Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:59]([CH3:61])[CH3:60])[C:7]([N:9]1[C@H:13]([C:14]2[NH:18][C:17]3[C:19]4[C:24]([CH:25]=[CH:26][C:16]=3[N:15]=2)=[CH:23][C:22]2[C:27]3[C:32]([CH2:33][O:34][C:21]=2[CH:20]=4)=[CH:31][C:30]([C:35]2[NH:39][C:38]([CH:40]4[CH2:44][CH2:43][CH2:42][N:41]4[C:45](=[O:55])[C@@H:46]([NH:50][C:51](=[O:54])[O:52][CH3:53])[CH:47]([CH3:49])[CH3:48])=[N:37][CH:36]=2)=[CH:29][CH:28]=3)[CH2:12][C@@H:11]2[CH2:56][CH2:57][CH2:58][C@H:10]12)=[O:8])=[O:4].[CH3:62][O:63][C:64](N[C@@H](C(C)C)C(O)=O)=O>>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:59]([CH3:61])[CH3:60])[C:7]([N:9]1[C@H:13]([C:14]2[NH:18][C:17]3[C:19]4[C:24]([CH:25]=[CH:26][C:16]=3[N:15]=2)=[CH:23][C:22]2[C:27]3[C:32]([CH2:33][O:34][C:21]=2[CH:20]=4)=[CH:31][C:30]([C:35]2[NH:39][C:38]([CH:40]4[CH2:44][CH2:43][CH2:42][N:41]4[C:45](=[O:55])[C@@H:46]([NH:50][C:51](=[O:54])[O:52][CH3:53])[CH:47]4[CH2:49][CH2:64][O:63][CH2:62][CH2:48]4)=[N:37][CH:36]=2)=[CH:29][CH:28]=3)[CH2:12][C@@H:11]2[CH2:56][CH2:57][CH2:58][C@H:10]12)=[O:8])=[O:4]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N1CCCC1c1ncc(-c2ccc3c(c2)COc2cc4c(ccc5nc([C@@H]6C[C@@H]7CCC[C@@H]7N6C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c54)cc2-3)[nH]1)C(C)C
Product: COC(=O)N[C@H](C(=O)N1[C@H](c2nc3ccc4cc5c(cc4c3[nH]2)OCc2cc(-c3cnc(C4CCCN4C(=O)[C@@H](NC(=O)OC)C4CCOCC4)[nH]3)ccc2-5)C[C@@H]2CCC[C@@H]21)C(C)C
Yield: 56 %

Procedure:
This compound was made in an analogous manner to methyl {(2S)-1-[2-(5-{2-[(2S,3aS,6aS)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}octahydrocyclopenta[b]pyrrol-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate, substituting (S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid for (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid to give methyl [(1S)-2-[2-(5-{2-[(2S,3aS,6aS)-1-{(2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl}octahydrocyclopenta[b]pyrrol-2-yl]-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl}-1H-imidazol-2-yl)pyrrolidin-1-yl]-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethyl]carbamate (0.039 g, 56%). MS (ESI) m/z 874.34 [M+H]+. 1H NMR (400 MHz, cd3od) δ 8.58 (s, 2H), 8.26-8.08 (m, 2H), 7.96-7.75 (m, 4H), 7.65-7.54 (m, 5H), 5.36-5.11 (m, 4H), 4.34-4.04 (m, 4H), 3.97-3.79 (m, 4H), 3.65 (s, 4H), 3.53-3.44 (m, 2H), 2.68-2.47 (m, 4H), 2.32-2.02 (m, 7H), 1.95-1.82 (m, 3H), 1.77-1.54 (m, 4H), 1.49-1.24 (m, 5H), 1.10-0.99 (m, 3H), 0.92-0.85 (m, 4H).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]([NH2:12])=[CH:5][C:6]([N+:9]([O-:11])=[O:10])=[CH:7][CH:8]=1.[CH3:13][N:14]=[C:15]=S>>[CH3:13][NH:14][C:15]1[N:2]([CH3:1])[C:3]2[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=2[N:12]=1
Reactant: CNc1ccc([N+](=O)[O-])cc1N
Reactant: CN=C=S
Product: CNc1nc2cc([N+](=O)[O-])ccc2n1C
Yield: 53.3 %

Procedure:
N1-methyl-4-nitro-benzene-1,2-diamine (2.0 g, 12.0 mmol) and methyl isothiocyanate (0.90 ml, 13.2 mmol) were coupled using the procedure of example one part B to give the title compound as a yellow solid (1.32 g, 53%). 1H NMR (300 MHz, d6-DMSO) δ 7.98 (d, J=2.1 Hz, 1H), 7.90 (dd, J=8.7 and 2.4 Hz, 1H), 7.32 (d, J=8.7 Hz, 1H), 7.15 (m, 1H), 3.55 (d, 3H), 2.95 (d, J=4.5 Hz, 3H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:15]=[CH:14][C:13]([N:16]4[C:20]([CH2:21][C@@H:22]5[CH2:26][CH2:25][N:24]([C:27]([CH:29]6[CH2:31][CH2:30]6)=[O:28])[CH2:23]5)=[N:19][NH:18][C:17]4=[O:32])=[CH:12][CH:11]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].I[CH:40]([CH3:42])[CH3:41].ClCCl>CN(C)C=O.O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:11]=[CH:12][C:13]([N:16]4[C:20]([CH2:21][C@@H:22]5[CH2:26][CH2:25][N:24]([C:27]([CH:29]6[CH2:30][CH2:31]6)=[O:28])[CH2:23]5)=[N:19][N:18]([CH:40]([CH3:42])[CH3:41])[C:17]4=[O:32])=[CH:14][CH:15]=3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: CC(C)I
Reactant: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4occc4c3)cc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: CC(C)n1nc(C[C@@H]2CCN(C(=O)C3CC3)C2)n(-c2ccc(-c3ccc4occc4c3)cc2)c1=O
Temperature: 80 °C
Reaction time: 16 h
Yield: 27.3 %

Procedure:
To a solution of 4-[4-(1-benzofuran-5-yl)phenyl]-5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-2,4-dihydro-3H-1,2,4-triazol-3-one (60 mg, 0.14 mmol) in N,N-dimethylformamide (1 mL) in a 5 mL microwaveable vial was added potassium carbonate (60 mg, 0.434 mmol, 3.1 eq) and 2-iodopropane (34 mg, 0.200 mmol, 1.4 eq). The vial was capped and purged with nitrogen gas, and the reaction was stirred for 16 h at 80° C. Analysis by LC/MS displayed the reaction had progressed only 15%. To the reaction mixture was added another equivalent of 2-iodopropane and the solution was irradiated in the microwave at 160° C. for 30 min. Analysis by LC/MS displayed the reaction had progressed to 35% completion. The reaction mixture was subjected to several iterations of microwave conditions, increasing the reaction temperature and reaction time, until the final conditions of 180° C. for 3 h was reached. It was determined via analysis by LC/MS that the reaction had proceeded to 90% completion. The reaction mixture was poured into a mixture of dichloromethane and water. The organic layer was separated. The aqueous layer was washed with dichloromethane. The organic extractions were combined and washed 3× with a dilute brine solution. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by reverse phase HPLC (LUNA C-18: 30×50 mm column; 25-65% acetonitrile w/0.1% TFA/water w/0.1% TFA). The product fractions were neutralized with the addition of saturated aq sodium bicarbonate, combined, and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the title compound (18 mg, 27%). MS(ES)+ m/e 471.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:11]2[CH2:16][CH2:15][CH:14]([NH:17][C:18]([C:20]3[NH:21][C:22]([CH3:25])=[CH:23][CH:24]=3)=[O:19])[CH2:13][CH2:12]2)[N:10]=1)[C:5](O)=[O:6].Cl.[O:27]([NH2:29])[CH3:28]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:11]2[CH2:16][CH2:15][CH:14]([NH:17][C:18]([C:20]3[NH:21][C:22]([CH3:25])=[CH:23][CH:24]=3)=[O:19])[CH2:13][CH2:12]2)[N:10]=1)[C:5]([NH:29][O:27][CH3:28])=[O:6]
Reactant: CON
Reactant: Cc1ccc(C(=O)NC2CCN(c3cc(C(=O)O)cc(Cl)n3)CC2)[nH]1
Agent: Cl
Product: CONC(=O)c1cc(Cl)nc(N2CCC(NC(=O)c3ccc(C)[nH]3)CC2)c1

Procedure:
The title compound was synthesised by an analogous method to Example 45 starting from 2-chloro-6-(4-{[(5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)isonicotinic acid (Example 332) and methoxylamine hydrochloride.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:10][C:11](=O)OC(C)(C)C.Cl.[CH:19](=O)/[CH:20]=C/C.[OH-].[NH4+].[CH3:26]O>O1CCOCC1.CCCCO>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]2[C:3]=1[N:10]=[C:11]([CH3:26])[CH:20]=[CH:19]2
Reactant: C/C=C/C=O
Reactant: COc1cccc(NC(=O)OC(C)(C)C)c1F
Reactant: CO
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CCCCO
Solvent: C1COCCO1
Product: COc1ccc2ccc(C)nc2c1F
Temperature: 106 °C
Yield: 67 %

Procedure:
A solution of tert-butyl 2-fluoro-3-methoxyphenylcarbamate (2.27 g, 9.41 mmol) in methanol (5 mL) was treated with 4N HCl in 1,4-dioxane (30 mL) for 2 hours. The solvent was removed under reduced pressure and the residue stirred in aqueous 6N HCl (20 mL) at 106° C. A solution of crotonaldehyde (1.56 mL, 18.8 mmol) in n-BuOH (2 mL) was added dropwise from an addition funnel over 20 minutes and the resulting mixture was heated at reflux for an additional 2 hours. The reaction was cooled to ambient temperature and the mixture carefully pH adjusted to 9 with ammonium hydroxide. The mixture was extracted with dichloromethane and the combined dichloromethane extracts were dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography (Biotage 40M; 10% ethyl acetate/hexanes) to afford 8-fluoro-7-methoxy-2-methylquinoline (1.20 g, 6.28 mmol, 67%).
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.II.[I:16](O)(=O)(=O)=O>C(O)(=O)C>[I:16][C:9]1[CH:8]=[CH:7][C:6]2[C:5]3[C:13](=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH2:12][C:11]=2[CH:10]=1
Reactant: [O-][I+3]([O-])([O-])O
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: II
Solvent: CC(=O)O
Product: Ic1ccc2c(c1)Cc1ccccc1-2
Temperature: 80 °C
Reaction time: 4 h
Yield: 644.4 %

Procedure:
A 250 mL round-bottomed flask was charged with 20.0 g (120 mmol) fluorene, 16.0 g (60 mmol) iodine and 4.0 g (17 mmol) periodic acid. 150 mL (80%) acetic acid was added to the reaction mixture. The mixture was stirred under nitrogen at 80° C. for 4 hours. The mixture was then allowed to cool to ambient temperature. The solid residue was vacuum filtered, dissolved in toluene and then washed with 5% sodium hydrogen sulphite (to remove excess iodine). The toluene solution was concentrated under vacuo and then passed through a flash column using toluene as the eluent to give 32.0 g (91% yield) of the product (off white solid).
Reaction SMILES: CS(O[CH:6]([C:9]1[N:10]=[C:11]2[CH2:26][CH2:25][CH2:24][CH2:23][N:12]2[C:13](=[O:22])[C:14]=1[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:7][CH3:8])(=O)=O.[NH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35].[I-].[K+].CO>CN(C=O)C.C(Cl)Cl>[NH3:10].[CH2:15]([C:14]1[C:13](=[O:22])[N:12]2[CH2:23][CH2:24][CH2:25][CH2:26][C:11]2=[N:10][C:9]=1[CH:6]([NH:27][CH2:28][CH2:29][CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[CH2:7][CH3:8])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: CCC(OS(C)(=O)=O)c1nc2n(c(=O)c1Cc1ccccc1)CCCC2
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: CCC(NCCCNC(=O)OC(C)(C)C)c1nc2n(c(=O)c1Cc1ccccc1)CCCC2
Product: N
Temperature: 60 °C
Reaction time: 24 h
Yield: 0.1 %
Yield: 28.6 %

Procedure:
A mixture of 0.106 g (0.28 mmol) of the product from Step 9 (25), 0.15 g (0.84 mmol) of tert-butyl 3-aminopropylcarbamate, and 0.005 g (0.03 mmol) of potassium iodide in 5 mL of DMF was stirred at 60° C. under nitrogen for 24 hours. The reaction was quenched with water, extracted with ethyl acetate (4×) and the combined organic layers were washed with saturated NaHCO3 and brine and dried over MgSO4. The solvent was removed in vacuo and the crude reaction mixture was subjected to flash chromatography on a 7 cm column. Elution with a gradient of 50% ethyl acetate in hexanes, 100% ethyl acetate, 3% methanol and 0.1% ammonia in DCM, and 10% methanol and 0.1% ammonia in DCM yielded 0.019 g (0.04 mmol, 15%) of tert-butyl 3-{[1-(3-benzyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-2-yl)propyl]amino}propylcarbamate (26) as a clear oil.
Reaction SMILES: [C:1]1(=[O:7])O[C:4](=[O:5])[CH:3]=[CH:2]1.[NH2:8][C:9]1[CH:47]=[CH:46][C:12]([O:13][C:14]2[CH:45]=[CH:44][C:17]([C:18]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([CH3:43])([CH3:42])[C:28]4[CH:33]=[CH:32][C:31]([O:34][C:35]5[CH:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=5)=[CH:30][CH:29]=4)=[CH:23][CH:22]=3)([CH3:20])[CH3:19])=[CH:16][CH:15]=2)=[CH:11][CH:10]=1>C1(C)C(C)=CC=CC=1.CN(C)C=O.P(=O)(O)(O)O>[C:1]1(=[O:7])[N:41]([C:38]2[CH:39]=[CH:40][C:35]([O:34][C:31]3[CH:32]=[CH:33][C:28]([C:27]([C:24]4[CH:25]=[CH:26][C:21]([C:18]([CH3:20])([CH3:19])[C:17]5[CH:16]=[CH:15][C:14]([O:13][C:12]6[CH:11]=[CH:10][C:9]([N:8]7[C:1](=[O:7])[CH:2]=[CH:3][C:4]7=[O:5])=[CH:47][CH:46]=6)=[CH:45][CH:44]=5)=[CH:22][CH:23]=4)([CH3:42])[CH3:43])=[CH:29][CH:30]=3)=[CH:36][CH:37]=2)[C:4](=[O:5])[CH:3]=[CH:2]1
Reactant: O=C1C=CC(=O)O1
Reactant: CC(C)(c1ccc(Oc2ccc(N)cc2)cc1)c1ccc(C(C)(C)c2ccc(Oc3ccc(N)cc3)cc2)cc1
Agent: O=P(O)(O)O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1C
Product: CC(C)(c1ccc(Oc2ccc(N3C(=O)C=CC3=O)cc2)cc1)c1ccc(C(C)(C)c2ccc(Oc3ccc(N4C(=O)C=CC4=O)cc3)cc2)cc1
Temperature: 25 °C
Yield: 96.5 %

Procedure:
In the same reactor used in Example 2A, there were placed 26.5 g (0.27 mole) of maleic anhydride, 0.7 g of phosphoric acid and 150 ml of mixed xylene. A solution was then added dropwise thereto under reflux of xylene, the solution having been prepared by thermally dissolving 52.8 g (0.1 mole) of 1,4-bis[4(4-aminophenoxy),α,α-dimethylbenzyl)benzene obtained in Example 1A in a mixture of 100 ml of mixed xylene and 50 ml of N,N-dimethylformamide. A dropping time of 5 hours and an aging time of 2 hours were used in order to carry out the reaction. The reaction solution was concentrated to about 1/2 the original amount and then cooled. When a temperature of 80° C. had been reached; 50 g of water was added thereto. Afterward, the solution was slowly cooled with stirring, so that crystals were precipitated. The crystals were then cooled to room temperature, filtered, and washed with cold methanol. 66.5 g of desired crude 1,4-bis[4-(4-maleimidophenoxy)-α, α-dimethylbenzyl]benzene was obtained. Its yield was 96.7%, and its purity according to HLC was 97.5%.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]2[C:9]([C:23]([OH:25])=O)=[C:10]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]([F:22])([F:21])[F:20])[S:11][C:5]=2[N:4]([CH2:26][CH:27]([CH3:29])[CH3:28])[C:3]1=[O:30].C(Cl)(=O)[C:32]([Cl:34])=O>ClCCl.CN(C)C=O>[Cl:34][CH2:32][C:23]([C:9]1[C:6]2[C:7](=[O:8])[N:2]([CH3:1])[C:3](=[O:30])[N:4]([CH2:26][CH:27]([CH3:28])[CH3:29])[C:5]=2[S:11][C:10]=1[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]([F:21])([F:22])[F:20])=[O:25]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(C(=O)O)c(Cc3ccccc3C(F)(F)F)sc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(C(=O)CCl)c(Cc3ccccc3C(F)(F)F)sc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1,2,3,4-Tetrahydro-3-methyl-1-(2-methylpropyl)-2,4-dioxo-6-[[2-(trifluoromethyl)phenyl]methyl]-thieno[2,3-d]pyrimidine-5-carboxylic acid, (prepared by the method of Example 8a) (3.665 g) was suspended in dichloromethane (70 ml) containing dimethyl formamide (1 drop) and treated with oxalyl chloride (1.47 ml). 1 hr after gas evolution ceased the reaction was concentrated in vacuo and stored under high vacuum for 1 h. The residue was redissolved in dichloromethane (50 ml) and treated with triethylamine (1 ml). To this solution was added trimethylsilyldiazomethane (7 mls of 2M solution in tetrahydrofuran) and the reaction was stirred at room temperature under an atmosphere of nitrogen for 4 hrs before HCl (8 ml, 4M in dioxane) was added. The reaction was stirred for 18 hrs before being concentrated in vacuo and the residue was purified by chromatography eluting with 2:1 isohexane:diethyl ether. The product was recrystallised from ethyl acetate and isohexane to yield the subtitle compound as white needles(4.616 g)
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[C:4]([C:6]1[C:7]2[CH:15]=[C:14]([C:16]([O:18]C)=[O:17])[CH:13]=[CH:12][C:8]=2[O:9][C:10]=1[CH3:11])=O.CO.[OH-].[Na+]>O1CCCC1>[C:16]([C:14]1[CH:13]=[CH:12][C:8]2[O:9][C:10]([CH3:11])=[C:6]([CH2:4][C:3]3[CH:20]=[CH:21][C:22]([Cl:24])=[CH:23][C:2]=3[Cl:1])[C:7]=2[CH:15]=1)([OH:18])=[O:17]
Reactant: COC(=O)c1ccc2oc(C)c(C(=O)c3ccc(Cl)cc3Cl)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1oc2ccc(C(=O)O)cc2c1Cc1ccc(Cl)cc1Cl

Procedure:
A mixture of 3-(2,4-dichlorobenzoyl)-5-(methoxycarbonyl)-2-methylbenzo-[b]furan (0.57 g, 1.6 mmol), methanol (6 ml), tetrahydrofuran (6 ml) and a 2M aqueous sodium hydroxide solution (8.5 ml) was refluxed under heating for 40 min. The reaction mixture was concentrated under reduced pressure and water was added to the residue. The mixture was acidified with 3N hydrochloric acid and the precipitated solid was extracted with hot ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The desiccant was filtered offhand the filtrate was concentrated under reduced pressure to give the objective compound (0.54 g, quantitative) as colorless crystals.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>C1COCC1>[S:20]([N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([CH:10]=[O:11])[C:4]=2[CH:3]=[CH:2]1)([C:17]1[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=1)(=[O:22])=[O:21]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=Cc1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C=O)cccc32)cc1
Reaction time: 0.5 h
Yield: 15 %

Procedure:
To a solution of 1H-indole-4-carbaldehyde (2.9 g, 20 mmol) in THF (50 mL) cooled in an ice bath was added NaH (0.96 g, 60% in oil, 24 mmol) with vigorous stirring. After stirring for 30 min, 4-toluenesulfonyl chloride (5.73 g, 30 mmol) was added. The mixture was stirred at RT overnight and the solvent was removed in vacuo. The residue was diluted with DCM (500 mL) and water (50 mL). The organic layer was separated, dried (MgSO4), filtered and concentrated. The crude product was purified by SiO2 chromatography eluting with a petroleum ether/EtOAc gradient (5 to 10% EtOAc) to afford 900 mg (15%) of 1-tosyl-1H-indole-4-carbaldehyde (42) as white solid: MS (ESI) m/z=300.1 [M+1]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH3:15])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:6]=2[CH:22]=1>CN(C)C=O.CCN(CN(CC)CC)CC.C(Cl)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][CH2:12][N:11]([CH2:5][CH3:4])[CH2:10][CH3:9])=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[C:6]=2[CH:22]=1
Reactant: Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccn1)=NC2
Agent: CCN(CC)CN(CC)CC
Solvent: CC(=O)Cl
Solvent: CN(C)C=O
Product: CCN(CC)CCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccn1)=NC2

Procedure:
In the manner given in Example 1, a solution of 8-chloro-1-methyl-6-(pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine in dimethylformamide, N,N,N',N'-tetraethyldiaminomethane and acetylchloride (in 0.5 molar excess compared to the N,N,N',N'-tetraethyldiaminomethane) are reacted together to give 8-chloro-1-[2-(diethylamino)ethyl]-6-(2-pyridyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:8])=[CH:6][C:5](=[O:9])[N:4]([CH3:10])[C:3]1=[O:11].[C:12](Cl)(=[O:14])[CH3:13]>C1C=CC=CC=1.[Cl-].[Zn+2].[Cl-]>[C:12]([C:6]1[C:5](=[O:9])[N:4]([CH3:10])[C:3](=[O:11])[N:2]([CH3:1])[C:7]=1[CH3:8])(=[O:14])[CH3:13]
Reactant: Cc1cc(=O)n(C)c(=O)n1C
Reactant: CC(=O)Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: c1ccccc1
Product: CC(=O)c1c(C)n(C)c(=O)n(C)c1=O

Procedure:
A mixture of Step 1 intermediate (10.0 g, 62.893 mmol), acetyl chloride (4.47 ml, 62.893 mmol) and anhydrous zinc chloride (8.57 g, 62.893 mmol) in dry benzene (150 ml) was refluxed for 48 h. The solvent was completely evaporated under reduced pressure, diluted with water (500 ml) and extracted with chloroform (3×150 ml). The combined organic layers were washed with water (150 ml), dried (Na2SO4) and concentrated. The residue obtained was purified by silica gel column chromatography by using 30% ethyl acetate in petroleum ether to afford 4.7 g of the product as a pale yellow solid; 1H NMR (300 MHz, CDCl3) δ 2.38 (s, 3H), 2.55 (s, 3H), 3.37 (s, 3H), 3.48 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH:36][CH3:37])(=[O:35])=[O:34])=[CH:29][CH:28]=1>>[CH3:37][NH:36][S:33]([C:30]1[CH:29]=[CH:28][C:27]([C:2]#[C:1][C:3]2[CH:4]=[N:5][N:6]3[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=4)=[N:8][C:7]=23)=[CH:32][CH:31]=1)(=[O:34])=[O:35]
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: CNS(=O)(=O)c1ccc(Br)cc1
Product: CNS(=O)(=O)c1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and 4-bromo-N-methyl-benzenesulfonamide (example B.27) (276 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (390 mg, 74%). MS (ISP) 525.2 [(M+H)+]; mp 231-233° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:12][CH:13]([CH3:15])[CH3:14])=[C:7]([CH:11]=1)[C:8]([OH:10])=O)#[N:2].FC(F)(F)C(O)=O.[F:23][C:24]([F:37])([F:36])[C:25]1[S:29][C:28]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)=[N:27][N:26]=1>>[CH:13]([O:12][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:11][C:7]=1[C:8]([N:33]1[CH2:32][CH2:31][N:30]([C:28]2[S:29][C:25]([C:24]([F:36])([F:23])[F:37])=[N:26][N:27]=2)[CH2:35][CH2:34]1)=[O:10])([CH3:15])[CH3:14]
Reactant: FC(F)(F)c1nnc(N2CCNCC2)s1
Reactant: CC(C)Oc1ccc(C#N)cc1C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Oc1ccc(C#N)cc1C(=O)N1CCN(c2nnc(C(F)(F)F)s2)CC1
Yield: 80 %

Procedure:
Prepared in analogy to example 1 (b) from 5-cyano-2-isopropoxy-benzoic acid (Example A28) and 1-(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-piperazine trifluoroacetate (Example 62(b)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) to yield the title compound as a white solid (yield 80%). MS (m/e): 426.0 (M+H+, 100%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]([OH:15])=O)[N:12]=2)=[C:4]([NH:16][CH:17]([CH3:19])[CH3:18])[CH:3]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][CH:22]([OH:26])[CH2:21]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]([N:20]3[CH2:25][CH2:24][CH2:23][CH:22]([OH:26])[CH2:21]3)=[O:15])[N:12]=2)=[C:4]([NH:16][CH:17]([CH3:19])[CH3:18])[CH:3]=1
Reactant: OC1CCCNC1
Reactant: CC(C)Nc1cc(Cl)ncc1-c1nc(C(=O)O)cs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Nc1cc(Cl)ncc1-c1nc(C(=O)N2CCCC(O)C2)cs1
Temperature: 25 °C

Procedure:
The 2-(6-chloro-4-(isopropylamino)pyridin-3-yl)thiazole-4-carboxylic acid (23a) (100 mg, 0.336 mmol) was dissolved in DMF (5 mL), piperidin-3-ol (1.679 mmol) was added and stirred at room temperature. Added DIPEA (1.343 mmol), followed by addition of HATU (1.008 mmol) and stirred for 3 h. The reaction mixture was concentrated under reduced pressure to remove excess of DMF. The residue obtained was partitioned between water and EtOAc. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The crude material obtained was purified by column chromatography through silica gel and MeOH: CHCl3 as eluent to afford the title compound, (2-(6-chloro-4-(isopropylamino)pyridin-3-yl)thiazol-4-yl)(3-hydroxypiperidin-1-yl)methanone.
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[CH:18][N:17]=3)[CH:5]=[CH:4][C:3]1=2.[C:25](O)(=[O:27])[CH3:26].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][C:2]1([CH3:24])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]#[C:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][O:23][C:25](=[O:27])[CH3:26])=[CH:18][N:17]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC(=O)O
Reactant: CC1(C)CCC(C)(C)c2cc(C#Cc3ccc(CO)cn3)ccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(=O)OCc1ccc(C#Cc2ccc3c(c2)C(C)(C)CCC3(C)C)nc1

Procedure:
A solution of 3.195 g (10 mmol) of 2-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)ethynyl]-5-hydroxymethylpyridine, 600 mg (10 mmol) of glacial acetic acid, 2.06 g (10 mmol) of dicyclohexylcarbodiimide and 460 mg (3.765 mmol) of 4-dimethylaminopyridine in 150 ml methylene chloride is stirred at room temperature for 48 hours. The reaction mixture is then filtered and the residue washed with 50 ml of methylene chloride. The filtrate is then concentrated in vacuo and the residue is purified by chromatography followed by recrystallation to give the title compound.