Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@H:9]2[N:13]([C:14]([C:16]3([C:19]([F:22])([F:21])[F:20])[CH2:18][CH2:17]3)=[O:15])[CH2:12][C@@H:11](OS(C3C=CC=CC=3)(=O)=O)[CH2:10]2)=[O:8])[CH2:5][CH2:4]1)#[N:2].C(=O)([O-])[O-].[K+].[K+].[Cl:39][C:40]1[CH:45]=[C:44]([O:46][C@@H:47]([CH3:52])[C:48]([F:51])([F:50])[F:49])[CH:43]=[CH:42][C:41]=1[SH:53].O>CC(N(C)C)=O.O1CCCC1>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:10][C@@H:11]([S:53][C:41]3[CH:42]=[CH:43][C:44]([O:46][C@@H:47]([CH3:52])[C:48]([F:49])([F:50])[F:51])=[CH:45][C:40]=3[Cl:39])[CH2:12][N:13]2[C:14]([C:16]2([C:19]([F:20])([F:22])[F:21])[CH2:18][CH2:17]2)=[O:15])=[O:8])[CH2:4][CH2:5]1)#[N:2]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@H](OS(=O)(=O)c3ccccc3)CN2C(=O)C2(C(F)(F)F)CC2)CC1
Reactant: C[C@H](Oc1ccc(S)c(Cl)c1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: O
Product: C[C@H](Oc1ccc(S[C@@H]2C[C@@H](C(=O)NC3(C#N)CC3)N(C(=O)C3(C(F)(F)F)CC3)C2)c(Cl)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 110.5 %

Procedure:
Benzenesulfonic acid (3S,5S)-5-(1-cyano-cyclopropylcarbamoyl)-1-(1-trifluoromethyl-cyclopropanecarbonyl)-pyrrolidin-3-yl ester (225 g, 477 mmol) was dissolved in dimethylacetamide (1.125 L) and potassium carbonate (166.5 g, 1.193 mol) was added. At room temperature, a solution of 2-chloro-4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-benzenethiol (142 g, 553.2 mmol) in tetrahydrofuran (135 mL) was added slowly, keeping the internal temperature below 29° C. (ice bath cooling necessary). The mixture was stirred for 5.5 h at room temperature. After addition of ice (700 g) and water (2 L), the mixture was extracted with tert-butyl-methylether (1×1.5 L, 3×750 mL). The combined organic extracts were washed with brine (450 mL) and concentrated in vacuo to yield the title compound as a brown viscous oil (300.4 g). The crude product (containing dimethylacetamide) was used in the next step without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[C:10]([O:11][CH2:12][CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])=[C:9]([O:23][CH3:24])[C:8]([Cl:25])=[C:7]([CH3:26])[C:6]=1[C:27](=[O:29])[CH3:28].[NH:30]1[CH:34]=[N:33][CH:32]=[N:31]1>>[Cl:25][C:8]1[C:7]([CH3:26])=[C:6]([C:27](=[O:29])[CH3:28])[C:5]([O:4][CH2:3][CH2:2][N:30]2[CH:34]=[N:33][CH:32]=[N:31]2)=[C:10]([O:11][CH2:12][CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)[CH3:15])[C:9]=1[O:23][CH3:24]
Reactant: c1nc[nH]n1
Reactant: COc1c(Cl)c(C)c(C(C)=O)c(OCCBr)c1OCCC(C)c1ccc(F)cc1
Product: COc1c(Cl)c(C)c(C(C)=O)c(OCCn2cncn2)c1OCCC(C)c1ccc(F)cc1
Yield: 72 %

Procedure:
Example 8a (85 mg, 0.17 mmol) was reacted with 1,2,4-triazole (2.5 eq.) and CsCO3 (1.94 eq.) as described under General Procedure L and the crude mixture was purified by flash chromatography (silica gel, Et2O) to afford the title compound as a pale yellow oil (58 mg, 72%). 1H NMR (300 MHz, CDCl3) δ 8.12 (s, 1H), 7.95 (s, 1H), 7.17 (m, 2H), 7.01-6.95 (m, 2H), 4.39-4.36 (m, 4H), 3.83-3.78 (m, 5H), 2.91 (m, 1H), 2.32 (s, 3H), 2.16 (s, 3H), 1.94-1.89 (m, 2H), 1.27 (d, J=6.9 Hz, 3H). MS (ES+) m/z 476.2 (M+H+).
Reaction SMILES: [C:1]1([C:7]([CH:9]=O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.OS([O-])=O.[Na+].[CH2:16]([NH2:19])[CH2:17][NH2:18].[C-:20]#[N:21].[Na+]>O.CO>[C:1]1([C:7]2[NH:19][CH2:16][CH2:17][NH:18][C:9]=2[C:20]#[N:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NCCN
Reactant: [C-]#N
Reactant: O=CC(=O)c1ccccc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#CC1=C(c2ccccc2)NCCN1
Temperature: 50 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
13.8 parts of phenylglyoxal and 40 parts by volume of water are initially taken and heated to about 50° C., 61 parts of 38% strength aqueous NaHSO3 solution are introduced, and methanol is added in an amount sufficient to dissolve virtually all solid material. Thereafter, 6 parts of ethylenediamine are added at about 30° C., the mixture is heated at 50° C. for 30 minutes and then cooled to about 10° C., a solution of 5.2 parts of 95% pure NaCN in 13 parts by volume of water is added at this temperature, stirring is continued for a further 2 hours at room temperature and working up is carried out as described under Example 4. 10 parts (54% of theory) of 1,4,5,6-tetrahydro-3-phenyl-2-cyanopyrazine are obtained in the form of a reddish brown, viscous oil. The mass spectrum of this product shows the molecular peak expected for the empirical formula C11H11N3, at e/m=185, and its NMR spectrum exhibits the bands typical of the different NH groups, at about 3.5 ppm (N1 -H) and about 6.15 ppm (N4 -H).
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[C:3](=[O:27])[CH2:4][O:5][C:6]1[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:9]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)[NH:8][N:7]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:42](O)(=[O:44])[CH3:43]>C1(C)C=CC=CC=1>[C:42]([N:8]1[C:9]([C:17]2[CH:18]=[CH:19][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:21][CH:22]=2)=[C:10]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:6]([O:5][CH2:4][C:3](=[O:27])[C:2]([CH3:29])([CH3:28])[CH3:1])=[N:7]1)(=[O:44])[CH3:43]
Reactant: CC(C)(C)C(=O)COc1n[nH]c(-c2ccc(S(C)(=O)=O)cc2)c1-c1ccccc1
Reactant: CC(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)n1nc(OCC(=O)C(C)(C)C)c(-c2ccccc2)c1-c1ccc(S(C)(=O)=O)cc1
Yield: 19 %

Procedure:
A mixture of 3,3-dimethyl-1-[(5-(4-(methylsulphonyl)phenyl)-4-phenyl-1H-pyrazol-3-yl)oxy]butan-2-one (145 mg, 0.35 mmol), prepared according to the method of Example 32B, p-toluene-sulfonic acid hydrate (15 mg), and molecular sieves (4 g) in toluene (35 mL) and acetic acid (5 mL) was refluxed for 24 hours. The mixture was concentrated in vacuo, and the residue was purified by chromatography (silica gel, 1:1 hexanes-ethyl acetate) to provide the desired product (yield: 30 mg; 19%). MP 189-191° C.; MS (APCI+) m/z 455 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ1.22 (s, 9H), 2.48 (s, 3H), 3.28 (s, 3H), 5.37 (s, 2H), 7.23 (m, 5H), 7.60 (d, J=9 Hz, 2H), 7.90 (d, J=9 Hz, 2H); Anal. calc. for C24H26N2O5S.0.5 H2O: C, 62.18; H, 5.87; N, 6.04. Found: C, 62.38; H, 5.81; N, 5.83.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:44]=[CH:45][CH:46]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[C:21]([O:32][CH3:33])=[N:22][C:23]([N:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]5)=[CH:24][CH:25]=4)[CH:18]=3)[N:13]([S:34]([C:37]3[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:12]=2)[CH:8]=[N:7]1.[CH3:47][C@H:48]1[CH2:50][O:49]1.CCN(C(C)C)C(C)C>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:44]=[CH:45][CH:46]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][N:29]([CH2:47][C@@H:48]([OH:49])[CH3:50])[CH2:28][CH2:27]5)=[N:22][C:21]=4[O:32][CH3:33])[CH:18]=3)[N:13]([S:34]([C:37]3[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:12]=2)[CH:8]=[N:7]1
Reactant: C[C@H]1CO1
Reactant: COc1nc(N2CCNCC2)ccc1-c1cnc2c(c1)c(-c1cnn(Cc3cccc(F)c3)c1)cn2S(=O)(=O)c1ccc(C)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COc1nc(N2CCN(C[C@H](C)O)CC2)ccc1-c1cnc2c(c1)c(-c1cnn(Cc3cccc(F)c3)c1)cn2S(=O)(=O)c1ccc(C)cc1
Yield: 108.2 %

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(2-methoxy-6-(piperazin-1-yl)pyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (52 mg. 0.081 mmol) was alkylated using (S)-2-methyloxirane (8 mg, 0.137 mmol), DIPEA (18 mg, 0.137 mmol) and ethanol (5 mL) to get 61 mg (95.3%) of the titled compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:8]2[N:9]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:14][CH2:13]3)[N:11]=[C:7]2[CH:6]=[C:5]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[Cl:28])[N:4]=1.Cl.Cl.[NH2:31][CH2:32][CH2:33][NH:34][C:35]1[CH:42]=[CH:41][C:38]([C:39]#[N:40])=[CH:37][N:36]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[ClH:2].[Cl:28][C:22]1[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=1[C:5]1[N:4]=[C:3]([NH:31][CH2:32][CH2:33][NH:34][C:35]2[N:36]=[CH:37][C:38]([C:39]#[N:40])=[CH:41][CH:42]=2)[N:8]2[N:9]=[C:10]([CH:12]3[CH2:13][CH2:14][N:15]([CH:18]([CH3:20])[CH3:19])[CH2:16][CH2:17]3)[N:11]=[C:7]2[CH:6]=1
Reactant: CC(C)N1CCC(c2nc3cc(-c4ccc(F)cc4Cl)nc(Cl)n3n2)CC1
Reactant: N#Cc1ccc(NCCN)nc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)N1CCC(c2nc3cc(-c4ccc(F)cc4Cl)nc(NCCNc4ccc(C#N)cn4)n3n2)CC1
Temperature: 130 °C

Procedure:
55 mg (0.11 mmol) of 5-chloro-7-(2-chloro-4-fluorophenyl)-2-[1-(propan-2-yl)piperidin-4-yl]-[1,2,4]triazolo[1,5-c]pyrimidine hydrochloride (Example 52A), 27.3 mg (0.14 mmol) of 6-[(2-aminoethyl)amino]pyridine-3-carbonitrile hydrochloride (Example 2A) and 0.12 ml (0.69 mmol) of N,N-diisopropylethylamine were initially charged in 1 ml of DMSO. The mixture was heated in the microwave at 130° C. for 30 min. This gave, after purification of the crude product by preparative HPLC (Method 11), 28 mg (43% of theory) of the product as a solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[CH3:10][NH:11][CH:12]1[CH2:29][CH2:28][C:15]2([CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH2:14][CH2:13]1.C(N(CC)CC)C>C(O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:11]([CH3:10])[CH:12]2[CH2:29][CH2:28][C:15]3([CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:17][CH2:16]3)[CH2:14][CH2:13]2)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CNC1CCC2(CC1)CCN(C(=O)OC(C)(C)C)CC2
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN(c1nc(Cl)ncc1Cl)C1CCC2(CC1)CCN(C(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.5 %

Procedure:
To a solution of 2,4,5-trichloropyrimidine (300 mg, 1.64 mmol) and tert-butyl 9-(methylamino)-3-azaspiro[5.5]undecane-3-carboxylate (511.18 mg, 1.81 mmol) in ethanol (15 mL) was added N,N-diethylethanamine (331.90 mg, 3.28 mmol). The reaction mixture was stirred at rt overnight and then concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/10 to 1/5) to give the title compound as yellow oil (101.83 mg, 14.5%).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[CH:13]([O:16][C:17]1[CH:22]=[CH:21][C:20]([S:23][C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=2[NH2:31])=[CH:19][CH:18]=1)([CH3:15])[CH3:14]>>[CH:13]([O:16][C:17]1[CH:18]=[CH:19][C:20]([S:23][C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=2[NH:31][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)=[CH:21][CH:22]=1)([CH3:15])[CH3:14]
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: Cc1ccc(Sc2ccc(OC(C)C)cc2)c(N)c1
Product: Cc1ccc(Sc2ccc(OC(C)C)cc2)c(Nc2ccnc3nc(C)ccc23)c1

Procedure:
The product from Example 1d (250 mg, 1.56 mmol) was reacted with the product from Example 56a (427 mg, 1.56 mmol) for 5 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the trifluoroacetic acid salt (185 mg, 23%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.23 (d, J=6.25 Hz, 6H) 2.34 (s, 3H) 2.76 (s, 3H) 4.48-4.58 (m, 1H) 6.27 (d, J=6.99 Hz, 1H) 6.81 (d, J=8.82 Hz, 2H) 7.14 (d, J=8.09 Hz, 1H) 7.22 (d, J=8.82 Hz, 2H) 7.27 (s, 1H) 7.30 (s, 1H) 7.79 (d, J=8.82 Hz, 1H) 8.41 (d, J=6.99 Hz, 1H) 8.99 (d, J=8.46 Hz, 1H) 10.99 (s, 1H) 14.36 (s, 1H); MS (ESI+) m/z 416 (M+H)+.
Reaction SMILES: [CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:26]([OH:28])=O)=[C:21]5[C:25]=4[O:24][CH2:23][CH2:22]5)[N:12]=[CH:11][C:10]=3[N:9]([CH3:29])[C:8](=[O:30])[C@H:7]2[CH2:31][CH3:32])[CH2:5][CH2:4][CH2:3][CH2:2]1.F[B-](F)(F)F.[N:38]1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[CH3:64][N:65]1[CH2:70][CH2:69][CH:68](N)[CH2:67][CH2:66]1.[Cl-].[Na+]>ClCCl>[CH:1]1([N:6]2[C:15]3[N:14]=[C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([C:26]([NH:38][CH:66]5[CH2:67][CH2:68][CH2:69][CH2:70][N:65]5[CH3:64])=[O:28])=[C:21]5[C:25]=4[O:24][CH2:23][CH2:22]5)[N:12]=[CH:11][C:10]=3[N:9]([CH3:29])[C:8](=[O:30])[C@H:7]2[CH2:31][CH3:32])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN1CCC(N)CC1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)O)c4c3OCC4)nc2N1C1CCCC1
Agent: F[B-](F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)NC4CCCCN4C)c4c3OCC4)nc2N1C1CCCC1
Reaction time: 0.17 h
Yield: 79 %

Procedure:
7-[[(7R)-8-Cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxylic acid 1q (300 mg, 0.68 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetra methyluronium tetrafluoroborate (148 mg, 0.46 mmol) were dissolved in 30 mL of dichloromethane, followed by the addition of diisopropylethylamine (131 mg, 1 mmol). The reaction solution was stirred for 10 minutes followed by the addition of 1-methyl-piperidin-4-yl amine (52 mg, 0.46 mmol), and stirred for another 3 hours. The reaction mixture was added with 30 mL of saturated sodium chloride solution and 30 mL of dichloromethane successively, then seperated. The organic phase was washed with saturated sodium carbonate solution (50 mL×2), water (50 mL) and saturated sodium chloride solution (50 mL) successively, then dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-N-(1-methyl-piperidyl)-2,3-dihydrobenzofuran-4-carboxamide 1 (194 mg, yield: 79%) as a white solid.
Reaction SMILES: [OH-].[Na+].Br[CH2:4][CH2:5][CH2:6][C:7]#[N:8].[CH3:9][C:10]1[NH:11][CH:12]=[CH:13][N:14]=1>O.CN(C)C=O>[CH3:9][C:10]1[N:11]([CH:6]([CH2:5][CH3:4])[C:7]#[N:8])[CH:12]=[CH:13][N:14]=1
Reactant: N#CCCCBr
Reactant: Cc1ncc[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(C#N)n1ccnc1C
Reaction time: 8 h

Procedure:
12.8 g of sodium hydroxide was dissolved in 12 ml of water and diluted with 150 ml of dimethylformamide containing 20.3 g of 2-methylimidazole. A solution of 50.0 g of 4-bromobutyronitrile in 100 ml of dimethylformamide was added slowly maintaining the temperature below 30° C. The resulting mixture was stirred overnight and was concentrated. The residue was taken up in 150 ml of brine and extracted with dichloromethane. The combined organic layers were dried over potassium carbonate and evaporated. The product was distilled. The early fractions were mostly 2-methylimidazole and were discarded. The main fraction 23.2 g, bp 160°-185° C./2.5 mm, was redistilled to give 14.7 g (31%) of (2-methyl-1H-imidazol-1-yl)-butanitrile, bp 140°-147° C./0.5 mm.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]([CH:11]1[CH2:16][CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]1)([OH:10])[CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH3:9]>C(O)(C(F)(F)F)=O.ClCCl>[F:25][C:2]([F:1])([F:24])[C:3]([CH:11]1[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]1)([OH:10])[CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH3:9]
Reactant: COCCCCC(O)(C1CCCN(C(=O)OC(C)(C)C)C1)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCCCC(O)(C1CCCNC1)C(F)(F)F
Reaction time: 0.5 h

Procedure:
Tert-butyl 3-(1,1,1-trifluoro-2-hydroxy-6-methoxyhexan-2-yl)piperidine-1-carboxylate (20 mg) was dissolved in 1:1 TFA/dichloromethane (4 mL). The mixture was stirred for 30 min. The mixture was concentrated to afford 1,1,1-trifluoro-6-methoxy-2-(piperidin-3-yl)hexan-2-ol which was used without purification.
Reaction SMILES: C[O-].[Na+].C([O:7][CH2:8][CH2:9][C:10]1[CH:11]=[C:12]([S:24]([NH2:27])(=[O:26])=[O:25])[C:13]2[C:18]([C:19]=1[Br:20])=[CH:17][CH:16]=[CH:15][C:14]=2[N+:21]([O-:23])=[O:22])(=O)C>CO>[Br:20][C:19]1[C:18]2[C:13](=[C:14]([N+:21]([O-:23])=[O:22])[CH:15]=[CH:16][CH:17]=2)[C:12]([S:24]([NH2:27])(=[O:25])=[O:26])=[CH:11][C:10]=1[CH2:9][CH2:8][OH:7]
Reactant: CC(=O)OCCc1cc(S(N)(=O)=O)c2c([N+](=O)[O-])cccc2c1Br
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: NS(=O)(=O)c1cc(CCO)c(Br)c2cccc([N+](=O)[O-])c12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 42 %

Procedure:
Sodium methoxide in methanol (23.7 mL of a 0.5M solution, 11.8 mmol) was added to a suspension of 3-(2-acetoxy-ethyl)-4-bromo-8-nitro-naphthalene-1-sulfonamide (4.70 g, 11.3 mmol) in methanol (33 mL). The mixture was stirred under a nitrogen atmosphere at room temperature for 90 minutes, then concentrated under vacuum to approximately half volume, diluted with ethyl acetate (200 mL), and washed with 2N hydrochloric acid. The organic solution was washed with water (100 mL) and brine (50 mL), dried over magnesium sulfate, filtered, and left to stand at room temperature. The organic solution deposited a solid which was collected by filtration, washed with ethyl acetate (2×15 mL), and vacuum dried to give the title compound (1.78 g). Additional product (1.88 g) was obtained from the mother liquors after concentration under vacuum and crystallization from diethyl ether.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:10][C:9](=[O:11])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:12][C:13]1[C:17]([CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[C:16]([CH3:27])[NH:15][C:14]=1[CH:28]=O.N1CCCCC1>C(O)C>[Cl:1][C:2]1[C:3]2[C:10](=[CH:28][C:14]3[NH:15][C:16]([CH3:27])=[C:17]([CH2:18][CH2:19][CH2:20][N:21]4[CH2:22][CH2:23][O:24][CH2:25][CH2:26]4)[C:13]=3[CH3:12])[C:9](=[O:11])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1[nH]c(C=O)c(C)c1CCCN1CCOCC1
Reactant: O=C1Cc2c(Cl)ncnc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1[nH]c(C=C2C(=O)Nc3ncnc(Cl)c32)c(C)c1CCCN1CCOCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 44.3 %

Procedure:
To a mixture of 4-chloro-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (85 mg, 0.5 mmol) and 3,5-dimethyl-4-(3-morpholin-4-yl-propyl)-1H-pyrrole-2-carbaldehyde (125 mg, 0.5 mmol) in ethanol (4 mL) was added 0.1 to 0.2 mL of piperidine. The mixture was stirred at room temperature for 20 hours. The yellow precipitate was filtered after cooled with an ice bath, washed with cold ethanol, and dried to give 89 mg (45%) of 4-chloro-5-[3,5-dimethyl-4-(3-morpholin-4-yl-propyl)-1H-pyrrol-2-ylmethylene]-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=3[C:28](=[O:29])[C:20]=2[C:19]2[C:14](=[CH:15][C:16]([NH:30][CH2:31][C:32]([O:34]CC)=[O:33])=[CH:17][CH:18]=2)[C:13]1=[O:37])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO.C1COCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]1[C:21]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=3[C:28](=[O:29])[C:20]=2[C:19]2[C:14](=[CH:15][C:16]([NH:30][CH2:31][C:32]([OH:34])=[O:33])=[CH:17][CH:18]=2)[C:13]1=[O:37])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CNc1ccc2c3c(n(CCCNC(=O)OC(C)(C)C)c(=O)c2c1)-c1ccccc1C3=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCn1c2c(c3ccc(NCC(=O)O)cc3c1=O)C(=O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 4 h
Yield: 785.3 %

Procedure:
The ester 39 (0.1 g, 0.02 mmol) was dissolved in MeOH-THF (10+10 mL) and aq NaOH (4 N, 5 mL) was added at room temperature. The reaction mixture was stirred at room temperature for 4 h. The solvent was removed on a rotary evaporator and the residue washed with 1 N HCl (30 mL) and extracted with CHCl3 (2×50 mL). The extract was dried over Na2SO4 and concentrated to afford pure 42 (0.075 g, 80%) which was obtained as a brown solid: mp 190-192° C. IR (KBr) 3350, 2973, 1692, 1645, 1619, 1578, 1520, 1364, 1164, 666 cm−1; 1H NMR (DMSO-d6, 300 MHz) δ 8.30 (d, J=8.7 Hz, 1H), 7.59 (m, 1H), 7.45 (m, 2H), 7.39 (m, 1H), 7.21 (dd, J=2.4, J=8.7 Hz, 1H), 7.12 (d, J=2.4 Hz, 1H), 7.07 (m, 1H), 4.40 (m, 2H), 3.90 (s, 2H), 3.09 (m, 2H), 1.86 (m, 2H), 1.33 (s, 9H); ESIMS (m/z, relative intensity) 500 (MNa+, 100); HRESIMS calcd for C26H27N3O6Na 500.1798 (MNa+). found 500.1806 (MNa+); HPLC purity: 95.5% (MeOH—H2O, 75:25).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[O:7])=[CH:4][C:3]=1[S:16](=[O:19])(=[O:18])[NH2:17].[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.Cl>O>[ClH:1].[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([C:2]2[CH:15]=[CH:14][C:5]([C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[O:7])=[CH:4][C:3]=2[S:16](=[O:19])(=[O:18])[NH2:17])[CH2:23][CH2:22]1
Reactant: NS(=O)(=O)c1cc(C(=O)N2CCOCC2)ccc1Cl
Reactant: CN1CCNCC1
Agent: Cl
Solvent: O
Product: CN1CCN(c2ccc(C(=O)N3CCOCC3)cc2S(N)(=O)=O)CC1

Procedure:
183 Grams of 4-chloro-3-sulfamoylbenzoic acid-morpholide (0.6 mole) were stirred with 0.3 l of N-methylpiperazine for 3 hours at 130° C. Subsequently the excess base was eliminated in vacuo, the residue was dissolved in 0.5 l of water, and the pH of the solution was adjusted to 7 by means of 5N HCl. After having stood in the refrigerator for several days, the reaction product which had separated in a crystalline form was suction-filtered and was recrystallized from ethanol of 90% strength.
Reaction SMILES: [H-].[Na+].[C@H:3]12[O:9][C@H:8]1[CH2:7][CH2:6][CH2:5][C@H:4]2[OH:10].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH2:19]>C1COCC1>[CH2:11]([O:10][C@:4]1([OH:19])[CH2:5][CH2:6][CH2:7][C@H:8]2[C@H:3]1[O:9]2)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O[C@@H]1CCC[C@@H]2O[C@H]12
Reactant: O
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O[C@@]1(OCc2ccccc2)CCC[C@@H]2O[C@H]21
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To a solution of sodium hydride (63%; 1.20 g, 31.5 mmol) in THF (20 mL), a solution of the (1R*,2R*,6S*)-7-oxabicyclo[4.1.0]heptan-2-ol (3.10 g, 27.2 mmol) prepared in Example 100a in THF (20 mL) was added with cooling on ice, and the mixture was stirred at room temperature for 1 hour. To the reaction solution, benzyl bromide (4.0 mL, 33.4 mmol) was added, and the mixture was stirred at room temperature for 12 hours. To the reaction solution, water (50 mL) was added, followed by extraction with ethyl acetate (50 mL). The thus obtained organic layer was dried over anhydrous sodium sulfate. After vacuum concentration, the residue was purified with silica gel chromatography (hexane/ethyl acetate=4:1) to yield the title compound (2.85 g, 51%) as a light brown oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[O:10][CH2:9][CH2:8][CH:7]([N:12]3[C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][N:14]=[CH:13]3)[C:6]=2[CH:5]=[C:4]([N+:21]([O-])=O)[CH:3]=1.[O-2].[Ca+2].[H][H]>[Pd].CO>[ClH:1].[NH2:21][C:4]1[CH:3]=[CH:2][C:11]2[O:10][CH2:9][CH2:8][CH:7]([N:12]3[C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][N:14]=[CH:13]3)[C:6]=2[CH:5]=1
Reactant: COC(=O)c1cncn1C1CCOc2c(Cl)cc([N+](=O)[O-])cc21
Reactant: [H][H]
Agent: [Pd]
Agent: [Ca+2]
Agent: [O-2]
Solvent: CO
Product: COC(=O)c1cncn1C1CCOc2ccc(N)cc21
Product: Cl
Yield: 35.3 %

Procedure:
A mixture of 48 parts of methyl 1-(8-chloro-2,3-dihydro-6-nitro-4H-1-benzopyran-4-yl)-1H-imidazole-5-carboxylate, 8 parts of calcium oxide and 400 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 5%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was taken up in trichloromethane. The organic layer was washed with water and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the hydrochloride salt in a mixture of 2-propanol and 2,2'-oxybispropane. The salt was filtered off and salt overnight in vacuo at 80° C., yielding 18.3 parts (35.3%) of methyl 1-(6-amino-2,3-dihydro-4H-1-benzopyran-4-yl)-1H-imidazole-5-carboxylate monohydrochloride.2-propanolate (1:1 ); mp. 146.0° C. (compound 1.135).