Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]([S:11]([OH:14])(=[O:13])=[O:12])=[CH:9][C:8](N)=[C:7]2[C:2]=1[CH:3]=[C:4](S(O)(=O)=O)[CH:5]=[C:6]2O.C1C2C(=CC=CC=2)C=CC=1.O.[S:32](=[O:36])(=[O:35])([OH:34])O.[OH:37][S:38](O)(=[O:40])=[O:39].O=S(=O)=O>>[C:8]1([S:38]([OH:40])(=[O:39])=[O:37])[C:7]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:1]=[C:10]([S:11]([OH:14])(=[O:13])=[O:12])[C:9]=1[S:32]([OH:34])(=[O:36])=[O:35]
Reactant: Nc1cc(S(=O)(=O)O)cc2cc(S(=O)(=O)O)cc(O)c12
Reactant: O=S(=O)(O)O
Agent: O=S(=O)=O
Solvent: c1ccc2ccccc2c1
Solvent: O
Product: O=S(=O)(O)c1cc2ccccc2c(S(=O)(=O)O)c1S(=O)(=O)O

Procedure:
It is known from FIAT Final Report No. 1,016, page 32 to 39, that H-acid can be prepared as follows: naphthalene is reacted with sulphuric acid monohydrate (=100% strength H2SO4) and 65% strength oleum, a particular temperature programme being maintained and sulphuric acid monohydrate and oleum being added stepwise, to give a naphthalene-trisulphonic acid isomer mixture, which is nitrated with mixed acid. After diluting with water, driving off the nitrous gases and separating off the sulphuric acid in the form of calcium sulphate, the isomer mixture of nitronaphthalene-trisulphonic acids is reduced with iron, and dissolved iron salts are then precipitated with magnesium oxide and separated off. The acid calcium sodium salt of T-acid (1-naphthylamine-3,6,8-trisulphonic acid) is precipitated by adding rock salt and hydrochloric acid and is filtered off and washed several times. This salt of T-acid is introduced into the wash water and sodium carbonate is added. The chalk which has precipitated is then pressed out and the salt solution is concentrated. The concentrated solution of the trisodium salt of T-acid is reacted with 50% strength sodium hydroxide solution under pressure. Thereafter, first sulphonic acid and then water are added and the H-acid is finally isolated, as the monosodium salt, by filtration, washing and drying.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[NH2:17][OH:18]>N1C=CC=CC=1>[OH:18][N:17]=[CH:4][C:3]1[CH:6]=[CH:7][C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:9][C:2]=1[OH:1]
Reactant: NO
Reactant: O=Cc1ccc(N2CCOCC2)cc1O
Agent: Cl
Solvent: c1ccncc1
Product: ON=Cc1ccc(N2CCOCC2)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.3 %

Procedure:
A solution of 2-hydroxy-4-morpholin-4-yl-benzaldehyde (0.135 g, 0.65 mmol) in pyridine (5 mL) was treated with hydroxylamine hydrochloride (45 mg, 0.65 mmol) and stirred for 30 min at room temperature. The reaction mixture was concentrated in vacuo and the residue was partitioned between EtOAc and 5% sodium bicarbonate. The organic layer was dried over Na2SO4 and concentrated in vacuo to afford the product as a pale yellow solid (51 mg, 35%).
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11]([N:14]3[CH:18]([CH3:19])[CH2:17][CH:16]([OH:20])[CH2:15]3)(=[O:13])=[O:12])[C:5]=2[CH:4]=[CH:3][N:2]=1.C(Cl)(=O)C(Cl)=O.CS(C)=O.C(N(CC)CC)C>ClCCl>[CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([S:11]([N:14]3[CH:18]([CH3:19])[CH2:17][C:16](=[O:20])[CH2:15]3)(=[O:12])=[O:13])[C:5]=2[CH:4]=[CH:3][N:2]=1
Reactant: CC1CC(O)CN1S(=O)(=O)c1cccc2cnccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1CC(=O)CN1S(=O)(=O)c1cccc2cnccc12

Procedure:
Then, in substantially the same manner as in Example 9, 2.34 g of the thus obtained 1-(5-isoquinolinesulfonyl)-3-hydroxy-5-methylpyrrolidine was reacted in dichloromethane with 1.08 g of oxalyl chloride, 0.67 g of dimethylsulfoxide and 0.60 g of triethylamine to obtain 1-(5-isoquinolinesulfonyl)-5-methyl-3-pyrrolidone.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C@H:7]([C:11]([OH:13])=O)[CH:8]([CH3:10])[CH3:9])=[O:5])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[S:28]1[C:32]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][N:40]([NH2:65])[CH2:41][C@H:42]([OH:64])[C@@H:43]([NH:51][C:52](=[O:63])[C@H:53]([C@H:59]([CH2:61][CH3:62])[CH3:60])[NH:54][C:55]([O:57][CH3:58])=[O:56])[CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[CH:35][CH:34]=2)=[CH:31][N:30]=[CH:29]1>CN(C=O)C>[S:28]1[C:32]([C:33]2[CH:34]=[CH:35][C:36]([CH2:39][N:40]([NH:65][C:11](=[O:13])[C@H:7]([CH:8]([CH3:9])[CH3:10])[NH:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:41][C@H:42]([OH:64])[C@@H:43]([NH:51][C:52](=[O:63])[C@H:53]([C@H:59]([CH2:61][CH3:62])[CH3:60])[NH:54][C:55]([O:57][CH3:58])=[O:56])[CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[CH:37][CH:38]=2)=[CH:31][N:30]=[CH:29]1
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2cncs2)cc1
Reactant: CCOC(=O)N[C@H](C(=O)O)C(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCOC(=O)N[C@H](C(=O)NN(Cc1ccc(-c2cncs2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)[C@@H](C)CC)C(C)C

Procedure:
Analogously to Example 7, 175 mg (0.92 mmol) of N-ethoxycarbonyl-(L)-valine, 332 mg (1.7 mmol) of EDC and 156 mg (1.15 mmol) of HOBT in 2.5 ml of DMF and 483 μl (3.47 mmol) of TEA are reacted with 0.578 mmol of 1-[4-(thiazol-5-yl)-phenyl]-4(S)-hydroxy-2-amino-5(S)-N-(N-methoxycarbonyl-(L)-iso-leucyl)amino-6-phenyl-2-azahexane (Example 11 b) in 5.2 ml of DMF to form the title compound: m.p: 200-203° C.; HPLC20-100 : tRet =14.6; FAB MS (M+H)+ =711.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13]Br)=[CH:7][CH:6]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(O[CH2:24][CH3:25])C>C(O)C>[Br-:1].[Br-:1].[N+:15]1([CH2:2][CH2:3][CH2:4][C:5]2[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][N+:15]3[CH:25]=[CH:24][CH:18]=[CH:17][CH:16]=3)=[CH:7][CH:6]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1ccncc1
Reactant: CCOCC
Reactant: BrCCCc1ccc(CCCBr)cc1
Solvent: CCO
Product: [Br-]
Product: c1cc[n+](CCCc2ccc(CCC[n+]3ccccc3)cc2)cc1

Procedure:
First, 320 mg of 1,4-bis(3-bromopropyl)benzene was dissolved in 5.0 ml of ethanol, 202 μl of pyridine was added thereto, the mixture was then refluxed for 18 hours. After cooling, to the reaction mixture was added 20 ml of ethyl ether. The resulting solids were recrystallized from ethanol/ethyl ether to obtain 215 mg of the title compound as a colorless crystal.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:31])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[S:27]([CH3:30])(=[O:29])=[O:28])=[CH:17][CH:16]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:30][S:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:13]([CH:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[O:31])=[CH:16][CH:17]=1)(=[O:29])=[O:28]
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)Nc1ccc(-c2ccccc2S(C)(=O)=O)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccccc1-c1ccc(NC(=O)C2CCCN2)cc1

Procedure:
2-(2′-Methanesulfonyl-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.8 g, 1.7 mmol) was dissolved in 25 mL DCM and 5 mL trifluoroacetic acid and stirred at ambient temperature for one hour and concentrated. Redissolved in 100 mL EtOAc and 100 mL sat. NaHCO3, separated layers, washed organics with brine, dried with MgSO4, filtered and concentrated to yield title compound as an oil (quant. yield) APCI (AP−): 343.1 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]([O:10][C:11](=[O:18])[CH2:12][C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH2:7][S:8][CH:9]=1)=[O:4].S(Cl)(Cl)(=O)=O>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([O:10][C:11](=[O:18])[CH2:12][C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:7][S:8][CH:9]=1)=[O:4]
Reactant: COC(=O)C1=CSCC1OC(=O)Cc1cccs1
Solvent: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cscc1OC(=O)Cc1cccs1
Yield: 75 %

Procedure:
1.86 Parts of 3-thiolacetoxy-dihydrothiophene-4-carboxylic acid methyl ester are reacted with 1.76 parts by volume of sulfuryl chloride in 25 parts by volume of chloroform in the course of one hour at 0° C. The end product is isolated from the reaction mixture by the method described in Example 1c. 1.4 parts (75% of theory) of 3-thiolacetoxy-thiophene-4-carboxylic acid methyl ester of melting point 92°-95° C. are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]2[CH2:7][CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1.[F:14][C:15]([F:26])([F:25])[C:16](O[C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])=[O:17].[N+:27]([O-:30])([O-:29])=[O:28].[K+]>C(#N)C>[F:14][C:15]([F:26])([F:25])[C:16]([N:9]1[CH2:10][CH2:11][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:13]([N+:27]([O-:29])=[O:28])=[CH:12][C:6]=2[CH2:7][CH2:8]1)=[O:17].[F:23][C:20]([F:21])([F:22])[C:19]([N:9]1[CH2:10][CH2:11][C:5]2[C:4]([N+:27]([O-:30])=[O:28])=[C:3]([O:2][CH3:1])[CH:13]=[CH:12][C:6]=2[CH2:7][CH2:8]1)=[O:24]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: O=[N+]([O-])[O-]
Reactant: COc1ccc2c(c1)CCNCC2
Agent: [K+]
Solvent: CC#N
Product: COc1cc2c(cc1[N+](=O)[O-])CCN(C(=O)C(F)(F)F)CC2
Product: COc1ccc2c(c1[N+](=O)[O-])CCN(C(=O)C(F)(F)F)CC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 38 %
Yield: 25 %

Procedure:
Into a 1-neck round-bottom flask 7-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (17.00 g, 0.096 mol) was dissolved in acetonitrile (100 mL). Trifluoroacetic anhydride (47.4 mL, 0.34 mol) was added at −20° C. After 10 minutes potassium nitrate (9.7 g, 0.096 mol) was added at the same temperature, and the reaction mixture was stirred for 1.5 hours. The reaction was quenched by addition of diluted NaHCO3, and allowed to warm to room temperature. Partition between saturated aqueous Na2CO3 and dichloromethane, extraction, drying (MgSO4), filtration, and concentration, provided the crude product. Flash chromatography separation on SiO2 with dichloromethane (100%) provided 2,2,2-trifluoro-1-(7-methoxy-8-nitro-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-ethanone (11.5 g, 38%) and 2,2,2-trifluoro-1-(7-methoxy-6-nitro-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-ethanone (7.5 g, 25%). 2,2,2-Trifluoro-1-(7-methoxy-8-nitro-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-ethanone: 1H-NMR (CDCl3; amide rotamers observed) δ 7.72(1H), 6.89 (1H), 3.95 (3H), 3.65-3.85 (4H), 2.95-3.07 (4H); LC/MS (ESI+): 319.20 (M+H). 2,2,2-Trifluoro-1-(7-methoxy-6-nitro-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-ethanone: 1H-NMR (CDCl3; amide rotamers observed) δ 7.24 (1H), 6.85 (1H), 3.88 (s, 3H), 3.65-3.81 (4H), 2.80-3.05 (4H).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.C(N(CC)C(C)C)(C)C.ClC(Cl)(O[C:41](=[O:47])OC(Cl)(Cl)Cl)Cl.[NH:49]1[C:57]2[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=2)[CH2:51][CH2:50]1>C(Cl)Cl>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:41]([N:49]5[C:57]6[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=6)[CH2:51][CH2:50]5)=[O:47])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Reactant: c1ccc2c(c1)CCN2
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1)N1CCc2ccccc21
Temperature: 25 °C

Procedure:
To a stirred mixture of N-trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (31.1 mg, 85 μmol) in DCM (1 ml) at room temperature N,N-diisopropylethylamine (110 mg, 148 μl, 850 μmol, Eq: 10) and triphosgene (27.7 mg, 93.5 μmol, Eq: 1.1) was added carefully and the solution stirred for minutes at room temperature. Indoline (12.2 mg, 102 μmol, Eq: 1.2) was added and stirred for 30 minutes at room temperature. The reaction mixture was quenched with 10 mL sat NaHCO3 and extracted with DCM (3×15 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 100 g, 0% to 10% MeOH in DCM) to yield the title compound as an white solid (27.6 mg, 68.1%), MS (ISP) m/z=477.2 [(M+H)+].
Reaction SMILES: N1C=CC=CC=1.Cl.[CH3:8][NH:9][O:10][CH3:11].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:22]=[CH:23][CH:24]=1)[CH:17]=[CH:18][C:19](Cl)=[O:20]>ClCCl>[CH3:11][O:10][N:9]([CH3:8])[C:19](=[O:20])/[CH:18]=[CH:17]/[C:16]1[CH:22]=[CH:23][CH:24]=[C:14]([O:13][CH3:12])[CH:15]=1
Reactant: CNOC
Reactant: COc1cccc(C=CC(=O)Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cccc(/C=C/C(=O)N(C)OC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.2 %

Procedure:
A solution of 3-methoxycinnamic acid (75.0 g, 0.42 mol) in thionyl chloride (250 mL) was heated at reflux for 1 h. The majority of the the thionyl chloride was then distilled off and the resulting residue was treated with dichloromethane and residual thionyl chloride was removed by codistillation to give 3-methoxycinnamic acid chloride of sufficient purity to be used without further purification. Pyridine (186 mL, 2.3 mol) and N,O-dimethylhydroxylamine hydrochloride (45.17 g, 0.46 mol) were added to a 0° C. solution of 3-methoxycinnamic acid chloride(0.42 mol) in dry dichloromethane (500 mL). The solution was stirred for 18 h at room temperature, diluted with dichloromethane (200 mL), and washed sequentially with 1N HCl, saturated sodium bicarbonate, and brine. It was then dried over MgSO4 and concentrated in vacuo to give the title compound as a dark oil (88.43 g, 95%): 1H NMR (300 MHz, CDCl3) δ3.25 (s, 3H), 3.68 (s, 3H), 3.84 (s, 3H), 6.82-6.86 (m, 1H), 7.00 (d, J=16.1 Hz, 1H), 7.10 (br s, 1H), 7.15-7.20 (m, 1H), 7.32 (t, J=6.6 Hz, 1H), 7.72 (d, J=16.0 Hz, 1H).
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1[C:3](O)=O.[N+:9]([C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1)([O-:11])=[O:10].[CH2:20]([N:24]1[C:28](=[O:29])C=[CH:26][C:25]1=[O:30])[CH2:21][CH2:22][CH3:23]>CN(C=O)C>[CH2:20]([N:24]1[C:25](=[O:30])[CH:26]2[CH:16]([C:15]3[CH:18]=[CH:19][C:12]([N+:9]([O-:11])=[O:10])=[CH:13][CH:14]=3)[N:1]3[CH:2]([CH:3]2[C:28]1=[O:29])[CH2:6][CH2:7][CH2:8]3)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCN1C(=O)C=CC1=O
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: O=C(O)[C@@H]1CCCN1
Solvent: CN(C)C=O
Product: CCCCN1C(=O)C2C(C1=O)C(c1ccc([N+](=O)[O-])cc1)N1CCCC21
Yield: 32 %

Procedure:
A mixture of L-proline (20 mmol), 4-nitrobenzaldehyde (20 mmol) and N-butylmaleimide (20 mmol) was heated to 80° C. in DMF (20 ml) for 24 hours. The solvent was removed in a high vacuum and the residue was separated chromatographically over silica gel (eluent hexane:ethyl acetate=1:1+1% triethylamine). (3aRS, 4SR,8aRS,8bSR)-2-Butyl-4-(4-nitro-phenyl)-hexahydro-pyrrolo[3,4-a]pyrrolizine-1,3-dione was obtained in 32% yield as a yellow solid (Rf =0.35). This product in 50 ml of ethanol was treated with 200 mg of 10% palladium on charcoal and reduced under hydrogen within 8 hours. After filtration of the catalyst and removal of the solvent in a vacuum (3aRS,4SR,8aRS,8bSR)-4-(4-amino-phenyl)-2-butyl-hexahydro-pyrrolo[3,4-a]pyrrolizine-1,3-dione was obtained as a pale yellow oil (Rf =0.23). 120 mg of this crude product were treated with 80 mg of 3,5-dimethyl-pyrazolyl-1-carboximidamidinium nitrate in 20 ml of DMF and heated at 80° C. for 48 hours. After removing the solvent in a vacuum the material remaining was separated on a RP-18 chromatography column with a water/methanol gradient. (3aRS,4SR,8aRS, 8bSR)-N-[4-(2-Butyl-1,3-dioxo-decahydro-pyrrolo[3,4-a]pyrrolizin-4-yl)-phenyl]-guanidinium nitrate was obtained in 12% yield as a pale yellow oil. ISP-MS: 483.4 ([M+H]+, 100).
Reaction SMILES: [C:1](Cl)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Cl.[OH:16][CH:17]1[O:25][C@H:24]([CH2:26][OH:27])[C@@H:22]([OH:23])[C@H:20]([OH:21])[C@H:18]1[NH2:19].O>O1CCCC1.C(=O)([O-])[O-].[Na+].[Na+]>[C:1]([NH:19][C@@H:18]1[C@@H:20]([OH:21])[C@H:22]([OH:23])[C@@H:24]([CH2:26][OH:27])[O:25][CH:17]1[OH:16])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCCC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O

Procedure:
55 g of dodecanoyl chloride were dissolved in 170 ml of tetrahydrofuran and added dropwise, with vigorous stirring, to a solution of 54 g of D-glucosamine hydrochloride in 330 ml of aqueous sodium carbonate solution (20%). After completion of the addition of the acid chloride, the mixture was stirred for a further hour, then 500 ml of water were added to the batch and the solid material was filtered off with suction and washed with water. The residue was recrystallised from isopropanol/water 10/1 (v/v) and dried under high vacuum.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.[O-:10][CH2:11][CH3:12].[Na+].O>C(O)C>[Cl:9][C:4]1[CH:5]=[C:6]([NH2:8])[CH:7]=[C:2]([O:10][CH2:11][CH3:12])[N:3]=1
Reactant: CC[O-]
Reactant: Nc1cc(Cl)nc(Cl)c1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOc1cc(N)cc(Cl)n1
Temperature: 150 °C
Yield: 87.8 %

Procedure:
To 2,6-dichloro-pyridin-4-ylamine (1.08 g, 6.6 mmol) in ethanol (1.5 mL) was added sodium ethoxide (2.5 M, 2.7 mL, 6.6 mmol) and the mixture was heated in a sealed tube at 150° C. for 6 h. Water was added, and the mixture was extracted with ethyl acetate. The extracts were concentrated and purified by silica gel flash column eluting with 30% ethyl acetate in hexanes to give the titled compound (1.0 g, 88%).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[C:15]3[S:16][C:17]([C:19]4[N:23]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[Cl:30])[CH:22]=[N:21][N:20]=4)=[CH:18][C:14]=3[CH2:13][CH2:12][O:11][C:10]=2[CH:31]=1)=[O:4].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>>[Cl:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[N:23]1[CH:22]=[N:21][N:20]=[C:19]1[C:17]1[S:16][C:15]2[C:9]3[CH:8]=[CH:7][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)=[CH:31][C:10]=3[O:11][CH2:12][CH2:13][C:14]=2[CH:18]=1
Reactant: O=C(CCl)Nc1ccc2c(c1)OCCc1cc(-c3nncn3-c3ccccc3Cl)sc1-2
Reactant: C1COCCN1
Product: O=C(CN1CCOCC1)Nc1ccc2c(c1)OCCc1cc(-c3nncn3-c3ccccc3Cl)sc1-2

Procedure:
Following the procedure in Example 147 for 237, 2-chloro-N-(2-(4-(2-chlorophenyl)-4H-1,2,4-triazol-3-yl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-8-yl)acetamide was reacted with morpholine to give 236. MS: (ESI+) 522.3
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[O:17][C:16](=O)[NH:15][C:14](=[O:20])[C:13]=3[CH2:12][O:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[OH-].[NH4+:22]>>[N:22]#[N:15].[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[NH:22][C:16](=[O:17])[NH:15][C:14](=[O:20])[C:13]=3[CH2:12][O:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: [NH4+]
Reactant: O=c1[nH]c(=O)c2c(o1)C(c1cc(F)cc(F)c1)COC2
Agent: [OH-]
Product: N#N
Product: O=c1[nH]c2c(c(=O)[nH]1)COCC2c1cc(F)cc(F)c1
Temperature: 80 °C
Yield: 166.7 %

Procedure:
The mixture of 8-(3,5-difluorophenyl)-7,8-dihydropyrano[3,4-e][1,3]oxazine-2,4(3H,5H)-dione (Preparation X3) (230 mg, 0.818 mmol) and ammonium hydroxide (2229 μL, 57.3 mmol) in a sealed bottle was heated at 80° C. for 4 h. Blowed by N2 overnight to get 8-(3,5-difluorophenyl)-7,8-dihydro-1H-pyrano[4,3-d]pyrimidine-2,4(3H,5H)-dione (191 mg, 0.682 mmol, 83% yield) which was used as is. LC-MS (M+H)+=281.1.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[O:13])[CH2:8][CH2:7]1.[N:21]([C:24]1[CH:33]=[C:32]([N+:34]([O-:36])=[O:35])[CH:31]=[CH:30][C:25]=1[C:26](OC)=[O:27])=[C:22]=[S:23]>O1CCCC1>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]([CH:9]2[CH2:8][CH2:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:1]3[C:26](=[O:27])[C:25]4[C:24](=[CH:33][C:32]([N+:34]([O-:36])=[O:35])=[CH:31][CH:30]=4)[NH:21][C:22]3=[S:23])[CH2:11][CH2:10]2)=[O:13])=[CH:15][CH:16]=1
Reactant: NCCCCN1CCC(C(=O)c2ccc(F)cc2)CC1
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1N=C=S
Solvent: C1CCOC1
Product: O=C(c1ccc(F)cc1)C1CCN(CCCCn2c(=S)[nH]c3cc([N+](=O)[O-])ccc3c2=O)CC1
Temperature: 40 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
To a stirred solution of 28 parts of [1-(4-aminobutyl)-4-piperidinyl](4-fluorophenyl)methanone in 135 parts of tetrahydrofuran was added dropwise during a 10 minutes-period a solution of 24 parts of methyl 2-isothiocyanato-4-nitrobenzoate in 180 parts of tetrahydrofuran (slightly exothermic reaction). Upon completion, stirring was continued overnight at room temperature. The solid was filtered off and crystallized from ethanol while stirring and cooling to 40° C. The product was filtered off, washed with ethanol and dried in vacuo at 80° C., yielding 30 parts (62%) of 3-[4-[4-(4-fluorobenzoyl)-1-piperidinyl]butyl]-2,3-dihydro-7-nitro-2-thioxo-4(1H)-quinazolinone; mp. 225° C. (20).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]([CH2:28][CH2:29][CH2:30][C:31]([F:37])([F:36])[C:32]([F:35])([F:34])[F:33])[C:25]([OH:27])=[O:26])=[C:12]([C:38]1[CH:43]=[CH:42][C:41]([O:44]C)=[CH:40][CH:39]=1)[CH:11]=[CH:10]2.O.C(#N)C>ClCCl>[OH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH:24]([CH2:28][CH2:29][CH2:30][C:31]([F:36])([F:37])[C:32]([F:33])([F:34])[F:35])[C:25]([OH:27])=[O:26])=[C:12]([C:38]1[CH:39]=[CH:40][C:41]([OH:44])=[CH:42][CH:43]=1)[CH:11]=[CH:10]2
Reactant: COc1ccc(-c2ccc3cc(OC)ccc3c2CCCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)O)cc1
Agent: BrB(Br)Br
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: O=C(O)C(CCCCCCCc1c(-c2ccc(O)cc2)ccc2cc(O)ccc12)CCCC(F)(F)C(F)(F)F
Temperature: 0 °C
Reaction time: 5 h
Yield: 81.2 %

Procedure:
A solution of boron tribromide in dichloromethane (1.0 M, 8.5 ml, 8.47 mmol) was added dropwise to a solution of 9-[6-methoxy-2-(4-methoxyphenyl)naphth-1-yl]-2-(4,4,5,5,5-pentafluoropentyl)nonanoic acid (820 mg, 1.41 mmol) in dichloromethane (20 ml) at −78° C. under argon atmosphere. The reaction mixture was warmed with stirring to 0° C. over 5 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=3/2), followed by column chromatography on reversed-phase silica gel RP-18 (eluent: acetonitrile containing 0.1% trifluoroacetic acid/water=3/2), to give 9-[6-hydroxy-2-(4-hydroxyphenyl)naphth-1-yl]-2-(4,4,5,5,5-pentafluoropentyl)nonanoic acid (633 mg, Yield 81%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[N:7]=[CH:6]2.[N-:18]=[N+:19]=[N-:20].[Na+].O>CN(C=O)C>[N:18]([CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[N:7]=[CH:6]2)=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=[N-]
Reactant: BrCc1ccc2c(cnn2C2CCCCO2)c1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1ccc2c(cnn2C2CCCCO2)c1
Temperature: 90 °C
Yield: 99.5 %

Procedure:
To a solution of 5-(bromomethyl)-1-(2-tetrahydropyranyl)indazole (compound 12-5, 3.0 g, 10.2 mmol) in DMF (30 mL), was added with sodium azide (Aldrich, 2.64 g, 40.6 mmol) in one portion. The suspension was heated at 90° C. for 30 minutes and a yellow solution was formed. After cooling to room temperature, the reaction mixture was poured into water (100 mL) and extracted with ether (2×150 mL). Combined organic layers were washed with brine, then dried (MgSO4). Evaporation of solvent gave the product (12-6) as a yellow oil (2.61 g, 99%). TLC Rf 0.63 (60:40 hexane-ethyl acetate); MS (electrospray) 258 (M+1); 1H NMR (CDCl3) δ2.03-2.15 (m, 2H), 2.55 (m, 1H), 3.72 (m, 1H), 4.02 (m, 1H), 4.52 (s, 1H), 5.71 (d, 1H, J=9.4 Hz), 7.32 (d, 1H, J=8.8 Hz), 7.56 (d, 1H, J=8.8 Hz), 7.63 (s, 1H), 8.00 (s, 1H).