Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].Cl[C:11]1[N:16]=[C:15](Cl)[C:14]([CH2:18][CH3:19])=[C:13]([Cl:20])[N:12]=1>O>[CH2:1]([O:8][C:11]1[N:16]=[C:15]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:14]([CH2:18][CH3:19])=[C:13]([Cl:20])[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1c(Cl)nc(Cl)nc1Cl
Reactant: OCc1ccccc1
Agent: [Na]
Solvent: O
Product: CCc1c(Cl)nc(OCc2ccccc2)nc1OCc1ccccc1
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a stirred solution of benzyl alcohol (80 mL) in water bath, was added sodium metal (2.17 g, 94.6 mmol) under nitrogen atmosphere. After complete reaction of sodium metal, the mixture was cooled in an ice bath and 2,4,6-trichloro-5-ethyl-pyrimidine (10.5 g, 49.6 mmol) was added in portions. After stirring for 30 min in an ice bath, the reaction mixture was stirred at room temperature for overnight. Excess benzyl alcohol was evaporated in vacuo and the residue was dissolved in ether, washed with water, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo to give a pale yellow oil. The crude product was purified by silica gel column chromatography (eluent, ether:hexane (4:96)) to give 14 g (80%) of a white solid; m.p. 53-54° C.; 1H NMR (200 MHz, CDCl3) δ: 1.14 (3H, t, J=7.4 Hz), 2.70 (2H, q, J=7.4 Hz), 5.41 (2H, s), 5.45 (2H, s), 7.34-7.53 (10H, m); m/z (EI): 354 (M+).
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:7][C:8]1[C:14]([CH3:15])=[CH:13][C:11]([NH2:12])=[CH:10][C:9]=1[CH3:16].C[Si]([C:21]#[N:22])(C)C>C(O)(=O)C>[Br:7][C:8]1[C:14]([CH3:15])=[CH:13][C:11]([NH:12][C:1]2([C:21]#[N:22])[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:10][C:9]=1[CH3:16]
Reactant: O=C1CCCC1
Reactant: Cc1cc(N)cc(C)c1Br
Reactant: C[Si](C)(C)C#N
Solvent: CC(=O)O
Product: Cc1cc(NC2(C#N)CCCC2)cc(C)c1Br
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a mixture of cyclopentanone (42 mg, 0.500 mmol) and 4-bromo-3,5-dimethylaniline (100 mg, 0.500 mmol) in acetic acid (0.5 mL), trimethylsilyl cyanide (0.063 ml, 0.500 mmol) was added at room temperature. The mixture was stirred at room temperature for 1.5 hours under nitrogen atmosphere. The reaction mixture was quenched with 28% aqueous ammonia (1 mL), diluted with water and extracted with dichloromethane. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to afford 1-((4-bromo-3,5-dimethylphenyl)amino)cyclopentanecarbonitrile as a crude product (152 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[C:12]3[N:13]=[C:14]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[N:15]=[C:16]([C:17]4[CH:18]=[N:19][C:20]([N:23]([CH2:33][C:34]5[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=5)[CH2:24][C:25]5[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=5)=[N:21][CH:22]=4)[C:11]=3[CH2:10][CH2:9]2)[CH:5]=[CH:4][N:3]=1.[NH2:48][CH2:49][CH2:50][CH2:51][N:52]1[CH2:57][CH2:56][O:55][CH2:54][CH2:53]1>>[CH3:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:23]([CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[C:20]2[N:19]=[CH:18][C:17]([C:16]3[C:11]4[CH2:10][CH2:9][N:8]([C:6]5[CH:5]=[CH:4][N:3]=[C:2]([NH:48][CH2:49][CH2:50][CH2:51][N:52]6[CH2:57][CH2:56][O:55][CH2:54][CH2:53]6)[CH:7]=5)[C:12]=4[N:13]=[C:14]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)[N:15]=3)=[CH:22][N:21]=2)=[CH:26][CH:27]=1
Reactant: NCCCN1CCOCC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccnc(Cl)c3)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccnc(NCCCN4CCOCC4)c3)cn2)cc1
Yield: 42.5 %

Procedure:
Using {5-[7-(2-chloro-pyridin-4-yl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrimidin-2-yl}-bis-(4-methoxy-benzyl)-amine (200 mg, 0.31 mmol) obtained in Step A instead of {5-[7-(6-chloro-pyridin-3-yl)-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrimidin-2-yl}-bis-(4-methoxy-benzyl)-amine, and N-(3-aminopropyl)morpholine (54 μl, 0.37 mmol) instead of N,N,N′-trimethyl ethylenediamine, in the same manner as Step B in Example 1-D-48, amination was carried out, to obtain a crude product of bis-(4-methoxy-benzyl)-(5-{2-morpholin-4-yl-7-[2-(3-morpholin-4-yl-propylamino)-pyridin-4-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}-pyrimidin-2-yl)-amine as a yellow solid (100 mg), and then the PMB groups were removed according to the above Deprotection method 2, to obtain the desired compound (D-69) as a yellow powder (27 mg, 17%).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:5]=1[CH2:6][Br:7])([O-:3])=[O:2].[C:13]1([P:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CCOC(C)=O>[Br-:7].[F:12][C:10]1[CH:9]=[CH:8][C:5]([CH2:6][P+:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[C:4]([N+:1]([O-:3])=[O:2])[CH:11]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=[N+]([O-])c1cc(F)ccc1CBr
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(F)ccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Yield: 70520.7 %

Procedure:
A solution of 117 g (0.5 mol) of 2-nitro-4-fluorobenzyl bromide and 131 g (0.5 mmol) of triphenylphosphine in 2 L of EtOAc was heated under reflux for 3 h. The mixture was cooled and the solid collected to give 175 g (70%) of [(4-fluoro-2-nitrophenyl)methyl]triphenylphosphonium bromide: 1H NMR (CDCl3) δ 8.2 (m, 1H); 7.8-7.5 (m, 16H); 7.4 (m, 1H); 6.1 (d, 2H). ##STR16##
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:34]/[O:35][CH3:36])/[C:8]([NH:10][C@@H:11]2[C:32](=[O:33])[N:13]3[C:14]([C:20]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)=[O:21])=[C:15]([CH2:18][I:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.[CH3:37][C:38]12[CH2:45][CH2:44][N:41]([CH2:42][CH2:43]1)[CH2:40][CH2:39]2>C(OCC)(=O)C.CO>[I-:19].[NH2:1][C:2]1[S:6][N:5]=[C:4](/[C:7](=[N:34]/[O:35][CH3:36])/[C:8]([NH:10][C@@H:11]2[C:32](=[O:33])[N:13]3[C:14]([C:20]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=4)=[O:21])=[C:15]([CH2:18][N+:41]45[CH2:44][CH2:45][C:38]([CH3:37])([CH2:43][CH2:42]4)[CH2:39][CH2:40]5)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: CC12CCN(CC1)CC2
Reactant: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc(OC)cc3)=C(CI)CS[C@H]12)c1nsc(N)n1
Solvent: CCOC(C)=O
Solvent: CO
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OCc3ccc(OC)cc3)=C(C[N+]34CCC(C)(CC3)CC4)CS[C@H]12)c1nsc(N)n1
Product: [I-]
Reaction time: 0.25 h
Yield: 109.9 %

Procedure:
p-Methoxybenzyl 7β-[(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-iodomethyl-3-cephem-4-carboxylate (700 mg) was dissolved in a mixed solution of ethyl acetate (50 ml) and methanol (1 ml). After the whole was ice-cooled, a solution of ethyl acetate (2.8 ml) of 4-methyl-quinuclidine (114 mg) was added thereto, and the mixture was stirred for 15 minutes. The resulting precipitate was recovered by filtration, followed by wasing with ethyl acetate to obtain p-methoxybenzyl 7β-[(Z)-2-(5-amino 1,2,4-thiadiazol-3-yl)-2-methoxyiminoacetamido]-3-(4-methyl-1-quinuclidinio)methyl-3-cephem-4-carboxylate iodide (770 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH:11]=[C:12]([C:14](O)=[O:15])[N:13]=1.CN(C(F)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:50][C@@H:51]1[CH2:56][CH2:55][CH2:54][CH2:53][C@H:52]1[OH:57]>ClCCCl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[CH:11]=[C:12]([C:14]([NH:50][C@@H:51]2[CH2:56][CH2:55][CH2:54][CH2:53][C@H:52]2[OH:57])=[O:15])[N:13]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: COc1ccc(-n2cc(C(=O)O)nc2-c2ccc(Cl)cc2Cl)cc1
Agent: CN(C)C(F)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: COc1ccc(-n2cc(C(=O)N[C@@H]3CCCC[C@H]3O)nc2-c2ccc(Cl)cc2Cl)cc1
Yield: 23 %

Procedure:
In a 20-mL screw-cap vial, 182 mg (0.5 mmol) 2-(2,4-dichlorophenyl)-1-(4-methoxyphenyl)-1H-imidazole-4-carboxylic acid, 145 mg (0.55 mmol) TFFH, and 5.0 equiv. PS-DIEA (loading level: 3.50 mmol/g, 716 mg, 2.5 mmol) were heated in 10 mL 1,2-dichloroethane at 35° C. overnight. The formation of acyl fluoride was monitored by LC-MS. To the mixture, 1.1 equiv. (84 mg, 0.55 mmol) trans-2-aminocyclohexanol hydrochloride was added and the reaction continued overnight. The mixture was filtered through a filter tube (polypropylene frit), and the filtrate was evaporated under reduced pressure. The crude product was redissolved in 1 mL MeOH and purified by preparative HPLC to give 53 mg of 2-(2,4-dichlorophenyl)-N-(trans-2-hydroxycyclohexyl)-1-(4-methoxyphenyl)-1H-imidazole-4-carboxamide (amber oil, 23% yield). 1H NMR (400 MHz, CD2Cl2) δ 7.90 (s, 1 H), 7.30-7.50 (m, 4 H), 7.10 (d, 2 H), 6.90 (d, 2 H), 3.85 (s, 3 H), 3.80 (m, 1 H), 3.50 (m, 1 H), 3.25 (bs, 1 H), 2.0 (m, 2 H), 1.75 (m, 2 H), 1.30-1.50 (m, 4 H); LC-MS m/z 460.2 (MH+), retention time 3.31 min (method 2).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:7](=NO)[CH3:8])=[CH:5][CH:6]=1.[N+:11]([O-])([OH:13])=[O:12].C=[O:16].O>S(=O)(=O)(O)O>[Br:1][C:2]1[S:3][C:4]([C:7](=[O:16])[CH3:8])=[CH:5][C:6]=1[N+:11]([O-:13])=[O:12]
Reactant: CC(=NO)c1ccc(Br)s1
Reactant: C=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)c1cc([N+](=O)[O-])c(Br)s1
Reaction time: 1 h

Procedure:
2-Bromo-5-acetyl thiophene oxime (35.2 g) (0.16 mole) was dissolved in concentrated sulphuric acid (80 ml) at 5°-10° C. A mixture of fuming nitric acid (95-98%) (10.6 g) (0.16 mole) in concentrated sulphuric acid (10 ml) was added dropwise at less than 10° C. The temperature, after the addition, was allowed to rise to room temperature and the system stirred there for 60 minutes. Paraformaldehyde (2.0 g) was then added carefully and the mixture stirred at room temperature for 15 minutes. This was followed by the addition of a further amount (15.0 g) of paraformaldehyde at about 20°-26° C. Stirring was continued at this temperature for 2-3 hours further, and then the mixture was drowned into water, stirred for 30 minutes and filtered. The solid 2-bromo-3-nitro-5-acetyl thiophene was washed with water and dried. The yield was 35.3 g (88.25%).
Reaction SMILES: Cl.[O:2]=[C:3]1[C:12]2[C:7]3[C:8](=[CH:13][CH:14]=[CH:15][C:6]=3[C:5](=[O:16])[N:4]1[CH2:17][CH2:18][CH2:19]CN1CCC(N(C3C=CC=CC=3)C(=O)CC)CC1)[CH:9]=[CH:10][CH:11]=2.[Br:38][CH2:39][CH2:40]CCCBr.BrCCCCBr>>[Br:38][CH2:39][CH2:40][CH2:19][CH2:18][CH2:17][N:4]1[C:5](=[O:16])[C:6]2[CH:15]=[CH:14][CH:13]=[C:10]3[C:11]=2[C:12](=[CH:7][CH:8]=[CH:9]3)[C:3]1=[O:2]
Reactant: CCC(=O)N(c1ccccc1)C1CCN(CCCCN2C(=O)c3cccc4cccc(c34)C2=O)CC1
Reactant: BrCCCCCBr
Agent: Cl
Solvent: BrCCCCBr
Product: O=C1c2cccc3cccc(c23)C(=O)N1CCCCCBr

Procedure:
Following the procedure of part (a) of example 31 but substituting 1,5-dibromopentane for the 1,4-dibromobutane, one obtains 2-(5-bromopentyl)-1H-benz[de]isoquinoline-1,3(2H)-dione; m.p. 113°-115°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.Cl.[NH2:13][CH2:14][CH2:15][C@H:16]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(N(CC)CC)C>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH:13][CH2:14][CH2:15][CH:16]([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:17]([O:19][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:18])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](CCN)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(CCNc1ncc(Br)cc1[N+](=O)[O-])C(=O)OC(C)(C)C
Yield: 92.7 %

Procedure:
A procedure similar to the method described in step C.1 is carried out, starting from 2 g (8.42 mmol) of 5-bromo-2-chloro-3-nitropyridine, 3.14 g (10.11 mmol) of tert-butyl(S)-4-amino-2-tert-butoxycarbonylaminobutanoate hydrochloride and 2.31 g (16.85 mmol) of triethylamine in 30 ml of dioxane. This time the mixture is heated for 12 hours. This gives 3.71 g of the expected product, which is used as it is in the remainder of the synthesis.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[CH2:14][C@@H:15]([C:17]([OH:19])=O)[CH2:16][C@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N=C=NCCCN(C)C)C.O.OC1C2N=NNC=2C=CC=1.[C:42]1([CH:48]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[NH2:49])[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>ClCCl.O>[CH:48]([NH:49][C:17]([C@@H:15]1[CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][C@@H:10]2[CH2:16]1)=[O:19])([C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCN2C[C@@H](C(=O)O)C[C@H]2C1
Agent: CCN=C=NCCCN(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN2C[C@@H](C(=O)NC(c3ccccc3)c3ccccc3)C[C@H]2C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (7S,8aS)-2-(tert-butoxycarbonyl)octahydropyrrolo[1,2-a]pyrazine-7-carboxylic acid (80 mg, 0.296 mmol) in dichloromethane (2 mL) was added a solution of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (68.9 mg, 0.444 mmol) and hydroxybenzotriazole hydrate (40.0 mg, 0.296 mmol) in dichloromethane (1 mL). The mixture was stirred at room temperature for 1 hour, and then diphenylmethanamine (54.2 mg, 0.296 mmol) was added. After stirring for three days the mixture was poured into water (10 mL). The mixture was extracted with dichloromethane (3×5 mL). The organic fractions were concentrated, and the residue was purified by flash chromatography (dichloromethane/methanol=25:1) to give the title compound. MS (ESI) m/z 436 (M+H)+.
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:15].[CH2:17]([CH:21]1[CH2:27][CH:26]2[NH:28][CH:23]([CH2:24][CH2:25]2)[CH2:22]1)[CH2:18][CH2:19][CH3:20]>CCN(CC)CC>[CH2:17]([CH:21]1[CH2:22][CH:23]2[N:28]([CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[O:8][CH2:7][C:6]3=[O:15])[CH:26]([CH2:25][CH2:24]2)[CH2:27]1)[CH2:18][CH2:19][CH3:20]
Reactant: C[C@H](CI)CN1C(=O)COc2ccccc21
Reactant: CCCCC1CC2CCC(C1)N2
Solvent: CCN(CC)CC
Product: CCCCC1CC2CCC(C1)N2C[C@@H](C)CN1C(=O)COc2ccccc21
Yield: 65.5 %

Procedure:
The compound (S)-4-(3-Iodo-2-methylpropyl]-4H-benzo[1,4]oxazin-3-one (108LM27-24) (0.092 g, 0.28 mmol) and 3-butyl-8-aza-bicyclo[3.2.1]octane (104KS29) (0.051 g, 0.31 mmol) in Et3N (½ mL) were reacted according to GP15 to give the title compound (108LM38-35) (0.068 g, 64%). 1NMR (CDCl3) δ 7.32 (d, J=6.7 Hz, 1H), 7.03-6.95 (m, 3H), 4.60 (ABq, J=7.2 Hz, J=10.8 Hz, CH2), 4.12-4.00 (m, 2H), 3.16 (bs, 1H), 3.07 (bs, 1H), 2.33 (dd, J=6.1 Hz, J=2.1 Hz, 1H), 2.12 (t, J=4.7 Hz, 1H), 2.01-1.78 (m, 2H), 1.58-1.40 (m, 5H), 1.38-1.13 (m, 9H), 0.92-0.84 (m, 6H); 13C NMR (CDCl3) δ 164.9, 145.7, 128.9, 123.7, 122.7, 117.1, 116.2, 67.9, 61.8, 60.0, 58.1, 45.4, 38.7, 38.6, 37.1, 31.6, 29.4, 28.2, 27.4, 26.5, 23.1, 17.1, 14.3; HPLC-MS (ammonium acetate) [M+H]+=371.3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13](S(C)(=O)=O)=[N:14][CH:15]=2)[NH:10][C:9]1=[O:22].[NH2:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([OH:30])[CH2:26][CH2:25]1.Cl>COCCOCCOC>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([NH:23][C@H:24]3[CH2:29][CH2:28][C@H:27]([OH:30])[CH2:26][CH2:25]3)=[N:14][CH:15]=2)[NH:10][C:9]1=[O:22]
Reactant: CS(=O)(=O)c1ncc2c(n1)NC(=O)N(c1ccccc1Cl)C2
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: Cl
Solvent: COCCOCCOC
Product: O=C1Nc2nc(N[C@H]3CC[C@H](O)CC3)ncc2CN1c1ccccc1Cl
Temperature: 102.5 °C

Procedure:
Sulfone 11.1 (0.400 g, 1.18 mmol) was combined with trans-4-aminocyclohexanol (0.272 g, 2.36 mmol) and 2-methoxyethyl ether (0.4 mL). The mixture was heated to 100-105° C. for 1 hour at which time it was cooled to room temperature and concentrated in vacuo. The residue was purified by column chromatography on silica gel using 9:1 dichloromethane/methanol. The column fractions containing product were combined and concentrated in vacuo to an oil which was re-dissolved in ethyl acetate and methanol. Addition of hydrochloric acid (1.0M/Et2O, 1.0 equivalent) gave the salt which dissolved in the solvents. The solution was concentrated in vacuo to a solid which was triturated in ether, filtered and dried to give 0.220 g of 3-(2-chlorophenyl)-7-(trans-4-hydroxycyclohexylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one.
Reaction SMILES: O.[NH2:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.Br[C:13]1[CH:42]=[CH:41][C:16]([CH2:17][C:18]2[NH:19][C:20](=[O:40])[C:21]3[C:26]([CH2:27][CH3:28])=[N:25][N:24]([CH:29]([CH3:39])[CH2:30][CH2:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:22]=3[N:23]=2)=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:42]=[CH:41][C:16]([CH2:17][C:18]3[NH:19][C:20](=[O:40])[C:21]4[C:26]([CH2:27][CH3:28])=[N:25][N:24]([CH:29]([CH3:39])[CH2:30][CH2:31][CH2:32][C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)[C:22]=4[N:23]=3)=[CH:15][CH:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: CCc1nn(C(C)CCCc2ccccc2)c2nc(Cc3ccc(Br)cc3)[nH]c(=O)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1nn(C(C)CCCc2ccccc2)c2nc(Cc3ccc(-c4cccc(N)c4)cc3)[nH]c(=O)c12
Temperature: 70 °C
Reaction time: 1 h
Yield: 6.4 %

Procedure:
697 mg (4.5 mmol) of 3-aminophenylboronic acid monohydrate and 150 mg of tetrakistriphenylphosphine-palladium are added under argon to a solution of 1.66 g (3.47 mmol) of 6-(4-bromo-benzyl)-1-(1-methyl-4-phenyl-butyl)-3-ethyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one in 38 ml of THF, and the mixture is stirred for one hour at 70° C. After 4.9 ml of 1N Na2CO3 solution have been added, the mixture is stirred for a further 4 hours at 70° C., the solvent is removed in vacuo, and the residue is taken up in CH2Cl2. The mixture is extracted with 2N HCl, and the aqueous phase is rendered alkaline with 1N NaOH and extracted twice with CH2Cl2. After the extract has been dried over Na2SO4, the solvent is removed in vacuo. Purification by chromatography (toluene/ethyl acetate=4:1) gives 110 mg (6.4%) of a pale yellow solid.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH3:14][N:15]1[C:21](=[O:22])[C:20]2[CH:23]=[CH:24][S:25][C:19]=2[N:18]2[CH:26]=[N:27][C:28]([C:29]([NH2:31])=O)=[C:17]2[CH2:16]1>O1CCOCC1.N1C=CC=CC=1>[CH3:14][N:15]1[C:21](=[O:22])[C:20]2[CH:23]=[CH:24][S:25][C:19]=2[N:18]2[CH:26]=[N:27][C:28]([C:29]#[N:31])=[C:17]2[CH2:16]1
Reactant: CN1Cc2c(C(N)=O)ncn2-c2sccc2C1=O
Solvent: c1ccncc1
Solvent: C1COCCO1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CN1Cc2c(C#N)ncn2-c2sccc2C1=O
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 90.9 %

Procedure:
8.7 ml (62.9 mmol) of trifluoroacetic anhydride were added dropwise at 5°-8° to a suspension of 15 g (57.2 mmol) of 5-methyl-4-oxo-5,6-dihydro-4H-imidazo[1,5-a]thieno[3,2-f][1,4]diazepine-7-carboxamide in 80 ml of dioxan and 20 ml of pyridine. The beige solution obtained was stirred at 50° for 2.5 hours and subsequently poured into 220 ml of ice-water. The resulting precipitate was filtered off. After drying at 70°/10 Torr there were obtained 12.70 g (91%) of 5-methyl-4-oxo-5,6-dihydro-4H-imidazo[1,5-a]thieno[3,2-f][1,4]diazepine-7-carbonitrile as a white powder of m.p. 197°-200°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH2:10])[CH3:9])=[CH:4][CH:3]=1.Cl[CH2:12][C:13](=[O:15])[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>O.C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][CH2:12][C:13](=[O:15])[CH3:14])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@H](N)c1ccc(F)cc1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)CN[C@@H](C)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (S)-1-(4-fluorophenyl)ethylamine (5.0 g), chloroacetone (4.78 mL), cesium carbonate (13.9 g), and DMF (50 mL) was stirred at room temperature overnight. The reaction solution was diluted with water and ethyl acetate, and then the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography using a silica gel (hexane:ethyl acetate=5:1 to 0:100) to obtain 5.1 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][C:33]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)([C:36](O)=[O:37])[CH2:32][CH2:31]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:45][N:46]([CH3:50])[CH2:47][CH2:48][NH2:49].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>ClCCl>[CH3:45][N:46]([CH3:50])[CH2:47][CH2:48][NH:49][C:36]([C:33]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:32][CH2:31][N:30]([CH2:29][CH2:28][C:9]2([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH2:35][CH2:34]1)=[O:37]
Reactant: CN(C)CCN
Reactant: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)O)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClCCCl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(=O)NCCN(C)C)(c4ccccc4)CC3)(c3ccc(Cl)c(Cl)c3)C2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 72 h

Procedure:
1-[2-[3-(3,4-Dichloro-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl]-4-phenyl-piperidine-4-carboxylic acid (0.2566 g, 0.4 mmol), N,N-dimethylethylene-diamine (0.05 mL, 0.48 mmol), HOBt (65 mg, 0.48 mmol), EDC (92 mg, 0.48 mmol), DIEA (0.08 mL, 0.48 mmol) were combined in dichloromethane (20 mL). The mixture was stirred for 72 h at ambient temperature. The mixture was extracted with H2O. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo to obtain a residue. The residue was chromatographed using a Vydac (25×250 mm) C-18 HPLC column to give the title compound:
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:31])[CH2:12][S:13][CH:14]2[C:18]([CH3:19])=[C:17]([CH3:20])[C:16](=[O:21])[N:15]2[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[N:6][CH:5]=1.N[C:34]1C=CC=C(C)N=1>>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][N:15]2[C:16](=[O:21])[C:17]([CH3:20])=[C:18]([CH3:19])[CH:14]2[S:13][CH2:12][C:11]([NH:10][C:7]2[CH:8]=[CH:9][CH:4]=[C:5]([CH3:34])[N:6]=2)=[O:31])=[CH:24][CH:25]=1
Reactant: COC(=O)c1ccc(NC(=O)CSC2C(C)=C(C)C(=O)N2Cc2ccc(OC)cc2)nc1
Reactant: Cc1cccc(N)n1
Product: COc1ccc(CN2C(=O)C(C)=C(C)C2SCC(=O)Nc2cccc(C)n2)cc1

Procedure:
The product from Example 1, Part C (0.3 g, 0.93 mmol) and 2-amino-6-picoline (0.152 g, 1.4 mmol) were converted to the title compound by the method described in Part B of Example 16 (271 mg, 70%). 1H NMR (300 MHz, CDCl3) δ 8.50 (broad s, 1H); 8.12 (d, J=5 Hz, 1H), 7.96 (s, 1H); 7.20 (d, J=8.4 Hz, 2H); 6.88 (d, J=5 Hz, 1H); 6.84 (d, J=8.4 Hz, 2H); 5.10 (d, J=14.6 Hz, 1H), 4.61 (s, 1H); 4.16 (d, 14.9 Hz, 1H); 3.76 (s, 3H); 2.90 (s, 2H); 2.36 (s, 3H); 1.95 (s, 3H); 1.84 (s, 3H). MS: m/z (MH+) 412.