Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCCC1=O.[CH3:18][C:19]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>O>[CH3:18][C:19]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:10][NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:22]
Reactant: Cc1cccc(C(=O)Cl)c1C
Reactant: NNC(=O)c1ccccc1
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cccc(C(=O)NNC(=O)c2ccccc2)c1C
Reaction time: 24 h
Yield: 91 %

Procedure:
First, 9.4 g (69.0 mmol) of benzoylhydrazine and 50 mL of N-methyl-2-pyrrolidinone (NMP) were put into a 300-mL three-neck flask and stiffed under nitrogen flow while being cooled with ice. To this mixed solution, a mixed solution of 13.0 g (77.1 mmol) of 2,3-dimethylbenzoyl chloride and 10 mL of NMP was slowly added dropwise, and the mixture was stiffed at room temperature for 24 hours. After reaction for the predetermined time, this reacted solution was slowly added to 500 mL of water, so that a white solid was precipitated. The precipitated solid was washed by repeating twice ultrasonic cleaning in which water and then 1M hydrochloric acid were used. Then, ultrasonic cleaning using hexane was performed, so that 16.9 g of a white solid of 1-(2,3-dimethylbenzoyl)-2-benzoylhydrazine was obtained in a yield of 91%. A synthesis scheme of Step 1 is shown in (d-1).
Reaction SMILES: [CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:9]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[CH:19])=[CH:14][CH:13]=2)[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C1C=CC=CC=1.[CH2:36]([O:38][C:39](=[O:47])[C:40]1[CH:45]=[CH:44][C:43](I)=[CH:42][CH:41]=1)[CH3:37]>C(N(CC)CC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:20]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]#[C:19][C:43]3[CH:44]=[CH:45][C:40]([C:39]([O:38][CH2:36][CH3:37])=[O:47])=[CH:41][CH:42]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: C#Cc1ccc(C2(N(Cc3ccccc3)Cc3ccccc3)CC2)cc1
Reactant: CCOC(=O)c1ccc(I)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C(O)c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(C3(N(Cc4ccccc4)Cc4ccccc4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Using General Procedure F; dibenzyl-[1-(4-ethynylphenyl)-cyclopropyl]-amine (Intermediate 129, 40.0 mg, 0.12 mmol) and ethyl-4-iodo benzoate (Reagent A, 60.0 mg, 0.22 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (8.0 mg, 0.04 mmol) and sparged with argon for 5 minutes. Dichlorobis (triphenylphosphine)palladium(II) (27 mg, 0.04 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (2-5% EtOAc-hexanes) afforded the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[C:10]1[N:11]([CH3:15])[N:12]=[CH:13][CH:14]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1>C(Cl)Cl>[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([C:10]3[N:11]([CH3:15])[N:12]=[CH:13][CH:14]=3)[CH:5]=2)=[O:25])=[CH:19][CH:18]=1
Reactant: COc1ccc(N)cc1-c1ccnn1C
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(Cl)cc2)cc1-c1ccnn1C
Yield: 81.1 %

Procedure:
4-Methoxy-3-(2-methyl-2H-pyrazol-3-yl)-phenylamine (0.291 g, 1.43 mmol) was treated with 4-chlorophenyl isocyanate (0.247 g, 1.57 mmol, 1.1 equiv.) in CH2Cl2 (5 mL), in a similar manner as described in Example 1.2 to afford Compound 75 (0.415 g, 1.16 mmol, 81%) as a white solid. LCMS m/z (%)=357 (M+H). 1H NMR (400 MHz, acetone-d6) δ: 8.21 (s, 1H), 8.07 (s, 1H), 7.58 (dd, J=2.8, 8.9 Hz, 1H), 7.56 (d, J=8.8 Hz, 2H), 7.44 (d, J=2.7 Hz, 1H), 7.39 (d, J=1.8 Hz, 1H), 7.28 (d, J=8.8 Hz, 2H), 7.08 (d, J=8.9 Hz, 1H), 6.20 (d, J=1.8 Hz, 1H), 3.81 (s, 3H), 3.68 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=2)[CH:7]=1.[C:15]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)#[CH:16]>>[C:11]([C:9]1[CH:10]=[C:5]2[N:4]=[CH:3][C:2]([C:16]#[C:15][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[CH:7][N:6]2[N:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: C#Cc1ccc(F)cc1
Reactant: CC(C)(C)c1cc2ncc(Br)cn2n1
Product: CC(C)(C)c1cc2ncc(C#Cc3ccc(F)cc3)cn2n1

Procedure:
The title compound, light yellow solid, MS: m/e=294.2 (M+H+), can be prepared in accordance with the general method of example 1 from 6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine (example 9, step 1) and 1-ethynyl-4-fluoro-benzene.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][N:6]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:7]1[CH:15]=[C:14]2[C:10]([C:11]([CH2:16][CH3:17])=[N:12][NH:13]2)=[CH:9][C:8]=1[CH3:18])[CH3:2].F[B-](F)(F)F.[CH3:31][O+](C)C>>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][N:6]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:7]1[C:8]([CH3:18])=[CH:9][C:10]2[C:14]([CH:15]=1)=[N:13][N:12]([CH3:31])[C:11]=2[CH2:16][CH3:17])[CH3:2]
Reactant: C[O+](C)C
Reactant: CCOC(=O)CN(CC(=O)OCC)c1cc2[nH]nc(CC)c2cc1C
Agent: F[B-](F)(F)F
Product: CCOC(=O)CN(CC(=O)OCC)c1cc2nn(C)c(CC)c2cc1C
Yield: 33 %

Procedure:
Using the compound (722 mg, 2.08 mmol) of step C, and trimethyloxonium tetrafluoroborate (527 mg, 3.56 mmol), and according to the method of Reference Example 137, step F, the title compound (248 mg, yield 33%) was obtained as a yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:12])([CH3:11])[C:3]1=[CH2:13].[OH:14][C:15]1[CH:27]=[C:26]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[C:18]2[O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:17]=2[C:16]=1[N:34]=O>CO>[CH3:1][N:2]1[C:3]2([CH2:13][NH:34][C:16]3[C:17]4[C:21]5[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=5[O:19][C:18]=4[C:26]([N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:27][C:15]=3[O:14]2)[C:4]([CH3:11])([CH3:12])[C:5]2[C:10]1=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: C=C1N(C)c2ccccc2C1(C)C
Reactant: O=Nc1c(O)cc(N2CCCCC2)c2oc3ccccc3c12
Solvent: CO
Product: CN1c2ccccc2C(C)(C)C12CNc1c(cc(N3CCCCC3)c3oc4ccccc4c13)O2
Reaction time: 41 h

Procedure:
A mixture of 1,3,3-trimethyl-2-methyleneindoline (0.435 g; 0.0025 mol) and 2-hydroxy-1-nitroso-4-piperidinodibenzofuran (0.675 g; 0.0025 mol) in methanol (25.0 ml) was heated under nitrogen and refluxed with stirring for 41 hours. The solution was evaporated to dryness and chromatographed over silica (eluent: dichloromethane) to yield 1,3,3-trimethyl-6'-piperidinospiro[2H-indole 2,3'-[3H]-[2H-[1,4]benzoxazino [6,5-b]benzofuran]] as an amber oil (0.35 g; 32%), which afforded a pale yellow solid upon trituration with diethyl ether, m.pt. 213.5°-216° C.; λmaxAbsorbance 570 nm (Polyurethane). ##STR13##
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9](I)[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:34][C@H:33]([CH3:35])[O:32][C@H:31]([CH3:36])[CH2:30]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1.[CH3:37][N:38]([CH3:45])[C:39]([NH:41][CH2:42][C:43]#[CH:44])=[O:40].CN(C=O)C>C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:10]=[C:9]([C:44]#[C:43][CH2:42][NH:41][C:39](=[O:40])[N:38]([CH3:45])[CH3:37])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:12][C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][CH2:28][N:29]3[CH2:34][C@H:33]([CH3:35])[O:32][C@H:31]([CH3:36])[CH2:30]3)=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1
Reactant: COc1cc2c(Nc3c(Cl)cc(I)c4c3OCO4)ncnc2cc1OCCCN1C[C@@H](C)O[C@@H](C)C1
Reactant: C#CCNC(=O)N(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3c(Cl)cc(C#CCNC(=O)N(C)C)c4c3OCO4)ncnc2cc1OCCCN1C[C@@H](C)O[C@@H](C)C1
Reaction time: 1 h
Yield: 84.4 %

Procedure:
N-(5-Chloro-7-iodo-1,3-benzodioxol-4-yl)-7-[3-(cis-2,6-dimethylmorpholin-4-yl)propoxy]-6-methoxyquinazolin-4-amine (250 mg, 0.40 mmol) and N,N-dimethyl-N′-prop-2-yn-1-ylurea (100 mg, 0.79 mmol) in ethyl acetate (8 ml) stirred at room temperature, under an atmosphere of nitrogen, and treated with bis(triphenylphosphine)palladium(II) dichloride (28 mg, 10 mol %) followed by copper(I) iodide (8 mg, 10 mol %) and diisopropylamnine (81 mg, 0.81 mmol). The reaction was stirred 1 hr then DMF (4 ml) added and the reaction stirred for a further 1 hr. The resulting orange solution was evaporated in vacuo then treated with dilute aqueous sodium bicarbonate solution and extracted with dichloromethane. The extract was dried over magnesium sulphate and evaporated to an orange oil. Purification was by column chromatography on silica using increasing concentrations of methanolic ammonia in dichloromethane as eluent gave the title compound (211 mg, 85%) as a pale orange solid;
Reaction SMILES: C[O:2][C:3]1[CH:17]=[CH:16][C:6]2=[C:7]3[C:12](=[C:13]([NH2:15])[N:14]=[C:5]2[CH:4]=1)[N:11]=[CH:10][CH:9]=[CH:8]3.B(Br)(Br)Br.N#N>C(Cl)Cl>[NH2:15][C:13]1[C:12]2[N:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]2[CH:16]=[CH:17][C:3]([OH:2])=[CH:4][C:5]=2[N:14]=1
Reactant: COc1ccc2c(c1)nc(N)c1ncccc12
Agent: BrB(Br)Br
Agent: N#N
Solvent: ClCCl
Product: Nc1nc2cc(O)ccc2c2cccnc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 8-methoxybenzo[f][1,7]naphthyridin-5-amine (from Example 10) (1.0 eq.) in DCM (0.04 M) was added BBr3 (2.5 eq.) dropwise under N2 at −20° C. The reaction was allowed to warm to ambient temperature over 30 minutes. The reaction was then stirred overnight. The reaction was quenched with saturated NaHCO3 and extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4 and concentrated en vaccuo to obtain a crude residue. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-20% MeOH/DCM to give 5-aminobenzo[f][1,7]naphthyridin-8-ol as a yellow solid: 1H NMR (acetone-d6): δ 8.90 (dd, 1H), 8.83 (dd, 1H), 8.32 (d, 1H), 7.83 (dd, 1H), 7.11 (br s, 2H), 7.10 (d, 1H), 6.96 (dd, 1H), 5.86 (br s, 1H). LRMS [M+H]=212.1.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][C:25]1[N:26]2[CH:35]=[CH:34][N:33]=[C:27]2[S:28][C:29]=1[C:30](O)=[O:31]>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:30]([C:29]2[S:28][C:27]3=[N:33][CH:34]=[CH:35][N:26]3[C:25]=2[CH3:24])=[O:31])=[O:10])[N:12]=1
Reactant: Cc1c(C(=O)O)sc2nccn12
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2sc3nccn3c2C)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 3-Methyl-imidazo[2,1-b]thiazole-2-carboxylic acid. LC-MS (basic): tR=0.82 min; [M+H]+=492.3.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH2:2][CH3:3].[NH2:6][CH2:7][C:8]1[N:12]([CH2:13][N:14]2[CH2:18][CH:17]([C:19]3[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[CH:20]=3)[CH2:16][C:15]2=[O:28])[CH:11]=[N:10][CH:9]=1.CCN(CC)CC>C(Cl)Cl>[O:28]=[C:15]1[CH2:16][CH:17]([C:19]2[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[CH:20]=2)[CH2:18][N:14]1[CH2:13][N:12]1[C:8]([CH2:7][NH:6][C:1](=[O:4])[CH2:2][CH3:3])=[CH:9][N:10]=[CH:11]1
Reactant: NCc1cncn1CN1CC(c2cc(F)c(F)c(F)c2)CC1=O
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)NCc1cncn1CN1CC(c2cc(F)c(F)c(F)c2)CC1=O
Reaction time: 1 h

Procedure:
In a three necked flask, under argon, propionyl chloride (0.0134 ml) is added to a solution of 1-(5-aminomethyl-imidazol-1-ylmethyl)-4-(3,4,5-trifluoro-phenyl)-pyrrolidin-2-one a34 (0.050 g, 0.15 mmol) and Et3N (0.29 ml) in CH2Cl2 (3 ml) at 0° C. After 1 h, the reaction mixture is quenched with ice-water, extracted with CH2Cl2, dried over MgSO4, filtered and evaporated in vacuo. The crude reaction mixture is purified by chromatography on reverse phase silicagel to afford N-[(1-{[2-oxo-4-(3,4,5-trifluorophenyl)pyrrolidin-1-yl]methyl}-1H-imidazol-5-yl)methyl]propanamide 86(37.2 mg).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:39])[C:10]1[CH:15]=[CH:14][C:13](B2OC(C)(C)C(C)(C)O2)=[C:12]([CH2:25][N:26]([CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]([CH:29]2[CH2:31][CH2:30]2)=[O:28])[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:40]([O:42][C:43](=[O:52])[CH2:44][C:45]1[CH:46]=[N:47][CH:48]=[C:49](Br)[CH:50]=1)[CH3:41]>>[CH2:40]([O:42][C:43](=[O:52])[CH2:44][C:45]1[CH:46]=[N:47][CH:48]=[C:49]([C:13]2[CH:14]=[CH:15][C:10]([C:9](=[O:39])[NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:11][C:12]=2[CH2:25][N:26]([CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:27]([CH:29]2[CH2:31][CH2:30]2)=[O:28])[CH:50]=1)[CH3:41]
Reactant: CCOC(=O)Cc1cncc(Br)c1
Reactant: CC1(C)OB(c2ccc(C(=O)NCc3ccccc3)cc2CN(Cc2ccccc2)C(=O)C2CC2)OC1(C)C
Product: CCOC(=O)Cc1cncc(-c2ccc(C(=O)NCc3ccccc3)cc2CN(Cc2ccccc2)C(=O)C2CC2)c1

Procedure:
N-Benzyl-3-[(N-benzyl-N-cyclopropanecarbonyl-amino)-methyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide and (5-bromo-pyridin-3-yl)-acetic acid ethyl ester were reacted as described in Example 3, Step 6 to provide (5-{4-benzylcarbamoyl-2-[(N-benzyl-N-cyclopropanecarbonyl-amino)-methyl]-phenyl}-pyridin-3-yl)-acetic acid ethyl ester.
Reaction SMILES: [CH3:1][N:2](C)C.Cl[C:6]1[N:11]=[C:10]([O:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([NH2:23])=[CH:15][CH:14]=2)[CH:9]=[CH:8][N:7]=1>CN(C)C=O.[C-]#N.C([N+](CC)(CC)CC)C>[NH2:23][C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([O:12][C:10]2[CH:9]=[CH:8][N:7]=[C:6]([C:1]#[N:2])[N:11]=2)=[CH:14][CH:15]=1
Reactant: Nc1ccc(Oc2ccnc(Cl)n2)c2ccccc12
Reactant: CN(C)C
Agent: CC[N+](CC)(CC)CC
Agent: [C-]#N
Solvent: CN(C)C=O
Product: N#Cc1nccc(Oc2ccc(N)c3ccccc23)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
To a 0° C. solution of trimethyl amine (20% solution in water, 3.8 mmol) in 2 mL of dimethylformamide was added 4-(2-chloro-pyrimidin-4-yloxy)-naphthalen-1-ylamine (270 mg, 1 mmol). The deep tan solution was warmed to room temperature for 3 h, during which the initially light suspension became a brown suspension. After this time, tetraethylammonium cyanide (156 mg, 1 mmol) was added all at once to provide a deep amber solution. After 1 h, the reaction was quenched with water, extracted with EtOAc and dried over magnesium sulfate. Column chromatography (10-60% EtOAc-hexanes) provided 142 mg (54%) of 4-(4-amino-naphthalen-1-yloxy)-pyrimidine-2-carbonitrile.
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:20]([CH3:22])([CH2:21][C@@H:2]12)[C@@H:19]1[C@H:8]([C@H:9]2[C@:16]([CH3:24])([CH2:17][C:18]1=[O:23])[C@@H:12]([C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]2)[CH2:7][CH2:6]3.[OH2:25]>C(O)(=O)CC>[OH:25][C@@H:3]1[C@@H:2]([O:1][C:2](=[O:1])[CH2:3][CH3:4])[CH2:21][C@@:20]2([CH3:22])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:19]2[C:18](=[O:23])[CH2:17][C@@:16]2([CH3:24])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:13](=[O:15])[CH3:14])[CH2:4]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3C(=O)C[C@]12C
Reactant: O
Solvent: CCC(=O)O
Product: CCC(=O)O[C@H]1C[C@@]2(C)[C@@H](CC[C@H]3[C@@H]4CC[C@H](C(C)=O)[C@@]4(C)CC(=O)[C@@H]32)C[C@@H]1O

Procedure:
2α,3α-Epoxy-5α-pregnane-11,20-dione (500 mg) was dissolved in propionic acid (10 ml) and the solution heated on a steam bath for 5 hours. The mixture was poured into water (200 ml) and the white precipitate extracted into ether. The ethereal solution was washed with 2N-sodium hydroxide solution until the aqueous layer remained basic, then water and then dried over anhydrous sodium sulphate. The dried solution was evaporated to a white foam (560 mg) which was purified by preparative T.L.C. using ethyl acetate/petrol (2/1). The main band (Rf 0.4-0.5) gave title compound (393 mg.) as a white foam. [α]D + 84.4° (c 1.05).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]([O:15][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[N:21]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[N:20]=[CH:19]3)[C@H:9]([CH2:11][CH:12]([CH3:14])[CH3:13])[NH2:10])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[CH3:39][O:40][CH2:41][C:42](Cl)=[O:43]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:15][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[N:21]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[N:20]=[CH:19]3)[C@@H:9]([NH:10][C:42](=[O:43])[CH2:41][O:40][CH3:39])[CH2:11][CH:12]([CH3:14])[CH3:13])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C[C@H](N)C(Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1cccc(F)c1
Reactant: COCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCC(=O)N[C@@H](CC(C)C)[C@@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1cccc(F)c1
Reaction time: 8 h
Yield: 27.8 %

Procedure:
(αS)-3-Fluoro-β-[[1-(4-fluorophenyl)-1H-indazole-5-yl]oxy]-α-(2-methylpropyl)benzeneethanamine (76.4 mg, 0.18 mmol) is dissolved in 7 mL dichloromethane. Triethylamine (0.06 mL, 0.44 mmol) and 2-methoxyacetyl chloride (0.02 mL, 0.22 mmol) are added. After stirring overnight the reaction mixture is diluted with dichloromethane, washed with water and brine and dried over Na2SO4. After filtration the solvent is evaporated and the residue is purified by chromatography (silicagel, eluents: ethylacetate/hexane). The obtained mixture of the two stereoisomers is separated by HPLC (Chiralpak AD-H 5 μm, eluents: hexane/ethanol) yielding 3.7 mg (10.2%) of the title stereoisomer and 24.7 mg (68%) of the stereoisomer N-{(1S)-1-[(S)-(3-fluorophenyl)-{[1-(4-fluorophenyl)-1H-indazole-5-yl]oxy}methyl}-3-methyl-butyl}-2-methoxyacetamide.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[CH3:12][CH:13]([N:15]([CH:20]([CH3:22])[CH3:21])[CH2:16][CH2:17][CH2:18][SH:19])[CH3:14]>>[CH3:8][C:6]1[CH:7]=[C:2]([S:19][CH2:18][CH2:17][CH2:16][N:15]([CH:20]([CH3:22])[CH3:21])[CH:13]([CH3:12])[CH3:14])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: CC(C)N(CCCS)C(C)C
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Product: Cc1cc(SCCCN(C(C)C)C(C)C)ccc1[N+](=O)[O-]

Procedure:
In a manner similar to Preparation 43 react 5-fluoro-2-nitrotoluene with 3-[bis(1-methylethyl)amino]propanethiol to obtain the tile compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([OH:29])=[O:28])=[C:22]([F:30])[CH:21]=2)[CH:7]=[N:8][C:9]=1[O:10]CC1C=CC(OC)=CC=1)[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4]1[C:9](=[O:10])[NH:8][CH:7]=[C:6]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([OH:29])=[O:28])=[C:22]([F:30])[CH:21]=2)[CH:5]=1)[CH3:2]
Reactant: CCOc1cc(-c2ccc(CC(=O)O)c(F)c2)cnc1OCc1ccc(OC)cc1
Agent: [Pd]
Solvent: CO
Product: CCOc1cc(-c2ccc(CC(=O)O)c(F)c2)c[nH]c1=O
Temperature: 26 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
A suspension of 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)acetic acid (120 mg, 0.292 mmol) in MeOH (10 mL) was added to a solution of Pd/C (31.0 mg, 0.292 mmol) in MeOH (10 mL). The mixture was stirred under a H2 atmosphere at 26° C. for 2 h. Then the solution was filtered and concentrated. The crude material was purified by preparative HPLC (MeCN/H2O as eluants, acidic condition) to yield a light yellow solid of 2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)acetic acid (80 mg, 0.275 mmol, 94.0% yield): 1H NMR (400 MHz, CD3OD) δ 7.14-7.53 (m, 5H), 4.01-4.21 (m, 2H), 3.60-3.68 (m, 2H), 1.46 (s, 3H); ES-LCMS m/z 292.1 (M+H).
Reaction SMILES: Cl[CH:2]1[CH2:6][N:5]([CH2:7][CH3:8])[N:4]([CH2:9][CH3:10])[CH2:3]1.[OH-].[NH4+:12]>>[NH2:12][CH:2]1[CH2:6][N:5]([CH2:7][CH3:8])[N:4]([CH2:9][CH3:10])[CH2:3]1
Reactant: [NH4+]
Reactant: CCN1CC(Cl)CN1CC
Agent: [OH-]
Product: CCN1CC(N)CN1CC

Procedure:
A mixture of 100 g. (0.615 mole) of 4-chloro-1,2-diethylpyrazolidine and 200 ml. of concentrated ammonium hydroxide in a closed steel chamber was heated at 150° C. for approximately 36 hours. The cooled reaction mixture was extracted with isopropyl ether, the aqueous layer saturated with potassium carbonate and continuously extracted with chloroform for six hours. The dried chloroform extract (sodium sulfate) was concentrated at reduced pressure and the residue distilled at 113°-115° C./40 mm. to give 40.5 g. (45.5%) of product.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.CS([C:17]1[S:18][C:19]2[CH:24]=[CH:23][N:22]=[CH:21][C:20]=2[N:25]=1)(=O)=O>ClC(Cl)Cl>[S:18]1[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][C:20]=2[N:25]=[C:17]1[NH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]1
Reactant: CCOC(=O)N1CCC(N)CC1
Reactant: CS(=O)(=O)c1nc2cnccc2s1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCC(Nc2nc3cnccc3s2)CC1
Reaction time: 1 h
Yield: 76 %

Procedure:
A mixture of 8.5 parts of ethyl 4-amino-1-piperidinecarboxylate and 2.6 parts of 2-(methylsulfonyl)thiazolo[4,5-c]pyridine was molten together for 1 hour at 120° C. After cooling, the mixture was taken up in trichloromethane. The whole was washed with water and sodium hydroxide, dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (99:1 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was stirred in warm 2,2'-oxybispropane. The product was filtered off and dried, yielding 2.8 parts (76%) of ethyl 4-[(thiazolo[4,5-c]-pyridin-2-yl)amino]-1-piperidinecarboxylate; mp. 213° C. (66).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[N+:9]([C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=O)([O-:11])=[O:10]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[CH:15][C:14]2[CH:17]=[CH:18][CH:19]=[C:12]([N+:9]([O-:11])=[O:10])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Solvent: CCO
Product: O=[N+]([O-])c1cccc(C=Nc2ccc(Cl)cc2)c1
Temperature: 25 °C
Yield: 92.1 %

Procedure:
A mixture of 4-chloro-phenylamine (6.4 g, 50 mmol) and 3-nitro-benzaldehyde (8.31 g, 55 mmol) in ethanol (100 mL) was prepared. The reaction mixture was heated to reflux for 3 h. Then the reaction mixture cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford (4-chloro-phenyl)-(3-nitro-benzylidene)-amine (12 g, 92%) as a light yellow oil: LC/MS m/e calcd for C13H9ClN2O2 (M+H)+: 261.68, observed: 261.0.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[N:13]1([C:19]2[S:20][C:21]3[C:27](=[O:28])[CH2:26][CH2:25][CH2:24][C:22]=3[N:23]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.CI>C1COCC1>[CH3:1][CH:26]1[CH2:25][CH2:24][C:22]2[N:23]=[C:19]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[S:20][C:21]=2[C:27]1=[O:28]
Reactant: CC(C)NC(C)C
Reactant: O=C1CCCc2nc(N3CCOCC3)sc21
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CC1CCc2nc(N3CCOCC3)sc2C1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 13.4 %

Procedure:
A solution of N,N-diisopropylamine (0.60 g, 0.83 mL, 5.9 mmol) in dry THF (5 mL) was cooled to −78° C. and n-butyllithium (2.36 mL, 2.5M in hexane, 5.9 mmol) was added dropwise. The reaction mixture was allowed to warm to 0° C., stirred for 15 minutes and cooled to −78° C. A suspension of Example 6 (1.4 g, 5.9 mmol) in THF (5 mL) was added slowly. The reaction mixture was warmed to 0° C. and stirred for 10 min at 0° C. before dropwise addition of methyl iodide (0.84 g, 0.37 mL, 5.9 mmol). A solid formed immediately. The reaction mixture was allowed to warm slowly to r.t. The solid was filtered, washed with THF and then purified by column chromatography (SiO2, 1:3 EtOAc/hexane) to give the title compound (0.20 g, 13%) as a white solid. δH (DMSO-d6) 3.70 (4H, t, J 4.9 Hz), 3.54 (4H, t, J 4.9 Hz), 2.80-2.72 (2H, m), 2.55-2.45 (1H, m), 2.15-2.09 (1H, m), 1.82-1.72 (1H, m), 1.10 (3H, d, J 6.9 Hz). LCMS (ES+) 253.0 (M+H)+.