Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[C:9]([O:10][CH3:11])=[N:8][C:7]([Br:12])=[CH:6][N:5]=1.[C:13]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:14]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:16]=[CH:17][CH:18]=1.Cl>C(COC)OC.O>[Br:12][C:7]1[N:8]=[C:9]([O:10][CH3:11])[C:4]([NH:3][S:19]([C:14]2[C:13]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:21])=[O:20])=[N:5][CH:6]=1
Reactant: O=S(=O)(Cl)c1ccccc1-c1ccccc1
Reactant: COc1nc(Br)cnc1N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1nc(Br)cnc1NS(=O)(=O)c1ccccc1-c1ccccc1
Reaction time: 0.25 h
Yield: 55.3 %

Procedure:
Sodium hydride (60% dispersion in oil; 0.198 g) was suspended in dimethoxyethane (5 ml) and 2-amino-5-bromo-3-methoxypyrazine (0.405 g) was added with stirring. After 15 minutes, 2-biphenylsulphonyl chloride (0.5 g) was added and the mixture was stirred for 18 hours. The reaction mixture was poured into water (20 ml) and acidified to pH2 with concentrated hydrochloric acid and extracted with ethyl acetate (3×25 ml). The combined organic extracts were evaporated and the residue was purified by flash chromatography on silica gel (30 g), eluting with hexane/ethyl acetate/glacial acetic acid (160/40/1 v/v), to give N-(5-bromo-3-methoxy-2-pyrazinyl)-2-biphenylsulphonamide (0.46 g); 1H NMR (d6 -DMSO): 3.82(s,3H), 7.2-7.4(m,6H), 7.53-7.7(m,2H), 7.78(s,1H), 8.08(dd,1H), 10.33(br,1H); mass spectrum (+ve FAB, methanol/NBA): 420(M+H)+.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH3:20][C:21]([O:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[CH:27][CH:26]=1)([CH3:23])[CH3:22]>>[CH3:23][C:21]([O:24][C:25]1[CH:26]=[CH:27][C:28]([CH2:29][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:31][CH:32]=1)([CH3:20])[CH3:22]
Reactant: CC(C)(C)Oc1ccc(C=O)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: CC(C)(C)Oc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-[(2-methylpropan-2-yl)oxy]benzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[[4-[(2-methylpropan-2-yl)oxy]phenyl]methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[N:10]=[CH:11][N:12]4[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[NH:15][CH2:14][C:13]=34)[N:5]=2)[CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26].CC1C=CN=C(N)C=1C.C(N(C(C)C)CC)(C)C>C1COCC1>[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]2[CH:11]=[N:10][C:9]([C:6]3[N:5]=[C:4]([CH:1]4[CH2:3][CH2:2]4)[O:8][N:7]=3)=[C:13]2[CH2:14]1)=[O:26]
Reactant: c1ccc2c(c1)NCc1c(-c3noc(C4CC4)n3)ncn1-2
Reactant: O=C(Cl)c1ccccc1Cl
Agent: Cc1ccnc(N)c1C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(c1ccccc1Cl)N1Cc2c(-c3noc(C4CC4)n3)ncn2-c2ccccc21
Reaction time: 1.5 h

Procedure:
A slurry consisting of 3-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-4,5-dihydroimidazo[1,5-a]quinoxaline (XXXlII, EXAMPLE 88, 0.492 g), 2-chlorobenzoyl chloride (0.268 ml), dimethyl-aminopyridine (0.0538 g), diisopropylethylamine (0.368 g), and THF (9 ml) is stirred at 20°-25° for 1.5 hr. The mixture is then partitioned between ethyl acetate, aqueous sodium bicarbonate, and saline. The product is poorly soluble in both the organic and aqueous phases, filtration of the extraction solvents gives additional material. The crude product is then triturated with ethyl ether and dried to give the title compound, mp 254°-256°; MS (m/z) at 417, 419; IR (mineral oil) 1659, 1576, 1508, 765 and 1394; NMR (CDCl3) 8.16 δ.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[C:5]([C:11]#[N:12])[CH:4]=1)#[N:2].CO.[H][H]>[Ni].[Cr].[OH-].[Na+].C1(C)C(C)=CC=CC=1>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([CH2:11][NH2:12])[CH:6]=[C:7]([CH2:9][NH2:10])[CH:8]=1
Reactant: N#Cc1cc(C#N)cc(C#N)c1
Reactant: [H][H]
Agent: [Cr]
Agent: [Ni]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CO
Product: NCc1cc(CN)cc(CN)c1
Yield: 79.1 %

Procedure:
In a 300-ml capacity autoclave equipped with a magnetic stirrer was sealed 15 g of 1,3,5-tricyanobenzene (MTN), together with 15 g of Raney nickel.chromium catalyst (atomic ratio of Ni:Cr=49:1), 27 ml of methanol, 63 ml of xylene and 0.18 g of caustic soda. Hydrogen gas was fed into it at initial pressure of 100 kg/cm2G, and the reaction was carried out at 100° C., whereby 0.59 mole of hydrogen was absorbed for 35 minutes. The catalyst was filtered out, and the solvent was evaporated, followed by concentration under reduced pressure. By the above procedure, there was obtained 12.8 g of colorless crystals of 1,3,5-tris(aminomethyl)benzene (MTA). The substance showed melting point of 49° to 51° C. and boiling point of 136° to 139° C./0.4 mmHg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[C:31]1[CH:36]=[CH:35][N:34]=[C:33]([CH3:37])[CH:32]=1)[CH2:5][NH:6][C:7]([C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)=[N:13][CH:14]=1)=[O:8].FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[C:31]1[CH:36]=[CH:35][N:34]=[C:33]([CH3:37])[CH:32]=1)[CH2:5][NH:6][C:7](=[O:8])[C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[N:13][CH:14]=1
Reactant: Cc1cc(-c2ccc(CNC(=O)c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)nc3)cc2F)ccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc(CNC(=O)c3ccc(N4CCNCC4)nc3)cc2F)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude tert-butyl 4-(5-((3-fluoro-4-(2-methylpyridin-4-yl)benzyl)carbamoyl)pyridin-2-yl)piperazine-1-carboxylate 20-2 in dichloromethane (2 mL) was treated with trifluoroacetic acid (TFA, 0.5 mL), and the solution was stirred overnight at room temperature. Evaporation under reduced pressure (with the addition of some toluene to aid evaporation of the residual TFA) followed by lyophilization gave crude N-(3-fluoro-4-(2-methylpyridin-4-yl)benzyl)-6-(piperazin-1-yl)nicotinamide 20-3.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[C@@:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)([CH3:15])[C@@:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)([CH3:23])[N:12]=[C:11]2[C:31]2[CH:32]=[N:33][C:34]([C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:35][C:36]=2[O:37][CH2:38][CH3:39])=[O:9])[CH2:4][CH2:3]1.[CH:44]([N:47]=[C:48]=[O:49])([CH3:46])[CH3:45]>>[C:40]([C:34]1[N:33]=[CH:32][C:31]([C:11]2[N:10]([C:8]([N:5]3[CH2:4][CH2:3][CH:2]([NH:1][C:48]([NH:47][CH:44]([CH3:46])[CH3:45])=[O:49])[CH2:7][CH2:6]3)=[O:9])[C@@:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)([CH3:15])[C@@:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)([CH3:23])[N:12]=2)=[C:36]([O:37][CH2:38][CH3:39])[CH:35]=1)([CH3:42])([CH3:41])[CH3:43]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N)CC1
Reactant: CC(C)N=C=O
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(NC(=O)NC(C)C)CC1

Procedure:
In a manner similar to the method described in example 160, (4-Amino-piperidin-1-yl)-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazol-1-yl]-methanone (example 204) was reacted with isopropyl isocyanate (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C38H49Cl2N6O3 [(M+H)+] 707.3238, observed 707.3236
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[C:26]([O:28][CH2:29][C:30]([F:33])([F:32])[F:31])[CH:25]=[CH:24][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][CH:15]([C:19]([O:21]CC)=[O:20])[O:16]2)=[CH:11][CH:10]=1.I[CH3:35]>>[Cl:1][C:2]1[CH:27]=[C:26]([O:28][CH2:29][C:30]([F:31])([F:33])[F:32])[CH:25]=[CH:24][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][C:15]([CH3:35])([C:19]([OH:21])=[O:20])[O:16]2)=[CH:11][CH:10]=1
Reactant: CI
Reactant: CCOC(=O)C1CCc2ccc(OCCCOc3ccc(OCC(F)(F)F)cc3Cl)cc2O1
Product: CC1(C(=O)O)CCc2ccc(OCCCOc3ccc(OCC(F)(F)F)cc3Cl)cc2O1

Procedure:
The title compound was prepared from ethyl 7-(3-(2-chloro-4-(2,2,2-trifluoroethoxy)phenoxy)propoxy)-chromane-2-carboxylate (Example 5, Step D) following the procedure described in Example 1, Step C employing iodomethane instead of iodoethane followed by hydrolysis as described in Example 5, Step E.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])C(C(F)(F)F)=[CH:10][C:9]=1[NH:24][C:25](=[O:40])[CH2:26][C:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([N:34]2[CH:38]=[CH:37][N:36]=[N:35]2)[CH:29]=1)(C)(C)C.[C:42](O)([C:44]([F:47])([F:46])[F:45])=O>C(Cl)Cl>[CH2:16]([N:14]([CH3:15])[C:12]1[C:42]([C:44]([F:47])([F:46])[F:45])=[CH:10][C:9]2[NH:24][C:25](=[O:40])[CH2:26][C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([N:34]4[CH:38]=[CH:37][N:36]=[N:35]4)[CH:29]=3)=[N:7][C:8]=2[CH:13]=1)[CH:17]([CH3:19])[CH3:18]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnn3)c2)cc1C(F)(F)F
Solvent: ClCCl
Product: CC(C)CN(C)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-n3ccnn3)c1)=N2

Procedure:
The title compound was prepared from {5-(isobutyl-methyl-amino)-2-[3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionylamino]-4-trifluoromethyl-phenyl}-carbamic acid tert-butyl ester (Example M124) (0.44 g, 0.77 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (170 mg, 49%).
Reaction SMILES: C([S:4][CH:5]1[CH2:8][N:7]([C:9]2[S:10][CH:11]=[C:12]([CH2:14][N:15]3[C:19](=[O:20])[CH2:18][CH2:17][C:16]3=[O:21])[N:13]=2)[CH2:6]1)(=O)C.C(O)(=O)C.NN.C1(P(O[C:43]2[C@H:44]([CH3:67])[C@H:45]3[C@@H:62]([C@H:63]([OH:65])[CH3:64])[C:61](=[O:66])[N:46]3[C:47]=2[C:48]([O:50][CH2:51][C:52]2[CH:57]=[CH:56][C:55]([N+:58]([O-:60])=[O:59])=[CH:54][CH:53]=2)=[O:49])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.C(=O)([O-])O.[Na+]>CN(C)C=O.C(#N)C.C(OCC)(=O)C>[C:16]1(=[O:21])[N:15]([CH2:14][C:12]2[N:13]=[C:9]([N:7]3[CH2:8][CH:5]([S:4][C:43]4[C@H:44]([CH3:67])[C@@H:45]5[C@@H:62]([C@H:63]([OH:65])[CH3:64])[C:61](=[O:66])[N:46]5[C:47]=4[C:48]([O:50][CH2:51][C:52]4[CH:53]=[CH:54][C:55]([N+:58]([O-:60])=[O:59])=[CH:56][CH:57]=4)=[O:49])[CH2:6]3)[S:10][CH:11]=2)[C:19](=[O:20])[CH2:18][CH2:17]1
Reactant: CC(=O)SC1CN(c2nc(CN3C(=O)CCC3=O)cs2)C1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(c3ccccc3)c3ccccc3)[C@H](C)[C@@H]12
Agent: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3CN(c4nc(CN5C(=O)CCC5=O)cs4)C3)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
To a solution of 3-acetylthio-1-(4-succinimidomethyl-1,3-thiazol-2-yl)azetidine (238 mg, 0.73 mmol) (obtained as described in Reference Example 69) in dimethylformamide (7 ml) was added hydrazine acetate (81 mg, 0.88 mmol) at room temperature under an atmosphere of nitrogen and the mixture was stirred for 1 hour. After checking the completion of the reaction, a solution of p-nitrobenzyl (1R,5S,6S)-2-(diphenylphosphoryloxy)-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (523 mg, 0.88 mmol) in acetonitrile (14 ml) was added dropwise into the resulting mixture in an ice bath under an atmosphere of nitrogen, followed by the addition of diisopropylethylamine (0.51 ml, 2.92 mmol). The mixture was stirred for 2 hours while gradually raising the temperature to room temperature. After checking the completion of the reaction, ethyl acetate and saturated aqueous sodium hydrogencarbonate solution were added to the reaction mixture. The resulting mixture was shaken in a separatory funnel and the ethyl acetate layer was separated, washed with 0.5 M hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluant: ethyl acetate→ethyl acetate:methanol (20:1)) to afford p-nitrobenzyl (1R,5S,6S)-2-[1-(4-succinimidomethyl-1,3-thiazol-2-yl)azetidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (211 mg, yield 46%) as a pale yellow solid.
Reaction SMILES: [Br-].[F:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1.CC(C)([O-])C.[K+].[F:35][C:36]1[CH:43]=[C:42]([C:44]2[CH:53]=[CH:52][C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[CH:45]=2)[CH:41]=[CH:40][C:37]=1[CH:38]=O.O>C1COCC1>[F:35][C:36]1[CH:43]=[C:42]([C:44]2[CH:53]=[CH:52][C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[CH:45]=2)[CH:41]=[CH:40][C:37]=1[CH:38]=[CH:7][C:6]1[CH:5]=[CH:4][C:3]([F:2])=[CH:28][CH:27]=1
Reactant: O=Cc1ccc(-c2ccc3ccccc3c2)cc1F
Reactant: Fc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Fc1ccc(C=Cc2ccc(-c3ccc4ccccc4c3)cc2F)cc1
Temperature: -30 °C
Yield: 83.8 %

Procedure:
In the step, 6.30 g (15.48 mmol) of (4-fluorobenzyl)triphenylphosphonium bromide was suspended in 50 ml of THF, and the suspension was cooled to −30° C. and added with 1.74 g (=15.48 mmols) of potassium t-butoxide under stirring. After the addition was finished, the reaction solution was stirred at the same temperature for 1 hour, a 25 ml THF solution of 3.00 g (11.99 mmol) of 2-fluoro-4-naphthalene-2-yl-benzaldehyde was dropped into the same, and then the mixture was slowly heated to room temperature. After being stirred for 18 hours, the reaction mixture was added into iced water, and the mixture was extracted thrice with toluene. The extract was washed thrice with water and then dried with anhydrous MgSO4. After the solvent was evaporated under a reduced pressure, the obtained yellow solid of 12.73 g was purified with silica gel chromatography using heptane as the eluent to obtain 3.44 g of 2-{3-fluoro-4-[2-(4-fluorophenyl)vinyl]phenyl}naphthalene as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH3:17])=[N:15][CH:16]=[C:10]2[CH:9]1[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[C:22]([F:30])[CH:21]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)[Cl:32].CO>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH3:17])=[N:15][C:16]([Cl:32])=[C:10]2[CH:9]1[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]([F:28])([F:29])[F:27])=[C:22]([F:30])[CH:21]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ncc2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)c(F)c1
Reactant: ClCCl
Solvent: CO
Product: Cc1nc(Cl)c2n1CCN(C(=O)OC(C)(C)C)C2CCc1ccc(C(F)(F)F)c(F)c1

Procedure:
Subsequent chlorination (70° C.; 4h30) of 8-[2-(3-fluoro-4-trifluoromethyl-phenyl)-ethyl]-3-methyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (8.080 g; 18.903 mmol), and purification by FC (DCM/MeOH=50/1) afforded 1-chloro-8-[2-(3-fluoro-4-trifluoromethyl-phenyl)-ethyl]-3-methyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as a yellow solid (4.730 g; 54%). LC-MS: tR=1.08 min.; [M+H]+=461.98 g/mol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[OH:12].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:13]([O:12][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: COc1ccc([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc([N+](=O)[O-])cc1OCc1ccccc1

Procedure:
A solution of 2-methoxy-5-nitrophenol (54.3 g, 321 mmol), benzyl bromide (26.5 mL, 223 mmol,) and cesium carbonate (73 g, 223 mmol) is stirred in N,N-dimethylformamide (250 mL) for 24 h at room temperature. The mixture is partitioned between water and ethyl acetate. The layers are separated and the organic layer washed three times with water, once with brine, dried (sodium sulfate), filtered and evaporated to give a crude solid. The crude product is recrystallized from ethyl acetate to yield the title compound, 56.4 g (68%), as a white crystalline solid.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([N:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH2:5][CH2:4]1.Cl[C:20]1[CH:25]=[C:24]([O:26][C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[C:29]([CH3:34])[CH:28]=2)[N:23]=[CH:22][N:21]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:34][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[CH3:33])[O:26][C:24]1[N:23]=[CH:22][N:21]=[C:20]([N:3]2[CH2:4][CH2:5][CH:6]([N:9]3[C:17]4[C:12](=[N:13][CH:14]=[CH:15][CH:16]=4)[NH:11][C:10]3=[O:18])[CH2:7][CH2:8]2)[CH:25]=1
Reactant: Cc1ccc(Oc2cc(Cl)ncn2)cc1C
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(Oc2cc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)ncn2)cc1C
Temperature: 150 °C
Reaction time: 4 h

Procedure:
291 mg (1.00 mmol) 1-piperidin-4-yl-1,3-dihydroimidazo[4,5-b]pyridin-2-one-dihydrochloride, 276 mg (1.00 mmol) 4-chloro-6-(3,4-dimethyl-phenoxy)-pyrimidine and 0.697 mL (4.00 mmol) DIPEA were combined in 3.0 mL DMF and stirred for 4 h at 150° C. The reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined, the acetonitrile was evaporated down and the residue was neutralised with 1N aqueous sodium hydroxide solution. The precipitate formed was suction filtered, washed with water and dried i. vac.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[C:9](Br)=[N:10][CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:16][Si:17]([C:20]#[CH:21])([CH3:19])[CH3:18]>C(N(CC)CC)C.CN(C=O)C.C(OCC)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[C:9]([C:21]#[C:20][Si:17]([CH3:19])([CH3:18])[CH3:16])=[N:10][CH:11]=[CH:12][CH:13]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cccnc1Br
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)Nc1cccnc1C#C[Si](C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 43 %

Procedure:
A mixture of (2-bromopyridin-3-yl)carbamic acid tert-butyl ester (1.09 mg, 4.00 mmol), (trimethylsilyl)acetylene (2.83 mL, 20.0 mmol), CuI (75.8 mg, 0.400 mmol), and dichlorobis(triphenylphosphine)palladium (II) (141 mg, 0.200 mmol) in a mixture of 12 mL of triethylamine and 3.0 mL of anhydrous DMF were stirred at room temperature overnight. The reaction was diluted with 50 mL of diethyl ether and quenched with 50 mL of saturated aqueous ammonium chloride solution. The organic layer was washed with 20 mL of saturated aqueous ammonium chloride solution and the combined aqueous layers were extracted with three 20 mL portions of diethyl ether. The combined organic layers were then washed with 20 mL of brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. Chromatography on SiO2 (20% to 30% ethyl acetate in hexanes, gradient) gave 500 mg of (2-trimethylsilanylethynylpyridin-3-yl)carbamic acid tert-butyl ester (43% yield).
Reaction SMILES: [CH3:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.O[N:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2N=N1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.C1(N)CCCCC1>ClCCl>[Cl:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([NH:13][CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:16]2)=[O:6])=[C:2]([CH3:1])[N:10]=1
Reactant: Cc1nc(Cl)ccc1C(=O)O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Solvent: NC1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(Cl)ccc1C(=O)NC1CCCCC1
Reaction time: 0.08 h
Yield: 76.9 %

Procedure:
A solution of 2-methyl-6-chloronicotinic acid (300 mg, 1.75 mmol) and 1-hydroxybenzotriazole (260 mg, 1.92 mmol) was stirred in dichloromethane (25 ml) then triethylamine (561 ul, 4.02 mmol) and EDAC (401 mg, 2.1 mmol) were added and stirred for 5 minutes then cyclohexylamine (201 ul, 1.75 mmol) was added and the reaction was stirred for a further 16 hours at room temperature. The reaction was diluted with dichloromethane (25 ml), washed with sat. NaHCO3, 1M HCl, water, brine and dried over MgSO4, filtered and the solvent evaporated to give 6-chloro-2-methyl-N-cyclohexylnicotinamide (340 mg, 77%) as a fawn coloured powder
Reaction SMILES: [S:1]1(=O)(=O)[C:5]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.CC(C[AlH]CC(C)C)C.CCO.Cl>C1(C)C=CC=CC=1.C1COCC1.O>[S:1]1[C:5]2[CH:6]=[C:7]([OH:10])[CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1
Reactant: O=S1(=O)CCc2ccc(O)cc21
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Solvent: Cc1ccccc1
Product: Oc1ccc2c(c1)SCC2
Yield: 46.2 %

Procedure:
A solution of the sulfone from stage (i) (4.84 g, 26.3 mmol) in toluene (100 mL) and THF (70 mL) was added to a solution of DIBAL in toluene (1M, 100 mL, 100 mmol) and the mixture was then heated at reflux for 16 h. After cooling to room temperature EtOH (75 mL) was added cautiously followed by water (100 mL) with stirring. 6M HCl was added to the resulting thick suspension and the organic layer was separated. The aqueous layer was extracted with EtOAc (3×150 mL) and the combined organic layers were dried (MgSO4) and evaporated to a beige solid. Purification by column chromatography [SiO2; DCM/MeOH/880 NH3 (97:3:0.25) increasing polarity to (95:5:0.5)] afforded the desired title phenol as a beige solid (1.85 g, 53%); δH (CD3OD, 400 MHz) 3.13 (2H, t), 3.30 (2H, m), 6.41 (1H, d), 6.60 (1H, s), 6.98 (1H, d); MS m/z (ES−) 151 (M−H+).
Reaction SMILES: [I:1][C:2]1[C:3](=[O:20])[C:4]2[C:5]([O:12][C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[N:6][C:7]([O:10]C)=[CH:8][CH:9]=2>Br.CC(O)=O>[I:1][C:2]1[C:3](=[O:20])[C:4]2[CH:9]=[CH:8][C:7](=[O:10])[NH:6][C:5]=2[O:12][C:13]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COc1ccc2c(=O)c(I)c(-c3ccccc3)oc2n1
Agent: Br
Solvent: CC(=O)O
Product: O=c1ccc2c(=O)c(I)c(-c3ccccc3)oc2[nH]1
Temperature: 60 °C

Procedure:
A suspension of 3-iodo-7-methoxy-2-phenyl-pyrano[2,3-b]pyridin-4-one (0.25 g, 0.66 mmol) in 33% hydrogen bromide solution in AcOH (3.5 mL) was heated in a microwave oven at 60° C. for 50 min. The resultant solution was evaporated to dryness. Toluene was added to the residual solid and evaporated. The orange solid was used without further purification. LCMS (Method B): RT=3.85 min, [M+H]+=366.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([OH:8])=[CH:6][CH:7]=1.[CH:10]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]([CH3:22])[CH:13]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][CH2:10][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[C:14]([CH3:22])[CH:13]=2)=[C:3]([CH3:9])[CH:4]=1
Reactant: Cc1cc(O)ccc1N
Reactant: COC(=O)c1ccc(C=O)cc1C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CNc2ccc(O)cc2C)cc1C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
4-Amino-m-cresol (242 g, 1.96 mol) is added to a slurry of 4-formyl-2-methyl-benzoic acid, methyl ester (350 g, 1.96 mol) and acetic acid (3100 mL) at room temperature. Sodium triacetoxyborohydride (728 g, 3.44 mol) is added portionwise, keeping the temperature below 30° C. using an ice water bath. After overnight stirring, the reaction mixture is concentrated under reduced pressure. The residue is adjusted to pH 5 using aqueous saturated sodium bicarbonate. The resulting solid is filtered off, washed with water, and dried under vacuum overnight to give the title compound (460 g, 82%) as a brown powder. ES/MS m/e 179 (M+1).