Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C12(COC3C(Cl)=CC(C(O)=O)=C(F)C=3)CC3CC(CC(C3)C1)C2.[C:24]12([CH2:34][O:35][C:36]3[CH:44]=[CH:43][C:39]([C:40](O)=[O:41])=[CH:38][C:37]=3[C:45]([F:48])([F:47])[F:46])[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2.N1(S(N)(=O)=O)CCOCC1.[CH3:59][S:60]([NH2:63])(=[O:62])=[O:61]>>[C:24]12([CH2:34][O:35][C:36]3[CH:44]=[CH:43][C:39]([C:40]([NH:63][S:60]([CH3:59])(=[O:62])=[O:61])=[O:41])=[CH:38][C:37]=3[C:45]([F:48])([F:47])[F:46])[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH2:25]1)[CH2:31]2
Reactant: O=C(O)c1ccc(OCC23CC4CC(CC(C4)C2)C3)c(C(F)(F)F)c1
Reactant: CS(N)(=O)=O
Agent: NS(=O)(=O)N1CCOCC1
Agent: O=C(O)c1cc(Cl)c(OCC23CC4CC(CC(C4)C2)C3)cc1F
Product: CS(=O)(=O)NC(=O)c1ccc(OCC23CC4CC(CC(C4)C2)C3)c(C(F)(F)F)c1

Procedure:
Following the procedure as described in Example 98 and making variations as required to replace 4-(adamantan-1-ylmethoxy)-5-chloro-2-fluorobenzoic acid with 4-(adamantan-1-ylmethoxy)-3-(trifluoromethyl)benzoic acid and morpholine-4-sulfonamide with methanesulfonamide, the title compound was obtained as a colorless solid (0.11 g, 51%): 1H NMR (300 MHz, DMSO-d6) δ 12.22 (s, 1H), 8.25-8.19 (m, 2H), 7.37 (d, J=8.8 Hz, 1H), 3.77 (s, 2H), 3.37 (s, 3H), 1.99 (br s, 3H), 1.75-1.63 (m, 12H); MS (ES−) m/z 430.3 (M−1); MS (ES+) m/z 432.2 (M+1).
Reaction SMILES: [CH:1]1([NH:4][CH3:5])[CH2:3][CH2:2]1.[CH3:6][N:7]1[C:11]([C:12](=[O:29])[NH:13][C:14]2[CH:15]=[CH:16][C:17]3[N:18]([N:20]=[C:21]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)[N:22]=3)[CH:19]=2)=[C:10]([C:30](O)=[O:31])[CH:9]=[N:8]1>>[CH:1]1([N:4]([CH3:5])[C:30]([C:10]2[CH:9]=[N:8][N:7]([CH3:6])[C:11]=2[C:12]([NH:13][C:14]2[CH:15]=[CH:16][C:17]3[N:18]([N:20]=[C:21]([C:23]4[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=4)[N:22]=3)[CH:19]=2)=[O:29])=[O:31])[CH2:3][CH2:2]1
Reactant: CNC1CC1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccc2nc(-c3cccnc3)nn2c1
Product: CN(C(=O)c1cnn(C)c1C(=O)Nc1ccc2nc(-c3cccnc3)nn2c1)C1CC1

Procedure:
Using cyclopropyl-methyl-amine and 1-methyl-5-(2-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid, the title compound was prepared in the same manner as described for example 2. White solid (71 mg, 44%). Mp.: 237° C. MS: m/z=417.3 (M+H+). Ames test negative.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][CH:13]3[C:8]=2[CH2:9][CH2:10][NH:11][CH2:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+].[CH:29](Br)([CH3:31])[CH3:30]>CN(C)C=O>[CH:29]([N:11]1[CH2:10][CH2:9][C:8]2[CH:13]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[C:7]=2[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:12]1)([CH3:31])[CH3:30]
Reactant: c1ccc(C2=C3CCNCC3Cc3ccccc32)cc1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N1CCC2=C(c3ccccc3)c3ccccc3CC2C1
Reaction time: 3.5 h

Procedure:
A mixture of 22.0 g of 1,2,3,4,10,10a-hexahydro-5phenylbenz[g]isoquinoline, 20.0 g of sodium carbonate and 0.2 g of sodium iodide in 180 ml of dimethylformamide are preheated to 50°. 16.5 g of isopropylbromide in 50 ml of dimethylformamide are added dropwise to the suspension over a 2 hour period, the reaction mixture further stirred for 3.5 hours at the same temperature, cooled and poured onto ice/water. The organic substance is extracted with benzene, the extracts washed with water, dried over sodium sulphate and evaporated and the title compound which remains converted to the fumarate form in isopropyl. M.P. 199°-200°.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][NH2:10])=[CH:4][N:3]=1.[C:11](=[O:13])=[O:12].C([OH:17])(C)C>>[C:11](=[O:17])([OH:13])[OH:12].[CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][NH2:10])=[CH:4][N:3]=1
Reactant: O=C=O
Reactant: CC(C)O
Agent: Cc1ncc(CN)c(N)n1
Product: O=C(O)O
Temperature: 10 °C

Procedure:
Into the same four-necked flask as used in Example 1 was charged a solution of 30.0 g (purity: 96.2 %, 0.209 mole) of crude 2-methyl-4-amino-5-aminomethylpyrimidine dissolved in 300 g of isopropanol, followed by maintaining the temperature of the solution at 10° C. Subsequently, 44 g (1 mole) of carbon dioxide was blown into the solution over about 2 hours and the reaction was carried out to precipitate a white crystal of 2-methyl-4-amino-5-aminomethylpyrimidine carbonate with extreme easiness. Then, the resulting crystal was filtered off, washed with a small amount of isopropanol, and dried in vacuo at 20° C. until it may have constant weight to obtain 37.8 g of 2-methyl-4-amino-5-aminomethylpyrimidine carbonate.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[CH2:12][NH:11][CH2:10]3)[CH2:3][CH2:2]1.[CH:16]([O:19][C:20]1[CH:28]=[CH:27][C:26]([S:29]([CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])(=[O:31])=[O:30])=[CH:25][C:21]=1[C:22](O)=[O:23])([CH3:18])[CH3:17]>>[CH:16]([O:19][C:20]1[CH:28]=[CH:27][C:26]([S:29]([CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])(=[O:31])=[O:30])=[CH:25][C:21]=1[C:22]([N:11]1[CH2:10][C:9]2[C:13](=[CH:14][CH:15]=[C:7]([CH:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[CH:8]=2)[CH2:12]1)=[O:23])([CH3:18])[CH3:17]
Reactant: c1cc2c(cc1C1CCOCC1)CNC2
Reactant: CC(C)Oc1ccc(S(=O)(=O)CC[Si](C)(C)C)cc1C(=O)O
Product: CC(C)Oc1ccc(S(=O)(=O)CC[Si](C)(C)C)cc1C(=O)N1Cc2ccc(C3CCOCC3)cc2C1

Procedure:
In analogy to the procedure described for the synthesis of example 1, step 2, the title compound was prepared from 5-(tetrahydro-pyran-4-yl)-2,3-dihydro-1H-isoindole (CAS: 905274-50-2) and 2-isopropoxy-5-(2-trimethylsilanyl-ethanesulfonyl)-benzoic acid. MS (m/e): 529.3 [M]+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:5]=1)=[O:3].Br.[OH2:15]>CS(C)=O>[O:3]=[C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:5]=1)[CH:1]=[O:15]
Reactant: CC(=O)c1cccc(C(F)(F)F)c1
Reactant: O
Agent: Br
Solvent: CS(C)=O
Product: O=CC(=O)c1cccc(C(F)(F)F)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 128 %

Procedure:
3-Trifluoromethylacetophenone (11.80 mmol, 2.22 g) was dissolved in dimethyl sulfoxide (13 mL), and 48% hydrobromic acid (5.4 mL) was gradually added at room temperature. After overnight stirring at 70° C., the reactor was cooled to room temperature. After addition of water, the reaction solution was extracted with chloroform, and the extract was dried and filtered, and the solvent was evaporated to give the desired product as a yellow liquid (3.04 g (crude), yield 128%).
Reaction SMILES: [CH3:1][O:2][C@H:3]([CH3:6])[CH2:4][OH:5].[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1>N1C=CC=CC=1>[CH3:1][O:2][C@H:3]([CH3:6])[CH2:4][O:5][S:13]([C:10]1[CH:11]=[CH:12][C:7]([CH3:17])=[CH:8][CH:9]=1)(=[O:15])=[O:14]
Reactant: CO[C@H](C)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: CO[C@H](C)COS(=O)(=O)c1ccc(C)cc1

Procedure:
By reacting (-)-(R)-2-methoxypropanol with p-toluenesulphonic acid chloride in pyridine analogously to R. S. Tipson [J. Org. Chem. 9 (1944) 235] the (+)-(R)-2-methoxypropyl-p-toluenesulphonate is obtained in the form of a yellowish oil with a specific rotation of [α]D25 =+3.7° (c=100) and analogously, from (+)-(S)-2-methoxy-propanol, the corresponding (-)-(S)-2-methoxypropyl-p-toluenesulphonate is obtained with a rotation of [α]D25 =-3.7° (c=100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[C:4]([I:10])[CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[N:30]([C:38](OC(C)C)=O)=NC(OC(C)C)=O.CC(C)(O)C#N>CCOCC>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:38]#[N:30])=[C:4]([I:10])[CH:3]=1
Reactant: CC(C)OC(=O)N=NC(=O)OC(C)C
Reactant: OCc1ccc(Cl)cc1I
Agent: CC(C)(O)C#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: N#CCc1ccc(Cl)cc1I
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
(4-Chloro-2-iodophenyl)methanol (4.67 g, 17 mmol) and PPh3 (6 mL, 26 mmol) were stirred in Et2O at 0° C. Diisopropyl azodicarboxylate (5 mL, 26 mmol) was added dropwise, and the reaction was stirred for 20 minutes (a white precipitate formed). A solution of acetone cyanohydrin (2 mL, 26 mmol) in diethyl ether (5 mL) was added dropwise to the reaction. The resulting solution was stirred for 5 minutes at 0° C. and then allowed to warm to room temperature over two hours. The reaction was monitored by TLC and LCMS. The mixture was filtered, and the filtrate was concentrated in vacuo. Purification was done using silica flash chromatography with a gradient of 0-15% EtOAc/hexanes. MS m/e=278 (M+H)+.
Reaction SMILES: [CH2:1]1[CH:3]([CH2:4][N:5]2[CH:14]3[CH2:15][C:16]4[CH:21]=[CH:20][C:19]([OH:22])=[C:18]5[O:23][C@H:9]6[C:10]7[NH:31][C:30]8[C:25](=[C:26]([N:32]=[C:33]([NH2:35])[NH2:34])[CH:27]=[CH:28][CH:29]=8)[C:11]=7[CH2:12][C@:13]3([OH:24])[C@:8]6([C:17]=45)[CH2:7][CH2:6]2)[CH2:2]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:2]1[CH:3]([CH2:4][N:5]2[CH:14]3[CH2:15][C:16]4[CH:21]=[CH:20][C:19]([OH:22])=[C:18]5[O:23][C@H:9]6[C:10]7[NH:31][C:30]8[CH:25]=[C:26]([N:32]=[C:33]([NH2:35])[NH2:34])[CH:27]=[CH:28][C:29]=8[C:11]=7[CH2:12][C@:13]3([OH:24])[C@:8]6([C:17]=45)[CH2:7][CH2:6]2)[CH2:1]1
Reactant: NC(N)=Nc1cccc2[nH]c3c(c12)C[C@@]1(O)C2Cc4ccc(O)c5c4[C@@]1(CCN2CC1CC1)[C@H]3O5
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(N)=Nc1ccc2c3c([nH]c2c1)[C@@H]1Oc2c(O)ccc4c2[C@@]12CCN(CC1CC1)C(C4)[C@]2(O)C3
Temperature: 25 °C
Reaction time: 36 h
Yield: 74 %

Procedure:
Compound 6b (500 mg, 0.75 mmol) was dissolved in a mixture of TFA (3.0 mL) and dried CH2Cl2 (28 mL) and allowed to stir under N2 atmosphere at room temperature for 36 h. The reaction was worked up according to the procedure for compound 4a and purified by preparative TLC to give 4b (260 mg, 74%) as a free base; IR KBr disk υ (cm−1): 3450–3150 (br), 1683 (s), 1506, 1463, 1433, 1330, 1202, 1132; 1H NMR (DMSO-d6): δ 11.50 (s, 1H, NH), 9.96 (s, 11H, NH), 9.29 (s, 1H, NH), 8.95 (s, 1H, Ar—OH), 7.36–7.09 (m, 3H, ArH and NH2), 6.77 (d, 1H, J=8.10 Hz, ArH), 6.59–6.52 (m, 2H, ArH), 6.39 (s, 1H), 5.67 (s, 1H, 5-H), 4.05 (b, 1H, 14-OH), 3.43–3.23 (m, 3H), 3.18–3.06 (m, 2H), 2.96–2.91 (m, 2H), 2.68–2.57 (m, 2H), 2.50 (m, 1H), 1.78 (d, 1H, J=11.7 Hz), 1.05 (m, 1H), 0.68 (m, 1H), 0.58 (m, 1H), 0.40 (m, 2H). HRMS (FAB) m/z 472.2356 (M+H)+, C27H29N5O3 requires 471.2270.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:8])[CH2:5][C:6]#[N:7])[CH3:2].[CH3:9][C:10]([CH3:12])=O>>[CH2:1]([O:3][C:4](=[O:8])[C:5](=[C:10]([CH3:12])[CH3:9])[C:6]#[N:7])[CH3:2]
Reactant: CCOC(=O)CC#N
Reactant: CC(C)=O
Product: CCOC(=O)C(C#N)=C(C)C

Procedure:
reacting ethylcyanoacetate with acetone to yield ethylisopropylidenecyanoacetate;
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@H:11]1[C@@H:15]2[O:16][C:17]([CH3:20])([CH3:19])[O:18][C@@H:14]2[C@@H:13]([C:21]([OH:23])=O)[O:12]1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:37][NH:38][O:39][CH3:40].N1C=CC=CC=1>ClCCl>[CH3:40][O:39][N:38]([CH3:37])[C:21]([C@@H:13]1[C@@H:14]2[C@@H:15]([O:16][C:17]([CH3:20])([CH3:19])[O:18]2)[C@H:11]([N:6]2[CH:5]=[N:4][C:3]3[C:7]2=[N:8][CH:9]=[N:10][C:2]=3[Cl:1])[O:12]1)=[O:23]
Reactant: CC1(C)O[C@@H]2[C@H](O1)[C@@H](C(=O)O)O[C@H]2n1cnc2c(Cl)ncnc21
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CON(C)C(=O)[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21
Temperature: 22 °C
Reaction time: 1 h
Yield: 65.3 %

Procedure:
(3aS,4S,6R,6aR)-6-(6-Chloro-purin-9-yl)-2,2-dimethyl-tetrahydro-furo[3,4-d][1,3]dioxole-4-carboxylic acid (35.88 g) was dissolved in dichloromethane (300 ml) and treated with 1,1′-carbonyldiimidazole (20.5 g) with ice-cooling. The solution was stirred at 22° C. for 1 h, N,O-dimethylhydroxylamine hydrochloride (12.3 g) and pyridine (15 ml) were added, and stirring was continued at 22° C. for 24 h. The solution was washed with 0.5M citric acid (250 ml) and 8% sodium bicarbonate (200 ml), dried (Na2SO4) and evaporated in vacuo. The residue was purified by flash chromatography over silica gel, eluting with ethyl acetate to afford the title compound as a colourless solid (26.4 g).
Reaction SMILES: N1C=CC=CC=1.[CH3:7][N:8]([CH2:10][CH2:11][OH:12])[CH3:9].[C:13](Cl)(=[O:23])[CH:14]=[CH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>O1CCCC1>[C:13]([O:12][CH2:11][CH2:10][N:8]([CH3:9])[CH3:7])(=[O:23])/[CH:14]=[CH:15]/[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCC=CC(=O)Cl
Reactant: CN(C)CCO
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCC/C=C/C(=O)OCCN(C)C

Procedure:
Thionyl chloride (8 ml) was added to trans-2-decenoic acid (3.4 g, 0.02 mol) followed by refluxing on a hot water bath for 2 hours. An excessive thionyl chloride was evaporated in vacuo to give 2-decenoic acid chloride. Pyridine (1 ml) was added to a solution of N,N-dimethylaminoethanol (2.0 g, 0.022 mol) in tetrahydrofuran (30 ml) followed by dropping into a solution of 2-decenoic acid chloride in tetrahydrofuran (20 ml). The reaction solution was heated to reflux on a hot water bath for 3 hours, tetrahydrofuran was evaporated in vacuo, water and ethyl acetate were added to the residue to partition and an ethyl acetate layer was collected therefrom. The ethyl acetate layer was washed with water and evaporated followed by purifying by silica gel column chromatography (developer: chloroform) to give the aimed compound as a light brown oily product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N+:13]([O-])=O)[C:11]=1[CH3:12])[N:8]=[CH:7][N:6]=[C:5]2[NH:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1.N.CO>CCO.[Pd]>[NH2:13][C:10]1[C:11]([CH3:12])=[CH:2][CH:3]=[C:4]2[C:9]=1[N:8]=[CH:7][N:6]=[C:5]2[NH:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1
Reactant: Cc1c(Br)cc2c(Nc3ccc(C#N)cc3)ncnc2c1[N+](=O)[O-]
Agent: [Pd]
Agent: N
Solvent: CO
Solvent: CCO
Product: Cc1ccc2c(Nc3ccc(C#N)cc3)ncnc2c1N
Reaction time: 8 h
Yield: 83.1 %

Procedure:
A mixture of 4-(6-bromo-7-methyl-8-nitroquinazolin-4-ylamino)benzonitrile (400 mg, 1.04 mmol) and Pd/C (10%˜30 mg) in EtOH (20 mL) was stirred under H2 gas (1 atm) overnight. 30 mL of NH3/MeOH (2 M) was added and the mixture was filtered through celite and washed with MeOH/DCM (˜1:1). After removal of solvent the product was purified by flash chromatography eluting with MeOH/DCM (1-5%) to give 4-(8-amino-7-methylquinazolin-4-ylamino)benzonitrile (238 mg, 83%). MS (ESI, pos. ion) m/z: 276 [M+H]+
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([S:12]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]2[CH2:21][OH:22])(=[O:14])=[O:13])=[C:7]([CH3:23])[CH:6]=1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>CCCCCC.CN(C)C=O.O>[CH3:31][S:32]([O:22][CH2:21][CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][N:15]1[S:12]([C:8]1[C:7]([CH3:23])=[CH:6][C:5]([O:4][CH3:3])=[CH:10][C:9]=1[CH3:11])(=[O:13])=[O:14])(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(C)c(S(=O)(=O)N2CCCCC2CO)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(C)c(S(=O)(=O)N2CCCCC2COS(C)(=O)=O)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (0.346 g, 8.679 mmol, 60%), washed with hexane and dried with an inert gas, was initially introduced into N,N-dimethylformamide (10 ml) under an inert gas, (1-(4-methoxy-2,6-dimethylphenylsulfonyl)piperidin-2-yl)methanol (1.36 g, 4.34 mmol) was added and the mixture was then stirred at room temperature for 30 min. Triethylamine (1.8 ml, 13.019 mmol) was added, the reaction mixture was cooled with ice-water, and methanesulfonyl chloride (0.838 ml, 10.849 mmol) in N,N-dimethylformamide (10 ml) was slowly added dropwise. After stirring at room temperature for 1 h, 5 ml of water were added and the solvent was removed in vacuo. The residue was taken up in saturated sodium bicarbonate solution (20 ml) and ethyl acetate (50 ml), the phases were separated and the aqueous phase was extracted with ethyl acetate (2×50 ml). The combined organic phases were washed with saturated sodium chloride solution (40 ml), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) with diethyl ether/hexane/methylene chloride (1:1:1). Yield: 1.66 g (97%)
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](Cl)[N:3]=1.C(OCC)(=O)C.O1C=CCCC1.C(N)(C)C>C(N(CC)CC)C>[N:3]1[CH:4]=[C:5]2[C:9]([N:8]=[CH:7][NH:6]2)=[N:10][CH:2]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: C1=COCCC1
Solvent: CC(C)N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: c1ncc2[nH]cnc2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 169.9 %

Procedure:
In a 100 ml three-mouth bottle, 2,6-dichloropurine (10 g), ethyl acetate (50 ml), pyridinium salt of paratoluenesulfonic acid (0.2 g) are mixed. The above mixture is stirred and heated to a temperature of 35° C., 2,3-dihydropyrane (12 ml) is added thereto within 5 min. The above mixture is reacted at 50˜60° C. for 3 h. The completion of reaction is checked with TCL analysis. Triethylamine (8 ml) is added to the bottle, and isopropylamine (7.7 ml) is added thereto under refluxing within 15 min. The above mixture is further reacted at the temperature for 0.5 h. The completion of reaction is checked with TCL analysis. The reaction mixture is cooled to room temperature. After filtration, a filter cake is completely washed with ethyl acetate, and a filtrate is washed with water for 3 times and delaminated. Organic layer is concentrated till large amount of solid is separated out. After filtration, a filter cake is washed with ethyl acetate for 3 times and then dried in vacuum at 50° C. for 5 h to obtain solid purin (10.8 g). The yield is about 70.0%.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8](Cl)=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:13]=[C:14]([NH:19][C:20]([C:22]2[CH:27]=[CH:26][N:25]=[C:24]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:23]=2)=[O:21])[CH:15]=[CH:16][C:17]=1[Cl:18]>>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:11][C:12]2[CH:13]=[C:14]([NH:19][C:20]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([N:28]4[CH2:29][CH2:30][O:31][CH2:32][CH2:33]4)[CH:23]=3)=[O:21])[CH:15]=[CH:16][C:17]=2[Cl:18])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: Nc1cc(NC(=O)c2ccnc(N3CCOCC3)c2)ccc1Cl
Product: O=C(Nc1ccc(Cl)c(NC(=O)c2ccc(Cl)nc2)c1)c1ccnc(N2CCOCC2)c1
Temperature: 80 °C
Yield: 58 %

Procedure:
Using an analogous procedure to that described in Example 2 except that the reaction mixture was heated to 80° C. for 16 hours, 6-chloropyridine-3-carbonyl chloride was reacted with N-(3-amino-4-chlorophenyl)-2-morpholinopyridine-4-carboxamide. The reaction mixture was evaporated and the residue was triturated under water. The resultant solid was isolated, washed with a saturated aqueous sodium bicarbonate solution and dried in a vacuum oven. The material so obtained was purified by column chromatography on an ion exchange column (isolute CBA column from International Sorbent Technology Limited, Hengoed, Mid-Glamorgan, UK) using methanol as eluent. There was thus obtained the title compound (0.493 g) in 58% yield; NMR Spectrum: (DMSOd6) 3.51 (m, 4H), 3.71 (m, 4H), 7.09 (d, 1H), 7.23 (s, 1H), 7.55 (d, 1H), 7.71 (d, 2H), 8.06 (s, 1H), 8.27 (d, 1H), 8.35 (d, 1H), 8.96 (s, 1H), 10.39 (s, 1H), 10.49 (s, 1H); Mass Spectrum: M+H+ 472.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[C:11]([O:15][C:16](=[O:30])[NH:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C@:19]1([CH2:28][OH:29])[CH2:24][CH2:25][CH2:26][OH:27])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl>[C:11]([O:15][C:16](=[O:30])[NH:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][CH2:20][C@:19]1([CH:28]=[O:29])[CH2:24][CH2:25][CH:26]=[O:27])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@]1(CO)CCCO
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@]1(C=O)CCC=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 0.1 %

Procedure:
A solution of dimethyl sulfoxide (16 g, 180 mmol) in dichloromethane (60 mL) was cooled to −78° C. in a cooling bath and treated dropwise with oxalyl chloride (14.2 g, 112 mmol). After the addition was complete, the solution was stirred for 30 minutes and then treated dropwise with a solution of [(1R,2S)-2-hydroxymethyl-2-(3-hydroxypropyl)-cyclohexyl]-carbamic acid tert-butyl ester (4.8 g, 16.7 mol) in dichloromethane (100 mL). After the addition was complete, the solution was stirred for 40 minutes and then treated with triethylamine (19 g, 190 mmol). The mixture was stirred for 30 minutes. The cooling bath was removed and the mixture was allowed to warm to room temperature where it stirred for 1 hour. The mixture was quenched with saturated aqueous sodium bicarbonate (100 mL). The organic phase was removed, washed successively with water and saturated aqueous sodium chloride, and then dried over sodium sulfate. The solvent was removed under vacuum to give an oil (4.75 g). 1H NMR (300 MHz, CDCl3) δ9.78 (s, 1H), 9.41 (s, 1H), 4.56 (bd, J=9 Hz, 1H), 4.05 (m, 1H), 2.60-1.30 (m, 21H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5]2.Cl[C:20]1[S:21][C:22]2[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=2[N:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1>[C:15]([O:14][C:12]([N:7]1[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([NH:1][C:20]3[S:21][C:22]4[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=4[N:24]=3)[CH:3]=2)[CH2:8]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: Clc1nc2ccccc2s1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(N)ccc2C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCc2cc(Nc3nc4ccccc4s3)ccc2C1
Yield: 100 %

Procedure:
A toluene solution of 6-amino-2N-Boc-1,2,3,4-tetrahydroisoquinoline (248 mg), 2-chlorobenzothiazole (186 mg), palladium acetate (22 mg), cesium carbonate (651 mg), and Xantphos (58 mg) was stirred at 120° C. for 1 hour under microwave irradiation. The reaction solution was purified by column chromatography to obtain the title compound (381 mg, quantitative yield).
Reaction SMILES: [CH2:1]([C:3]1[C:7]([CH2:8][CH3:9])=[CH:6][NH:5][C:4]=1[CH:10]=O)[CH3:2].[C:12]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:13].C(NCC)C>C(O)C>[CH2:18]([O:17][C:15](=[O:16])[C:14]([C:12]#[N:13])=[CH:10][C:4]1[NH:5][CH:6]=[C:7]([CH2:8][CH3:9])[C:3]=1[CH2:1][CH3:2])[CH3:19]
Reactant: CCc1c[nH]c(C=O)c1CC
Reactant: CCOC(=O)CC#N
Solvent: CCO
Solvent: CCNCC
Product: CCOC(=O)C(C#N)=Cc1[nH]cc(CC)c1CC
Temperature: 25 °C

Procedure:
The 3,4-diethyl-2-formylpyrrole (14.1 g, 93.1 mmol) was dissolved in 200 mL of dry ethanol, and ethyl cyanoacetate (20 mL, 137.9 mmol) and diethylamine (20 mL, 193.3 mmol) were added to the solution. The reaction mixture was heated to reflux under an inert atmosphere and stirred under reflux for 2 hours, after which it was cooled to room temperature and then placed in an ice bath. The resulting dark suspension was filtered through a medium filter, and the light brown solids were washed with cold ethanol. The collected filtrates were concentrated under reduced pressure, precipitating more solids. The thick suspension was filtered, and the combined solids were separated and purified to give 2-cyano-3-(3,4-diethyl -1H-pyrrol-2-yl) acrylic acid ethyl ester, a compound of formula 201 in which R1 and R2 are both ethyl.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=O)[C:5]2[C:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=3[S:8][C:6]=2[N:7]=1.O=P(Cl)(Cl)[Cl:18].C(Cl)(Cl)Cl>C(OC(=O)C)(=O)C>[Cl:18][C:4]1[C:5]2[C:10]3[CH2:11][CH2:12][CH2:13][CH2:14][C:9]=3[S:8][C:6]=2[N:7]=[C:2]([CH3:1])[N:3]=1
Reactant: Cc1nc2sc3c(c2c(=O)[nH]1)CCCC3
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: Cc1nc(Cl)c2c3c(sc2n1)CCCC3
Yield: 81 %

Procedure:
To a 50 mL flask was added 5 (220 mg, 1 mmol) and 5 mL POCl3. The resulting mixture was refluxed for 2 h, and the solvent was removed under reduced pressure to afford a dark residue. To this was added 30 mL of CHCl3 and 300 mg of silica gel. The solvent was evaporated to afford a plug Column chromatography of the plug with hexane:acetyl acetate=20:1 as eluent afford 192 g (81%) of 6 as a yellow solid: 1H NMR (DMSO-d6) δ 1.82 (m, 4H), 2.63 (s, 3H), 2.84 (m, 2H), 2.96 (m, 2H).