Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:7](=[O:17])[C:6]([C:18](OCC)=[O:19])=[C:5]2[OH:23].C(N(C(C)C)C(C)C)C.Cl.[C:34]([O:38][C:39](=[O:43])[C@@H:40]([CH3:42])[NH2:41])([CH3:37])([CH3:36])[CH3:35]>O1CCOCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:7](=[O:17])[C:6]([C:18]([NH:41][C@@H:40]([C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:43])[CH3:42])=[O:19])=[C:5]2[OH:23]
Reactant: C[C@@H](N)C(=O)OC(C)(C)C
Reactant: CCOC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCOCC2)C1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[C@@H](NC(=O)C1=C(O)c2cc(Cl)ccc2C2(CCOCC2)C1=O)C(=O)OC(C)(C)C
Temperature: 80 °C
Yield: 54.9 %

Procedure:
Ethyl 6-chloro-4-hydroxy-2-oxo-2′,3′,5′,6′-tetrahydro-spiro[naphthalene-1,4′-pyran]-3-carboxylate (705 mg, 2093 μmol, prepared in Example 1 A-C) was dissolved in 1,4-dioxane (2093 μL) and N-ethyl-N-isopropylpropan-2-amine (1094 μL, 6280 μmol). D-Alanine tert-butyl ester hydrochloride (570 mg, 3140 μmol) was added, and the reaction mixture was heated to 80° C. for 24 hours. The resulting mixture was then diluted with 150 mL of EtOAc, added to a separatory funnel, partitioned with NaHCO3 (saturated, aqueous), washed 2 times with 75 mL of NaHCO3 (saturated, aqueous), separated, dried over Na2SO4, and concentrated in vacuo to give the title compound (501 mg) after flash chromatography. MS (m/z)=436 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C([O-])([O-])=O.[K+].[K+].Cl[CH2:19][CH2:20][N:21]([CH3:23])[CH3:22]>CC#N>[CH3:22][N:21]([CH3:23])[CH2:20][CH2:19][O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CN(C)CCCl
Reactant: COC(=O)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cccc(OCCN(C)C)c1
Temperature: 60 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
To a stirred mixture of methyl 3-hydroxybenzoate (200 mg, 1.32 mmol), and K2CO3 (169 mg, 1.58 mmol) in MeCN (50 mL) was added 2-chloro-N,N-dimethylethanamine (137 mg, 1.58 mmol). The mixture was stirred at 60° C. for 16 h. The reaction mixture was filtered and the filtrate was concentrated to give the title compound that was used without further purification (300 mg, Yield 98%). 1H NMR (CDCl3, 400 MHz): δ 7.61-7.53 (m, 1H), 7.53-7.47 (m, 1H), 7.26-7.23 (m, 1H), 7.06-7.04 (m, 1H), 4.05 (t, J=5.6 Hz, 2H), 3.84 (s, 3H), 2.69 (t, J=5.6 Hz, 2H), 2.28 (s, 6H). LCMS (m/z): 224.2 (M+1).
Reaction SMILES: Br[CH:2]1[C:7](=O)[CH2:6][CH2:5][CH:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3]1.[C:14]([NH2:22])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.ClC(Cl)C>C(Cl)Cl>[C:15]1([C:14]2[O:21][C:2]3[CH2:3][CH:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:6][C:7]=3[N:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)C1CCC(=O)C(Br)C1
Reactant: NC(=O)c1ccccc1
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CCOC(=O)C1CCc2nc(-c3ccccc3)oc2C1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
16.0 g (64.23 mmol) ethyl 3-bromo-4-oxo-cyclohexanecarboxylate are combined with 7.8 g (64.39 mmol) benzamide and 50 ml of dichloroethane in a pressure vessel and stirred overnight at 120° C. The reaction mixture is diluted with DCM and washed 2× with 5% potassium carbonate solution as well as 1× with sat. saline solution. The org. phase is dried on magnesium sulphate and the solv. is eliminated completely in vacuo, the residue is purified through silica gel (eluant cyclohexane/EA).
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH2:4][OH:5].[C:7]([O-:13])([O-])([O:9][CH2:10][CH3:11])[CH3:8].[CH2:14](O)[CH3:15]>>[CH2:14]([O:13][C:7]([O:9][CH2:10][CH3:11])([O:5][CH2:4][CH:3]=[C:2]([CH3:6])[CH3:1])[CH3:8])[CH3:15]
Reactant: CCOC(C)([O-])[O-]
Reactant: CC(C)=CCO
Reactant: CCO
Product: CCOC(C)(OCC)OCC=C(C)C
Reaction time: 0.5 h

Procedure:
A mixture of 4.3 g of 3-methyl-2-buten-1-ol and 16.2 g of ethyl orthoacetate was heated with stirring. The temperature was raised slowly over 2 hours to 120°, during which time 1.8 g of ethanol was evolved and removed. Heating was continued at 120° for 30 minutes and the reaction mixture was then distilled to give, after removal of 8.5 g of unreacted ethyl orthoacetate (b.p. 50°-65°/57 mm), 4.25 g of 1,1-diethoxy-1-(3-methyl-2-buten-1-yloxy)ethane, b.p. 75°-76°/6 mm.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([Cl:9])[CH:3]=1.[Li]CCCC.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][C:25]2([CH2:32][CH2:31][C:30](=[O:33])[CH2:29][CH2:28]2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>C1COCC1>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][C:25]2([CH2:28][CH2:29][C:30]([C:2]3[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([Cl:9])[CH:3]=3)([OH:33])[CH2:31][CH2:32]2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: Clc1ccc(Br)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(=O)CC2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CCC(O)(c1ccc(Cl)c(Cl)c1)CC2
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 35.3 %

Procedure:
1-Bromo-3,4-dichlorobenzene (1.35 g, 5.98 mmol) in THF (10 mL) was added drop-wise to a solution of n-BuLi (1.6 M in hexanes, 4 mL) at −78° C. The mixture was stirred for 40 min at −78° C. A solution of 9-oxo-3-aza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester (1 g, 3.74 mmol) in THF (10 mL) was added drop-wise and the mixture was stirred for 1 h at −78° C. The reaction was quenched with aqueous ammonium chloride and the aqueous layer was extracted twice with diethyl ether. The combined organic phase was washed with brine dried (sodium sulfate), filtered and evaporated to give 2.2 g of crude material. Precipitation in heptane and diethyl ether gave 547 mg of 9-(3,4-dichloro-phenyl)-9-hydroxy-3-aza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester. LC-ESI-HRMS of [M+H]+ shows 296.0983 Da. Calc. 296.09728 Da, dev. 3.4 ppm.
Reaction SMILES: Cl[CH:2](C)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)=O.[CH2:14]1[O:17]C1C.CC(C)=[O:20]>[Hg]>[CH3:12][O:11][C:8]1[CH:7]=[CH:6][C:5]([CH:3]([CH3:2])[C:14]([OH:17])=[O:20])=[CH:10][CH:9]=1
Reactant: CC(C)=O
Reactant: CC1CO1
Reactant: COc1ccc(C(=O)C(C)Cl)cc1
Agent: [Hg]
Product: COc1ccc(C(C)C(=O)O)cc1

Procedure:
A solution comprising 15 parts of 2-chloro-1-(4'-methoxyphenyl)-1-propanone and 10 parts of propylene oxide in 500 parts of 10% v/v aqueous acetone was irradiated by means of a 450W mercury vapour lamp for 8 hours. The solvent was removed by distillation and the resulting acid was extracted with 5% w/v aqueous sodium hydroxide. Acidification yielded 9.5 parts of α-(4'-methoxyphenyl)-propionic acid, m.p. 55° C. to 57° C.
Reaction SMILES: F[C:2](F)(F)[C:3]([O:5][C:6]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]([F:15])[C:7]=1[F:16])=[O:4].[N:19]1([CH2:24][CH:25]=[CH:26][C:27]2[CH:28]=[CH:29][C:30]([CH2:36][CH2:37][C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)=[C:31]([CH:35]=2)[C:32]([OH:34])=[O:33])[CH:23]=[CH:22][N:21]=[CH:20]1.N1C=CC=CC=1>CN(C=O)C>[N:19]1([CH2:24]/[CH:25]=[CH:26]/[C:27]2[CH:35]=[CH:31][C:30]([CH2:36][CH2:37][C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)=[C:2]([CH:28]=2)[C:3]([O:5][C:6]2[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]([F:15])[C:7]=2[F:16])=[O:4])[CH:23]=[CH:22][N:21]=[CH:20]1.[N:19]1([CH2:24]/[CH:25]=[CH:26]\[C:27]2[CH:28]=[CH:29][C:30]([CH2:36][CH2:37][C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)=[C:31]([CH:35]=2)[C:32]([O:34][C:6]2[C:7]([F:16])=[C:8]([F:15])[C:9]([F:14])=[C:10]([F:13])[C:11]=2[F:12])=[O:33])[CH:23]=[CH:22][N:21]=[CH:20]1
Reactant: O=C(O)c1cc(C=CCn2ccnc2)ccc1CCc1ccc(F)cc1
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1cc(/C=C/Cn2ccnc2)ccc1CCc1ccc(F)cc1
Product: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1cc(/C=C\Cn2ccnc2)ccc1CCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Pentafluorophenyl trifluoroacetate (1.47 ml; 8.6 mmol) was added to a solution of 5-[3-(imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenethyl)benzoic acid (2.5 g, 7.14 mmol) and pyridine (0.7 ml; 8.6 mmol) in DMF (7 ml). After stirring at ambient temperature overnight, the mixture was evaporated to dryness and the residue extracted with ethyl acetate, washed with saturated sodium hydrogen carbonate solution and saturated brine. After evaporation the reaction mixture was purified by flash chromatography, eluting with dichloromethane/ethanol (99/1) to give E isomer pentafluorophenyl 5-[(E)-3-(imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenethyl)benzoate and Z isomer pentafluorophenyl 5-[(Z)-3-(imidazol-1-yl)prop-1-en-1-yl]-2-(4-fluorophenethyl)benzoate. Yield: 68%
Reaction SMILES: C[O:2][C:3](=[O:46])[CH:4]([N:16]1[CH2:21][CH2:20][N:19]([C:22](=[O:40])[CH:23]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH:18]([CH2:41][CH:42]2[CH2:44][CH2:43]2)[C:17]1=[O:45])[CH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1.CO.[Li+].[OH-].Cl>C1COCC1.O>[C:36]([O:35][C:33]([NH:32][CH:23]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)[C:22]([N:19]1[CH2:20][CH2:21][N:16]([CH:4]([CH2:5][C:6]2[CH:15]=[CH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]=2)[C:3]([OH:46])=[O:2])[C:17](=[O:45])[CH:18]1[CH2:41][CH:42]1[CH2:44][CH2:43]1)=[O:40])=[O:34])([CH3:39])([CH3:37])[CH3:38]
Reactant: COC(=O)C(Cc1ccc2ccccc2c1)N1CCN(C(=O)C(Cc2ccc(F)cc2)NC(=O)OC(C)(C)C)C(CC2CC2)C1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(Cc1ccc(F)cc1)C(=O)N1CCN(C(Cc2ccc3ccccc3c2)C(=O)O)C(=O)C1CC1CC1
Reaction time: 4 h

Procedure:
To a solution of 2-{4-[2-tert-butoxycarbonylamino-3-(4-fluorophenyl)-propionyl]-3-cyclopropylmethyl-2-oxo-piperazin-1-yl}-3-naphthalen-2-yl-propionic acid methyl ester, 15, (531 mg, 0.842 mmol) in a mixture of THF (5 mL)/CH3OH (1 mL)/H2O (2 mL) is added LiOH (100 mg, 4.17 mmol). The reaction mixture is stirred for 4 hours, acidified with 1N HCl to pH 3 and extracted several times with EtOAc. The combined extracts are dried over Na2SO4, filtered, concentrated in vacuo and dried under high vacuum to give the free acid in quantitative yield, which is used directly without further purification. 1H NMR (300 MHz, CD3OD, Rotamers) δ 7.72–7.87 (m, 3H), 7.68 (s, 1H), 7.37–7.53 (m, 3H), 7.12–7.28 (m, 2H), 6.99–7.06 (m, 2H), 5.54–5.66 (m, 1H), 4.52–4.80 (m, 1.5H), 3.82–4.38 (m, 1.5H), 3.18–3.64 (m, 4H), 2.70–3.02 (m, 3H), 0.80–1.43 (m, 11H), −0.78–0.10 (m, 5H); 13C NMR (75 MHz, CD3OD, Rotamers) δ 171.68, 171.58, 170.23, 169.29, 167.86, 163.70, 156.08, 134.69, 134.57, 133.71, 133.14, 132.70, 131.26, 131.15, 130.73, 130.64, 128.19, 128.12, 127.55, 127.38, 127.29, 127.07, 126.12, 125.64, 79.61, 79.34, 58.68, 57.04, 56.18, 52.13, 51.65, 43.21, 42.29, 41.29, 38.61, 37.32, 37.21, 36.27, 34.23, 33.93, 27.50, 27.41, 6.45, 3.92, 3.66, 3.33; MS (ESMS) m/z 618.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[CH:15](=[O:23])[C:16]1[C:17](=[CH:19][CH:20]=[CH:21][CH:22]=1)[OH:18].O.C(OCC)(=O)C>N1C=CC=CC=1>[F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([O:18][C:17]2[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=2[CH:15]=[O:23])(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: O=Cc1ccccc1O
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=Cc1ccccc1OS(=O)(=O)c1ccc(C(F)(F)F)cc1
Reaction time: 8 h
Yield: 52.3 %

Procedure:
A solution of 4-(trifluoromethyl)benzenesulphonyl chloride (2.4 g, 9.84 mmol) in pyridine (40 mL) is cooled to 0° C. Salicylaldehyde (1.44 g, 11.8 mmol) is added and stirred overnight. Water and ethyl acetate are added to the reaction and shaken. The organic layer is washed with dilute HCl (0.1 N×2), H2O, bicarbonate solution, H2O and dried with sodium sulfate. The organic layer is evaporated to dryness to give a yellow solid, which is recrystallized from ether/hexane to give 2-formylphenyl 4-(trifluoromethyl)benzenesulfonate as a yellow powder (1.70 g, 52%).
Reaction SMILES: C([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2COC(=O)C1C=CC=CC=1)(=O)C(C)C.CC1C=CC=CC=1N>O1CCOCC1>[N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[CH:6][CH:7]=1
Reactant: CC(C)C(=O)c1cnc2c(COC(=O)c3ccccc3)cccc2c1Cl
Solvent: Cc1ccccc1N
Solvent: C1COCCO1
Product: c1ccc2ncccc2c1
Reaction time: 1 h
Yield: 113 %

Procedure:
A solution of 3-isobutyryl-4-chloro-8-benzoyloxymethylquinoline (3.68 g, 10 mmol) and 2-methylaniline (2.13 ml, 20 mmol) in dioxan (50 ml) was heated at reflux for 2 hours, then evaporated, taken up in dichloromethane, washed with aqueous sodium bicarbonate, water and brine, dried and evaporated to an oil. This was taken up in 1% methanolic sodium hydroxide solution (100 ml) and stirred vigorously for 1 hour. The methanol was evaporated, water and dichloromethane added, the aqueous phase adjusted to pH 10 and extracted with dichloromethane. The organic extracts were dried, evaporated and chromatographed (silica, gel, 1%-2% methanol in dichloromethane). Trituration of the product fractions with ether followed by recrystallization from aqueous methanol gave 3-isobutyryl-4-(2-methylphenylamino)-8-hydroxymethyl)quinoline (1.46 g, 44%), m.p. 116°-118°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16](Cl)=[C:11]3[C:10]([I:18])=[N:9]2)=[CH:5][CH:4]=1.C([O-])(=[O:23])C.[Cs+].CN(C=O)C>O>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:12]3[N:13]=[CH:14][CH:15]=[C:16]([OH:23])[C:11]=3[C:10]([I:18])=[N:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Cn2nc(I)c3c(Cl)ccnc32)cc1
Reactant: CC(=O)[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cn2nc(I)c3c(O)ccnc32)cc1
Temperature: 100 °C
Yield: 33.4 %

Procedure:
A mixture of 1-(4-methoxybenzyl)-4-chloro-3-iodo-1H-pyrazolo[3,4-b]pyridine (7.00 g, 17.52 mmol, obtained from Example 84, Step D), cesium acetate (33.62 g, 175.2 mmol) and DMF (175 mL) was heated to 100° C. for 12 hours. The reaction was cooled to room temperature, diluted with water (50 mL), extracted with EtOAc (100 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography (5% MeOH in CH2Cl2) to afford the product (2.23 g, 79% yield) as a light orange solid. LRMS (APCI pos) m/e 381.9 (M+H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]([CH:10]([F:12])[F:11])=[N:8][CH:9]=1.C(=O)(OC(C)(C)C)[O:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=O.C(N(CC)CC)C>C1COCC1>[C:23]([O:22][C:20]([NH:2][CH2:3][C:4]1[CH:5]=[C:6]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]([CH:10]([F:12])[F:11])=[N:8][CH:9]=1)=[O:19])([CH3:26])([CH3:25])[CH3:24]
Reactant: CCOC(=O)c1cc(CN)cnc1C(F)F
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(CNC(=O)OC(C)(C)C)cnc1C(F)F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.4 %

Procedure:
Combine ethyl 5-(aminomethyl)-2-(difluoromethyl)pyridine-3-carboxylate hydrochloride (17.849 mmol, 4.760 g), THF (180 mL) and tert-butoxycarbonyl tert-butyl carbonate (21.419 mmol, 4.675 mL). Stir the mixture at room temperature for about 10 minutes. Add triethylamine (5.225 mL, 37.484 mmol), and stir at room temperature 16 hours. Remove the solids by vacuum filtration, and rinse with EtOAc. Concentrate the filtrate under reduced pressure. Purify the resulting yellow oil by silica gel chromatography (220 g RediSep® silica gel column) eluting with a gradient of 5-45% EtOAc gradient in hexane to give the title compound (3.62 g, 68% yield) as a light yellow crystalline solid. 1H NMR (399.80 MHz, d6-DMSO) δ 8.71 (d, J=2.1 Hz, 1H), 8.15-8.13 (m, 1H), 7.56-7.24 (m, 2H), 4.33 (q, J=7.1 Hz, 2H), 4.24-4.21 (m, 2H), 1.36 (s, 9H), 1.30 (t, J=7.1 Hz, 3H). LCMS (m/z) 331 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[O:20]1[C:25]2[CH:26]=[CH:27][C:28]([NH2:30])=[CH:29][C:24]=2[O:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCO>[O:20]1[C:25]2[CH:26]=[CH:27][C:28]([NH:30][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=4)[N:5]=[CH:4][C:3]=3[C:18]#[N:19])=[CH:29][C:24]=2[O:23][CH2:22][CH2:21]1
Reactant: Nc1ccc2c(c1)OCCO2
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1OCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCO
Product: CCOc1cc2ncc(C#N)c(Nc3ccc4c(c3)OCCO4)c2cc1OCC
Temperature: 100 °C
Yield: 93 %

Procedure:
A solution of 400 mg (1.44 mM) of 4-chloro-6,7-diethoxy-quinoline-3-carbonitrile and 232 mg (1.54 mM) of 1,4-Benzodioxane-6-amine in 15 ml of 2-methoxyethanol was refluxed for 3 hours. To the warm solution was added 1 ml of 1M sodium carbonate and the sample was heated for 5 minutes at 100° C., then poured into 300 ml of ice water. The solid was collected, washed with water followed by ether and dried under vacuum at 80° C. to yield 526 mg of 4-(2,3-Dihydro-benzo[1,4]dioxin-6-ylamino)-6,7-diethoxy-quinoline-3-carbonitrile as a yellow solid: mass spectrum (electrospray, m/e): M+H 402.9, mp=225-227° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:22][C:23](=O)[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]#[N:34])[CH:28]=1)=[O:26])C.C(C1C=C(C=CC=1)C(Cl)=O)#N>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH:18][C:23](=[O:22])[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]#[N:34])[CH:28]=1)=[O:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: CCOC(=O)CC(=O)c1cccc(C#N)c1
Agent: N#Cc1cccc(C(=O)Cl)c1
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(C#N)c2)cc1Cl

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-dimethylamino-phenyl)-carbamic acid tert.-butyl ester (Example J1) (0.5 mmol) and 3-(3-cyano-phenyl)-3-oxo-propionic acid ethyl ester [CAS-No. 62088-13-5; prepared from 3-cyanobenzoyl chloride according to general procedure K, method a] (0.55 mmol) according to the general procedure M. Obtained as a white solid (160 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17]O)=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].CCOCC.C(Cl)Cl.P(Br)(Br)[Br:29]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:19])[NH:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH2:17][Br:29])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nn1ccc2cc(CO)ccc21
Reactant: BrP(Br)Br
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Nn1ccc2cc(CBr)ccc21
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 86.4 %

Procedure:
To an ice-cold solution of 5-hydroxymethylindole-1-carbamic acid tert-butyl ester (0.51 g, 2.1 mmol) in 4:1 Et2O/CH2Cl2 (4 mL) was added PBr3 (0.2 mL, 2.2 mmol), and the reaction mixture was stirred for 40 min. The reaction mixture was diluted with CH2Cl2, washed a saturated solution of NaHCO3 (3×10 mL), dried (Na2SO4), filtered, and the solvent was removed under reduced pressure to provide 5-bromomethyl-indole-1-carbamic acid tert-butyl ester as a yellow solid (0.59 g, 93%). 1H NMR (300 MHz, CDCl3) δ 8.07 (d, J=9 Hz, 1H), 7.68-7.62 (m, 2H) 7.33 (d, J=9 Hz, 1H), 6.60 (s, 1H), 4.68 (s, 2H), 1.67 (s, 9H).
Reaction SMILES: Cl[C@H:2]1[CH2:19][C@@:18]2([CH3:20])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][C@H:11]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[C@@H:12]2[OH:21])[CH2:4][C@@H:3]1[OH:28].[CH3:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH3:29][N:30]1[CH2:35][CH2:34][N:33]([C@H:2]2[CH2:19][C@@:18]3([CH3:20])[C@@H:5]([CH2:6][CH2:7][C@@H:8]4[C@@H:17]3[CH2:16][CH2:15][C@@:13]3([CH3:14])[C@H:9]4[CH2:10][C@H:11]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)[C@@H:12]3[OH:21])[CH2:4][C@@H:3]2[OH:28])[CH2:32][CH2:31]1
Reactant: C[C@]12C[C@H](Cl)[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCCCC3)C[C@@H]12
Reactant: CN1CCNCC1
Product: CN1CCN([C@H]2C[C@@]3(C)[C@@H](CC[C@@H]4[C@@H]3CC[C@]3(C)[C@@H](O)[C@@H](N5CCCCC5)C[C@@H]43)C[C@@H]2O)CC1
Yield: 67 %

Procedure:
The compound was prepared according to Example 11 from 2β-chloro-3α,17β-dihydroxy-16β-piperidino-5α-androstane and from N-methyl-piperazine. Yield: 67.0% of 2β-N-methyl-piperazino-16β-piperidino-3α,17β-dihydroxy-5α-androstane; m.p. 230°-234° C; [α]D25 = +81.7 (c = 1 in chloroform).
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([F:13])[CH:3]=1.[N:14]1([CH2:19][C:20]2([CH2:23][NH2:24])[CH2:22][CH2:21]2)[CH2:18][CH2:17][CH2:16][CH2:15]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][C:5]([C:6]([NH:24][CH2:23][C:20]2([CH2:19][N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:21][CH2:22]2)=[O:8])=[C:4]([F:13])[CH:3]=1
Reactant: COc1cc(C(=O)O)c(F)cc1N
Reactant: NCC1(CN2CCCC2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NCC2(CN3CCCC3)CC2)c(F)cc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 23 %

Procedure:
4-amino-2-fluoro-5-methoxy-benzoic acid (Intermediate 183; 500 mg, 2.70 mmol), [1-(pyrrolidin-1-ylmethyl)cyclopropyl]methanamine (Intermediate 33; 417 mg, 2.70 mmol), HATU (1.545 g, 4.05 mmol) and DIPEA (1.415 mL, 8.10 mmol) were dissolved in DMF (8 mL) and left to stir for 3 hours at room temperature. The reaction mixture was loaded onto an SCX-3 column pre-washed with methanol. The column was washed with methanol eluted with 2% 7N ammonia/methanol. Product containing fractions were combined and evaporated and the residue purified on a silica column (5-12% MeOH ammonia/DCM gradient elution) to yield the title compound as an orange-brown solid (200 mg, 23%).
Reaction SMILES: [CH:1]1([N:7]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16]C#N)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.SC[C@@H]([C@@H](CS)O)O.Cl[CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>>[CH:19]1([N:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16][CH2:34][CH2:35][N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[CH:14][N:15]=2)=[O:9])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: ClCCN1CCOCC1
Reactant: N#CSc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Agent: O[C@H](CS)[C@@H](O)CS
Product: O=C(Nc1ncc(SCCN2CCOCC2)s1)N(C1CCCCC1)C1CCCCC1

Procedure:
Prepared as described in general procedure (H) using 1,1-dicyclohexyl-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritol and N-(2-chloroethyl)-morpholine
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15]O)=[CH:11][CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:37]>>[Cl:37][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][O:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)=[CH:10][CH:11]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: OCc1ccc(COc2ccccn2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: ClCc1ccc(COc2ccccn2)cc1
Temperature: 25 °C
Yield: 51.1 %

Procedure:
A mixture of (4-(pyridin-2-yloxymethyl)-phenyl)methanol (540 mg, 2.51 mmol) described in Manufacturing Example 2-1-1, triphenylphosphine (856 mg, 3.27 mmol) and carbon tetrachloride (10.8 g, 10.2 mmol) was stirred under reflux for 2 hours and 10 minutes. The reaction solution was cooled to room temperature, and concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:acetic acid=8:1) to obtain the title compound (300 mg, 51.1%).