Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:15]=[CH:16][C:17]4[O:21][CH2:20][CH2:19][C:18]=4[CH:22]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[C:4]([CH3:23])[C:3]=1[CH3:24].[CH3:25][O:26][C:27]1[CH:32]=[C:31](B(O)O)[CH:30]=[CH:29][N:28]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[O:21]1[C:17]2[CH:16]=[CH:15][C:14]([C:11]3([C:9]([NH:8][C:6]4[N:7]=[C:2]([C:31]5[CH:30]=[CH:29][N:28]=[C:27]([O:26][CH3:25])[CH:32]=5)[C:3]([CH3:24])=[C:4]([CH3:23])[CH:5]=4)=[O:10])[CH2:13][CH2:12]3)=[CH:22][C:18]=2[CH2:19][CH2:20]1
Reactant: Cc1cc(NC(=O)C2(c3ccc4c(c3)CCO4)CC2)nc(Cl)c1C
Reactant: COc1cc(B(O)O)ccn1
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: COCCOC
Solvent: CCOC(C)=O
Product: COc1cc(-c2nc(NC(=O)C3(c4ccc5c(c4)CCO5)CC3)cc(C)c2C)ccn1
Temperature: 80 °C
Yield: 88.8 %

Procedure:
To N-(6-chloro-4,5-dimethylpyridin-2-yl)-1-(2,3-dihydrobenzofuran-5-yl)cyclopropanecarboxamide (100 mg, 0.29 mmol), 2-methoxypyridin-4-ylboronic acid (67 mg, 0.44 mmol) and tetrakis(triphenylphosphine)palladium (0) (34 mg, 0.029 mmol) in 1,2-dimethoxyethane (3.0 mL), 2 M Na2CO3 (438 μL, 0.87 mmol) was added. The reaction mixture was stirred and heated at 80° C. for 16 hours under N2 atmosphere. Product and starting material were observed. 0.5 Equivalents of 2-methoxypyridin-4-ylboronic acid and 0.05 equivalents of tetrakis(triphenylphosphine)palladium (0) were added and continued heating for 40 hours. The reaction mixture was diluted with ethyl acetate (5 mL), dried over Na2SO4, filtered and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-30% ethyl acetate in hexane) to yield 1-(2,3-dihydrobenzofuran-5-yl)-N-(2′-methoxy-3,4-dimethyl-2,4′-bipyridin-6-yl)cyclopropanecarboxamide as a yellow solid (107 mg, 88%). ESI-MS m/z calc. 415.5. found 416.7 (M+1)+. Retention time 1.74 minutes.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4](NC2C=CC(CP(=O)(OCC)OCC)=CC=2)[N:3]=1.[F:28][C:29]([F:49])([F:48])[CH2:30][O:31][P:32]([CH2:40][C:41]1[CH:46]=[CH:45][C:44]([NH2:47])=[CH:43][CH:42]=1)(=[O:39])[O:33][CH2:34][C:35]([F:38])([F:37])[F:36].ClC1N=C(Cl)C(C(F)(F)F)=CN=1>>[Cl:1][C:2]1[C:7]([C:8]([F:10])([F:9])[F:11])=[CH:6][N:5]=[C:4]([NH:47][C:44]2[CH:45]=[CH:46][C:41]([CH2:40][P:32](=[O:39])([O:33][CH2:34][C:35]([F:36])([F:37])[F:38])[O:31][CH2:30][C:29]([F:28])([F:48])[F:49])=[CH:42][CH:43]=2)[N:3]=1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Reactant: Nc1ccc(CP(=O)(OCC(F)(F)F)OCC(F)(F)F)cc1
Agent: FC(F)(F)c1cnc(Cl)nc1Cl
Product: O=P(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)(OCC(F)(F)F)OCC(F)(F)F

Procedure:
The title compound was prepared according to the procedure for diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate using (4-Aminobenzyl)phosphonic acid bis-(2,2,2-trifluoroethyl) ester (Compound 165B) and 2,4-dichloro-5-(trifluoromethyl)pyrimidine. The desired product was isolated using MDP (ammonium bicarbonate basic buffer pH 9). 1H NMR (400 MHz, DMSOd6) δ ppm 10.69 (s, 1H), 8.81 (s, 1H), 7.65 (d, J=8.1 Hz, 2H), 7.26 (dd, J=8.7, 2.7 Hz, 2H), 4.56-4.72 (m, 4H), 3.51 (d, J=22.2 Hz, 2H). MS (ES+): m/z 532.01/534.02 (100/64) [MH+]. HPLC: tR=1.70 min (TOF, polar—3 min).
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[CH2:3][C:2]1=[O:10].Cl[C:12]1[CH:17]=[CH:16][C:15]([CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:14][N+:13]=1[O-]>>[O:22]1[CH2:23][CH2:24][N:19]([CH2:18][C:15]2[CH:16]=[CH:17][C:12]([C:3]3[C:4]4[C:5](=[CH:6][N:7]=[CH:8][CH:9]=4)[NH:1][C:2]=3[OH:10])=[N:13][CH:14]=2)[CH2:20][CH2:21]1
Reactant: O=C1Cc2ccncc2N1
Reactant: [O-][n+]1cc(CN2CCOCC2)ccc1Cl
Product: Oc1[nH]c2cnccc2c1-c1ccc(CN2CCOCC2)cn1
Yield: 14 %

Procedure:
Prepared as described in examples 2.2 and 2.3 starting from 352 mg (2.62 mmol) of 1H-pyrrolo[2,3-c]pyridin-2(3H)-one and 500 mg (2.19 mmol of 2-chloro-5-(morpholinomethyl)pyridine 1-oxide). Amount 33 mg. Yield 14%.
Reaction SMILES: [C:1]([O:5]C([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([N:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([C:25]3[C:26](=[O:41])[NH:27][C:28](=[O:40])[C:29]=3[C:30]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32]([CH3:39])[CH:31]=3)=[CH:17]2)[CH:13]=[CH:14][CH:15]=1)=O)(C)(C)C.Cl.[OH-:43].[NH4+].[C:45]([O:48][CH2:49][CH3:50])(=[O:47])[CH3:46]>>[C:45]([O:48][CH2:49][CH3:50])(=[O:47])[CH3:46].[CH3:1][OH:5].[OH-:43].[NH4+:8].[NH2:8][CH2:9][C:10]1[CH:11]=[C:12]([N:16]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]([C:25]3[C:26](=[O:41])[NH:27][C:28](=[O:40])[C:29]=3[C:30]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[N:32]([CH3:39])[CH:31]=3)=[CH:17]2)[CH:13]=[CH:14][CH:15]=1
Reactant: Cn1cc(C2=C(c3cn(-c4cccc(CNC(=O)OC(C)(C)C)c4)c4ccccc34)C(=O)NC2=O)c2ccccc21
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CO
Product: Cn1cc(C2=C(c3cn(-c4cccc(CN)c4)c4ccccc34)C(=O)NC2=O)c2ccccc21

Procedure:
The product from step b) (66.0 mg, 0.12 mmol), tetrhydrofuran (5 mL) and 5 mL of 5 M HCl (aq) were heated at 50° C. for 45 min. The mixture was poured into ethyl acetate and dilute ammonium hydroxide. The organic phase was washed 3 times with dilute ammonium hydroxide and once with water, and then evaporated. Chromatography (ethyl acetate/methanol/ammonium hydroxide: 95/5/1) gave 54 mg of the title product.
Reaction SMILES: [O:1]=[C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([NH:13][CH:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:15](OC)=[O:16])=[O:12])[CH2:10][CH:5]2[C:4]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:3]1.[BH4-].[Li+].O>O1CCCC1>[OH:16][CH2:15][CH:14]([NH:13][C:11]([N:9]1[CH2:8][CH2:7][N:6]2[C:2](=[O:1])[O:3][C:4]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:5]2[CH2:10]1)=[O:12])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)C(NC(=O)N1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1)c1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(NC(CO)c1ccccc1)N1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
Methyl α-[[(tetrahydro-3-oxo-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazin-7(1H)-yl)carbonyl]amino]benzeneacetate (0.15 g, 0.31 mmol) was dissolved in tetrahydrofuran (2 mL). Lithium borohydride (14 mg, 0.64 mmol) was added thereto, and the mixture was stirred at room temperature for 2 hours. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, and then concentrated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate) and powder was formed from hexane to obtain the title compound (0.13 g, yield 90%).
Reaction SMILES: [CH:1]1([S:4](Cl)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[NH2:8][C:9]1[C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35](=[O:46])[NH:36][C:37]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)([CH3:39])[CH3:38])[CH:30]=2)=[CH:27][C:12]2[C:13]([C:23]([NH:25][CH3:26])=[O:24])=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[O:15][C:11]=2[CH:10]=1>N1C=CC=CC=1>[CH:1]1([S:4]([NH:8][C:9]2[C:28]([C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([C:35](=[O:46])[NH:36][C:37]([C:40]4[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=4)([CH3:39])[CH3:38])[CH:30]=3)=[CH:27][C:12]3[C:13]([C:23]([NH:25][CH3:26])=[O:24])=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=4)[O:15][C:11]=3[CH:10]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N)c(-c3cccc(C(=O)NC(C)(C)c4ccccc4)c3)cc12
Reactant: O=S(=O)(Cl)C1CC1
Solvent: c1ccncc1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(=O)(=O)C3CC3)c(-c3cccc(C(=O)NC(C)(C)c4ccccc4)c3)cc12
Reaction time: 2 h
Yield: 71.5 %

Procedure:
Cyclopropanesulfonyl chloride (8 μL, 0.058 mmol) was added to a stirring solution of 6-amino-2-(4-fluorophenyl)-N-methyl-5-(3-(2-phenylpropan-2-ylcarbamoyl)phenyl)benzofuran-3-carboxamide (20 mg, 0.038 mmol) in Pyridine (0.5 mL) at rt. It was allowed to stir for 2 hours. The mixture was concentrated purified by preparative reverse phase HPLC on a C18 column using a suitably buffered H2O/CH3CN gradient, and concentrated to give the titled compound (17 mg, 70%). 1H NMR (500 MHz, CD3OD) δ ppm 8.41 (1H, br. s.), 7.91-8.01 (3H, m), 7.78-7.86 (2H, m), 7.61-7.71 (2H, m), 7.58 (1H, t, J=7.63 Hz), 7.41-7.49 (2H, m), 7.24-7.33 (4H, m), 7.18 (1H, t, J=6.87 Hz), 2.94 (3H, s), 2.34-2.43 (1H, m), 1.77 (6H, s), 0.80-1.03 (4H, m). LC-MS retention time: 1.53 min; m/z (MH+): 626. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5 u 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. Additional HPLC method: Solvent A=5% CH3CN/95% H2O/0.1% TFA, Solvent B=95% CH3CN/5% H2O/0.1% TFA, Start % B=10, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min. Column: Waters Sunfire C-18, 4.6×150 mm, 3.5 mm, Rt=15.40 min, purity=99%; Column: Waters Xbridge Phenyl column 4.6×150 mm, 3.5 mm, Rt=12.65 min, purity=99%.
Reaction SMILES: C1C[NH:6][C:4](=[O:5])[NH:3]C1.C(N(CC)CC)C.[Cl:15][CH2:16][CH2:17][C:18](Cl)=[O:19]>C1(C)C=CC=CC=1>[Cl:15][CH2:16][CH2:17][C:18]([NH:3][C:4]([NH2:6])=[O:5])=[O:19]
Reactant: O=C1NCCCN1
Reactant: O=C(Cl)CCCl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: NC(=O)NC(=O)CCCl
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 79.8 %

Procedure:
20.0 g of N,N'-trimethyleneurea are partially dissolved in 1000 ml of toluene under reflux and admixed with 20.2 g of triethylamine and then dropwise, in the course of 90 minutes, with a solution of 25.4 g of 3-chloropropionyl chloride. Subsequent stirring for 30 minutes, cooling down to 5° C., removal of undissolved matter by filtration and evaporating the filtrate in vacuo gives 24 g of chloropropionylurea of the formula ##STR70## as a beige powder.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[C:18]1N=CNN=1.C1COCC1.[Li+].[OH-:31].[OH2:32]>>[F:1][C:2]([F:24])([F:23])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[C:18]([OH:32])=[O:31]
Reactant: Fc1ccc(-c2nc[nH]n2)c(-c2ccccc2OCC(F)(F)F)c1
Reactant: [OH-]
Reactant: O
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1ccc(F)cc1-c1ccccc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 0.75 g (2.29 mol) of Methyl 1-3-((2-trifluoroethoxy)phenyl)-4-fluorobenzoate (Example 8, Step B) in 11.5 Ml of a 3:1 mixture of THF:water was added 0.164 g (6.86 mmol) of LiOH and the reaction mixture was stirred at RT for 18 hr. The reaction mixture was concentrated and the Ph was adjusted to Ph=2 with 1N HCl solution. The mixture was extracted with EtOAc and the combine organic fractions were washed with brine, dried over MgSO4, filtered and the filtrate was concentrated to give the title compound which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:12])[CH2:9][CH2:10][CH3:11])[CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:15])=O>C1(C)C=CC=CC=1>[Cl:15][C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)([OH:12])[CH2:9][CH2:10][CH3:11]
Reactant: CCCC(O)c1cccc(Br)c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: CCCC(O)(Cl)c1cccc(Br)c1

Procedure:
4.0 g (17.5 mmol) of 1-(3-bromophenyl)-butanol is stirred with 4 ml of thionyl chloride for 1 hour at room temperature. 10 ml of toluene is added to the reaction mixture. 1-Chloro-1-(3-bromophenyl)-butanol is obtained after concentration by evaporation in a vacuum. 1.3 g of imidazole is dissolved in 20 ml of dimethylformamide and mixed with 0.6 g of sodium hydride (80% in oil) under argon protective gas atmosphere. It is stirred for 1 hour at room temperature. The chlorine compound is instilled into 15 ml of dimethylformamide and allowed to stand overnight. The mixture is precipitated in 200 ml of water and extracted with ethyl acetate. The organic phase is concentrated by evaporation in a vacuum and then distilled on a bulb tube at 150° C./0.03 mbar. 1.6 g of 1-[1-(3-bromophenyl)-butyl]-imidazole is obtained as a viscous oil.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[CH3:28][N:29]1[CH:33]=[C:32]([S:34](Cl)(=[O:36])=[O:35])[N:31]=[CH:30]1>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][S:34]([C:32]5[N:31]=[CH:30][N:29]([CH3:28])[CH:33]=5)(=[O:36])=[O:35])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Agent: Cl
Product: Cn1cnc(S(=O)(=O)N[C@H]2CC[C@H](CCN3CCN(c4cccc5c4OCO5)CC3)CC2)c1

Procedure:
The title compound, white solid (23 mg, 59.3%), MS (ISP) m/z=476.1 [(M+H)+], was prepared in accordance with the general method of example 66 from N-trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (30 mg, 81.5 μmol) and 1-methyl-1H-imidazole-4-sulfonyl chloride.
Reaction SMILES: [F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C:16]2=[O:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:43])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][C@H:27]1[CH2:31][S:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=1.[BH4-].[Na+]>O1CCCC1.C(O)C.O>[F:1][C@H:2]1[CH2:19][C@@:17]2([CH3:18])[C@@H:13]([CH2:14][CH2:15][C@@H:16]2[OH:20])[C@H:12]2[C@H:3]1[C:4]1[CH:5]=[CH:6][C:7]([OH:43])=[CH:8][C:9]=1[CH2:10][C@H:11]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][CH2:28][C@H:27]1[CH2:31][S:32][C:33]1[CH:34]=[CH:35][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:37][CH:38]=1
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCN4CCC[C@H]4CSc4ccc(C(F)(F)F)cc4)[C@H]3[C@@H]1CCC2=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCN4CCC[C@H]4CSc4ccc(C(F)(F)F)cc4)[C@H]3[C@@H]1CC[C@@H]2O
Temperature: 0 °C
Reaction time: 2 h
Yield: 74.2 %

Procedure:
A solution of 0.43 g of 11β-fluoro-3-hydroxy-7α-{5-[(2S)-2-(4-trifluoromethylphenylthiomethyl)-pyrrolidin-1-yl]-pentyl}-estra-1,3,5(10)-trien-17-one in 4 ml of tetrahydrofuran, 2.3 ml of ethanol and 1 ml of water is mixed in portions at 0° C. with 111 mg of sodium borohydride, and it is stirred for 2 hours. Then, it is added to ice water, extracted three times with ethyl acetate, washed with common salt solution, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with dichloromethane/acetone. 0.32 g of 11β-fluoro-7α-{5-[(2S)-2-(4-trifluoromethylphenylthiomethyl)-pyrrolidin-1-yl]-pentyl}-estra-1,3,5(10)-triene-3,17β-diol with [α]D22 =+16.2° (c=0.51% in methanol) is obtained.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)CC)C.[Cl:22][C:23]1[N:28]=[CH:27][C:26]([C:29](Cl)=[O:30])=[CH:25][CH:24]=1.O>C(Cl)Cl>[Cl:22][C:23]1[N:28]=[CH:27][C:26]([C:29]([N:7]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[CH2:10][N:4]3[CH:3]=[CH:2][CH:1]=[C:5]3[CH2:6]2)=[O:30])=[CH:25][CH:24]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(c1ccc(Cl)nc1)N1Cc2cccn2Cc2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.1 %

Procedure:
To a solution of 1.0 g of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine in 50 ml of dry methylene chloride, under nitrogen, and 7.0 ml of triethylamine is added 1.43 g of 6-chloro-pyridine-3-carbonyl chloride. The reaction mixture is stirred at room temperature for 16 hours and poured into 100 ml of water. The organic layer is separated, washed with 2% HCl, water, saturated NaHCO3, and dried(Na2SO4). The solvent is evaporated in vacuo to give a residue which is columned on silica gel by elution with 7:1 to 1:1 ethyl acetate:hexane to give 1.76 g of the desired product as a yellowish crystalline solid.M+H=324.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Br:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[H-].[Na+].[N+:18]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1)([O-:20])=[O:19].O>CS(C)=O.CCCCCC>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:25][C:24]2[CH:27]=[CH:28][C:21]([N+:18]([O-:20])=[O:19])=[CH:22][CH:23]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Br:15])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CCOC(=O)c1cc2cc(Br)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)c1cc2cc(Br)ccc2n1Cc1ccc([N+](=O)[O-])cc1
Reaction time: 2 h
Yield: 81.3 %

Procedure:
To a stirring solution of 5-bromo-1H-indole-2-carboxylic acid ethyl ester (2.68 g, 10 mmol, ICN) in dry dimethylsulfoxide (42 ml) at room temperature under nitrogen was added sodium hydride (264 mg, 11 mmol) as a slurry in hexane in four equal portions over about ten minutes. 4-Nitrobenzyl bromide (2.16 g, 10 mmol) in dry dimethylsulfoxide (12 ml) was added dropwise over about five minutes. The mixture was stirred 2 hours, poured into water (50 ml) and extracted with ethyl acetate. The solution was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was flash chromatographed on silica gel (110 g, methylene chloride) to give the title compound (3.28 g).
Reaction SMILES: N1([S:6]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)(=[O:8])=[O:7])C=CN=C1.COS(C(F)(F)F)(=O)=O.[CH2:24]1[C:26]2([CH2:31][N:30]([C:32]3[C:33]4[CH:40]=[CH:39][NH:38][C:34]=4[N:35]=[CH:36][N:37]=3)[CH2:29][CH2:28][NH:27]2)[CH2:25]1>C(Cl)Cl.CS(C)=O>[N:9]1([S:6]([N:27]2[CH2:28][CH2:29][N:30]([C:32]3[C:33]4[CH:40]=[CH:39][NH:38][C:34]=4[N:35]=[CH:36][N:37]=3)[CH2:31][C:26]32[CH2:24][CH2:25]3)(=[O:8])=[O:7])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: c1nc(N2CCNC3(CC3)C2)c2cc[nH]c2n1
Reactant: O=S(=O)(N1CCCCC1)n1ccnc1
Agent: COS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=S(=O)(N1CCCCC1)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1-(imidazole-1-sulfonyl)-piperidine (intermediate 13) (0.047 mmol) in dry CH2Cl2 (1 mL) was cooled to 0° C. and added trifluoro-methanesulfonic acid methyl ester (0.047 mmol). The reaction mixture was allowed to warm up freely to rt over a period of 4 h and then concentrated in vacuo. The residual oil was redissolved in dry CH3CN (1.5 mL), added a solution of 4-(4,7-diaza-spiro[2.5]oct-7-yl)-7H-pyrrolo[2,3-d]pyrimidine (intermediate 21) (0.047 mmol) in DMSO (1 mL) and then stirred at 50° C. for 3 h. The pure compound was obtained by standard preparative HPLC purification of the reaction mixture.
Reaction SMILES: [CH3:1][N:2]([CH2:6][CH:7]1[CH2:11][CH2:10][N:9](CC2C=CC=CC=2)[CH2:8]1)[C:3](=[O:5])[CH3:4].C([OH:21])C>C(O)(=O)C.[OH-].[OH-].[Pd+2]>[C:3]([OH:5])(=[O:21])[CH3:4].[CH3:1][N:2]([CH2:6][CH:7]1[CH2:11][CH2:10][NH:9][CH2:8]1)[C:3](=[O:5])[CH3:4]
Reactant: CC(=O)N(C)CC1CCN(Cc2ccccc2)C1
Reactant: CCO
Agent: [Pd+2]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(=O)N(C)CC1CCNC1

Procedure:
0.05 mole of the compound obtained in stage C in 130 cm3 of ethanol and 3 cm3 of acetic acid is hydrogenated in the presence of 1.3 g of palladium dihydroxide at 50° C. and at a pressure of 5 kilograms/cm2. The mixture is evaporated and then filtered. 12 g of the expected compound are obtained.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:13][C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=3)[CH:8]=2)[N:3]=1.[Mn]([O-])(=O)(=O)=[O:25].[K+].[OH2:30]>C(O)(=O)C>[NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:13]([C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[CH:15]=3)(=[O:25])=[O:30])[CH:8]=2)[N:3]=1
Reactant: Nc1nc(N)c2cc(Sc3ccc4ccccc4c3)ccc2n1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O
Agent: [K+]
Solvent: CC(=O)O
Product: Nc1nc(N)c2cc(S(=O)(=O)c3ccc4ccccc4c3)ccc2n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 2.0 grams (0.006 mole) of 2,4-diamino-6-(naphth-2-ylthio)quinazoline (prepared in Example 7) in 80 mL of acetic acid was stirred, and a solution of 2.0 grams (0.013 mole) of potassium permanganate in 75 mL of water was added dropwise during a 1 hour period. Upon completion of addition, the reaction mixture was stirred at ambient temperature for about 18 hours. After this time, the reaction mixture was filtered through diatomaceous earth. The filtrate was made basic by adding an excess amount of concentrated ammonium hydroxide. The resultant precipitate was collected by filtration and was washed in turn with water, methanol, and acetone. The precipitate was stirred in hot N,N-dimethylformamide and treated with decolorizing carbon. The mixture was filtered hot, and the filtrate was set aside. The residue collected by the filtration was again stirred with hot N,N-dimethylformamide and filtered. The two filtrates were combined and poured into 500 grams of ice. The resultant solid was collected by filtration, yielding 0.9 gram of 2,4-diamino-6-(naphth-2-ylsulfonyl)quinazoline, mp 300°-302° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][N:2]1[C:14]2[CH2:13][CH2:12][CH2:11][C:10](=[O:15])[C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[CH3:16][C:17]1[NH:18][CH:19]=[CH:20][N:21]=1.N1(CN2CCCCC2)CCCC[CH2:23]1.Cl[Si](C)(C)C>CN(C)C=O.O>[CH3:1][N:2]1[C:14]2[CH2:13][CH2:12][CH:11]([CH2:23][N:18]3[CH:19]=[CH:20][N:21]=[C:17]3[CH3:16])[C:10](=[O:15])[C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: Cc1ncc[nH]1
Reactant: Cn1c2c(c3ccccc31)C(=O)CCC2
Reactant: C1CCN(CN2CCCCC2)CC1
Agent: C[Si](C)(C)Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nccn1CC1CCc2c(c3ccccc3n2C)C1=O
Temperature: 90 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
2.0 g of 1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one, 1.65 g of 2-methyl imidazole and 2.74 g of dipiperidinomethane were suspended in 20 ml of N,N-dimethylformamide, and then 4 ml of chlorotrimethylsilane was slowly added thereto. The reaction mixture was stirred for 8 hours at 90° C. 100 ml of water was added to the reaction mixture. The resulting solid was filtered and dried, which was then suspended in acetone and stirred for 3 hours, and then filtered and dried under a reduced pressure to give 1.99 g of title compound (yield 68%).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5](Cl)=[C:4]2[CH:9]=[N:10][C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:12][C:3]=12.[CH3:19][CH:20]1[O:25][CH2:24][CH2:23][NH:22][CH2:21]1>>[CH3:19][CH:20]1[CH2:21][N:22]([C:2]2[N:7]=[N:6][C:5]([N:22]3[CH2:23][CH2:24][O:25][CH:20]([CH3:19])[CH2:21]3)=[C:4]3[CH:9]=[N:10][C:11]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:12][C:3]=23)[CH2:23][CH2:24][O:25]1
Reactant: Clc1nnc(Cl)c2cc(-c3ccccc3)ncc12
Reactant: CC1CNCCO1
Product: CC1CN(c2nnc(N3CCOC(C)C3)c3cc(-c4ccccc4)ncc23)CCO1

Procedure:
2.0 parts by weight of 1,4-dichloro-7-phenylpyrido(3,4-d)pyridazine is added to 20 parts by volume of 2-methylmorpholine, and the resulting mixture is heated at 130° to 140° C for 4 hours. The excess amount of 2-methylmorpholine is removed by evaporation under reduced pressure. Water is added to the residue to obtain crude crystals, which is recrystallized from n-hexane to obtain 1,4-bis(2'-methylmorpholino)-7-phenylpyrido(3,4-d)pyridazine as yellow prisms melting at 75° to 81° C. Elementary analysis for C23H27O2N5