Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][CH:3]=1.[CH2:9]([OH:12])[C:10]#[CH:11]>C(NCC)C.[Cu]I>[I:8][C:5]1[CH:6]=[CH:7][C:2]([C:11]#[C:10][CH2:9][OH:12])=[CH:3][CH:4]=1
Reactant: Ic1ccc(I)cc1
Reactant: C#CCO
Agent: [Cu]I
Solvent: CCNCC
Product: OCC#Cc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.4 %

Procedure:
A mixture of 1,4-diiodobenzene (24.7 g), propargyl alcohol (1.68 g), BTPC (0.21 g) and CuI (28 mg) in diethylamine (180 ml) was stirred at room temperature under nitrogen for 18 h. The solvent was evaporated in vacuo at 35°, the residual solid taken up in MC (200 ml) and the solution washed with 2N hydrochloric acid (150 ml). The aqueous phase was extracted with further MC (75 ml), the organic layers combined, dried and purified by FCC eluting with EA-CX (1:6) and then EA-CX (1:3) to yield the title compound as a fawn crystalline solid (4.9 g) m.p. 101°-102°.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6](F)[CH:5]=1.C(N(C(C)C)CC)(C)C.[CH2:24]([NH2:28])[CH2:25][CH2:26][CH3:27]>CN(C=O)C>[CH3:1][NH:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([NH:28][CH2:24][CH2:25][CH2:26][CH3:27])[CH:5]=1
Reactant: CCCCN
Reactant: CNC(=O)c1ccc([N+](=O)[O-])c(F)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCNc1cc(C(=O)NC)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-methyl-3-fluoro-4-nitrobenzamide (300 mg, 1.64 mmol) and diisopropylethylamine (0.43 mL, 2.46 mmol) in DMF (7 mL) was added butylamine (0.203 mL, 2.05 mmol) and the solution was stirred at room temperature overnight. The solution was concentrated, the residue dissolved in ethyl acetate and washed with 1 N HCl. The organic phase was dried over MgSO4 and concentrated to give N-methyl-3-butylamino-4-nitrobenzamide as a yellow oil that was used without further purification (380 mg, 92%).
Reaction SMILES: [NH2:1][CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12])[C:3]#[N:4].[NH:13]=[C:14](SC)[C:15]([O:17][CH2:18][CH3:19])=[O:16]>O1CCOCC1>[NH2:4][C:3]1[NH:13][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:1][C:2]=1[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12]
Reactant: N#CC(N)Cc1ccccc1F
Reactant: CCOC(=O)C(=N)SC
Solvent: C1COCCO1
Product: CCOC(=O)c1nc(Cc2ccccc2F)c(N)[nH]1

Procedure:
A solution of 0.90 g (5.45 mmol) of 2-amino-3-(2-fluorophenyl)propanenitrile from example 8A and 2.20 g (9.27 mmol) of ethyl imino(methylthio)acetate [D. Catarzi et al., J. Med. Chem. 1995, 38, 2196-2201] in 10 ml of dioxane is stirred at RT for two days. The solution is then concentrated in vacuo, and the residue is purified by preparative HPLC. 770 mg (54% of theory) of the desired product are obtained.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH2:11])[CH2:4]2.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1/[CH:19]=[CH:20]/[C:21](O)=[O:22]>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:21](=[O:22])/[CH:20]=[CH:19]/[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[Cl:12])[CH2:4]2
Reactant: N[C@H]1CN2CCC1CC2
Reactant: O=C(O)/C=C/c1ccccc1Cl
Agent: Cl
Product: O=C(/C=C/c1ccccc1Cl)N[C@H]1CN2CCC1CC2

Procedure:
Prepared as a free base by a method analogous to that described in Example 1 from (R)-1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and E-3-(2-chlorophenyl)propenoic acid; MS (ES+) 291 and 293 (MH+).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH:13]([C:15]1[O:16][CH:17]=[C:18]2[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[CH:20][C:19]=12)O.C([SiH](CC)CC)C.C(OCC)(=O)C>FC(F)(F)C(O)=O.[Pt]=O>[NH2:24][C:22]1[CH:23]=[CH:18][C:17]2[O:16][C:15]([CH2:13][C:3]3[N:4]=[C:5]([C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=4)[O:6][C:2]=3[CH3:1])=[CH:19][C:20]=2[CH:21]=1
Reactant: Cc1oc(-c2ccccc2)nc1C(O)c1occ2cc([N+](=O)[O-])ccc12
Agent: O=[Pt]
Agent: CC[SiH](CC)CC
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1oc(-c2ccccc2)nc1Cc1cc2cc(N)ccc2o1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
alpha-(5-Methyl-2-phenyl-4-oxazolyl)-5-nitro-2-benzofuranmethanol (57 g, 0.16 mol) was dissolved in trifluoroacetic acid (350 ml), while cooling to 0° C. Triethylsilane (64 ml, 0.40 mol) was added. The solution was stirred 1.5 hours at 0° C. and overnight at room temperature. The solution was concentrated to near-dryness and the residue dissolved in ethyl acetate (750 ml). This solution was washed with water. The precipitate formed during the wash was collected. The organic solution was washed with satured sodium bicarbonate, during which more precipitate formed and was collected. The ethyl acetate phase of the filtrate was washed again with saturated sodium bicarbonate, then with brine, dried over sodium sulfate and concentrated. The residue was triturated with isopropyl ether and a solid was obtained. The combined solids obtained hereabove (51 g, 0.15 mol) were placed in a Parr bottle together with platinum oxide (3 g) and ethyl acetate (1.5 1) and hydrogenated at 40 psi for 1.25 hours. The catalyst was filtered through Celite, and after washing the filtering pad with more ethyl acetate, the solvent was removed in vacuo to give a yellow residue which was triturated with isopropyl ether (200 ml). The pale yellow solid was collected (37.1 g, mp 161.5°-162.5° C).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1.CCN(C(C)C)C(C)C>C(O)CCC>[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH:19][C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:16][CH:15]=1
Reactant: COc1ccc(CN)cc1
Reactant: FC(F)(F)c1cccnc1Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNc2ncccc2C(F)(F)F)cc1
Temperature: 140 °C
Yield: 83.1 %

Procedure:
A mixture of commercially available 2-chloro-3-trifluoromethylpyridine (64.83 g, 357 mmol), 4-methoxybenzylamine (56 mL, 429 mmol) and DIPEA (73.4 mL, 429 mmol) in n-butanol (100 mL) was refluxed (oil bath temp. 140° C.) for 3.5 days. Concentrated in vacuum, partitioned between 25% HCl and TBME, reextracted the organic layer twice with 25% HCl, the aqueous layer was made alkaline with 32% NaOH, extracted with TBME, washed with brine and dried over Na2SO4. Removal of the solvent in vacuum left a brown oil (105.21 g, >100%). Vacuum distillation gave the product as a colorless liquid (83.766 g, 83%, bp 139-141° C. at 1.4 mbar). MS (ISP) 283.1 [(M+H)+].
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][N:5]([C:13]1[CH:18]=[C:17]([N:19]2[C:23]3[N:24]=[C:25]([N:53]4[CH2:58][CH2:57][O:56][CH2:55][CH2:54]4)[N:26]=[C:27]([C:28]4[CH:29]=[N:30][C:31]([N:34]([CH2:44][C:45]5[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=5)[CH2:35][C:36]5[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][CH:37]=5)=[N:32][CH:33]=4)[C:22]=3[CH2:21][CH2:20]2)[CH:16]=[CH:15][N:14]=1)[C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C(OCC)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[C:9]([O:8][C:6](=[O:7])[N:5]([C:13]1[CH:18]=[C:17]([N:19]2[C:23]3[N:24]=[C:25]([N:53]4[CH2:58][CH2:57][O:56][CH2:55][CH2:54]4)[N:26]=[C:27]([C:28]4[CH:29]=[N:30][C:31]([N:34]([CH2:35][C:36]5[CH:37]=[CH:38][C:39]([O:42][CH3:43])=[CH:40][CH:41]=5)[CH2:44][C:45]5[CH:46]=[CH:47][C:48]([O:51][CH3:52])=[CH:49][CH:50]=5)=[N:32][CH:33]=4)[C:22]=3[CH2:21][CH2:20]2)[CH:16]=[CH:15][N:14]=1)[CH2:4][CH2:3][OH:2])([CH3:12])([CH3:10])[CH3:11]
Reactant: COC(=O)CN(C(=O)OC(C)(C)C)c1cc(N2CCc3c(-c4cnc(N(Cc5ccc(OC)cc5)Cc5ccc(OC)cc5)nc4)nc(N4CCOCC4)nc32)ccn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccnc(N(CCO)C(=O)OC(C)(C)C)c3)cn2)cc1
Temperature: 0 °C
Yield: 56 %

Procedure:
A THF solution (5 ml) of {[4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-pyridin-2-yl]-tert-butoxycarbonyl-amino}-acetic acid methyl ester (135 mg, 0.168 mmol) obtained in Step B was cooled to −40°, and 1.0M diethyl ether solution (0.20 ml, 0.20 mmol) of lithium aluminium hydride was added, which was gradually raised to 0° C. over 1 hour. The reaction mixture was quenched with aqueous potassium sodium tartrate solution, followed by extraction with dichloromethane (15 ml×2). The organic layers were combined, and washed with saturated aqueous sodium chloride solution. After the organic layer was dried over magnesium sulfate, the magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=50:1), to obtain [4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-pyridin-2-yl]-(2-hydroxy-ethyl)-carbamic acid tert-butyl ester as a yellow solid (73 mg, 56%).
Reaction SMILES: [CH2:1]([S:3]([CH2:6][CH2:7][CH2:8][C:9]12[CH2:16][CH2:15][C:12]([C:17]([OH:19])=O)([CH2:13][CH2:14]1)[CH2:11][CH2:10]2)(=[O:5])=[O:4])[CH3:2].C(Cl)(=O)C(Cl)=O.[CH3:26][NH2:27]>C(Cl)Cl.CN(C=O)C>[CH2:1]([S:3]([CH2:6][CH2:7][CH2:8][C:9]12[CH2:16][CH2:15][C:12]([C:17]([NH:27][CH3:26])=[O:19])([CH2:13][CH2:14]1)[CH2:11][CH2:10]2)(=[O:5])=[O:4])[CH3:2]
Reactant: CN
Reactant: CCS(=O)(=O)CCCC12CCC(C(=O)O)(CC1)CC2
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCS(=O)(=O)CCCC12CCC(C(=O)NC)(CC1)CC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Carboxylic acid 11-8 (3.0 g, 11 mmol) was dissolved in 50 mL of anhydrous methylene chloride under nitrogen atmosphere, treated with oxalyl chloride (2 M in methylene chloride, 16.2 mL, 32.4 mmol) and subsequently with 5 drops of DMF. The reaction was stirred at room temperature under nitrogen atmosphere for 90 min, then evaporated and placed under vacuum for 20 min. The acid chloride was dissolved in anhydrous methylene chloride (12 mL), cooled in an ice-bath, and then treated dropwise with a solution of methylamine (2M in THF, 27 mL, 54 mmol). Upon addition of the methylamine, the cooling bath was removed and the reaction stirred at ambient temperature for 30 min. The mixture was diluted with 200 mL of methylene chloride and washed with 1N aqueous HCl, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was subjected to chromatography on silica gel eluting with a gradient from 0 to 3% methanol in ethyl acetate to give 4-[3-(ethylsulfonyl)propyl]-N-methylbicyclo[2.2.2]octane-1-carboxamide 11-9 as a white powder. MS (ESI+)=302 (M+1).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][C:18]1[C:19]([CH:25]([CH3:27])[CH3:26])=[N:20][CH:21]=[CH:22][C:23]=1[Cl:24]>CN(C=O)C>[Cl:24][C:23]1[CH:22]=[CH:21][N:20]=[C:19]([CH:25]([CH3:26])[CH3:27])[C:18]=1[CH2:17][S:8][C:6]1[N:5]=[C:4]([OH:9])[CH:3]=[C:2]([CH3:1])[N:7]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: CC(C)c1nccc(Cl)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(O)nc(SCc2c(Cl)ccnc2C(C)C)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.7 %

Procedure:
6-methyl-2-sulfanylpyrimidin-4-ol (434 mg, 3.0 mmol) was dissolved in anhydrous DMF (15 mL), and then potassium carbonate (1.27 g, 9.2 mmol) and 3-(bromomethyl)-4-chloro-2-(propan-2-yl)pyridine (4.0 mmol) in DMF (5 mL) were added. The mixture was stirred overnight at room temperature. The solid was removed by filtration and washed with methanol, and the filtrate was evaporated. The residue was dissolved in DCM/MeOH and purified on silica gel using 5-10% DCM/MeOH to afford 2-({[4-chloro-2-(propan-2-yl)pyridin-3-yl]methyl}sulfanyl)-6-methylpyrimidin-4-ol (239 mg, 25% yield for 2 steps); 1H NMR (400 MHz, DMSO-d6): δ 1.20 (d, J=6.7 Hz, 6H), 2.23 (bs, 3H), 3.50-3.57 (m, 1H), 4.65 (s, 2H), 6.00 (bs, 1H), 7.43 (d, J=5.2 Hz, 1H), 8.45 (d, J=5.2 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:9]([CH:10]=1)[N:8]=[C:7]([S:11][CH3:12])[N:6]=[C:5]2Cl.[BH4-].[Na+].C(Cl)Cl>C(O)(C)C>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]([CH:10]=1)[N:8]=[C:7]([S:11][CH3:12])[N:6]=[CH:5]2
Reactant: CSc1nc(Cl)c2cc(Br)cn2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: CSc1ncc2cc(Br)cn2n1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
Into a round bottom flask, 6-Bromo-4-chloro-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (6.00 g, 21.5 mmoles) was suspended in Isopropyl alcohol (69 mL) at 55° C. Sodium borohydride (1.71 g, 0.0452 mol) was added and heated at 60° C. for 3 hours. The reaction was allowed to cool to RT. The solid was filtered and washed with DCM. The solvent was removed under vacuum to a viscous oil. Methylene chloride (100 mL, 2 mol) was added to the viscous oil. Dichlorodicyanoquinone (5.38 g, 0.0237 mol) was then added portion wise over 15 minutes. The mixture was stirred for 30 minutes. The solid was filtered through Celite and washed with DCM. The solvent was removed under vacuum. The reaction was purified via ISCO column chromatography with hexane and EtOAca as eluant (0 to 8% EtOAC). The collected fractions afforded 6-Bromo-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine as a light yellow solid (1.46, 27%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[CH:16]=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:14]3[C:24](=[O:28])[NH:25][C:26](=[O:27])[C:13]=3[C:12]=2[C:11]2[CH:10]=[C:9]([OH:29])[CH:8]=[CH:7][C:6]1=2.[NH:30]1[CH:34]=[CH:33][N:32]=[CH:31]1>>[OH:29][C:9]1[CH:8]=[CH:7][C:6]2[N:5]([CH2:4][CH2:3][CH2:2][N:30]3[CH:34]=[CH:33][N:32]=[CH:31]3)[C:17]3[CH:16]=[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:14]4[C:24](=[O:28])[NH:25][C:26](=[O:27])[C:13]=4[C:12]=3[C:11]=2[CH:10]=1
Reactant: O=C1NC(=O)c2c1c(-c1ccccc1)cc1c2c2cc(O)ccc2n1CCCBr
Reactant: c1c[nH]cn1
Product: O=C1NC(=O)c2c1c(-c1ccccc1)cc1c2c2cc(O)ccc2n1CCCn1ccnc1
Yield: 53 %

Procedure:
Bromide (204) (80 mg, 0.18 mmol) prepared as described in example 173 was reacted with imidazole according to the procedure described in example 179 to give amine (212) (41 mg, 53%) as a yellow powder, mp 309–311° C. 1H NMR δ [(CD3)2SO] 11.06 (s, 1H), 9.36 (s, 1H), 8.40 (d, J=2.3 Hz, 1H), 7.69 (s, 1H), 7.64 (m, 3H), 7.47 (m, 4H), 7.22 (s, 1H), 7.14 (dd, J=8.8, 2.3 Hz, 1H), 6.89 (s, 1H), 4.44 (t, J=7.4 Hz, 2H), 4.07 (t, J=7.3 Hz, 2H), 2.24 (m, 2H). Found: C, 70.31; H, 4.78; N, 12.43. C26H20N4O3.1/2H2O requires: C, 70.10; H, 4.75; N, 12.57.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[C:12]([CH3:24])=[N:13][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[CH:15]=3)=[CH:9][N:8]([S:25]([C:28]3[CH:34]=[CH:33][C:31]([CH3:32])=[CH:30][CH:29]=3)(=[O:27])=[O:26])[C:5]2=[N:6][CH:7]=1.[F:35][C:36]1[CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:39]=[CH:38][C:37]=1[C:51]1[CH2:56][CH2:55][N:54]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:53][CH:52]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[F:35][C:36]1[CH:41]=[C:40]([C:2]2[CH:3]=[C:4]3[C:10]([C:11]4[C:12]([CH3:24])=[N:13][N:14]([CH2:16][C:17]5[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=5)[CH:15]=4)=[CH:9][N:8]([S:25]([C:28]4[CH:29]=[CH:30][C:31]([CH3:32])=[CH:33][CH:34]=4)(=[O:26])=[O:27])[C:5]3=[N:6][CH:7]=2)[CH:39]=[CH:38][C:37]=1[C:51]1[CH2:56][CH2:55][N:54]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:53][CH:52]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2F)CC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cn(Cc4cccc(F)c4)nc3C)c3cc(Br)cnc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cn(Cc4cccc(F)c4)nc3C)c3cc(-c4ccc(C5=CCN(C(=O)OC(C)(C)C)CC5)c(F)c4)cnc32)cc1
Yield: 61.8 %

Procedure:
Using similar reaction conditions as described in step-i of example-1, 5-bromo-3-(1-(3-fluorobenzyl)-3-methyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (300 mg, 0.55 mmol) was coupled with tert-butyl 4-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (intermediate 70) (270 mg, 0.66 mmol) using sodium carbonate (175 mg, 1.65 mmol) and Pd(PPh3)2Cl2 (20 mg, 0.027 mmol) in DME/water (10/2.5 ml) to afford 250 mg (61.2% yield) of the pure product after column purification using 50% ethyl acetate in hexane as eluent. MS: m/z=736.4 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:12])=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5](Cl)=[O:6].[Si:13]([O:20][CH2:21][CH2:22][NH:23][CH3:24])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].[OH-].[Na+]>C(Cl)Cl>[Si:13]([O:20][CH2:21][CH2:22][N:23]([CH3:24])[C:5](=[O:6])[C:4]1[CH:8]=[CH:9][C:10]([F:11])=[C:2]([Cl:1])[C:3]=1[F:12])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:14])[CH3:15]
Reactant: CNCCO[Si](C)(C)C(C)(C)C
Reactant: O=C(Cl)c1ccc(F)c(Cl)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1ccc(F)c(Cl)c1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 68.2 %

Procedure:
3-Chloro-2,4-difluorobenzoyl chloride (1.92 g, 9.1 mmol) was added slowly to a stirred solution of (2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)methylamine (1.89 g, 10.0 mmol) in a 1:1 mixture of 10% sodium hydroxide solution and DCM at 0° C. The reaction mixture was then allowed to warm up to RT and left to stir for 5 hours. The phases were separated and the aqueous phase was extracted with DCM (3×50 mL). The combined extracts were dried (MgSO4), filtered and evaporated to give a pale yellow oil. Purification by column chromatography on silica, eluting with 0-50% ethyl acetate in hexanes, gave the title compound as a colourless oil (2.26 g) 1H NMR δ (CDCl3): 0.00 (s, 6H), 0.82 (s, 9H), 2.93 (s, 3H), 3.58 (t, 2H), 3.81 (t, 2H), 6.95 (dtd, 1H), 7.16-7.22 (m, 1H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.[C:20](Cl)(=[O:22])[CH3:21].O>N1C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:20](=[O:22])[CH3:21])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1
Reactant: Cc1ccc(F)cc1-c1ccc2cc(N)ncc2c1
Reactant: CC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Nc1cc2ccc(-c3cc(F)ccc3C)cc2cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 15.2 %

Procedure:
To a solution of 7-(5-fluoro-2-methylphenyl)isoquinolin-3-amine (150 mg, 0.595 mmol) in pyridine (2 mL) was added acetyl chloride (56 mg, 0.714 mmol) dropwise at a temperature below 0° C. After the resulting mixture was stirred at room temperature for 2 h, water (2 mL) was added and it was concentrated under reduced pressure. The solid was washed with methanol and water to give the desired product (26.7 mg, 15.2%). LCMS (ESI): RT (min)=1.150, M+H+=294.8, method=A; 1H NMR (400 MHz, DMSO-d6) δ 10.62, (s, 1H), 9.14 (s, 1H), 8.47 (s, 1H), 8.00 (s, 1H), 7.93 (d, J=8.0 Hz, 1H), 7.68 (d, J=6.8 Hz, 1H), 7.35 (s, 1H), 7.15 (d, J=8.8 Hz, 2H), 2.22 (s, 3H), 2.12 (s, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=2[Cl:18])[C:8]([CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:7][N:6]=1.Cl[C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][N:28]=1>>[Cl:18][C:12]1[CH:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]=1[C:9]1[C:8]([CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:7][N:6]=[C:5]([NH:4][CH2:3][CH2:2][NH:1][C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][N:28]=2)[N:10]=1
Reactant: NCCNc1ncc(CN2CCOCC2)c(-c2ccc(Cl)cc2Cl)n1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Product: O=[N+]([O-])c1ccc(NCCNc2ncc(CN3CCOCC3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Yield: 60 %

Procedure:
Using the conditions described in the previous example, (2-aminoethyl)[4-(2,4-dichlorophenyl)-5-(morpholin-4-ylmethyl)pyrimidin-2-yl]amine and 9.7 mg (0.061 mmol) of 2-chloro-5-nitropyridine gave [4-(2,4-dichlorophenyl)-5-(morpholin-4-ylmethyl)pyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine in 60% yield following chromatography (silica gel, 5% methanol/methylene chloride).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]([Cl:12])([Cl:11])[CH:5]([OH:10])[C:6]([Cl:9])([Cl:8])[Cl:7].O.S(OC)(O[CH3:18])(=O)=O>>[CH:5]([O:10][CH3:18])([C:6]([Cl:9])([Cl:8])[Cl:7])[C:4]([Cl:12])([Cl:11])[Cl:3]
Reactant: OC(C(Cl)(Cl)Cl)C(Cl)(Cl)Cl
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(C(Cl)(Cl)Cl)C(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.5 %

Procedure:
A 50% NaOH solution, 9.9 g (0.12 mole), was added to a mixture of 33.0 g (0.12 mole) of 1,1,1,3,3,3-hexachloro-2-propanol and 44.5 g (2.47 moles) of water at 0°-10° C. over 30 minutes. This cold mixture was warmed to room temperature and 15.6 g (0.12 mole) of dimethyl sulfate was added slowly at 20°-25° C. over 30 minutes. The reaction mixture was stirred for another 2 hours at room temperature. The crude product was washed with dilute NaOH solution, water and saturated NaCl solution to yield 29.5 g of a colorless liquid. Fractional distillation of the liquid at 93°-93.5° C. and 5 mm Hg gave 26.2 g of the methyl ether at 98.7% purity by GC analysis. This represents a 74.5% yield. The product was purified further by a second distillation to afford greater than 99.6% of purity. Elemental analysis: C4H4Cl6O Calculated C 17.11%, H 1.43%, Cl 75.75%. Found C 17.03%, H 1.43%, Cl 75.31%. ηD20 1.5195.
Reaction SMILES: [H-].[Na+].[C:3](#[N:7])[CH2:4][C:5]#[N:6].I[C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH2:16])=[CH:11][CH:10]=1.Cl>COCCOC.C1COCC1>[CH:15]([C:12]1[CH:13]=[CH:14][C:9]([CH:4]([C:3]#[N:7])[C:5]#[N:6])=[CH:10][CH:11]=1)=[CH2:16]
Reactant: C=Cc1ccc(I)cc1
Reactant: N#CCC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COCCOC
Product: C=Cc1ccc(C(C#N)C#N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
To an ice-cooled suspension of NaH (0.792 g, 33.0 mmol) in anhydrous 1,2-dimethoxyethane (20 mL) was added dropwise via syringe a solution of malononitrile (0.99 g, 15 mmol) in anhydrous 1,2-dimethoxyethane (5 mL) under N2. The mixture was stirred for 1 h at room temperature under N2. Next, 1-iodo-4-vinyl-benzene (1.15 g, 5.00 mmol), dry THF (15 mL), and tetrakis(triphenyphophine)palladium(0) (0.58g, 0.50 mmol) were added to the resulting pink suspension under an N2 flow, and the reaction mixture stirred at 85° C. for 2 h. After cooling to room temperature, the reaction mixture was poured into ice, neutralized with 10% HCl, and extracted with CH2Cl2 (100 mL). The organic layer was separated, dried over anhydrous Na2SO4, and concentrated in vacuo. The crude product was then purified by flash chromatography on silica gel eluting with 1:1 hexane: CH2Cl2, to give 0.603 g (71.8%) of the title compound as pale yellow solid: mp 40-42° C. ° C; 1H NMR (400 MHz, CDCl3): δ 7.526 (d, 2H, J=7.6 Hz), 7.462 (d, 2H, J=7.6 Hz), 6.738 (d×d, 1H, J1=17.6 Hz, J2=10.8 Hz), 5.846 (d, 1H, J=17.6 Hz), 5.398 (d, 1H, J=10.8 Hz), 5.075 (s, 1H); 13C NMR (100 MHz, CDCl3): δ 139.840, 135.372, 127.766, 127.556, 125.245, 116.619, 111.897, 28.050; Anal. Calcd. for C11H8N2: C, 78.55; H, 4.79; N, 16.66. Found; C, 78.76; H, 4.75; N, 16.02.