Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[C:12]([CH3:28])=[N:13][C:14]([NH:17][CH2:18][CH2:19][CH2:20][CH:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[N:15][CH:16]=3)[NH:7][C:6]=2[CH:5]=[C:4]([CH3:29])[CH:3]=1.O.O.O.O.[OH:34][CH:35](C(O)C(O)=O)C(O)=O.CC1C2N=C(C3C(C)=NC(NCCCC4CCN(C)CC4)=NC=3)NC=2C=C(C)C=1.[C:73]([OH:80])(=[O:79])/[CH:74]=[CH:75]/[C:76]([OH:78])=[O:77]>CCOC(C)=O.CO>[CH3:35][O-:34].[C:73]([O-:80])(=[O:79])/[CH:74]=[CH:75]/[C:76]([O-:78])=[O:77].[CH3:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]3[C:12]([CH3:28])=[N:13][C:14]([NH:17][CH2:18][CH2:19][CH2:20][CH:21]4[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]4)=[N:15][CH:16]=3)[NH:7][C:6]=2[CH:5]=[C:4]([CH3:29])[CH:3]=1
Reactant: O=C(O)C(O)C(O)C(=O)O
Reactant: O=C(O)/C=C/C(=O)O
Agent: Cc1cc(C)c2nc(-c3cnc(NCCCC4CCN(C)CC4)nc3C)[nH]c2c1
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: C[O-]
Product: O=C([O-])/C=C/C(=O)[O-]
Temperature: 25 °C

Procedure:
To a 500 mL Erlenmeyer flask which contained 10.012 g (0.0255 mol) of 5-(4,6-dimethyl-1H-benzimidazol-2-yl)-4-methyl-N-[3-(1-methyl-4-piperidinyl)propyl]-2-pyrimidinamine), compound 2, was added 6.2155 g of fumaric acid (2.1 equivalents) and a stir bar. To that solid mixture, about 300 mL of 1:1 (weight ratio) hot MeOH:EtOAc were added while heating and stirring. The term “hot solvent” is used here so that such solvent is warm based on such solvent boiling point. In some embodiments, hot MeOH:EtOAc was used at a temperature of about 50° C. to 60° C. Additional solvent can be added until all the solids are completely dissolved. The solution mixture was allowed to heat at boiling temperature for another 10 min to give a yellow homogenous solution. The reaction mixture was removed from the heating plate and allowed to cool down to room temperature (rt) on the bench top. Precipitate formed as clusters in the bottom of the flask after 2 days. 13.0702 g of 5-(4,6-dimethyl-1H-benzimidazol-2-yl)-4-methyl-N-[3-(1-methyl-4-piperidinyl)-propyl]-2-pyrimidinamine fumarate methanolate (1:2:1), compound 4, as a light yellow solid crystalline were collected by vacuum filter. XRD profiles confirmed the unique pattern of the desired fumarate salt and according to IR-off gas analysis, this material is a methanol solvate of the fumarate salt (4.1% weight loss). Table 8 and FIG. 5 display the impurity profiles for compounds 2 and 4.
Reaction SMILES: O.[NH2:2][NH2:3].[OH:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9](=O)[C:10]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[C:11]([CH3:15])[O:12]2)=[CH:7][CH:6]=1>C(O)C>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([C:10]2[C:9]([C:8]3[CH:7]=[CH:6][C:5]([OH:4])=[CH:14][C:13]=3[OH:12])=[N:2][NH:3][C:11]=2[CH3:15])=[CH:17][CH:18]=1
Reactant: COc1ccc(-c2c(C)oc3cc(O)ccc3c2=O)cc1
Reactant: NN
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2c(-c3ccc(O)cc3O)n[nH]c2C)cc1

Procedure:
Hydrazine hydrate (2 ml, ˜55%) was added to a suspension of 7-hydroxy-3-(4-methoxy-phenyl)-2-methyl-chromen-4-one (0.57 g, 2 mmol) in ethanol (15 ml) and the mixture heated under reflux for ˜5 hrs., to give a pale brown solution. The solution was allowed to cool and concentrated to a pale yellow solid, the solids were washed with water, to give the pyrazole as an off-white solid, dried in vacuo, (0.45 g). Sample was recrystallised from boiling toluene, to give the 4-[4-(4-methoxy-phenyl)-5-methyl-1H-pyrazol-3-yl]-benzene-1,3-diol as a pale brown crystalline solid, washed with hexane, dried in vacuo.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]=[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=O)[CH3:21])[N:15]=1)[CH3:13])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([O:43][C:44]1[C:50]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[CH:49][C:47]([NH2:48])=[CH:46][C:45]=1[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42]>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]=[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20](=[N:48][C:47]2[CH:46]=[C:45]([C:57]3[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=3)[C:44]([O:43][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[C:50]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[CH:49]=2)[CH3:21])[N:15]=1)[CH3:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCCCCCCCCCCCCCCCCCOc1c(-c2ccccc2)cc(N)cc1-c1ccccc1
Reactant: CC(=O)c1cccc(C(C)=Nc2ccccc2C(C)(C)C)n1
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCCCOc1c(-c2ccccc2)cc(N=C(C)c2cccc(C(C)=Nc3ccccc3C(C)(C)C)n2)cc1-c1ccccc1
Reaction time: 24 h

Procedure:
2-[1-(2-tert-butylphenylimino)ethyl]-6-acetylpyridine (487 mg, 1.65 mmol), prepared according to the method described in WO 02/28805, and 4-eicosanoxy-3,5-diphenylaniline (900 mg, 1.65 mmol) were dissolved in 50 ml of toluene. To this solution, 4 Å molecular sieves were added. After standing for 1 day the mixture was filtered. The solvent was removed in vacuo. The residue was crystallised from ethanol. The product N was isolated as an yellow solid (600 mg, 0.73 mmol, 44%).
Reaction SMILES: [CH3:1][N:2]([CH3:38])[CH2:3][CH2:4][NH:5][C:6](=[O:37])[CH:7]([N:9]1[C:13]2=[N:14][CH:15]=[N:16][C:17]([NH2:18])=[C:12]2[C:11]([C:19]2[CH:24]=[CH:23][C:22]([NH:25][C:26]3[O:27][C:28]4[C:34](C)=[CH:33][C:32](C)=[CH:31][C:29]=4[N:30]=3)=[CH:21][CH:20]=2)=[N:10]1)[CH3:8].O1C2C=CC=CC=2N=C1NC1C=CC(B2OC(C)(C)C(C)(C)O2)=CC=1>>[CH3:38][N:2]([CH3:1])[CH2:3][CH2:4][NH:5][C:6](=[O:37])[CH:7]([N:9]1[C:13]2=[N:14][CH:15]=[N:16][C:17]([NH2:18])=[C:12]2[C:11]([C:19]2[CH:20]=[CH:21][C:22]([NH:25][C:26]3[O:27][C:28]4[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=4[N:30]=3)=[CH:23][CH:24]=2)=[N:10]1)[CH3:8]
Reactant: Cc1cc(C)c2oc(Nc3ccc(-c4nn(C(C)C(=O)NCCN(C)C)c5ncnc(N)c45)cc3)nc2c1
Agent: CC1(C)OB(c2ccc(Nc3nc4ccccc4o3)cc2)OC1(C)C
Product: CC(C(=O)NCCN(C)C)n1nc(-c2ccc(Nc3nc4ccccc4o3)cc2)c2c(N)ncnc21

Procedure:
The procedure described in the preparation of N1-[2-(dimethylamino)ethyl]-2-(4-amino-3-{4-[(5,7-dimethyl-1,3-benzoxazol-2-yl)amino]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-1-yl)propanamide was employed, except that the Suzuki coupling procedure employed N-(1,3-benzoxazol-2-yl)-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine. Purification of the product by preparative HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 20 min at 21 mL/min using an 8μ Hypersil HS C18, 250×21 mm column, Rt 5.5-7.0 min) afforded N1-[2-(dimethylamino)ethyl]-2-{4-amino-3-[4-(1,3-benzoxazol-2-ylamino)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl}propanamide as an off-white solid (0.003 g, 0.006 mmol); RP-HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 10 min at 1 mL/min using a 5μ Hypersil HS C18, 250×4.6 mm column) Rt 6.70 min; MS (MH)+ 486.
Reaction SMILES: [Cl:1][CH2:2][C:3]([NH:5][C:6]([O:8][CH:9]1[CH2:14][CH2:13][C:12]([CH2:16][S:17]([CH3:19])=[O:18])([OH:15])[CH:11]([C:20]2([CH3:28])[O:27][CH:21]2[CH2:22][CH:23]=[C:24]([CH3:26])[CH3:25])[CH:10]1[O:29][CH3:30])=[O:7])=[O:4].Cl[C:32]1[CH:37]=[CH:36]C=[C:34](C(OO)=O)[CH:33]=1.C(OCC)(=[O:44])C>ClCCl>[Cl:1][CH2:2][C:3]([NH:5][C:6]([O:8][CH:9]1[CH2:14][CH2:13][C:12]([CH2:16][S:17]([C:19]2[CH:36]=[CH:37][CH:32]=[CH:33][CH:34]=2)(=[O:44])=[O:18])([OH:15])[CH:11]([C:20]2([CH3:28])[O:27][CH:21]2[CH2:22][CH:23]=[C:24]([CH3:25])[CH3:26])[CH:10]1[O:29][CH3:30])=[O:7])=[O:4]
Reactant: CCOC(C)=O
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC1C(OC(=O)NC(=O)CCl)CCC(O)(CS(C)=O)C1C1(C)OC1CC=C(C)C
Solvent: ClCCl
Product: COC1C(OC(=O)NC(=O)CCl)CCC(O)(CS(=O)(=O)c2ccccc2)C1C1(C)OC1CC=C(C)C
Yield: 30 %

Procedure:
4-O-(chloroacetylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-hexenyl)-3-methoxy-1-methylsulfinylmethyl-1,4-cyclohexanediol (300 mg) was dissolved in dichloromethane (2 ml), to which was added, under ice-cooling, m-chloroperbenzoic acid (179 mg), and the mixture was stirred for one hour. The reaction mixture was diluted with ethyl acetate (70 ml), which was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous saline solution, followed by drying over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by a silica gel column chromatography (carrier 15 g, developing solvent: ethyl acetate - hexane 2:1) to afford 4-O-(chloroacetylcarbamoyl)-2-(1,2-epoxy-1,5-dimethyl-4-h-exenyl)-3-methoxy-1-phenylsulfonylmethyl-1,4-cyclohexanediol (91 mg: yield 30%) as colorless powder.
Reaction SMILES: [F:1][C:2]1([F:44])[CH2:7][CH2:6][CH2:5][C@H:4]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([S:16]([N:19](CC3C=CC(OC)=CC=3OC)[C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)(=[O:18])=[O:17])=[C:11]([F:37])[CH:10]=2)[C@H:3]1[C:38]1[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:44][C:2]1([F:1])[CH2:7][CH2:6][CH2:5][C@H:4]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([S:16]([NH:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)(=[O:17])=[O:18])=[C:11]([F:37])[CH:10]=2)[C@H:3]1[C:38]1[N:42]([CH3:43])[N:41]=[CH:40][CH:39]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(F)c(O[C@H]3CCCC(F)(F)[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nccc1[C@@H]1[C@@H](Oc2cc(F)c(S(=O)(=O)Nc3ccncn3)cc2F)CCCC1(F)F
Yield: 114.4 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 4-{[(1S*,2R*)-3,3-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2,5-difluoro-N-(pyrimidin-4-yl)benzenesulfonamide (260 mg, 0.398 mmol) prepared in Example 117e, triethylsilane (0.20 mL), trifluoroacetic acid (2.0 mL) and dichloromethane (2.0 mL), to yield the title compound (221 mg, 90%) as a colorless solid.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26](O)=[O:27])[CH2:10]2)=[O:8])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.CN(C(O[N:37]1N=N[C:39]2[CH:40]=[CH:41]C=[N:43][C:38]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.ON=C(C1CC1)N>CN(C)C=O>[CH:39]1([C:38]2[N:43]=[C:26]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]([F:24])([F:25])[F:23])=[CH:17][CH:16]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:2][CH2:3][S:4][CH2:5][CH2:6]4)=[O:8])[CH2:10]3)[O:27][N:37]=2)[CH2:41][CH2:40]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCSCC2)C1
Agent: F[P-](F)(F)(F)(F)F
Agent: NC(=NO)C1CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N1CCSCC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(C3CC3)no2)C1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
600 mg (1.43 mmol) of the compound from Example 25A in dimethylformamide (29.0 ml) were admixed at RT with 654 mg (1.72 mmol) of HATU and 0.55 ml (498 mg, 3.16 mmol) of N,N-diisopropylethylamine, and the mixture was stirred for 30 min. Subsequently, 158 mg (1.58 mmol) of N′-hydroxycyclopropanecarboximidamide were added and the mixture was stirred at RT overnight. The reaction solution was heated to 120° C. and stirred at this temperature for 1 h. The reaction solution was subsequently purified directly by means of preparative HPLC. Yield: 315 mg (45% of theory)
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([CH:25]=C)[CH:22]=[C:21]([Cl:27])[CH:20]=2)[C:12]=1[F:28])=[O:8].I([O-])(=O)(=O)=[O:38].[Na+]>O1CCOCC1.O.CCOC(C)=O.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([CH:25]=[O:38])[CH:22]=[C:21]([Cl:27])[CH:20]=2)[C:12]=1[F:28])=[O:8]
Reactant: C=Cc1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3c(Cl)ncn3COCC[Si](C)(C)C)c2F)c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(Cl)cc(C=O)c2)c1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 78.6 %

Procedure:
To a solution of 4-chloro-N-({4-chloro-3-[(3-chloro-5-ethenylphenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (240 mg, 0.420 mmol) and sodium periodate (270 mg, 1.261 mmol) in dioxane (5 mL) and water (3 ml) was added osmium tetroxide (2.5% solution in t-butanol) (0.106 ml, 8.44 μmol) and the mixture was stirred at room temperature for 5 hours. The mixture was diluted with EtOAc, washed with water and the solvent was removed. The crude material was purified via silica gel chromatography to give 4-chloro-N-({4-chloro-3-[(3-chloro-5-formylphenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (189 mg, 0.330 mmol, 78% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 9.92 (s, 1H), 8.79 (t, 1H), 8.00 (s, 1H), 7.65-7.82 (m, 1H), 7.48-7.57 (m, 1H), 7.37-7.49 (m, 2H), 7.28 (d, 1H), 5.51 (s, 2H), 4.51 (d, 2H), 3.21-3.60 (m, 2H), 0.77 (t, 2H), −0.07 (s, 9H)
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[NH:10][C@H:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][C@@H:13]([CH3:21])[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:32][N:33]([CH3:43])[C:34]1[CH:42]=[CH:41][C:37]([C:38](Cl)=[O:39])=[CH:36][CH:35]=1.O>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:22])[NH:10][C@H:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([C:38](=[O:39])[C:37]2[CH:36]=[CH:35][C:34]([N:33]([CH3:32])[CH3:43])=[CH:42][CH:41]=2)[C@@H:13]([CH3:21])[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)c1ccc(C(=O)Cl)cc1
Reactant: C[C@H]1C[C@@H](NC(=O)OCc2ccccc2)c2ccccc2N1
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1C[C@@H](NC(=O)OCc2ccccc2)c2ccccc2N1C(=O)c1ccc(N(C)C)cc1
Temperature: 25 °C
Yield: 89 %

Procedure:
To a solution of (±)-cis-(2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl)-carbamic acid benzyl ester (500 mg, 1.68 mmol) in methylene chloride (20 mL) at room temperature was added diisopropylethylamine (542 mg, 749 uL, 4.2 mmol) followed by 4-dimethylaminobenzoyl chloride and stirred at room temperature until no starting material was present. The mixture was poured into water and extracted with ethyl acetate. The extracts were washed with 1 M (aq) NaOH and brine, dried over sodium sulfate, filtered dried and concentrated. The crude residue was purified by silica gel chromatography (100% hexanes to 70% hexanes/30% ethyl acetate gradient) to afford the amide (665 mg, 89%).
Reaction SMILES: N1C=CC=CC=1.[F:7]N1N=C(F)C=C(F)N1.[CH2:16]([NH:18][C:19]1[N:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:20]=1[C:21](O)=[O:22])[CH3:17]>ClCCl>[CH2:16]([NH:18][C:19]1[N:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:20]=1[C:21]([F:7])=[O:22])[CH3:17]
Reactant: FC1=CC(F)=NN(F)N1
Reactant: CCNc1nc(Cl)ccc1C(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCNc1nc(Cl)ccc1C(=O)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.7 %

Procedure:
2 ml (24.8 mmol) of pyridine and 4.2 ml (49.8 mmol) of 2,4,6-trifluorotriazine are added to a suspension of 5.0 g (24.8 mmol) of 2-(ethylamino)-6-chloronicotinic acid in 125 ml of dichloromethane. The mixture is stirred at ambient temperature for 3 hours and then filtered. The solid is rinsed with 50 ml of dichloromethane and the filtrate is washed twice with 60 ml of ice-cold water. The organic phase is dried over Na2SO4 and the solvent is evaporated under reduced pressure. 5.01 g of product are obtained in the form of an orange oil. Yield=99%.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][NH:8][CH2:7]1)=[O:5])[CH3:2].[O:12]1[CH2:14][C@@H:13]1[CH2:15][O:16][C:17]1[CH:26]=[CH:25][CH:24]=[C:23]2[C:18]=1[CH:19]=[CH:20][CH:21]=[N:22]2>C(O)C>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([CH2:14][CH:13]([OH:12])[CH2:15][O:16][C:17]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:18]=2[CH:19]=[CH:20][CH:21]=[N:22]3)[CH2:7]1)=[O:5])[CH3:2]
Reactant: c1cc(OC[C@H]2CO2)c2cccnc2c1
Reactant: CCOC(=O)C1CCCNC1
Solvent: CCO
Product: CCOC(=O)[C@@H]1CCCN(CC(O)COc2cccc3ncccc23)C1
Temperature: 25 °C

Procedure:
Piperidine-3-carboxylic acid ethyl ester (43) (1.0 g; 6.36 mmol) and (R)-5-oxiranylmethoxy-quinoline (2) (1.28 g; 6.36 mmol) are combined in 10 mL of absolute ethanol. The mixture is heated at reflux for 16 hours. After cooling to ambient temperature, the solution is concentrated in vacuo at 40° C. The residue is chromatographed on silica gel (1:1 acetone:hexanes) affording the desired product (44) as an oil. ESMS: MH+ 359
Reaction SMILES: N1C=CC(N)=NC1=O.[F:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][C:15]=1[F:16].NC1C=CN(C2C=CC(F)=CC=2)C(=O)N=1.[Cl:35][CH2:36][C:37]1[N:38]=[C:39]2[CH:44]=[CH:43][N:42](C3C=CC(F)=CC=3)[C:41](=[O:52])[N:40]2[CH:53]=1>>[Cl:35][CH2:36][C:37]1[N:38]=[C:39]2[CH:44]=[CH:43][N:42]([C:12]3[CH:13]=[CH:14][C:15]([F:16])=[C:10]([F:9])[CH:11]=3)[C:41](=[O:52])[N:40]2[CH:53]=1
Reactant: O=c1n(-c2ccc(F)cc2)ccc2nc(CCl)cn12
Reactant: OB(O)c1ccc(F)c(F)c1
Agent: Nc1cc[nH]c(=O)n1
Agent: Nc1ccn(-c2ccc(F)cc2)c(=O)n1
Product: O=c1n(-c2ccc(F)c(F)c2)ccc2nc(CCl)cn12

Procedure:
2-chloromethyl-6-(3,4-difluoro-phenyl)-6H-imidazo[1,2-c]pyrimidin-5-one was prepared from cytosine and 3,4-difluorophenylboronic acid using the methods as described above for the preparation of 4-amino-1-(4-fluoro-phenyl)-1H-pyrimidin-2-one and 2-chloromethyl-6-(4-fluoro-phenyl)-6H-imidazo[1,2-c]pyrimidin-5-one.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.C(N(CC)CC)C.[N:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[S:29](Cl)(=[O:31])=[O:30])[CH:22]=[CH:21][CH:20]=1>C(Cl)(Cl)Cl>[N:10]1[C:11]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][S:29]([C:27]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:28]=2[N:19]=[CH:20][CH:21]=[CH:22]3)(=[O:30])=[O:31])[CH:7]=[CH:8][CH:9]=1
Reactant: Nc1cccc2cccnc12
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=S(=O)(Nc1cccc2cccnc12)c1cccc2cccnc12
Temperature: 65 °C
Reaction time: 1 h
Yield: 23 %

Procedure:
The product has already been described in: V. M. Dziomko et al., Azotsoderzhashchie Geterotsikly 1967, 281-284; but by a different method of synthesis. Several grains of activated 4 Å molecular sieve are added to a solution under argon of 8-aminoquinoline (200 mg; 1.39 mmol) and triethylamine (0.30 ml; 2.15 mmol) in 10 ml of CHCl3 and the mixture is stirred slowly for 1 hour. 8-quinolinesulfonyl chloride (350 mg; 1.54 mmol) is added and the mixture is heated to 65° C. for 15 hours. After cooling, 50 ml of CHCl3 are added and the mixture is washed in water (2×50 ml) then dried over anhydrous Na2SO4 and the solvent is evaporated under reduced pressure. The solid is washed with 5 ml of CH2Cl2 to yield after drying 25 in the form of a beige powder (108 mg; 0.32 mmol, yield=23%). NMR-1H (250 MHz, DMSO-d6) δ, ppm: 10.44 (s, 1H); 9.11 (dd, 3J (H, H)=4.5 Hz, 4J (H, H)=1.5 Hz, 1H); 8.83 (dd, 3J (H, H)=4.0 Hz, 4J (H, H)=1.5 Hz, 1H); 8.47 (dd, 3J (H, H)=7.5 Hz, 4J (H, H)=1.5 Hz, 1H); 8.40 (dd, 3J (H, H)=8.5 Hz, 4J (H, H)=1.5 Hz, 1H); 8.22 (dd, 3J (H, H)=8.0 Hz, 4J (H, H)=1.5 Hz, 1H); 8.20 (dd, 3J (H, H)=8.0 Hz, 4J (H, H)=1.5 Hz, 1H); 7.80 (dd, 3J (H, H)=7.5 Hz, 4J (H, H)=1.5 Hz, 1H); 7.70 (dd, 3J (H, H)=8.0 and 7.5 Hz, 1H); 7.62 (dd, 3J (H, H)=8.5 and 4.5 Hz, 1H); 7.51 ((dd, 3J (H, H)=8.5 and 4.0 Hz, 1H); 7.50 (dd, 3J (H, H)=8.5 Hz, 4J (H, H)=1.0 Hz, 1H); 7.42 (dd, 3J (H, H)=8.0 and 7.5 Hz, 1H). NMR-13C (63 MHz, DMSO-d6) δ, ppm: 151.5 (CH); 148.9 (CH); 142.1 (Cq); 137.6 (Cq); 136.9 (CH); 136.3 (CH); 134.4 (CH); 134.2 (Cq); 133.7 (Cq); 131.7 (CH); 128.2 (Cq); 127.8 (Cq); 126.6 (CH); 125.5 (CH); 122.6 (CH); 122.3 (CH); 122.1 (CH); 113.8 (CH). MS (CID, NH3): m/z=336 (MH+). Analysis (%) for C18H13N3O2S.0.2H2O: calculated C, 63.78; H, 3.98; N, 12.40. found C, 63.53; H, 3.70; N, 12.23.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([N:7]2[CH2:12][CH:11]([CH3:13])[NH:10][CH:9]([CH3:14])[CH2:8]2)=[N:4][CH:3]=1.[CH3:15][O:16][C:17](=[O:20])[CH2:18]Br.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:15][O:16][C:17](=[O:20])[CH2:18][N:10]1[CH:11]([CH3:13])[CH2:12][N:7]([C:5]2[S:6][C:2]([Br:1])=[CH:3][N:4]=2)[CH2:8][CH:9]1[CH3:14]
Reactant: CC1CN(c2ncc(Br)s2)CC(C)N1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CN1C(C)CN(c2ncc(Br)s2)CC1C
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 74 %

Procedure:
A mixture of 1-(5-bromothiazole-2-yl)-3,5-dimethyl piperazine (21.5 g), bromo acetic acid methyl ester (8.8 mL), potassium carbonate (12.9 g) and dimethylformamide (150 mL) was stirred at 60° C. for 2.5 hours. To the reaction solution was added water and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over magnesium sulphate. The solvent was evaporated under reduced pressure. The residue was purified by column chromatograph on silica gel to give the title compound (20.1 g). Yield: 74%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:34])[CH2:5][N:6]([C@H:14]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)[C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22](O)=[O:23])=[O:16])[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH3:2].[NH2:35][CH2:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][CH:46]=1)[C:43]([NH2:47])=[N:42][CH:41]=[CH:40]2.CN1CCOCC1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:34])[CH2:5][N:6]([C@H:14]([CH2:25][C:26]1[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=1)[C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22](=[O:23])[NH:35][CH2:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][CH:46]=1)[C:43]([NH2:47])=[N:42][CH:41]=[CH:40]2)=[O:16])[C:7]([O:9][C:10]([CH3:12])([CH3:13])[CH3:11])=[O:8])[CH3:2]
Reactant: NCc1ccc2c(N)nccc2c1
Reactant: CCOC(=O)CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc(OC)cc1)C(=O)N1CCC[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc(OC)cc1)C(=O)N1CCC[C@H]1C(=O)NCc1ccc2c(N)nccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.5 %

Procedure:
A mixture of {[2-{2(S)-Carboxy-pyrrolidin-1-yl}-1-(R)-(4-methoxybenzyl)-2-oxo-ethyl]-tert.-butoxycarbonyl-amino}-acetic acid ethyl ester (0.240 g), 6-aminomethyl-isoquinolin-1-ylamine (0.092 g), N-methyl morpholine (0.170 mL) and 0.160 g of 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) in 8 mL of dry N,N-dimethyl formamide was stirred for 3 h at ambient temperature. Removal of the solvent in vacuo followed by purification of the remaining residue by silica chromatography (dichloromethane/methanol 80/20) gave 0.310 g (100%) of the title compound as a light yellow solid. (+)-APCI-MS: 634 (MH+).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:11][N:12]3[CH:16]=[C:15]([CH2:17][OH:18])[C:14]([C:19]([F:22])([F:21])[F:20])=[N:13]3)[CH:8]=2)[CH2:3]1.C(N(CC)CC)C.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>O1CCCC1.CS(C)=O>[OH:18][CH2:17][C:15]1[C:14]([C:19]([F:22])([F:21])[F:20])=[N:13][N:12]([CH2:11][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[CH2:3][C@@H:2]([NH:1][S:31]([CH3:30])(=[O:33])=[O:32])[CH2:10]3)[CH:16]=1
Reactant: N[C@@H]1Cc2ccc(Cn3cc(CO)c(C(F)(F)F)n3)cc2C1
Reactant: CS(=O)(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)N[C@@H]1Cc2ccc(Cn3cc(CO)c(C(F)(F)F)n3)cc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.4 %

Procedure:
(R)-(1-((2-amino-2,3-dihydro-1H-inden-5-yl)methyl)-3-(trifluoromethyl)-1H-pyrazol-4-yl)methanol (0.16 mmol, 50 mg), prepared as in Example 3 (step e) above was dissolved in tetrahydrofuran (2 mL) and triethylamine (0.299 mmol, 42 μL, 30 mg) followed by methanesulfonyl chloride (0.16 mmol, 18.4 mg) and the solution stirred at room temperature overnight. The reaction was concentrated before partitioning between dichlormethane (3 mL) and 1N HCl. (3 mL). The organic layer was collected and dried using a hydrophobic frit and concentrated under a stream of nitrogen to give a brown residue which was dissolved in DMSO (1 mL) and purified on preparative basic HPLC to give (R)—N-(5-((4-(hydroxymethyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)methyl)-2,3-dihydro-1H-inden-2-yl)methanesulfonamide (18.3 mg, 0.047 mmol, 29.2%) MS (ESI): m/z [M+H]+ 390.0