Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([C:15](=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=1)=[N:8][CH:7]=[C:6]2[C:25]([OH:27])=O.C(OC(Cl)=O)C(C)C.Cl.[CH2:37]([O:39][C:40](=[O:43])[CH2:41][NH2:42])[CH3:38]>CN(C)C=O.C(N(CC)CC)C.C(OCC)(=O)C>[CH2:37]([O:39][C:40](=[O:43])[CH2:41][NH:42][C:25]([C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]([C:15](=[O:24])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=[N:8][CH:7]=1)=[O:27])[CH3:38]
Reactant: COc1cccc(C(=O)c2ncc(C(=O)O)c3cc(OC)c(OC)cc23)c1
Reactant: CCOC(=O)CN
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)c1cnc(C(=O)c2cccc(OC)c2)c2cc(OC)c(OC)cc12
Temperature: 25 °C
Yield: 6.3 %

Procedure:
A solution of 6,7-dimethoxy-1-(3-methoxy-benzoyl)-isoquinoline-4-carboxylic acid (30.0 mg, 81.65 mmol) in dry, N,N-dimethylformamide (2 mL) chilled in an ice-bath under argon. With stirring, triethylamine (14.4 uL, 102 mmol) and isobutylchloroformate (13.4 uL, 102 mmol) were added. The solution was stirred for 30 min and then solution of glycine ethyl ester hydrochloride (227 mg, 1,633 mM) in 4 mL of dimethylformamide and triethylamine (0.229 mL, 1.633 mM) were added and the reaction was allowed to warm to room temperature with stirring for 1 hr. and then diluted with ethyl acetate (30 mL), The ethyl acetate solution was washed sequentially with saturated sodium bicarbonate solution (2×5 mL), water (5 mL), and saturated sodium chloride solution (5 mL), dried over magnesium sulfate, filtered and concentrated in vacuo to afford 46 mg solid. This crude material was purified by flash chromatography, eluting with 50% ethyl acetate in hexanes (containing 1% acetic acid) and then increasing gradually to 80% ethyl acetate in hexanes After tlc analysis, fractions were pooled and evaporated to yield 36 mg (79.4%) of white, powder as an acetate salt: APCI-MS m/e calcd for C24H24N2O7 (M+H) 453.5, found 453; H NMR (300 MHz) compatible
Reaction SMILES: [CH2:1](B([C@H]1C[C@H]2C[C@H](C2(C)C)[C@@H]1C)[C@H]1C[C@H]2C[C@H](C2(C)C)[C@@H]1C)[CH:2]=[CH2:3].[Cl:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]([CH:32]=[O:33])[C:27]=1[F:34].[OH-].[Li+].OO.[OH-].[Na+]>CCCCC.C1COCC1.CCOC(C)=O.CO>[Cl:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]([C@H:32]([OH:33])[CH2:3][CH:2]=[CH2:1])[C:27]=1[F:34]
Reactant: C=CCB([C@H]1C[C@H]2C[C@@H]([C@@H]1C)C2(C)C)[C@H]1C[C@H]2C[C@@H]([C@@H]1C)C2(C)C
Reactant: O=Cc1nccc(Cl)c1F
Agent: OO
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCC
Solvent: CO
Product: C=CC[C@@H](O)c1nccc(Cl)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
A solution of 1 M allylbis((1S,2R,3S,5S)-2,6,6-trimethylbicyclo[3.1.1]heptan-3-yl)borane in pentane in anhydrous THF (10 mL) was cooled to −78° C. To the solution was added 4-chloro-3-fluoropicolinaldehyde (0.5 g, 3.13 mmol) in 10 mL of THF dropwise for 20 min. The resulting solution was stirred for additional 1 h. To the mixture was added MeOH (1 mL), followed addition of lithium hydroxide (0.300 g, 12.54 mmol), hydrogen peroxide (0.384 mL, 12.54 mmol) and 10 mL of 1 N NaOH. The content was allowed to warm up to rt and stirred for 1 h. The reaction mixture was diluted with EtOAc, washed with brine (2×20 mL), dried over Na2SO4, concentrated and purified by silica gel chromatography to provide (R)-1-(4-chloro-3-fluoropyridin-2-yl)but-3-en-1-ol (0.54 g, 85%). MS (ESI) m/z: 202.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9](Cl)=[O:10])=[C:4]([Cl:12])[N:3]=1.C(=O)(O)[O-].[Na+].[CH3:18][NH:19][CH3:20]>C(Cl)Cl.O>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([N:19]([CH3:20])[CH3:18])=[O:10])=[C:4]([Cl:12])[N:3]=1
Reactant: O=C(Cl)c1c(Cl)nc(Cl)nc1Cl
Reactant: CNC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CN(C)C(=O)c1c(Cl)nc(Cl)nc1Cl

Procedure:
To a solution of the subtitle product of step ii) (2.0 g) in DCM (20 ml) and sodium bicarbonate (1.36 g) in water (20 ml) at 0° C. was added dimethylamine (1.00 ml, 40% aqueous) dropwise. The reaction mixture was stirred at room temperature for 2 h before DCM (40 ml) was added and the aqueous layer separated. The organic layer was washed with water (20 ml), brine (10 ml) and dried (MgSO4). The solid was filtered and the solvent evaporated to dryness under reduced pressure. The residue was purified by column chromatography (EtOAc/isohexane (1:1)) to yield the subtitle compound as an off white solid. Yield 1.9 g
Reaction SMILES: [C:1]([CH2:3][C:4](O)=[O:5])#[N:2].[CH:7]1([NH:12][C:13]([NH2:15])=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8]1>C(OC(=O)C)(=O)C>[NH2:2][C:1]1[N:12]([CH:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[C:13](=[O:14])[NH:15][C:4](=[O:5])[CH:3]=1
Reactant: N#CCC(=O)O
Reactant: NC(=O)NC1CCCC1
Solvent: CC(=O)OC(C)=O
Product: Nc1cc(=O)[nH]c(=O)n1C1CCCC1
Reaction time: 2 h

Procedure:
To a solution of 136 g (1.6 mol) cyanoacetic acid and 400 ml of acetic anhydride was added 192 g (1.5 mol) of cyclopentylurea. The solution was stirred at 60°-70° C. for 2 hours. After cooling white crystals were filtered off and washed with ethanol. Yield 192 g (66%) (XIII). This was stirred in 500 ml of hot water and 195 ml of 5N NaOH was added in portions so the solution the whole time was basic. The reaction mixture was refluxed for 20 minutes and then neutralized with 5N HCl. After cooling, white crystals of cyclopentylurea were filtered off (159 g). The filtrate was evaporated and the residue was refluxed with 200 ml of 1N NaOH. After cooling the cyclopentylurea was filtered off and the filtrate was neutralized with 5N HCl. The crystals were filtered off. Yield 3.8 g (2%) (XIV) NMR.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21]CC)[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6]([C:24]3[CH:25]=[N:26][CH:27]=[C:28]([CH2:30][OH:31])[CH:29]=3)=[CH:5][C:4]=2[N:3]=1.B(Br)(Br)Br.CO>ClCCl>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][OH:21])[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[N:8]=[CH:7][C:6]([C:24]3[CH:25]=[N:26][CH:27]=[C:28]([CH2:30][OH:31])[CH:29]=3)=[CH:5][C:4]=2[N:3]=1
Reactant: CCOCc1nc2c(N)nc3cc(-c4cncc(CO)c4)cnc3c2n1CC(C)(C)O
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: CC(C)(O)Cn1c(CO)nc2c(N)nc3cc(-c4cncc(CO)c4)cnc3c21
Temperature: -78 °C
Reaction time: 3.5 h
Yield: 30 %

Procedure:
A suspension of 1-{4-amino-2-(ethoxymethyl)-7-[5-(hydroxymethyl)pyridin-3-yl]-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl}-2-methylpropan-2-ol (627 mg, 1.48 mmol), obtained from the filtrate from the trituration in Example 68, in dichloromethane (25 mL) was cooled to −78° C. Boron tribromide (15 mL of a 1 M solution in dichloromethane) was added dropwise, and the reaction was allowed to warm to room temperature and stirred for 3.5 hours. Methanol (50 mL) was carefully added, and the resulting solution was stirred at room temperature for 30 minutes and concentrated under reduced pressure. A solution of ammonia in methanol (50 mL of 1 M) was added, and the mixture was stirred for 30 minutes. Silica gel was added, and the mixture was concentrated under reduced pressure. The resulting mixture was purified by automated flash chromatography (FLASH 40+M cartridge, eluting with 15% to 30% methanolic ammonia in dichloromethane). All fractions containing product were combined and concentrated, and the residue was dissolved in methanol (50 mL) and treated with 6 M hydrochloric acid. The solution was heated at 50° C. for two hours, concentrated under reduced pressure, and diluted with 2 N ammonia in methanol. Silica gel was added, and the mixture was concentrated under reduced pressure. Chromatographic purification was carried out again as described above with the modification that the elution gradient began with 5% methanolic ammonia in dichloromethane. The resulting product was dissolved in methanol (20 mL), divided in ten equal portions, and loaded onto ten Waters Oasis Sample Extractions Cartridge MCX columns (500 mg) according to the following procedure. Each column was washed with methanol (2 volumes) and 1 N ammonia in methanol (3 volumes), and the ammonia washes were combined and concentrated under reduced pressure. The resulting solid (200 mg) was triturated with acetonitrile, isolated by filtration, washed with acetonitrile, and dried in a vacuum oven to provide 175 mg of 1-{4-amino-2-(hydroxymethyl)-7-[5-(hydroxymethyl)pyridin-3-yl]-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl}-2-methylpropan-2-ol as a light yellow solid, mp 149-151° C.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=3[O:15][CH2:16][C:17]([O:19]CC)=[O:18])[C:5]=2[N:6]=1.[Cl:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29](Br)[C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)=[CH:25][CH:24]=1>>[Cl:22][C:23]1[CH:24]=[CH:25][C:26]([CH:29]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[S:1][C:2]2[S:3][C:4]3[CH2:14][CH2:13][C:12]4[C:7](=[CH:8][CH:9]=[CH:10][C:11]=4[O:15][CH2:16][C:17]([OH:19])=[O:18])[C:5]=3[N:6]=2)=[CH:27][CH:28]=1
Reactant: CCOC(=O)COc1cccc2c1CCc1sc(S)nc1-2
Reactant: Clc1ccc(C(Br)c2ccc(Cl)cc2)cc1
Product: O=C(O)COc1cccc2c1CCc1sc(SC(c3ccc(Cl)cc3)c3ccc(Cl)cc3)nc1-2
Yield: 77 %

Procedure:
Using ethyl [(2-mercapto-4,5-dihydronaphtho-[1,2-d]thiazol-6-yl)oxy]acetate and bis(4-chlorophenyl)methyl bromide, the procedure of Example 63 was otherwise repeated to synthesize the title compound. Yield 77%.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13]([O:30][CH2:31][CH2:32][O:33][CH3:34])[C:14]=3[N:16]3[CH2:21][CH2:20][CH2:19][C@@H:18]([NH:22]C(=O)OC(C)(C)C)[CH2:17]3)[NH:9][CH:8]=2)=[O:5])[CH2:3][CH2:2]1.[ClH:35]>CC(O)C>[ClH:35].[NH2:22][C@@H:18]1[CH2:19][CH2:20][CH2:21][N:16]([C:14]2[C:13]([O:30][CH2:31][CH2:32][O:33][CH3:34])=[CH:12][N:11]=[C:10]3[NH:9][CH:8]=[C:7]([NH:6][C:4]([CH:1]4[CH2:2][CH2:3]4)=[O:5])[C:15]=23)[CH2:17]1
Reactant: COCCOc1cnc2[nH]cc(NC(=O)C3CC3)c2c1N1CCC[C@@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CC(C)O
Product: COCCOc1cnc2[nH]cc(NC(=O)C3CC3)c2c1N1CCC[C@@H](N)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.8 %

Procedure:
(R)-tert-Butyl 1-(3-(cyclopropanecarboxamido)-5-(2-methoxyethoxy)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (0.110 g, 0.232 mmol) was dissolved in 5N HCl (2.32 mL, 11.6 mmol) in IPA and stirred at room temperature for 2 hours. The reaction was concentrated to dryness, suspended in acetonitrile (5 mL) and stirred at room temperature for 30 minutes. The resulting precipitate was filtered and dried to yield (R)—N-(4-(3-aminopiperidin-1-yl)-5-(2-methoxyethoxy)-1H-pyrrolo[2,3-b]pyridin-3-yl)cyclopropanecarboxamide hydrochloride (0.094 g, 90.7% yield) as a solid. 1H NMR (400 MHz, D2O) δ 7.82 (s, 1H), 7.21 (s, 1H), 4.13 (m, 2H), 3.75-3.81 (m, 3H), 3.47 (m, 2H), 3.30 (s, 3H), 3.22 (m, 2H), 2.07 (m, 1H), 1.74 (m, 2H), 1.57-1.65 (m, 2H), 0.88 (m, 2H), 0.93 (m 2H). LCMS (APCI+) m/z 374.2 (M+H).
Reaction SMILES: O([C:8]([O:10][CH2:11][CH2:12][S:13][C:14]1[N:19]2[CH:20]=[CH:21][N:22]=[C:18]2[CH:17]=[CH:16][CH:15]=1)=[O:9])C1C=CC=CC=1.[NH2:23][CH2:24][CH2:25][CH2:26][OH:27]>C(Cl)(Cl)Cl>[OH:27][CH2:26][CH2:25][CH2:24][NH:23][C:8]([O:10][CH2:11][CH2:12][S:13][C:14]1[N:19]2[CH:20]=[CH:21][N:22]=[C:18]2[CH:17]=[CH:16][CH:15]=1)=[O:9]
Reactant: NCCCO
Reactant: O=C(OCCSc1cccc2nccn12)Oc1ccccc1
Solvent: ClC(Cl)Cl
Product: O=C(NCCCO)OCCSc1cccc2nccn12
Temperature: 120 °C
Reaction time: 1.5 h
Yield: 55.6 %

Procedure:
To 5-[2-(phenoxycarbonyloxy)ethylthio]imidazo[1,2-a]pyridine (1.10 g, 3.50 mmoles) was added 3-aminopropanol (0.27 ml, 3.52 mmoles) and the mixture was stirred at 120° C. for 1.5 hours. The reaction mixture was cooled by standing and chloroform was added thereto, which was washed with water and dried over anhydrous magnesium sulfate, and then the solvent was distilled off. Then, the residue was purified by column chromatography (eluent: methanol/chloroform=1:20) to obtain 575 mg of the desired product (55.6%, colorless crystals).
Reaction SMILES: C([O:3][C:4](=[O:28])/[CH:5]=[CH:6]/[N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([CH2:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)[C:8]1=[O:27])C.[OH-].[Na+].Cl>CO>[C:17]1([CH2:16][N:9]2[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:7](/[CH:6]=[CH:5]/[C:4]([OH:28])=[O:3])[C:8]2=[O:27])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)/C=C/n1c(=O)n(Cc2cccc3ccccc23)c2ccccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)/C=C/n1c(=O)n(Cc2cccc3ccccc23)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 29 %

Procedure:
To a solution of (E)-3-(3-Naphthalen-1-ylmethyl-2-oxo-2,3-dihydro-benzimidazol-1-yl)-acrylic acid ethyl ester (0.1 g, 0.30 mmol) in MeOH (10 mL) was added 2N NaOH (5 mL). The reaction mixture was stirred at room temperature for 3 h. Since the mixture was heterogeneous, the mixture was heated to 60° C. for 2 h. The reaction mixture was then treated with 1N HCl and extracted with CH2Cl2. The organic phase was dried over Na2SO4 and concentrated. The resulting residue was purified by silica gel prep TLC using 10:1 CH2Cl2:MeOH as an eluent to afford 30 mg of the title compound as an off-white solid. LCMS (ESMS): m/z 345.12 (M+H+).
Reaction SMILES: [C:1]([O:8][CH3:9])(=[O:7])[CH2:2][CH2:3][C:4]([O-:6])=O.P(=O)(O)(O)O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH2:28]([C:30]1[C:34]([C:35]2[NH:36][C:37]3[C:42]([CH:43]=2)=[CH:41][CH:40]=[CH:39][CH:38]=3)=[C:33]([CH3:44])[O:32][N:31]=1)[CH3:29]>C(#N)C.CCOCC.O>[CH2:28]([C:30]1[C:34]([C:35]2[NH:36][C:37]3[C:42]([C:43]=2[C:4](=[O:6])[CH2:3][CH2:2][C:1]([O:8][CH3:9])=[O:7])=[CH:41][CH:40]=[CH:39][CH:38]=3)=[C:33]([CH3:44])[O:32][N:31]=1)[CH3:29]
Reactant: CCc1noc(C)c1-c1cc2ccccc2[nH]1
Reactant: COC(=O)CCC(=O)[O-]
Agent: O=P(O)(O)O
Solvent: O
Solvent: CC#N
Solvent: CCOCC
Product: CCc1noc(C)c1-c1[nH]c2ccccc2c1C(=O)CCC(=O)OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 59.4 grams (0.45 mole) of mono-methyl succinate in 300 ml acetonitrile is treated by dropwise addition with 5.5 grams of 85% phosphoric acid and then by dropwise addition with 63.5 ml (0.45 mole) of trifluoroacetic acid anhydride. The mixture is stirred 15 minutes at room temperature and then treated by dropwise addition with 33.9 grams (0.15 mole) of 2-(3-ethyl-5-methyl-4-isoxazolyl)-indole in 300 ml of acetonitrile. The mixture is stirred at room temperature overnight, after which 1.5 liters of water and 1 liter of ether are added. The two layers are separated, and the ether is washed with water and made basic by the addition of solid sodium carbonate and water. The mixture is stirred 1 hour at room temperature, following which the layers are separated. The ether layer is then washed with water, dried over MgSO4, filtered and evaporated to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:22])[C:7]([C:17]([O:19]CC)=[O:18])=[CH:8][N:9]2[C:12]2[S:16][N:15]=[CH:14][N:13]=2)=[CH:4][C:3]=1[F:23]>O1CCCC1>[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:22])[C:7]([C:17]([OH:19])=[O:18])=[CH:8][N:9]2[C:12]2[S:16][N:15]=[CH:14][N:13]=2)=[CH:4][C:3]=1[F:23]
Reactant: CCOC(=O)c1cn(-c2ncns2)c2nc(Cl)c(F)cc2c1=O
Solvent: C1CCOC1
Product: O=C(O)c1cn(-c2ncns2)c2nc(Cl)c(F)cc2c1=O
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
Compound No. 164 (1.1 g) obtained in Example 99 was dissolved in a mixture of tetrahydrofuran (40 ml) and c-HCl (10 ml). The solution was stirred at 80° C. for 1.5 hour. After the solvent was removed in vacuo, the precipitate was filtrated and washed with ethanol, ether and n-hexane. The title compound No. 165 was obtained as a slightly yellow solid.
Reaction SMILES: [CH:1]([C:3]1[CH:23]=[CH:22][C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][N:17]=4)[CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1)=O.[NH2:24][O:25][CH3:26].Cl>>[CH3:26][O:25][N:24]=[CH:1][C:3]1[CH:23]=[CH:22][C:6]2[N:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([C:16]4[CH:21]=[CH:20][N:19]=[CH:18][N:17]=4)[CH:11]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1
Reactant: O=Cc1ccc2c(c1)ncn2-c1cccc(-c2ccncn2)c1
Reactant: CON
Agent: Cl
Product: CON=Cc1ccc2c(c1)ncn2-c1cccc(-c2ccncn2)c1
Yield: 28.1 %

Procedure:
was synthesized as described in Example 22 but using (62) (200 mg, 0.66 mmol) instead of (55) and NH2OMe.HCl (250 mg, 2.0 mmol). The reaction gave (64) (61 mg, 28%). Mp. 180-182° C.
Reaction SMILES: [N:1]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5][CH:4]([C:7](OC)=[O:8])[CH2:3][CH2:2]1.[Li+].[BH4-]>C1COCC1>[OH:8][CH2:7][CH:4]1[CH2:5][CH2:6][N:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:2][CH2:3]1
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CO)CC1
Temperature: 0 °C
Yield: 82 %

Procedure:
To a stirred solution of 1-tert-butyl 4-methyl piperidine-1,4-dicarboxylate (171.3 mmol, 1 eq) in THF (250 ml) was added LiBH4 (342.6 mmol, 2 eq) at 0° C. The reaction mixture was then heated at reflux for 2 h and then cooled to 0° C. Ice-water (100 g) was added and the aqueous layer was extracted with ethyl acetate (200 ml). The organic layer was washed with brine (50 ml), the layers were separated, and the organics dried over Na2SO4, concentrated and employed in the next step without further purification. Yield: 82%
Reaction SMILES: CS(O[CH2:6][C:7]1([C:12]#[N:13])[CH2:10][C:9](=[CH2:11])[CH2:8]1)(=O)=O.[C-]#N.[K+].[CH3:17][N:18](C)C=O>O>[C:17]([CH2:6][C:7]1([C:12]#[N:13])[CH2:10][C:9](=[CH2:11])[CH2:8]1)#[N:18]
Reactant: C=C1CC(C#N)(COS(C)(=O)=O)C1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [K+]
Solvent: O
Product: C=C1CC(C#N)(CC#N)C1
Temperature: 65 °C

Procedure:
A mixture of (1-cyano-3-methylenecyclobutyl)methyl methanesulfonate (0.41 g, 0.0020 mol) and potassium cyanide (0.66 g, 0.010 mol) in N,N-dimethylformamide (5 mL, 0.06 mol) was heated at 65° C. overnight. After diluting with water, the resulting mixture was extracted with EtOAc. The combined organic layers were washed with water, brine, dried and evaporated to dry. The residue was used directly in next step.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH2:11].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[CH3:46][O:47][CH:48]([O:56][CH3:57])[CH2:49][C:50]#[C:51][C:52]([CH3:55])([CH3:54])[CH3:53].C1(N(C2CCCCC2)C)CCCCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C)C=O>[C:52]([C:51]1[NH:11][C:3]2[C:2]([C:50]=1[CH2:49][CH:48]([O:56][CH3:57])[O:47][CH3:46])=[CH:7][CH:6]=[C:5]([N+:8]([O-:10])=[O:9])[CH:4]=2)([CH3:55])([CH3:53])[CH3:54]
Reactant: COC(CC#CC(C)(C)C)OC
Reactant: Nc1cc([N+](=O)[O-])ccc1Br
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: CN(C1CCCCC1)C1CCCCC1
Solvent: CN(C)C=O
Product: COC(Cc1c(C(C)(C)C)[nH]c2cc([N+](=O)[O-])ccc12)OC
Temperature: 100 °C
Reaction time: 24 h
Yield: 17 %

Procedure:
2-Bromo-5-nitro-phenylamine (4.9 g, 22.6 mol), Pd2(dba)3 (207 mg, 0.226 mmol), and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (431 mg, 0.904 mmol) was added in a dry 500 mL round-bottom flask. The flask was evacuated and purged with nitrogen three times. 1,1-Dimethoxy-5,5-dimethyl-hex-3-yne (4.61 g, 27.1 mmol), dicyclohexyl-methyl-amine (14.5 mL, 67.8 mmol) and N,N-dimethylformamide (56.5 mL) was added. The reaction mixture was stirred at 100° C. for 24 h, cooled to room temperature, and filtered through a pad of Celite, which was rinsed with ethyl acetate. The filtrate and wash were combined, washed with water and a saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel column chromatography to give the title compound as an orange powder (1.41 g, 20%). LCMS (m/z): 307.1 (M+1).
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:20])=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])=[N:8][CH:9]=1)([O-])=O.O.O.[Cl:23][Sn]Cl.[OH-].[Na+]>Cl>[Cl:23][C:9]1[C:4]([NH2:1])=[C:5]([NH2:20])[CH:6]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[N:8]=1
Reactant: Cl[Sn]Cl
Reactant: Nc1cc(-c2ccccc2C(F)(F)F)ncc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1cc(-c2ccccc2C(F)(F)F)nc(Cl)c1N
Temperature: 90 °C
Reaction time: 1 h

Procedure:
5-Nitro-2-(2-trifluoromethyl-phenyl)-pyridin-4-ylamine (749 mg, 2.65 mmol, prepared as in the previous step) was dissolved in concentrated HCl (12 mL) and heated to 90° C. SnCl2.2H2O (2.98 g, 13.2 mmol) was added to the stirred mixture in small portions and resulting mixture was stirred at 90° C. for 1 h. After completion of addition, the resulting mixture was cooled to 0° C. in an ice bath, treated with 6 M aqueous NaOH (30 mL) and then extracted with DCM (3×40 mL). The combined extracts were dried over MgSO4 and filtered. The solvent was removed under reduced pressure and the residue was chromatographed on a 40-g SiO2 pre-packed column eluting with 0:1-3:2 EtOAc/hexanes to yield 2-chloro-6-(2-trifluoromethyl-phenyl)-pyridine-3,4-diamine. 1H-NMR (400 MHz, CDCl3) δ: 7.67 (d, J=7.8 Hz, 1H), 7.47-7.55 (m, 1H), 7.37-7.46 (m, 2H), 6.57 (s, 1H), 4.09 (br s., 2H), 3.74 (br. s., 2H).
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:17]2[C@:16]3([C:20]#N)[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[CH2:11][C@H:10]([OH:22])[CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.C(=O)(O)[O-:34].[Na+]>C1(C)C=CC=CC=1>[OH:1][C:2]1[CH:19]=[CH:18][C:17]2[C@:16]3([CH:20]=[O:34])[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[CH2:11][C@H:10]([OH:22])[CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1
Reactant: O=C([O-])O
Reactant: C[C@]12CC[C@]3(C#N)c4ccc(O)cc4CC[C@H]3[C@@H]1C[C@@H](O)C2
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C[C@]12CC[C@]3(C=O)c4ccc(O)cc4CC[C@H]3[C@@H]1C[C@@H](O)C2
Temperature: -20 °C
Yield: 52 %

Procedure:
A suspension that consists of 100 mg (0.34 mmol) of 3,16α-dihydroxyestra-1,3,5(10)-triene-9 carbonitrile in 40 ml of toluene is cooled to about −20° C. while being stirred. After 0.9 ml (1.35 mmol) of diisobutylaluminium hydride is added, the reaction is mixed after about 10 minutes with sodium bicarbonate solution, filtered over Celite, and the filtering adjuvant is extracted again with ethyl acetate. The combined organic phases are washed with water. By concentration by evaporation of the solution in a vacuum, 84.6 mg of a light yellow foam is obtained. The product that is contained in the mixture corresponds to a yield of about 52% of theory and is used without further chromatographic working-up in the next stage.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3]1[CH:28]=[CH:27][C:6]([C:7]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[C:14]([NH:19]C(=O)OC(C)(C)C)[CH:13]=[CH:12]3)=[O:8])=[CH:5][CH:4]=1>C(O)(C(F)(F)F)=O.ClCCl>[NH2:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([C:7]([C:6]1[CH:27]=[CH:28][C:3]([N:2]([CH3:29])[CH3:1])=[CH:4][CH:5]=1)=[O:8])[CH:18]=[CH:17]2
Reactant: CN(C)c1ccc(C(=O)c2ccc3cc(NC(=O)OC(C)(C)C)ccc3c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)c1ccc(C(=O)c2ccc3cc(N)ccc3c2)cc1
Yield: 95.7 %

Procedure:
The compound 9 (70 mg, 0.18 mmol) was stirred in 10% TFA in dichloromethane (10 mL) at room temperature for 1 hour and extracted with ethyl acetate with aqueous NaHCO3. The organic layer was dried over Na2SO4, and the filtrate was concentrated to give intermediate D (50 mg, 96%). 1H-NMR (CD3OD) 8.02 (s, 1H), 7.59-7.78 (m, 5H), 7.00-7.07 (m, 2H), 6.80 (m, 3H), 3.09 (s, 6H) ppm; ESI-MS m/z calcd for C19H18N2O: 290.3590. found 291.1821 [M+1].