Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:42]=[CH:41][N:40]2[N:43]=[CH:44][N:45]=[C:39]2[CH:38]=1>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[CH:42]=[CH:41][N:40]4[N:43]=[CH:44][N:45]=[C:39]4[CH:38]=3)=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: Brc1ccn2ncnc2c1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccn3ncnc3c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Yield: 68 %

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-3-{(S)-1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-ethyl}-[1,3]oxazinan-2-one and 7-bromo-[1,2,4]triazolo[1,5-a]pyridine following a procedure analogous to that described in EXAMPLE 7. Yield: 68% of theory; Mass spectrum (ESI+): m/z=471 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 0.82 (s, 3H), 1.19 (s, 3H), 1.49 (d, J=7.1 Hz, 3H), 2.03 (s, 2H), 2.14-2.23 (m, 1H), 2.39-ca. 2.55 (m, 2H) superimposed on DMSO-d5, 3.01-3.09 (m, 1H), 4.23 (s, 1H), 5.46 (q, J=7.1 Hz, 1H), 7.02 (dm, J=8.3 Hz, 2H), 7.27-7.41 (m, 5H), 7.46 (dm, J=7.2, 1.8 Hz, 1H), 7.62 (dm, J=8.3 Hz, 2H), 8.06 (hardly resolved d, 1H), 8.52 (s, 1H), 8.98 (d, J=7.2 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][C:6]=1[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[Cl:15]N1C(=O)CCC1=O>ClCCl>[NH2:1][C:2]1[S:3][C:4]([Cl:15])=[CH:5][C:6]=1[C:7]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:8]
Reactant: Nc1sccc1C(=O)c1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: Nc1sc(Cl)cc1C(=O)c1ccccc1
Yield: 34.3 %

Procedure:
To a stirred solution of 0.1 g (0.49 mmol) (2-amino-thiophen-3-yl)-phenyl-methanone (the preparation of which is described in example 20) in 10 ml dichloromethane at 0° C. was added 68 mg (0.49 mmol) N-chloro-succinimide (NCS). The mixture was then stirred from 0° C. to RT over night, and then poured onto water and extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (heptane/ethyl acetate 3:1) afforded 40 mg (34%) (2-amino-5-chloro-thiophen-3-yl)-phenyl-methanone as a yellow solid.
Reaction SMILES: [CH:1]1([N:7]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16]C#N)=[CH:14][N:15]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.SC[C@@H]([C@@H](CS)O)O.[CH2:33]([N:35]([CH2:39][CH3:40])[CH2:36][CH2:37]S)[CH3:34]>>[CH:1]1([N:7]([CH:19]2[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)[C:8]([NH:10][C:11]2[S:12][C:13]([S:16][CH2:34][CH2:33][N:35]([CH2:39][CH3:40])[CH2:36][CH3:37])=[CH:14][N:15]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: N#CSc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1
Reactant: CCN(CC)CCS
Agent: O[C@H](CS)[C@@H](O)CS
Product: CCN(CC)CCSc1cnc(NC(=O)N(C2CCCCC2)C2CCCCC2)s1

Procedure:
Prepared as described in general procedure (H) using 1,1-dicyclohexyl-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritol and 2-diethylamino-ethanethiol
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:33])[N:10]([CH2:31][CH3:32])[CH2:11][C:12]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=1B1OC(C)(C)C(C)(C)O1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][O:35][C:36](=[O:46])[CH2:37][C:38]1[CH:43]=[C:42](Br)[CH:41]=[CH:40][C:39]=1[F:45]>>[CH3:34][O:35][C:36](=[O:46])[CH2:37][C:38]1[CH:43]=[C:42]([C:13]2[CH:14]=[CH:15][C:16]([C:18]([F:20])([F:19])[F:21])=[CH:17][C:12]=2[CH2:11][N:10]([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:33])[CH2:31][CH3:32])[CH:41]=[CH:40][C:39]=1[F:45]
Reactant: COC(=O)Cc1cc(Br)ccc1F
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)OCc1ccccc1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1ccc(F)c(CC(=O)OC)c1)C(=O)OCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: ethyl-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-carbamic acid benzyl ester and (5-bromo-2-fluoro-phenyl)-acetic acid methyl ester.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([N+:11]([O-])=O)=[CH:8][CH:9]=2)[CH:4]=[N:3]1.[OH-].[Na+]>Cl.[Fe]>[NH2:11][C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:2]([CH3:1])[N:3]=[CH:4]2
Reactant: Cn1ncc2cc([N+](=O)[O-])ccc21
Agent: [Fe]
Agent: Cl
Agent: [Na+]
Product: Cn1ncc2cc(N)ccc21
Temperature: 72.5 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 1-methyl-5-nitroindazole (3.24 g, commercially available) in concentrated hydrochloric acid (75 ml) was added iron powder (3.53 g) in portions over 10 minutes, allowing the reaction temperature to gradually rise to 52° C. On complete addition, the reaction mixture was heated to 70-75° C. for 1 hour, cooled to ambient temperature and stored for 18 hours. The mixture was chilled by the addition of ice then taken to pH 9 with aqueous sodium hydroxide filtered and the filtrate and insoluble solids extracted with ethyl acetate (three times). The extracts were combined, washed with brine and dried over magnesium sulphate then evaporated under reduced pressure to give 5-amino-1-methylindazole as a pale brown solid.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]([O:23][C:24]([N:26]1[C:34]2[C:29](=[CH:30][C:31]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:32][CH:33]=2)[C:28]([C:43]2[N:44]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[C:45]3[C:50]([CH:51]=2)=[CH:49][C:48]([O:52][SiH2]C(C)(C)C)=[CH:47][CH:46]=3)=[N:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>O1CCCC1>[C:19]([O:23][C:24]([N:26]1[C:34]2[C:29](=[CH:30][C:31]([O:35][CH2:36][C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)=[CH:32][CH:33]=2)[C:28]([C:43]2[N:44]([C:58]([O:60][C:61]([CH3:64])([CH3:63])[CH3:62])=[O:59])[C:45]3[C:50]([CH:51]=2)=[CH:49][C:48]([OH:52])=[CH:47][CH:46]=3)=[N:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)n1nc(-c2cc3cc(O[SiH2]C(C)(C)C)ccc3n2C(=O)OC(C)(C)C)c2cc(OCc3ccccc3)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1nc(-c2cc3cc(O)ccc3n2C(=O)OC(C)(C)C)c2cc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.6 %

Procedure:
6.15 g of tetrabutylammonium fluoride are added to a solution of 13.4 g of 5-benzyloxy-3-(1-tert-butoxycarbonyl-5-tert-butylsilanyloxy-1H-indol-2-yl)-indazole-1-carboxylic acid tert-butyl ester in 140 ml of tetrahydrofuran. The medium is stirred for 30 minutes at ambient temperature. The reaction crude is washed with 3 times 25 ml of water, the organic phase is then dried over magnesium sulfate and then filtered, and the solvent is evaporated off under reduced pressure in a rotary evaporator. 14.4 g of crude product are obtained, which are purified by flash chromatography (silica 40-63 μm), eluent: dichloromethane/methanol 98:2 to obtain 8.54 g of 5-benzyloxy-3-(1-tert-butoxycarbonyl-5-hydroxy-1H-indol-2-yl)-indazole-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)[CH3:2]>CCOC(C)=O.CO>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)[CH:7]=[CH:8][C:9]=1[NH2:10])[CH3:2]
Reactant: CCOc1cc(-c2ccncc2)ccc1[N+](=O)[O-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOc1cc(-c2ccncc2)ccc1N
Reaction time: 6 h
Yield: 83.4 %

Procedure:
4-[3-(Ethyloxy)-4-nitrophenyl]pyridine (3.57 g, 14.62 mmol) was place in a 250 mL high pressure vessel and dissolved in 60 mL of 1 to 1 EtOAc/MeOH. 5 wt % Platinum(sulfided)/carbon (2.85 g, 0.73 mmol) was added followed quickly by a rubber septum. The flask was evacuated and filled with N2 six times to remove any oxygen. The vessel was then pressurized with H2 (60 psi). The solution stirred for 6 hours. The vessel was evacuated and filled with N2 six times to remove any H2. The solution was filtered through celite and evaporated to give the title compound of step C (2.62 g, 12.2 mmol, 83%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.44-8.48 (m, 2H), 7.57 (dd, J=4.58, 1.46 Hz, 2H), 7.16-7.21 (m, 2H), 6.70 (d, J=7.87 Hz, 1H), 5.09 (bs, 2H), 4.09 (q, J=6.96 Hz, 2H), 1.34 (t, J=6.96 Hz, 3H).
Reaction SMILES: Cl[C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[CH2:10][N:9]([C:23]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:24])[CH2:8]2)[O:4][N:3]=1.[CH3:31][C:32]1([NH2:36])[CH2:35][CH2:34][CH2:33]1>C(O)C>[CH3:31][C:32]1([NH:36][C:2]2[N:6]=[C:5]([CH:7]3[CH2:12][CH:11]([C:13]4[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=4)[CH2:10][N:9]([C:23]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[O:24])[CH2:8]3)[O:4][N:3]=2)[CH2:35][CH2:34][CH2:33]1
Reactant: CC1(N)CCC1
Reactant: O=C(N1CCOCC1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(Cl)no2)C1
Solvent: CCO
Product: CC1(Nc2noc(C3CC(c4ccc(C(F)(F)F)cc4)CN(C(=O)N4CCOCC4)C3)n2)CCC1
Reaction time: 2 h

Procedure:
To a solution of 100 mg (0.225 mmol) of the oxadiazole from Example 23A in 1.5 ml of ethanol were added 383 mg (4.50 mmol) of 1-methylcyclobutanamine, and then the reaction mixture was stirred in the microwave at 80 for 2 h and then at 90° C. for 2 h. Another 383 mg (4.50 mmol) of 1-methylcyclobutanamine were added and the mixture was stirred in the microwave at 90° C. for a further 6 h and then at 100° C. for 6 h. Subsequently, another 383 mg (4.50 mmol) of 1-methylcyclobutanamine were added and the mixture was stirred in the microwave at 100 for a further 20 h. The solvent was removed under reduced pressure and the crude product was purified by means of preparative HPLC. Yield: 27.2 mg (24% of theory)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][S:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[S:15](Cl)(=[O:18])(=[O:17])[OH:16].C(N(C(C)C)C(C)C)C.C([O-])([O-])=O.[Na+].[Na+].OP(O)(O)=O>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][S:8][CH2:9][CH2:10][CH:11]([S:15]([OH:18])(=[O:17])=[O:16])[C:12]([OH:14])=[O:13]
Reactant: O=S(=O)(O)Cl
Reactant: O=C(O)CCCSSc1ccccn1
Agent: O=C([O-])[O-]
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)C(CCSSc1ccccn1)S(=O)(=O)O
Temperature: 75 °C
Reaction time: 0.75 h
Yield: 44.2 %

Procedure:
Alternative procedure: 4-(pyridin-2-yldisulfanyl)butanoic acid (106 mg, 0.462 mmol) was coevaporated with 1,2-dichloreoethane (2×5 ml), redisolved in 5 ml of 1,2-dichloreoethane and placed in a preheated 75° C. oil bath. To this solution, sulfurochloridic acid (154 μL, 2.311 mmol) and N-ethyl-N-isopropylpropan-2-amine (161 μL, 0.924 mmol) were added. The mixture was placed in the pre-heated 75° C. oil bath for 45 min. Another portion of sulfurochloridic acid (45 μL, 0.675 mmol) was added and the reaction was heated at 75° C. for 1 more hour until the reaction was completed (monitored by HPLC). To the mixture was added concentrated Na2CO3 until pH 11. The resulting mixture was stirred for 10 min, neutralized with H3PO4 to pH 7.5 and concentrated. The crude product was purified by HPLC on a C-18 column eluting with a gradient of 100% of water (0.5% HAc) to 80% water (0.5% HAc)/20% of MeOH to afford 4-(pyridin-2-yldisulfanyl)-2-sulfobutanoic acid (63 mg, 0.204 mmol, 44.1% yield).
Reaction SMILES: [CH2:1]([N:4]([CH2:10][CH2:11][CH3:12])[CH2:5][CH2:6][CH2:7][C:8]#[N:9])[CH2:2][CH3:3].[OH-].[Na+].[H][H]>[Ni].C(O)C>[CH2:10]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][NH2:9])[CH2:11][CH3:12]
Reactant: CCCN(CCC)CCCC#N
Reactant: [H][H]
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCN(CCC)CCCCN
Yield: 66.8 %

Procedure:
30 g (0.178 mol) of 4-dipropylaminobutyronitrile (3) was charged in a 500 ml three-necked flask, 150 ml of ethanol and 90 ml of a 1N sodium hydroxide aqueous solution was added thereto, and the mixture was stirred. 3.0 g of(10 wt %) the Raney nickel prepared in Example 1 was slowly added to the solution. After replacing the atmosphere in the flask with nitrogen and then with hydrogen, the mixture was allowed to react at room temperature for seven days with stirring while using a hydrogen balloon. After confirming that the raw material content had decreased to 1% or less by GC, the reaction solution was filtered through celite and washed with 400 ml of ethanol. After concentrating the filtrate, the residue was dissolved in 400 ml of chloroform and extracted with 200 ml of water. The chloroform layer was washed with 400 ml of a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated, thereby obtaining 27.8 g of a colorless oily substance (yield: 90%). The resulting substance was distilled under reduced pressure to obtain 20.5 g of 4-dipropylaminobutylamine (4) (yield: 66.7%, GC: 99%).
Reaction SMILES: [OH:1][C:2]1[CH2:7][C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:5][C:4](=[O:22])[CH:3]=1.CCN(CC)CC.[C:30](Cl)(=O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CC(C)(O)C#N.C([BH3-])#N.[Na+]>C(O)(=O)C.C(#N)C.C(Cl)Cl>[OH:1][C:2]1[CH2:7][C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:5][C:4](=[O:22])[C:3]=1[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: O=C1C=C(O)CC(CCc2ccccc2)(c2ccccc2)O1
Agent: CC(C)(O)C#N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1OC(CCc2ccccc2)(c2ccccc2)CC(O)=C1Cc1ccccc1

Procedure:
The title compound was prepared as described in General Method 8 using the following: 5,6-dihydro-4-hydroxy-6-phenyl-6-(2-phenylethyl)-2H-pyran-2-one (0.250 g, 0.850 mmol), Et3N (0.26 mL, 1.94 mmol), benzoyl chloride (0.109 mL, 0.94 mmol), CH2Cl2 (2.0 mL), acetonitrile (5.0 mL), acetone cyanohydrin (0.04 mL, 0.43 mmol), Et3N (0.26 mL, 1.9 mmol), glacial acetic acid (10.0 mL), sodium cyanoborohydride (0.151 g, 2.4 mmol). Purification was achieved by submitting the final residue to column chromatograpy (SiO2, 100% CH2Cl2 to 2% MeOH in CH2 Cl2) to provide a thick oil (0.384 g). 1H NMR (400 MHz, DMSO-d6) δ10.922 (bs, 1H), 7.395-7.315 (m, 5H), 7.297-7.126 (m, 3H), 7.084-7.028 (m, 5H), 6.775-6.611 (m, 2H), 3.423 (s, 2H), 3.248 (d, 1H, J=17 Hz), 3.175 (d, 1H, J=17 Hz), 2.619-2.551 (m, 1H), 2.292-2.227 (m, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][C:13]([OH:15])=[O:14])=[C:7]([F:16])[CH:6]=2.[CH3:17][N:18]1[CH:22]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:20]=[N:19]1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[F:16][C:7]1[CH:6]=[C:5]2[C:10]([CH:11]=[C:2]([C:21]3[CH:20]=[N:19][N:18]([CH3:17])[CH:22]=3)[CH:3]=[N:4]2)=[CH:9][C:8]=1[CH2:12][C:13]([OH:15])=[O:14]
Reactant: O=C(O)Cc1cc2cc(Br)cnc2cc1F
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1cc(-c2cnc3cc(F)c(CC(=O)O)cc3c2)cn1
Yield: 83.1 %

Procedure:
Nitrogen gas was bubbled through a suspension of (3-bromo-7-fluoro-quinolin-6-yl)-acetic acid (5 g, 17.7 mmol), 1-methyl-4-pyrazoleboronic acid pinacol ester (3.86 g, 18.6 mmol), potassium carbonate (7.3 g, 53 mmol) in 1,4-dioxane (50 mL) and water (20 mL) for 10 minutes. After such time dichlorobis(triphenylphosphine)palladium (II) (248 mg, 0.35 mmol) was added and the mixture heated to reflux for 3 hours. The aqueous phase was removed via pipette, diluted with 2N aqueous potassium carbonate (15 mL) and washed with ethyl acetate (2×30 mL). The aqueous phase was then acidified to pH 3 with concentrated hydrochloric acid. The formed precipitate was collected via filtration and washed with water and dried to return the title compound as a white solid (4.2 g, 14.7 mmol, 83% yield). 1H NMR 500 MHz (DMSO-d6): δ 3.84 (2H, s), 3.92 (3H, s), 7.71 (1H, d), 7.90 (1H, d), 8.10 (1H, s), 8.39 (1H, s), 8.47 (1H, d), 9.18 (1H, d). ES-MS m/z: 286 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[F-].[K+].[NH3:14].CCCCCCCCCCC>CO>[NH2:14][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccc(Cl)cc1
Reactant: N
Agent: [F-]
Agent: [K+]
Solvent: CCCCCCCCCCC
Solvent: CO
Product: Nc1ccc(C(F)(F)F)cc1
Temperature: 200 °C
Yield: 12.8 %

Procedure:
A mixture of 4.806 g of para-chlorobenzotrifluoride, 0.4991 g of cuprous chloride, 3.103 g of potassium fluoride, 13 g of ammonia, 17.9241 g of methanol, and 0.1961 g of n-undecane was heated at 200° C for 5 hrs in an 80 ml Hastelloy shaker tube. After cooling and venting the ammonia, the product mixture was removed. Most of the methanol and para-chlorobenzotrifluoride were distilled out of the product mixture. The remaining solution was diluted with diethyl ether and extracted with 0.5 M KOH to remove copper and ammonium salts as well as potassium fluoride. The ether layer was dried over CaSO4. Vacuum distillation of the ether layer gave 0.55 g of para-aminobenzotrifluoride.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12].[CH3:14][S:15](Cl)(=[O:17])=[O:16].C(N(CC)CC)C.O>ClCCl>[CH3:14][S:15]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12])(=[O:17])=[O:16]
Reactant: C=CCCCCCCCCCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: C=CCCCCCCCCCCS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of l1 -dodecen-1-ol (5.5 g, 29.9 mmol) in dichloromethane (70 ml) at 0° C. was added methanesulfonyl chloride (3.55 g, 2.40 ml, 31.0 mmol) followed by triethylamine (4.38 g, 46.0 mmol). After stirring for 10 minutes at 0° C., the reaction was allowed to warm to 25° C. and stirred for 2 hours. The reaction was poured into water (60 ml), separated and washed with dichloromethane (50 ml). The organic portions were combined, dried with magnesium sulfate, and evaporated, yielding 12-methanesulfonyl-1-dodecene as a yellow oil which was used without further purification. To a suspension of sodium theobromine (6.00 g, 30.0 mmol) in dimethylsulfoxide (60 mL) was added 12-methanesulfonyl-1-dodecene. The resulting reaction mixture was stirred for 16 hours at 60° C. The mixture was then poured into water (120 ml) and extracted with diethyl ether (2×100 ml). The organic portions were combined, dried with magnesium sulfate. The evaporated solvent left a cream-colored solid. Recrystallization from ethyl acetate/hexane (1:1) yielded 6.97 g of a white solid, 1-(l1-dodecenyl)-3,7-dimethylxanthine as a white solid (67% yield).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]([NH2:18])[P:10](=[O:17])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[O:19]([CH2:26][CH2:27][CH2:28]Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH2:12]([O:11][P:10]([CH:9]([NH:18][CH2:28][CH2:27][CH2:26][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[P:4]([O:5][CH2:6][CH3:7])(=[O:8])[O:3][CH2:1][CH3:2])(=[O:17])[O:14][CH2:15][CH3:16])[CH3:13]
Reactant: BrCCCOc1ccccc1
Reactant: CCOP(=O)(OCC)C(N)P(=O)(OCC)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOP(=O)(OCC)C(NCCCOc1ccccc1)P(=O)(OCC)OCC

Procedure:
3.03 g (0.01 mol) of aminomethylenediphosphonic acid tetraethyl ester, 2.3 g (0.01 mol) of 3-phenoxypropylbromide and 1.4 g (0.01 mol) of potassium carbonate are dissolved in 50 ml of dioxane and stirred under reflux for 24 hours. The major part of the solvent is distilled off, and the residue is partitioned between water and ethyl acetate. The organic layer is separated, washed with water, dried over sodium sulphate and evaporated to dryness yielding raw N-(3-phenoxypropyl)aminomethanediphosphonic acid tetraethyl ester which may be used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[CH:4]([NH:15][C:16](=[O:18])[CH3:17])[CH:3]1O)=[N:10][O:11][N:12]=3.O1CCCC1.[H-].[Na+]>O>[CH3:1][C:2]1([CH3:20])[O:14][C:6]2=[CH:7][C:8]3[C:9]([CH:13]=[C:5]2[C:4]([NH:15][C:16](=[O:18])[CH3:17])=[CH:3]1)=[N:10][O:11][N:12]=3
Reactant: CC(=O)NC1c2cc3nonc3cc2OC(C)(C)C1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)NC1=CC(C)(C)Oc2cc3nonc3cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 32.1 %

Procedure:
To a mixture of 80 mg (0.289 m mol) of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-acetylamino-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole and 5 ml of dried tetrahydrofuran were added 25 mg of sodium hydride (oil, content of more than 55%) with stirring for 1 hour at the room temperature. After the mixture was carefully added with water and extracted thrice with ethyl acetate. The combined ethyl acetate layer was washed successively with 0.5N hydrochloric acid, water and saturated aqueous NaCl solution and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was subjected to a preparative thin layer column chromatography using a developing solvent of ethyl acetate-methanol (10:1 (v/v)) to obtain 24 mg (yield: 32%) of the intended compound. The obtained compound was recrystallized from ethanol to obtain the pure intended compound.
Reaction SMILES: [Cl:1][C:2]1[C@H:3]([OH:8])[CH2:4][CH2:5][CH2:6][CH:7]=1.[Cl:9][C:10]([Cl:14])([Cl:13])[C:11]#[N:12]>>[Cl:9][C:10]([Cl:14])([Cl:13])[C:11](=[NH:12])[O:8][C@@H:3]1[CH2:4][CH2:5][CH2:6][CH:7]=[C:2]1[Cl:1]
Reactant: N#CC(Cl)(Cl)Cl
Reactant: O[C@@H]1CCCC=C1Cl
Product: N=C(O[C@@H]1CCCC=C1Cl)C(Cl)(Cl)Cl

Procedure:
reacting (R)-2-chloro-cyclohex-2-enylalcohol with trichloroacetonitrile to give (R)-2,2,2-trichloro-1-(2-chloro-cyclohex-2-enyloxy)-ethylideneamine;
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](/[CH:15]=[C:16]3/[C:17](=[O:22])[NH:18][C:19](=[O:21])[S:20]/3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH2:33]1[C@@H:38]2[CH2:39][CH2:40][CH2:41][N:37]2[CH2:36][C@H:35]([CH2:42]O)[O:34]1>>[F:32][C:2]([F:31])([F:1])[C:3]1[CH:26]=[C:25]([C:27]([F:29])([F:28])[F:30])[CH:24]=[CH:23][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](/[CH:15]=[C:16]3/[C:17](=[O:22])[N:18]([CH2:42][C@@H:35]4[O:34][CH2:33][C@@H:38]5[CH2:39][CH2:40][CH2:41][N:37]5[CH2:36]4)[C:19](=[O:21])[S:20]/3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: OC[C@H]1CN2CCC[C@H]2CO1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)C(=O)N1C[C@H]1CN2CCC[C@H]2CO1

Procedure:
(5Z)-5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-[(3R,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-ylmethyl]-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 6) and [(3R,8aS)-hexahydro-1H-pyrrolo[2,1-c][1,4]oxazin-3-yl]methanol (prepared as described in WO 2004/006846) following General Procedure J.