsequently heated to 90° C. for one hour. After cooling, contents were filtered and the precipitate was washed with 10 mL water and dried under reduced pressure to provide the product in 47% yield as a brown solid in HCl salt form, which was used without further purification. 1H NMR (CD3OD, 300 MHz) δ 8.10 (d, J=9 Hz, 1H), 7.82 (d, J=3 Hz, 1H), 7.60 (dd, J=3, 9 Hz, 1H), 3.89-3.76 (m, 2H), 3.58-3.53 (m, 1H) 3.42-3.23 (m, 4H), 2.38-2.30 (m, 1H), 2.16-2.06 (m, 2H), 1.83-1.75 (m, 1H), 1.51 (d, J=6 Hz, 3H). MS (ESI) [M]+ at 336.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH2:7]([Br:10])[CH:8]=[CH2:9].[C:11]([O:14][C@H:15]1[C@@H:20]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:19][C@H:18]2[C@H:26]3[C@H:36]([CH2:37][CH2:38][C@:16]12[CH3:17])[C@:34]1([CH3:35])[C@H:29]([CH2:30][C@H:31]([OH:45])[C@@H:32]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)[CH2:33]1)[CH2:28][CH2:27]3)(=[O:13])[CH3:12]>ClCCl>[Br-:10].[C:11]([O:14][C@H:15]1[C@@H:20]([N+:21]2([CH2:9][CH:8]=[CH2:7])[CH2:22][CH2:23][CH2:24][CH2:25]2)[CH2:19][C@H:18]2[C@H:26]3[C@H:36]([CH2:37][CH2:38][C@:16]12[CH3:17])[C@:34]1([CH3:35])[C@H:29]([CH2:30][C@H:31]([OH:45])[C@@H:32]([N:39]2[CH2:40][CH2:41][O:42][CH2:43][CH2:44]2)[CH2:33]1)[CH2:28][CH2:27]3)(=[O:13])[CH3:12]
Reactant: CC(=O)O[C@H]1[C@@H](N2CCCC2)C[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](N5CCOCC5)C[C@]4(C)[C@H]3CC[C@@]21C
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: C=CC[N+]1([C@H]2C[C@H]3[C@@H]4CC[C@H]5C[C@H](O)[C@@H](N6CCOCC6)C[C@]5(C)[C@H]4CC[C@]3(C)[C@H]2OC(C)=O)CCCC1
Product: [Br-]
Temperature: 22.5 °C
Reaction time: 0.08 h

Procedure:
In a three neck flask equipped with heated mantle, thermometer and magnetic stirrer, was charged dichloromethane (20 mL), sodium carbonate (2.0 g, 0.081 mol) and slowly allyl bromide (0.692 mL, 0.00818 mol) at 20-22° C. under N2 atmosphere. The mixture was stirred during 5 min and 2β-(4-morpholinyl)-16β-(1-pyrrolidinyl)-5α-androstan-3α,17β-diol 17-acetate (Compound VIII) (2.0 g, 4.09×10−3 mol) was added. The resulting mixture was stirred during 5-10 min. The resulting solution was stirred under reflux for 22 hours. The mixture was then cooled to room temperature (20-25° C.) and filtered (membrane 0.45 microns) under nitrogen atmosphere. The solvent was removed under vacuum keeping the temperature below 20° C. The foam obtained was dissolved with dichloromethane (10 mL) and concentrated under vacuum keeping the temperature below 20° C.; this procedure was repeated twice. Once again the residue was dissolved at room temperature under nitrogen atmosphere in dichloromethane (22 mL).
Reaction SMILES: [NH2:1][C@H:2]([CH2:5][C:6]1[CH:11]=[C:10](Br)[CH:9]=[CH:8][C:7]=1[F:13])[CH2:3][OH:4].[Cl:14][CH:15]([CH3:19])[C:16](Cl)=O.Br.Br[C:22]1[N:23]=[N:24][CH:25]=[CH:26][CH:27]=1>>[ClH:14].[F:13][C:7]1[CH:8]=[CH:9][C:10]([C:22]2[N:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[CH:11][C:6]=1[CH2:5][C@H:2]1[NH:1][CH2:16][C@@H:15]([CH3:19])[O:4][CH2:3]1
Reactant: CC(Cl)C(=O)Cl
Reactant: Brc1cccnn1
Reactant: N[C@@H](CO)Cc1cc(Br)ccc1F
Agent: Br
Product: C[C@@H]1CN[C@H](Cc2cc(-c3cccnn3)ccc2F)CO1
Product: Cl

Procedure:
The title compound was prepared from (R)-2-amino-3-(5-bromo-2-fluorophenyl)propan-1-ol (Chiral Quest) and rac-2-chloropropanoyl chloride, in analogy to the sequence of reactions described for the preparation of B-18 substituting 2-bromopyrimidine for 3-bromopyridazine hydrobromide. LC-MS A: tR=0.52 min; [M+H]+=288.25.
Reaction SMILES: C([O:4][C:5]1[CH:40]=[CH:39][C:8]([CH2:9][N:10]2[C:20]3[C:15](=[CH:16][C:17]([N:21]4[CH2:26][CH2:25][N:24]([C:27](=[O:38])[C:28]5[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=5)[CH2:23][CH2:22]4)=[CH:18][CH:19]=3)[CH2:14][CH2:13][C:11]2=[O:12])=[CH:7][CH:6]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[OH:4][C:5]1[CH:40]=[CH:39][C:8]([CH2:9][N:10]2[C:20]3[C:15](=[CH:16][C:17]([N:21]4[CH2:22][CH2:23][N:24]([C:27](=[O:38])[C:28]5[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([O:36][CH3:37])[CH:29]=5)[CH2:25][CH2:26]4)=[CH:18][CH:19]=3)[CH2:14][CH2:13][C:11]2=[O:12])=[CH:7][CH:6]=1
Reactant: COc1ccc(C(=O)N2CCN(c3ccc4c(c3)CCC(=O)N4Cc3ccc(OC(C)=O)cc3)CC2)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1ccc(C(=O)N2CCN(c3ccc4c(c3)CCC(=O)N4Cc3ccc(O)cc3)CC2)cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.5 %

Procedure:
1-(4-Acetoxybenzyl)-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril (2 g) was dissolved in methanol (20 ml). To the solution was added a solution of potassium carbonate (1.53 g) in water (20 ml) and the mixture was stirred at room temperature for 30 minutes. After completion of reaction, the reaction mixture was poured into water and extracted with chloroform. The extract was washed with saturated saline solution, dried over magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethanol to give 1-(4-hydroxybenzyl)-6-[4-(3,4-dimethoxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril (950 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH3:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].I[CH3:16].[H-].[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:8]([CH3:16])[C@@H:9]([CH2:13][CH3:14])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CI
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[C@@H](C(=O)O)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.2 %

Procedure:
To a 0° C. solution of (S)-2-(tert-butoxycarbonylamino)butanoic acid (1.00 g, 4.92 mmol) in THF (16.4 ml) was added iodomethane (2.45 ml, 39.4 mmol) followed by sodium hydride (60% w/w dispersion in mineral oil, 590 mg, 14.8 mmol), portionwise. The reaction was allowed to warm to rt and stirred for 18 h, then cooled to 0° C., quenched by the careful addition of H2O, and washed with Et20. The aqueous layer was acidified by the addition of 1 M aq. HCl and extracted with Et20. The combined organic layers were washed with sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated to provide (S)-2-(tert-butoxycarbonyl(methyl)amino)butanoic acid (1.05 g, 98%) as a white solid. MS m/z 240 (MNa)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH:17]([CH2:21][CH3:22])[C:18]([OH:20])=O)[CH:12]([CH2:15][CH3:16])[C:13]#[CH:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[N+:38](=[CH2:40])=[N-:39]>CCOCC.CC(O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH:17]([CH2:21][CH3:22])[C:18](=[O:20])[CH:40]=[N+:38]=[N-:39])[CH:12]([CH2:15][CH3:16])[C:13]#[CH:14])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: C=[N+]=[N-]
Reactant: C#CC(CC)N(C(CC)C(=O)O)S(=O)(=O)c1ccc(Cl)cc1
Agent: CC(C)COC(=O)Cl
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C#CC(CC)N(C(CC)C(=O)C=[N+]=[N-])S(=O)(=O)c1ccc(Cl)cc1
Temperature: -30 °C
Reaction time: 0.25 h

Procedure:
To a solution of the compound 60 (498 mg, 1.45 mmol) in 7.5 mL of Et2O were added sequentially 0.24 mL of triethylamine (1.2 eq), 0.23 mL of isobutyl chloroformate (1.2 eq) at −30° C. After being stirred at −30° C. for 15 min, diazomethane (prepared by mixing MNNG and KOH in diethyl ether) (excess) was added to the above mixture at 0° C. and stirred there for 5 hours. Glacial HOAc (1.5 mL) was added to destroy the excess diazomethane and the solution was extracted with EtOAc. The organic phase was washed with sat NaHCO3, water, brine and dried (MgSO4). LCMS 368.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([NH:14][CH3:15])[CH2:12][N:11]([C:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:20][CH2:19]3)=[O:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[F:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]([CH3:42])([CH3:41])[C:38]([OH:40])=O)=[CH:33][CH:32]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][N:11]([C:16]([CH:18]3[CH2:19][CH2:20][N:21]([C:24]([C:26]4([CH3:29])[CH2:27][CH2:28]4)=[O:25])[CH2:22][CH2:23]3)=[O:17])[CH2:12][CH:13]2[N:14]([CH3:15])[C:38](=[O:40])[C:37]([C:34]2[CH:33]=[CH:32][C:31]([F:30])=[CH:36][CH:35]=2)([CH3:42])[CH3:41])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C(=O)O)c1ccc(F)cc1
Reactant: CNC1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Product: CN(C(=O)C(C)(C)c1ccc(F)cc1)C1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 97, the title compound N-{(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-2-(4-fluoro-phenyl)-N-methyl-isobutyramide was prepared from {4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using 2-(4-fluoro-phenyl)-2-methyl-propionic acid instead of 4-chloro-3-(trifluoromethyl)benzoic acid and was obtained as a light brown oil. MS m/e: 602.3 [M]+.