Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:12][CH:13]=[CH:14][C:15]=1[OH:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]([O:20][CH:21]1[CH:26]([O:27][C:28](=[O:30])[CH3:29])[CH:25]([O:31][C:32](=[O:34])[CH3:33])[CH:24]([CH2:35][O:36][C:37](=[O:39])[CH3:38])[O:23][CH:22]1Br)(=[O:19])[CH3:18].C(=O)([O-])[O-].[K+].[K+].C(=O)(O)[O-].[Na+]>[Cl-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1.ClCCl.O>[C:37]([O:36][CH2:35][CH:24]1[CH:25]([O:31][C:32](=[O:34])[CH3:33])[CH:26]([O:27][C:28](=[O:30])[CH3:29])[CH:21]([O:20][C:17](=[O:19])[CH3:18])[CH:22]([O:16][C:15]2[CH:14]=[CH:13][S:12][C:11]=2[C:9](=[O:10])[NH:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[O:23]1)(=[O:39])[CH3:38]
Reactant: O=C(NCc1ccccc1)c1sccc1O
Reactant: CC(=O)OCC1OC(Br)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: O
Product: CC(=O)OCC1OC(Oc2ccsc2C(=O)NCc2ccccc2)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O
Temperature: 22 °C
Reaction time: 40 h

Procedure:
1.12 g of N-benzyl-3-hydroxy-thiophene-2-carboxamide, 3.16 g of 4,5-diacetoxy-6-acetoxymethyl-2-bromo-tetrahydro-pyran-3-yl acetate, 3.30 g of potassium carbonate and 235 mg of benzyltributylammonium chloride were dissolved in 25 ml of dichloromethane, and 2.00 ml of water were added. The reaction mixture was stirred at 22° C. for 40 h. 50 ml of saturated sodium bicarbonate solution were added to the reaction mixture, which was extracted twice with 50 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate and concentrated. The crude product was purified by column chromatography (SiO2, ethyl acetate/n-heptane=1:1).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=O)[CH3:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[NH2:24][O:25][CH2:26][CH:27]([OH:30])[CH2:28][OH:29].OCC(ON1C(=O)C2C(=CC=CC=2)C1=O)CO>>[OH:30][CH:27]([CH2:28][OH:29])[CH2:26][O:25]/[N:24]=[C:21](/[C:18]1[N:17]=[C:16]2[N:12]([CH2:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)[N:13]=[N:14][C:15]2=[N:20][CH:19]=1)\[CH3:22]
Reactant: CC(=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Reactant: NOCC(O)CO
Agent: O=C1c2ccccc2C(=O)N1OC(CO)CO
Product: C/C(=N\OCC(O)CO)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Yield: 40 %

Procedure:
The title compound was prepared from 1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone (22.4) and (3-(aminooxy)propane-1,2-diol) (intermediate B) in 40% yield using the same procedure as described in the synthesis of example 22 and example 7B. 1H-NMR (400 MHz, CD3OD) δ ppm 9.40 (s, 1H), 8.86 (m, 1H), 8.38 (d, 1H), 8.05 (m, 2H), 7.90 (dd, 1H), 7.57 (dd, 1H), 6.23 (s, 2H), 4.45 (m, 1H), 4.34 (m, 1H), 4.01 (m, 1H), 3.63 (m, 2H), 2.41 (s, 3H). LCMS (method B): [MH]+=394, tR=1.96 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH:16]([CH3:21])[CH2:17][NH:18][CH2:19][CH3:20])[C:11]1[CH:10]=[C:9]([C:22]#[N:23])[CH:8]=[CH:7][C:6]=1[S:5]2.I[CH2:25][CH3:26].C(=O)([O-])[O-].[Na+].[Na+].O>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH:16]([CH3:21])[CH2:17][N:18]([CH2:25][CH3:26])[CH2:19][CH3:20])[C:11]1[CH:10]=[C:9]([C:22]#[N:23])[CH:8]=[CH:7][C:6]=1[S:5]2
Reactant: CCNCC(C)N1c2ccc(Cl)cc2Sc2ccc(C#N)cc21
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCN(CC)CC(C)N1c2ccc(Cl)cc2Sc2ccc(C#N)cc21

Procedure:
A mixture of 7-chloro-10-[(2RS)-1-ethylamino-2-propyl]-2-phenothiazinecarbonitrile (5 g), iodethane (2.2 cc) and sodium carbonate (2 g) in dimethylformamide (50 cc) is charged, and the mixture is brought for 9 hours to 160° C. After cooling, the reaction mixture is poured into a mixture of distilled water (500 cc) and ethyl acetate (500 cc). The organic phase is separated after settling has taken place, washed with distilled water (4×300 cc), dried over magnesium sulphate, filtered and concentrated to dryness at 40° C. under reduced pressure (30 mm Hg; 4 kPa) to give 7-chloro-10-[(2RS)-1-diethylamino-2-propyl]-2-phenothiazinecarbonitrile (5 g).
Reaction SMILES: Br[C:2]1[N:3]([CH3:23])[C:4]([C:13]2[S:14][C:15]3[N:16]=[CH:17][N:18]=[C:19]([NH2:22])[C:20]=3[N:21]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[N:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].CCOC(C)=O>CN(C=O)C>[CH3:23][N:3]1[C:4]([C:13]2[S:14][C:15]3[N:16]=[CH:17][N:18]=[C:19]([NH2:22])[C:20]=3[N:21]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=[C:2]1[C:27]1[CH:28]=[CH:29][N:24]=[CH:25][CH:26]=1
Reactant: Cn1c(Br)nc(-c2ccccc2)c1-c1nc2c(N)ncnc2s1
Reactant: OB(O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1c(-c2ccncc2)nc(-c2ccccc2)c1-c1nc2c(N)ncnc2s1
Temperature: 25 °C
Yield: 30.1 %

Procedure:
2-(2-Bromo-1-methyl-4-phenyl-1H-imidazol-5-yl)[1,3]thiazolo[5,4-d]pyrimidin-7-amine (Example 26) (20 mg), PdCl2dppf (8 mg), pyridine-4-boronic acid (8 mg) and 2M sodium carbonate (2.0 mL) were heated in DMF (2.0 mL) at 100° C. under an inert atmosphere. After 3 hours the reaction mixture was cooled to ambient temperature, EtOAc (25 mL) added then washed with water (15 mL), brine (2×10 mL), dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica eluting with 6% MeOH/DCM gave a dark brown solid which was washed with diethyl ether then dried under high vacuum to give the title compound as light brown solid (6 mg, 31%);
Reaction SMILES: [C:1]([O:4][CH:5]1[C:6]([OH:53])([CH3:52])[CH2:7][CH2:8][CH:9]([O:44][Si:45]([CH2:50][CH3:51])([CH2:48][CH3:49])[CH2:46][CH3:47])[CH2:10][C:11]([O:13][CH:14](/[C:19](/[CH3:43])=[CH:20]/[CH:21]=[CH:22]/[C:23]([OH:42])([CH3:41])[CH2:24][CH:25]2[O:40][CH:26]2[CH:27]([CH3:39])[CH:28]([O:31][Si:32]([CH2:37][CH3:38])([CH2:35][CH3:36])[CH2:33][CH3:34])[CH2:29][CH3:30])[CH:15]([CH3:18])[CH:16]=[CH:17]1)=[O:12])(=[O:3])[CH3:2].[CH2:54]([O:56][CH:57]=[CH2:58])[CH3:55]>ClCCl.C(OCC)(=O)C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[C:1]([O:4][CH:5]1[C:6]([O:53][CH:1]([O:4][CH2:5][CH3:17])[CH3:2])([CH3:52])[CH2:7][CH2:8][CH:9]([O:44][Si:45]([CH2:46][CH3:47])([CH2:48][CH3:49])[CH2:50][CH3:51])[CH2:10][C:11]([O:13][CH:14](/[C:19](/[CH3:43])=[CH:20]/[CH:21]=[CH:22]/[C:23]([O:42][CH:57]([O:56][CH2:54][CH3:55])[CH3:58])([CH3:41])[CH2:24][CH:25]2[O:40][CH:26]2[CH:27]([CH3:39])[CH:28]([O:31][Si:32]([CH2:33][CH3:34])([CH2:35][CH3:36])[CH2:37][CH3:38])[CH2:29][CH3:30])[CH:15]([CH3:18])[CH:16]=[CH:17]1)=[O:12])(=[O:3])[CH3:2]
Reactant: CCC(O[Si](CC)(CC)CC)C(C)C1OC1CC(C)(O)/C=C/C=C(\C)C1OC(=O)CC(O[Si](CC)(CC)CC)CCC(C)(O)C(OC(C)=O)C=CC1C
Reactant: C=COCC
Agent: CCC(O[Si](CC)(CC)CC)C(C)C1OC1CC(C)(O)/C=C/C=C(\C)C1OC(=O)CC(O[Si](CC)(CC)CC)CCC(C)(O)C(OC(C)=O)/C=C/C1C
Agent: CCOC(C)OC(C)(/C=C/C=C(\C)C1OC(=O)CC(O[Si](CC)(CC)CC)CCC(C)(OC(C)OCC)C(OC(C)=O)/C=C/C1C)CC1OC1C(C)C(CC)O[Si](CC)(CC)CC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(C)OC(C)(/C=C/C=C(\C)C1OC(=O)CC(O[Si](CC)(CC)CC)CCC(C)(OC(C)OCC)C(OC(C)=O)C=CC1C)CC1OC1C(C)C(CC)O[Si](CC)(CC)CC
Reaction time: 8 h

Procedure:
To a solution of Compound 129 (8E,12E,14E)-7-acetoxy-6,16-dihydroxy-6,10,12,16,20-pentamethyl-3,21-bis(triethylsiloxy)-18,19-epoxytricosa-8,12,14-trien-11-olide (320 mg, 0.41 mmol) obtained in Example 129 and ethylvinyl ether (589 mg, 8 mmol) in dichloromethane (6 mL) was added a solution of pyridinium p-toluenesulfonate (5 mg, 20 μmol) in dichloromethane (1 mL) at room temperature, and the reaction mixture was stirred at the same temperature overnight. The reaction mixture was diluted with ethyl acetate, washed with water and a saturated aqueous solution of sodium bicarbonate, dried over anhydrous magnesium sulfate and evaporated. The resulting residue was purified by silica gel column chromatography (Kanto silica gel 60N, 40 to 50 μm; ethyl acetate-hexane, 1:9 to 1:7) to give the title compound (252 mg, 67%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9]([CH3:10])=[CH:8][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)=[N:6][C:5]=1[OH:21].[CH3:23]OC(C1C(=O)NC(C2C=CC=C(C(F)(F)F)C=2)=CC=1C)=O.C(=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C=O)C>[CH3:1][O:2][C:3]([C:4]1[C:5](=[O:21])[N:6]([CH3:23])[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:19])[F:20])[CH:12]=2)=[CH:8][C:9]=1[CH3:10])=[O:22]
Reactant: COC(=O)c1c(C)cc(-c2cccc(C(F)(F)F)c2)[nH]c1=O
Reactant: COC(=O)c1c(C)cc(-c2cccc(C(F)(F)F)c2)nc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1c(C)cc(-c2cccc(C(F)(F)F)c2)n(C)c1=O
Temperature: 25 °C
Reaction time: 70 h
Yield: 32.3 %

Procedure:
A solution of 0.62 g (2.0 mmol) of 2-hydroxy-4-methyl-6-(3-trifluoromethyl-phenyl)-nicotinic acid methyl ester/4-methyl-2-oxo-6-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylic acid methyl ester in 20 ml of DMF was treated with 0.78 g (2.4 mmol) of cesium carbonate, followed by 0.62 ml=1.41 g (10.0 mmol) of iodomethane. This mixture was stirred for 70 hours at RT, then poured into crashed ice and extracted twice with CH2Cl2; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (heptane/EtOAc 4:1 to 0:1) to give 0.21 g (33%) of the title compound as light yellow solid; [MS: 326.1 (MH+)] and 0.42 g (65%) of 2-methoxy-4-methyl-6-(3-trifluoromethyl-phenyl)-nicotinic acid methyl ester as light yellow oil. MS: 326.1 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][NH:6][CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[CH3:2].[CH2:23]([O:33][C:34]([NH:36][C:37]1[N:45]=[CH:44][N:43]=[C:42]2[C:38]=1[N:39]=[CH:40][N:41]2[CH2:46][C:47](O)=[O:48])=[O:35])[C:24]1[CH:32]=[CH:31][C:30]2[O:29][CH2:28][O:27][C:26]=2[CH:25]=1>>[CH2:1]([O:3][C:4](=[O:22])[CH2:5][N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]1[S:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1)(=[O:12])=[O:11])[C:47](=[O:48])[CH2:46][N:41]1[CH:40]=[N:39][C:38]2[C:42]1=[N:43][CH:44]=[N:45][C:37]=2[NH:36][C:34]([O:33][CH2:23][C:24]1[CH:32]=[CH:31][C:30]2[O:29][CH2:28][O:27][C:26]=2[CH:25]=1)=[O:35])[CH3:2]
Reactant: CCOC(=O)CNCCNS(=O)(=O)c1nc2ccccc2s1
Reactant: O=C(O)Cn1cnc2c(NC(=O)OCc3ccc4c(c3)OCO4)ncnc21
Product: CCOC(=O)CN(CCNS(=O)(=O)c1nc2ccccc2s1)C(=O)Cn1cnc2c(NC(=O)OCc3ccc4c(c3)OCO4)ncnc21
Yield: 85 %

Procedure:
The title compound (2.96 g, 85%) was synthesized by the reaction of N-[2-(benzothiazole-2-sulfonylamino)-ethyl]-glycine ethyl ester (1.72 g, 5 mmol) and [6-N-(piperonyloxycarbonyl)-adenin-9-yl]-acetic acid (1.86 g, 5 mmol) as per the procedure of Example 20. 1H NMR (500 MHz; DMSO-d6) δ 10.63 (s, 1H), 8.98 (brs, 0.6H), 8.77 (brs, 0.4H), 8.57 (s, 0.4H), 8.52 (s, 0.6H), 8.29 (d, 1H), 8.27 (m, 1H), 8.17 (d, 1H), 7.65 (m, 2H), 7.04 (s, 1H), 6.94 (d, 1H), 6.90 (d, 1H), 6.01 (s, 2H), 5.36 (s, 1.2H), 5.15 (s, 0.8H), 5.10 (s, 2H), 4.45 (s, 0.8H), 4.17 (q, 0.8H), 4.07 (s, 1.2H), 4.01 (q, 1.2H), 3.70 (t, 1.2H), 3.48 (t, 1.2H), 3.41 (t, 0.8H), 3.22 (t, 0.8H), 1.23 (t, 1.2H), 1.12 (t, 1.8H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:8]([CH:9]=[C:10]3[C:15]=1[N:14]=[C:13]([C:16]1[N:17]([C:25]4[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][N:26]=4)[N:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=1)[O:12][C:11]3=[O:32])=[N:7][C:6]([C:33]([F:36])([F:35])[F:34])=[CH:5][CH:4]=2.[CH3:37][NH2:38]>C1COCC1>[CH3:37][NH:38][C:11]([C:10]1[CH:9]=[C:8]2[C:3]([CH:4]=[CH:5][C:6]([C:33]([F:35])([F:34])[F:36])=[N:7]2)=[C:2]([Cl:1])[C:15]=1[NH:14][C:13]([C:16]1[N:17]([C:25]2[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][N:26]=2)[N:18]=[C:19]([C:21]([F:22])([F:24])[F:23])[CH:20]=1)=[O:12])=[O:32]
Reactant: CN
Reactant: O=c1oc(-c2cc(C(F)(F)F)nn2-c2ncccc2Cl)nc2c(Cl)c3ccc(C(F)(F)F)nc3cc12
Solvent: C1CCOC1
Product: CNC(=O)c1cc2nc(C(F)(F)F)ccc2c(Cl)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl

Procedure:
9-Chloro-2-[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-6-trifluoromethyl-3-oxa-1,5-diaza-anthracen-4-one is reacted with methylamine in THF analogously to the procedure given in step i) of example H-18. The title product is obtained as yellow crystals after flash column chromatography eluting with 1:1 hexane:ethyl acetate. m.p.: 235-237° C.
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]4[C:24]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[CH:25][CH:26]=[CH:27][CH:28]=4)=[O:22])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)C=CC=CC=1.[H][H]>CO.[Pd]>[NH:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]3[C:24]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:22])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1
Reactant: O=C(Nc1ccc(C2CCN(Cc3ccccc3)CC2)cc1)c1ccccc1-c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C(Nc1ccc(C2CCNCC2)cc1)c1ccccc1-c1ccccc1
Yield: 94.8 %

Procedure:
A mixture of intermediate (18) (0.145 mol) in methanol (500 ml) was hydrogenated at 50° C. during 48 hours with Pd/C (10%, 3 g) as a catalyst. After uptake of hydrogen (1 equivalent), the catalyst was filtered off and the filtrate was evaporated. The residue was triturated in DIPE. The precipitate was filtered off and dried, yielding 49 g of N-[4-(4-piperidinyl)phenyl]-[1,1′-biphenyl]-2-carboxamide (intermediate 19).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[N+:11]([C:6]1[CH:7]=[CH:8][C:9]2[C:4](=[CH:3][C:2](=[O:10])[N:1]=2)[CH:5]=1)([O-:13])=[O:12]
Reactant: O=C1Cc2ccccc2N1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C1C=c2cc([N+](=O)[O-])ccc2=N1
Yield: 92.4 %

Procedure:
1,3-Dihydro-indol-2-one 30a (20.0 g, 150 mmol) was dissolved in sulfuric acid (100 ml, 98%) in an ice-water bath under stirring, and added dropwise with nitric acid (10 ml, 65%-68%) while maintaining the temperature below 0° C. Upon completion of the addition, the mixture was stirred for 1 hour at 0° C. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was added with ice and filtered after ice-out. The filter cake was washed with water (20 ml×3), and the resulting solid was recrystallized to obtain the title compound 5-nitro-indol-2-one 30b (25.3 g, yield 92.4%) as an orange solid.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[C:16]3[C:11]4[C:12](=[CH:17][CH:18]=[CH:19][C:10]=4[C:9]2=S)[CH:13]=[CH:14][CH:15]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:21]1([CH2:26][CH2:27][CH2:28][NH2:29])[CH:25]=[CH:24][N:23]=[CH:22]1>C(O)C>[C:1]1([CH2:7][N:8]2[C:16]3[C:11]4[C:12](=[CH:17][CH:18]=[CH:19][C:10]=4[C:9]2=[N:29][CH2:28][CH2:27][CH2:26][N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)[CH:13]=[CH:14][CH:15]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: S=C1c2cccc3cccc(c23)N1Cc1ccccc1
Reactant: NCCCn1ccnc1
Solvent: CCO
Product: c1ccc(CN2C(=NCCCn3ccnc3)c3cccc4cccc2c34)cc1
Yield: 66.3 %

Procedure:
A mixture of 3.0 g 1-(phenylmethyl)benz[cd]indole-2(1H)-thione (Cc), 1.34 g of 1H-imidazole-1-propaneamine, 10.0 ml ethyl alcohol, and 3.5 g of mercuric acetate is reacted as described in Example 3, giving 2.6 g of the desired product, mp. 90°-93° C.
Reaction SMILES: [O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([N:19]=[CH:20]C(C)C)[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1.CO.[BH4-].[Li+].Cl.O1[CH2:38][CH2:37][CH2:36][CH2:35]1>O>[O:1]=[S:2]1(=[O:28])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:17](=[O:18])[N:16]([NH:19][CH2:20][CH2:35][CH2:36][CH2:37][CH3:38])[C:15]3[CH:24]=[CH:25][S:26][C:14]=3[C:13]=2[OH:27])=[N:3]1
Reactant: CC(C)C=Nn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Reactant: C1CCOC1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: O
Product: CCCCCNn1c(=O)c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2sccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 269A (0.081 g, 0.19 mmol) in tetrahydrofuran (4 mL) and methanol (0.020 mL, 0.5 mmol) at 0° C. was treated dropwise with a 2.0M solution of lithium borohydride in tetrahydrofuran (0.150 mL, 0.3 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1 M hydrochloric acid to a pH of approximately 2-4, diluted with water (15 mL), and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with 1% methanol in chloroform to give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.88 (t, J=6.99 Hz, 3 H) 1.34 (m, 4 H) 1.53 (m, 2 H) 3.01 (t, J=6.62 Hz, 2 H) 6.64 (s, 1 H) 7.43 (d, J=5.15 Hz, 1 H) 7.55 (t, J=7.72 Hz, 1 H) 7.64 (d, J=8.09 Hz, 1 H) 7.78 (t, J=7.91 Hz, 1 H) 7.93 (d, J=8.09 Hz, 1 H) 8.35 (d, J=5.52 Hz, 1 H) 14.21 (s, 1 H) 14.81 (s, 1 H). MS (ESI−) m/z 431 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][CH2:7][C:8]2[C:9]([C:15]([O:17][CH3:18])=[O:16])=[N+:10]([O-])[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.CN(C=[O:25])C>FC(F)(F)C(OC(=O)C(F)(F)F)=O>[F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][CH2:7][C:8]2[C:9]([C:15]([O:17][CH3:18])=[O:16])=[N:10][C:11]([OH:25])=[CH:12][CH:13]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1c(CCc2ccc(F)cc2)ccc[n+]1[O-]
Reactant: CN(C)C=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COC(=O)c1nc(O)ccc1CCc1ccc(F)cc1

Procedure:
A solution of 3-(4-fluorophenethyl)-2-(methoxycarbonyl)pyridine-1-oxide (7.96 g) in DMF (100 ml) and trifluoroacetic anhydride (40.9 ml) was stirred under an inert atmosphere at ambient temperature for 24 hours. The reaction mixture was concentrated under reduced pressure, diluted with saturated aqueous sodium bicarbonate (150 ml) and extracted with dichloromethane (3×100 ml). The combined organic extracts were dried and concentrated under reduced pressure and the residue purified on a silica flash column eluting with methanol/dichloromethane (1:9) to give methyl 3-(4-fluorophenethyl)-6-hydroxypyridin-2-carboxylate as a cream solid (7.7 g).
Reaction SMILES: [C:1]1([CH2:7][CH:8]([PH:20](=[O:22])[OH:21])[NH:9][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23][CH:24]([CH3:33])[CH2:25][C:26](=[CH2:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28].C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.C(OCC)(=O)C.O>C(#N)C>[OH:22][P:20]([CH2:32][CH:26]([CH2:25][CH:24]([CH3:23])[CH3:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28])([CH:8]([NH:9][C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:21]
Reactant: O=C(NC(Cc1ccccc1)[PH](=O)O)OCc1ccccc1
Reactant: C=C(CC(C)C)C(=O)OCC
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C(CC(C)C)CP(=O)(O)C(Cc1ccccc1)NC(=O)OCc1ccccc1
Yield: 81.3 %

Procedure:
To a solution of 1 g (3.13 mmol) of [2-phenyl-1-[[(phenylmethoxy)carbonyl]amino]ethyl]phosphinic acid synthesized in 1.4., 2.2 g (14.10 mmol) of ethyl 4-methyl-2-methylenepentanoate and 0.52 ml of N,O-bis(trimethylsilyl)acetamide in 0.27 ml of acetonitrile is stirred at a temperature in the region of 20° C. for 24 hours. 60 ml of a 1/1 ethyl acetate/water mixture are added. The aqueous phase is extracted with ethyl acetate and the combined organic phases are washed with water, dried over sodium sulphate, filtered and evaporated under vacuum. The product is purified by recrystallization from a mixture of ethyl acetate and hexane. 1.21 g of product are recovered (yield=81.3%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:15][CH:16]2[CH2:18][O:17]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N-:19]=[N+:20]=[N-:21].[Na+].C(OC)=O.CO>O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH2:15][CH:16]([OH:17])[CH2:18][N:19]=[N+:20]=[N-:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(CCCCCCCOCC2CO2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: COC=O
Solvent: CO
Product: [N-]=[N+]=NCC(O)COCCCCCCCc1ccccc1
Yield: 98.4 %

Procedure:
A procedure similar to that described in Preparation 12 was repeated, except that 1.1 g of 7-phenylheptyloxymethyloxirane (prepared as described in Preparation 67), 1.4 g of sodium azide, 15 ml of methyl formate and 60 ml of an 8:1 by volume mixture of methanol and water were used, to give 1.27 g of the title compound having an Rf value of 0.45 (on silica gel thin layer chromatography, using a 1:3 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:9]1[CH2:15][NH:14][C:13](=S)[C@H:12]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:11][CH2:10]1.[NH2:25][CH2:26][C:27](=O)[C:28]([CH3:31])([CH3:30])[CH3:29].C(N(CC)CC)C>C(O)C.[Hg](Cl)Cl>[C:28]([C:27]1[N:14]2[CH2:15][C@H:9]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=3[F:1])[CH2:10][CH2:11][C@@H:12]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:13]2=[N:25][CH:26]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC(C)(C)C(=O)CN
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CNC1=S
Agent: Cl[Hg]Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(C(C)(C)C)cnc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 119.2 %

Procedure:
Mercury(II) chloride (10 mg, 0.036 mmol) was added to a solution of tert-butyl [(3R,6S)-6-(2,3-difluorophenyl)-2-thioxoazepan-3-yl]carbamate (10 mg, 0.028 mmol), hydrobromide salt of 1-amino-3,3-dimethylbutan-2-one (11 mg, 0.056 mmol), and triethylamine (10 μL, 0.07 mmol) in ethanol (1 mL) at 70° C. After 18 h, the reaction was allowed to cool to ambient temperature. The mixture was filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→95% dichloromethane/methanol) gave the title compound (14 mg). MS 420.2 (M+1).
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[C:14]([O:15][CH3:16])=[C:13]([S:17][CH2:18][CH3:19])[CH:12]=[CH:11][C:5]=1[C:6]([O:8]CC)=[O:7]>O.C(O)C>[Br:3][C:4]1[C:14]([O:15][CH3:16])=[C:13]([S:17][CH2:18][CH3:19])[CH:12]=[CH:11][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)c1ccc(SCC)c(OC)c1Br
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCSc1ccc(C(=O)O)c(Br)c1OC

Procedure:
A solution of potassium hydroxide (1.46 g) in water was added to a mixture of ethyl 2-bromo-4-ethylsulphenyl-3-methoxybenzoate (3.98 g) in ethanol with stirring. The mixture was stirred and heated at reflux for 4 hours. It was cooled and evaporated then water was added and the mixture was washed with ethyl acetate then acidified to pH1. It was extracted with ethyl acetate, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness to give 2-bromo-4-ethylsulphenyl-3-methoxybenzoic acid as an off-white solid NMR (CDCl3) 1.5(t,3H) 3.05(q,2H) 3.9(s,3H) 7.15(d,1H) 7.6(d,1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([CH2:11][N:12]2[C:16]([CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])=[CH:15][C:14]([C:26]([OH:28])=O)=[N:13]2)=[O:10])=[N:6][CH:7]=1.Cl.[CH:30]([N:33]1[CH2:38][CH2:37][CH:36]([NH2:39])[CH2:35][CH2:34]1)([CH3:32])[CH3:31].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1>C(Cl)Cl.CCN(CC)CC>[CH:30]([N:33]1[CH2:38][CH2:37][CH:36]([NH:39][C:26]([C:14]2[CH:15]=[C:16]([CH2:17][O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH3:25])[N:12]([CH2:11][C:9](=[O:10])[NH:8][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=3)[N:13]=2)=[O:28])[CH2:35][CH2:34]1)([CH3:32])[CH3:31]
Reactant: COCCOCCOCc1cc(C(=O)O)nn1CC(=O)Nc1ccc(Cl)cn1
Reactant: CC(C)N1CCC(N)CC1
Agent: Cl
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCOCCOCc1cc(C(=O)NC2CCN(C(C)C)CC2)nn1CC(=O)Nc1ccc(Cl)cn1
Reaction time: 16 h

Procedure:
To 400 mg 1-[(5-Chloro-pyridin-2-ylcarbamoyl)-methyl]-5-[2-(2-methoxy-ethoxy)-ethoxymethyl]-1H-pyrazole-3-carboxylic acid in 5 ml DCM and 0.3 ml NEt3, 217 mg 1-Isopropyl-piperidin-4-ylamine hydrochloride and 250 mg BOP-Cl were added at RT and the rmixture was stirred for 16 h. The mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC (C18 reverse phase column, elution with a H2O/MeCN gradient with 0.1% TFA). The fractions containing the product were evaporated and lyophilized to yield a white solid.