Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:13][C:14]([C:17]([NH:19][C:20]1[CH:21]=[N:22][C:23]([O:26][C:27]2[CH:36]=[CH:35][CH:34]=[C:33]3[C:28]=2[CH2:29][CH:30]([CH3:37])[CH2:31][O:32]3)=[CH:24][CH:25]=1)=[O:18])([CH3:16])[NH2:15]>ClCCl>[CH3:16][C:14]1([CH3:13])[NH:15][C:2](=[O:4])[N:19]([C:20]2[CH:21]=[N:22][C:23]([O:26][C:27]3[CH:36]=[CH:35][CH:34]=[C:33]4[C:28]=3[CH2:29][CH:30]([CH3:37])[CH2:31][O:32]4)=[CH:24][CH:25]=2)[C:17]1=[O:18]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC1COc2cccc(Oc3ccc(NC(=O)C(C)(C)N)cn3)c2C1
Solvent: ClCCl
Product: CC1COc2cccc(Oc3ccc(N4C(=O)NC(C)(C)C4=O)cn3)c2C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 123.1 %

Procedure:
In a 50 ml round-bottomed flask 2-methyl-N1-{6-[(3-methyl-3,4-dihydro-2H-chromen-5-yl)oxy]-3-pyridinyl}alaninamide (Intermediate 121, 72.6 mg) was dissolved in dichloromethane (5 ml) to give a pale yellow solution. TEA (0.142 ml, 1.021 mmol) was added and the reaction mixture was cooled at 0° C. A solution of triphosgene (27.3 mg, 0.092 mmol) in 1 ml of dichloromethane was added to the reaction mixture which was stirred at 0° C. After 15 minutes, additional solution of triphosgene (27.3 mg, 0.092 mmol) in 1 ml of dichloromethane was added to the reaction mixture. After 15 minutes, the reaction mixture was evaporated under vacuum to give the crude product which was purified via Biotage SP1 (using Cyclohexane/EtOAc as eluents from 3:1 to 1:2 in 10 CV; then 1:2 for 5 CV; 10 g SNAP Silica column). The collected fractions afforded the title compound 5,5-dimethyl-3-{6-[(3-methyl-3,4-dihydro-2H-chromen-5-yl)oxy]-3-pyridinyl}-2,4-imidazolidinedione as a colourless oil (41.6 mg).
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([Cl:25])[C:16]=1[O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])C=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].ClC1C=CC=C([C:33]([O:35]O)=[O:34])C=1>ClCCl.O>[CH:33]([O:35][C:11]1[CH:14]=[C:15]([Cl:25])[C:16]([O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:19])[CH3:20])=[C:9]([O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3])[CH:10]=1)=[O:34]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(C=O)cc(Cl)c1O[Si](C)(C)C(C)(C)C
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cc(OC=O)cc(Cl)c1O[Si](C)(C)C(C)(C)C
Yield: 69.1 %

Procedure:
To a solution of 1.73 g (4.30 mmol) of 13 in 15 mL of dichloromethane under argon was added 2.03 g (6.50 mmol) of 55% m-chloroperbenzoic acid (MCPBA). After refluxing for 10 h, the solution was diluted with 30 mL of water and extracted three times with diethyl ether (50 mL each). The combined extracts were washed twice with saturated aqueous NaHCO3 (30 mL each), 30 mL of water, and 30 mL of brine, dried (MgSO4), concentrated, and column chromatographed on silica gel using hexane as eluent to give 1.24 g (70% yield) of 3,4-bis-(t-butyldimethylsilyloxy)-5-chlorophenyl formate. 1H NMR (CDCl3) δ 8.22 (s, 1H, CHO), 6.79 (d,J=3.2 Hz, 1H), 6.58 (d,J=3.2 Hz, 1H), 1.03 (s, 9H, t-Bu), 0.96 (s, 9H, t-Bu), 0.22 (s, 6H, Me), 0.19 (s, 6H, Me); 13C NMR (CDCl3) δ 159.0 (s, C═O), 148.8 (s), 143.0 (s), 142.4 (s), 127.1 (s), 115.5 (d), 113.1 (d), 26.2 (q, 6C, t-Bu), 18.8 (s, 2C, t-Bu), −3.3 (q, 2C, Me), −3.6 (q, 2C, Me).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[S:9](Cl)(=[O:11])=[O:10].[CH3:13][N:14]1[CH2:19][CH:18]=[C:17]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([OH:29])[CH:27]=3)[NH:22][CH:21]=2)[CH2:16][CH2:15]1.[OH-].[Na+]>C1COCC1>[CH3:13][N:14]1[CH2:15][CH:16]=[C:17]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([O:29][S:9]([C:3]4[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])(=[O:11])=[O:10])[CH:27]=3)[NH:22][CH:21]=2)[CH2:18][CH2:19]1
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Reactant: CN1CC=C(c2c[nH]c3ccc(O)cc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN1CC=C(c2c[nH]c3ccc(OS(=O)(=O)c4c(F)cccc4F)cc23)CC1
Yield: 28.2 %

Procedure:
By a method similar to Example 31, using a solution of 2,6-difluorobenzenesulfonyl chloride (380 mg, 1.79 mmol) in THF (5 mL) was added to a mixture of 3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-5-hydroxy-1H-indole (340 mg, 1.49 mmol) in 0.2 N sodium hydroxide (8.2 mL, 1.64 mmol) and THF (5 mL) gave 170 mg (28%) of homogeneous product as a tan solid. The product was crystallized from ethyl acetate to give 96 mg (16%) of the title compound as a yellow powder: mp 183° C. dec; MS(m/e): 405 (M+1), 403 (M−1); Calculated for C20H18F2N2O3S: C, 59.40; H, 4.49; N, 6.93. Found: C, 59.22; H, 4.24; N, 6.65.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]2[CH2:18][O:17]C(C)(C)[O:15][CH2:14]2)=[C:4]([NH2:21])[N:3]=1>C(O)(=O)C>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]([CH2:18][OH:17])[CH2:14][OH:15])=[C:4]([NH2:21])[N:3]=1
Reactant: CC1(C)OCC(CCn2cnc3c(N)nc(N)nc32)CO1
Solvent: CC(=O)O
Product: Nc1nc(N)c2ncn(CCC(CO)CO)c2n1
Yield: 62.8 %

Procedure:
A solution of 2,6-diamino-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]purine (180 mg, 0.6 mmol) in 70% acetic acid (10 ml) was stirred for 1 hour at room temperature. The solvent was removed, the residue was suspended in methanol and sodium methoxide was added to neutralise. Column chromatography on silica gel eluting with chloroform-methanol mixtures (6:1, 4:1 and 3:1) gave 2,6-diamino-9-(4-hydroxy-3-hydroxymethylbut-1-yl)purine (95 mg, 63%), m.p. 187-190° C.; λmax (H2O, pH6.5) 215 (ε 25,500), 255 (ε 7,290), and 280 (ε 9,170) nm; νmax 3150, 1680, 1650, 1605, 1590, and 1410 cm−1; δH [(CD3)2SO] 1.46 (1H, m, CHCH2CH2), 1.73 (2H, q, J 7.1 Hz, CHCH2CH2), 3.3-3.5 (4H, ddd (ABX), JAB 10.6 Hz, JAX 5.5 Hz and JBX 5.9 Hz, 2×CH2O), 4.01 (2H, t, J 7.3 Hz, CH2N), 4.41 (2H, br, D2O exchangeable, 2×OH), 5.70 (2H, s, D2O exchangeable, NH2), 6.56 (2H, s, D2O exchangeable, NH2), and 7.69 (1H, s, 8-H) (Found: C, 46.09; H, 6.32; N, 31.69%; C10H16N6O2.0.1CHCl3 requires C, 45.91; H, 6.14; N, 31.81%).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:4]=[CH:3]1.C([Li])CCC.CN(C)[CH:20]=[O:21]>C1COCC1.CCOC(C)=O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:4]=[C:3]1[CH:20]=[O:21]
Reactant: CN(C)C=O
Reactant: Cn1cnc(-c2ccccc2)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1cc(-c2ccccc2)nc1C=O
Temperature: -40 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-methyl-4-phenyl-1H-imidazole 42 (0.512 g, 3.24 mmol) in THF (15 mL) at −40° C. was added n-butyllithium (2.40 mL, 3.84 mmol) (1.6 M in hexanes), stirred at −40° C. for 30 min, cooled to −78° C., and N,N-dimethylformamide (0.325 mL, 4.21 mmol) was added. The reaction mixture was warmed to room temperature over 1 h, stirred at room temperature for 2 h, diluted with EtOAc, washed with water (1×), brine (1×), dried over MgSO4, filtered, and concentrated. The crude product was dissolved in DCM (˜20 mL), diluted with hexanes (˜50 mL), and concentrated to a volume of approximately 30 mL. The solution was cooled to 0° C. and the solid was collected by filtration, washed with hexanes, and dried under high vacuum to give 1-methyl-4-phenyl-1H-imidazole-2-carbaldehyde 43. Mass spectrum: calculated for C11H10N2O 186.1; found 187.1 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH2:16])[CH2:11][C:10]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:9]2)=[CH:4][CH:3]=1.[O:17]=[C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](=[O:27])N1C(OCC)=O>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([N:16]3[C:18](=[O:17])[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[C:20]3=[O:27])[CH2:11][C:10]3([O:12][CH2:13][CH2:14][O:15]3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: NC1(c2ccc(Br)cc2)CC2(C1)OCCO2
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Solvent: ClC(Cl)Cl
Product: O=C1c2ccccc2C(=O)N1C1(c2ccc(Br)cc2)CC2(C1)OCCO2
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(4-bromophenyl)-5,8-dioxaspiro[3.4]octan-2-amine (7-1) (2.7 g, 9.50 mmol), ethyl 1,3-dioxo-1,3-dihydro-2H-isoindole-2-carboxylate (4.2 g, 19.0 mmol), and TEA (5.3 mL, 38.0 mmol) in CHCl3 (50 mL) was stirred at 70° C. for overnight. The solvent was evaporated under reduced pressure, and to the residue was added MeOH. The resulting solid was collected by filtration to give 2-[2-(4-bromophenyl)-5,8-dioxaspiro[3.4]oct-2-yl]-1H-isoindole-1,3(2H)-dione (7-2) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C@H:4]([NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]([NH2:13])[CH:7]=1.[C:26](O)(=O)[CH3:27].O.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3](=[O:25])[C@H:4]([NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]2[NH:12][C:26]([CH3:27])=[N:13][C:8]=2[CH:7]=1
Reactant: COC(=O)[C@@H](Cc1ccc(N)c(N)c1)NC(=O)OCc1ccccc1
Reactant: CC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COC(=O)[C@@H](Cc1ccc2[nH]c(C)nc2c1)NC(=O)OCc1ccccc1
Temperature: 0 °C
Yield: 95 %

Procedure:
A solution of (R)-2-benzyloxycarbonylamino-3-(3,4-diamino-phenyl)-propionic acid methyl ester-acetic acid (640 mg) in acetic acid (8 mL) was heated at 130° C. for 4 h. The mixture was then poured into water and cooled to 0° C. The pH was adjusted to 8 by gradual addition of solid sodium bicarbonate. The mixture was then extracted with ethyl acetate (3×100 mL), and the combined organic layers were washed with water, brine and dried over sodium sulfate. After filtration, solvents were removed to afford the title compound as a brownish foamy solid (95%). 1H-NMR (CDCl3, 500 MHz) δ 7.39 (d, J=8.5 Hz, 1H), 7.35 (s, 1H), 7.26-7.22 (m, 5H), 7.06 (d, J=8.0 Hz, 1H), 5.03 (d, J=12.5 Hz, 1H), 4.99 (d, J=13.0 hz, 1H), 4.51 (dd, J=8.5, 5.5 Hz, 1H), 3.70 (s, 3H), 3.27 (dd, J=13.5, 5.0 Hz, 1H), 3.03 (dd, J=14.0, 9.0 Hz, 1H), 2.55 (s, 3H). Mass spec.: 368.19 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([O:14]N2C3C=CC=CC=3N=N2)=O)=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1.[CH3:24][N:25]1[CH2:30][CH2:29][CH2:28][C@@H:27]([O:31][C:32]2[C:37]([NH2:38])=[CH:36][N:35]=[CH:34][N:33]=2)[CH2:26]1>CN1C(=O)CCC1>[NH2:1][C:2]1[C:11]([C:12]([NH:38][C:37]2[C:32]([O:31][C@@H:27]3[CH2:28][CH2:29][CH2:30][N:25]([CH3:24])[CH2:26]3)=[N:33][CH:34]=[N:35][CH:36]=2)=[O:14])=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1
Reactant: CN1CCC[C@@H](Oc2ncncc2N)C1
Reactant: Nc1nn2cc(F)cnc2c1C(=O)On1nnc2ccccc21
Solvent: CN1CCCC1=O
Product: CN1CCC[C@@H](Oc2ncncc2NC(=O)c2c(N)nn3cc(F)cnc23)C1
Temperature: 25 °C

Procedure:
A solution of benzotriazol-1-yl 2-amino-6-fluoro-pyrazolo[1,5-a]pyrimidine-3-carboxylate 6a (125 mg, 0.3990 mmol) and 4-[[(3R)-1-methyl-3-piperidyl]oxy]pyrimidin-5-amine 7a (83.10 mg, 0.3990 mmol) in NMP (2 mL) was heated at 100° C. overnight. The reaction mixture was cooled to RT, passed through a SCX cartridge, eluting with 2M ammonia in methanol. The product fractions were combined, concentrated in vacuo and purified by HPLC. The title product I-A-1 was isolated (60 mg., 38.9%)
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[C:15]([C:17]1[CH:23]=[CH:22][C:20]([NH2:21])=[CH:19][CH:18]=1)#[N:16].CC(C)([O-])C.[K+].Cl>CN(C)C=O>[Cl:8][C:6]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]([N+:12]([O-:14])=[O:13])=[C:2]([CH:7]=1)[NH:21][C:20]1[CH:22]=[CH:23][C:17]([C:15]#[N:16])=[CH:18][CH:19]=1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)cc1Cl
Reactant: N#Cc1ccc(N)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Nc2cc(Cl)c([N+](=O)[O-])cc2[N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2,4-Dichloro-1,5-dinitrobenzene (II-1, 1.2 g, 5 mmol) and p-cyanoaniline (III-1, 0.59 g, 5 mmol) were dissolved in N,N-dimethylformamide (DFM, 10 ml). To the solution was added potassium tert-butoxide (1.4 g, 12.5 mmol) in batches in ice water bath. The mixture was allowed to react at room temperature for 45 minutes. The reaction liquid was poured into ice water. The pH value was adjusted to about 6 with dilute hydrochloric acid. The mixture was stirred for 30 minutes to precipitate a solid. The solid was filtered, washed with water to neutrality, dried, and separated on silica gel column (eluted with ethyl acetate: petroleum ether) to obtain a compound VI-1 (1.44 g, faint yellow solid). 1H NMR (CDCl3) δ ppm 7.41 (1H, s, ArH-6), 7.57 (2H, d, J=8.7 Hz, ArH-3′, 5′), 7.91 (2H, d, J=8.7 Hz, ArH-2′, 6′), 8.90 (1H, s, ArH-3), 10.07 (1H, s, NH).
Reaction SMILES: FC(F)(F)C([N:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]#[N:15])=[CH:11][CH:12]=2)[CH2:7][CH2:6]1)=O>C1COCC1.[OH-].[Na+]>[NH:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]#[N:15])=[CH:11][CH:12]=2)[CH2:7][CH2:6]1
Reactant: N#Cc1ccc2c(c1)CCN2C(=O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N#Cc1ccc2c(c1)CCN2
Temperature: 25 °C
Reaction time: 5 h

Procedure:
1-(2,2,2-Trifluoroacetyl)-2,3-dihydro-1H-indole-5-carbonitrile (13 g, 0.0542 mol; see step (iii) above) was dissolved in THF (100 mL), to which 1% NaOH was then added. After stirring for 5 h at RT, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and solvent was evaporated to provide the sub-title compound as a pale yellow solid. Yield: 8 g.
Reaction SMILES: CNC1SC(NC)=NN=1.C([O:12]CCNC1SC(NC)=NN=1)C.CO[CH2:25][CH2:26][NH:27][C:28]1S[C:30]([NH:33][CH2:34][CH2:35]OC)=[N:31][N:32]=1.C(OCCNC1SC(NCCOC)=NN=1)C.COCCNC1SC(NC2C=CC=CC=2)=NN=1.COC1C=CC(NC2SC(NCCOC)=NN=2)=CC=1>[Ag]Cl>[CH2:26]([NH:27][C:28]1[O:12][C:30]([NH:33][CH2:34][CH3:35])=[N:31][N:32]=1)[CH3:25]
Reactant: COCCNc1nnc(NCCOC)s1
Reactant: CCOCCNc1nnc(NC)s1
Agent: Cl[Ag]
Agent: CCOCCNc1nnc(NCCOC)s1
Agent: CNc1nnc(NC)s1
Product: CCNc1nnc(NCC)o1

Procedure:
The photographic element of claim 10 comprising a silver chloride emulsion layer incorporating a silver halide developing agent which is 2,5-bis-(methylamino)-1,3,4-thiadiazole; 2-methylamino-5-ethylamino-1,3,4,thiadiazole; 2-(2-ethoxyethylamino)-5-methylamino-1,3,4-thiadiazole; 2,5-bis(2-methoxyethylamino)-1,3,4-thiadiazole; 2-(2-ethoxyethylamino)-5-(2-methoxyethylamino)-1,3,4-thiadiazole; 2-(2-methoxyethylamino)-5-phenylamino-1,3,4-thiadiazole; 2-(p-methoxyphenylamino)-5-(2-methoxyethylamino)-1,3,4-thiadiazole; or
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][S:15][CH2:16][C@H:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.CCN(C(C)C)C(C)C.Cl.[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]2[CH2:44][CH2:45][NH:46][CH2:47][CH:48]=2)=[CH:39][CH:38]=1>C(#N)CC>[Cl:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]2[CH2:48][CH2:47][N:46]([CH2:2][C:3]3[CH:12]=[N:11][C:10]4[N:9]5[CH2:13][CH2:14][S:15][CH2:16][C@H:8]5[C:7](=[O:17])[NH:6][C:5]=4[CH:4]=3)[CH2:45][CH:44]=2)=[CH:39][CH:38]=1
Reactant: Clc1ccc(C2=CCNCC2)cc1
Reactant: O=C1Nc2cc(CO)cnc2N2CCSC[C@@H]12
Agent: C[P+](C)(C)CC#N
Agent: Cl
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C1Nc2cc(CN3CC=C(c4ccc(Cl)cc4)CC3)cnc2N2CCSC[C@@H]12
Temperature: 90 °C

Procedure:
To a suspension of (R)-3-(hydroxymethyl)-6a,7,9,10-tetrahydropyrido[3,2-e][1,4]thiazino[4,3-a]pyrazin-6(5H)-one (70 mg, 0.279 mmol) in propiononitrile (Volume: 696 μl) was added (cyanomethyl)trimethylphosphonium iodide (81 mg, 0.334 mmol), DIEA (146 μl, 0.836 mmol) and finally 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (64.1 mg, 0.279 mmol). The vial was heated to 90° C. for 12 hours. Cooled to rt and concentrated to a brown residue which was treated with MeOH (5 mL). The precipitate was filtered, the solids were collected, taken up in EtOH (15 mL) and refluxed 2 hours. Let sit at RT ON. Filtered, dried in vacuum and retrieved 75.6 mg (63.6%) of the title compound as a white solid. 1H NMR (CHLOROFORM-d) δ (ppm): 7.80 (d, J=1.8 Hz, 1H), 7.66 (br. s., 1H), 7.30 (d, J=3.8 Hz, 5H), 7.04 (br. s., 1H), 6.02-6.09 (m, 1H), 5.06 (ddd, J=13.5, 2.8, 2.7 Hz, 1H), 4.42 (dd, J=10.5, 3.2 Hz, 1H), 3.54 (br. s., 2H), 3.10-3.26 (m, 3H), 3.00 (td, J=12.8, 2.7 Hz, 1H), 2.85-2.92 (m, 1H), 2.75 (br. s., 2H), 2.56 (br. s., 2H), 2.35-2.44 (m, 1H). [M+H] calc'd for C22H23ClN4OS, 427; found, 427.
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([CH3:28])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[N:20]=[N:21][NH:22][C:23]=3[Si](C)(C)C)[CH:14]=2)[C:8]1=[O:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[F-].[K+]>C(O)C.Cl>[CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([CH3:28])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[NH:20][N:21]=[N:22][CH:23]=3)[CH:14]=2)[C:8]1=[O:29])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN1CC2C(C1=O)C2(C)c1cccc(-c2nn[nH]c2[Si](C)(C)C)c1
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: CCO
Product: CCCCCCN1CC2C(C1=O)C2(C)c1cccc(-c2cnn[nH]2)c1
Temperature: 25 °C

Procedure:
To a solution of 3-hexyl-6-methyl-6-{3-[5-(trimethylsilyl)-1H-1,2,3-triazol4-yl]phenyl}-3-azabicyclo[3.1.0]hexan-2-one (Preparation 39, 1.2 g, 2.88 mmol) in ethanol (15 ml) was added potassium fluoride (183 mg, 3.17 nmnol) and a few drops of concentrated hydrochloric acid. The mixture was heated at reflux for 1.5 hours and then cooled to room temperature. The solvent was removed in vacuo and the crude residue was dissolved in dichloromethane (40 ml) and washed with 10% potassium carbonate solution. The extract was dried (MgSO4), filtered and concentrated in vacuo to give the crude product which was used directly in the next step.
Reaction SMILES: [Br:1]Br.[N:3]1[C:8]2[NH:9][CH:10]=[CH:11][C:7]=2[CH:6]=[N:5][CH:4]=1.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>CN(C=O)C.O>[Br:1][C:11]1[C:7]2[CH:6]=[N:5][CH:4]=[N:3][C:8]=2[NH:9][CH:10]=1
Reactant: c1ncc2cc[nH]c2n1
Reactant: BrBr
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1c[nH]c2ncncc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of bromine (0.086 mL, 1.68 mmol) in DMF (5.5 mL) was added to a solution of 7H-pyrrolo[2,3-d]pyrimidine (200 mg, 1.68 mmol) in DMF (5.5 mL). The reaction mixture was stirred at RT for 4 h and poured into a mixture of ice and water containing Na2S2O3. A saturated aqueous solution of NaHCO3 was added (until basic pH), the layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated. The material thus obtained was used without further purification in the next step. TLC, Rf (CH2Cl2/MeOH 9:1)=0.45; MS (UPLC/MS): 198.1/200.1 [M+H]+, 196.1/198.1 [M−H]−.
Reaction SMILES: C(=O)([O-])[O-].[Ba+2:5].[P:6](=[O:10])([OH:9])([OH:8])[OH:7]>>[P:6](=[O:7])([O-:10])([O-:9])[O-:8].[Ba+2:5].[P:6](=[O:7])([O-:10])([O-:9])[O-:8].[Ba+2:5].[Ba+2:5]
Reactant: O=P(O)(O)O
Agent: O=C([O-])[O-]
Agent: [Ba+2]
Product: O=P([O-])([O-])[O-]

Procedure:
The composition was calcined at 1000° C. for about 3 hours to obtain 15.5 g of black product (Ba:77%). The crushed black product and 10.0 g of barium carbonate were dissolved in pure phosphoric acid to obtain 315 g of barium salt-phosphoric acid mixture (H3PO4 :50%; Ba:6.00%). A 205.0 g sample of the barium salt-phosphoric acid mixture was added to 1000 g of the extracted phosphoric acid of Example 1 to treat it under the same conditions. The product was treated with the powdery active carbon to obtain substantially the same results of Example 1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:31]2[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH:36]=2)[C:9]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)[CH2:13][CH2:12]2)=O)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.CCOCC.N>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:31]2[CH2:32][CH2:33][N:34]([CH3:37])[CH2:35][CH:36]=2)[CH2:9][N:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=[CH:23][CH:22]=3)[CH2:15][CH2:16]2)=[CH:6][CH:7]=1
Reactant: CN1CC=C(C(C(=O)N2CCN(CCCCc3cccc4ccccc34)CC2)c2ccc(F)cc2)CC1
Agent: N
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN1CC=C(C(CN2CCN(CCCCc3cccc4ccccc34)CC2)c2ccc(F)cc2)CC1
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 41.2 %

Procedure:
0.25 g of 4-{1-(4-Fluorophenyl)-2-[4-(4-naphthalen-1-yl-butyl)piperazin-1-yl]-2-oxoethyl}-1-methyl-3,6-dihydro-2H-pyridine was dissolved in 3 ml of tetrahydrofuran, and 18 mg of lithium aluminum hydride was added, followed by stirring at 50° C. for 15 minutes. The reaction solution was cooled to room temperature and diluted with ether, and 25% aqueous ammonia solution was added dropwise. The precipitate was removed by Celite filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by a silica gel column chromatography (Chromatorex NH, hexane:ethyl acetate=4:1) to give 0.10 g of 1-[2-(4-fluorophenyl)-2-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)ethyl]-4-(4-naphthalen-1-yl-butyl)piperazine as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[CH:3]=1.C1C(=O)N([Br:17])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH2:9][Br:17])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(C)cc(Br)c1
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1cc(Br)cc(CBr)c1
Temperature: 25 °C
Yield: 112.3 %

Procedure:
A mixture of 1-bromo-3,5-dimethylbenzene (25.0 g, 135 mmol), NBS (24.0 g, 135 mmol) and BPO (1.30 g) in CCl4 (250 mL) was refluxed for 6 h. After cooling to room temperature, the mixture was filtered, and the filtrate was washed successively with saturated sodium bicarbonate (100 mL), water (2×50 mL) and brine (2×50 mL). The combined organic phases were dried (Na2SO4) and concentrated in vacuum to give 40.0 g of crude product 1-bromo-3-(bromomethyl)-5-methylbenzene.
Reaction SMILES: [O-]CC.[Na+].Cl.[CH3:6][N:7]1[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][CH2:15][NH:16][C:17]([NH2:19])=[NH:18])[CH2:9][CH2:8]1.[C:20]([C:23](=[CH:26]OCC)[C:24]#[N:25])(=O)[CH3:21]>C(O)C>[CH3:21][C:20]1[C:23]([C:24]#[N:25])=[CH:26][N:19]=[C:17]([NH:16][CH2:15][CH2:14][CH2:13][CH:10]2[CH2:9][CH2:8][N:7]([CH3:6])[CH2:12][CH2:11]2)[N:18]=1
Reactant: CN1CCC(CCCNC(=N)N)CC1
Reactant: CCOC=C(C#N)C(C)=O
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1nc(NCCCC2CCN(C)CC2)ncc1C#N
Temperature: 25 °C

Procedure:
A flask containing sodium ethoxide (0.64 mL of a 21 wt % solution in ethanol, 1.7 mmol) and N-[3-(1-methyl-piperidin-4-yl)-propyl]-guanidine-HCl (200 mg, 0.85 mmol) in ethanol (2.45 mL) was aged for 15 minutes at room temperature. To the resultant mixture was then added 2-acetyl-3-ethoxy-acrylonitrile (148 mg, 1.06 mmol). The resultant mixture was warmed to 80° C. for 5 h, then cooled to room temperature and concentrated. The resultant residue was partitioned between 1 N NaOH and dichloromethane. After separation of the layers, the aqueous layer was extracted with additional dichloromethane (2×). The combined organic layers were dried over MgSO4, filtered, and concentrated to yield the title compound as a solid.