Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1O[C:6](=[O:8])[C:5]2[CH:9]=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:4]=2[N:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([Mg]Br)=[CH:18][CH:17]=1>C1(C)C=CC=CC=1.CCOCC>[NH2:3][C:4]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:5]=1[C:6]([C:19]1[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=1)=[O:8]
Reactant: COc1ccc2nc(C)oc(=O)c2c1
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: COc1ccc(N)c(C(=O)c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-methyl-6-(methyloxy)-4H-3,1-benzoxazin-4-one (for a preparation see Reference compound A) (40.0 g, 0.21 mol) in a toluene/ether (2/1) mixture (760 ml) at 0° C. was added dropwise a solution of 4-chlorophenylmagnesium bromide (170 ml, 1M in diethyl ether, 0.17 mol). The reaction mixture was allowed to warm to room temperature and stirred for 1 h before being quenched with 1N HCl (200 ml). The aqueous layer was extracted with EtOAc (3×150 ml) and the combined organics were washed with brine (100 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude compound was then dissolved in ethanol (400 ml) and 6N HCl (160 ml) was added. The reaction mixture was refluxed for 2 h before being concentrated to one-third in volume. The resulting solid was filtered and washed twice with ether before being suspended in EtOAc and neutralised with 1N sodium hydroxide. The aqueous layer was extracted with EtOAc (3×150 ml) and the combined organics were washed with brine (150 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The title compound was obtained as a yellow solid (39 g, 88% yield) LC/MS (Method D): m/z 262 [M+H]+, Rt 2.57 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:14][O:15]CC3CCCCC3)[C:11]3[CH:29]=[C:30]([F:34])[C:31]([F:33])=[CH:32][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.Br[CH2:36][C:37]1[CH:46]=[CH:45][C:40]([C:41]([O:43][CH3:44])=[O:42])=[CH:39][C:38]=1[O:47][CH3:48]>>[CH3:44][O:43][C:41](=[O:42])[C:40]1[CH:45]=[CH:46][C:37]([CH2:36][O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:29]=[C:30]([F:34])[C:31]([F:33])=[CH:32][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[C:38]([O:47][CH3:48])[CH:39]=1
Reactant: Fc1cc2nc(-c3ccc(Cl)cc3)n(C(COCC3CCCCC3)C3CCCCC3)c2cc1F
Reactant: COC(=O)c1ccc(CBr)c(OC)c1
Product: COC(=O)c1ccc(COCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(OC)c1

Procedure:
The title compound was prepared in analogy to Example 26, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Example 1, intermediate c) and methyl 4-(bromomethyl)-3-methoxybenzoate (commercially available), to give the compound as light yellow solid (73%). MS (Turbo Spray): m/z=569.4 [M+H].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH3:14].CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.[Cl:34][C:35]1[CH:36]=[C:37]([S:42](Cl)(=[O:44])=[O:43])[CH:38]=[CH:39][C:40]=1[CH3:41]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([S:42]([C:37]2[CH:38]=[CH:39][C:40]([CH3:41])=[C:35]([Cl:34])[CH:36]=2)(=[O:43])=[O:44])[C:6]=1[CH3:14]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1Cl
Reactant: COC(=O)Cc1c(C)[nH]c2ncccc12
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)n(S(=O)(=O)c2ccc(C)c(Cl)c2)c2ncccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester (0.06 g, 0.294 mmol) in DMF (0.5 mL) is added a solution of BEMP (0.136 mL, 0.47 mmol) in DMF (0.5 mL). After 1 hour, a solution of 3-chloro-4-methyl-benzenesulfonyl chloride (0.105 g, 0.47 mmol) in DMF (0.5 mL) is added. The reaction mixture is stirred at room temperature overnight, then concentrated under reduced pressure to a minimum volume. The residue is loaded on a pre-packed Isolute™ silica column and eluted using a gradient eluent from 100% iso-hexane to 30% ethyl acetate in iso-hexane to afford [1-(3-chloro-4-methyl-benzenesulfonyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester; MH+=393.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:26]=[CH:25][C:17]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][OH:24])=[CH:16][C:15]=3[CH3:27])=[CH:7][C:6]=2[C:5]2[CH:28]=[CH:29][C:30]([CH3:32])=[CH:31][C:4]=2[N:3]=1.BrCCOCCO[CH2:40][CH2:41][CH2:42][P:43](=[O:50])([O:47][CH2:48][CH3:49])[O:44][CH2:45][CH3:46]>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:26]=[CH:25][C:17]([O:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:40][CH2:41][CH2:42][P:43](=[O:50])([O:47][CH2:48][CH3:49])[O:44][CH2:45][CH3:46])=[CH:16][C:15]=3[CH3:27])=[CH:7][C:6]=2[C:5]2[CH:28]=[CH:29][C:30]([CH3:32])=[CH:31][C:4]=2[N:3]=1
Reactant: CCOP(=O)(CCCOCCOCCBr)OCC
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OCCOCCO)cc3C)cc12
Product: CCOP(=O)(CCCOCCOCCOc1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)c(C)c1)OCC

Procedure:
Diethyl 3-(2-(2-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)ethoxy)ethoxy)propylphosphonate was prepared from following the procedure described for Example 139, but using 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenol (from Example 148) and diethyl 3-(2-(2-bromoethoxy)ethoxy)propylphosphonate 1H NMR (Acetone-d6): δ 8.75 (s, 1H), 8.70 (s, 1H), 8.26 (d, 1H), 7.42 (s, 1H), 7.16 (d, 1H), 7.09 (d, 1H), 6.77 (s, 1H), 6.71 (d, 1H), 6.58 (br, 2H), 3.95-4.11 (m, 6H), 3.76-3.80 (m, 2H), 3.63-3.67 (m, 2H), 3.55-3.58 (m, 2H), 3.57-3.51 (m, 2H), 3.14-3.18 (m, 2H), 3.04-3.05 (m, 2H), 2.46 (s, 3H), 2.29 (s, 3H), 1.71-1.87 (m, 4H), 1.22-1.29 (m, 8H). LRMS [M+H]=610.3.
Reaction SMILES: [BH4-].[Na+].[I-].[CH3:4][O:5][C:6]1[CH:7]=[N+:8]([CH3:25])[CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([O:21][CH:22]([CH3:24])[CH3:23])[CH:13]=1.O.C(OCC)(=O)C>C(O)C>[CH3:4][O:5][C:6]1[CH2:7][N:8]([CH3:25])[CH2:9][CH2:10][C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[C:14]([O:21][CH:22]([CH3:24])[CH3:23])[CH:13]=1
Reactant: COc1c[n+](C)ccc1-c1ccc([N+](=O)[O-])c(OC(C)C)c1
Agent: [BH4-]
Agent: [I-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: COC1=C(c2ccc([N+](=O)[O-])c(OC(C)C)c2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
672 mg of NaBH4 are added, in portions, to a suspension of 5.09 g of 3-methoxy-1-methyl-4-[4-nitro-3-(propan-2-yloxy)phenyl]pyridinium iodide in 90 ml of ethanol brought to 5° C. the reaction medium is stirred for 30 minutes at ambient temperature. 50 ml of water and 100 ml of ethyl acetate are added. The two phases are separated, and the aqueous phase is washed with twice 50 ml of ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered and evaporated. Purification is carried out by flash chromatography on silica gel (40-63 μm), elution being carried out with a mixture of dichloromethane and acetone (95/5 to 80/20). 2.78 g of 5-methoxy-1-methyl-4-[4-nitro-3-(propan-2-yloxy)phenyl]-1,2,3,6-tetrahydropyridine are obtained in the form of a brown oil.
Reaction SMILES: [C:1]12([C:11]3[N:12]([CH2:22][C:23]([NH:25][C:26]([NH2:28])=[NH:27])=[O:24])[C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:14][CH:15]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C(N(CC)CC)C.[CH2:36]([S:38](Cl)(=[O:40])=[O:39])[CH3:37]>C(Cl)Cl>[C:1]12([C:11]3[N:12]([CH2:22][C:23](/[N:25]=[C:26](/[NH2:28])\[NH:27][S:38]([CH2:36][CH3:37])(=[O:40])=[O:39])=[O:24])[C:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:14][CH:15]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: N=C(N)NC(=O)Cn1c(-c2ccccc2)ccc1C12CC3CC(CC(C3)C1)C2
Reactant: CCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)N/C(N)=N\C(=O)Cn1c(-c2ccccc2)ccc1C12CC3CC(CC(C3)C1)C2
Reaction time: 0.21 h

Procedure:
A solution of 1 equivalent of N-[2-(2-adamantan-1-yl-5-phenyl-pyrrol-1-yl)-acetyl]-guanidine in 2.0 mL CH2Cl2 was cooled to 7° C. To the solution 1.0 equivalent of triethylamine was added. The reaction was stirred for 10-15 minutes, after which time ethylsulfonyl chloride was added. The reaction was concentrated and the residue is dissolved in a mixture of DMSO, MeOH and water (1.5 mL total) and purified by Gilson preparative HPLC system. HPLC conditions: YMC Pro C18 column, 20 mm×50 mm ID, 5 uM; 2 mL injection; Solvent A: Water (0.05% NH4OH buffer); Solvent B: acetonitrile (0.05% NH4OH buffer); Gradient: Time 0: 5% B; 2 min: 5% B; 12 min: 95% b, Hold 95% B 3 min; Flow rate 22.5 mL/min; Detection: 254 nm DAD. [M+H] 469, retention time 2.7 min.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]#N)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:18].[Na+].C[OH:21]>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([OH:21])=[O:18])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: [OH-]
Reactant: N#CCc1ccc(OCc2ccccc2)cn1
Agent: [Na+]
Product: O=C(O)Cc1ccc(OCc2ccccc2)cn1
Yield: 89 %

Procedure:
To a solution of 1.45 g (6.46 mmol) [5-(benzyloxy)-2-pyridinyl]acetonitrile (obtained in 6 steps from 6-methyl-3-pyridinol, see: W. M. Golebiewski and J. T. Wrobel, Bull. Pol. Acad. Sci., 1990, 38, 17) in MeOH (9 mL) was added 25% NaOH (3 mL). The reaction mixture was stirred at reflux for 48 h. After being cooled, most of the MeOH was removed in vacuo, water (10 mL) was added and the aqueous solution was washed with diethyl ether (2×10 mL) followed by acidification (pH ˜6.0). The mixture was extracted with EtOAc (3×20 mL), dried over MgSO4 and concentrated to give pale yellow crystals (1.4 g, 89%). MS (ESI) (M+H)+=244.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][NH:7][C:8]1[C:9]([N+:25]([O-])=O)=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[N:13]([CH2:19][CH2:20][O:21][C:22](=[O:24])[CH3:23])[CH:12]=[CH:11]2)(=[O:3])[CH3:2].C(O)C.[Cl-].[NH4+].O>[Fe].C(Cl)Cl>[C:1]([O:4][CH2:5][CH2:6][NH:7][C:8]1[C:9]([NH2:25])=[C:10]2[C:15](=[CH:16][CH:17]=1)[C:14](=[O:18])[N:13]([CH2:19][CH2:20][O:21][C:22](=[O:24])[CH3:23])[CH:12]=[CH:11]2)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCNc1ccc2c(=O)n(CCOC(C)=O)ccc2c1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: CC(=O)OCCNc1ccc2c(=O)n(CCOC(C)=O)ccc2c1N
Reaction time: 1 h

Procedure:
A mixture of 2-(2-(2-acetoxyethyl)-5-nitro-1-oxo-1,2-dihydroisoquinolin-6-ylamino)ethyl acetate (350 mg, 0.00093 mol), ethanol (20 mL, 0.3 mol), ammonium chloride (496.1 mg, 0.009275 mol) and water (10 mL, 0.6 mol) was added at 85° C. Iron (207 mg, 0.00371 mol) was added in two portions five minutes apart and the reaction was stirred at that temperature for 1 hour. The reaction mixture was then poured into methylene chloride (100 mL) and the layers were separated and the organic layer was washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure and used for the next reaction without purification. MS m/z=348.5 (M+H).
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[F:11])[CH2:3][NH2:4].C[C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20](=O)[CH3:21])=[CH:15][CH:14]=1.[CH:23]1C=CC=CC=1>>[CH3:23][C:15]1[CH:14]=[CH:13][CH:18]=[CH:17][C:16]=1[CH2:19][CH:20]([NH:4][CH2:3][CH:2]([OH:1])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[F:11])[CH3:21]
Reactant: c1ccccc1
Reactant: CC(=O)Cc1ccc(C)cc1
Reactant: NCC(O)c1ccccc1F
Product: Cc1ccccc1CC(C)NCC(O)c1ccccc1F

Procedure:
A mixture of 2-hydroxy-2-(2-fluorophenyl)ethanamine (1.54 g) and 4-methylphenylacetone (1.48 g) was refluxed in benzene (70 ml) under Dean & Stark conditions for 4h. The solvent was removed under reduced pressure, replaced with methanol and sodium borohydride (3 g) added portionwise. The solvent was evaporated under reduced pressure, the residue partitioned between water and ether and the ether layer dried (MgSO4). Removal of the solvent under reduced pressure gave an oil which was chromatographed on Kieselgel 60. Elution with 1% methanol-chloroform gave the title compound (1.58 g) as a 49:51 mixture of diastereoisomers, mp 65-68 (hexane).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]#[CH:22])=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:24][O:25][C:26](=[O:55])[NH:27][CH:28]([C:32]([N:34]1[CH2:38][CH2:37][CH2:36][CH:35]1[C:39]1[NH:43][C:42]2[CH:44]=[C:45]([C:48]3[CH:53]=[CH:52][C:51](Br)=[CH:50][CH:49]=3)[CH:46]=[CH:47][C:41]=2[N:40]=1)=[O:33])[CH:29]([CH3:31])[CH3:30].C(N(CC)CC)C.O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I>[CH3:24][O:25][C:26](=[O:55])[NH:27][CH:28]([C:32]([N:34]1[CH2:38][CH2:37][CH2:36][CH:35]1[C:39]1[NH:43][C:42]2[CH:44]=[C:45]([C:48]3[CH:53]=[CH:52][C:51]([C:22]#[C:21][C:18]4[NH:17][C:16]([CH:12]5[CH2:13][CH2:14][CH2:15][N:11]5[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:23])[CH:6]([CH3:8])[CH3:7])=[N:20][CH:19]=4)=[CH:50][CH:49]=3)[CH:46]=[CH:47][C:41]=2[N:40]=1)=[O:33])[CH:29]([CH3:31])[CH3:30]
Reactant: C#Cc1cnc(C2CCCN2C(=O)C(NC(=O)OC)C(C)C)[nH]1
Reactant: COC(=O)NC(C(=O)N1CCCC1c1nc2ccc(-c3ccc(Br)cc3)cc2[nH]1)C(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(C#Cc2ccc(-c3ccc4nc(C5CCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]c4c3)cc2)[nH]1)C(C)C
Temperature: 80 °C
Reaction time: 3 h
Yield: 11.2 %

Procedure:
{1-[2-(5-Ethynyl-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (62 mg, 0.195 mmol), (1-{2-[6-(4-Bromo-phenyl)-1H-benzoimidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (73 mg, 0.146 mmol), Pd(PPh3)4 (11 mg, 0.00975 mmol), CuI (4 mg, 0.0195 mmol) and triethylamine (0.271 mL, 1.95 mmol) were suspended in DMF (2 mL). The reaction mixture was stirred at 80° C. for 3 hours then 1 mL of water was added and the mixture was purified by reverse phase preparative HPLC, giving (1-{2-[6-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-ylethynyl}-phenyl)-1H-benzoimidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (12 mg, 11%). 1H NMR (MeOH-d4, 400 MHz) 7.66-7.64 (m, 2H), 7.59-7.50 (m, 4H), 7.24 (s, 1H), 6.98 (m, 1H), 5.28 (m, 1H), 5.12 (m, 1H), 4.28-4.19 (m, 2H), 4.04-3.82 (m, 4H), 3.66 (s, 3H), 3.65 (s, 3H), 2.43-2.01 (m, 10H), 0.99-0.87 (m, 12H); MS (ESI) m/z 737 [M+H]+.
Reaction SMILES: [CH3:1][Mg]Br.[CH3:4][O:5][C:6]1[CH:46]=[CH:45][C:9]([CH2:10][N:11]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)[C:12]2[N:17]=[C:16]([CH3:18])[N:15]=[C:14]([C:19]3[C:20]([NH:27][C:28]4[CH:29]=[N:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=4)=[N:21][CH:22]=[C:23]([CH:26]=3)[CH:24]=[O:25])[N:13]=2)=[CH:8][CH:7]=1.[Cl-].[NH4+].O>C1COCC1>[CH3:44][O:43][C:40]1[CH:39]=[CH:38][C:37]([CH2:36][N:11]([CH2:10][C:9]2[CH:8]=[CH:7][C:6]([O:5][CH3:4])=[CH:46][CH:45]=2)[C:12]2[N:17]=[C:16]([CH3:18])[N:15]=[C:14]([C:19]3[CH:26]=[C:23]([CH:24]([OH:25])[CH3:1])[CH:22]=[N:21][C:20]=3[NH:27][C:28]3[CH:29]=[N:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=3)[N:13]=2)=[CH:42][CH:41]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C=O)cnc3Nc3ccc(OC)nc3)n2)cc1
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)O)cnc3Nc3ccc(OC)nc3)n2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
Methylmagnesium bromide (1.4 M in 3:1 toluene/THF) (Aldrich, St. Louis, Mo.; 1.787 mL, 2.502 mmol) was added (dropwise, over 10 min) to a yellow-brown solution of 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)nicotinaldehyde (Example 144, Step 1; 451.7 mg, 0.782 mmol) in THF (5.0 mL) at 0° C., and the resulting brown solution was stirred at 0° C. for 1 h. Saturated ammonium chloride (10 ml) and water (10 ml) were then added, THF was removed in vacuo, and the resulting mixture was extracted with EtOAc (2×60 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Trituration of the residue with hexanes (10 mL) furnished 1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(6-methoxypyridin-3-ylamino)pyridin-3-yl)ethanol (331.1 mg, 0.558 mmol, 71.3% yield) as a yellow-brown solid. m/z (ESI, +ve) 594.2 (M+H)+.
Reaction SMILES: O[CH2:2][C:3]1[O:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[CH:6][CH:7]=1.S(Br)([Br:20])=O>CN(C)C=O>[Br:20][CH2:2][C:3]1[O:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: OCc1ccc(-c2cccc(C(F)(F)F)c2)o1
Reactant: O=S(Br)Br
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(-c2ccc(CBr)o2)c1

Procedure:
The hydroxymethyl compound (4.84 g; 0.02 mole) prepared in (a) above, was dissolved in dimethylformamide (30 ml) cooled to 0°-5° C. and thionyl bromide (1.7 ml; 0.02 mole) was added dropwise with stirring. After 2 hours the greenish-yellow solution was poured onto ice/water and extracted via diethyl ether. The ether extract was washed with NaCl (saturated solution) dried over molecular sieve 3A and evaporated to give a light brown oil which slowly crystallised (4.6 g).
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH2:2][CH2:3][CH3:4].[CH:12](OCC)(OCC)OCC.C(OC(=O)C)(=O)C.[CH3:29][C:30]1[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=1[NH2:32]>>[C:1]([C:6](=[CH:12][NH:32][C:31]1[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=1[CH3:29])[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccccc1N
Reactant: CCOC(OCC)OCC
Reactant: CCCC(=O)CC(=O)OCC
Solvent: CC(=O)OC(C)=O
Product: CCCC(=O)C(=CNc1ccccc1C)C(=O)OCC
Yield: 38.6 %

Procedure:
A mixture of ethyl butyrylacetate (100 g, 0.63 mol), triethyl orthoformate (210 ml, 1.26 mol) and acetic anhydride (60 ml, 0.63 mol) was heated under reflux for 6 hours, then excess triethyl orthoformate evaporated in vacuo. 2-Methyl aniline (67 ml, 0.63 mol) was added to the residue, the mixture heated at reflux for 30 minutes then poured into petroleum ether. Filtration and washing gave ethyl 2-butyryl-3-(2-methylphenylamino)acrylate (67 g, 38%) as a mixture of E and Z isomers. The mother liquors were evaporated, taken up in ethyl acetate, washed with dilute hydrochloric acid, dried, evaporated and triturated with petroleum ether to give a further 57 g (33%) of ethyl 2-butyryl-3-(2-methylphenylamino)-acrylate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([NH:14][NH2:15])=[O:13])[CH:6]=[CH:5]2.[F:23][C:24]([F:37])([F:36])[O:25][C:26]1[CH:31]=[CH:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.C1(S(Cl)(=O)=O)C=CC=CC=1>>[NH:14]([C:12]([CH:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][S:32]([C:29]3[CH:28]=[CH:27][C:26]([O:25][C:24]([F:23])([F:36])[F:37])=[CH:31][CH:30]=3)(=[O:34])=[O:33])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1)[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:13])[NH2:15]
Reactant: O=S(=O)(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: NNC(=O)C(Cc1ccccc1)n1ccc2cc(N)ccc21
Agent: O=S(=O)(Cl)c1ccccc1
Product: NNC(=O)C(Cc1ccccc1)n1ccc2cc(NS(=O)(=O)c3ccc(OC(F)(F)F)cc3)ccc21

Procedure:
N-[1-(1-Hydrazinocarbonyl-2-phenyl-ethyl)-1H-indol-5-yl]-4-trifluoromethoxy-benzenesulfonamide was prepared from 2-(5-amino-indol-1-yl)-3-phenyl-propionic acid hydrazide following the procedure of Example 2 Step 1 substituting 4-trifluoro methoxy-benzene sulfonyl chloride for benzenesulfonyl chloride: MS (ESI) m/z 519, MS (ESI) m/z 517.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:10]=[CH:9][C:8](=[O:11])[N:7]([CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][CH:17]([N:20]([CH2:28][C:29]4[N:34]=[CH:33][C:32]5[O:35][CH2:36][CH2:37][O:38][C:31]=5[CH:30]=4)[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:16][CH2:15]3)[C:6]=2[N:39]=1.[C:40](=[O:47])([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])[NH2:41].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[C:43]([O:42][C:40]([NH:41][C:2]1[CH:3]=[CH:4][C:5]2[N:10]=[CH:9][C:8](=[O:11])[N:7]([CH2:12][CH2:13][N:14]3[CH2:15][CH2:16][CH:17]([N:20]([CH2:28][C:29]4[N:34]=[CH:33][C:32]5[O:35][CH2:36][CH2:37][O:38][C:31]=5[CH:30]=4)[C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:26])[CH3:24])[CH2:18][CH2:19]3)[C:6]=2[N:39]=1)=[O:47])([CH3:46])([CH3:45])[CH3:44]
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCN(CCn2c(=O)cnc3ccc(Cl)nc32)CC1
Reactant: CC(C)(C)OC(N)=O
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1ccc2ncc(=O)n(CCN3CCC(N(Cc4cc5c(cn4)OCCO5)C(=O)OC(C)(C)C)CC3)c2n1
Temperature: 85 °C
Reaction time: 2 h
Yield: 61.9 %

Procedure:
To a solution of 0.11 g of tert-butyl (1-(2-(6-chloro-3-oxopyrido(2,3-b)pyrazin-4(3H)-yl)ethyl)piperidin-4-yl)(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)carbamate in 3 mL of dioxane, 25 mg of tert-butyl carbamate and 82 mg of cesium carbonate were added. Thereto were added 2.5 mg of tris(dibenzylideneacetate)dipalladium(0) and 3.1 mg of 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene under an argon atmosphere. The mixture was stirred at 80 to 90° C. for 2 hours under an argon atmosphere. The insoluble substance was filtered off, and the solvent was distilled off under reduced pressure. The resultant residue was purified by basic silica gel column chromatography using an eluent of chloroform:methanol=20:1 to obtain 78 mg of tert-butyl (1-(2-(6-((tert-butoxycarbonyl)amino)-3-oxopyrido(2,3-b)pyrazin-4(3H)-yl)ethyl)piperidin-4-yl)(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)carbamate as a light brown oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([CH:8]=1)[NH2:7].[N:10]([O-])=O.[Na+].O.O.[Sn](Cl)(Cl)(Cl)Cl>O.Cl>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([NH:7][NH2:10])[CH:8]=1
Reactant: Cc1ccc(Cl)cc1N
Reactant: O=N[O-]
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Product: Cc1ccc(Cl)cc1NN
Temperature: 0 °C
Reaction time: 2 h
Yield: 152.2 %

Procedure:
To an ice-cooled suspension of 5-chloro-2-methylaniline (1.4362 g, 10.143 mmol, 1.00 equiv) in water (10 mL) was added concentrated hydrochloric acid (10 mL). To this reaction mixture was added dropwise a solution of sodium nitrite (0.791 g, 11.5 mmol, 1.13 equiv) in water (5 mL) at 0° C. After 2 hours, the reaction mixture was slowly added to a stirring ice-cooled solution of tin chloride dihydrate (5.88 g, 25.8 mmol, 2.55 equiv) in concentrated hydrochloric acid (8 mL). Water was added as needed to maintain the stirring while solids formed. The reaction was kept at 0° C. for 45 minutes. The white solids were filtered and rinsed with diethyl ether (2×50 mL). The solids were dried under vacuum to provide 1.49 g (76%) of (5-chloro-2-methylphenyl)hydrazine hydrochloride. 1H NMR (400 MHz, DMSO-d6) δ: 10.08 (s, 3H), 7.98 (s, 1H), 7.13 (d, 1H), 6.97 (s, 1H), 6.91 (d, 1H), 2.14 (s, 3H).