Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5](=[O:8])[N:4]([CH3:9])[C:3]1=[O:10].C1(C)C(S([CH2:20][N+:21]#[C-:22])(=O)=O)=CC=CC=1.CC([O-])(C)C.[K+]>CC1OCCC1.CO>[CH3:1][N:2]1[C:7]2=[CH:20][NH:21][CH:22]=[C:6]2[C:5](=[O:8])[N:4]([CH3:9])[C:3]1=[O:10]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccccc1C
Reactant: Cn1ccc(=O)n(C)c1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CO
Solvent: CC1CCCO1
Product: Cn1c(=O)c2c[nH]cc2n(C)c1=O
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
1,3-Dimethylpyrimidine-2,4(1H,3H)-dione (commercially available, 40 g, 285 mmol) and toluenesulfonylmethyl isocyanide (commercially available, 84 g, 428 mmol) were dissolved in 2-MeTHF (1000 mL) under nitrogen at 30° C. and held for 5 mins. The vessel was cooled to 0° C. (internal). A solution of KOtBu (commercially available, 64.1 g, 571 mmol) in 2-MeTHF (500 mL was then added to the solution via a dropping funnel over 0.5 h, such that the internal temperature remained below 5° C. On addition of the KOtBu solution, an orange precipitate formed. An additional portion of 2-MeTHF (455 mL) was then charged via dropping funnel over 5 mins. After 40 mins, the dark orange suspension was quenched with sat NH4Cl solution (2×400 mL) charged via dropping funnel over 15 mins. The suspension was diluted with EtOAc (1 L), the layers were separated and the aqueous extracted with EtOAc (3×1 L). The combined organics were dried (MgSO4) and filtered under reduced pressure. The solvent was removed under reduced pressure to afford a brown semi-solid. The solids were suspended in MeOH (300 mL), sonicated and stirred at room temperature for 15 mins, filtered by reduced pressure filtration and washed with MeOH (100 mL). The solid was dried under vacuum at 50° C. for 24 h. The title compound was obtained as a pale brown amorphous solid;
Reaction SMILES: [O-]CC.[Na+].C1(C)C=CC=CC=1.[C:12]([O:15][CH2:16][CH3:17])(=[O:14])[CH3:13].C[O:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=1)=O>C(O)(=O)C>[CH2:16]([O:15][C:12](=[O:14])[CH2:13][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=1)=[O:19])[CH3:17]
Reactant: CCOC(C)=O
Reactant: COC(=O)c1cccc(C)n1
Agent: CC[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(=O)c1cccc(C)n1
Temperature: 92 °C
Reaction time: 1 h
Yield: 112.6 %

Procedure:
Stir a mixture of sodium ethoxide (90 g, 1.32 mol), toluene (0.5 L), and ethyl acetate (0.2 L, 1.98 mol) in a 2 L flask equipped with reflux condenser, mechanical stirrer, and nitrogen inlet. After 1 h, add 6-methyl-pyridine-2-carboxylic acid methyl ester (Cheung, Y, Tetrahedron Lett. 1979, 40, 3809-10; 100 g, 0.66 mol). Heat the mixture at reflux (92° C.) for 20 h. Cool the mixture to room temperature and acidify with glacial acetic acid to pH 6. Wash the resulting gel with water (0.5 L). Separate the layers and extract the aqueous layer with toluene (1×0.5 L). Dry the combined organic layers (sodium sulfate), filter, and concentrate in vacuo to yield the subtitled product (154 g) as a dark oil in 86% purity by HPLC analysis. MS (ES) m/z=208 (M+H).
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:13]=[C:14]([C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[C:31]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])[CH:30]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:57][O:58][C:59]1[CH:64]=[CH:63][C:62]([O:65][CH3:66])=[CH:61][CH:60]=1>C(Cl)Cl>[CH3:57][O:58][C:59]1[C:64]2[C:34]3[C:29](=[CH:30][C:31]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])=[C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH:33]=3)[C:14]3[C:15](=[CH:16][C:17]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[C:12]([O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:13]=3)[C:63]=2[C:62]([O:65][CH3:66])=[CH:61][CH:60]=1
Reactant: CCCCCCCCCCOc1ccc(-c2ccc(OCCCCCCCCCC)c(OCCCCCCCCCC)c2)cc1OCCCCCCCCCC
Reactant: COc1ccc(OC)cc1
Solvent: ClCCl
Product: CCCCCCCCCCOc1cc2c3cc(OCCCCCCCCCC)c(OCCCCCCCCCC)cc3c3c(OC)ccc(OC)c3c2cc1OCCCCCCCCCC
Temperature: 25 °C
Reaction time: 12 h
Yield: 84 %

Procedure:
Solid 3a (5.50 g, 7.06 mmol) was added to an ice cold suspension of anhydrous FeCl3 (9.16 g, 56.5 mmol) in dry CH2Cl2 (250 mL). Within 2 min 1,4-dimethoxybenzene (3.90 g, 28.2 mmol) was added to the green reaction mixture. The reaction mixture was allowed to warm slowly to room temperature and then stir for an additional 12 h. The reaction mixture was quenched with anhydrous MeOH (30 mL). The volume of the mixture was reduced to 50 mL under reduced pressure and MeOH (200 mL) was added to the resulting oil. The slightly violet product was called on a frit and washed with MeOH. The product was further purified by column chromatography using a 50% CH2Cl2/50% hexane solvent mixture to afford 4a (RF=0.24) as a colorless solid in 84% yield (mp 69-70° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]2[NH:13][N:12]=[N:11][N:10]=2)[CH:3]=1.[Cl:14][C:15]1[CH:16]=[C:17]([N:22]=[C:23]=[O:24])[CH:18]=[C:19]([Cl:21])[CH:20]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:23]([NH:22][C:17]2[CH:18]=[C:19]([Cl:21])[CH:20]=[C:15]([Cl:14])[CH:16]=2)=[O:24])=[C:4]([C:9]2[NH:13][N:12]=[N:11][N:10]=2)[CH:3]=1
Reactant: Nc1ccc(Cl)cc1-c1nnn[nH]1
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Solvent: Cc1ccccc1
Product: O=C(Nc1cc(Cl)cc(Cl)c1)Nc1ccc(Cl)cc1-c1nnn[nH]1
Yield: 73.4 %

Procedure:
4-Chloro-2-(1H-tetrazol-5-yl)-phenylamine (500 mg) dissolved in toluene (15 ml) was treated with 3,5-dichlorophenylisocyanate (500 mg) and stirred for a week. The precipitated product was filtered, washed with toluene, dissolved in acetone, filtered through celite, precipitated again with water, filtered and dried. This residue was slurried in 96% EtOH, and adjusted to basic pH with 10 N NaOH. The solution was filtered through celite and re-acidified with 4N HCl and a little water. The precipitated product was filtered and washed with water to afford 1-[4-Chloro-2-(1H-tetrazol-5-yl)-phenyl]-3-(3,5-dichloro-phenyl)-urea as a white solid (720 mg ). Mp.=234-236° C.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10](/[C:13](=[CH:20]\[CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)/[C:14](N(OC)C)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH:27]([Mg]Br)=[CH2:28].Cl>O1CCCC1>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10](/[C:13](/[C:14](=[O:15])[CH:27]=[CH2:28])=[CH:20]\[CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: C=C[Mg]Br
Reactant: CON(C)C(=O)/C(=C/C1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: C=CC(=O)/C(=C/C1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
To a solution (10 mL) of (2E)-2-[4-(cyclopropylsulfonyl)phenyl]-N-methoxy-N-methyl-3-(tetrahydro-2H-pyran-4-yl)propan-2-enamide (1.13 g) in tetrahydrofuran was added vinylmagnesium bromide (1.0M tetrahydrofuran solution, 9 mL) under ice-cooling, and the mixture was warmed to room temperature and stirred overnight. An excess amount of 1M hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (426 mg, yield 41%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (3:2, volume ratio). MS: 347 (MH+).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C:14]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:19][CH:18]=2)=[O:15])[CH2:4]1.[C:27]([C:30]1[C:39]2[O:38][CH2:37][CH2:36][O:35][C:34]=2[CH:33]=[CH:32][CH:31]=1)(=O)[CH3:28]>C1COCC1>[O:35]1[C:34]2[CH:33]=[CH:32][CH:31]=[C:30]([CH:27]([NH:1][CH2:2][C@@H:3]3[C@@H:7]([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[CH2:6][N:5]([C:14]([O:16][C:17]4[CH:18]=[CH:19][C:20]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:22]=4)=[O:15])[CH2:4]3)[CH3:28])[C:39]=2[O:38][CH2:37][CH2:36]1
Reactant: CC(=O)c1cccc2c1OCCO2
Reactant: COC(=O)c1ccc(OC(=O)N2C[C@H](CN)[C@@H](c3ccccc3)C2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC(=O)N2C[C@H](CNC(C)c3cccc4c3OCCO4)[C@@H](c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.6 %

Procedure:
A 2.0 ml THF solution of 253 mg of 4-(methoxycarbonyl)phenyl(3S,4S)-3-(aminomethyl)-4-phenylpyrrolidine-1-carboxylate and 144 mg of 5-acetylbenzodioxane was mixed with 0.12 ml of a boron trifluoride diethyl ether complex at 0° C. and stirred overnight at room temperature. The reaction solution was concentrated under a reduced pressure, and the thus obtained residue was purified by a silica gel chromatography (chloroform-methanol) to obtain 146 mg of 4-(methoxycarbonyl)phenyl(3S,4S)-3-({[1-(2,3-dihydro-1,4-benzodioxin-5-yl)ethyl]amino}methyl)-4-phenylpyrrolidine-1-carboxylate as a colorless amorphous substance. EP: 517.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:34])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:33])[CH2:12][CH2:13][C@@:14]3([C:30](O)=[O:31])[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:36])[CH3:35])(=[O:3])[CH3:2].[Cl-].[CH3:38][CH:39]1[CH2:44][CH2:43][CH2:42][N:41]([CH2:45][C@H:46]2[CH2:50][CH2:49][C@@H:48]([NH2:51])[CH2:47]2)[CH2:40]1.C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@@H:7]([CH2:8][CH2:9][C@:10]3([CH3:34])[C@@H:19]2[CH2:18][CH2:17][C@H:16]2[C@@:11]3([CH3:33])[CH2:12][CH2:13][C@@:14]3([C:30](=[O:31])[NH:51][C@@H:48]4[CH2:49][CH2:50][C@H:46]([CH2:45][N:41]5[CH2:42][CH2:43][CH2:44][CH:39]([CH3:38])[CH2:40]5)[CH2:47]4)[CH2:26][CH2:25][C@@H:24]([C:27]([CH3:29])=[CH2:28])[C@@H:15]32)[C:6]1([CH3:36])[CH3:35])(=[O:3])[CH3:2]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: CC1CCCN(C[C@H]2CC[C@@H](N)C2)C1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)N[C@@H]3CC[C@H](CN4CCCC(C)C4)C3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](OC(C)=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,11bR,13aR,13bR)-9-acetoxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (0.5 g, 1.04 mmol) (Prepared as described in J. Med. Chem. 2009. 52, 3248-3258) in 50 ml DCM, Oxallyl chloride (2 ml, 15.87 mmol) was added and stirred at room temperature for about 6 hours. Completion of the reaction was monitored by TLC. The reaction mixture was concentrated under reduced pressure. The residue was taken in DCM (15 ml) then kept under N2 atmosphere. (1R,3S)-3-((3-methylpiperidin-1-yl)methyl)cyclopentanamine (Intermediate 10, 0.21 g) in DCM, triethyl amine (0.3 ml, 3.12 mmol) was added at 0° C. and stirred for about 15 minutes followed by above prepared acid chloride was added and stirred at room temperature for about 8 hours. Completion of the reaction was monitored by TLC. The reaction mixture was neutralized with sat. NaHCO3 and extracted with DCM, the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 50% ethyl acetate in hexane as eluent to furnish the title compound as a white solid. 1H NMR (300 MHz, CDCl3): 0.57-0.97 (m, 19H); 1.18-1.21 (m, 8H); 1.25-1.41 (m, 12H); 1.49-1.62 (m, 8H); 1.65-1.82 (m, 10H); 1.85-1.98 (m, 4H); 2.56-2.69 (m, 2H); 2.88-3.06 (m, 3H); 3.29-3.38 (m, 1H); 3.89-3.90 (m, 1H); 4.25-4.70 (m, 4H); 5.78 (s, 1H); 6.12-6.15 (m, 1H); MASS: 763 (100%).
Reaction SMILES: [CH:1]1([S:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[NH2:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:15]([S:17](Cl)(=[O:19])=[O:18])[CH3:16].Cl>N1C=CC=CC=1>[CH:1]1([S:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[NH:10][S:17]([CH2:15][CH3:16])(=[O:19])=[O:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCS(=O)(=O)Cl
Reactant: Nc1ccccc1SC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1ccccc1SC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.6 %

Procedure:
In 10 ml of pyridine was dissolved 2.0 g of 2-(cyclohexylthio)aniline obtained in Example 2 (2), 1.2 g of ethanesulfonyl chloride was added dropwise under ice cooling, and then the mixture was stirred at room temperature overnight. The reaction solution was poured into ice water, made acidic with dilute hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed, in turn, with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (eluent:n-hexaneethyl acetate=10:1) to give 2.7 g of N-[2-(cyclohexylthio)phenyl]ethanesulfonamide as an oil.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.P(C#N)(=O)(OCC)OCC.[Cl:28][C:29]1[CH:37]=[C:36]2[C:32]([C:33](=[O:50])[N:34]([C:42]3[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=3)[CH:35]2[CH2:38][C:39](O)=[O:40])=[CH:31][CH:30]=1>CN(C)C=O>[Cl:28][C:29]1[CH:37]=[C:36]2[C:32](=[CH:31][CH:30]=1)[C:33](=[O:50])[N:34]([C:42]1[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=1)[CH:35]2[CH2:38][C:39]([N:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)=[O:40]
Reactant: COc1ccc(N2C(=O)c3ccc(Cl)cc3C2CC(=O)O)cc1
Reactant: C1CC2(CCN1)OCCO2
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(N2C(=O)c3ccc(Cl)cc3C2CC(=O)N2CCC3(CC2)OCCO3)cc1
Temperature: 0 °C
Yield: 90.3 %

Procedure:
With ice-cooling and stirring, 1.57 g of 1,4-dioxa-8-azaspiro[4.5]decane, 2.3 ml of triethylamine and 2.12 g of diethyl phosphorocyanidate were successively added to a solution of 3.32 g of 6-chloro-2-(4-methoxyphenyl)-3-oxoisoindoline-1-acetic acid in 30 ml of dimethylformamide. The mixture was stirred with ice-cooling for an hour. To the reaction mixture was added 150 ml of ice water and the mixture was allowed to stand to give a crystalline precipitate, which was collected by filtration, washed with water and dried. Recrystallization from ether gave 4.13 g of colorless crystals melting at 156°-157° C.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:25]([OH:27])=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:28]1([S:34](Cl)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:28]1([S:34]([NH:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]([C:25]([OH:27])=[O:26])[NH:18][C:16]([O:15][CH2:14][CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[O:17])(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: O=S(=O)(Cl)c1ccccc1
Product: O=C(N[C@@H](CCCCNS(=O)(=O)c1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Yield: 68 %

Procedure:
Nα-(9-fluorenylmethoxycarbonyl)-L-lysine was reacted with benzenesulfonyl chloride under the conditions used in example 2 giving 68% of the title compound.
Reaction SMILES: O.[CH2:2]([O:9][C:10]([CH3:14])([CH:12]=C)[CH3:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.I([O-])(=O)(=O)=[O:16].[Na+]>[Os](=O)(=O)(=O)=O.O1CCOCC1>[CH2:2]([O:9][C:10]([CH3:11])([CH3:14])[CH:12]=[O:16])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: C=CC(C)(C)OCc1ccccc1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
A mixture of 100 mL of water, 300 mL of dioxane, 20 g (0.11 mol) of 2-benzyloxy-2-methyl-3-butene and 1 g of osmium tetroxide was stirred at room temperature for 30 minutes then 51 g (0.22 mol) of finely ground sodium periodate was added in portions over 30 minutes. Stirring was continued for 2 hours then the mixture filtered and the filtrate extracted with several portions of ether. The combined extracts were dried over magnesium sulfate, filtered and the filtrate concentrated under vacuum. Distillation afforded 7.3 g (0.041 mol,37%) of product, b.p. 85°-88° C. (2 mm).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[CH2:3][NH:4][C:5](=[O:27])[C:6]1[CH:11]=[C:10]([N+:12]([O-])=O)[C:9]([NH:15][CH3:16])=[CH:8][C:7]=1[N:17]1[CH2:22][CH2:21][CH:20]([C:23]([OH:26])([CH3:25])[CH3:24])[CH2:19][CH2:18]1.C1COCC1>[Pd].CO>[F:29][C:2]([F:1])([F:28])[CH2:3][NH:4][C:5](=[O:27])[C:6]1[CH:11]=[C:10]([NH2:12])[C:9]([NH:15][CH3:16])=[CH:8][C:7]=1[N:17]1[CH2:22][CH2:21][CH:20]([C:23]([OH:26])([CH3:25])[CH3:24])[CH2:19][CH2:18]1
Reactant: CNc1cc(N2CCC(C(C)(C)O)CC2)c(C(=O)NCC(F)(F)F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CNc1cc(N2CCC(C(C)(C)O)CC2)c(C(=O)NCC(F)(F)F)cc1N
Reaction time: 7 h

Procedure:
A mixture of N-(2,2,2-trifluoroethyl)-2-[4-(1-hydroxy-1-methyl-ethyl)-piperidinyl]-4-methylamino-5-nitro-benzoic acid amide (crude product from the reaction above), Pd/C (10 mg), THF (5 ml) and MeOH (5 ml) is stirred under 3 bar H2-atmosphere for 7 h. The mixture is filtered and the filtrate is concentrated and directly used in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:4]=1.[N+:16]([O-])([OH:18])=[O:17].[OH-].[Na+]>S(=O)(=O)(O)O>[F:15][C:12]1[CH:13]=[CH:14][C:9]([C:5]2[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][N:6]=2)=[CH:10][C:11]=1[N+:16]([O-:18])=[O:17]
Reactant: COc1ccnc(-c2ccc(F)cc2)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COc1ccnc(-c2ccc(F)c([N+](=O)[O-])c2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of 4-(4-methoxypyridin-2-yl)fluorobenzene (0.71 g) in sulfuric acid (10 ml) was added fuming nitric acid (0.176 ml) dropwise at 0° C., and the mixture was stirred at 0° C. for 30 minutes. The reaction mixture was poured into an aqueous sodium hydroxide solution (4N) and extracted with ethyl acetate. The separated organic layer was washed with water and brine, dried over sodium sulfate and evaporated under reduced pressure to give 2-fluoro-5-(4-methoxypyridin-2-yl)nitrobenzene (831 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[CH:10]=1.[CH:11](=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[OH:18])[S:7][C:6]=2[CH:10]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1ccc2ccsc2c1
Product: Cc1ccc2cc(C(O)c3ccccc3)sc2c1

Procedure:
Using general procedure B, 6-methyl-benzo[b]thiophene was reacted with benzaldehyde to give (6-methyl-benzo[b]thiophen-2-yl)-phenyl-methanol as an off-white solid. MS: 236.9 ([M+H—H2O]+).
Reaction SMILES: C([O:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8]([CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([CH2:20][O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[F:28])[CH2:16][CH2:15]2)[N:7]=1)(C)(C)C.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>C(OCC)(=O)C.Cl.C(OCC)(=O)C>[F:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[O:21][CH2:20][CH:17]1[CH2:16][CH2:15][N:14]([CH2:13][CH2:12][C:8]2[NH:7][C:6](=[O:5])[CH:11]=[N:10][CH:9]=2)[CH2:19][CH2:18]1
Reactant: CC(C)(C)Oc1cncc(CCN2CCC(COc3ccccc3F)CC2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=c1cncc(CCN2CCC(COc3ccccc3F)CC2)[nH]1
Reaction time: 0.5 h
Yield: 79.1 %

Procedure:
After dissolving 167 mg of 2-tert-butoxy-6-[2-[4-(2-fluorophenoxymethyl)piperidino]ethyl]pyrazine in 3 ml of ethyl acetate, 3 ml of 4N hydrogen chloride/ethyl acetate was added and the mixture was all owed to stand at room temperature for 30 minutes. Aqueous sodium carbonate solution was added to the reaction solution and extraction was performed with dichloromethane. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Diethyl ether was added to the residue and the mixture was filtered to obtain the title compound (113 mg, 79% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7](Cl)[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][CH:4]=1.[NH2:13][CH:14]([CH2:17][OH:18])[CH2:15][OH:16]>C(O)C>[CH3:1][O:2][C:3]1[N:8]=[C:7]([NH:13][CH:14]([CH2:17][OH:18])[CH2:15][OH:16])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][CH:4]=1
Reactant: NC(CO)CO
Reactant: COc1ccc([N+](=O)[O-])c(Cl)n1
Solvent: CCO
Product: COc1ccc([N+](=O)[O-])c(NC(CO)CO)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
6-Methoxy-2-chloro-3-nitropyridine (36.94 g, 195.9 mmol) and 2-aminopropane-1,3-diol (35.65 g, 391.3 mmol, 2 eq.) were stirred in ethanol (500 ml) at reflux under argon for 3 hours. The mixture was allowed to cool to room temperature and left overnight. The solvent was partially removed under reduced pressure (to ca. 150 ml) and the resulting bright yellow slurry was poured into ice-water (1.5 L) with vigorous stirring. The mixture was stirred for 1 hour then filtered with suction while cold. The solid was washed with ice-cold water (200 ml) and air-dried to give the title compound as a bright yellow solid (45.03 g, 94%). LCMS showed desired product (93%) plus 7% starting material. The product was used without further purification.
Reaction SMILES: [I-].[NH2:2][C:3]1[S:4][C:5]2[CH:12]=[C:11]([C:13]3[S:14][C:15]4[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:16]=4[N:17]=3)[CH:10]=[CH:9][C:6]=2[N+:7]=1[CH3:8].O.[OH-].[Na+]>CS(C)=O>[NH:2]=[C:3]1[N:7]([CH3:8])[C:6]2[CH:9]=[CH:10][C:11]([C:13]3[S:14][C:15]4[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:16]=4[N:17]=3)=[CH:12][C:5]=2[S:4]1
Reactant: Cc1ccc2nc(-c3ccc4c(c3)sc(N)[n+]4C)sc2c1
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc2nc(-c3ccc4c(c3)sc(=N)n4C)sc2c1
Yield: 89.7 %

Procedure:
2-amino-3-methyl-6-(6-methyl-benzothiazol-2-yl)-benzothiazolium iodide (0.3 g, 0.68 mmol) was taken up in DMSO (10 ml). Water was added (20 ml) and the mixture was basified to pH 10 with aqueous NaOH (20%). The precipitate was collected by filtration and washed with water to produce 3 as a light yellow solid (0.19 g, 89%). Mp 146-148° C.; 1H NMR (DMSO): 2.45 (3H, s, Ar—CH3), 3.38 (3H, s, N—CH3), 7.16 (1H, d, J=8.4, ArH), 7.33 (1H, d, J=8.4, ArH), 7.87 (1H, s, ArH), 7.90 (1H, s; ArH), 7.93 (1H, d, J=8.4, ArH), 8.16 (1H, s, ArH), 8.55 (1H, s, NH); 13C NMR analysis was not possible due to poor solubility of 4 in available deuterated solvents; HR-FAB-MS m/z Found: 312.0619 C16H14N3S2 (M+H+): requires M, 312.0629.