Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][C:34]([S:37][CH3:38])=[CH:33][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2[N:20]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:19]3[CH:29]=[CH:30][CH:31]=[CH:32][C:18]=3[N:17]=2)[CH2:11][CH2:10]1)=[O:5].[C:39](N1C=CN=C1)(N1C=CN=C1)=[O:40]>O1CCCC1>[F:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][N:20]2[C:19]3[CH:29]=[CH:30][CH:31]=[CH:32][C:18]=3[N:17]=[C:16]2[NH:15][CH:12]2[CH2:11][CH2:10][N:9]([CH2:8][CH2:7][N:6]3[C:4](=[O:5])[C:3]4[C:2](=[CH:36][CH:35]=[C:34]([S:37][CH3:38])[CH:33]=4)[NH:1][C:39]3=[O:40])[CH2:14][CH2:13]2)=[CH:23][CH:24]=1
Reactant: CSc1ccc(N)c(C(=O)NCCN2CCC(Nc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CSc1ccc2[nH]c(=O)n(CCN3CCC(Nc4nc5ccccc5n4Cc4ccc(F)cc4)CC3)c(=O)c2c1
Yield: 85 %

Procedure:
A mixture of 6 parts of 2-amino-N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-5-(methylthio)benzamide, 1.78 parts of 1,1'-carbonylbis[1H-imidazole] and 90 parts of tetrahydrofuran was stirred and refluxed overnight. The reaction mixture was evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 5.2 parts (85%) of 3-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-6-(methylthio)-2,4(1H,3H)-quinazolinedione; m.p. 238° C. (compound 126).
Reaction SMILES: [OH:1][C:2]1([CH2:13][NH:14][CH3:15])[CH2:7][CH2:6][N:5](C(OCC)=O)[CH2:4][CH2:3]1.[ClH:16]>>[ClH:16].[ClH:16].[OH:1][C:2]1([CH2:13][NH:14][CH3:15])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)N1CCC(O)(CNC)CC1
Agent: Cl
Product: CNCC1(O)CCNCC1

Procedure:
3 g (13.9 mmol) of ethyl 4-hydroxy-4-methylaminomethylpiperidine-1-carboxylate are heated overnight under reflux with 30 ml of concentrated hydrochloric acid. The product is concentrated, and the crystals are stirred with acetone, filtered off with suction and dried in a vacuum desiccator over P4O10.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:19]([CH3:20])=[CH:18][C:6]([O:7][CH2:8][CH2:9][CH2:10][C:11]([CH3:17])([CH3:16])[C:12]([O:14]C)=[O:13])=[C:5]([CH3:21])[CH:4]=1.[OH-].[K+]>CO>[CH3:1][O:2][C:3]1[C:19]([CH3:20])=[CH:18][C:6]([O:7][CH2:8][CH2:9][CH2:10][C:11]([CH3:16])([CH3:17])[C:12]([OH:14])=[O:13])=[C:5]([CH3:21])[CH:4]=1
Reactant: COC(=O)C(C)(C)CCCOc1cc(C)c(OC)cc1C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(C)c(OCCCC(C)(C)C(=O)O)cc1C
Yield: 86.3 %

Procedure:
A solution containing 11.8 g (40.1 mmol) of 5-(4-methoxy-2,5-dimethylphenoxy)-2,2-dimethylpentanoic acid, methyl ester (Example 1), 40 mL of 2N potassium hydroxide and 150 mL of methanol is stirred at reflux for 18 hours overnight. The methanol is removed on a rotary evaporator and the aqueous solution diluted with water. After the aqueous solution is extracted with diethyl ether it is acidified with excess 6N hydrochloric acid solution and the precipitate is isolated with diethyl ether. The diethyl ether solution is washed with brine, dried (magnesium sulfate) and evaporated leaving a crystalline residue. Recrystallization from 50 mL of acetonitrile in the presence of charcoal affords after refrigeration, 9.7 g of the title compound as colorless crystals; mp 85°-86° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[C:5]([C:10]([OH:12])=O)=[N:6][CH:7]=[CH:8][CH:9]=1.C(N1CCOCC1)C.ON1C2C=CC=CC=2N=N1.S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH2:42]([O:50][C:51](=[O:54])[CH2:52][NH2:53])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49].NCC(O)=O>ClCCl.C1(C)C=CC=CC=1.O.C(O)CCCCCCC>[CH2:42]([O:50][C:51]([CH2:52][NH:53][C:10]([C:5]1[C:4]([O:3][CH3:2])=[CH:9][CH:8]=[CH:7][N:6]=1)=[O:12])=[O:54])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49]
Reactant: COc1cccnc1C(=O)O
Reactant: CCCCCCCCOC(=O)CN
Agent: CCN1CCOCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCCCCCCCO
Solvent: O
Product: CCCCCCCCOC(=O)CNC(=O)c1ncccc1OC

Procedure:
2.5 g (13 mmol) of 3-methoxypyridine-2-carboxylic acid hydrochloride (m.p. 170° C. with decomp. (from ethyl acetate)), 5.5 ml (45 mmol) N-ethylmorpholine, 2 g (15 mmol) of 1-hydroxy-(1H)-benzotriazole, 4.7 g (13 mmol) of glycine octyl ester tosylate (prepared from glycine, octanol and p-Tos OH on a water separator using toluene) and 6.3 g (15 mmol) of CMC (cf. Example 146) were stirred for 48 h in 350 ml of anhydrous dichloromethane. Following a working up which was analogous to that in Example 146, the crude product was chromatographed on silica gel using dichloromethane (with the addition of up to 2.5% methanol during the course of this). 3.6 g were obtained of the colorless, oily title compound, 1H NMR (CDCl3): δ=4.26 (d, CH2 -glycine).
Reaction SMILES: C([O:8][C:9]1[CH:30]=[CH:29][C:12]([CH2:13][C:14]2[CH:18]=[C:17]([C:19]3[C:20]([NH2:28])=[N:21][C:22]([CH2:25][O:26][CH3:27])=[CH:23][CH:24]=3)[O:16][N:15]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.ClCCl.B(Br)(Br)Br>CO>[NH2:28][C:20]1[C:19]([C:17]2[O:16][N:15]=[C:14]([CH2:13][C:12]3[CH:29]=[CH:30][C:9]([OH:8])=[CH:10][CH:11]=3)[CH:18]=2)=[CH:24][CH:23]=[C:22]([CH2:25][O:26][CH3:27])[N:21]=1
Reactant: COCc1ccc(-c2cc(Cc3ccc(OCc4ccccc4)cc3)no2)c(N)n1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: COCc1ccc(-c2cc(Cc3ccc(O)cc3)no2)c(N)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 19.7 %

Procedure:
To a mixture of 3-(3-(4-benzyloxy-benzyl)-isoxazol-5-yl)-6-methoxymethyl-pyridin-2-ylamine (30 mg, 0.075 mmol) described in Example 26 and dichloromethane (1 mL) was added boron tribromide (220 μL, 1 M dichloromethane solution, 0.22 mmol) at −78° C., which was stirred for 1 hour at 0° C. The reaction mixture was cooled to −78° C., methanol was added at the same temperature, and the excess boron tribromide was quenched. The reaction mixture was gradually allowed to room temperature, a sodium acetate aqueous solution was added to the reaction mixture at room temperature, which was neutralized, after which water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and was concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=2:1) to obtain the title compound (4.6 mg, 20%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH:22]([F:24])[F:23])=[C:17]([CH3:25])[CH:16]=3)[NH:13][C:12](=O)[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.F[B-](F)(F)F.C[O+](C)C.[Cl-].[NH4+:36]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH:22]([F:24])[F:23])=[C:17]([CH3:25])[CH:16]=3)[CH2:9][O:10][CH2:11][C:12]([NH2:36])=[N:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: [NH4+]
Reactant: Cc1cc(C2(c3cccc(Br)c3)COCC(=O)N2)ccc1OC(F)F
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc(C2(c3cccc(Br)c3)COCC(N)=N2)ccc1OC(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.7 %

Procedure:
In a vacuum dried flask under an argon atmosphere, a solution of (RS)-5-(3-bromo-phenyl)-5-(4-difluoromethoxy-3-methyl-phenyl)-morpholin-3-one (2.5 g, 1 eq) in dichloromethane (80 ml) was treated with trimethyloxonium tetrafluoroborate (2.7 g, 3 eq). The reaction mixture was stirred at room temperature overnight. The incomplete reaction was then washed with a saturated solution of sodium hydrogen carbonate (50 ml). The organic layer was dried over sodium sulfate and evaporated. The crude was dissolved in methanol (15 ml) and the solution transferred under an nitrogen atmosphere into a dried pressure tube. After the addition of ammonium chloride (0.182 g, 3.4 mmol) the sealed pressure tube was heated at 100° C. for 16 hours. After cooling, the reaction mixture was filtered and evaporated to dryness, taken up with dichloromethane (30 ml) and filtered again. The solvent was removed and the residue was passed through a SCX (50 g) cartridge, washing with a mixture of dichloromethane and methanol. The product was recovered eluting with a solution of ammonia (2M) in methanol. 1.45 g of the (RS)-5-(3-bromo-phenyl)-5-(4-difluoromethoxy-3-methyl-phenyl)-5,6-dihydro-2H-[1,4]oxazin-3-ylamine were obtained as a white solid (58% of theory). MS (ISP): m/z=412.9 [M+H]+.
Reaction SMILES: [CH:1]12[CH2:14][CH:6]([CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=31)[CH2:5][NH:4][CH2:3][CH2:2]2.C(=O)(O)[O-].[Na+].[CH2:20](Br)[CH:21]=[CH2:22].[ClH:24]>CCOCC.CO>[ClH:24].[CH2:22]([N:4]1[CH2:3][CH2:2][CH:1]2[CH2:14][CH:6]([CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=32)[CH2:5]1)[CH:21]=[CH2:20]
Reactant: C=CCBr
Reactant: c1ccc2c(c1)CC1CNCCC2C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: C=CCN1CCC2CC(Cc3ccccc32)C1

Procedure:
1.87 g of 2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzazonine, 1.25 g of sodium bicarbonate and 1.33 g of allyl bromide were added into 30 ml of methanol, and the mixture was refluxed for 5 hours and subjected to distillation under reduced pressure. The residue was dissolved in 15 ml of 10% hydrochloric acid. The solution was washed once with 5 ml of benzene, and the water layer was made alkaline with sodium hydroxide and extracted with ether. Ether was distilled from the ether extract and the residue was subjected to vacuum distillation to obtain 2 g of a colorless oily substance as a fraction boiling at 110° to 120° C. (bath temperature) under 0.7 mmHg. The product was dissolved in 15 ml of ether and gaseous hydrochloric acid was blown into the solution to form a white precipitate. The precipitate was recovered by filtration and dried to obtain 4-allyl-2,3,4,5,6,7-hexahydro-1,6-methano-1H-4-benzazonine hydrochloride. Recrystallization from isopropanol gave a white crystalline powder melting at 212.5° to 214.5° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:8][C:7]=12)#[CH:2].[NH2:26][C:27]1[CH:32]=[CH:31][C:30](Br)=[CH:29][N:28]=1>>[F:15][C:12]([F:14])([F:13])[C:11]1[N:6]2[N:5]=[CH:4][C:3]([C:1]#[C:2][C:30]3[CH:31]=[CH:32][C:27]([NH2:26])=[N:28][CH:29]=3)=[C:7]2[N:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:10]=1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Nc1ccc(Br)cn1
Product: Nc1ccc(C#Cc2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cn1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.1) (355 mg, 1.0 mmol) and commercially available 2-amino-5-bromopyridine (156 mg, 1.0 mmol) according to general procedure II. Obtained as a dark-red solid (80 mg, 17%). MS (ISP) 448.2[(M+H)+]; mp 227-229° C.
Reaction SMILES: C(O)(=O)C.[CH2:5]([N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[CH2:16][O:17][C:18]1[CH:50]=[CH:49][C:21]([CH2:22][CH:23]2[S:27][C:26](=[O:28])[N:25](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:24]2=[O:48])=[CH:20][CH:19]=1)[CH3:6].C(=O)([O-])O.[Na+]>O>[CH2:5]([N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[CH2:16][O:17][C:18]1[CH:50]=[CH:49][C:21]([CH2:22][CH:23]2[S:27][C:26](=[O:28])[NH:25][C:24]2=[O:48])=[CH:20][CH:19]=1)[CH3:6]
Reactant: CCn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2cccnc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2cccnc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 46.3 %

Procedure:
12 ml of a 3: 1 by volume mixture of acetic acid and water were added to 300 mg of 5-{4-(3-ethylimidazo[5,4-b]pyridin-2-ylmethoxy)benzyl}-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 29), and the resulting mixture was stirred at 60° C. for 2 hours. At the end of this time, the reaction mixture was neutralized by the addition of sodium hydrogencarbonate, after which it was extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, after which the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using ethyl acetate as the eluent, to give 85 mg of the title compound, melting at 210°-212° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][C:3]=1[CH2:4][OH:5].C(N(C(C)C)CC)(C)C.[CH3:21][O:22][CH2:23]Cl.O>ClCCl>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][C:3]=1[CH2:4][O:5][CH2:21][O:22][CH3:23]
Reactant: COCCl
Reactant: N#Cc1ccc(Br)c(CO)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COCOCc1cc(C#N)ccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.4 %

Procedure:
To a solution of 2-bromo-5-cyanobenzyl alcohol (4.59 g, 21.7 mmol) in dichloromethane (80 mL) were added diisopropylethylamine (5.6 mL, 32 mmol) and chloromethyl methyl ether (2.3 mL, 30 mmol) at 0° C., and the reaction mixture was stirred at room temperature overnight. Water was added, and the mixture was extracted with chloroform. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (6:1 hexane/ethyl acetate) to give 18f (4.08 g, 71%): 1H NMR (300 MHz, CDCl3) δ (ppm) 3.43 (s, 3H), 4.65 (s, 2H), 4.80 (s, 2H), 7.43 (dd, J=8.2, 4.1 Hz, 1H), 7.66 (d, J=8.2 Hz, 1H), 7.82 (d, J=4.1 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][C@@H:26]4[CH2:30][CH2:29][CH2:28][N:27]4C(OC(C)(C)C)=O)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:38])[NH:6]2.Cl>O1CCOCC1.CO>[F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][C@@H:26]4[CH2:30][CH2:29][CH2:28][NH:27]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:38])[NH:6]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OC[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OC[C@@H]1CCCN1
Yield: 91.8 %

Procedure:
Using an analogous procedure to that described for the preparation of the starting material in Example 11, tert-butyl (2S)-2-[(4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazolin-7-yloxy)methyl]pyrrolidine-1-carboxylate (170 mg, 0.33 mmol) was reacted with hydrogen chloride in dioxane. The solid was dissolved in methanol and absorbed onto an Isolute SCX column which was washed through with methanol and then the product was eluted with 7N ammonia in methanol to give 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-[(2S)-pyrrolidin-2-ylmethoxy]quinazoline (128 mg, 93%).
Reaction SMILES: [N:1]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@H:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][C@H:2]1[C:3]([OH:5])=O.[C:24]([NH2:28])([CH3:27])([CH3:26])[CH3:25].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[N:1]1([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@H:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:6][C@H:2]1[C:3]([NH:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:5]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)C[C@H]1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H](OCc2ccccc2)CN1C(=O)OC(C)(C)C

Procedure:
In a DMF solution containing 100 mg of Boc-Hyp(Bzl)-OH, 33 μl of t-butylamine, 48 mg of HOBt and 71 mg of EDC hydrochloride were added and the resultant mixture was stirred for 14 hr. The reaction mixture was treated similarly to that in Example 33 (Process 3) to give 88 mg of the title compound.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[NH2:12][C@@H:13]1[C:49]([CH3:51])([CH3:50])[C@H:48]2[C@@:16]3([O:44][C:20]4[C:21]5[CH2:22][N:23]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:24](=[O:36])[C:25]=5[CH:26]=[C:27]([O:28][CH2:29][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[C:19]=4[CH2:18][C@:17]3([CH3:53])[C@@H:45]([CH3:52])[CH2:46][CH2:47]2)[CH2:15][CH2:14]1>ClCCl>[C:8]([NH:12][C@@H:13]1[C:49]([CH3:51])([CH3:50])[C@H:48]2[C@@:16]3([O:44][C:20]4[C:21]5[CH2:22][N:23]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:24](=[O:36])[C:25]=5[CH:26]=[C:27]([O:28][CH2:29][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)[C:19]=4[CH2:18][C@:17]3([CH3:53])[C@@H:45]([CH3:52])[CH2:46][CH2:47]2)[CH2:15][CH2:14]1)(=[O:10])[CH3:9]
Reactant: CC(=O)Cl
Reactant: C[C@H]1CC[C@H]2C(C)(C)[C@@H](N)CC[C@]23Oc2c(c(OCc4ccccc4)cc4c2CN(C(=O)OC(C)(C)C)C4=O)C[C@]13C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N[C@H]1CC[C@@]23Oc4c(c(OCc5ccccc5)cc5c4CN(C(=O)OC(C)(C)C)C5=O)C[C@]2(C)[C@@H](C)CC[C@H]3C1(C)C
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 82 %

Procedure:
Under nitrogen, 25 μl (0.18 mmol) of triethylamine and 8 μl (0.11 mmol) of acetyl chloride was added to a solution of Compound (45a) (50 mg, 0.087 mmol) in 2.0 ml of dry dichloromethane under ice-cooling, and the mixture stirred for 40 min at the same temperature. After addition of ice-water, the reaction was extracted with ethyl acetate. The extract was washed with aqueous saturated sodium hydrogen carbonate and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by a preparative thin layer chromatography (Merck, Kieselgel 60 F254, 0.5 mm; chloroform:methanol=30:1) to give 44 mg (82%) of Compound (45b).
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][CH2:10][CH2:11][C:12]2[N:13]=[CH:14][NH:15][CH:16]=2)=[N:4][C:5](Cl)=[N:6][CH:7]=1.[N:17]1([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=2)[CH2:21][CH2:20][CH2:19][CH2:18]1.Cl.ClCCl.CO>CO>[Br:1][C:2]1[C:3]([NH:9][CH2:10][CH2:11][C:12]2[N:13]=[CH:14][NH:15][CH:16]=2)=[N:4][C:5]([NH:29][C:26]2[CH:25]=[CH:24][C:23]([CH2:22][N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:28][CH:27]=2)=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(NCCc2c[nH]cn2)n1
Reactant: Nc1ccc(CN2CCCC2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: Brc1cnc(Nc2ccc(CN3CCCC3)cc2)nc1NCCc1c[nH]cn1
Yield: 4.6 %

Procedure:
A mixture of 5-bromo-4-(2-(1H-imidazol-4-yl)-ethylamino)-2-chloro-pyrimidine (60 mg), 4-pyrrolidin-1-ylmethyl-phenylamine (35 mg) and hydrochloric acid (37% in water, 40 μL) in methanol (2 mL) was refluxed overnight. The reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution, the organic phase dried (Na2SO4) and evaporated, which gave, after chromatography on silica using dichloromethane/methanol, the title compound (4 mg).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:19])=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.CO[CH:22](OC)[N:23](C)C.Cl.NO.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)([O-])O.[Na+]>CC(O)C.C1COCC1>[Br:1][C:2]1[C:3]([CH3:19])=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:16])[F:17])[CH:10]=2)[C:5]2[N:6]([N:23]=[CH:22][N:8]=2)[CH:7]=1
Reactant: COC(OC)N(C)C
Reactant: Cc1c(Br)cnc(N)c1-c1cccc(C(F)(F)F)c1
Agent: Cl
Agent: NO
Agent: O=C([O-])O
Solvent: CC(C)O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: Cc1c(Br)cn2ncnc2c1-c1cccc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 97.6 %

Procedure:
A suspension of 5-bromo-4-methyl-3-(3-trifluoromethyl-phenyl)-pyridin-2-ylamine (Int. 1, 1.0 g, 3.02 mmol) in IPA (3 mL) was treated with dimethylformamide dimethyl acetal (522 μL, 3.93 mmol) then heated at reflux for 3 hrs. The reaction mixture was cooled to 50° C. and hydroxylamine hydrochloride (273 mg, 3.93 mmol) was added. The reaction mixture was stirred at 50° C. for 1.5 hrs then allowed to cool and the resultant precipitate was collected by filtration, washing with IMS. The solid thus obtained was dissolved in THF (10 mL) and cooled to 0° C. before dropwise addition of trifluoroacetic anhydride (481 μL, 3.46 mmol), keeping the internal temperature below 10° C. Once addition was complete the reaction mixture was stirred at room temperature for 18 hrs. Sodium hydrogen carbonate (5% solution, 25 mL) was added and the mixture was extracted with EtOAc (2×25 mL). The combined organic extracts were washed with 5% sodium hydrogen carbonate solution (15 mL), then dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as a white solid (1.05 g).
Reaction SMILES: [O:1]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][NH:4][C:3](=[O:12])[CH2:2]1.[CH:13]1([N:18]2[C:22]3[N:23]=[C:24]([NH:27][C:28]4[N:33]=[N:32][C:31](Cl)=[CH:30][CH:29]=4)[N:25]=[CH:26][C:21]=3[C:20]3[CH:35]=[CH:36][N:37]=[CH:38][C:19]2=3)[CH2:17][CH2:16][CH2:15][CH2:14]1.C(N(CC)C(C)C)(C)C>CN1CCCC1=O>[CH:13]1([N:18]2[C:22]3[N:23]=[C:24]([NH:27][C:28]4[N:33]=[N:32][C:31]([N:9]5[CH2:8][CH2:7][C:6]6([O:1][CH2:2][C:3](=[O:12])[NH:4][CH2:5]6)[CH2:11][CH2:10]5)=[CH:30][CH:29]=4)[N:25]=[CH:26][C:21]=3[C:20]3[CH:35]=[CH:36][N:37]=[CH:38][C:19]2=3)[CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: O=C1COC2(CCNCC2)CN1
Reactant: Clc1ccc(Nc2ncc3c4ccncc4n(C4CCCC4)c3n2)nn1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C1COC2(CCN(c3ccc(Nc4ncc5c6ccncc6n(C6CCCC6)c5n4)nn3)CC2)CN1
Temperature: 160 °C
Yield: 4.6 %

Procedure:
To a mixture of compound 400 (110.0 mg, 646 μmol) and compound 140 (40.0 mg, 109 μmol) in N-methylpyrrolidinone (1.50 mL) was added N,N-diisopropylethylamine (DIEA) (0.100 mL, 575 μmol). The resulting mixture was heated at 160° C. under microwave irradiation for 6 h. The crude material was purified by reverse phase HPLC (acetonitrile/H2O containing 0.1% TFA each, 25 min from 10 to 40%). The isolated material was further purified by prep-TLC (10% methanol in DCM with 1% NH4OH) to give compound 396 as a yellow solid (2.5 mg, 5%). 1H NMR (500 MHz, CD3OD) δ 9.21 (s, 1 H) 8.91 (s, 1 H) 8.37-8.46 (m, 2 H) 8.08 (d, J=5.38 Hz, 1 H) 7.46 (d, J=10.03 Hz, 1 H) 5.43 (quin, 1 H) 4.21 (s, 2 H) 4.06 (ddd, J=13.27, 3.48, 3.30 Hz, 2 H) 3.37-3.42 (m, 4 H) 2.44 (dd, J=12.96, 8.31 Hz, 2 H) 2.08-2.24 (m, 4 H) 2.03 (d, J=13.45 Hz, 2 H) 1.84-1.93 (m, 2 H) 1.74-1.83 (m, 2 H) ppm; LCMS-ESI (POS), M/Z, M+1: Found 500.2, Calculated 500.2.