Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=[N:20][OH:21])[C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[CH2:6][N:7]([CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH3:8].[CH3:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][N:24]1[C:29]1[CH:37]=[CH:36][C:32]([C:33]([OH:35])=O)=[CH:31][C:30]=1[C:38]([F:41])([F:40])[F:39]>>[CH3:8][N:7]([CH2:6][C:5]1[CH:17]=[CH:18][CH:19]=[C:3]([C:2]2[N:1]=[C:33]([C:32]3[CH:36]=[CH:37][C:29]([N:24]4[CH2:25][CH2:26][CH2:27][CH2:28][CH:23]4[CH3:22])=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:31]=3)[O:21][N:20]=2)[CH:4]=1)[CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11].[CH3:8][N:7]([CH2:6][C:5]1[CH:17]=[CH:18][CH:19]=[C:3]([C:2]2[N:1]=[C:33]([C:32]3[CH:36]=[CH:37][C:29]([N:24]4[CH2:25][CH2:26][CH2:27][CH2:28][CH:23]4[CH3:22])=[C:30]([C:38]([F:40])([F:39])[F:41])[CH:31]=3)[O:35][N:20]=2)[CH:4]=1)[CH2:9][C:10]([OH:12])=[O:11]
Reactant: CN(CC(=O)OC(C)(C)C)Cc1cccc(C(N)=NO)c1
Reactant: CC1CCCCN1c1ccc(C(=O)O)cc1C(F)(F)F
Product: CC1CCCCN1c1ccc(-c2nc(-c3cccc(CN(C)CC(=O)O)c3)no2)cc1C(F)(F)F
Product: CC1CCCCN1c1ccc(-c2nc(-c3cccc(CN(C)CC(=O)OC(C)(C)C)c3)no2)cc1C(F)(F)F

Procedure:
Tert-butyl N-methyl-N-(3-{5-[4-(2-methylpiperidin-1-yl)-3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}benzyl)glycinate was prepared following the general procedure 7 starting from Intermediate 21 and Intermediate 4. It was hydrolyzed following procedure 8, affording the title compound as a white powder. 1H NMR (DMSO-d6, 300 MHz) δ 8.50-8.37 (m, 2H), 8.32 (br s, 1H), 8.21 (d, J=7.4 Hz, 1H), 7.88 (d, J=8.6 Hz, 1H), 7.82-7.67 (m, 2H), 4.47 (s, 2H), 4.09 (s, 2H), 3.18 (m, 1H), 3.03-2.91 (m, 1H), 2.80 (s, 3H), 2.69-2.57 (m, 1H). 1.89-1.16 (m, 6H), 0.79 (d, J=6.1 Hz, 3H). LC/MS (Method B): 487.4 (M−H)−, 489.4 (M+H)+. HPLC (Method A) Rt 5.10 min (Purity: 100%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([C:13]([F:16])([F:15])[F:14])=[CH:5][C:6](=[O:12])[NH:7]2.C(NC(C)C)(C)C.[Br:24]N1C(=O)CCC1=O.Cl>CCOC(C)=O>[Br:24][C:11]1[C:2]([OH:1])=[C:3]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:12])[CH:5]=[C:4]2[C:13]([F:16])([F:14])[F:15]
Reactant: O=c1cc(C(F)(F)F)c2c(O)cccc2[nH]1
Reactant: O=C1CCC(=O)N1Br
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: O=c1cc(C(F)(F)F)c2c(O)c(Br)ccc2[nH]1
Reaction time: 1 h
Yield: 76.5 %

Procedure:
To a solution of 5-hydroxy-4-(trifluoromethyl)-1H-quinolin-2-one (4.38 g, 19.1 mmol) and diisopropylamine (14 mL, 100 mmol) in 100 mL EtOAc was added a solution of N-bromosuccinimide (3.74 g, 21.0 mmol) in 70 mL EtOAc at −10° C. over 30 min. The reaction mixture was stirred for 1 h, then acidified to pH 1 by the addition of 6M HCl. The mixture was extracted with EtOAc (3×150 mL) and the combined organic layers were washed with brine (200 mL), dried over MgSO4, filtered and concentrated under reduced pressure. Recrystallization from chloroform:hexanes afforded 4.5 g (77%) of 6-bromo-5-hydroxy-4-(trifluoromethyl)-1H-quinolin-2-one, an off-white solid. Rf0.4 (1:1 EtOAc:hexanes); 1H NMR (400 MHz, acetone-d6) δ 11.1 (broad s, 1H), 8.75 (broad s, 1H), 7.76 (d, 1H, J=8.8), 7.04 (d, 1H, J=8.8), 6.98 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]([CH3:30])[C:8](=[O:29])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([CH:22](O)[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[N:11][CH:10]=1.C(N(CC)CC)C.CS([Cl:51])(=O)=O.C1(C)C=CC=CC=1>ClCCl>[F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]([CH3:30])[C:8](=[O:29])[C:9]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])=[CH:13][C:12]([CH:22]([Cl:51])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[N:11][CH:10]=1
Reactant: CCCCCC(O)c1cc(-c2ccccc2C)c(C(=O)N(C)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Reactant: CS(=O)(=O)Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCC(Cl)c1cc(-c2ccccc2C)c(C(=O)N(C)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 83.7 %

Procedure:
A solution of 50 mg (0.090 mmol) (RS)-N-(3,5-bis-trifluoromethyl-benzyl)-6-(1-hydroxy-hexyl)-N-methyl-4-o-tolyl-nicotinamide (Example 77) and 0.032 ml (0.23 mmol) triethylamine in 3 ml dichloromethane was treated with 0.008 ml (0.1 mmol) methanesulfonyl chloride at 0° C. The reaction mixture was stirred at 0° C. for 10 min and then allowed to warm to room temperature. After 1 h 3 ml toluene were added, and the mixture was stirred at 80° C. over night. Cooling to room temperature was followed by dilution with dichloromethane, washing with water, drying with sodium sulfate and concentration. Column chromatography gave 43 mg (83%) of the title compound as a light yellow viscous oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])=[CH:9][N:10]=2)[N:7]=1.Cl.[NH2:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]1.C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[C:14]([C:13]1[CH:12]=[C:11]([C:8]2[N:6]3[N:7]=[C:2]([NH:20][CH:21]4[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23][CH2:22]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)[CH:18]=[CH:17][CH:16]=1)#[N:15]
Reactant: N#Cc1cccc(-c2cnc3ccc(Cl)nn23)c1
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: N#Cc1cccc(-c2cnc3ccc(NC4CCC(O)CC4)nn23)c1
Temperature: 180 °C
Reaction time: 0.75 h
Yield: 28 %

Procedure:
To a solution of 3-(6-chloroimidazo[1,2-b]pyridazin-3-yl)benzonitrile (300 mg, 1.18 mmol) and trans-4-aminocyclohexanol hydrogenchloride (678 mg, 5.89 mmol) in NMP (2.0 mL) was added NaHCO3 (496 mg, 5.89 mmol), the mixture was stirred at 180° C. for 45 mins under microwave irridation. The mixture was purified by flash chromatograph to give 4-((3-(3-cyano phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)cyclohexanol (110 mg, 28%) as a pale yellow solid.
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH:12]1([NH2:15])[CH2:14][CH2:13]1>>[CH:12]1([NH:15][C:1](=[O:10])[C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[OH:4])[CH2:14][CH2:13]1
Reactant: COC(=O)c1ccccc1O
Reactant: NC1CC1
Product: O=C(NC1CC1)c1ccccc1O
Temperature: 90 °C
Yield: 53.3 %

Procedure:
A mixture of of methyl salicylate (4.36 g, 28.69 mmol) and cyclopropylamine (1.64 g) was heated in a sealed tube at 80-100° C. for 3 h. An additional 0.5 g of cyclopropylamine was added and heated at 70° C. overnight. The volatiles were removed in vacuo and the residue was purified by silica gel flash chromatography to give the subtitled compound (2.71 g).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9][NH2:10])=[CH:4][CH:3]=1.[C:17]([N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C:21]1=O)(=[O:19])[CH3:18].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9][NH:10][CH:23]2[CH2:24][CH2:25][N:20]([C:17](=[O:19])[CH3:18])[CH2:21][CH2:22]2)=[CH:4][CH:3]=1
Reactant: CC(=O)N1CCCCC1=O
Reactant: NCc1ccccc1Oc1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(=O)N1CCC(NCc2ccccc2Oc2ccc(Cl)cc2)CC1
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 80.7 %

Procedure:
A solution of 2-(4-chlorophenoxy)benzylamine (AMR01073, 100 mg, 0.428 mmol), 1-acetylpiperidone (121 mg, 0.856 mmol) and acetic acid (0.13 mL, 2.14 mmol) in DCE (2 mL) was treated with NaBH(OAc)3 (227 mg, 1.07 mmol) and stirred under microwave irradiation for 15 min at 100° C. The reaction mixture was diluted with DCM (10 mL) and quenched with saturated NaHCO3 solution. The aqueous layer was washed with DCM (2×20 mL), and the combined organic layers were dried (MgSO4), filtered and evaporated to dryness. Column chromatography on silica gel of the crude product using AcOEt to AcOEt/MeOH 9:1 gradient as eluent gave 1-{4-[2-(4-chlorophenoxy)benzylamino]piperidin-1-yl}ethanone (124 mg, 81%) as a colorless oil. Rf: 0.14 (AcOEt/MeOH 9:1) LC/MS (APCI) tr=4.79 min, m/z 361.46 (35), 359.51 (M++H, 100). HPLC tr=3.04 min (97.37%) 1H NMR (270 MHz, CDCl3) δ 1.25 (2H, m, CH2), 1.68 (br s, NH), 1.79 (2H, m, CH2), 2.05 (3H, S, CH3), 2.67 (2H, m, CH2), 3.02 (1H, m, CH), 3.70 (1H, m, ½CH2), 3.82 (2H, s, CH2), 4.33 (1H, m, ½CH2), 6.84 (2H, AA′BB′, ArH), 6.86 (1H, m, ArH), 7.11 (1H, m, ArH), 7.21 (1H, m, ArH), 7.24 (2H, AA′BB′, ArH) and 7.38 (1H, dd, J=7.2, 1.5 Hz, ArH). 13C NMR (270 MHz, CDCl3) δ 21.10 (CH3), 31.49, 32.32, 39.64, 44.47, 45.05 (CH2), 53.21 (CH), 118.49, 119.04, 124.04, 127.51, 128.30, 129.36, 130.14, 131.02, 153.89, 155.80 (ArC), and 168.42 (C═O).
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:16]=[CH:15][C:8]([C:9]([O:11]C(C)C)=[O:10])=[CH:7][C:6]=1[C:17]([F:20])([F:19])[F:18])[CH3:3].[OH-].[Na+]>C(O)C>[CH3:3][CH:2]([O:4][C:5]1[CH:16]=[CH:15][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[C:17]([F:18])([F:20])[F:19])[CH3:1]
Reactant: CC(C)OC(=O)c1ccc(OC(C)C)c(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Oc1ccc(C(=O)O)cc1C(F)(F)F
Yield: 86.4 %

Procedure:
To a mixture of 1-methylethyl 4-[(1-methylethyl)oxy]-3-(trifluoromethyl)benzoate (Preparation 38) (3.63 g, 12.5 mmol) in ethanol (100 ml) was added aqueous sodium hydroxide (12.5 M, 10.0 ml, 125 mmol) and the reaction heated to reflux for 3 hrs. The mixture was concentrated in vacuo and the residue partitioned between EtOAc (100 ml) and water (100 ml) and acidified with aqueous hydrochloric acid. The aqueous layer was extracted further with EtOAc (100 ml) and the combined organic layers dried and concentrated in vacuo to give the title compound as a yellow solid (2.68 g, 10.8 mmol). MS (ES−): C11H11F3O3 requires 248; found 247 [M−H+].
Reaction SMILES: ICI.[Sn](Cl)(Cl)(Cl)Cl.C(Cl)Cl.[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=O)[CH:20]([F:22])[F:21])=[CH:15][CH:14]=1.[C:24](=O)(O)[O-].[Na+]>C1COCC1.[Zn]>[Br:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([CH:20]([F:22])[F:21])=[CH2:24])=[CH:15][CH:14]=1
Reactant: O=C([O-])O
Reactant: O=C(c1ccc(Br)cc1)C(F)F
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Agent: [Zn]
Solvent: ClCCl
Solvent: ICI
Solvent: C1CCOC1
Product: C=C(c1ccc(Br)cc1)C(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To activated zinc dust (13.3 g, 0.2 mol) in a 1 L flask was added THF (200 mL). Diiodomethane (8.9 mL, 110 mmol) was added dropwise over ˜10 min. The mixture was stirred at room temperature for 30 min. The mixture was cooled with an ice-acetone bath, a solution of tin(iv) chloride 1M in CH2Cl2 (22.1 mL, 22.1 mmol) was added over ˜15 min (needle tip inserted inside the mixture). The mixture was stirred for 15 min and the cooling bath was removed. The mixture was stirred at r.t for 30 min. After cooling back with an ice-acetone bath, a solution of 1-(4-bromophenyl)-2,2-difluoroethanone (5.2 g, 22.12 mmol) in THF (30 mL) was added dropwise over ˜10 min. The cooling bath was removed and the mixture was stirred at room temperature for 30 min. The mixture was then poured portionwise to a mixture of sodium bicarbonate (300 mL, 300 mmol) and hexanes (300 mL) at 0° C. After stirring for 15 min, the mixture was filtered through celite. The organic layer was separated, washed with brine, dried (Na2SO4) and concentrated. Chromatography over silica gel and elution with hexanes: Ethyl acetate (20:1) gave the title compound as a pale yellow liquid.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:19][CH2:18][NH:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>ClCCl>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]3[CH2:19][CH2:18][N:17]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)Cl
Reactant: COc1ccc(C2CCNC2)cc1OC1CCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCC(c2ccc(OC)c(OC3CCCC3)c2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 15.7 %

Procedure:
460 mg of 3-(3-cyclopentyloxy-4-methoxyphenyl) pyrrolidine and 214 mg of triethylamine were dissoved in 15 ml of dichloromethane and cooled in an ice bath. During agitation, 229 mg of ethyl chloroformate was added in drops. After dropping, agitation was continued for 1 hour at a room temperature. Thereafter, the agitated solution was poured into ice water and then extracted with dichloromethane. After organic layers were cleaned by water and dried over magnesium sulfate, it was concentrated under a reduced pressure. The residue was purified by means of the silica gel column chromatography to obtain 92 mg of Compound No. 4 in Table 1.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]([NH2:10])=[S:9].Br[CH2:13][C:14](=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[C:1]1([CH3:11])[C:2]([NH:7][C:8]2[S:9][CH:13]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:10]=2)=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: Cc1ccccc1NC(N)=S
Product: CCOC(=O)c1csc(Nc2ccccc2C)n1

Procedure:
Following a procedure similar to that described in Preparation 42, the desired compound was prepared from 20 g of o-tolylthiourea, 23 g of ethyl bromopyruvate and 200 ml of giving the desired compound as pale yellow prismatic crystals having the following physical properties.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([OH:15])=O)[O:10][C:11]=1[CH3:12].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].CC(OC(N[C@H](C(O)=O)CC1C=CC=CC=1C(F)(F)F)=O)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][N:5]([CH3:16])[C:6]=1[C:7]1[CH:8]=[C:9]([C:13]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)[CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[O:15])[O:10][C:11]=1[CH3:12]
Reactant: N[C@@H](Cc1ccc(F)cc1)CN1C(=O)c2ccccc2C1=O
Reactant: Cc1oc(C(=O)O)cc1-c1c(Cl)cnn1C
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1C(F)(F)F)C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cc1oc(C(=O)N[C@@H](Cc2ccc(F)cc2)CN2C(=O)c3ccccc3C2=O)cc1-c1c(Cl)cnn1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.1 %

Procedure:
To a 50 mL round-bottomed flask was added 4-(4-chloro-1-methyl-1H-pyrazol-5-yl)-5-methyl-2-furancarboxylic acid (248 mg, 0.97 mmol) [prepared according to the procedure of Example 184], 2-[(2S)-2-amino-3-(4-fluorophenyl)propyl]-1H-isoindole-1,3(2H)-dione (321 mg, 0.96 mmol) [prepared according to the procedure of Preparation 6, except substituting N-{[(1,1-dimethylethyl)oxy]carbonyl}-4-fluoro-L-phenylalanine (4.95 g, 17.5 mmol) for N-{[(1,1-dimethylethyl)oxy]carbonyl}-2-(trifluoromethyl)-L-phenylalanine] and PyBrop (557 mg, 1.19 mmol) in chloroform (9.5 mL). DIEA (840 μL, 4.81 mmol) was added and the reaction stirred overnight at room temperature. The mixture was adsorbed onto silica and purified via column chromatography (25-70% EtOAc/Hex) affording the title compound (167 mg, 0.26 mmol, 67%): LC-MS (ES) m/z=521 (M+H)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:9]2[CH2:10][C@@H:11]([CH:18]3[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:20][CH2:19]3)[O:12][C@@H:13]([CH2:14][NH:15]C=O)[C:8]=2[CH:7]=[CH:6][C:5]=1[O:32][CH3:33].[OH-].[Na+]>Cl.CCO.O>[NH2:15][CH2:14][C@H:13]1[C:8]2[CH:7]=[CH:6][C:5]([O:32][CH3:33])=[C:4]([O:3][CH3:2])[C:9]=2[CH2:10][C@@H:11]([CH:18]2[CH2:19][CH2:20][N:21]([CH2:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH2:22][CH2:23]2)[O:12]1
Reactant: COc1ccc2c(c1OC)C[C@@H](C1CCN(CCc3ccccc3)CC1)O[C@H]2CNC=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc2c(c1OC)C[C@@H](C1CCN(CCc3ccccc3)CC1)O[C@H]2CN

Procedure:
A mixture of cis-N-[3,4-dihydro-5,6-dimethoxy-3-[1-(2-phenylethyl)-4-piperidinyl]-1H-2-benzopyran-1-ylmethyl]formamide hydrochloride (4.7 g, 10 mmol) and its free base (2.1 g, 4.7 mmol) was dissolved in 3N HCl (30 ml)-EtOH (30 ml), and refluxed for 2 h. The reaction was diluted with water, and then stirred and cooled in an ice bath, while 50% aqueous NaOH was added dropwise. A white solid separated from solution and this was collected to afford the titled compound. The compound was recrystallized from toluene to afford the amine as a white solid, mp 100-102° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[NH:17][C:16]2=[NH:24])[CH:6]=1)[CH3:2].[Br:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1>CC(=O)CC>[BrH:26].[CH2:1]([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH2:12][CH2:13][CH2:14][N:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[N:17]([CH2:31][C:30]3[CH:33]=[CH:34][C:27]([Br:26])=[CH:28][CH:29]=3)[C:16]2=[NH:24])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc(OCCCn2c(=N)[nH]c3ccccc32)c1
Reactant: BrCc1ccc(Br)cc1
Solvent: CCC(C)=O
Product: Br
Product: CCOC(=O)c1cccc(OCCCn2c(=N)n(Cc3ccc(Br)cc3)c3ccccc32)c1
Temperature: 80 °C
Yield: 72.5 %

Procedure:
To a solution of 3-[3-(2-imino-2,3-dihydro-benzoimidazol-1-yl)-propoxy]-benzoic acid ethyl ester (2.45 g, 7.3 mmol) in 2-butanone (125 ml) was added 4-bromobenzylbromide (2.88 g, 11.7 mmol). The reaction was heated to 80° C. where it was maintained for 24 h. After this time the mixture was cooled to rt and filtered. The collected solids were washed with additional cold 2-butanone and then dried to give 3-{3-[3-(4-bromo-benzyl)-2-imino-2,3-dihydro-benzoimidazol-1-yl]-propoxy}-benzoic acid ethyl ester, hydrobromide salt (2.5 g, 59%). HPLC-MS 508, 510 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:10]([F:13])([F:12])[F:11])=[C:6]([CH:9]=1)[CH2:7]Cl.[CH3:14][CH:15]([CH3:33])[CH2:16][CH2:17][NH:18][C:19]([C:21]1[N:22]=[N:23][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:25][CH:26]=1)=[O:20]>>[CH3:14][CH:15]([CH3:33])[CH2:16][CH2:17][NH:18][C:19]([C:21]1[N:22]=[N:23][C:24]([N:27]2[CH2:32][CH2:31][N:30]([CH2:7][C:6]3[CH:9]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[C:10]([F:13])([F:12])[F:11])[CH2:29][CH2:28]2)=[CH:25][CH:26]=1)=[O:20]
Reactant: Fc1ccc(C(F)(F)F)c(CCl)c1
Reactant: CC(C)CCNC(=O)c1ccc(N2CCNCC2)nn1
Product: CC(C)CCNC(=O)c1ccc(N2CCN(Cc3cc(F)ccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 11, making variations only as required to use 5-fluoro-2-trifluoromethylbenzyl chloride in place of 2-trifluoromethylbenzyl chloride to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl)amide, the title compound was obtained as a white solid (34% yield). 1H NMR (300 MHz, CDCl3) δ 8.02, 7.82-7.92, 7.57-7.68, 7.00-7.09, 6.96, 3.79, 3.71, 3.50, 2.64, 1.64-1.78, 1.51, 0.94. MS (ES+) m/z 454 (M+1).
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:10]([C:11]([O:13]CC)=[O:12])=[CH:9][C:8]([F:16])=[C:7]([N:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)[N:6]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>C1COCC1.O>[CH:1]1([NH:4][C:5]2[C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]([F:16])=[C:7]([N:17]3[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]3)[N:6]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cc(F)c(N2CCN(C)CC2)nc1NC1CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN(c2nc(NC3CC3)c(C(=O)O)cc2F)CC1
Yield: 63.6 %

Procedure:
Following the procedure of Example G-2, the reaction of ethyl 2-cyclopropylamino-5-fluoro-6-(4-methylpiperazinyl)-3-pyridinecarboxylate (Example F-2, 0.86 g, 2.67 mmol) with NaOH (1.40 g, 35 mmol) in THF (5 mL) and water (2 mL) provided 0.50 g of the title compound as a foam.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:15]=1[NH2:16]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:16][C:15]1[CH:17]=[C:18]([C:21]([F:23])([F:24])[F:22])[CH:19]=[CH:20][C:14]=1[O:13][CH3:12])=[O:9]
Reactant: COc1ccc(C(F)(F)F)cc1N
Reactant: O=C(O)c1cc(Br)ccc1O
Product: COc1ccc(C(F)(F)F)cc1NC(=O)c1cc(Br)ccc1O
Yield: 71.3 %

Procedure:
Using 5-bromosalicylic acid and 2-methoxy-5-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][C:13]([CH:25]=[O:26])=[C:14]2Cl)[CH2:6]1)(=[O:3])[CH3:2].[N:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[NH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][C:13]([CH:25]=[O:26])=[C:14]2[N:27]2[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[N:29]=[CH:28]2)[CH2:6]1)(=[O:3])[CH3:2]
Reactant: c1ccc2[nH]cnc2c1
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(Cl)=C(C=O)C[C@@H]32)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(n4cnc5ccccc54)=C(C=O)C[C@@H]32)C1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 88.5 %

Procedure:
A mixture of 3β-Acetoxy-17-chloro-16-formylandrosta-5,16-diene (2, 2.5 g, 6.65 mmol), benzimidazole (2.35 g, 19.9 mmol), and K2CO3 (2.76 g, 23.9 mmol) in dry DMF (20 mL) is stirred at ca. 80° C. under Ar for 1.5 h. After cooling to room temperature, the reaction mixture is poured onto ice-cold water (250 mL) and the resulting precipitate is filtered, washed with water, and dried to give a crude dirty white solid (ca. 2.9 g). Purification by FCC [petroleum ether/EtOAc/Et3N (6:4:0.3)] gives 2.7 g (88.7%) of pure compound 3: mp 227-230° C.; IR (CHCl3) 3691, 3024, 2951, 2359, 1725, 1670, 1604, 1491, 1452, 1375, 1253, 1032, 897, 852, 818, 700, 657, 618, 576, 565, 550, 529, 511, 476 cm−1; 1H NMR (300 MHz, CDCl3) δ 1.07 (s, 6H, 18- and 19-CH3), 2.04 (s, 3H, 3β-OCH3), 4.60 (m, 1H, 3α-H), 5.43 (br s, 1H, 6-H), 7.35 (br. s, 2H, aromatic-Hs), 7.85 (s, 1H, aromatic-H), 7.98 (s, 1H, aromatic-H), 7.98 (s, 1H-21-H) and 9.59 (s, 1H, 16-CHO). HRMS calcd 481.2462 (C29H34O3N2.Na+). found 481.2454.
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21]([NH:23][CH2:24][CH2:25][C:26](=[O:31])[C:27]([O:29]C)=[O:28])=[O:22])[N:4]=1)#[N:2].O.CCOC(C)=O.Cl>CO.[OH-].[Na+]>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:11]=2)[C:6]([OH:20])=[C:5]([C:21]([NH:23][CH2:24][CH2:25][C:26](=[O:31])[C:27]([OH:29])=[O:28])=[O:22])[N:4]=1)#[N:2]
Reactant: COC(=O)C(=O)CCNC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1nc(C(=O)NCCC(=O)C(=O)O)c(O)c2ccc(Oc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl 4-(1-cyano-4-hydroxy-7-phenoxyisoquinoline-3-carboxamido)-2-oxobutanoate (34 mg, 0.08 mmol) was dissolved in MeOH (2 mL) and 2 N NaOH (2 mL). After stirring for 2 hours at room temperature, H2O (15 mL) and EtOAc (15 mL) were added. To the stirred mixture was added 1 N hydrochloric acid until pH was 1. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-20% MeOH/CH2Cl2) to give the title compound in 20 mg. MS: (−) m/z 404.14 (M−1).
Reaction SMILES: [OH:1][C:2]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)([CH2:5][CH3:6])[CH2:3][CH3:4].C([Li])CCC.[C:17](=[O:19])=[O:18]>C1COCC1>[OH:1][C:2]([C:7]1[S:8][C:9]([C:17]([OH:19])=[O:18])=[CH:10][CH:11]=1)([CH2:3][CH3:4])[CH2:5][CH3:6]
Reactant: O=C=O
Reactant: CCC(O)(CC)c1cccs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(O)(CC)c1ccc(C(=O)O)s1
Temperature: 25 °C
Yield: 53 %

Procedure:
To a −78° C. mixture of 2-(3-hydroxy-3-pentyl)thiophene (0.34 g, 2.0 mmol) in THF (2 ml) is added of 1.6 M n-butyllithium in Hex (2.75 ml, 4.4 mmol). The mixture is allowed to warm to RT and powderized dry ice (CO2) is added. After one h, the mixture is partitioned between diethyl ether and 1N NaHCO3. The aqueous layer is washed with ether, acidified with conc. HCl and extracted with ether. The organic layer is Na2SO4 dried, filtered, and concentrated to give the title compound (0.236 g, 53%).