Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:19])[O:17][CH3:18])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([N:19]=[C:16]([N:7]2[CH2:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8]2)[O:17][CH3:18])=[O:26])=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: COC(=N)N1Cc2ccccc2-c2ccccc2C1
Product: COC(=NC(=O)c1ccc(F)cc1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from methyl 5,7-dihydro-6H-dibenz[c,e]-azepine-6-carboximidate and p-fluorobenzoyl chloride, there is obtained methyl N-(p-fluorobenzoyl)-5,7-dihydro-6H-dibenz[c,e]azepine-6-carboximidate, m.p. 136°-137.5° C.;
Reaction SMILES: [CH2:1]([C:3]1[O:7][C:6]([CH2:8][C:9]2[CH:14]=[C:13]([NH:15]C(=O)C(F)(F)F)[CH:12]=[CH:11][C:10]=2[S:22](Cl)(=[O:24])=[O:23])=[N:5][N:4]=1)[CH3:2].[NH2:26][C:27]1[CH:28]=[CH:29][C:30]2[CH2:34][O:33][B:32]([OH:35])[C:31]=2[CH:36]=1.N1C=CC=CC=1>C(#N)C>[NH2:15][C:13]1[CH:12]=[CH:11][C:10]([S:22]([NH:26][C:27]2[CH:28]=[CH:29][C:30]3[CH2:34][O:33][B:32]([OH:35])[C:31]=3[CH:36]=2)(=[O:23])=[O:24])=[C:9]([CH2:8][C:6]2[O:7][C:3]([CH2:1][CH3:2])=[N:4][N:5]=2)[CH:14]=1
Reactant: CCc1nnc(Cc2cc(NC(=O)C(F)(F)F)ccc2S(=O)(=O)Cl)o1
Reactant: Nc1ccc2c(c1)B(O)OC2
Solvent: c1ccncc1
Solvent: CC#N
Product: CCc1nnc(Cc2cc(N)ccc2S(=O)(=O)Nc2ccc3c(c2)B(O)OC3)o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 112.1 %

Procedure:
To a stirred solution of 2-((5-ethyl-1,3,4-oxadiazol-2-yl)methyl)-4-(2,2,2-trifluoroacetamido)benzene-1-sulfonyl chloride (335 mg, 0.84 mmol) and 6-aminobenzo[c][1,2]oxaborol-1(3H)-ol (125 mg, 0.84 mmol) in 5 mL of ACN was added pyridine (205 uL, 2.53 mmol) dropwise. The reaction mixture was stirred at room temperature for 3 hours. After the mixture was concentrated, the residue was extracted with ethyl acetate and washed with water, 1N HCl and brine. The organic layer was dried over Na2SO4 and concentrated to give the desired compound as a yellow solid (390 mg, yield 91%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:5]([CH3:7])[N:6]=1.[CH2:13]([CH:15]([C:21]([CH3:23])=O)[C:16](OCC)=[O:17])[CH3:14]>>[CH2:21]([C:15]1[C:16](=[O:17])[N:6]2[C:5]([CH3:7])=[C:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[S:3][C:2]2=[N:1][C:13]=1[CH3:14])[CH3:23]
Reactant: CCOC(=O)c1sc(N)nc1C
Reactant: CCOC(=O)C(CC)C(C)=O
Product: CCOC(=O)c1sc2nc(C)c(CC)c(=O)n2c1C
Temperature: 100 °C
Reaction time: 4 h

Procedure:
2-amino-4-methyl-thiazole-5-carboxylic acid, ethyl ester (10 g) was reacted with ethyl 2-ethyl-acetoacetate (17 g) in polyphosphoric acid (50 g) under stirring at 100° C. for 4 hours. After cooling, dilution with ice water and neutralization with 35% NaOH, the precipitate was filtered, washed with water until neutral and crystallized from hexane to give 6-ethyl-3,7-dimethyl-5-oxo-5H-thiazolo[3,2-a]pyrimidine-2-carboxylic acid, ethyl ester, m.p. 122°-124° C. (9.9 g) which was reacted with N-bromo succinimide (13.75 g) in benzene (260 ml) at the reflux temperature for 11 hours.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1.[H-].[Na+].I[CH:22]([CH3:24])[CH3:23]>>[F:1][C:2]1[C:10]2[C:6](=[C:7]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[N:8]([CH:22]([CH3:24])[CH3:23])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)I
Reactant: COc1ccc(-c2n[nH]c3c(F)cccc23)cc1
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(-c2c3cccc(F)c3nn2C(C)C)cc1
Yield: 4.9 %

Procedure:
Prepared according to Method D step B from 7-fluoro-3-(4-methoxyphenyl)-1H-indazole (0.121 g, 0.5 mmol), sodium hydride (60% in oil, 0.024 g, 0.6 mmol) and 2-iodopropane (0.10 mL, 1.0 mmol) to give the title compound (0.007 g).
Reaction SMILES: [N+]([O-])(O)=O.[NH2:5][C:6]([NH2:8])=[NH:7].[H-].[Na+].Cl[C:12]1[S:16][N:15]=[C:14]([CH2:17][Cl:18])[N:13]=1.O>CN(C)C=O>[Cl:18][CH2:17][C:14]1[N:13]=[C:12]([NH:7][C:6]([NH2:8])=[NH:5])[S:16][N:15]=1
Reactant: ClCc1nsc(Cl)n1
Reactant: N=C(N)N
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: O=[N+]([O-])O
Product: N=C(N)Nc1nc(CCl)ns1
Reaction time: 0.5 h

Procedure:
Guanidine nitrate (244 g.) was slurried in dimethylformamide (500 ml., dried over molecular sieve) and sodium hydride paste (58 g. of a 63% w/w dispersion in oil) was added over 30 minutes with external cooling in an acetone/solid CO2 bath to maintain the internal temperature at 25°-30°. The mixture was stirred for 30 minutes at 25° then cooled to 20°. 5-Chloro-3-chloromethyl-1,2,4-thiadiazole (84.5 g.) was added at 20°-25° over 20 minutes with external cooling at 5°-10°. The mixture was stirred for 20 minutes at 25° then poured into water (5000 ml.) and extracted with ethyl acetate (2×5000 ml.). The combined upper layers were extracted with 2 N HCl (2×500 ml.) and the combined acid extracts were basified with 2 N NaOH. The product was filtered off, washed with water, sucked dry and then dried over P2O5 at 1 m.m. to give 3-chloromethyl-5-guanidino-1,2,4-thiadiazole.
Reaction SMILES: CS(N)(=O)=O.[CH3:6][O:7][CH2:8][CH2:9][S:10]([NH2:13])(=[O:12])=[O:11].C(C1(COC2C(C3CC3)=CC(C(O)=O)=C(F)C=2)C2CC3CC(CC1C3)C2)#N.[CH:41]1([C:44]2[C:45]([O:54][CH2:55][C:56]34[C:62]([F:64])([F:63])[CH:61]3[CH2:60][CH2:59][CH2:58][CH2:57]4)=[CH:46][C:47]([F:53])=[C:48]([CH:52]=2)[C:49](O)=[O:50])[CH2:43][CH2:42]1>>[CH:41]1([C:44]2[C:45]([O:54][CH2:55][C:56]34[C:62]([F:64])([F:63])[CH:61]3[CH2:60][CH2:59][CH2:58][CH2:57]4)=[CH:46][C:47]([F:53])=[C:48]([CH:52]=2)[C:49]([NH:13][S:10]([CH2:9][CH2:8][O:7][CH3:6])(=[O:12])=[O:11])=[O:50])[CH2:43][CH2:42]1
Reactant: COCCS(N)(=O)=O
Reactant: O=C(O)c1cc(C2CC2)c(OCC23CCCCC2C3(F)F)cc1F
Agent: CS(N)(=O)=O
Agent: N#CC1(COc2cc(F)c(C(=O)O)cc2C2CC2)C2CC3CC(C2)CC1C3
Product: COCCS(=O)(=O)NC(=O)c1cc(C2CC2)c(OCC23CCCCC2C3(F)F)cc1F

Procedure:
Following the procedure as described in Example 332 Step 7 and making non-critical variations to replace methanesulfonamide with 2-methoxyethanesulfonamide and to replace 4-((2-cyanoadamantan-2-yl)methoxy)-5-cyclopropyl-2-fluorobenzoic acid with 5-cyclopropyl-4-((7,7-difluorobicyclo[4.1.0]heptan-1-yl)methoxy)-2-fluorobenzoic acid, the title compound was obtained following purification by reverse-phase HPLC as a colorless powder (0.045 g, 74%): 1H NMR (300 MHz, DMSO-d6) δ 11.92 (br s, 1H), 7.13 (d, J=8.3 Hz, 1H), 6.94 (d, J=12.8 Hz, 1H), 4.23-3.92 (m, 2H), 3.72 (s, 3H), 3.39-3.28 (m, 2H), 3.23-3.18 (m, 2H), 2.08-1.58 (m, 6H), 1.38-1.16 (m, 4H), 0.96-0.84 (m, 2H), 0.74-0.64 (m, 2H); MS (ES+) m/z 463.0 (M+1)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[C:10]2[CH:11]=[C:12](Br)[CH:13]=[CH:14][C:9]=2[O:8][C:7]=1[CH3:16])[CH3:2].[C:18]([Cu])#[N:19].[C-]#N.[Na+]>CN(C=O)C.O>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[C:10]2[CH:11]=[C:12]([C:18]#[N:19])[CH:13]=[CH:14][C:9]=2[O:8][C:7]=1[CH3:16])[CH3:2]
Reactant: CCOC(=O)Cc1c(C)oc2ccc(Br)cc12
Reactant: N#C[Cu]
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1c(C)oc2ccc(C#N)cc12
Temperature: 165 °C
Yield: 77.3 %

Procedure:
A mixture of (5-bromo-2-methyl-benzofuran-3-yl)-acetic acid ethyl ester (6.8 g, 22.9 mmol) and CuCN (3.1 g, 34.3 mmol) in anhydrous DMF (20 mL) is heated for 16 h at reflux (165° C.) under an argon atmosphere. After cooling to room temperature a solution of NaCN (5.8 g, 114 mmol) in water (30 mL) is added. The reaction mixture is partitioned between water and toluene, the layers are separated and the aqueous phase is extracted with toluene. The combined organic layers are washed with a 10% aqueous NaCN solution and brine, dried over Na2SO4, filtered and concentrated at reduced pressure to afford the title compound as a brown solid (4.31 g, 17.7 mmol, 77%). 1H NMR (400 MHz, CDCl3, 298 K): δ=7.82 (d, J=1.7 Hz, 1H), 7.51-7.43 (m, 2H), 4.16 (q, J=7.1 Hz, 2H), 3.59 (s, 2H), 2.46 (s, 3H), 1.26 (t, J=7.1 Hz, 3H). MS (ES+): 244 (M(Cl4H13NO3)+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])[C:7]=1[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:5])[CH3:2].[F:30][C:31]([F:42])([F:41])[C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:35]3[CH:36]=[CH:37][C:32]([C:31]([F:42])([F:41])[F:30])=[CH:33][CH:34]=3)[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])[C:7]=1[CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccccc1OC
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(C(F)(F)F)cc3)ccc2n1-c1ccccc1OC

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 2-ethoxycarbonylmethyl-1-(2-methoxyphenyl)-5-hydroxyindole-3-carboxylic acid ethyl ester (139 mg, 0.35 mmol, see step (b) Example 11) and 4-trifluoromethylphenylboronic acid (100 mg, 0.53 mmol). Yield 120 mg (63%).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([C:23]1[S:24][C:25]([CH2:28][N:29]2[CH:33]=[CH:32][N:31]=[N:30]2)=[CH:26][CH:27]=1)[NH:6][C:7](=[O:22])[CH:8]([CH2:17][S:18]C(=O)C)[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)C.CO>C(Cl)(Cl)Cl>[N:29]1([CH2:28][C:25]2[S:24][C:23]([CH:5]([C:4]([OH:34])=[O:3])[NH:6][C:7](=[O:22])[CH:8]([CH2:17][SH:18])[CH2:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:27][CH:26]=2)[CH:33]=[CH:32][N:31]=[N:30]1
Reactant: CCOC(=O)C(NC(=O)C(CCc1ccccc1)CSC(C)=O)c1ccc(Cn2ccnn2)s1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(NC(C(=O)O)c1ccc(Cn2ccnn2)s1)C(CS)CCc1ccccc1

Procedure:
The title compound was prepared from 2-[5-(1,2,3-triazol-1-ylmethyl)thien-2-yl]-N-[2-(acetylthiomethyl)-4-phenylbutyryl]glycine ethyl ester (Description 57) by the procedure described in Example 24 except that the eluent used was 20% methanol indichloromethane. vmax (CHCl3) 3292, 1731, 1648 and 1602 cm-1. δ (CD3SOCD3) 1.70-1.82 (2H, m), 2.46-2.74 (5H, m), 5.22 (1H, d, J 6.85 Hz), 5.72 (2H, s), 6.85-7.31 (7H, m), 7.68 and 7.72 (1H, two s's), 8.11 and 8.14 (1H, two s's).
Reaction SMILES: [S:1]([O:5][C:6]1[C:7](=[CH:9][CH:10]=[CH:11][CH:12]=1)[OH:8])([OH:4])(=[O:3])=O.[NH2:13][C:14]1[C:37]([Br:38])=[CH:36][C:17]([CH2:18][C@H:19]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([CH:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)[CH2:25][CH2:24]2)=[O:22])[NH2:20])=[CH:16][C:15]=1[Br:39].C(N(CC)CC)C>CN(C)C=O.C[C@H]1O[C@H]2[C@H](O)[C@@H](O)[C@H](OC3C4C(=CC5OCOC=5C=4)[C@@H](C4C=C(OC)C(O)=C(OC)C=4)[C@@H]4[C@@H]3COC4=O)O[C@@H]2CO1.C1COP(NCCCl)(=O)N(CCCl)C1.[NH2-].[NH2-].Cl[Pt+2]Cl>[NH2:13][C:14]1[C:15]([Br:39])=[CH:16][C:17]([CH2:18][C@H:19]([C:21]([N:23]2[CH2:24][CH2:25][N:26]([CH:29]3[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]3)[CH2:27][CH2:28]2)=[O:22])[NH:20][S:1]([O:5][C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[OH:8])(=[O:3])=[O:4])=[CH:36][C:37]=1[Br:38]
Reactant: CN1CCC(N2CCN(C(=O)[C@H](N)Cc3cc(Br)c(N)c(Br)c3)CC2)CC1
Reactant: O=S(=O)(O)Oc1ccccc1O
Agent: Cl[Pt+2]Cl
Agent: COc1cc([C@@H]2c3cc4c(cc3C(O[C@@H]3O[C@@H]5CO[C@@H](C)O[C@H]5[C@H](O)[C@H]3O)[C@H]3COC(=O)[C@H]23)OCO4)cc(OC)c1O
Agent: O=P1(NCCCl)OCCCN1CCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CCC(N2CCN(C(=O)[C@@H](Cc3cc(Br)c(N)c(Br)c3)NS(=O)(=O)Oc3ccccc3O)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Whilst cooling externally with ice 1.377 g (7.998 mmol) of pyrocatechol sulfate was added to a solution of 2.000 g (3.974 mmol) of 1-(4-amino-3,5-dibromo-D-phenylalanyl)-4-(1-methyl-4-piperidinyl)piperazine and 0.61 mL (0.004 mmol) of triethylamine in 50 mL of dimethylformamide and the mixture was then stirred for 1 hour whilst still being cooled with ice and for 2 hours at room temperature. The reaction mixture was concentrated by evaporation in vacuo at a maximum bath temperature of +40° C., the residue was triturated with diethylether, dried in air and used in the next step without further purification. Yield: 2.68 g (100% of theory).
Reaction SMILES: Cl[C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]([CH3:12])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C)C=O>[N:16]([C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]([CH3:12])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1)=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(Cl)c([N+](=O)[O-])c(C)c1[N+](=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(N=[N+]=[N-])c([N+](=O)[O-])c(C)c1[N+](=O)[O-]
Temperature: 80 °C

Procedure:
A mixture of 5-chloro-2,4-dinitro-m-xylene (707 mg, 3.1 mmol), sodium azide (219 mg, 3.37 mmol) and N,N-dimethylformamide (10 mL) is heated at 80° C. for 45 minutes then cooled to room temperature, poured into ice/water and extracted with ethyl acetate (3×50 mL). The combined organic layers are dried (magnesium sulfate), filtered, and concentrated via rotary evaporation to provide 5-azido-2, 4-dinitro-m-xylene as a yellow/brown solid. (650 mg, 2.7 mmol), 10% palladium-on-carbon (100 mg) and 80% formic acid (20 mL) is heated to 80° C. for 30 minutes, cooled to room temperature, and filtered through a plug of silica gel (eluting with water). The filtrate is basified (˜pH 10) with 28% ammonium hydroxide and extracted with ethyl acetate (3×100 mL). The combined organic layers are dried (magnesium sulfate), filtered, and concentrated to afford 4,6-dimethyl-5-nitrobenzimidazole as a yellow oil.
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:40])[C@@H:15]([NH:26][C:27]([C:29]2[CH:38]=[C:37]([OH:39])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]=2)=[O:28])[CH2:16][CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].[C:47]([O:51][C:52](=[O:55])[CH2:53]Br)([CH3:50])([CH3:49])[CH3:48]>CN(C=O)C.O>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:40])[C@@H:15]([NH:26][C:27]([C:29]2[CH:38]=[C:37]([O:39][CH2:53][C:52]([O:51][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:55])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]=2)=[O:28])[CH2:16][CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@H](CCOCc2ccccc2)NC(=O)c2cc(O)c3ccccc3n2)CC1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCOCc2ccccc2)NC(=O)c2cc(OCC(=O)OC(C)(C)C)c3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 900 mg 4-{(S)-4-Benzyloxy-2-[(4-hydroxy-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid butyl ester in 6.7 ml of DMF, 587 mg of cesium carbonate and 351 mg of Bromo-acetic acid tert-butyl ester was added and the reaction mixture was stirred for 5 h at RT. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The isolated crude product was pure enough for the next reaction step. Yield: 1.1 g.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:14][CH:13]=1>C(=O)(O)[O-].[Na+]>[CH3:22][O:21][C:19](=[O:20])[CH2:18][C:15]1[CH:14]=[CH:13][C:12]([NH:11][CH:1]=[O:3])=[CH:17][CH:16]=1
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)Cc1ccc(N)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Product: COC(=O)Cc1ccc(NC=O)cc1
Reaction time: 8 h
Yield: 73.6 %

Procedure:
A solution of acetic anhydride (14.3 mL, 151 mmol) and formic acid (22.8 mL, 605 mmol) was stirred at room temperature for 1 h. Methyl (4-aminophenyl)acetate (5.00 g, 30.3 mmol) was added and the resulting mixture was stirred overnight. Saturated aqueous sodium bicarbonate (10 mL) was added and the resulting mixture was extracted with DCM (2×10 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound (4.31 g) as a yellow oil, which was used in the next reaction without further purification.
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[N:6][N:5]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=2[Cl:19])[N:4]=1.[S-:20][C:21]#[N:22].[K+].O1CCCC1>O>[Cl:19][C:9]1[CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:13]([Cl:14])[C:8]=1[N:5]1[N:6]=[C:7]([S:20][C:21]#[N:22])[C:3]([CH3:2])=[N:4]1
Reactant: FC(F)(F)c1cc(Cl)c(-n2ncc(CBr)n2)c(Cl)c1
Reactant: N#C[S-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1SC#N

Procedure:
4-Bromomethyl-2-(2,6-dichloro-4-trifluoromethylphenyl)-2H-1,2,3-triazole (9.55 g), potassium thiocyanate (1 g) and tetrahydrofuran (50 ml) were heated under reflux for 3 hours. The mixture was poured into water, solid collected and recrystallised from ethyl aceteate/hexane to give 2-(2,6-dichloro-4-trifluoromethylphenyl)-4-thiocyanato-methyl-2H-1,2,3-triazole, m.p. 115°-117°. (Compound 23)
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=1[C:5]([N:7]1[CH2:11][C:10]2[CH2:12][N:13]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[CH2:14][C:9]=2[CH2:8]1)=[O:6].Cl.[CH:31]1([CH2:36][NH2:37])[CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH:31]1([CH2:36][NH:37][C:19](=[O:20])[C:18]2[CH:22]=[CH:23][C:15]([N:13]3[CH2:12][C:10]4[CH2:11][N:7]([C:5](=[O:6])[C:4]5[CH:24]=[CH:25][CH:26]=[CH:27][C:3]=5[C:2]([F:28])([F:29])[F:1])[CH2:8][C:9]=4[CH2:14]3)=[N:16][CH:17]=2)[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: NCC1CCCC1
Reactant: O=C(O)c1ccc(N2CC3=C(CN(C(=O)c4ccccc4C(F)(F)F)C3)C2)nc1
Agent: Cl
Product: O=C(NCC1CCCC1)c1ccc(N2CC3=C(CN(C(=O)c4ccccc4C(F)(F)F)C3)C2)nc1
Yield: 69 %

Procedure:
6-[5-(2-Trifluoromethylbenzoyl)-3,4,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl]nicotinic acid (50 mg, 0.124 mmol) were reacted with C-cyclopentylmethylamine, hydrochloride analogously to example 3d. Yield: 69%, M+H+: 485.28.
Reaction SMILES: [F:1][C:2]([F:10])(S(F)(=O)=O)C(O)=O.[CH3:11][N:12]([CH3:37])[C:13]([C:15]1[N:16]=[CH:17][C:18]([O:21][C:22]2[CH:23]=[C:24]([CH:29]=[C:30]([O:32][C@@H:33]([CH3:36])[CH2:34][OH:35])[CH:31]=2)[C:25]([O:27][CH3:28])=[O:26])=[N:19][CH:20]=1)=[O:14]>C(#N)C.[Cu]I>[F:1][CH:2]([F:10])[O:35][CH2:34][C@@H:33]([O:32][C:30]1[CH:29]=[C:24]([CH:23]=[C:22]([O:21][C:18]2[CH:17]=[N:16][C:15]([C:13](=[O:14])[N:12]([CH3:11])[CH3:37])=[CH:20][N:19]=2)[CH:31]=1)[C:25]([O:27][CH3:28])=[O:26])[CH3:36]
Reactant: COC(=O)c1cc(Oc2cnc(C(=O)N(C)C)cn2)cc(O[C@@H](C)CO)c1
Reactant: O=C(O)C(F)(F)S(=O)(=O)F
Agent: [Cu]I
Solvent: CC#N
Product: COC(=O)c1cc(Oc2cnc(C(=O)N(C)C)cn2)cc(O[C@@H](C)COC(F)F)c1
Yield: 62 %

Procedure:
2,2-Difluoro-2-fluorosulfonyl-acetic acid (CAS no. 1717-59-5) (0.84 mL, 8.05 mmol) in acetonitrile (20 mL) was added with a syringe pump dropwise over 90 minutes to a degassed stirring mixture of methyl 3-[5-(dimethylcarbamoyl)pyrazin-2-yl]oxy-5-[(2S)-1-hydroxypropan-2-yl]oxy-benzoate (1.5 g, 22.0 mmol) and copper (I) iodide (154 mg, 4.55 mmol) in acetonitrile (300 mL) at 55° C. The volatiles were removed under reduced pressure and the residue taken up in DCM. The mixture was filtered to and the solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica, eluting with a gradient of 25%-100% ethyl acetate in isohexane to afford the product (16.5 g, 62%). 1H NMR δ (CDCl3): 1.38 (3H, d), 3.15 (3H, s), 3.18 (3H, s), 3.91 (3H, s), 3.93-4.05 (2H, m), 4.62-4.68 (1H, m), 6.27 (1H, t), 6.95 (1H, t), 7.44-7.45 (1H, m), 7.49-7.51 (1H, m), 8.36 (1H, s), 8.53 (1H, s); m/z 404 (M+H+)
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18](Cl)=[N:19][C:20]=4[CH3:21])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([O:29][CH:30]([F:32])[F:31])[C:25]([F:28])([F:27])[F:26])=[CH:4][CH:3]=1.[CH3:33][CH:34]([CH3:36])[O-:35].[Li+]>CC(O)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:35][CH:34]([CH3:36])[CH3:33])=[N:19][C:20]=4[CH3:21])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([O:29][CH:30]([F:31])[F:32])[C:25]([F:27])([F:28])[F:26])=[CH:4][CH:3]=1
Reactant: CC(C)[O-]
Reactant: Cc1nc(Cl)nc(C)c1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Agent: [Li+]
Solvent: CC(C)O
Product: Cc1nc(OC(C)C)nc(C)c1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Temperature: 70 °C
Reaction time: 17 h

Procedure:
A mixture of 9-chloro-1-(2-chloro-4,6-dimethylpyrimidin-5-yl)-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole (161 mg, 0.324 mmol) and lithium isopropoxide (64.3 mg, 0.973 mmol) in 2-propanol (2.2 mL) was stirred at 70° C. for 17 hr. The mixture was concentrated in vacuo, diluted with water and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 30-70% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was purified by preparative HPLC to give a mixture contained an intermediate of the title compound as the trifluoroacetic acid salt. The mixture was washed with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound as a colorless crystal (71.0 mg, 0.137 mmol, 42%).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[O:8][C@@H:6]1[SH:7])(=[O:3])[CH3:2].I[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:32][C@H:33]1[CH2:57][CH2:56][C@@:55]2([CH3:58])[C:35](=[CH:36][CH2:37][C@@H:38]3[C@@H:54]2[CH2:53][CH2:52][C@@:51]2([CH3:59])[C@H:39]3[CH2:40][CH2:41][C@@H:42]2[C@H:43]([CH3:50])[CH2:44][CH2:45][CH2:46][CH:47]([CH3:49])[CH3:48])[CH2:34]1.C(N(CC)CC)C>ClCCl>[C:1]([O:4][C@H:5]1[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:10]([O:16][C:17](=[O:19])[CH3:18])[C@@H:9]([CH2:20][O:21][C:22](=[O:24])[CH3:23])[O:8][C@H:6]1[S:7][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][O:32][C@H:33]1[CH2:57][CH2:56][C@@:55]2([CH3:58])[C:35](=[CH:36][CH2:37][C@@H:38]3[C@@H:54]2[CH2:53][CH2:52][C@@:51]2([CH3:59])[C@H:39]3[CH2:40][CH2:41][C@@H:42]2[C@H:43]([CH3:50])[CH2:44][CH2:45][CH2:46][CH:47]([CH3:49])[CH3:48])[CH2:34]1)(=[O:3])[CH3:2]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCI)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(=O)OC[C@H]1O[C@H](S)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OC[C@H]1O[C@@H](SCCCCCCO[C@H]2CC[C@@]3(C)C(=CC[C@H]4[C@@H]5CC[C@H]([C@H](C)CCCC(C)C)[C@@]5(C)CC[C@@H]43)C2)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.7 %

Procedure:
To a solution of 2,3,4,6-tetra-O-acetyl-1-thio-α-D-mannopyranose (287 mg, 0.79 mmol) in dichloromethane (6 ml) was added cholest-5-en-3β-yl 6-iodohexyl ether (470 mg, 0.79 mmol) and triethylamine (0.11 ml, 0.79 mmol). After stirring under dry nitrogen atmosphere overnight at room temperature, the solvent was removed at reduced pressure and the residue chromatographed on silica gel eluted with 5-25% ethyl acetate in hexanes to give 6-(cholest-5-en-3β-yloxy)hexyl 2,3,4,6-tetra-O-acetyl-1-thio-β-D-mannopyranoside (0.36 g, 55% yield), m.p. 103°-103.5° C. This product was dissolved in 1:1 (v/v) ethanol-tetrahydrofuran (10 ml) and treated with a suspension of Bio-Rad AG-1-X2 OH-- ion-exchange resin (2.5-3 fold excess) in ethanol (5 ml). After stirring a room temperature for 45 minutes, the resin was filtered and washed with warm tetrahydrofuran (3×5 ml), and the combined filtrates concentrated to give 6-(5-cholesten-3 β-yloxy)hexyl 1-thio-α-D-mannopyranoside (250 mg, 91% yield) as needles from warm tetrahydrofuran, m.p. (endothermic transitions) 64-64, 81-82, and 226°-227° C.