Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26]OS(C)(=O)=O)=[CH:20][C:5]=1[C:6]([NH:8][CH2:9][C:10]12[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]3)[CH2:11]1)[CH2:17]2)=[O:7].[C:32]([O:35]CC)(=[O:34])[CH3:33]>>[C:32]([OH:35])(=[O:34])[CH3:33].[Cl:3][C:4]1[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][CH2:26][NH:2][CH3:1])=[CH:20][C:5]=1[C:6]([NH:8][CH2:9][C:10]12[CH2:19][CH:14]3[CH2:13][CH:12]([CH2:18][CH:16]([CH2:15]3)[CH2:17]1)[CH2:11]2)=[O:7]
Reactant: CN
Reactant: CS(=O)(=O)OCCCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Reactant: CCOC(C)=O
Product: CC(=O)O
Product: CNCCCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Temperature: 70 °C

Procedure:
Methylamine (2 M tetrahydrofuran, 8 ml) was added to 2-chloro-5-[3-[(methylsulfonyl)oxy]propyl]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.250 g, Example 6e) and heated in a sealed tube at 70° C. for 18 h. On cooling to ambient temperature, the solution was diluted with ethyl acetate and extracted twice with saturated sodium hydrogencarbonate solution and once with brine, dried over magnesium sulfate and concentrated under reduced pressure. Purification by preperative reverse phase HPLC (eluting with a gradient of acetonitrile in 0.1% aqueous ammonium acetate/25-95%) gave the title compound as the acetate salt (0.140 g).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([CH2:17][CH3:18])[C:11]2([C:14]([OH:16])=O)[CH2:13][CH2:12]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.CCOC(OC(OCC)=O)=O.[F:30][C:31]([F:47])([F:46])[C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[C:42]([CH2:44][NH2:45])[CH:41]=[CH:40][N:39]=2)=[CH:34][CH:33]=1>C1COCC1>[Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([CH2:17][CH3:18])[C:11]2([C:14]([NH:45][CH2:44][C:42]3[CH:41]=[CH:40][N:39]=[C:38]([C:35]4[CH:36]=[CH:37][C:32]([C:31]([F:47])([F:30])[F:46])=[CH:33][CH:34]=4)[CH:43]=3)=[O:16])[CH2:12][CH2:13]2)(=[O:8])=[O:9])=[CH:4][CH:3]=1
Reactant: CCN(C1(C(=O)O)CC1)S(=O)(=O)c1ccc(Cl)s1
Reactant: NCc1ccnc(-c2ccc(C(F)(F)F)cc2)c1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: CCN(C1(C(=O)NCc2ccnc(-c3ccc(C(F)(F)F)cc3)c2)CC1)S(=O)(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 16.9 %

Procedure:
Acid 18 (0.3 g, 1.09 mmol) was dissolved in 15 ml of THF and at rt DEPC (1.3 equiv, 0.21 mL) and [2-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 21A (1.1 mol equiv., 0.37 g) were added to the solution. The mixture was stirred at rt overnight then evaporated. The residue was dissolved in AcOEt (30 mL) and washed with water (1×20 mL) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude by chromatographic column (EtOAc 3/petroleum ether 7) afforded 100 mg of a white solid. Yield=18% 1HNMR (DMSO, 200 MHz) δ 1.24 (m, 5H), 1.35 (m, 2H), 3.45 (m, 2H), 4.44 (d, 2H, J=6.2), 7.26 (m, 3H), 6.61 (d, 1H, J=2.1), 7.88 (d, 2H, J=7.8), 7.94 (s, 1H), 8.31 (d, 3H, J=8), 8.64 (d, 1H, J=4.1). [M+1] 543.95 (C23H21ClF3N3O3S2 requires 544.01).
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][NH:3]1.[Cl:12][CH2:13][C:14](Cl)=[O:15]>C1(C)C=CC=CC=1>[Cl:12][CH2:13][C:14]([N:3]1[CH2:4][CH2:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:2]1[CH3:1])=[O:15]
Reactant: CC1NCCc2ccccc21
Reactant: O=C(Cl)CCl
Solvent: Cc1ccccc1
Product: CC1c2ccccc2CCN1C(=O)CCl

Procedure:
A reaction vessel was charged with 50 ml toluene and 2 g 1-methyl-1,2,3,4-tetrahydroisoquinoline (prepared by procedure of Example 1,--Method A). Then, 2 ml 2-chloroacetyl chloride was added gradually to the mixture. The reaction mixture was stirred and heated until a homogeneous solution appeared. The mixture was filtered, stripped of solvent, and subjected to Kugelrohr distillation 130° C. @ 0.2 mm Hg) to provide 2.7 g of an amber oil product having the elemental analysis reported in Table I.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[C:8]([CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[NH:19][CH:18]=3)[CH2:13][CH2:12]2)[CH:7]=[CH:6][C:5]=1[O:26][CH3:27].Cl.Cl[CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1>>[CH3:27][O:26][C:5]1[CH:6]=[CH:7][C:8]([CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]([CH2:31][C:32]4[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=4)[CH:18]=3)[CH2:13][CH2:12]2)=[CH:9][C:4]=1[C:3]([OH:2])=[O:28]
Reactant: COC(=O)c1cc(CN2CCC(c3c[nH]c4ccccc34)CC2)ccc1OC
Reactant: ClCc1cccnc1
Agent: Cl
Product: COc1ccc(CN2CCC(c3cn(Cc4cccnc4)c4ccccc34)CC2)cc1C(=O)O

Procedure:
This compound was prepared following the procedure described in example 1 (part E) starting with 0.054 g (0.13 mmol) of 5-[4-(1H-indol-3-yl)-piperidin-1-ylmethyl]-2-methoxy-benzoic acid methyl ester and 0.029 mg (0.16 mmol) of 3-chloromethyl-pyridine hydrochloride. After the described purification, 0.007 g (11% of yield) of the expected acid was obtained.
Reaction SMILES: NC1C=CC(F)=CC=1C(NC)=O.[CH3:13][C:14]1[C:23](=[O:24])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[N+:25]([O-])=O)[NH:16][CH:15]=1>>[NH2:25][C:21]1[CH:20]=[CH:19][CH:18]=[C:17]2[C:22]=1[C:23](=[O:24])[C:14]([CH3:13])=[CH:15][NH:16]2
Reactant: Cc1c[nH]c2cccc([N+](=O)[O-])c2c1=O
Agent: CNC(=O)c1cc(F)ccc1N
Product: Cc1c[nH]c2cccc(N)c2c1=O

Procedure:
The title compound was prepared according to procedure for 2-Amino-5-fluoro-N-methylbenzamide (Compound 102A) using 3-methyl-5-nitroquinolin-4(1H)-one (Eur J Med Chem. 1992, 37, 547-570). 1H NMR (DMSO-d6, 400 MHz): δ=1.87 (d, J=0.76 Hz, 3H), 6.21 (dd, J=7.83, 1.01 Hz, 1H), 6.40 (dd, J=8.08, 1.01 Hz, 1H), 7.12 (t, J=8.08 Hz, 1H), 7.62 (dd, J=5.94, 0.88 Hz, 1H), 11.19 (d, J=5.05 Hz, 1H). MS (ES+): m/z 175.07 [MH+] (TOF, polar).
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][C:7]([CH3:10])([CH3:9])[C:6]2[CH:11]=[CH:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][C:5]=2[NH:4][C:3]1=[O:18].[N:19]1([C:24](Cl)=[O:25])[CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH3:9][C:7]1([CH3:10])[C:6]2[CH:11]=[CH:12][C:13]([N+:15]([O-:17])=[O:16])=[CH:14][C:5]=2[NH:4][C:3](=[O:18])[CH:2]([NH:1][C:24]([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:25])[CH2:8]1
Reactant: O=C(Cl)N1CCCC1
Reactant: CC1(C)CC(N)C(=O)Nc2cc([N+](=O)[O-])ccc21
Product: CC1(C)CC(NC(=O)N2CCCC2)C(=O)Nc2cc([N+](=O)[O-])ccc21

Procedure:
Pyrrolidine-1-carboxylic acid (5,5-dimethyl-8-nitro-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)-amide was prepared from 3-Amino-5,5-dimethyl-8-nitro-1,3,4,5-tetrahydro-1-benzazepin-2-one and Pyrrolidine-1-carbonyl chloride in an analogous manner to Example 1271d as a pale yellow solid (256 mg, 92%). LCMS 347 (M+H). HPLC purity 99%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:5]([F:15])[CH:4]=1)#[N:2].C(O[CH:19](OCC)[N:20]([CH3:22])[CH3:21])C>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=[CH:19][N:20]([CH3:22])[CH3:21])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:5]([F:15])[CH:4]=1)#[N:2]
Reactant: CCOC(=O)Cc1ccc(C#N)cc1F
Reactant: CCOC(OCC)N(C)C
Product: CCOC(=O)C(=CN(C)C)c1ccc(C#N)cc1F

Procedure:
The title compound was prepared in a manner similar to Example Preparation 10 using ethyl 2-(4-cyano-2-fluorophenyl)acetate and 1,1-diethoxy-N,N-dimethylmethanamine to give the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10 (t, J=7.07 Hz, 3H) 2.71 (br. s., 6H) 4.00 (quin, J=6.76 Hz, 2H) 7.37 (t, J=7.71 Hz, 1H) 7.60 (dd, J=7.96, 1.64 Hz, 1H) 7.64 (s, 1H) 7.75 (dd, J=9.47, 1.64 Hz, 1H). MS m/z [M+H]+ 236.2, 263.2.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[N:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[C:27]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2>CN(C=O)C.C1COCC1>[Br:1][C:24]1[CH:25]=[CH:26][C:27]2[N:15]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][N:9]=3)[C:16]3[C:21]([C:22]=2[CH:23]=1)=[CH:20][CH:19]=[CH:18][CH:17]=3
Reactant: c1ccc(-n2c3ccccc3c3ccccc32)nc1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Brc1ccc2c(c1)c1ccccc1n2-c1ccccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-bromosuccinimide (17.8 g, 100 mmol) in DMF (50 mL) was added slowly to 9-(pyridin-2-yl)-9H-carbazole (24 g, 100 mmol) in THF (250 mL) at 0° C. over 30 min. The reaction was allowed to warm to room temperature and stir overnight. The reaction mixture was then evaporated and extracted with dichloromethane, and the organic layer was dried over magnesium sulfate and the solvent was then evaporated. The residue was then purified by column using toluene:hexane (1:1, v/v) as eluent and the product was further purified by recrystallization from toluene:ethanol (1:1, v/v), and after cooling, 24.3 g (75%) of the product was collected as a white solid after filtration.
Reaction SMILES: FC1C(F)=CC(C2C=CN=CC=2N([CH2:32][CH2:33][S:34]([CH3:37])(=[O:36])=[O:35])C(=O)C2C=C(C(F)(F)F)N=C(C(F)(F)F)C=2)=C(OC)C=1.[C:40]([O:44][C:45](=[O:64])[NH:46][C:47]1[CH:48]=[N:49][CH:50]=[CH:51][C:52]=1[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[O:59][C:60]([F:63])([F:62])[F:61])([CH3:43])([CH3:42])[CH3:41].ClCCS(C)(=O)=O>CCCCCC.CCOC(C)=O>[C:40]([O:44][C:45](=[O:64])[N:46]([CH2:32][CH2:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:47]1[CH:48]=[N:49][CH:50]=[CH:51][C:52]=1[C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[O:59][C:60]([F:61])([F:62])[F:63])([CH3:43])([CH3:41])[CH3:42]
Reactant: COc1cc(F)c(F)cc1-c1ccncc1N(CCS(C)(=O)=O)C(=O)c1cc(C(F)(F)F)nc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)Nc1cnccc1-c1ccccc1OC(F)(F)F
Agent: CS(=O)(=O)CCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(CCS(C)(=O)=O)c1cnccc1-c1ccccc1OC(F)(F)F

Procedure:
The title compound was prepared in analogy to example 298, intermediate b, from [4-(2-trifluoromethoxy-phenyl)-pyridin-3-yl]-carbamic acid tert-butyl ester and 1-chloro-2-(methylsulfonyl)ethane and using a gradient of n-hexane:EtOAc (50:50 to 40:60) for the chromatographic purification. Colourless sticky solid (96%). MS (ESI): m/z=461.4 [M+H]+.
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[NH:8][C:9]4[C:14]([C:15]=3[CH2:16][S:17][C:5]=2[CH:4]=[CH:3][CH:2]=1)=[CH:13][C:12]([OH:18])=[CH:11][CH:10]=4.N1C=CC=CC=1.[C:25](Cl)([C:27]([CH3:30])([CH3:29])[CH3:28])=[O:26]>C(Cl)Cl>[CH:1]1[C:6]2[C:7]3[NH:8][C:9]4[C:14]([C:15]=3[CH2:16][S:17][C:5]=2[CH:4]=[CH:3][CH:2]=1)=[CH:13][C:12]([O:18][C:25](=[O:26])[C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:11][CH:10]=4
Reactant: CC(C)(C)C(=O)Cl
Reactant: Oc1ccc2[nH]c3c(c2c1)CSc1ccccc1-3
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Oc1ccc2[nH]c3c(c2c1)CSc1ccccc1-3
Temperature: 25 °C

Procedure:
6,11-dihydro-5-thia-11-aza-benzo[a]fluoren-8-ol (1.01 g, 3.99 mmoL) in CH2Cl2 (5 mL) was treated with pyridine (0.387 mL, 4.788 mmoL) followed by PivCl (0.541 mL, 4.389 mmoL) at 0° C. The reaction mixture was slowly warmed to room temperature over 2 hours. The reaction mixture was then partitioned between CH2Cl2 and saturated NH4Cl. The aqueous phase was extracted two times with CH2Cl2. The organic layer from each extraction was combined, washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated to yield a brown oil. The crude material (the oil) was then purified by column chromatography (silica gel, hexanes:EtOAc 4:1 as eluent) to yield the title compound as a pale foam.
Reaction SMILES: [ClH:1].[NH:2]1[CH2:7][CH2:6][CH:5]=[C:4]([CH:8]=O)[CH2:3]1.Cl.[CH3:11][O:12][NH2:13]>O>[ClH:1].[CH3:11][O:12][N:13]=[CH:8][C:4]1[CH2:3][NH:2][CH2:7][CH2:6][CH:5]=1
Reactant: O=CC1=CCCNC1
Reactant: CON
Agent: Cl
Solvent: O
Product: CON=CC1=CCCNC1
Yield: 79.9 %

Procedure:
To a solution of 5 g (0.034 mol) of 1,2,5,6-tetrahydropyridin-3-carboxaldehyde hydrochloride, (CHEM. BER. 40, 4685, 1907)-- in 30 cm3 of water, 2.85 g (0.034 mol) of O-methyl-hydroxylamine hydrochloride is added with agitation for 1 hour at ambient temperature. The reactional mixture is evaporated to dryness and the residue is recrystallized from absolute ethanol. 4.8 g (80%) of product is obtained with m.p.. 208° C.(decomposes) White crystalline powder.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([N:13]([CH2:21][CH2:22][O:23][Si](C(C)(C)C)(C)C)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1>C(O)(=O)C.O.C1COCC1>[F:1][C:2]([F:31])([F:32])[C:3]1[CH:4]=[C:5]([N:13]([CH2:21][CH2:22][OH:23])[C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: CC(C)(C)OC(=O)N(CCO[Si](C)(C)C(C)(C)C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CCO)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 88.8 %

Procedure:
A mixed solution of the compound (0.50 g) obtained in step 3 in acetic acid (6 mL), water (2 mL) and THF (2 mL) was stirred at 50° C. for 14 hr, poured into water, and extracted with diethyl ether. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (solvent gradient; 10→33% ethyl acetate/hexane) to give tert-butyl [3,5-bis(trifluoromethyl)phenyl](2-hydroxyethyl)carbamate (0.34 g, 87%) as a colorless oil.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[O:16])[CH2:11][CH:10]2[O:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]3[O:35][CH2:34][CH2:33][N:32]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[C:31]=3[CH:41]=2)=[CH:5][CH:4]=1.[H-].[Na+].Cl[C:45](Cl)(Cl)[C:46]#N.F[C:51](F)(F)S(O)(=O)=O.C(=O)([O-])O.[Na+]>C(Cl)(Cl)(Cl)Cl.ClCCl.CC(O)C>[CH:46]([O:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:16])[CH2:11][CH:10]2[O:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]3[O:35][CH2:34][CH2:33][N:32]([CH2:36][CH2:37][CH2:38][O:39][CH3:40])[C:31]=3[CH:41]=2)=[CH:7][CH:8]=1)([CH3:45])[CH3:51]
Reactant: N#CC(Cl)(Cl)Cl
Reactant: O=S(=O)(O)C(F)(F)F
Reactant: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(CO)cc3)cc21
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(C)O
Product: COCCCN1CCOc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(COC(C)C)cc3)cc21
Temperature: -30 °C
Reaction time: 0.33 h

Procedure:
The solution of 0.200 g of benzyl 4-(4-hydroxymethylphenyl)-3-[4-(3-methoxypropyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate (Example 270c) in 8 ml of carbon tetrachloride at 0° C. is admixed with 0.019 g of sodium hydride and then stirred for 20 minutes. The reaction mixture is admixed with 0.326 g of trichloroacetonitrile and stirred at 0° C. for 3 hours. Afterwards, a solution of 0.0322 g of 2-propanol in 5 ml of dichloromethane is added and the reaction mixture is cooled to −30° C. and admixed slowly with 0.108 g of trifluoromethanesulphonic acid. The reaction solution is stirred at −20° C. for 19 hours and subsequently poured onto 25 ml of aqueous saturated sodium hydrogencarbonate solution. The mixture is extracted twice with 50 ml of tert-butyl methyl ether. The combined organic phases are washed with 30 ml of brine, dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.15 (1:2 EtOAc-heptane); Rt=5.92.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:19][N:18]([C:20]3[N:24]([CH3:25])[N:23]=[C:22]([CH:26]([CH3:28])[CH3:27])[CH:21]=3)[CH2:17][CH2:16][C:4]=2[N:5]=[C:6]([C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:15])[N:7]=1.C(N(C(C)C)CC)(C)C.[CH3:38][C@@H:39]1[CH2:44][NH:43][CH2:42][CH2:41][NH:40]1.Br[CH2:46][C:47]([NH2:49])=[O:48]>CC#N>[CH3:15][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]([CH3:14])[C:8]=1[C:6]1[N:7]=[C:2]([N:43]2[CH2:42][CH2:41][N:40]([CH2:46][C:47]([NH2:49])=[O:48])[C@H:39]([CH3:38])[CH2:44]2)[C:3]2[CH2:19][N:18]([C:20]3[N:24]([CH3:25])[N:23]=[C:22]([CH:26]([CH3:28])[CH3:27])[CH:21]=3)[CH2:17][CH2:16][C:4]=2[N:5]=1
Reactant: C[C@@H]1CNCCN1
Reactant: Cc1cccc(C)c1-c1nc(Cl)c2c(n1)CCN(c1cc(C(C)C)nn1C)C2
Reactant: NC(=O)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cccc(C)c1-c1nc2c(c(N3CCN(CC(N)=O)[C@H](C)C3)n1)CN(c1cc(C(C)C)nn1C)CC2
Temperature: 100 °C

Procedure:
MeCN (2 mL) was added to 4-chloro-2-(2,6-dimethylphenyl)-6-(3-isopropyl-1-methyl-1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine, prepared as described in Example 16, (110 mg, 0.278 mmol) in a microwave vial. The vial was then charged with diisopropylethylamine (0.24 mL, 1.38 mmol) and (R)-2-methylpiperazine (56 mg, 0.556 mmol). The vial was sealed and heated via microwave irradiation at 100° C. for 45 minutes. The mixture was cooled to room temperature and then charged with 2-bromoacetamide (115 mg, 0.833 mmol), re-sealed and heated via microwave irradiation at 100° C. for 10 minutes. The reaction was then cooled to room temperature and adsorbed in vacuo onto silica and loaded onto a silica gel flash chromatography column for purification [0-10% (10% NH4OH)MeOH/DCM]. The material was then further purified by additional silica gel flash chromatography {0-35% [10% MeOH (containing 1% NH4OH)/EtOAc]/DCM} to furnish (R)-2-(4-(2-(2,6-dimethylphenyl)-6-(3-isopropyl-1-methyl-1H-pyrazol-5-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)-2-methylpiperazin-1-yl)acetamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.27 (br. s., 1 H) 7.17 (d, J=7.58 Hz, 1 H) 7.13 (br. s., 1 H) 7.08 (d, J=7.58 Hz, 2 H) 5.72 (s, 1 H) 3.98 (s, 2 H) 3.59 (s, 3 H) 3.51-3.58 (m, 2 H) 3.25-3.32 (m, 3 H) 3.16-3.24 (m, 1 H) 3.11 (d, J=16.17 Hz, 1 H) 2.94 (br. s., 3 H) 2.71-2.85 (m, 3 H) 2.56-2.65 (m, 1 H) 2.05 (s, 6 H) 1.11-1.19 (m, 6 H) 1.00 (d, J=6.06 Hz, 3 H); MS (ESI+) m/z 517.34 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:5][O:6][C:7]2[C:12]3[C:13]([O:16][CH2:17][CH:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)=[N:14][O:15][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH2:4][CH2:3][CH2:2]1.O=[CH:25][CH2:26][C:27]1([C:33]([O:35][CH3:36])=[O:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(C1(C(OC)=O)CCC1)=O>>[CH:1]1([CH2:5][O:6][C:7]2[C:12]3[C:13]([O:16][CH2:17][CH:18]4[CH2:19][CH2:20][N:21]([CH2:25][CH2:26][C:27]5([C:33]([O:35][CH3:36])=[O:34])[CH2:28][CH2:29][O:30][CH2:31][CH2:32]5)[CH2:22][CH2:23]4)=[N:14][O:15][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: COC(=O)C1(CC=O)CCOCC1
Reactant: c1cc(OCC2CCC2)c2c(OCC3CCNCC3)noc2c1
Agent: COC(=O)C1(C=O)CCC1
Product: COC(=O)C1(CCN2CCC(COc3noc4cccc(OCC5CCC5)c34)CC2)CCOCC1

Procedure:
The title compound was prepared according to the procedure described in Step 3 of EXAMPLE 2 using 4-(cyclobutylmethoxy)-3-(piperidin-4-ylmethoxy)-1,2-benzisoxazole (EXAMPLE 17, Step 4) and methyl 4-(2-oxoethyl)tetrahydro-2H-pyran-4-carboxylate (WO 2004/043958) instead of 3-(piperidin-4-ylmethoxy)-4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazole and methyl 1-formylcyclobutanecarboxylate.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][C@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].Cl.[CH3:22][C:23]1[N:24]=[C:25]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[S:26][C:27]=1[C:28]([F:31])([F:30])[F:29]>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:14][C@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])=[C:9]([C:10]([N:35]2[CH2:36][CH2:37][N:32]([C:25]3[S:26][C:27]([C:28]([F:31])([F:29])[F:30])=[C:23]([CH3:22])[N:24]=3)[CH2:33][CH2:34]2)=[O:12])[CH:13]=1)(=[O:3])=[O:4]
Reactant: Cc1nc(N2CCNCC2)sc1C(F)(F)F
Reactant: C[C@@H](Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Agent: Cl
Product: Cc1nc(N2CCN(C(=O)c3cc(S(C)(=O)=O)ccc3O[C@H](C)C(F)(F)F)CC2)sc1C(F)(F)F
Yield: 57 %

Procedure:
Prepared in analogy to example 1 (b) from 5-methanesulfonyl-2-((R)-2,2,2-trifluoro-1-methyl-ethoxy)-benzoic acid (Example A16) and 1-(4-methyl-5-trifluoromethyl-thiazol-2-yl)-piperazine hydrochloride (Example 79(g)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) to yield the title compound as a white crystalline solid (yield 57%). MS (m/e): 546.0 (M+H+, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)=[O:4].II.FC(F)(F)C(O[I:17](C1C=CC=CC=1)OC(=O)C(F)(F)F)=O.ClCCl>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([I:17])=[CH:8][CH:9]=1)=[O:4]
Reactant: COC(=O)c1cccs1
Reactant: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Agent: II
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(I)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 115.4 %

Procedure:
To a solution of thiophene-2-carboxylic acid methyl ester (5.0 g, 28.7 mmol) in 35 mL of anhydrous carbon tetrachloride was added iodine (3.65 g, 14.37 mmol) and [Bis(trifluoroacetoxy)iodo] benzene (6.67 g, 15.52 mmol). This mixture was stirred overnight at room temperature. Dichloromethane was then added and the mixture was extracted with a solution of sodium thiosulfate 10%. The organic layer was evaporated and the residue was purified flash chromatography (hexane 40%:chloroform 60%) to give a solid which was triturated with pentane in order to remove remaining starting material affording compound P-1 as a white solid (4.8 g, 63% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].[BH4-].[Na+].C[CH2:14][O:15]C(C)=O.[CH3:19]O>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:7]([O:15][CH3:14])[O:8][CH3:19])[CH:9]=1
Reactant: CO
Reactant: O=Cc1cc(Br)ccc1O
Reactant: CCOC(C)=O
Agent: [BH4-]
Agent: [Na+]
Product: COC(OC)c1cc(Br)ccc1O
Temperature: 25 °C

Procedure:
To a solution of 5-bromo-2-hydroxy-benzaldehyde (1 g, 4.9 mmol, Aldrich Chemical Company) in MeOH (25 mL) at 0° C., sodium borohydride (226 mg, 5.9 mmol) was added slowly with stirring. After the addition, the reaction was allowed to warm to rt and stir for an additional hour. Reaction mixture was dissolved into EtOAc and washed with brine (20 mL×2). The organic layer was dried over sodium sulfate. Removal of the solvents in vacuo gave the title compound (1.2 g, quantitative) a yellow oil which was used with out further purification. 1H-NMR (CD3OD): δ 7.35 (m, 2H), 6.75–6.77 (d, 1H, J=7.2 Hz), 5.55 (s, 1H), 3.33 (s, 6H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C@@H:8]1[CH2:25][C:24]2[CH:23]=[C:22]([OH:26])[CH:21]=[CH:20][C:19]=2[C@@H:18]2[C@@H:9]1[C@H:10]1[C@@:14]([CH2:16][C@@H:17]2[F:27])([CH3:15])[C:13](=[O:28])[CH2:12][CH2:11]1.[I-:29].[Na+].O>C(C(C)=O)C>[F:27][C@H:17]1[CH2:16][C@@:14]2([CH3:15])[C@@H:10]([CH2:11][CH2:12][C:13]2=[O:28])[C@H:9]2[C@H:18]1[C:19]1[CH:20]=[CH:21][C:22]([OH:26])=[CH:23][C:24]=1[CH2:25][C@H:8]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][I:29]
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCCCl)[C@H]3[C@@H]1CCC2=O
Reactant: [I-]
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: O
Product: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCCI)[C@H]3[C@@H]1CCC2=O
Temperature: 90 °C
Reaction time: 8 h
Yield: 102.8 %

Procedure:
2.7 g of 7α-(6-chlorohexyl)-11β-fluoro-3-hydroxy-estra-1,3,5(10)-trien-17-one is dissolved in 40 ml of ethylmethylketone, mixed with 3.0 g of sodium iodide and stirred overnight at a bath temperature of 90° C. For working-up, the reaction mixture is cooled to room temperature, stirred into water, extracted 3 times with ethyl acetate, washed with common salt solution, dried on magnesium sulfate and concentrated by evaporation in a vacuum. 3.4 g of 11β-fluoro-3-hydroxy-7α-(6-iodohexyl)-estra-1,3,5(10)-trien-17-one is obtained as a crude product, which is used without further purification in the next stage.