Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:34])=[C:24]([NH:27][C:28]([NH:30][CH:31]3[CH2:33][CH2:32]3)=[O:29])[CH:25]=2)[NH:20][C:19](=[O:35])[C:18]=1[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([Br:42])[CH:37]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[Br:42][C:38]1[CH:37]=[C:36]([C:18]2[C:19](=[O:35])[NH:20][C:21]3[C:26]([C:17]=2[O:16][CH2:15][CH2:14][CH:9]2[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]2)=[CH:25][C:24]([NH:27][C:28]([NH:30][CH:31]2[CH2:33][CH2:32]2)=[O:29])=[C:23]([Cl:34])[CH:22]=3)[CH:41]=[CH:40][CH:39]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CCOc1c(-c2cccc(Br)c2)c(=O)[nH]c2cc(Cl)c(NC(=O)NC3CC3)cc12
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc2c(OCCC3CCCCN3)c(-c3cccc(Br)c3)c(=O)[nH]c2cc1Cl)NC1CC1
Temperature: 25 °C
Yield: 50.5 %

Procedure:
To a solution of 2-{2-[3-(3-bromophenyl)-7-chloro-6-(3-cyclopropyl-ureido)-2-oxo-1,2-dihydroquinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (14 mg in 2.0 mL methylene chloride) was added 2 drops of anisole followed by 2.0 mL of trifluoroacetic acid and the mixture stirred at room temperature. After 30 minutes the solvents were removed in vacuo and the resulting residue purified by flash chromatography on silica gel (methylene chloride:methanol:ammonium hydroxide, 95:5:1; then 90:10:1) to give the title compound (6.0 mg).
Reaction SMILES: Cl.C[O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].BrCC(OC)OC.CCN(CC)CC>CN(C=O)C>[NH2:6][C@H:5]([C:4]([OH:11])=[O:3])[CH2:7][CH:8]([CH3:10])[CH3:9]
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: COC(CBr)OC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](N)C(=O)O

Procedure:
A solution containing L-leucine methyl ester hydrochloride (2.9 g, 16 mmol), 2-bromo-1,1-dimethoxy ethane (1.9 ml, 2.7 g, 16 mmol), NEt3 (6.7 ml, 48 mmol) and a catalytic amount of KI in DMF (190 ml) was stirred at 120° C. for 3 days. The reaction mixture was concentrated under reduced pressure, diluted with water and extracted with DCM. The organic layer was then washed with brine, dried over Na2SO4 and evaporated. The crude product was purified by column chromatography (silica gel, EtOAc/P.E. 1:1) to afford compound of formula (III), where R=Leu side chain, as a yellow oil (1.2 g, 32% yield).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10](=[O:19])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]>C(OCC)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:10]([OH:19])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1=O
Agent: [Li]
Solvent: CCOCC
Product: CCOC(=O)C1CCN(Cc2ccccc2)CC1O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Ethyl 1-benzyl-3-oxo-4-piperidinecarboxylate (1.0 g, 3.8 mmol) in diethyl ether (50 mL) was treated with lithium aluminumhydride (150 mg, 3.9 mmol) at and −78° C. After stirring at −78° C. for 30 minutes, the mixture was allowed to warm to room temperature over 2 hours. The mixture was quenched with saturated ammonium chloride. Standard work-up gave a crude product which was purified via chromatography (SiO2, ethyl acetate:hexanes, 1:6) to provide the title compound. MS (EI, M+H)+ 264.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:14])[C:11]([OH:13])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].O=S(Cl)Cl.[CH3:19][O:20][C:21](=[O:30])[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[NH2:29].CCCCCC>CCOC(C)=O>[CH3:19][O:20][C:21](=[O:30])[C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=1[NH:29][C:11](=[O:13])[CH:10]([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[CH3:14]
Reactant: COC(=O)c1ccc(Cl)cc1N
Reactant: CC(C(=O)O)c1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(Cl)cc1NC(=O)C(C)c1ccc([N+](=O)[O-])cc1
Yield: 94.6 %

Procedure:
The objective compound was prepared by the same procedure for the intermediate 1, using a 2-(4-nitro-phenyl)-propionic acid (1.95 g, 10.0 mmol), SOCl2 (3.6 mL, 33.4 mmol), and 2-amino-4-chloro-benzoic acid methyl ester (1.24 g, 6.67 mmol). After normal workup, the pure objective compound (2.29 g, 95%) was obtained as slightly yellow solid by a flash column chromatography (n-hexane:EtOAc=8:1): 1H NMR (200 MHz, CDCl3) δ 1.65 (d, J=7.3 Hz, 3H, CH3), 3.83-3.93 (m, 4H, CO2CH3 & CH), 7.04 (dd, J=8.5, 2.0 Hz, 1H, ArH), 7.58 (d, J=8.9 Hz, 2H, ArH), 7.93 (d, J=8.5 Hz, 1H, ArH), 8.21 (d, J=8.9 Hz, 2H, ArH), 8.79 (d, J=2.0 Hz, 1H, ArH), 11.09 (br s, 1H, NH).
Reaction SMILES: C(C1C=C2C(C3C=C(C=CC=3)CNC(C3C(=O)N(CC4C=CC(F)=C(F)C=4)C=CC=3)=O)=CNC2=NC=1)#N.CC1(C)C(C)(C)OB([C:46]2[S:50][C:49]([CH2:51][NH:52][C:53]([C:55]3[C:56](=[O:70])[N:57]([CH2:61][C:62]4[CH:67]=[CH:66][C:65]([F:68])=[C:64]([F:69])[CH:63]=4)[CH:58]=[CH:59][CH:60]=3)=[O:54])=[CH:48][CH:47]=2)O1.[B].[F:73][C:74]1[CH:75]=[C:76]2[C:82](I)=[CH:81][NH:80][C:77]2=[N:78][CH:79]=1>>[F:73][C:74]1[CH:75]=[C:76]2[C:82]([C:46]3[S:50][C:49]([CH2:51][NH:52][C:53]([C:55]4[C:56](=[O:70])[N:57]([CH2:61][C:62]5[CH:67]=[CH:66][C:65]([F:68])=[C:64]([F:69])[CH:63]=5)[CH:58]=[CH:59][CH:60]=4)=[O:54])=[CH:48][CH:47]=3)=[CH:81][NH:80][C:77]2=[N:78][CH:79]=1
Reactant: Fc1cnc2[nH]cc(I)c2c1
Reactant: CC1(C)OB(c2ccc(CNC(=O)c3cccn(Cc4ccc(F)c(F)c4)c3=O)s2)OC1(C)C
Agent: N#Cc1cnc2[nH]cc(-c3cccc(CNC(=O)c4cccn(Cc5ccc(F)c(F)c5)c4=O)c3)c2c1
Agent: [B]
Product: O=C(NCc1ccc(-c2c[nH]c3ncc(F)cc23)s1)c1cccn(Cc2ccc(F)c(F)c2)c1=O

Procedure:
Except where indicated, 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid [5-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-thiophen-2-ylmethyl]-amide was synthesized as per Example 68, 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid 3-(5-cyano-1H-pyrrolo[2,3-b]pyridin-3-yl)-benzylamide using 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid [5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophen-2-ylmethyl]-amide as activated boron species and 5-Fluoro-3-iodo-1H-pyrrolo[2,3-b]pyridine as substituted bicyclic heterocycle, to produce the title compound. 1H NMR (400 MHz, CDCl3-MeOH-d4) d ppm 8.570 (d, J=7.0 Hz, 1H) 8.500 (d, J=7.6 Hz, 1H) 8.287 (s, 1H) 7.744 (s, 1H) 7.555 (d, J=6.3 Hz, 1H) 7.186-6.972 (m, 5H) 6.478 (t, J=6.7 Hz, 1H) 5.135 (s, 2H) 4.788 (s, 2H); MS m/z=495.29 M+H.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH2:11][C:12](O)=[O:13])=[CH:4][CH:3]=1.CSC.B>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][O:10][CH2:11][CH2:12][OH:13])=[CH:6][CH:7]=1
Reactant: O=C(O)COCCc1ccc(Br)cc1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: OCCOCCc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.6 %

Procedure:
To a solution of [2-(4-bromophenyl)ethoxy]acetic acid (14 g, 0.054 mol; see step (ii) above) in dry THF (150 mL), borane methyl sulphide (6.16 g, 0.082 mol) was added, dropwise at from 0 to 5° C. The resulting mixture was stirred at room temperature for 3 h. After cooling the reaction mixture to between 0 and 5° C., 1.5 NHCl (80 mL) was added, dropwise, and the resulting mixture was refluxed for 30 minutes. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water and brine and concentrated to give the sub-title compound (yield: 10.8 g, 81%).
Reaction SMILES: [CH2:1]([O:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[N:8]([CH2:17][CH:18]([CH3:20])[CH3:19])[C:7]1(/[CH:30]=[CH:31]/[C:32](O)=[O:33])[CH2:21][NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:2][CH2:3][CH3:4].Cl.C([N:38]=C=NCCCN(C)C)C.[NH4+].ON1C2C=CC=CC=2N=N1.O>CN(C)C=O>[CH2:1]([O:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[N:8]([CH2:17][CH:18]([CH3:19])[CH3:20])[C:7]1(/[CH:30]=[CH:31]/[C:32]([NH2:38])=[O:33])[CH2:21][NH:22][C:23]([O:25][C:26]([CH3:27])([CH3:29])[CH3:28])=[O:24])[CH2:2][CH2:3][CH3:4]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCCCOC1c2ccccc2C(=O)N(CC(C)C)C1(/C=C/C(=O)O)CNC(=O)OC(C)(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOC1c2ccccc2C(=O)N(CC(C)C)C1(/C=C/C(N)=O)CNC(=O)OC(C)(C)C
Yield: 86.6 %

Procedure:
A solution of (E)-3-(4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)-2-propenic acid (0.47 g, 1 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.38 g, 2 mmol) and 1-hydroxybenzotriazole ammonium salt (0.30 g, 2 mmol) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 2 h. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-n-hexane to give (E)-3-(4-butoxy-3-[[(tert-butoxycarbonyl)amino]methyl]-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl)-2-propenamide (0.41 g, 87.2%) as crystals.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6](/[CH:9]=[C:10]2/[C:11]([NH:16][CH2:17][C:18]#[CH:19])=[N:12][C:13](=[O:15])[S:14]/2)[CH2:5][CH2:4]1.[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[C:23]([C:29]([F:32])([F:31])[F:30])[CH:22]=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C.O>[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:3]2[CH2:8][CH2:7][CH:6](/[CH:9]=[C:10]3/[C:11]([NH:16][CH2:17][C:18]#[CH:19])=[N:12][C:13](=[O:15])[S:14]/3)[CH2:5][CH2:4]2)=[C:23]([C:29]([F:30])([F:31])[F:32])[CH:22]=1
Reactant: O=Cc1ccc(Cl)cc1C(F)(F)F
Reactant: C#CCNC1=NC(=O)S/C1=C\C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(Cl)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.8 %

Procedure:
To a solution of (5Z)-5-(piperidin-4-ylmethylidene)-4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one dihydrochloride (1.00 g) in DMF (15.5 mL) were added 4-chloro-2-(trifluoromethyl)benzaldehyde (1.10 g) and triethylamine (1.95 mL). The reaction mixture was stirred at room temperature for 1.5 hr, and sodium triacetoxyborohydride (2.28 g) was added. The reaction mixture was stirred at room temperature for 1 hr, poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.04 g).
Reaction SMILES: C[O:2][C:3]([CH2:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4].[OH-].[Na+]>CO>[C:3]([CH2:5][CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:15]=2)[NH:10][CH:9]=1)([OH:4])=[O:2]
Reactant: COC(=O)CCCc1c[nH]c2cc(C(=O)OC)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1ccc2c(CCCC(=O)O)c[nH]c2c1
Temperature: 20 °C
Reaction time: 48 h
Yield: 78.1 %

Procedure:
To a solution of methyl 3-(3-methoxycarbonylpropyl)-indole-6-carboxylate (656 mg) in methanol (24 ml) was added 1N aqueous sodium hydroxide (2.46 ml), and the mixture was stirred at 20° C. for 2 days. The resulting mixture was evaporated in vacuo, and the residue was acidified with 1N hydrochloric acid (2.6 ml) and extracted with ethyl acetate. The organic chase was washed with brine, dried over sodium sulfate and evaporated in vacuo. The residue was triturated with ether to give methyl 3-(3-carboxypropyl)indole-6-carboxylate (486 mg) as solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl.O.[NH:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1>[Pt](=O)=O>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:16]3[CH2:17][CH2:18][NH:13][CH2:14][CH2:15]3)=[CH:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc2cc[nH]c2c1
Reactant: O=C1CCNCC1
Agent: O=[Pt]=O
Agent: Cl
Solvent: O
Product: Fc1ccc2c(C3CCNCC3)c[nH]c2c1
Yield: 39.6 %

Procedure:
This compound was prepared following the procedure described in example 1 (parts A and B) starting with 1 g (7.4 mmol) of 6-fluoroindol and 2.84 g (18.5 mmol) of 4-piperidone monohydrate hydrochloride. In this case, the hydrogenation step took place for 1 hour at 30 psi and the catalyst used was platinum (IV) oxide. 0.640 g (51% yield) of 6-fluoro-3-piperidin-4-yl-1H-indole were obtained.
Reaction SMILES: [C:1]([O:13]C)(=O)[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[CH:4][CH:3]=1.[CH2:15]([OH:22])[C:16]([NH2:21])([CH2:19][OH:20])[CH2:17][OH:18]>CO>[OH:22][CH2:15][C:16]([NH:21][C:6](=[O:8])[C:5]1[CH:4]=[CH:3][C:2]([C:1]([NH:21][C:16]([CH2:19][OH:20])([CH2:17][OH:18])[CH2:15][OH:22])=[O:13])=[CH:11][CH:10]=1)([CH2:19][OH:20])[CH2:17][OH:18]
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Reactant: NC(CO)(CO)CO
Solvent: CO
Product: O=C(NC(CO)(CO)CO)c1ccc(C(=O)NC(CO)(CO)CO)cc1

Procedure:
In a 1-liter, three-neck, round-bottom flask equipped with a thermometer, stirrer and condenser were placed 194 g (1.0 mole) of dimethyl terephthalate, 242 g (2.0 mole) tris(hydroxymethyl) aminomethane and 1 liter of methanol. The mixture was refluxed for 8 hours and then allowed to cool. The title compound crystallized and was removed by filtration and dried. The melting point was 188°-190° C.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].CC[N:14]([CH:18]([CH3:20])[CH3:19])C(C)C.[OH-:21].[Na+]>C(Cl)Cl>[OH:21][CH:10]1[CH2:11][C:19]2[C:18]([NH:14][C:2](=[O:3])[O:4][CH2:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:20][CH:5]=[CH:6][C:7]=2[CH2:8][CH2:9]1
Reactant: [OH-]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCN(C(C)C)C(C)C
Agent: [Na+]
Solvent: ClCCl
Product: O=C(Nc1cccc2c1CC(O)CC2)OCc1ccccc1
Reaction time: 0.25 h
Yield: 61 %

Procedure:
A solution of benzyl chloroformate (5.84 mL, 41.1 mmol) in 5 mL CH2Cl2 was added dropwise via addition funnel to Example 24A (3.05 g, 18.7 mmol) and Hunig's base (8.14 mL, 46.7 mmol) in dichloromethane (55 mL) at ambient temperature. After 18 hr IN (aq) NaOH solution (50 mL) was added and the reaction was stirred vigorously for 15 min. The separated organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude product was triturated with diethyl ether and the solid collected by suction filtration. The result was 3.37 g (61% yield) of the title compound as a brown solid. 1H NMR (300 MHz, DMSO-d6) δ 8.82 (s, 1H), 7.30-7.45 (m, 5H), 7.14 (m, 1H), 7.05 (t, 1H), 6.90 (m, 1H), 5.12, (s, 2H), 4.77 (d, 1H), 3.87 (m, 1H), 2.86 (m, 2H), 2.71 (m, 1H), 2.43 (m, 1H), 1.84 (m, 1H), 1.58 (m, 1H). MS (APCI+) m/z 298 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.[N:18]1[C:23]2[O:24][CH2:25][CH2:26][O:27][C:22]=2[CH:21]=[C:20]([CH:28]=O)[N:19]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.CO>[N:18]1[C:23]2[O:24][CH2:25][CH2:26][O:27][C:22]=2[CH:21]=[C:20]([CH2:28][NH:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[O:9])[CH2:6][CH2:7]2)[N:19]=1
Reactant: NC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: O=Cc1cc2c(nn1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC(NCc2cc3c(nn2)OCCO3)CC1
Reaction time: 2 h
Yield: 62 %

Procedure:
A mixture of phenylmethyl 4-amino-1-piperidinecarboxylate (for a synthesis see WO 2004/058144 Example 99(e)) (14.4 g crude, equivalent to 11 g, 47 mmol) and 6,7-dihydro[1,4]dioxino[2,3-c]pyridazine-3-carbaldehyde (for a preparation see Example 6(e)) (6.46 g, 39 mmol) in DCM (200 ml) and MeOH (10 ml) was stirred for 4 h at rt, then cooled in ice as sodium triacetoxyborohydride (12.4 g) was added over 15 min. After stirring for another 2 h, the mixture was treated with aqueous sodium bicarbonate to neutralise. The aqueous phase was extracted with DCM and the organic fractions were dried and evaporated. Chromatography on silica (750 g), eluting with 0-10% MeOH/DCM, gave the product (11.1 g, 62%).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][CH2:20]S)=[CH:11]1.C1C=CC2NC=C(CCO)C=2C=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[CH2:8]([O:7][C:1](=[O:6])[CH2:2][C:3]1([CH3:5])[C:11]2[NH:10][C:18]3[C:13]([C:12]=2[CH2:19][CH2:20][O:4]1)=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH3:9]
Reactant: SCCc1c[nH]c2ccccc12
Reactant: CCOC(=O)CC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: OCCc1c[nH]c2ccccc12
Solvent: c1ccccc1
Product: CCOC(=O)CC1(C)OCCc2c1[nH]c1ccccc21
Reaction time: 0.17 h

Procedure:
Ethyl acetoacetate (23.4 g., 0.18 moles) is added to a solution of the starting material of formula II, tryptophol (10.0 g., 0.06 moles), in 200 ml. of benzene. After standing for 10 minutes, p-toluenesulfonic acid (1.3 g.) and about 5 g. of hydrated alkali-aluminum silicate (Molecular Sieves No. 4) are added. The mixture is subjected to reflux for thirty minutes, 600 mg. more of p-toluenesulfonic acid is added and refluxing continued for 21/2 hours. The molecular sieves are collected and the benzene solution washed successively with 5% sodium bicarbonate and water, dried over sodium sulfate, and evaporated under reduced pressure to dryness affording an oil. The oil is subjected to chromatography on silica gel. Elution with 5% ether in benzene yields the ester, 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid ethyl ester, as an oil,γmaxCHCl3 1715 cm-1.
Reaction SMILES: [Cl-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[OH:9][C:10]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=[O:13].O>C1COCC1>[CH3:18][C:17]1[C:10]2[O:9][CH2:2][CH:12]([OH:13])[C:11]=2[CH:14]=[CH:15][CH:16]=1
Reactant: Cc1cccc(C=O)c1O
Reactant: C[S+](C)(C)=O
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc2c1OCC2O
Yield: 44.4 %

Procedure:
To a stirred suspension of trimethyl sulfoxonium chloride (3.78 g, 0.03 mole) in dry THF (60 ml) was added sodium hydride (1.16 g, 0.03 mole) and the whole warmed to reflux for 1 h. 2-Hydroxy-3-methyl-benzaldehyde (Lancaster) (4 g, 0.03 mole) was added in 30 ml THF via syringe and the resulting orange suspension stirred at reflux for 5 h. Water (50 ml) was added, and the organics were extracted with ether (3×50 ml). The combined organics were dried (MgSO4), filtered and evaporated in vacuo to an orange oil which was purified by column chromatography using 15-25% EtOAc in pentane to give the title product (2 g, 45%); 1HNMR (400 MHz, CDCl3) δ: 2.2 (s, 3H), 4.45 (m, 2H), 5.3 (m, 1H), 6.8 (t, 1H), 7.1 (d, 1H), 7.2 (d, 1H); LRMS: M+H, 151. (ES+).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:11]([OH:23])[CH:10]=1)(=[O:4])[NH:2][NH2:3].[CH3:24][C:25]1([CH3:41])[CH2:30][CH:29]([NH:31][C:32](=[O:38])[C:33](OCC)=[O:34])[CH2:28][C:27]([CH3:40])([CH3:39])[NH:26]1>CO>[CH3:24][C:25]1([CH3:41])[CH2:30][CH:29]([NH:31][C:32](=[O:38])[C:33]([NH:3][NH:2][C:1]([O:5][CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:22])[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[C:11]([OH:23])[CH:10]=2)=[O:4])=[O:34])[CH2:28][C:27]([CH3:40])([CH3:39])[NH:26]1
Reactant: NNC(=O)OCCOc1ccc(C(=O)c2ccccc2)c(O)c1
Reactant: CCOC(=O)C(=O)NC1CC(C)(C)NC(C)(C)C1
Solvent: CO
Product: CC1(C)CC(NC(=O)C(=O)NNC(=O)OCCOc2ccc(C(=O)c3ccccc3)c(O)c2)CC(C)(C)N1
Temperature: 70 °C

Procedure:
Into a 100 ml 3-neck flask was added 6.4 grams (0.027 mole) of 2-(3-hydroxy-4-benzoylphenoxy)ethyl carbazate from (A), 8.1 grams (0.027 mole) of a 60% solution of ethyl N-(2,2,6,6-tetramethyl-4-piperidinyl)oxamate and 25 ml of methanol. The flask was equipped with a magnetic stirrer, thermometer and a Dean Stark trap with a reflux condenser. The reaction was heated in an oil bath and the methanol was slowly distilled off through the Dean Stark trap. After the methanol stopped coming over, the reaction was heated one hour, a vacuum was applied to the system to remove any residual methanol and the reaction was heated for another 11/2 hours at 70° C. The reaction was dissolved in 50 ml of hot methanol. The solution was filtered to remove a small amount of insoluble material. The methanol was stripped from the filtrate on a rotating evaporator, leaving 9.4 grams of a yellow crystalline solid. Liquid chromatography indicated the product was about 85-90% pure.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([C@@H:22]([F:24])[CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C:14](=[CH:15][C:16](=[O:25])[CH2:17][CH2:18]1)[C@H:13]1O[C@@H:12]31)(=[O:3])[CH3:2].[ClH:27]>C(O)(=O)C>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:21]([C@@H:22]([F:24])[CH2:23][C@:6]12[CH3:7])[C@:19]1([CH3:20])[C:14](=[CH:15][C:16](=[O:25])[CH2:17][CH2:18]1)[C:13]([Cl:27])=[CH:12]3)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3[C@@H]4O[C@@H]4C4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](F)C[C@]12C
Reactant: Cl
Solvent: CC(=O)O
Product: CC(=O)O[C@H]1CC[C@H]2[C@@H]3C=C(Cl)C4=CC(=O)CC[C@]4(C)[C@H]3[C@@H](F)C[C@]12C
Temperature: 0 °C
Reaction time: 24 h

Procedure:
500 mg. of 17β-acetoxy-6α,7α-epoxy-11β-fluoro-4-androsten-3-one is introduced at room temperature into 25 ml. of glacial acetic acid saturated with gaseous hydrogen chloride. After 24 hours, the solution is poured into ice/water. The thus-precipitated product is vacuum-filtered, taken up in methylene chloride, washed with water, and dried. After recrystallization of the crude product from acetone/hexane, 210 mg. of 17β-acetoxy-6-chloro-11β-fluoro-4,6-androstadien-3-one is obtained. UV: ε283 = 20,300.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]=[CH:5][C:6]1[CH:23]=[CH:22][C:9]2[N:10]([CH2:15][CH2:16][N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C:11]([CH2:13][NH2:14])=[N:12][C:8]=2[CH:7]=1.C(N(CC)C(C)C)(C)C.ClCCl.[CH3:37][C:38]([CH3:43])([CH3:42])[C:39](Cl)=[O:40]>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:24])[CH:4]=[CH:5][C:6]1[CH:23]=[CH:22][C:9]2[N:10]([CH2:15][CH2:16][N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])[C:11]([CH2:13][NH:14][C:39](=[O:40])[C:38]([CH3:43])([CH3:42])[CH3:37])=[N:12][C:8]=2[CH:7]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: CCN(CC)CCn1c(CN)nc2cc(C=CC(=O)OC)ccc21
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCN(CC)CCn1c(CNC(=O)C(C)(C)C)nc2cc(C=CC(=O)OC)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a pre-stirred solution of 3-[2-aminomethyl-1-(2-diethylamino-ethyl)-1H-benzoimidazol-5-yl]-acrylic acid methyl ester (61-6, 0.10 g, 0.23 mmol), N,N-diisopropylethylamine (97 μL, 0.58 mmol) and dichloromethane (1.17 mL) was added 2,2-dimethyl-propionyl chloride (34.6 μL, 0.28 mmol) and the resulting reaction mixture was stirred at room temperature for 1 h. When the reaction has completed, ethyl acetate (20 mL) was added to dilute the mixture. The organic contents were washed with saturated sodium hydrogencarbonate (2×20 mL) and brine (2×20 mL), before drying in Na2SO4. The mixture was filtered and concentrated in vacuo. The product 3-{1-(2-diethylamino-ethyl)-2-[(2,2-dimethyl-propionylamino)-methyl]-1H-benzoimidazol-5-yl}-acrylic acid methyl ester (61-7) was obtained in 76.6% (74.1 mg). LCMS m/z: 415 ([M+H]+).