Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=2)[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([O:29][CH3:30])[CH:22]=3)[C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc([N+](=O)[O-])cc23)cc1OC
Reactant: c1nc[nH]n1
Product: COc1ccc(CNc2nc(-n3cncn3)nc3sc([N+](=O)[O-])cc23)cc1OC

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 2-chloro-6-nitro-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-6-nitro-4-(3,4-dimethoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C1COCC1.[F:12][C:13]([F:61])([C:51]([F:60])([F:59])[C:52]([F:58])([F:57])[C:53]([F:56])([F:55])[F:54])[CH2:14][CH2:15][CH2:16][N:17]([CH2:35][CH2:36][CH2:37][C:38]([F:50])([F:49])[C:39]([F:48])([F:47])[C:40]([F:46])([F:45])[C:41]([F:44])([F:43])[F:42])[C:18](=O)[CH2:19][CH2:20][C:21]([F:33])([F:32])[C:22]([F:31])([F:30])[C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25]>O>[F:12][C:13]([F:61])([C:51]([F:59])([F:60])[C:52]([F:57])([F:58])[C:53]([F:54])([F:55])[F:56])[CH2:14][CH2:15][CH2:16][N:17]([CH2:18][CH2:19][CH2:20][C:21]([F:33])([F:32])[C:22]([F:30])([F:31])[C:23]([F:28])([F:29])[C:24]([F:25])([F:26])[F:27])[CH2:35][CH2:36][CH2:37][C:38]([F:50])([F:49])[C:39]([F:48])([F:47])[C:40]([F:46])([F:45])[C:41]([F:44])([F:43])[F:42]
Reactant: O=C(CCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)N(CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: FC(F)(F)C(F)(F)C(F)(F)C(F)(F)CCCN(CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F)CCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 86 %

Procedure:
A 250-ml 3-necked flask equipped with a stir bar, condenser, nitrogen inlet and an addition funnel was charged with LiAlH4 (1.3 g) and 20 ml THF. To the mixture was added a THF (30 ml) solution of N,N-bis(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)-4,4,5,5,6,6,7,7,7-nonafluoroheptanamide (20.6 g, 25.4 mmol) dropwise at RT. The resulting mixture was refluxed for 30 min. After being cooled, the mixture was carefully treated with water (3 ml) to decompose excess LiAlH4. Another 50 ml water were added and the mixture was extracted with ether (3×100 ml). The combined ether extracts were washed with water, dried over Na2SO4, concentrated to give a residue which was distilled to afford tris(4,4,5,5,6,6,7,7,7-nonafluoroheptyl)amine, 17.5 g, yield 86%, bp 153-155° C./270 Pa absolute. 19F NMR (CDCl3) -81.8 (tt, J=10, 3 Hz, 9F), -115.2 (m, 6F), -125.3 (m, 6F), -126.7 (m, 6F) ppm. 1H NMR (CDCl3) 1.92 (m, 6H), 2.10 (m, 6H), 2.48 (t, J=6 Hz, 6H) ppm. 13C NMR (CDCl3) 18.3, 28.7 (t, J=23 Hz), 52.9, 108-123 (m) ppm. Anal. Calcd. for C21H18F27N: C, 31.63; H, 2.28; N, 1.76; F 64.33. Found: C, 31.49; H, 2.52; N, 1.77; F, 64.52. MS (m/e) 550 (M+ -C4F9 (CH2)2, 100%), 512 (0.4%), 462 (0.6%), 362 (0.8%), 290 (11.3%), 276 (1.9%), 219 (0.3%), 169 (3.9%), 119 (7.1%), 69 (23.7%).
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[OH-].[Na+].O.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)C>[C:8]([C:7]1[CH:10]=[CH:11][C:4]([C:1](=[O:3])[CH:2]=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:5][CH:6]=1)#[N:9]
Reactant: O=Cc1ccccc1
Reactant: CC(=O)c1ccc(C#N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(C(=O)C=Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.7 %

Procedure:
4-Acetylbenzonitrile (44al, 1.00 g, 6.9 mmol), sodium hydroxide (0.40 g, 10.0 mmol) and water (20 ml) were combined in ethanol (20 ml) and stirred for 15 min at room temperature. Benzaldehyde (1b, 0.70 ml, 6.9 mmol) was added and the mixture stirred for 2 hr at room temperature. The resulting mixture was filtered and recrystallized from ethanol to give 1.46 g (91%) of a yellow solid: mp 120° C. [expected mp 119-120° C.]; 1H NMR: δ 7.34 (m, 3H), 7.62 (m, 2H), 7.80 (m, 4H), 8.06 (d, 2H, J=8.1 Hz); 13C NMR: δ 115.9, 117.9, 121.1, 128.6, 128.8, 129.0, 131.0, 132.4, 134.3, 141.4, 146.4, 188.9.
Reaction SMILES: Cl.C([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=3[F:28])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1OC)C1C=CC=CC=1.[C:31](O)(C(F)(F)F)=[O:32]>>[F:28][C:22]1[CH:23]=[C:24]([CH3:27])[CH:25]=[CH:26][C:21]=1[NH:20][C:14]1[C:13]2[C:18](=[CH:19][C:10]([OH:9])=[CH:11][CH:12]=2)[N:17]=[C:16]([O:32][CH3:31])[N:15]=1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cc2c(Nc3ccc(C)cc3F)ncnc2cc1OCc1ccccc1
Agent: Cl
Product: COc1nc(Nc2ccc(C)cc2F)c2ccc(O)cc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
A solution of 7-benzyloxy-4-(2-fluoro-4-methylanilino)-6-methoxyquinazoline hydrochloride (2 g, 4.7 mmol) in TFA (20 ml) was heated at 80° C. for 5 hours and stirred at ambient temperature overnight. The volatiles were removed under vacuum and the residue was suspended in water (50 ml). Solid sodium hydrogen carbonate was added until the pH was approximately 7. The precipitate was then collected by filtration, washed with water and dried under vacuum. The solid was purified by column chromatography eluting with methanol/methylene chloride (5/95). After removal of the solvent by evaporation, the solid was triturated with ether, collected by filtration, washed with ether and dried under vacuum to give 4-(2-fluoro-4-methylanilino)-7-hydroxy-methoxyquinazoline (1.04 g, 74%).
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH:52]([C:54]3[CH:59]=[CH:58][N:57]=[CH:56][CH:55]=3)[CH3:53])[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[CH3:68][N:69]([CH3:81])[CH2:70][CH2:71][O:72][C:73]1[CH:80]=[CH:79][C:76]([CH:77]=O)=[CH:75][CH:74]=1>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH:52]([C:54]3[CH:59]=[CH:58][N:57]=[CH:56][CH:55]=3)[CH3:53])[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:77]([C:76]3[CH:79]=[CH:80][C:73]([O:72][CH2:71][CH2:70][N:69]([CH3:68])[CH3:81])=[CH:74][CH:75]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: CC(c1ccncc1)N1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Reactant: CN(C)CCOc1ccc(C=O)cc1
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(c1ccncc1)N1CCN(c2c(Br)cnc3[nH]c(-c4ccc(OCCN(C)C)cc4)nc23)CC1
Reaction time: 6 h
Yield: 22.1 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(1-(pyridin-4-yl)ethyl)piperazin-1-yl)pyridin-2-amine (30 mg, 0.074 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.22 mmol, 0.22 mL) and 4-(2-(dimethylamino)ethoxy)benzaldehyde (1.1 eq, 0.088 mmol, 17 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 85:15) gave the product (9 mg, 21%) as a colourless solid; δH (500 MHz, DMSO-d6) 1.35 (d, J=6.7 Hz, 3H, CHCH3), 2.25 (s, 6H, N(CH3)2), 2.51-2.55 (m, 2H, piperazine NCH2), 2.63-2.65 (m, 2H, piperazine NCH2), 2.67 (t, J=5.6 Hz, 2H, Me2NCH2), 3.57 (q, J=6.7 Hz, 1H, CHCH3), 3.63-3.66 (m, 4H, piperazine N(CH2)2), 4.14 (q, J=5.8 Hz, 2H, OCH2), 7.10 (d, J=8.9 Hz, 2H, phenyl H-3 & H-5), 7.39 (d, J=6.0 Hz, 2H, pyridine H-3 & H-5), 8.11 (d, J=8.8 Hz, 2H, phenyl H-2 & H-6), 8.19 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.54 (d, J=5.9 Hz, 2H, pyridine H-2 & H-6), 13.33 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [N+:1]([CH2:4][CH3:5])([O-])=O.C(O[C:9](=[O:19])[CH:10]=[CH:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)C.[OH-].C[N+](C)(C)CC1C=CC=CC=1.C1(C)C=CC=CC=1>CO>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([CH:11]2[CH:4]([CH3:5])[NH:1][C:9](=[O:19])[CH2:10]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)C=Cc1ccc(Cl)cc1
Reactant: CC[N+](=O)[O-]
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CO
Solvent: Cc1ccccc1
Product: CC1NC(=O)CC1c1ccc(Cl)cc1

Procedure:
A mixture of 150 g. (2 mole) of nitroethane, 105 g. (0.5 mole) of ethyl-p-chlorocinnamate and 6.6 g. of Triton B (a 35% solution of trimethyl-benzyl-ammonium hydroxide in methanol) is heated for 20 hours at 80°C. After the reaction has finished, toluene is added, washing is carried out with a saturated solution of sodium chloride and the organic solution is dried and evaporated to dryness and the residue is distilled. Yield: 80%; B.P.: 150°-155°C./0.3 mm.Hg.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[N:20]1([CH2:26][CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][NH2:37])[CH2:30]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.N>ClCCl.CO>[N:20]1([CH2:26][CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][NH:37][C:2]([N:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[C:8](=[O:15])[NH:7][C:6]4[CH:16]=[CH:17][CH:18]=[N:19][C:5]3=4)=[O:3])[CH2:30]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Reactant: NCCN1CCCC(CCCN2CCCCC2)C1
Agent: N
Solvent: CO
Solvent: ClCCl
Product: O=C1Nc2cccnc2N(C(=O)NCCN2CCCC(CCCN3CCCCC3)C2)c2ccccc21
Yield: 14 %

Procedure:
Prepared analogously to Example 46 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2[3-[3-(piperidin-1-yl)propyl]-piperidin-1-yl]ethanamine in a yield of 14% of theory. Colourless amorphous substance, RF 0.13 (Macherey-Nagel, Polygram® SIL G/UV254, pre-coated plastic sheets for TLC, eluant: dichloromethane/methanol/conc. ammonia 90/10/1 v/v).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:15][CH2:14][C@H:13]([CH2:16]OS(C4C=CC(Br)=CC=4)(=O)=O)[O:12][C:8]3=2)[N:3]=1.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(=O)(O)[O-].[Na+]>CS(C)=O>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:15][CH2:14][CH:13]([CH2:16][N:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)[O:12][C:8]3=2)[N:3]=1
Reactant: C1CNCCN1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](COS(=O)(=O)c1ccc(Br)cc1)O3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1ccc2c3c(ccc2n1)OCC(CN1CCNCC1)O3
Temperature: 75 °C
Yield: 82 %

Procedure:
A mixture of [(2R)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl-4-bromobenzene sulfonate (1.35 g, 3 mmol) and piperazine (2.58 g, 30 mmol) in dimethylsulfoxide (16 mL) is heated at 75° C. under nitrogen for 1 hour, cooled and poured into saturated aqueous sodium bicarbonate. The mixture is extracted with ethyl acetate and the extracts are dried over anhydrous magnesium sulfate and evaporated to dryness. The residue is flash chromatographed on silica gel Merck-60 using a gradient of methanol (5–25%) in dichloromethane containing 0.2% ammonium hydroxide to provide the title compound as an off-white oil (0.736 g) identical to the compound of example 1B, step B′.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1.O>CS(C)=O>[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][O:1][N:2]2[C:3](=[O:12])[C:4]3=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]3[C:6]2=[O:7])=[CH:22][CH:21]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: Fc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1OCc1ccc(F)cc1
Reaction time: 8 h

Procedure:
N-Hydroxyphthalimide (12.0 g) in 130 ml dimethyl sulphoxide is treated with anhydrous finely divided potassium carbonate (6.6 g), when the dark red colour of the anion develops. The mixture is then treated dropwise at room temperature with p-fluorobenzyl chloride (20 g) and the mixture is stirred overnight or until the red colour is discharged. The reaction mixture is poured into water, and the resultant crystalline product is filtered off. Recrystallisation from ethanol gives N-p-fluorobenzyloxyphthalimide in pure form as white needles. (16.4 g, 82%), m.p. 156°-157° C.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].B1C2CCCC1CCC2.C1COCC1.[OH-].[Na+].Br[C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[C:31](=[O:35])[CH2:30][CH2:29]2>>[CH2:1]([C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[C:31](=[O:35])[CH2:30][CH2:29]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C1CCc2cc(Br)ccc21
Reactant: C=CCCCCCC
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCCCCCCc1ccc2c(c1)CCC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.3 %

Procedure:
A Boron complex was first created by adding 1-octene (0.744 g, 6.633 mmol) to a stirring solution of 0.5M 9-BBN in THF (13.27 mL, 6.633 mmol). The reaction was left to stir at room temperature overnight. 3M NaOH (2.34 mL) was then added to the stirring solution followed by the addition of 5-Bromo-indan-1-one (1 g, 4.7 mmol) and Pd(Ph3)4 (0.145 g, 0.126 mmol). The reaction was refluxed for twelve hours. The resulting solution was concentrated and purified using silica gel chromatography eluding with hexanes-EtOAc (9:1). The reaction provided 2 (1.094 g, 4.48 mmol, 95%) as a clear liquid.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[C:21]12([C:31](Cl)=[O:32])[CH2:30][CH:25]3[CH2:26][CH:27]([CH2:29][CH:23]([CH2:24]3)[CH2:22]1)[CH2:28]2.C(N(CC)CC)C>C(Cl)Cl>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][CH:2]([NH:1][C:31]([C:21]23[CH2:30][CH:25]4[CH2:24][CH:23]([CH2:29][CH:27]([CH2:26]4)[CH2:28]2)[CH2:22]3)=[O:32])[C:3]1=[O:20]
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1C(=O)C(NC(=O)C23CC4CC(CC(C4)C2)C3)N=C(c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and adamantane-1-carboxylic acid chloride were mixed in methylene chloride. The pH was adjusted to 8.5 with triethylamine and the reaction stirred 10 mins at 25° C. The mixture was flash chromatographed on silica gel (5% Et2O in Et2O in Ch2Cl2CH2CL2) and the title compound obtained by trituration with ethyl acetate: (mp 256°-257° C.).
Reaction SMILES: Cl[S:2]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]2[O:16][CH2:17][O:18][C:12]=2[CH:11]=1)(=[O:4])=[O:3].[NH2:19][C:20]1[O:24][N:23]=[C:22]([CH3:25])[C:21]=1[Br:26]>>[Br:26][C:21]1[C:22]([CH3:25])=[N:23][O:24][C:20]=1[NH:19][S:2]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]2[O:16][CH2:17][O:18][C:12]=2[CH:11]=1)(=[O:4])=[O:3]
Reactant: O=S(=O)(Cl)c1sccc1-c1ccc2c(c1)OCO2
Reactant: Cc1noc(N)c1Br
Product: Cc1noc(NS(=O)(=O)c2sccc2-c2ccc3c(c2)OCO3)c1Br
Yield: 60 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-3-[3,4-(methylenedioxy)phenyl]-thiophene-2-sulfonamide was prepared in the same manner as described in Example 1 by reaction of 2-chlorosulfonyl-3-[3,4-(methylenedioxy)phenyl]thiophene with 5-amino-4-bromo-3-methylisoxazole resulting in a 60% yield, m.p. 183-186° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].[Cl:18][C:19]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:20]=1[CH:21]=O>O.O1CCCC1>[Cl:18][C:19]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:20]=1/[CH:21]=[CH:9]/[C:7]#[N:8]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: N#C/C=C/c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 65.4 %

Procedure:
To a solution of 8 g of potassium carbonate in 10 cm3 of water, 6 g (0.034 mol) of diethyl cyanomethylphosphonate are added followed by 5 g of 2,4-dichlorobenzaldehyde solubilized in 10 cm3 of anhydrous tetrahydrofuran. The mixture is left stirred for 10 minutes at room temperature and 20 cm3 of water are added. The precipitate formed is washed with water to neutrality (8 times with 20 cm3 of water), and then washed with an ether/hexane mixture. 3.7 g (74%) of trans-2,4-dichlorocinnamonitrile are obtained in the form of white crystals, m.p. 156° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1Cl.[C:10]([NH:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)(=[O:12])[CH3:11].C(N(CC)CC)C>CN1C(=O)CCC1>[Cl:9][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[N:17]1[CH2:18][CH2:19][CH:14]([NH:13][C:10](=[O:12])[CH3:11])[CH2:15][CH2:16]1
Reactant: Clc1cncc(Cl)c1Cl
Reactant: CC(=O)NC1CCNCC1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CC(=O)NC1CCN(c2c(Cl)cncc2Cl)CC1
Yield: 9 %

Procedure:
General procedure C was followed using 3,4,5-trichloropyridine (50 mg, 0.27 mmol), 4-acetamidopiperidine (43 mg, 0.30 mmol), triethylamine (76 μL, 0.54 mmol) and NMP (1.5 mL). The crude product was purified by flash column chromatography on silica gel (hexane, EtOAc, MeOH, 1:1:0.05) to furnish the title compound as white solid (7 mg, 9%), LC-MS (ESI, 3.5 min) Rt 2.25 min; m/z (ESI) C12H16Cl2N3O requires 288.0665 found [M+H]+ 288.0664; HPLC Rt 5.98 min, 100%.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][N:10]2[C:19](OC2C=CC([N+]([O-])=O)=CC=2)=[O:20])=[CH:5][CH:4]=1.[NH2:33][C:34]1[CH:41]=[CH:40][C:37]([C:38]#[N:39])=[CH:36][C:35]=1[F:42].[H-].[Na+].O>CC#N>[C:38]([C:37]1[CH:40]=[CH:41][C:34]([NH:33][C:19]([N:10]2[CH2:11][CH2:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@H:9]2[C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:31])([F:1])[F:32])=[CH:4][CH:5]=2)=[O:20])=[C:35]([F:42])[CH:36]=1)#[N:39]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1
Reactant: N#Cc1ccc(N)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: N#Cc1ccc(NC(=O)N2CCc3ccccc3[C@H]2c2ccc(C(F)(F)F)cc2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of (R)-4-nitrophenyl 1-(4-(trifluoromethyl)phenyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (50 mg, 113 μmol, example 88) and 4-amino-3-fluorobenzonitrile (17 mg, 124 mop in MeCN (0.7 mL) was subjected to a microwave irradiation at 120° C. for 15 min and at 150° C. for 15 min. Then, NaH (60% dispersion in mineral oil, 20 mg) was added and the mixture was then stirred at RT for overnight. Then, H2O (1.0 mL) was added and the mixture was extracted with EtOAc (2×1.5 mL). The combined organic extracts were dried over MgSO4 and concentrated. The residue was then dissolved in a solution of DMSO and MeOH (1:1, 0.1 mL). The solution mixture was then purified by preparative HPLC (0%-100% MeCN 0.1% TFA/H2O 0.1% TFA) to give a desired product, which was then dissolved in MeOH (1.0 mL). The solution was then washed through PL-HCO3 MP-resin and the resin was washed with MeOH (2×0.5 mL). The combined washings were concentrated and dried under vacuum to give the title compound as a colorless solid. MS (ESI, positive ion) m/z: 440 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C(N(CC)CC)C>C(COC)OC>[N+:12]([C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)([O-:14])=[O:13]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1N1CCOCC1

Procedure:
4-(2-Nitro-4-trifluoromethylphenyl)morpholine was prepared by reaction of 4-chloro-3-nitrobenzotrifluoride with equimolar amounts of morpholine and triethylamine in monoglyme. The resultant product melts at 37° - 39° C.
Reaction SMILES: [CH3:1][C:2]([NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:7])([CH3:4])[CH3:3].C([Li])CCC.[Br-].[Na+].[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=1>C1COCC1>[CH3:4][C:2]([NH:5][C:6]([C:8]1[C:13]([CH2:14][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([F:22])=[CH:24][CH:25]=2)=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:7])([CH3:1])[CH3:3]
Reactant: Fc1ccc(CCl)cc1
Reactant: Cc1cccnc1C(=O)NC(C)(C)C
Agent: [Br-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)c1ncccc1CCc1ccc(F)cc1
Temperature: -5 °C
Yield: 99 %

Procedure:
Cool a solution of N-(1,1-dimethylethyl)-3-methyl-2-pyridinecarboxamide (38.4 g, 0.2 mole) in dry THF (250 mL) to −40° C. and add n-butyl lithium (185 mL, 0.44 mole). Add sodium bromide (1.9 g, 18 mmol.) and stir for 15 minutes. Add 4-fluorobenzylchloride (31.8 g, 0.22 mole) and stir for 2.5 hours while warming to −5° C. Quench the reaction with water and extract the product twice with EtOAc, then wash with brine (2×). Dry the organic phase over Na2SO4, filter and remove the solvent to give the title compound. (60.0 g, Yield 99%, m.p. 59-61° C.)
Reaction SMILES: [OH:1][C:2]1[C:11](S([O-])(=O)=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:16]([O-:19])(=[O:18])=[O:17])[CH:8]=2)[CH:3]=1.[Na+].[Na+].[OH-:22].[Na+]>O>[OH:1][C:2]1[C:11]([OH:22])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:16]([OH:19])(=[O:18])=[O:17])[CH:8]=2)[CH:3]=1
Reactant: O=S(=O)([O-])c1ccc2cc(O)c(S(=O)(=O)[O-])cc2c1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: O=S(=O)(O)c1ccc2cc(O)c(O)cc2c1
Yield: 96.3 %

Procedure:
Disodium 2-hydroxynaphthalene-3,6-disulfonate (348 g) was added to 176 g of a 50% aqueous solution of sodium hydroxide, and the mixture was stirred. Then, 900 g of a hydrogenated triphenyl mixture was mixed, and the resulting mixture was dehydrated. The dehydrated mixture was reacted at 270° C. for 1.5 hours in a nitrogen stream. After cooling, 2 liters of water was added to the reaction mixture to separate the reaction medium layer. The aqueous layer was decolorized with activated carbon, and then precipitated with an acid to give 231 g (yield 96.3%) of 2,3-dihydroxynaphthalene-6-sulfonic acid.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:26][CH2:27][CH3:28])[C:4](=[O:25])[C:5]2[NH:6][C:7]([C:11]3[CH:12]=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=4[F:24])[CH:15]=3)=[N:8][C:9]=2[N:10]=1.C([O-])=O.[NH4+].CN(C=O)C>[Pd].O>[F:24][C:18]1[C:19]([F:23])=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][N:14]1[CH:15]=[C:11]([C:7]2[NH:6][C:5]3[C:4](=[O:25])[N:3]([CH2:26][CH2:27][CH3:28])[CH:2]=[N:10][C:9]=3[N:8]=2)[CH:12]=[N:13]1
Reactant: CCCn1c(Cl)nc2nc(-c3cnn(Cc4cccc(F)c4F)c3)[nH]c2c1=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCn1cnc2nc(-c3cnn(Cc4cccc(F)c4F)c3)[nH]c2c1=O
Temperature: 87.5 °C
Yield: 30 %

Procedure:
A mixture of 2-Chloro-8-[1-(2,3-difluoro-benzyl)-1H-pyrazol-4-yl]-1-propyl-1,7-dihydro-purin-6-one (0.04 g, 0.09 mmol), ammonium formate (0.134 g, 1.97 mmol), Pd\C (10%) (0.02 g), DMF (2 ml) and H2O (0.5 ml) were heated at 85-90° C. for 15 hours. Reaction mixture was cooled to 20-25° C. and then it was filtered through celite bed washed with methanol (10 ml). The filtrate was concentrated under vacuum. To this residue water (1 ml) was added and acidified with citric acid up to pH (1-2). Solid precipitated was filtered off and washed sequentially with cold water, diethyl ether to obtain pure 8-[1-(2,3-difluoro-benzyl)-1H-pyrazol-4-yl]-1-propyl-1,7-dihydro-purin-6-one (0.01 g, 28%) as a off white solid.