Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[NH2:2][C:3]1[C:4]([CH3:14])=[C:5]([CH:10]=[C:11]([Br:13])[CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[O:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1>>[Br:13][C:11]1[CH:12]=[C:3]([NH:2][CH:18]2[CH2:19][CH2:20][O:15][CH2:16][CH2:17]2)[C:4]([CH3:14])=[C:5]([CH:10]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)c1cc(Br)cc(N)c1C
Reactant: O=C1CCOCC1
Agent: Br
Product: COC(=O)c1cc(Br)cc(NC2CCOCC2)c1C

Procedure:
Scheme 1 below outlines a particular embodiment for the production of the free base of Compound I, as well as the hydrobromide of Compound I. Briefly, methyl 3-amino-5-bromo-2-methylbenzoate (1) is reacted with dihydro-2H-pyran-4(3H)-one under reductive amination conditions to form methyl 5-bromo-2-methyl-3-((tetrahydro-2H-pyran-4-yl)amino)benzoate (2) in step 1. In step 2, reductive amination is again used to form 5-bromo-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzoate (3). This compound is then reacted under Suzuki coupling conditions in step 3 to form methyl 5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4-methyl-4′-(morpholinomethyl)-[1,1′-biphenyl]-3-carboxylate (4), which is hydrolyzed to the corresponding acid (5) in step 4. In step 5, acid (5) is reacted under amide coupling reaction conditions with 3-(aminomethyl)-4,6-dimethyl-dihydro-pyridin-2(1H)-one hydrochloride to form Compound I.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH2:5][CH2:6][CH3:7].C(=O)([O-])[O-].[K+].[K+].Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>O.C1COCC1.O>[CH2:22]([O:21][C:19]([NH:2][C@H:3]([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH2:5][CH2:6][CH3:7])=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCCC[C@H](N)C(=O)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCCC[C@H](NC(=O)OCc1ccccc1)C(=O)OC
Temperature: 0 °C
Reaction time: 8 h

Procedure:
12 g (66.1 mmol) of rac-methyl norleucinate hydrochloride were initially charged in 974 ml of water/THF (8:1), and 28.3 g (204.8 mmol) of potassium carbonate were added. The reaction mixture was cooled to 0° C. 12.3 ml (72.7 mmol) of benzyl chloroformate were slowly added dropwise and the reaction mixture was stirred at RT overnight. The mixture was diluted with 480 ml of water and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulphate, filtered off and concentrated. The residue was purified by silica gel chromatography (cyclohexane/ethyl acetate=4:1). This gave 18.0 g (97.6% of theory, purity 100%) of the target compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)(Cl)(Cl)[Cl:35].CO>CC#N>[Cl:35][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: OC(c1ccccn1)c1ccccn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: CC#N
Product: ClC(c1ccccn1)c1ccccn1
Reaction time: 8 h
Yield: 56 %

Procedure:
To di(2-pyridinyl)methanol (8.73 g, 46.94 mmol) in CH3CN (100 ml) at 0° C. was added a solution of PPh3 (14.77 gram, 56.32 mmol) in of CCl4 (80 mL) in 1.5 h. The solution was left standing overnight. After addition of MeOH (10 ml) and stirring for 15 min the mixture was concentrated in vacuum to ca 50 ml. To the residue was added of water (100 ml) and the mixture was acidified with 2M HCl to pH=1, and washed twice with 100 ml of CHCl3, the aqueous layer was neutralized with K2CO3 and extracted 4 times with 75 ml of ether. Drying and evaporation of the solvent yielded 2-[chloro(2-pyridinyl)methyl]pyridine (5.41 gram, 56%) as a pale brown solid. Analytically pure material was obtained by column chromatography on silica (ether). 1H-NMR (200 MHz, CDCl3) δ 6.20 (s, 1H), 7.14-7.20 (m, 2H), 7.60-7.73 (m, 4H). 8.51-8.54 (m, 2H). 13C-NMR (50.3 MHz, CDCl3) δ 62.84 (d), 121.3 (d), 121.5 (d), 135.7 (d), 147.7 (d), 156.9 (s). Anal. Cald. for C11H9ClN2: C 64.56, H 4.43, Cl 17.32, N 13.69; Found: C 64.48, H 4.45, Cl 17.29, N 13.49.
Reaction SMILES: [N+:1]([CH2:4][CH:5]([CH2:12][CH2:13][CH3:14])[CH2:6][C:7]([O:9]CC)=O)([O-])=O.C([O-])=O.[NH4+].[CH:19]([Si:22]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[N:23]1[C:27]2=[N:28][CH:29]=[C:30]([CH:32]=O)[CH:31]=[C:26]2[CH:25]=[CH:24]1)([CH3:21])[CH3:20]>CO.CCOCC.[Pd]>[CH2:12]([CH:5]1[CH2:4][N:1]([CH2:32][C:30]2[CH:31]=[C:26]3[CH:25]=[CH:24][N:23]([Si:22]([CH:19]([CH3:21])[CH3:20])([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35])[C:27]3=[N:28][CH:29]=2)[C:7](=[O:9])[CH2:6]1)[CH2:13][CH3:14]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(C=O)cnc21
Reactant: CCCC(CC(=O)OCC)C[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: CCOCC
Product: CCCC1CC(=O)N(Cc2cnc3c(ccn3[Si](C(C)C)(C(C)C)C(C)C)c2)C1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75 %

Procedure:
Ethyl 3-(nitromethyl)hexanoate (0.52 g, 1.1 eq, 2.55 mmol) is dissolved in absolute methanol (8 ml). Then 10% Pd/C (0.2 g) and ammonium formate (1 g) are added under vigorous stirring. After 15 min, the mixture is diluted with ether (100 ml) and filtered. The solid on the filter is washed with ether (2×50 ml). A solution of aldehyde x255 (0.7 g, 1 eq, 2.3 mmol) in methanol (5 ml) is added immediately. The combined solution is evaporated in the vacuum of a rotary evaporator. The residue is dissolved in methanol (10 ml), CH(OMe)3 (0.5 ml) is added, and the obtained solution is stirred at room temperature for 16 h. An excess of NaBH4 (1 g in several small portions) is then added to the reaction solution under vigorous stirring for 20 min. The reaction mixture is evaporated in the vacuum of a rotary evaporator. The residue is partitioned between ethyl acetate and water. The organic phase is separated, dried with anhydrous sodium sulfate, and evaporated. The residue is dissolved in acetonitrile (10 ml), and the solution is refluxed for 24 h to complete the cyclization. The solvent is distilled off. The residue is purified by chromatography on silicagel (CCl4/MeCN) to afford 4-propyl-1-{[1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]methyl}pyrrolidin-2-one x256.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([CH2:16]O)=[CH:12][C:11]=1[O:18][C:19]([F:22])([F:21])[F:20].S(Cl)([Cl:25])=O>C(Cl)Cl>[Cl:25][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([C:3]2[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=2[F:1])=[C:11]([O:18][C:19]([F:22])([F:21])[F:20])[CH:12]=1
Reactant: COc1ccc(F)c(-c2ccc(CO)cc2OC(F)(F)F)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(F)c(-c2ccc(CCl)cc2OC(F)(F)F)c1
Reaction time: 8 h
Yield: 5.2 %

Procedure:
To a solution of 46.2 (0.164 g, 0.52 mmol) in DCM (5 mL) was added thionyl chloride (76 μL, 1.04 mmol) in one portion at room temperature. The mixture was stirred overnight and concentrated. The crude product was chromatographed on silica gel (0-10% EtOAc/hexane) to afford 46.3 (0.009 g, 5%) as a colorless oil.
Reaction SMILES: Cl.C=O.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][CH:14]=1)[C:9]([OH:11])=[O:10].[CH2:15](NCC)C>>[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:12]([CH2:15][O:10][C:9]2=[O:11])=[CH:13][CH:14]=1
Reactant: CCNCC
Reactant: COc1cccc(C(=O)O)c1
Agent: C=O
Agent: Cl
Product: COc1ccc2c(c1)C(=O)OC2
Reaction time: 0.5 h
Yield: 32.6 %

Procedure:
Concentrated HCl (1l) was added with 40% w/v formaldehyde (65 ml, 0.86 mole) under vigorous stirring, then with 3-methoxybenzoic acid (100 g, 0.66 mole) and the mixture was heated to 100° C. controlling the generation of gas, for 30 minutes. The cooling of the mixture yielded a precipitate which was filtered and stored, while the mixture was washed with water, then with 5% NaOH. The new precipitate was twice extracted with CH2Cl2, the extract anhydrified, concentrated, joined to the previously filtered solid and both were dissolved in CH2Cl2 and treated with diethylamine (120 ml, 1.15 moles). After 24 hours it was extracted with 10% HCl and the phases were separated and extracted with CH2Cl2. The organic phase was washed with 10% NaOH, discoloured with charcoal, anhydrified and concentrated. The residue was dissolved in CH2Cl2 and treated, under stirring, with 10% HCl for 30 minutes. The organic phase was washed with water, anhydrified and dried. The residue was dissolved in CH2Cl2 and treated with 10% NaOH under stirring for 30 minutes. The organic phase was washed with water, anhydrified and concentrated to give a solid which was crystallised from CH3OH/H2O 65:35 and dried at 50° C. over P2O5, then crystallised again from CH3OH/H2O 6:4 to give 35.28 g of the title compound (yield: 32%). m.p.: 115-117° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]=[C:8]([Cl:19])[N:9]=[C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH:20]1[CH2:25][CH2:24][CH:23]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:22][CH2:21]1>>[Cl:19][C:8]1[N:9]=[C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:11]2[N:12]=[C:3]([CH2:2][N:20]3[CH2:25][CH2:24][CH:23]([C:26]([OH:29])([CH3:28])[CH3:27])[CH2:22][CH2:21]3)[CH:4]=[CH:5][C:6]=2[N:7]=1
Reactant: CC(C)(O)C1CCNCC1
Reactant: Clc1nc(N2CCOCC2)c2nc(CBr)ccc2n1
Product: CC(C)(O)C1CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1

Procedure:
Following General Procedure B, 4-(6-(bromomethyl)-2-chloropyrido[3,2-d]pyrimidin-4-yl)morpholine 7 and 2-(piperidin-4-yl)propan-2-ol were reacted to give 2-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[N:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N:19]4[N:28]=[CH:27][C:26]5[C:21](=[C:22]([F:33])[CH:23]=[C:24]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:25]=5)[C:20]4=[O:34])[C:14]=3[CH2:35][OH:36])[CH:9]=[C:10]([C:11]#[N:12])[C:5]2=[CH:4][CH:3]=1.C([OH:39])C>O>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([N:19]4[N:28]=[CH:27][C:26]5[C:21](=[C:22]([F:33])[CH:23]=[C:24]([C:29]([CH3:31])([CH3:32])[CH3:30])[CH:25]=5)[C:20]4=[O:34])[C:14]=3[CH2:35][OH:36])[CH:9]=[C:10]([C:11]([NH2:12])=[O:39])[C:5]2=[CH:4][CH:3]=1
Reactant: CCO
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C#N)c5ccc(Br)nc54)c3CO)ncc2c1
Solvent: O
Product: CC(C)(C)c1cc(F)c2c(=O)n(-c3cccc(-n4cc(C(N)=O)c5ccc(Br)nc54)c3CO)ncc2c1
Temperature: 45 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
In a 25 mL round-bottomed flask, 6-bromo-1-(3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-2-(hydroxymethyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (14 mg, 25.6 μmol) and [hydrogen bis(dimethylphosphinito-kP)]platinum (II) (110 μg, 0.256 μmol, Eq: 0.01) were combined with Ethanol (2.99 ml) and Water (2.99 ml) to give a colorless solution. The reaction mixture was heated to 45° C. and stirred for 1 h. The crude reaction mixture was concentrated in vacuo. Purification by HPLC gave 6-bromo-1-[3-(6-tert-butyl-8-fluoro-1-oxo-1H-phthalazin-2-yl)-2-hydroxymethyl-phenyl]-1H-pyrrolo[2,3-b]pyridine-3-carboxylic acid amide (11 mg, 77%, [M+H]+ 565).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:17]2[C:21]([CH2:22][N:23]3C(=O)C4=CC=CC=C4C3=O)=[N:20][N:19]=[C:18]2[CH2:34][N:35]2C(=O)C3=CC=CC=C3C2=O)=[C:6]([CH:16]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[F:15])=O.O.NN>C(O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:17]3[C:18]([CH2:34][NH2:35])=[N:19][N:20]=[C:21]3[CH2:22][N:23]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[F:15])[C:6]=2[CH:16]=1
Reactant: O=C(c1ccccc1F)c1cc(Br)ccc1-n1c(CN2C(=O)c3ccccc3C2=O)nnc1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: NCc1nnc2n1-c1ccc(Br)cc1C(c1ccccc1F)=NC2

Procedure:
In the manner given in Example 22, 5-bromo-2'-fluoro-2-[3,5-bis(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone in ethanol is heated with hydrazine hydrate to give 8-bromo-1-(aminomethyl)-6-(o-fluorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [ClH:1].[N:2]1([CH2:8][C:9]2[O:13][C:12]([C:14](O)=[O:15])=[CH:11][CH:10]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1.C(Cl)[Cl:18]>S(Cl)(Cl)=O.CN(C=O)C>[ClH:18].[N:2]1([CH2:8][C:9]2[O:13][C:12]([C:14]([Cl:1])=[O:15])=[CH:11][CH:10]=2)[CH2:7][CH2:6][O:5][CH2:4][CH2:3]1
Reactant: ClCCl
Reactant: O=C(O)c1ccc(CN2CCOCC2)o1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=C(Cl)c1ccc(CN2CCOCC2)o1
Temperature: 25 °C
Yield: 83 %

Procedure:
A suspension of 5-morpholin-4-ylmethyl-furan-2-carboxylic acid hydrochloride in thionyl chloride with 2 drops of DMF was refluxed under N2 for 3 hours, then cooled to room temperature. Dry CH2Cl2 was added and solvents were evaporated in vacuo. The residue was triturated with dry CH2Cl2, and the resulting solid was filtered, washed with dry CH2Cl2 and dried in vacuo to give 373 mg (83% yield) of 5-morpholin-4-ylmethyl-furan-2-carbonyl chloride hydrochloride as a white solid. 1H-NMR (d6-DMSO) δ: 11.54 (broad s, 1H), 7.26 (d, 1H), 6.92 (d, 1H), 4.49 (s, 2H), 3.94 (m, 2H), 3.74 (m, 2H), 3.28 (m, 2H), 3.09 (broad s, 2H).
Reaction SMILES: [C:1]([CH:6]([CH2:18][CH3:19])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[C:13](=[O:17])[CH2:14][CH2:15][CH:16]=1)([O:3][CH2:4][CH3:5])=[O:2].[CH2:20]([CH:22](C(OCC)=O)[C:23](OCC)=O)[CH3:21]>>[C:1]([CH:6]([C:18]1[CH:23]=[CH:22][CH:20]=[CH:21][CH:19]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[C:13](=[O:17])[CH2:14][CH2:15][CH:16]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)C(CC)CCCCCC1=CCCC1=O
Reactant: CCOC(=O)C(CC)C(=O)OCC
Product: CCOC(=O)C(CCCCCC1=CCCC1=O)c1ccccc1

Procedure:
This cyclopentenone is prepared by the procedure described in Belgium Pat. No. 786,215 (Jan. 15, 1973) for the preparation of 2-(6-carbethoxyoctyl)cyclopent-2-en-1-one by substituting diethyl phenylmalonate for diethyl ethylmalonate.
Reaction SMILES: [CH3:1][Si:2]([CH3:41])([CH3:40])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:32][O:33][CH2:34][CH2:35][Si:36]([CH3:39])([CH3:38])[CH3:37])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:23][CH:22]3[N:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:19]([CH2:20][CH2:21]3)[CH2:18]2)[CH:9]=1.[I:42]N1C(=O)CCC1=O>CC#N.C(Cl)Cl>[CH3:39][Si:36]([CH3:38])([CH3:37])[CH2:35][CH2:34][O:33][CH2:32][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:40])[CH3:41])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([I:42])=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:23][CH:22]3[N:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:19]([CH2:20][CH2:21]3)[CH2:18]2)[CH:9]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n1)C2
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C2CCC1CC(c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n1)C2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87.7 %

Procedure:
To the “anti” tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (6.04 g, 10 mmol) in CH3CN (40 mL) and DCM (40 mL) was added N-iodosuccinimide (2.5 g, 11 mmol) portionwise and the resulting mixture was stirred at room temperature for 1.5 h, at which time LC/MS confirmed full conversion of starting material to product. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel. Elution with EtOAc/Hexanes (0-50%) gave tert-butyl 3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (6.4 g, 88%).
Reaction SMILES: [C:1]([C:3]1[N:7]2[CH:8]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:10]=[C:11]([C:12]#[N:13])[C:6]2=[N:5][CH:4]=1)#[CH:2].[NH2:24][C:25]1[CH:30]=[CH:29][C:28](I)=[CH:27][N:26]=1>>[NH2:24][C:25]1[N:26]=[CH:27][C:28]([C:2]#[C:1][C:3]2[N:7]3[CH:8]=[C:9]([C:14]4[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:16][CH:15]=4)[CH:10]=[C:11]([C:12]#[N:13])[C:6]3=[N:5][CH:4]=2)=[CH:29][CH:30]=1
Reactant: C#Cc1cnc2c(C#N)cc(-c3ccc(C(F)(F)F)cc3)cn12
Reactant: Nc1ccc(I)cn1
Product: N#Cc1cc(-c2ccc(C(F)(F)F)cc2)cn2c(C#Cc3ccc(N)nc3)cnc12

Procedure:
The title compound was prepared from 3-ethynyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine-8-carbonitrile (example C.23) (150 mg, 0.5 mmol) and commercially available 2-amino-5-iodopyridine (106 mg, 0.5 mmol) according to general procedure II. Obtained as a light brown solid (15 mg, 7%). MS (ISP) 404.3 [(M+H)+].
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH:13]1([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:15][CH2:14]1.[Br:25][C:26]1[CH:31]=[C:30]([CH2:32]Br)[CH:29]=[CH:28][C:27]=1[Cl:34].[Cl-].[NH4+]>C1COCC1>[Br:25][C:26]1[CH:31]=[C:30]([CH2:32][CH:17]([CH:13]2[CH2:14][CH2:15][CH2:16]2)[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:29]=[CH:28][C:27]=1[Cl:34]
Reactant: CC(C)(C)OC(=O)CC1CCC1
Reactant: Clc1ccc(CBr)cc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(Cc1ccc(Cl)c(Br)c1)C1CCC1
Temperature: -20 °C
Reaction time: 0.5 h

Procedure:
Under argon, 2.9 ml (20.8 mmol) of diisopropylamine were dissolved in 30 ml of dry THF, and the mixture was cooled to −20° C. 8.3 ml (20.8 mmol) of n-butyllithium solution (2.5 M in hexane) were added dropwise, and the resulting mixture was stirred to −20° C. for 30 min and then cooled to −78° C. At this temperature, a solution of 2.60 g (about 15.3 mmol, crude) of tert-butyl cyclobutylacetate in 10 ml of THF was added. After 4 h of stirring at −78° C., a solution of 3.95 g (13.9 mmol) of 2-bromo-4-(bromomethyl)-1-chlorobenzene in 10 ml of THF was added. The reaction mixture was slowly warmed to RT overnight, and saturated aqueous ammonium chloride solution was then added. The mixture was extracted three times with ethyl acetate. The combined organic phases were dried over magnesium sulphate and concentrated under reduced pressure. The solid that remained was triturated with 30 ml of cyclohexane/dichloromethane (1:1) and filtered off. The solid was once more triturated with 10 ml of cyclohexane/dichloromethane (1:1) and again filtered off; this procedure was repeated once more. All filtrates were collected, combined and concentrated under reduced pressure. This residue was then purified further by chromatography on silica gel (mobile phase from pure cyclohexane to cyclohexane/dichloromethane 20:1 to 10:1). This gave 2.24 g of the title compound (43.2% of theory).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH2:15][CH3:16])[CH:12]=3)[CH:7]=[C:6]2[C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[CH2:3][CH2:2]1.[Br:26]N1C(=O)CCC1=O>CN(C=O)C.O>[Br:26][C:7]1[C:8]2[C:13](=[CH:12][C:11]([O:14][CH2:15][CH3:16])=[CH:10][CH:9]=2)[N:5]([CH2:4][CH:1]2[CH2:3][CH2:2]2)[C:6]=1[C:17]1[CH:18]=[CH:19][C:20]([N+:23]([O-:25])=[O:24])=[CH:21][CH:22]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOc1ccc2cc(-c3ccc([N+](=O)[O-])cc3)n(CC3CC3)c2c1
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc2c(Br)c(-c3ccc([N+](=O)[O-])cc3)n(CC3CC3)c2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 87.9 %

Procedure:
To 1-cyclopropylmethyl-6-ethoxy-2-(4-nitro-phenyl)-1H-indole (200 mg, 0.6 mmol) in DMF (2.5 mL) was added a solution of N-bromosuccinimide (107 mg, 0.6 mmol) in DMF (1.5 mL) dropwise. The reaction mixture was stirred at room temperature for 90 minutes. The reaction mixture was diluted in H2O and extracted with EtOAc. The organic layer was washed with H2O and brine and then dried, concentrated and purified by silica gel chromatography (1:1 CH2Cl2/hexane) to provide 3-bromo-1-cyclopropylmethyl-6-ethoxy-2-(4-nitro-phenyl)-1H-indole (219 mg, 88%) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[N:20][C:21]([CH2:24][N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[CH:22][CH:23]=1.[Cl:30][C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[C:33]([Cl:46])[C:32]=1[OH:47]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C:18]2[CH:19]=[N:20][C:21]([CH2:24][N:25]4[CH2:26][CH2:27][CH2:28][CH2:29]4)=[CH:22][CH:23]=2)=[CH:3][C:2]([C:35]2[CH:36]=[C:31]([Cl:30])[C:32]([OH:47])=[C:33]([Cl:46])[CH:34]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:16][CH2:15]1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: O=C(c1cnc2ccc(Br)cc2c1Nc1ccc(CN2CCCC2)nc1)C1CC1
Product: O=C(c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1ccc(CN2CCCC2)nc1)C1CC1
Yield: 63.7 %

Procedure:
Following general procedure F, {6-Bromo-4-[6-(pyrrolidin-1-ylmethyl)pyridin-3-ylamino]quinolin-3-yl}(cyclopropyl)methanone (45 mg, 0.100 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (43 mg, 0.150 mmol) to afford the desired product (34 mg, 64%) as a yellow solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.40 (s, 1H), 8.72 (d, J=2.5 Hz, 1H), 8.30 (dd, J=8.8, 2.0 Hz, 1H), 8.16-8.06 (m, 2H), 7.96 (dd, J=8.3, 2.5 Hz, 1H), 7.65 (d, J=8.3 Hz, 1H), 7.46 (s, 2H), 4.65 (s, 2H), 3.63-3.59 (m, 2H), 3.21-3.12 (m, 2H), 2.85-2.76 (m, 1H), 2.20-2.16 (m, 2H), 2.09-2.01 (m, 2H), 1.20-1.10 (m, 4H); ESI MS m/z 533 [C29H26Cl2N4O2+H]+; HPLC 98.8% (AUC), tR=10.76 min.
Reaction SMILES: [CH2:1]([NH2:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[Br:9][CH2:10][C:11](Br)=[O:12]>C1COCC1>[Br:9][CH2:10][C:11]([NH:8][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])=[O:12]
Reactant: O=C(Br)CBr
Reactant: CCCCCCCN
Solvent: C1CCOC1
Product: CCCCCCCNC(=O)CBr
Yield: 99.9 %

Procedure:
To a solution of n-heptylamine (2.30 g, 20 mmol) in THF (20 ml) was dropped a solution of bromoacetyl bromide (2.02 g, 10 mmol) in THF (10 ml) with ice-cooling and stirring and the mixture was stirred at 0° C. for 1 hour. The reaction solution was concentrated in vacuo, water was added to the residue and the mixture was extracted with ether. The organic layer was washed with water and a saturated sodium chloride solution successively and dried over anhydrous sodium sulfate and the solvent was evaporated therefrom to provide 2.36 g (yield 99%) of crude 2-bromo-N-heptylacetamide as oil.
Reaction SMILES: [C:1]([O:9][C:10]1[C:20](=[O:21])[N:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:13]2=[N:12][C:11]=1[C:22]([O:24][CH3:25])=[O:23])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:26]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[C:1]([O:9][C:10]1[C:20](=[O:21])[N:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([Br:26])[C:13]2=[N:12][C:11]=1[C:22]([O:24][CH3:25])=[O:23])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1nc2n(c(=O)c1OC(=O)c1ccccc1)CCCCC2
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1nc2n(c(=O)c1OC(=O)c1ccccc1)CCCCC2Br
Temperature: 25 °C

Procedure:
A mixture of methyl 3-(benzoyloxy)-4-oxo-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepine-2-carboxylate, N-bromo-succinimide (2 eq.) and α,α′-azoisobutyronitrile (0.45 eq.) in carbon tetrachloride was stirred under reflux for 14 hour. The mixture was cooled to room temperature, the succinimide was filtered off and the solvent was removed under reduced pressure. Methyl 3-(benzoyloxy)-10-bromo-4-oxo-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepine-2-carboxylate was obtained after flash chromatography (eluents petroleum ether/ethyl acetate, 8:2) as a pale yellow solid.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH:10]1([NH2:15])[CH2:14][CH2:13][CH2:12][CH2:11]1.CCN(C(C)C)C(C)C>CCO>[Br:1][C:2]1[C:3]([NH:15][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: NC1CCCC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ncc(Br)c(NC2CCCC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
In a large sealed tube is added 5-bromo-2,4-dichloropyrimidine (3 g, 13.2 mmol) in 100 mL of EtOH. Then cyclopentyl amine (1.95 mL, 19.75 mmol) and N,N′-diisopropylethylamine (3.36 mL, 19.8 mmol) are added to the solution at rt. The solution is then stirred rt overnight. Solvent is evaporated and the crude is purified using silica gel chromatography (15% ethyl acetate/85% hexane) to give (5-bromo-2-chloro-pyrimidin-4-yl)-cyclopentyl-amine as a white solid (3.25 g, 89%). MS (ESI) m/z 278.4 (M+H)+