Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([C:11]2[S:12][CH:13]=[CH:14][N:15]=2)[N:3]=1.[CH2:16]([C:18]1[C:22]2=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=[C:21]2[N:20]([NH2:31])[CH:19]=1)[CH3:17].C[N+]1(C2N=C(OC)N=C(OC)N=2)CCOCC1.[Cl-]>CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+]>[CH2:16]([C:18]1[C:22]2=[N:23][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:25][CH:26]=[C:21]2[N:20]([NH:31][C:8]([C:7]2[C:2]([CH3:1])=[N:3][C:4]([C:11]3[S:12][CH:13]=[CH:14][N:15]=3)=[N:5][CH:6]=2)=[O:10])[CH:19]=1)[CH3:17]
Reactant: Cc1nc(-c2nccs2)ncc1C(=O)O
Reactant: CCc1cn(N)c2ccc(C(F)(F)F)nc12
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CCc1cn(NC(=O)c2cnc(-c3nccs3)nc2C)c2ccc(C(F)(F)F)nc12
Temperature: 50 °C
Reaction time: 8 h
Yield: 43.4 %

Procedure:
A solution of 4-methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid (88 mg, 0.40 mmol) and 3-ethyl-5-trifluoromethyl-pyrrolo[3,2-b]pyridin-1-ylamine (89 mg, 0.40 mmol) in DMF (5 mL) is stirred at 50° C. for 1 h. The mixture is treated with DMTMM (113 mg, 0.41 mmol) and stirred at 50° C. overnight. The mixture is diluted with saturated aqueous Na2CO3 (5 mL) and stirred for 10 min. The precipitate is collected by filtration, washed with H2O (50 mL) and heptane (50 mL), and dried in vacuo to afford 4-methyl-2-thiazol-2-yl-pyrimidine-5-carboxylic acid (3-ethyl-5-trifluoromethyl-pyrrolo[3,2-b]pyridin-1-yl)-amide (75 mg, 40%). MS: 433 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 12.19 (s, NH, 1H), 9.28 (s, 1H), 8.15 (m, 2H), 8.08 (d, 1H), 7.87 (s, 1H), 7.72 (d, 1H), 2.83 (q, 2H), 2.77 (s, 3H), 1.35 (t, 3H).
Reaction SMILES: C([O:5][C@H:6]1[CH2:15][CH2:14][CH2:13][C@@H:12]2[C@:7]1([CH3:20])[CH2:8][CH2:9][CH2:10][C@@H:11]2[O:16][C:17](=[O:19])[CH3:18])(C)(C)C.C[Si](I)(C)C.CO>C(Cl)(Cl)(Cl)Cl>[OH:5][C@H:6]1[CH2:15][CH2:14][CH2:13][C@@H:12]2[C@:7]1([CH3:20])[CH2:8][CH2:9][CH2:10][C@@H:11]2[O:16][C:17](=[O:19])[CH3:18]
Reactant: CC(=O)O[C@H]1CCC[C@]2(C)[C@@H](OC(C)(C)C)CCC[C@@H]12
Agent: C[Si](C)(C)I
Solvent: CO
Solvent: ClC(Cl)(Cl)Cl
Product: CC(=O)O[C@H]1CCC[C@]2(C)[C@@H](O)CCC[C@@H]12
Reaction time: 0.25 h
Yield: 88.1 %

Procedure:
A solution of 4.08 g (14.45 mMol) of acetic acid (1S,4aS,5S,8aR)-5-tert-Butoxy-4a-methyl-decahydronaphtalen-1-yl ester in 7.25 ml of carbon tetrachloride is treated dropwise under stirring and argon atmosphere with 2.56 ml (18.8 mMol) of trimethylsilyliodide by keeping room temperature. After the addition is complete, the reaction mixture is stirred for another 30 minutes, then 1.79 ml of methanol are added and the reaction kept for 15 minutes. The reaction mixture is evaporated in vacuo to dryness to yield 5.52 g. The residue is chromatographed over 500 g of silica gel with hexane/ethylacetate 4/1 to give 2.88 g (88%) of pure acetic acid (1S,4aS,5S,8aR)-5-hydroxy-4a-methyl-decahydronaphtalen-1-yl ester.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[C:3]([NH:5][C:6]1[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1[CH:15]([CH3:17])[CH3:16])=[O:4].[CH:19](Br)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>C(#N)C>[CH3:16][CH:15]([C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([CH:12]([CH3:13])[CH3:14])[C:6]=1[NH:5][C:3](=[O:4])[C@@H:2]([NH:1][CH:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:18])[CH3:17]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)[C@H](C)N
Reactant: BrC(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)c1cccc(C(C)C)c1NC(=O)[C@H](C)NC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 57.5 %

Procedure:
A solution of (S)-2-amino-N-[2,6-bis(1-Methylethyl)phenyl]propanamide (5.0 g, 20 mmol), benzhydryl bromide (5.0 g, 20 mmol), and triethylamine (2.8 mL, 20 mmol) in acetonitrile (100 mL) was heated under reflux for 5 hours. The resulting solution was cooled (25° C.) and concentrated in vacuo. The residue was taken up in ethyl acetate (300 mL), washed with water (1×100 mL), washed with saturated sodium bicarbonate (1×100 mL), washed with brine (1×100 mL), then dried (MgSO4) and concentrated in vacuo. The resulting solid was recrystallized from ether/hexane to yield 4.77 g (57.1%) of the title compound as fine white needles, mp 134°-138.5° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(O)CCC>[N+:8]([C:7]1[C:2]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Nc1ccccc1
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cccnc1Nc1ccccc1
Temperature: 25 °C
Yield: 85.3 %

Procedure:
2-chloro-3-nitropyridine (25 g, 158 mmol), aniline (17.62 g, 189 mmol), and triethylamine (19.15 g, 189 mmol) were mixed in 1-butanol (500 mL). The reaction was heated to reflux overnight. After it cooled to room temperature, the solvent was distilled. The residue was purified by column chromatography using hexanes/ethyl acetate to give 3-nitro-N-phenylpyridin-2-amine (29 g, 85% yield).
Reaction SMILES: [OH:1][C@H:2]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:21]2[CH2:20][C@@H:19]([OH:26])[C@@:18]2([CH3:27])[C@@:8]43[O:28][CH:9]4[CH2:10][C@@H:11]2[C:12]2([O:17][CH2:16][CH2:15][O:14]2)[CH3:13])[CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[OH:1][C@H:2]1[CH2:24][CH2:23][C@@:22]2([CH3:25])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:21]2[CH2:20][C@@H:19]([OH:26])[C@@:18]2([CH3:27])[C@:8]3([OH:28])[CH2:9][CH2:10][C@@H:11]2[C:12]2([O:17][CH2:16][CH2:15][O:14]2)[CH3:13])[CH2:3]1
Reactant: CC1([C@H]2CC3O[C@@]34[C@@H]3CC=C5C[C@@H](O)CC[C@]5(C)[C@H]3C[C@@H](O)[C@]24C)OCCO1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC1([C@H]2CC[C@]3(O)[C@@H]4CC=C5C[C@@H](O)CC[C@]5(C)[C@H]4C[C@@H](O)[C@]23C)OCCO1
Yield: 82.7 %

Procedure:
The 14,15-epoxide (24) (300 mg, 0.77 mmol) in dry tetrahydrofuran (10 ml) is added to a suspension of lithium aluminium hydride (300 mg, 7.89 mmol) in tetrahydrofuran and the reaction refluxed for 48 h. After the addition of water (0.3 ml), sodium hydroxide (15% soln, 0.3 ml) and filtration as described earlier, the mixture is purified by silica gel column chromatography using methanol:chloroform (1:9) as solvent to give the trihydroxy pregnene (25) (250 mg, 83%).
Reaction SMILES: Cl.[Cl:2][CH2:3][CH:4]([NH2:9])[CH2:5][CH:6]([CH3:8])[CH3:7].C(N(CC)CC)C.[CH2:17]([O:19][C:20]1[N:21]([CH2:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[C:45]3[NH:49][N:48]=[N:47][N:46]=3)=[CH:35][CH:34]=2)[C:22]2[C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=1)[CH3:18].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[Cl:2][CH2:3][CH:4]([NH:9][C:29]([C:28]1[C:22]2[N:21]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=4[C:45]4[NH:49][N:48]=[N:47][N:46]=4)=[CH:35][CH:34]=3)[C:20]([O:19][CH2:17][CH3:18])=[N:24][C:23]=2[CH:25]=[CH:26][CH:27]=1)=[O:30])[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: CC(C)CC(N)CCl
Reactant: CCOc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1nc2cccc(C(=O)NC(CCl)CC(C)C)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
1-Chloromethyl-3-methylbutylamine hydrochloride (39 mg, 230 μmol) and triethylamine (31.6 μL, 1 equiv) were dissolved in DCM (2.00 mL). 2-Ethoxy-3-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-benzimidazole-4-carboxylic acid (100 mg, 1 equiv) was added, followed by HOBt (31 mg, 1 equiv) and EDC HCl (51 mg, 1.1 equiv). The reaction was stirred overnight at room temperature, then diluted with DCM (10 mL), washed (H2O, 10 mL), dried over NaSO4, decanted, and the solvent evaporated. The residue was purified by flash chromatography (5% MeOH/DCM) to afford the title compound as a white solid (19 mg, 15%). ESMS [M+H]+ calcd for C30H32ClN7O2 557.3. found 558.3.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[N:13]=[C:14]([CH3:24])[S:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:11].Cl[C:26]1[O:27][C:28]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][C:29]=2[N:30]=1.CCN(C(C)C)C(C)C>CC#N>[F:35][C:32]1[CH:33]=[CH:34][C:28]2[O:27][C:26]([NH:1][CH2:2][C@@H:3]3[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]3[C:10]([C:12]3[N:13]=[C:14]([CH3:24])[S:15][C:16]=3[C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)=[O:11])=[N:30][C:29]=2[CH:31]=1
Reactant: Cc1nc(C(=O)N2CCC[C@@H](C)[C@H]2CN)c(-c2ccc(F)cc2)s1
Reactant: Fc1ccc2oc(Cl)nc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1nc(C(=O)N2CCC[C@@H](C)[C@H]2CNc2nc3cc(F)ccc3o2)c(-c2ccc(F)cc2)s1
Temperature: 25 °C

Procedure:
A mixture of ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone (40 mg, 115 μmol), 2-chloro-5-fluorobenzoxazole (24 mg, 138 μmol) and DIPEA (60 μl, 345 μmol) in CH3CN (2 mL) was heated at reflux overnight. The mixture was cooled to rt and the solvent was removed in vacuo. The crude was dissolved in EtOAc and washed with satd. NaHCO3 and brine. The solvent was removed and the crude was purified by reverse-phase preparative HPLC to afford the title compound. MS (ESI) 483 (M+H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][S:9](Cl)(=[O:11])=[O:10].[NH:13]1[CH2:18][CH2:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:29][C@H:28]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])[O:27][C:26]3=[O:35])=[CH:21][CH:20]=2)=[CH:15][CH2:14]1>ClCCl>[CH3:8][S:9]([N:13]1[CH2:18][CH2:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:29][C@H:28]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])[O:27][C:26]3=[O:35])=[CH:21][CH:20]=2)=[CH:15][CH2:14]1)(=[O:11])=[O:10]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3=CCNCC3)cc2)C(=O)O1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=CCN(S(C)(=O)=O)CC3)cc2)C(=O)O1

Procedure:
Triethylamine (253 mg), followed by a solution of methanesulfonyl chloride (69 mg) in dichloromethane (1 ml) was added, with ice-bath cooling, to a stirred suspension of N-((5S)-3-(4-(1,2,5,6-tetrahydropyrid-4-yl)phenyl)-2-oxooxazolidin-5-ylmethyl)acetamide (215 mg, Example 2) in dichloromethane (10 ml). TLC showed complete reaction after 2 hours. The reaction mixture was washed with 2N. HCl, water, saturated sodium hydrogen carbonate and brine. The organic phase was dried over anhydrous sodium sulfate and evaporated to give the title compound as a crystalline solid which was recrystallised from acetonitrile (yield=117 mg, 60%).
Reaction SMILES: OC(C(F)(F)F)=O.[CH:8]([C@:11]1([C:17]([N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][C:23]([C:29]([F:32])([F:31])[F:30])=[CH:24][CH:25]=3)[CH2:20]2)=[O:18])[CH2:15][CH2:14][C@@H:13]([NH2:16])[CH2:12]1)([CH3:10])[CH3:9].[OH:33][C:34]1([C:41]2[S:45][CH:44]=[N:43][CH:42]=2)[CH2:39][CH2:38][C:37](=O)[CH2:36][CH2:35]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C([O-])(O)=O.[Na+]>[CH:8]([C@:11]1([C:17]([N:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][C:23]([C:29]([F:32])([F:30])[F:31])=[CH:24][CH:25]=3)[CH2:20]2)=[O:18])[CH2:15][CH2:14][C@@H:13]([NH:16][CH:37]2[CH2:36][CH2:35][C:34]([C:41]3[S:45][CH:44]=[N:43][CH:42]=3)([OH:33])[CH2:39][CH2:38]2)[CH2:12]1)([CH3:10])[CH3:9]
Reactant: CC(C)[C@]1(C(=O)N2CCc3ccc(C(F)(F)F)cc3C2)CC[C@@H](N)C1
Reactant: O=C1CCC(O)(c2cncs2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)[C@]1(C(=O)N2CCc3ccc(C(F)(F)F)cc3C2)CC[C@@H](NC2CCC(O)(c3cncs3)CC2)C1
Reaction time: 8 h

Procedure:
To a solution of (1R,3S)-3-isopropyl-3-{[7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}cyclopentanamine TFA salt (30.0 mg, 0.0846 mmol) from Step C-2 of Example 1 and 4-hydroxy-4-(1,3-thiazol-5-yl)cyclohexanone (23.4 mg, 0.119 mmol) in dichloromethane (8 mL) was added triethylamine (0.0236 mL, 0.169 mmol) followed by sodium triacetoxyborohydride (42 mg, 0.20 mmol) at room temperature. After being stirred overnight, the mixture was diluted with dichloromethane and neutralized with saturated NaHCO3. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography on silica gel eluting with 5% MeOH/CH2Cl2 to give two isomers. LC-MS for both isomers: calculated for C28H36F3N3O2S (M+H)+536; found 536.2.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:33])[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([C:29]#[N:30])=[CH:27][C:26]([CH:31]=O)=[CH:25][N:24]=2)=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:33])[C:17]1[CH:18]=[CH:19][C:20]([C:23]2[C:28]([C:29]#[N:30])=[CH:27][C:26]([CH2:31][N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[CH:25][N:24]=2)=[CH:21][CH:22]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(-c2ncc(C=O)cc2C#N)cc1
Reactant: C1CCNCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(-c2ncc(CN3CCCCC3)cc2C#N)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.4 %

Procedure:
A solution of N-(2-t-butoxycarbonylaminophenyl)-4-(3-cyano-5-formylpyridin-2-yl)benzamide (400 mg, 0.905 mmol, prepared as described in Method 15) in dichloromethane (5 ml) was added over 20 min to a stirred mixture of piperidine (0.1 ml, 1.00 mmol) sodium triacetoxyborohydride (212 mg, 1.0 mmol), powdered 3A molecular sieve (500 mg) and dichloromethane (15 ml) at −20° C. under nitrogen. The reaction mixture was stirred for 16 hours at ambient temperature before being filtered and washed with saturated aqueous sodium hydrogen carbonate, dried over sodium sulfate and evaporated. The crude product was purified by chromatography on silica eluting with ethyl acetate to afford the title compound as a cream solid (252 mg, 55%); NMR Spectrum: (DMSO-d6) 1.40 (m, 2H), 1.45 (s, 9H), 1.46 (m, 4H), 2.39 (m 4H), 3.58 (s, 2H), 7.17 (m, 2H), 7.56 (m, 2H), 8.01 (d, 2H), 8.12 (d, 2H), 8.31 (d, 1H), 8.69 (s, 1H), 8.87 (d, 1H), 9.94 (s, 1H); Mass Spectrum: M+H+512.
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[C:6]([S:10]([Cl:13])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)=[O:3].[CH3:14][OH:15]>C1COCC1>[CH3:14][O:15][C:2]([C:4]1[CH:5]=[C:6]([S:10]([Cl:13])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)=[O:3]
Reactant: CO
Reactant: O=C(Cl)c1cccc(S(=O)(=O)Cl)c1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(S(=O)(=O)Cl)c1
Temperature: 25 °C
Reaction time: 13 h
Yield: 100 %

Procedure:
To a solution of 3-chlorocarbonylbenzenesulfonyl chloride (5.0 g, 21 mmol) in THF (100 ml) was added methanol 1.7 ml (42 mmol) and the mixture was stirred at room temperature for 13 hours. After the reaction was completed, the resultant was concentrated under reduced pressure to give 5.14 g (21 mmol) of the titled compound as a pale purple solid. Yield: 100%.
Reaction SMILES: Cl[CH:2]([CH3:6])[C:3]([OH:5])=[O:4].[OH-].[Na+].[F:9][C:10]([F:26])([F:25])[C:11]1[CH:24]=[CH:23][C:14]([O:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[CH:13][CH:12]=1.P(=O)(O)(O)O>O.C1(C)C(C)=CC=CC=1>[F:9][C:10]([F:25])([F:26])[C:11]1[CH:24]=[CH:23][C:14]([O:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH:2]([CH3:6])[C:3]([OH:5])=[O:4])=[CH:20][CH:21]=2)=[CH:13][CH:12]=1
Reactant: CC(Cl)C(=O)O
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Agent: O=P(O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1C
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)O
Temperature: 90 °C
Reaction time: 0.25 h

Procedure:
132.5 Parts of 2-chloropropionic acid (98% strength) and 199 parts of 50% sodium hydroxide solution are added simultaneously but separately at 110°-115° C. to a solution of 254 parts of 4-(4'-trifluoromethylphenoxy)-phenol in 1,000 parts of xylene. During the addition, the reaction temperature is maintained by azeotropic distillation of water in a water trap. The addition being complete, stirring is continued for 15 minutes at 110°-115° C., the batch is cooled to 90° C. and after addition of 400 parts of water, it is stirred for a further 10 minutes at 85° C., then acidified at this temperature with 120 parts of phosphoric acid, and stirred for a further 10 minutes. After elimination of the water phase, xylene is distilled off in a water jet vacuum, and the solids are dried at 60° C. and 250 mbar. 326 parts of 2-[4'-(4" -trifluoromethylphenoxy)-phenoxy]-propionic acid are obtained. The content of pure final product is 99.6% corresponding to a yield of 99.6% of theory. The residual content of 4-(4'-trifluoromethyl-phenoxy)-phenol is 0.35%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([NH:13][C:14]2[CH:15]=[C:16]([CH2:20][CH:21]([NH:27][C:28](=[O:37])[CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[Sn](Cl)Cl>>[NH2:1][C:4]1[CH:5]=[C:6]([S:10]([NH:13][C:14]2[CH:15]=[C:16]([CH2:20][CH:21]([NH:27][C:28](=[O:37])[CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:17]=[CH:18][CH:19]=2)(=[O:11])=[O:12])[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)C(Cc1cccc(NS(=O)(=O)c2cccc([N+](=O)[O-])c2)c1)NC(=O)CCc1ccccc1
Agent: Cl[Sn]Cl
Product: CCOC(=O)C(Cc1cccc(NS(=O)(=O)c2cccc(N)c2)c1)NC(=O)CCc1ccccc1

Procedure:
Corresponding to Example 3d, 1.53 g of (6c) were treated with tin-(II) chloride. A yellowish solid was obtained (yield: 1.1 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:17]2[CH2:16][CH2:15][C:14]3[NH:13][N:12]=[CH:11][C:10]=3[C:9]=2[N:8]([CH3:18])[CH:7]=1)=[O:5])[CH3:2].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[C:17]2[C:9](=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][N:12]=[CH:11]3)[N:8]([CH3:18])[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(C)c2c1CCc1[nH]ncc1-2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: CCOC(=O)c1cn(C)c2c1ccc1[nH]ncc12
Reaction time: 2 h

Procedure:
To a mixture of 1-methyl-1,4,5,6-tetrahydro-1,6,7-triaza-as-indacene-3-carboxylic acid ethyl ester A1 (1.65 mmol) in dioxane (45 mL) under argon, DDQ (1.2 eq) was added and the reaction was kept at 100° C. for 2 h. The residue obtained after solvent evaporation was taken up with AcOEt and the organic phase was washed with water, dried (Na2SO4) and concentrated to give a crude product that was purified using the Biotage Horizon system (AcOEt/hexane 2:8). The title product was obtained as a solid (30% yield). ESI (+) MS: m/z 244 (MH+). 1H NMR: 1.34 (t, 3H), 4.13 (s, 3H), 4.28 (q, 2H), 7.40 (d, 1H), 7.96 (s, 1H), 8.00 (d, 1H), 8.41 (s, 1H), 13.28 (bs, 1H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[F:5][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[C:13]1([CH:16]=[C:17]([F:20])[CH2:18][OH:19])[CH2:15][CH2:14]1.C1C=CC=CC=1>N1C=CC=CC=1>[C:1]([O:19][CH2:18][C:17]([F:20])=[CH:16][C:13]1([C:7]2[CH:8]=[CH:9][C:10]([F:12])=[CH:11][C:6]=2[F:5])[CH2:14][CH2:15]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: OCC(F)=CC1(c2ccc(F)cc2F)CC1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC(=O)OCC(F)=CC1(c2ccc(F)cc2F)CC1
Yield: 92 %

Procedure:
The method of Example 17 was repeated using acetyl chloride (0.46 ml), 1-(2,4-difluorophenyl)-1-(2-fluoro-3-hydroxyprop-1-enyl)cyclopropane (Example 15) (0.21 g), benzene (12 ml) and pyridine (0.09 ml) to yield the title compound (0.22 g, 92%).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].Br[CH2:6][C:7]1[CH:11]=[CH:10][S:9][N:8]=1>>[S:9]1[CH:10]=[CH:11][C:7]([CH2:6][NH:3][CH2:2][CH2:1][NH2:4])=[N:8]1
Reactant: NCCN
Reactant: BrCc1ccsn1
Product: NCCNCc1ccsn1

Procedure:
By the procedure of Example 34, ethylenediamine is reacted with 3-bromomethylisothiazole to give N-(3-isothiazolylmethyl)ethylenediamine. This intermediate is heated under reflux with S-methylisothiouronium sulphate in water for 3 hours by the procedure of Example 1 to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][N:9](CC3C=CC(OC)=CC=3)[C:8](=[O:21])[NH:7][C:6]=2[N:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[C:11]2[CH2:10][NH:9][C:8](=[O:21])[NH:7][C:6]=2[N:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(CN2Cc3c(Cl)ccnc3NC2=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C1NCc2c(Cl)ccnc2N1
Temperature: 80 °C
Reaction time: 8 h
Yield: 101.7 %

Procedure:
1 (90 mg, 0.3 mmol) and TFA (2 mL) were added to a 5 mL sealed tube, and stirred overnight at 80° C. The TFA was removed, and the material was suspended in ether. The resulting precipitate was filtered to provide 3 (56 mg, 99% yield). LC-MS (M+H=184, obsd.=184). 1H NMR: (DMSO-D6) δ 4.37 (s, 2H); 7.03(d, 2H); 7.13 (s, 1H); 8.02 (d, 1H); 9.77 (s, 1H).
Reaction SMILES: O[CH2:2][C:3]1[O:7][C:6]([CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=[CH:5][CH:4]=1.S(Cl)([Cl:22])=O>>[Cl:22][CH2:2][C:3]1[O:7][C:6]([CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=[CH:5][CH:4]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(CO)o1
Reactant: O=S(Cl)Cl
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(CCl)o1

Procedure:
2-(5-Hydroxymethyl-2-furanylmethyl)-1H-isoindole-1,3(2H)- dione (10 g) was dissolved in thionyl chloride (15 ml) with the aid of gentle heat. The solution was evaporated to dryness and the solid residue re-evaporated with cyclohexanebenzene (1:1). The residue was suspended in ether, the suspension filtered, washed with ether and dried to give 2-(5-chloromethyl-2-furanylmethyl)-1H-isoindole-1,3(2H)- dione (10.1 g) m.p. 119°-122° (dec.). Analysis Found: C, 61.32; H, 3.71; N, 5.00. C14H10ClNO4 requires: C, 60.99; H, 3.66; N, 5.08%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH2:7][C@H:8]3[N:20]([CH3:21])[CH2:19][CH2:18][C@:14]45[C:15]=2[C:16]=1[O:17][C@H:13]4[C:12](=[O:22])[CH2:11][C@@H:10]([CH3:23])[C@@:9]35[O:24][CH3:25].C([O-])([O-])=O.[Na+].[Na+].[N:32]#CBr>C(Cl)(Cl)Cl>[C:21]([N:20]1[CH2:19][CH2:18][C@:14]23[C:15]4[C:16]5[O:17][C@H:13]2[C:12](=[O:22])[CH2:11][C@@H:10]([CH3:23])[C@@:9]3([O:24][CH3:25])[C@H:8]1[CH2:7][C:6]=4[CH:5]=[CH:4][C:3]=5[O:2][CH3:1])#[N:32]
Reactant: COc1ccc2c3c1O[C@H]1C(=O)C[C@@H](C)[C@@]4(OC)[C@@H](C2)N(C)CC[C@]314
Reactant: N#CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1ccc2c3c1O[C@H]1C(=O)C[C@@H](C)[C@@]4(OC)[C@@H](C2)N(C#N)CC[C@]314
Yield: 97 %

Procedure:
A solution of 3,14-dimethoxy-8α,17-dimethyl-4,5α-epoxymorphinan-6-one (2) (0.89 g, 2.59 mmol) in a mixture of 25 milliliters CHCl3 /25 milliliters CH2Cl2 was treated with anhydrous Na2CO3 (1.6 g, 15.09 mmol), followed by cyanogen bromide (1.6 g, 15.10 mmol). The reaction mixture was refluxed overnight with stirring while being kept under a nitrogen atmosphere. The sodium carbonate was removed by filtration and the filtrate concentrated under reduced pressure to give 0.89 g (97%) of the title compound as a brownish solid. The product, which showed only a single spot on tlc, was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[C:7]1([CH2:12][CH2:11][N:10](C(OCC)=O)[CH2:9][CH2:8]1)[CH2:6]2.Cl>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:19](=[CH:20][CH:21]=1)[C:18](=[O:22])[C:7]1([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)[CH2:6]2
Reactant: CCOC(=O)N1CCC2(CC1)Cc1cc(OC)ccc1C2=O
Agent: Cl
Product: COc1ccc2c(c1)CC1(CCNCC1)C2=O
Yield: 113.3 %

Procedure:
A stirred solution of ethyl 5-methoxy-1-oxo-1,3-dihydrospiro[indene-2,4′-piperidine]-1′-carboxylate (590 mg, 1.95 mmol) in HCl (6.5 mL, 38.9 mmol) was heated at 100° C. overnight. The reaction mixture was concentrated to dryness to give the title compound (511 mg, 2.21 mmol) without any additional purification. MS calculated for C14H17NO2 232.3. found (ESI) m/z 232.4 (M+H)+, retention time 0.90 min.