Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[S:8][CH:9]=[C:10]([Sn](C)(C)C)[N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:16]C1SC=C(Br)N=1.O>N1CCCCC1>[N:1]1([C:7]2[S:8][CH:9]=[C:10]([Br:16])[N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Sn](C)(C)c1csc(N2CCCCC2)n1
Reactant: Brc1csc(Br)n1
Solvent: C1CCNCC1
Solvent: O
Product: Brc1csc(N2CCCCC2)n1
Temperature: 50 °C
Yield: 100 %

Procedure:
Synthesis of 2-Piperidinyl-4-(trimethylstannyl)thiazole 373 as illustrated in FIG. 53. 2,4-Dibromothiazole (358; 1.0 equiv) was dissolved in piperidine (0.5 M) and the reaction was warmed to 50° C. for 8 h, upon which completion of the reaction was indicated by TLC. The mixture was poured into water and extracted with ether (2×). Drying (MgSO4) and evaporation of the solvents gave 2-piperidinyl-4-bromothiazole 372, which was isolated after flash column chromatography (silica gel, 5% EtOAc in hexanes) in 100% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[OH:11][C:12]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[CH:17][C:13]=1[C:14](O)=[O:15].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[CH3:22][O:21][C:19]1[CH:18]=[CH:17][C:13]([C:14]([NH:1][C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[CH:4]=[CH:5][NH:6]3)=[O:15])=[C:12]([OH:11])[CH:20]=1
Reactant: COc1ccc(C(=O)O)c(O)c1
Reactant: Nc1cccc2[nH]ccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Nc2cccc3[nH]ccc23)c(O)c1
Yield: 84.6 %

Procedure:
A mixture of 3.96 g of 4-amino-1H-indole, 70 ml of tetrahydrofuran, 5 g of 2-hydroxy-4-methoxy-benzoic acid and 6.2 g of dicyclohexylcarbodiimide was refluxed for 24 hours and was evaporated to dryness under reduced pressure at 50° C. The residue was taken up in ethyl acetate and excess 4-amino-1H-indole was removed by washing with 2N hydrochloric acid. The mixture was evaporated to dryness under reduced pressure and the residue was taken up in ether and dried at 50° C. to obtain 7.1 g of 4-methoxy-2-hydroxy-N-(1H-indol-4-yl)-benzamide melting at 190° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6]([NH:11][C:12](=[O:35])[CH:13]([CH2:31][C:32]([OH:34])=[O:33])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[N+](=[CH2:38])=[N-]>CCOCC>[CH:1]1[C:10]2[C:5](=[C:6]([NH:11][C:12](=[O:35])[CH:13]([CH2:31][C:32]([O:34][CH3:38])=[O:33])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: C=[N+]=[N-]
Reactant: CCCCCCCCCCCCCCCCCC(CC(=O)O)C(=O)Nc1cccc2cnccc12
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCCC(CC(=O)OC)C(=O)Nc1cccc2cnccc12

Procedure:
Commercially available N-(isoquinolin-5-yl )-2-(carboxymethyl)nonadecanoic amide was esterified with diazomethane in ether to give the title compound.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([CH3:16])([N+:13]([O-])=O)[CH3:12])=[CH:4][C:3]=2[O:2]1.C(O)(=O)C.COCCOC>[H][H].[Pt](=O)=O>[CH3:16][C:11]([NH2:13])([CH3:12])[CH2:10][C:5]1[CH:6]=[CH:7][C:8]2[O:9][CH2:1][O:2][C:3]=2[CH:4]=1
Reactant: CC(C)(Cc1ccc2c(c1)OCO2)[N+](=O)[O-]
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: COCCOC
Solvent: CC(=O)O
Product: CC(C)(N)Cc1ccc2c(c1)OCO2
Yield: 72.2 %

Procedure:
A mixture of 0.8 g of 1-(3,4-methylenedioxyphenyl)-2-methyl-2-nitropropane, 100 mg of platinum dioxide, one ml of acetic acid and 20 ml of 1,2-dimethoxyethane is shaken at 60°-70° C. for 18 hours in hydrogen gas atmosphere under elevated pressure (initial pressure: 80 atmospheric pressures). After the reaction, the insoluble materials are removed by filtration, and the filtrate is evaporated to remove solvent. The residue is dissolved in ethyl acetate, and the solution is extracted with 5% hydrochloric acid. The extract is alkalized with potassium carbonate, and then extracted with ethyl acetate. The extract is washed with a saturated sodium chloride solution, dried and then evaporated to remove solvent. The residue (oil) is distilled at 100°-120° C. (bath temperature) under reduced pressure (0.04 mm Hg). 0.5 g of α,α-dimethyl-3,4-methylenedioxyphenethylamine are thereby obtained as an oil.
Reaction SMILES: [Na].Cl[C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:14][N:15]3[CH:19]=[CH:18][N:17]=[CH:16]3)[CH:9]=2)[N:4]=1.[CH2:20]([OH:23])[CH2:21][CH3:22]>>[N:15]1([CH2:14][C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[N:4]=[C:3]([O:23][CH2:20][CH2:21][CH3:22])[CH:12]=[C:11]3[CH3:13])[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: Cc1cc(Cl)nc2ccc(Cn3ccnc3)cc12
Reactant: CCCO
Agent: [Na]
Product: CCCOc1cc(C)c2cc(Cn3ccnc3)ccc2n1
Reaction time: 2 h
Yield: 31.9 %

Procedure:
To a stirred solution of 2 parts of sodium in 24 parts of 1-propanol was added a solution of 3.2 parts of 2-chloro-6-(1H-imidazol-1-ylmethyl)-4-methylquinoline in 16 parts of 1-propanol at room temperature under nitrogen atmosphere. After stirring for 2 hours at reflux temperature, the mixture was evaporated. The residue was taken up in a potassium carbonate solution and the product was extracted with ethyl acetate. The extract was dried, filtered and evaporated. The residue was purified by column chromatograhpy over silica gel using a mixture of dichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-propanone. The product was filtered off and dried, yielding 1.8 parts (31.9%) of 6-(1H-imidazol-1-ylmethyl)-4-methyl-2-propoxyquinoline; mp. 137.9° C. (compound 35).
Reaction SMILES: [C:1]([C:3]1([CH3:17])[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1)#[CH:2].Br[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1.C(OCC)(=O)C>C(Cl)Cl>[CH3:17][C:3]1([C:1]#[C:2][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH2:8][CH2:7][C:6]2[C:9]([CH3:16])=[C:10]([OH:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C:5]=2[O:4]1
Reactant: C#CC1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Reactant: Brc1cccnc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1c(C)c2c(c(C)c1O)CCC(C)(C#Cc1cccnc1)O2
Reaction time: 18 h

Procedure:
Rac-3,4-dihydro-2-ethynyl-2,5,7,8-tetramethyl-2H-1-benzopyran-6-ol, 4,6g, was reacted as described in Example 4 with 4.74 g of 3-bromopyridine. The reaction time was extended to 18 hours. The product was isolated by chromatography over 150 g of silica gel using 10 % (v/v) of ethyl acetate in methylene chloride for elution. Crystallization of the combined clean fractions from ethyl acetate/hexane gave off-white crystals with m.p. 172°-175° C. The analytical sample was recrystallized from tetrahydrofuran/hexane and had m.p. 175-178° C.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[CH:11]=[C:10]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=3)[CH:9]=[C:8]([C:19]([OH:21])=O)[C:7]=2[C:6]([CH3:22])=[N:5]1)([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:54][CH2:55][C:56]1[C:57](=[O:64])[NH:58][C:59]([CH3:63])=[CH:60][C:61]=1[CH3:62]>C(Cl)Cl>[CH3:62][C:61]1[CH:60]=[C:59]([CH3:63])[NH:58][C:57](=[O:64])[C:56]=1[CH2:55][NH:54][C:19]([C:8]1[C:7]2[C:6]([CH3:22])=[N:5][N:4]([CH:1]([CH3:2])[CH3:3])[C:12]=2[CH:11]=[C:10]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:9]=1)=[O:21]
Reactant: Cc1cc(C)c(CN)c(=O)[nH]1
Reactant: Cc1nn(C(C)C)c2cc(-c3cccnc3)cc(C(=O)O)c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cccnc3)cc3c2c(C)nn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 31 %

Procedure:
To a stirred solution of 1-isopropyl-3-methyl-6-(pyridin-3-yl)-1H-indazole-4-carboxylic acid (0.5 g, 1.69 mmol) in DCM (30 mL) was added EDC.HCl (0.39 g, 2.03 mmol), HOBT (2.74 g, 2.03 mmol) followed by DIPEA (1.47 mL, 8.45 mmol) and stirred at room temperature for 15 min. To the resulting reaction mixture, 3-(amino methyl)-4,6-dimethylpyridin-2(1H)-one (0.257 g, 1.69 mmol) was added and stirred at room temperature for overnight. The reaction mixture was filtered and the precipitate was washed with water followed by ether and dried. The solid compound was further purified by silica gel chromatography (eluent: 10% MeOH in ethyl acetate) to afford the title compound as an off-white solid (225 mg, 31%). 1H NMR (DMSO-d6, 400 MHz): δ 1.461 (d, J=6.4 Hz, 6H), 2.109 (s, 3H), 2.240 (s, 3H), 2.438 (s, 3H), 4.372 (d, J=4.8 Hz, 2H), 5.042-5.107 (m, 1H), 5.870 (s, 1H), 7.410 (s, 1H), 7.501-7.533 (m, 1H), 8.061 (s, 1H), 8.215 (d, J=8 Hz, 1H), 8.461 (t, J=4.8 Hz, 1H), 8.593 (d, J=4.8 Hz, 1H), 9.036 (s, 1H), 11.489 (brs, 1H). LCMS (ES+) m/z: 430.12
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8](=[NH:34])[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]([C@H:19]2[N:23]3[C:24](=[O:33])[C:25]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])=[CH:26][N:27]=[C:22]3[CH2:21][CH2:20]2)=[O:18])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(OC(=O)NC([C:45]1[CH:50]=[CH:49]C(CNC([C@H]2N3C(=O)C(N)=CN=C3CC2)=O)=[CH:47][CH:46]=1)=N)(C)(C)C.C1(S(Cl)(=O)=O)C=CC=CC=1>>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8](=[NH:34])[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]([C@H:19]2[N:23]3[C:24](=[O:33])[C:25]([NH:28][S:29]([C:32]4[CH:49]=[CH:50][CH:45]=[CH:46][CH:47]=4)(=[O:31])=[O:30])=[CH:26][N:27]=[C:22]3[CH2:21][CH2:20]2)=[O:18])=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(NS(C)(=O)=O)c(=O)n32)cc1
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(N)c(=O)n32)cc1
Agent: O=S(=O)(Cl)c1ccccc1
Product: CC(C)(C)OC(=O)NC(=N)c1ccc(CNC(=O)[C@@H]2CCc3ncc(NS(=O)(=O)c4ccccc4)c(=O)n32)cc1
Yield: 80.1 %

Procedure:
Following a procedure similar to that for the preparation of intermediate 16a, intermediate 1j (50 mg, 0.117 mmol) and benzene sulfonyl chloride (22.8 mg, 0.129 mmol) yielded 53.6 mg (80.1%) of intermediate 17a. MS (ESI) 567.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:14])[CH2:12][CH3:13])=[C:4](Cl)[N:3]=1.C(O)CCC.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)(C)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:14])[CH2:12][CH3:13])=[C:4]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:3]=1
Reactant: Nc1ccccc1
Reactant: CCC(C)n1cnc2c(Cl)nc(Cl)nc21
Solvent: CC(C)O
Solvent: CCCCO
Product: CCC(C)n1cnc2c(Nc3ccccc3)nc(Cl)nc21
Reaction time: 22 h

Procedure:
The operation is carried out as in Stage 2 of Example 9 starting from 200 mg of the product obtained in Stage 1 of Example 9 and 4 ml of butanol and using 0.091 ml of aniline in place of the benzylamine. Agitation is carried out at ambient temperature then the reaction medium is taken to a temperature of 80 to 85° C. for approximately 22 hours, left to return to ambient temperature, diluted with 4 ml of isopropanol and placed for two days at a temperature of approximately 0° C., followed by separating, washing with 5 ml of isopropanol and drying at a temperature of approximately 80° C. After purification on silica eluting with methylene chloride/ethyl acetate in a proportion of 90/10, 176 mg of expected product is obtained in the form of white crystals.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5](I)=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.C([O:17][B:18](OC(C)C)[O:19]C(C)C)(C)C.C([Li])CCC.Cl>C1COCC1>[Cl:1][C:2]1[C:11]2[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7][C:6]=2[C:5]([B:18]([OH:19])[OH:17])=[CH:4][N:3]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1ccc2c(I)cnc(Cl)c2n1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc2c(B(O)O)cnc(Cl)c2n1
Temperature: -75 °C
Reaction time: 1 h
Yield: 57.6 %

Procedure:
8-Chloro-5-iodo-2-methyl-[1,7]naphthyridine (Example I) (2.5 g, 8.2 mmol) and triisopropylborate (1.9 ml, 8.2 mmol) were dissolved in 80 ml THF and cooled to −75° C. n-Butyllithium (1.6M in hexane) (5.1 ml, 8.2 mmol) was added drop wise at −70° C. The reaction mixture was stirred for 1 hour at −75° C. and for 1 hour without ice-bath. 10 ml 2N HCl-solution were added and extracted three times with ethyl acetate. The organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was crystallized in acetonitrile to get the desired compound as a red solid (1.05 g, 58%), MS: m/e=221.3 (M−H+).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[S:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1.[CH:14]1[C:23]2[C:18](=[C:19]([CH:24]([CH3:28])[C:25](O)=[O:26])[CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1.C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1>>[CH:14]1[C:23]2[C:18](=[C:19]([CH:24]([CH3:28])[C:25]([NH:9][CH2:8][C:7]3[CH:10]=[CH:11][C:4]([S:3][C:2]([F:12])([F:1])[F:13])=[CH:5][CH:6]=3)=[O:26])[CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1
Reactant: NCc1ccc(SC(F)(F)F)cc1
Reactant: CC(C(=O)O)c1cccc2cnccc12
Agent: O=C(O)Cc1cccc2cnccc12
Product: CC(C(=O)NCc1ccc(SC(F)(F)F)cc1)c1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 222B using 4-[(trifluoromethyl)thio]benzylamine and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 391 (M+H)+; MS (ESI−) m/z 389 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.57 (d, J 7.1, 3H), 4.33 (d, J 6.1, 2H), 4.65 (q, J 7.1, 1H), 7.33 (d, J 8.1, 1H), 7.65 (m, 2H), 7.76 (m, 1H), 7.98 (m, 2H), 8.19 (d, J 7.1, 1H), 8.42 (d, J 7.8, 1H), 8.61 (br s, 1H), 8.62 (d, J 6.8, 1H), 8.73 (d, J 6.8, 1H), 8.96 (t, J 5.8, 1H), 9.86 (s, 1H); Anal. Calcd for C20H17F3N2OS+2.1HCl: C, 51.44; H, 4.12. Found: C, 51.35; H, 3.91.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[OH:12].[CH3:13][OH:14].C[O-].[Na+]>O>[CH3:13][O:14][CH2:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:4]=1[OH:12]
Reactant: O=[N+]([O-])c1ccc(O)c(CCl)c1
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: COCc1cc([N+](=O)[O-])ccc1O

Procedure:
18.7 g (0.1 mol) of 2-chloromethyl-4-nitrophenol and 50 ml of pure methanol were mixed together and refluxed for 2 hours 30 minutes. 37 ml of sodium methoxide (0.2 mol, 5.4 N solution in MeOH) were added and the mixture was refluxed for another 30 minutes. The resulting mixture was cooled in an ice bath and diluted with 350 ml of water, and the insoluble matter formed was filtered off. The filtrate was acidified with acetic acid (10 ml). The crystalline product was filtered off by suction, reslurried in ice-cold water and then dried over P2O5 at 40° C. 11.4 g of crude products were isolated and then recrystallized from 15 ml of isopropyl acetate to give 7.5 g of expected product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:13][OH:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CCN(CC)CC.[S:22](Cl)([CH3:25])(=[O:24])=[O:23]>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:13][O:14][S:22]([CH3:25])(=[O:24])=[O:23])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: OCC1(c2ccc(Br)cc2)CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCC1(c2ccc(Br)cc2)CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a stirred of [1-(4-bromophenyl)-cyclopentyl]-methanol (226) (47.0 g, 184.19 mmol) in dichloromethane (300 mL) was added Et3N (51.3 mL, 368.39 mmol) followed by dropwise addition of mesyl chloride (17.1 mL, 221.03 mmol) at 0° C., and the reaction mixture stirred at room temperature for 1 h. The reaction was quenched by the addition of water, extracted with dichloromethane, washed with water, dried over Na2SO4 and concentrated. The crude product was purified by 100-200 silica column chromatography using 5% ethyl acetate in hexane as the eluent to give methanesulfonic acid 1-(4-bromophenyl)-cyclopentylmethyl ester (227) (52.8 g, 86%) as a white solid.
Reaction SMILES: Cl.[CH2:2]([NH:4][CH2:5][C:6]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:7]=1[OH:13])[CH3:3].Cl[C:15]1[N:16]=[N:17][C:18]([C:21]#[N:22])=[CH:19][CH:20]=1>>[Br:12][C:10]1[CH:9]=[CH:8][C:7]([OH:13])=[C:6]([CH:11]=1)[CH2:5][N:4]([C:15]1[N:16]=[N:17][C:18]([C:21]#[N:22])=[CH:19][CH:20]=1)[CH2:2][CH3:3]
Reactant: CCNCc1cc(Br)ccc1O
Reactant: N#Cc1ccc(Cl)nn1
Agent: Cl
Product: CCN(Cc1cc(Br)ccc1O)c1ccc(C#N)nn1
Yield: 50 %

Procedure:
The title compound was prepared by reacting N-ethyl-5-bromo-2-hydroxybenzylamine hydrochloride and 3-chloro-6-cyanopyridazine using a similar method to that of reference example 18 except eluting with 2% diethyl ether/dichloromethane in the chromatography (yield 50%).
Reaction SMILES: [Br-].[CH3:2][CH:3]([O:7][C:8]1[CH:33]=[CH:32][C:31]([I:34])=[CH:30][C:9]=1[CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:4](=O)[CH3:5].[Na].[CH2:36](OCC)C.O>C(O)C>[I:34][C:31]1[CH:32]=[CH:33][C:8]2[O:7][C:3]([CH3:2])([CH3:36])[C:4]([CH3:5])=[CH:10][C:9]=2[CH:30]=1
Reactant: CC(=O)C(C)Oc1ccc(I)cc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOCC
Agent: [Br-]
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CC1=Cc2cc(I)ccc2OC1(C)C
Yield: 85 %

Procedure:
To a suspension of 2-(1-methyl-2-oxo-propyloxy)-5-iodobenzyltriphenylphosphonium bromide (0.71 g, 0.00108 mol) in absolute ethanol (3 ml) was added dropwise at room temperature a solution of sodium (0.025 g) in absolute ethanol (1 ml). After twelve hours at room temperature, diethyl ether and water were added. The organic phase was separated, dried and evaporated. The residue was chromatographed on silica gel, eluting with a mixture of dichloromethane/heptane (50/50) to give 0.29 g (85%) of 6-iodo-2,2,3-trimethyl-1(2H)-benzopyran, as an oil, 1NMR (CDCl3): δ1.4 (s, 6H), 1.8 (s, 3H), 6.0 (s, 1H), 6.55 (d, 1H), 7.2 (d, 1H), 7.35 (d, 1H).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[O:12][CH:13]=[C:14]([C:16]([OH:18])=O)[N:15]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[NH2:19][C@@H:20]([CH3:36])[CH2:21][N:22]1[CH:26]=[CH:25][C:24]([C:27]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[C:29]([Cl:35])[CH:28]=2)=[N:23]1>>[Cl:35][C:29]1[CH:28]=[C:27]([C:24]2[CH:25]=[CH:26][N:22]([CH2:21][C@@H:20]([NH:19][C:16]([C:14]3[N:15]=[C:11]([CH:8]4[CH2:7][CH2:6][N:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH2:10][CH2:9]4)[O:12][CH:13]=3)=[O:18])[CH3:36])[N:23]=2)[CH:34]=[CH:33][C:30]=1[C:31]#[N:32]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: CS(=O)(=O)N1CCC(c2nc(C(=O)O)co2)CC1
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1coc(C2CCN(S(C)(=O)=O)CC2)n1
Yield: 87 %

Procedure:
(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-2-(1-(methylsulfonyl)piperidin-4-yl)oxazole-4-carboxamide was prepared using the method of Example 34(d) starting from 2-(1-(methylsulfonyl)piperidin-4-yl)oxazole-4-carboxylic acid (0.4 g, 01.458 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.317 g, 01.215 mmol). The product was purified by extracting it from DCM with 0.1 M HCl, 1 M Na2CO3, water and brine. Yield 87%. 1H-NMR (400 MHz; CDCl3): δ 1.25 (d, 3H), 1.97 (m, 2H), 2.15 (m, 2H), 2.83 (s, 3H), 2.89 (m, 3H), 3.81 (m, 2H), 4.30 (dd, 1H), 4.41 (dd, 1H), 4.57 (m, 1H), 6.63 (d, 1H), 7.46 (d, 1H), 7.49 (d, 1H), 7.68 (dd, 1H), 7.79 (dd, 1H), 8.01 (dd, 1H), 8.11 (s, 1H).
Reaction SMILES: [Si]([O:18][C:19]1[CH:55]=[CH:54][C:22]([O:23][CH2:24][C@@H:25]([OH:53])[CH2:26][NH:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][C:33]([NH:36][CH:37]3[CH2:42][CH2:41][N:40]([S:43]([C:46]4[CH:51]=[CH:50][C:49]([CH3:52])=[CH:48][CH:47]=4)(=[O:45])=[O:44])[CH2:39][CH2:38]3)=[CH:32][CH:31]=2)=[CH:21][CH:20]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C(Cl)(Cl)Cl.CO>[OH:53][C@@H:25]([CH2:26][NH:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][CH:37]2[CH2:42][CH2:41][N:40]([S:43]([C:46]3[CH:47]=[CH:48][C:49]([CH3:52])=[CH:50][CH:51]=3)(=[O:45])=[O:44])[CH2:39][CH2:38]2)=[CH:32][CH:31]=1)[CH2:24][O:23][C:22]1[CH:54]=[CH:55][C:19]([OH:18])=[CH:20][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)cc4)cc3)CC2)cc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1ccc(S(=O)(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)cc1
Yield: 38.3 %

Procedure:
(2S)-1-(4-{[tert-Butyl(diphenyl)silyl]oxy}phenoxy)-3-{[4-({1-[(4-methylphenyl)sulfonyl]-4-piperidinyl}amino)phenethyl]amino}-2-propanol (0.130 g, 0.167 mmol) was reacted according to Procedure H (eluant: 5:1 chloroform-methanol) to give the title compound (0.035 g, 0.064 mmol).
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[CH:13]=2)[C:8]2[CH:7]=[C:6]([C:20]#[C:21][C:22]3[CH:32]=[CH:31][C:25]([C:26]([O:28]CC)=[O:27])=[CH:24][CH:23]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+].Cl>CCO.C1COCC1>[CH3:1][C:2]1([CH3:33])[CH2:11][CH:10]=[C:9]([C:12]2[CH:13]=[C:14]([CH3:19])[CH:15]=[C:16]([CH3:18])[CH:17]=2)[C:8]2[CH:7]=[C:6]([C:20]#[C:21][C:22]3[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:31][CH:32]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2cc(C)cc(C)c2)=CCC3(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1cc(C)cc(C2=CCC(C)(C)c3ccc(C#Cc4ccc(C(=O)O)cc4)cc32)c1
Temperature: 50 °C

Procedure:
To a solution of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(3,5-dimethylphenyl)-2-naphthalenyl)ethynyl]-benzoate (Compound 4) 90.0 mg (0.207 mmol) in 3 ml of EtOH and 2 ml of THF was added 48.0 mg (1.20 mmol, 1.20 ml) of NaOH (1.0M aqueous solution). The solution was heated to 50° C. for 2 hours, cooled to room temperature, and acidified with 10% HCl. Extraction with EtOAc, followed by drying over Na2SO4, and removal of the solvents under reduced pressure afforded the title compound as a colorless solid. 1H NMR (DMSO): δ 7.90 (2H, d, J=8.2 Hz), 7.59 (2H, d, J=8.2 Hz), 7.45 (2H, s), 7.00 (1H, s), 6.97 (1H, s), 5.97 (1H, t, J=4.5 Hz), 2.31 (2H, d, J=4.5 Hz), 2.30 (6H, s), 1.29 (6H, s).
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@@:5]3([CH3:27])[CH:9]([CH:10]4[CH2:11][C@H:12]([F:21])[C:13]5[C@@:18]([CH3:19])([C@:2]124)[CH:17]=[CH:16][C:15](=[O:20])[CH:14]=5)[CH2:8][C@@H:7]([CH3:22])[C@:6]3([OH:26])[C:23]([OH:25])=[O:24].[O:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[C:33](Cl)=[O:34].Cl.C(Cl)Cl>N1C=CC=CC=1>[O:1]1[C@H:3]2[CH2:4][C@@:5]3([CH3:27])[CH:9]([CH:10]4[CH2:11][C@H:12]([F:21])[C:13]5[C@@:18]([CH3:19])([C@:2]124)[CH:17]=[CH:16][C:15](=[O:20])[CH:14]=5)[CH2:8][C@@H:7]([CH3:22])[C@:6]3([O:26][C:33]([C:29]1[O:28][CH:32]=[CH:31][CH:30]=1)=[O:34])[C:23]([OH:25])=[O:24]
Reactant: O=C(Cl)c1ccco1
Reactant: C[C@@H]1CC2C3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]34O[C@H]4C[C@]2(C)[C@@]1(O)C(=O)O
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: C[C@@H]1CC2C3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]34O[C@H]4C[C@]2(C)[C@@]1(OC(=O)c1ccco1)C(=O)O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(6S,9S,10S,11S,13S,16R,17R)-9,11-Epoxy-6-fluoro-17-hydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-17-carboxylic acid (5 g) is dissolved in pyridine (15 mL) and cooled to 0° C. 2-Furoyl chloride (1.82 g) is added and the reaction mixture is stirred at room temperature. After 2 hours, the reaction mixture is added dropwise to a vigorously stirred solution of 6M HCl. DCM is added, the phases are separated and the organic phase is washed with water and brine. After drying over magnesium sulphate, evaporation affords furan-2-carboxylic acid (6S,9S,10S,11S,13S,16R,17R)-9,11-epoxy-6-fluoro-17-carboxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl ester. Selected 1H-NMR signals (CDCl3) δ 6.30 (1H, dd), 6.5 (2H, m), 6.55 (1H, d), 7.20-7.65 (m, 2H).
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:11].[Br:12][CH2:13][CH2:14][CH2:15][CH2:16]Br>>[Br:12][CH2:13][CH2:14][CH2:15][CH2:16][N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=[O:11]
Reactant: BrCCCCBr
Reactant: O=C1CCc2ccccc2N1
Product: O=C1CCc2ccccc2N1CCCCBr

Procedure:
from 3,4-dihydroquinolin-2(1H)-one and 1,4-dibromobutane