Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH3:10][C:11]([CH3:13])=[O:12].[OH-].[Na+].O>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:10][C:11](=[O:12])[CH:13]=[CH:1][C:2]2[CH:9]=[CH:8][CH:7]=[C:4]([CH3:5])[CH:3]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: Cc1cccc(C=O)c1
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cccc(C=CC(=O)C=Cc2cccc(C)c2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.7 %

Procedure:
3-Methylbenzaldehyde (1ab, 3.00 ml, 25.4 mmol) and acetone (19, 0.94 ml, 12.7 mmol) were combined in ethanol (20 ml) and stirred for 15 min at room temperature. A solution of sodium hydroxide (1.50 g, 37.5 mmol) and water (20 ml) was added and the mixture stirred for 18 hr at room temperature. The resulting mixture was extracted into ethyl acetate, washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to afford a solid. The crude solid was recrystallized from ethanol to give 2.39 g (72%) of a yellow solid: mp 68-72° C. [expected mp 68-72° C.]; 1H NMR: δ 2.38 (s, 6H), 7.06 (d, 2H, J=15.9 Hz), 7.26 (m, 4H), 7.40 (m, 4H), 7.70 (d, 2H, J=15.9 Hz); 13C NMR: δ 21.3, 125.1, 125.4, 128.6, 128.8, 131.1, 134.6, 138.4, 143.1, 188.6.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12].F[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=1[N+:27]([O-:29])=[O:28]>CS(C)=O>[N+:27]([C:18]1[CH:19]=[C:20]([C:23]([F:24])([F:25])[F:26])[CH:21]=[CH:22][C:17]=1[NH:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12])([O-:29])=[O:28]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Reactant: CCOC(=O)c1c(N)sc2ccccc12
Solvent: CS(C)=O
Product: CCOC(=O)c1c(Nc2ccc(C(F)(F)F)cc2[N+](=O)[O-])sc2ccccc12
Yield: 129.4 %

Procedure:
In the same manner as in Starting Material Synthesis Example 4 and using ethyl 2-aminobenzo[b]thiophene-3-carboxylate (5.0 g), 4-fluoro-3-nitrobenzotrifluoride (5.1 g) and dirnethyl sulfoxide (65 ml), ethyl 2-(2-nitro-4-trifluoromethylanilino)benzo[b]thiophene-3-carboxylate (12 g) was obtained. Without purification, in the same manner as in Starting Material Synthesis Example 21 and using ethanol (50 ml), 18% hydrochloric acid (50 ml) and tin(II) chlorihe.dihydrate (10.9 g), ethyl 2-(2-amino-4-trifluoromethylanilino)benzo[b]thiophene-3-carboxylate (2.8 g) was obtained.
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][C:4]=1[NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([NH:21]C(OC(C)(C)C)=O)[CH2:17][CH2:16]1)#[N:2]>ClCCl.FC(F)(F)C(O)=O>[NH2:21][C@H:18]1[CH2:19][CH2:20][C@H:15]([NH:14][C:4]2[CH:5]=[C:6]([CH:12]=[CH:13][C:3]=2[C:1]#[N:2])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:16][CH2:17]1
Reactant: CCOC(=O)c1ccc(C#N)c(N[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ccc(C#N)c(N[C@H]2CC[C@H](N)CC2)c1

Procedure:
ethyl 4-cyano-3-{[trans-4-({[(1,1-dimethylethyl)oxy]carbonyl}-amino)cyclohexyl]amino}benzoate (0.37 g, 0.97 mmol) was stirred in a mixture of dichloromethane (2 mL) and trifluoroacetic acid (2 mL) at room temperature for 1 hour. The solvent was rotary evaporated, and the residue was dried in vacuo to give ethyl 3-[(trans-4-aminocyclohexyl)amino]-4-cyanobenzoate (0.490 g, 99% yield) as trifluoroacetic acid salt. MS (EI) for C16H21N3O2: 288 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:14](=O)[CH3:15])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([N+:17]([O-])=O)[C:3]1=[O:20].[Cl-].[NH4+]>C(O)C.O.[Fe]>[CH3:15][C:14]1[NH:17][C:4]2[C:3](=[O:20])[N:2]([CH3:1])[CH:7]=[CH:6][C:5]=2[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C(C(C)=O)c1ccn(C)c(=O)c1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c(C)[nH]c2c(=O)n(C)ccc12
Yield: 72.8 %

Procedure:
To a solution of ethyl 2-(1-methyl-3-nitro-2-oxo-1,2-dihydropyridin-4-yl)-3-oxobutanoate (2.5 g, 8.8 mmol) in ethanol (50 mL) was added ammonium chloride (0.5 g, 9 mmol) in water (5 mL) at room temperature. The mixture was stirred and heated to reflux. Then iron powder (0.5 g, 8.9 mmol) was added in one portion. The mixture was stirred at reflux for 2 hours. Once starting material was consumed, the resultant mixture was filtered when it was hot, and the filtrate was concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to give ethyl 2,6-dimethyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-3-carboxylate (1.5 g, 75%) as a brown solid. LRMS (M+H+) m/z: calcd 234.1. found 234. 1H NMR (400 MHz, d6-DMSO): h 12.54 (s, 1H), 7.30 (d, J=5.1 Hz, 1H), 6.78 (d, J=5.1 Hz, 1H), 4.24 (q, J=5.1 Hz, 2H), 3.51 (s, 3H), 2.56 (s, 3H), 1.32 (t, 0.1=5.1 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)=[N:6][CH:7]=1.Br[C:16]1[CH:17]=[CH:18][C:19]2[C:20]3[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][CH2:26][C:21]=3[N:22]([CH3:25])[C:23]=2[CH:24]=1>>[CH3:25][N:22]1[C:23]2[CH:24]=[C:16]([N:11]3[CH:12]=[CH:13][C:8]([C:5]4[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=4)=[CH:9][C:10]3=[O:14])[CH:17]=[CH:18][C:19]=2[C:20]2[CH2:29][N:28]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:27][CH2:26][C:21]1=2
Reactant: Cn1c2c(c3ccc(Br)cc31)CN(C(=O)OC(C)(C)C)CC2
Reactant: Cc1ccc(-c2cc[nH]c(=O)c2)nc1
Product: Cc1ccc(-c2ccn(-c3ccc4c5c(n(C)c4c3)CCN(C(=O)OC(C)(C)C)C5)c(=O)c2)nc1
Yield: 64.7 %

Procedure:
4-(5-Methylpyridin-2-yl)pyridin-2(1H)-one (150 mg, 0.81 mmol) and tert-butyl 7-bromo-5-methyl-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (294 mg, 0.805 mmol) were reacted following the procedure of Example 30 (step g) to provide the title compound (245 mg, 64%) as a yellow/green solid: 1H NMR (300 MHz, CDCl3) δ 8.57 (d, J=2.0 Hz, 1H), 7.71 (d, J=8.0 Hz, 1H), 7.64-7.60 (m, 1H), 7.55-7.51 (m, 2H), 7.37 (d, J=1.6 Hz, 1H), 7.17 (d, J=1.6 Hz, 1H), 7.10-7.03 (m, 2H), 4.66 (br m, 2H), 3.85 (br m, 2H), 3.65 (s, 3H), 2.84 (br m, 2H), 2.42 (s, 3H), 1.51 (s, 9H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:24]5[N:34]=[C:35]([CH3:37])[NH:36][C:23]=5[CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C>C(O)(C(F)(F)F)=O>[CH3:37][C:35]1[NH:36][C:23]2[CH2:22][CH2:21][C:20]3[N:19]=[C:18]([C:15]4[CH:14]=[CH:13][C:12]([C:8]5([NH2:7])[CH2:11][CH2:10][CH2:9]5)=[CH:17][CH:16]=4)[C:27]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:26][C:25]=3[C:24]=2[N:34]=1
Reactant: Cc1nc2c([nH]1)CCc1nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc1-2
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2c([nH]1)CCc1nc(-c3ccc(C4(N)CCC4)cc3)c(-c3ccccc3)cc1-2
Reaction time: 0.01 h
Yield: 115.5 %

Procedure:
tert-butyl(1-(4-(2-methyl-8-phenyl-4,5-dihydro-3H-imidazo[4,5-f]quinolin-7-yl)phenyl)cyclobutyl)carbamate (25 mg, 0.049 mmol) was dissolved in TFA (1 mL) and stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (˜2 mL) and concentrated to dryness under reduced pressure three times. The residue was then slurried in diethyl ether (2 mL) and after settling the supernatant solvent removed by pipette. This was repeated three times. The remaining solvent was removed under reduced pressure and freeze-dried to give the desired product as an off-white solid (23 mg, 74% yield). 1H-NMR (500 MHz, CD3OD) δ 7.90 (1H, s), 7.49 (2H, d), 7.44 (2H, d), 7.31-7.35 (3H, m), 7.23-7.27 (2H, m), 3.44 (2H, t), 3.20 (2H, t), 2.73-2.81 (2H, m), 2.72 (3H, s), 2.55-2.65 (2H, m), 2.19-2.30 (1H, m), 1.92-2.03 (1H, m). LCMS (Method A) RT=3.02 min, M+H+=407.14.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[CH:10][N:9]2[CH:21]=1)=[O:4].ClC1C=CC=C(C(OO)=[O:30])C=1>C(Cl)Cl>[CH3:1][O:2][C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([S:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)=[O:30])=[CH:10][N:9]2[CH:21]=1)=[O:4]
Reactant: COC(=O)Nc1cn2cc(Sc3ccccn3)ccc2n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COC(=O)Nc1cn2cc(S(=O)c3ccccn3)ccc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 0.300 g. (1 mmole) of 2-methoxycarbonylamino-6-(pyridylthio)-imidazo [1,2-a] pyridine in 50 ml. of methylene chloride is added 0.189 g. (1.1 mmoles) of m-chloroperbenzoic acid. The reaction is stirred at room temperature overnight, and the resultant solution is washed 3 times with saturated sodium bicarbonate solution. The methylene chloride layer is dried and evaporated to dryness in vacuo affording 2-methoxycarbonylamino-6-(2-pyridylsulfinyl) imidazo [1,2-a] pyridine, m.p. 231°-235° C.
Reaction SMILES: S1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]3[C:14]([C:15]4[CH:16]=[C:17]([CH:38]=[CH:39][CH:40]=4)[CH2:18][NH:19][C:20]([C:22]4[C:23](=[O:37])[N:24]([CH2:28][C:29]5[CH:34]=[CH:33][C:32]([F:35])=[C:31]([F:36])[CH:30]=5)[CH:25]=[CH:26][CH:27]=4)=[O:21])=[CH:13][NH:12][C:9]3=[N:10][CH:11]=2)=[CH:2]1.[N:41]1C=CC=C(B(O)O)[CH:42]=1.B(O)O>>[N:41]1[CH:42]=[CH:5][CH:4]=[C:3]([C:6]2[CH:7]=[C:8]3[C:14]([C:15]4[CH:16]=[C:17]([CH:38]=[CH:39][CH:40]=4)[CH2:18][NH:19][C:20]([C:22]4[C:23](=[O:37])[N:24]([CH2:28][C:29]5[CH:34]=[CH:33][C:32]([F:35])=[C:31]([F:36])[CH:30]=5)[CH:25]=[CH:26][CH:27]=4)=[O:21])=[CH:13][NH:12][C:9]3=[N:10][CH:11]=2)[CH:2]=1
Reactant: O=C(NCc1cccc(-c2c[nH]c3ncc(-c4ccsc4)cc23)c1)c1cccn(Cc2ccc(F)c(F)c2)c1=O
Reactant: OB(O)c1cccnc1
Agent: OBO
Product: O=C(NCc1cccc(-c2c[nH]c3ncc(-c4cccnc4)cc23)c1)c1cccn(Cc2ccc(F)c(F)c2)c1=O

Procedure:
Except where indicated, 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid 3-(5-pyridin-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-benzylamide was synthesized as per Example 91, 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid 3-(5-thiophen-3-yl-1H-pyrrolo[2,3-b]pyridin-3-yl)-benzylamide (Scheme 10) using 3-Pyridylboronic acid as boronic acid to yield the product. 1H NMR (400 MHz, DMSO-d6) d ppm 12.153 (s, 1H) 10.089 (t, J=5.8 Hz, 1H) 9.177 (s, 1H) 8.714 (d, J=4.9 Hz, 1H) 8.670 (s, 1H) 8.603 (s, 1H) 8.546 (d, J=7.3 Hz, 1H) 8.374 (d, J=7.3 Hz, 1H) 8.197 (d, J=6.8 Hz, 1H) 7.954 (s, 1H) 7.797 (s, 1H) 7.813-7.742 (m, 1H) 7.684 (d, J=7.3 Hz, 1H) 7.440-7.307 (m, 3H) 7.220 (d, J=7.3 Hz, 1H) 7.142-7.083 (m, 1H) 6.555 (t, J=6.8 Hz, 1H) 5.147 (s, 2H) 4.594 (d, J=5.8 Hz, 2H); MS m/z=548.07 M+H.
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9]([OH:11])=O.S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:18]=[C:19]([CH:32]=[CH:33][CH:34]=1)[C:20]([C:22]1[CH:30]=[C:29]2[C:25]([CH2:26][C:27](=[O:31])[NH:28]2)=[CH:24][CH:23]=1)=[O:21]>C1COCC1>[O:31]=[C:27]1[CH2:26][C:25]2[C:29](=[CH:30][C:22]([C:20]([C:19]3[CH:18]=[C:17]([NH:16][C:9]([C:3]4[C:4]([CH3:8])=[N:5][N:6]([CH3:7])[C:2]=4[Cl:1])=[O:11])[CH:34]=[CH:33][CH:32]=3)=[O:21])=[CH:23][CH:24]=2)[NH:28]1
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Reactant: Cc1nn(C)c(Cl)c1C(=O)O
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cc1nn(C)c(Cl)c1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Temperature: 79 °C
Reaction time: 2 h
Yield: 71.9 %

Procedure:
A dry 25 mL flask was charged with 5-Chloro-1,3-dimethyl-1H-pyrazole-4-carboxylic acid (0.180 g, 0.873 mmol) and thionyl chloride (10 mL) and allowed to stir at 79° C. for 2 h. The thionyl chloride was then removed by rotary evaporation. The crude acid chloride dissolved in THF (5 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 0.200 g, 0.794 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux for 2 h. The reaction mixture was then allowed to cool to room temperature and the precipitate was filtered and washed with THF (˜5 mL) affording pure 5-Chloro-1,3-dimethyl-1H-pyrazole-4-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (0.233 g, 0.571 mmol, 72%).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11](=[O:23])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[C:13]=2[F:22])[N:7]([CH2:24][C@H:25]2[CH2:29][CH2:28][CH2:27][O:26]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].S(OC)(O[CH3:34])(=O)=O>C1(C)C=CC=CC=1>[C:1]([C:5]1[N:6]([CH3:34])[N:7]([CH2:24][C@H:25]2[CH2:29][CH2:28][CH2:27][O:26]2)/[C:8](=[N:10]/[C:11](=[O:23])[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[C:13]=2[F:22])/[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)c2cccc(C(F)(F)F)c2F)n(C[C@H]2CCCO2)n1
Reactant: COS(=O)(=O)OC
Solvent: Cc1ccccc1
Product: Cn1c(C(C)(C)C)c/c(=N\C(=O)c2cccc(C(F)(F)F)c2F)n1C[C@H]1CCCO1
Yield: 80 %

Procedure:
A mixture of Example 6C (400 mg, 0.97 mmol) and dimethyl sulfate (0.37 mL, 3.88 mmol) in toluene (2 mL) was heated in a microwave reactor (300 W, CEM Explorer®) at 150° C. for 1 hour. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (silica gel; solvent A=EtOAc/MeOH/Et3N (90:10:0.5); solvent B=hexane in 10-60% gradient A/B) to yield 331.5 mg (80%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.44 (s, 9H), 1.50-1.67 (m, 1H), 1.75-1.96 (m, 2H), 1.99-2.14 (m, 1H), 3.64-3.84 (m, 2H), 4.12 (s, 3H), 4.18-4.26 (m, 1H), 4.55-4.77 (m, 2H), 6.98 (s, 1H), 7.63 (t, J=7.73 Hz, 1H), 8.00-8.13 (m, 2H); MS (ESI) m/z 428 (M+1H).
Reaction SMILES: F[C:2]1[CH:7]=[C:6](OC)[CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1.F[C:20]1C=CC=C(C)C=1B(O)O>>[F:10][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:20])[C:3]=1[C:11]1[S:12][CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=1
Reactant: COc1cc(F)c(-c2nc(C(=O)O)cs2)c(F)c1
Reactant: Cc1cccc(F)c1B(O)O
Product: Cc1cccc(F)c1-c1nc(C(=O)O)cs1

Procedure:
Following the procedure of Intermediate 104, replacing 2,6-difluoro-4-methoxyphenylboronic acid with (2-fluoro-6-methylphenyl)boronic acid gave the title compound.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=[S:14])[N:11]3[N:15]=[CH:16][CH:17]=[C:10]3[CH:9]=2)=[CH:4][CH:3]=1.Cl.[CH3:19]O>[OH-].[Na+].CI>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:13]=[C:12]([S:14][CH3:19])[N:11]3[N:15]=[CH:16][CH:17]=[C:10]3[CH:9]=2)=[CH:6][CH:7]=1
Reactant: S=c1[nH]c(-c2ccc(I)cc2)cc2ccnn12
Reactant: CO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Product: CSc1nc(-c2ccc(I)cc2)cc2ccnn12
Yield: 62 %

Procedure:
To a solution of 5-(4-iodo-phenyl)-6H-pyrazolo[1,5-c]pyrimidine-7-thione (compound E1)(2.09 g) in 2M aqueous NaOH (3 ml) and methanol (40 ml), methyl iodide (0.376 ml) is added at ambient temperature. After 30 min at this temperature further methyl iodide (0.376 ml) is added. After 60 min the mixture is neutralized with 2M hydrochloric acid and evaporated. The residue is partitioned between dichloromethane and water and the organic phase is washed twice with water. The organic phase is dried over sodium sulfate and the crude product is purified by silica gel flash chromatography. A nearly colorless solid (1.35 g, 62%) is obtained.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[F:16][C:17]([F:21])([F:20])[CH2:18]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)(C)C)=O)=O)(C)(C)C>C1COCC1>[F:16][C:17]([F:21])([F:20])[CH2:18][O:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: OCC(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COCC(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 36 h
Yield: 46.4 %

Procedure:
tert-Butyl 4-(hydroxymethyl)piperidine-1-carboxylate (0.300 g, 1.393 mmol), 2,2,2-trifluoroethan-1-ol (1.00 mL, 13.935 mmol), triphenylphosphine (0.440 g, 1.672 mmol) and N-{[(tert-butoxy)carbonyl]imino}(tert-butoxy)formamide (0.390 g, 1.672 mmol) were combined in THF (10 mL) and stirred at room temperature for 36 h before being heated to 75 C for 18 h. The reaction mixture was concentrated under reduced pressure and purified by FCC (EtOAc: heptane, 1:1) to afford the title compound (0.192 g, 50%). Method B HPLC-MS: MH+ requires m/z=297 Found: m/z=242 (MH+-tBu), Rt=2.25 min (100%).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:34])[C:16]([NH:18][C:19]2[N:23](C(OC(C)(C)C)=O)[N:22]=[C:21]([CH:31]3[CH2:33][CH2:32]3)[CH:20]=2)=[O:17])=[CH:11][CH:10]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]([CH3:34])[C:16]([NH:18][C:19]2[CH:20]=[C:21]([CH:31]3[CH2:33][CH2:32]3)[NH:22][N:23]=2)=[O:17])=[CH:13][CH:14]=1
Reactant: CC(C(=O)Nc1cc(C2CC2)nn1C(=O)OC(C)(C)C)c1ccc(NC(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C(=O)Nc1cc(C2CC2)[nH]n1)c1ccc(N)cc1
Yield: 68.8 %

Procedure:
11.8 g (25.26 mmol) of tert-butyl 5-[(2-{4-[(tert-butoxycarbonyl)amino]phenyl}propanoyl)amino]-3-cyclopropyl-1H-pyrazole-1-carboxylate were dissolved in 200 ml of dichloromethane and 30 ml of trifluoroacetic acid were added. After 2.5 hours at room temperature the solvent was evaporated and the residue taken up with dichloromethane and washed with a saturated solution of sodium hydrogenocarbonate. The organic layer was then dried over sodium sulphate and evaporated to dryness, affording 4.7 g (70% yield) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:8][N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10](Cl)=[O:11]>>[N:5]1[CH:6]=[CH:7][C:2]([O:1][C:10](=[O:11])[N:9]([CH3:8])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:3][CH:4]=1
Reactant: Oc1ccncc1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)Oc1ccncc1)c1ccccc1

Procedure:
The title product was prepared from 4-hydroxypyridine and N-methyl-N-phenylcarbamoyl chloride. The crude product was subjected to preparative HPLC. (11%, yellow solid). HPLC-MS: m/z=229.2 (M+1); Rt: 1.66 min, purity: 67%.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:8]=1[CH:9]=O.[CH2:18]([NH2:26])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:8]=1[CH:9]=[N:26][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:17]
Reactant: COc1ccc(OCCCN(C)C)c(C=O)c1
Reactant: NCCc1ccccc1
Solvent: Cc1ccccc1
Product: COc1ccc(OCCCN(C)C)c(C=NCCc2ccccc2)c1
Yield: 83 %

Procedure:
2-[3-(Dimethylamino)propoxy]-5-methoxybenzaldehyde (33.5 g) and 17.4 g of phenethylamine are reacted in 140 ml of toluene following the procedure described in Example 1B yielding 39.9 g of the title compound, boiling point 197°-202° C. at 0.2-0.3 mm of Hg.
Reaction SMILES: [H-].[Na+].[OH:3][C@H:4]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@@H:6]([C:16]([O:18][CH3:19])=[O:17])[CH2:5]1.Br[CH2:21][CH:22]=[CH2:23]>CN(C)C=O.[Ag]=O>[CH2:23]([O:3][C@H:4]1[CH2:8][N:7]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[C@@H:6]([C:16]([O:18][CH3:19])=[O:17])[CH2:5]1)[CH:22]=[CH2:21]
Reactant: COC(=O)[C@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Reactant: C=CCBr
Agent: O=[Ag]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCO[C@@H]1C[C@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.8 %

Procedure:
1.55 g (38.6 mmol) of sodium hydride are added in portions under nitrogen to the solution of 10.3 g (42 mmol) of 1-tert-butyl 2-methyl (2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxylate and 36.34 ml (420 mmol) of 3-bromo-1-propene in 100 ml of dimethylformamide (DMF), and the mixture is subsequently stirred at room temperature for 15 minutes. 9.73 g (42 mmol) of silver oxide are then added in portions to the reaction mixture, and the reaction mixture is left to stir at room temperature for a further 12 hours. The reaction mixture is then filtered, the filtrate is evaporated to dryness under reduced pressure, and the residue is taken up in 20 ml of saturated citric acid solution. After the precipitate has been filtered off, the filtrate is extracted twice with 20 ml of ethyl acetate each time. Drying of the combined organic phases over sodium sulfate and stripping-off of the solvent gives 11.6 g of 1-tert-butyl 2-methyl (2R,4R)-4-allyloxypyrrolidine-1,2-dicarboxylate as a red-brown oil; ESI 286.
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:11]2[C:6](=[C:7]([CH2:12][CH2:13]O)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH:4]1[CH3:15].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1.[Br:40]N1C(=O)CCC1=O>>[Br:40][CH2:13][CH2:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[CH2:5][CH:4]([CH3:15])[CH:3]2[O:2][CH3:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC1c2cccc(CCO)c2CC1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC1c2cccc(CCBr)c2CC1C
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a mixture of 12.9 g (62.5 mmol) of 2-(1-methoxy-2-methyl-2,3-dihydro-1H-inden-4-yl)ethanol and 16.4 g (62.5 mmol) of PPh3 in 300 ml of THF 11.1 g (62.5 mmol) of N-bromosuccinimide was added at vigorous stirring for 5 minutes at 0° C. This mixture was stirred for 2 hours at room temperature and then evaporated to dryness. A solution of the residue in 200 ml of hexanes was filtered through glass frit (G3), and the precipitate was additionally washed by 3×100 ml of hexanes. The combined organic extract was evaporated to dryness. The product was isolated from the residue using flash chromatography on silica gel 60 (40-63 μm, eluent: hexanes-ether=20:1, vol.). Yield 12.1 g (72%) of ca. 1 to 1 mixture of the diastereomers A and B. Anal. calc. for C13H17BrO: C, 58.01; H, 6.37. Found: C, 58.24; H, 6.22. 1H NMR (CDCl3): δ 7.30 (m, 2H, 6-H in indenyl of A and B), 7.20 (m, 2H, 7-H in indenyl of A and B), 7.12 (m, 2H, 5-H in indenyl of A and B), 4.52 (m, 1H, 1-H in indenyl of A), 4.41 (m, 1H, 1-H in indenyl of B), 3.53 (m, 4H, CH2CH2Br of A and B), 3.47 (s, 3H, OMe of B), 3.42 (s, 3H, OMe of A), 3.22 (dd, J=15.8 Hz, J=7.6 Hz, 1H, 3-H in indenyl of B), 3.15 (m, 4H, CH2CH2Br of A and B), 2.92 (dd, J=14.9 Hz, J=6.7 Hz, 1H, 3-H in indenyl of A), 2.48-2.71 (m, 3H, 2,3-H in indenyl of A and 2-H in indenyl of B), 2.42 (dd, J=15.8 Hz, J=4.8 Hz, 1H, 3-H in indenyl of B), 1.18 (d, J=7.1 Hz, 3H, 2-Me in indenyl of B), 1.13 (d, J=6.6 Hz, 3H, 2-Me in indenyl of A). 13C{1H} NMR (CDCl3): δ 143.1, 142.6, 142.2, 141.7, 135.1, 135.0, 128.5, 128.4, 126.8, 126.5, 124.1, 123.8, 91.3, 85.9, 56.7, 56.5, 39.4, 38.5, 36.80, 36.78, 36.7, 36.5, 31.7, 31.6, 19.4, 13.6.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([S:18][C:19]#[N:20])[CH:15]=[CH:14][C:12]=2[N:13]=1>N1C=CC=CC=1>[C:5]([NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([S:18][C:19]#[N:20])[CH:15]=[CH:14][C:12]=2[N:13]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: N#CSc1ccc2nc(N)sc2c1
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2ccc(SC#N)cc2s1
Reaction time: 0.08 h

Procedure:
5 cm3 of acetic anhydride are added dropwise to 7 cm3 of pyridine at 20° C. After 5 min, 1 g of 2-amino-6-thiocyanatobenzothiazole (commercial) is added. The yellow suspension is stirred for 4 h and then concentrated to dryness under vacuum. The residue is made into a paste in ethyl ether. The insoluble material is isolated by filtration, to give 1.1 g of 2-(acetylamino)-1,3-benzothiazol-6-ylthiocyanate in the form of a yellow solid, the characteristics of which are as follows: