Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:16][CH2:15][N:14]=[N:13]2)=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.[CH2:18]([O:20][CH2:21][CH2:22][N:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=[C:24]1[NH:32][CH:33]1[CH2:38][CH2:37][N:36]([CH2:39][CH2:40][C:41]2([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH2:45][CH2:44][NH:43][CH2:42]2)[CH2:35][CH2:34]1)[CH3:19]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:16][CH2:15][N:14]=[N:13]2)=[CH:8][C:4]=1[C:5]([N:43]1[CH2:44][CH2:45][C:41]([CH2:40][CH2:39][N:36]2[CH2:37][CH2:38][CH:33]([NH:32][C:24]3[N:23]([CH2:22][CH2:21][O:20][CH2:18][CH3:19])[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[N:25]=3)[CH2:34][CH2:35]2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:42]1)=[O:7]
Reactant: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reactant: COc1ccc(N2CCN=N2)cc1C(=O)O
Agent: Cl
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(N5CCN=N5)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 59.1 using 2-methoxy-5-(4H-triazol-1-yl)benzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:3][CH2:2]1.N1([C:18]2[CH:19]=[CH:20][C:21]3[N:22]([C:24]([C:27]([F:30])([F:29])[F:28])=[N:25][N:26]=3)[N:23]=2)CCNCC1>>[CH:1]1([CH2:4][O:5][CH:6]2[CH2:11][CH2:10][N:9]([C:18]3[CH:19]=[CH:20][C:21]4[N:22]([C:24]([C:27]([F:28])([F:30])[F:29])=[N:25][N:26]=4)[N:23]=3)[CH2:8][CH2:7]2)[CH2:2][CH2:3]1
Reactant: C1CC(OCC2CC2)CCN1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: FC(F)(F)c1nnc2ccc(N3CCC(OCC4CC4)CC3)nn12
Yield: 69 %

Procedure:
A mixture of 4-(cyclopropylmethoxy)piperidine and 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by an analogous method to Example 216 to give 6-[4-(cyclopropylmethoxy)piperidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine in 69% yield.
Reaction SMILES: [NH3:1].[CH3:2][C:3]([O:6][C:7](=[O:22])[CH2:8][N:9]([C:13]1[C:16](=[O:17])[C:15](=[O:18])[C:14]=1OCC)[CH2:10][CH:11]=[CH2:12])([CH3:5])[CH3:4]>>[CH3:2][C:3]([O:6][C:7](=[O:22])[CH2:8][N:9]([C:13]1[C:16](=[O:17])[C:15](=[O:18])[C:14]=1[NH2:1])[CH2:10][CH:11]=[CH2:12])([CH3:5])[CH3:4]
Reactant: C=CCN(CC(=O)OC(C)(C)C)c1c(OCC)c(=O)c1=O
Reactant: N
Product: C=CCN(CC(=O)OC(C)(C)C)c1c(N)c(=O)c1=O
Yield: 71 %

Procedure:
Ethanolic ammonia (25 mL) was added to a flask containing N-(2-ethoxy-3,4-dioxo-1-cyclobuten-1-yl)-N-(2-propenyl)glycine 1,1-dimethylethyl ester (2.5 g, 8.5 mmol) at room temperature. After 5 hours the reaction mixture was concentrated and purified by flash chromatography (5 cm diameter, elution with 5% methanol in dichloromethane) to yield N-(2-amino-3,4-dioxo-1-cyclobuten-1-yl)-N-(2-propenyl)glycine 1,1-dimethylethyl ester as a white solid (1.6 g, 71%, mp 175°-176° C.); IR (KBr, cm-1): 3300, 3140, 1810, 1740, 1670, 1650; MS (EI): 266 (M+, 34), 210 (24), 165 (100), 109 (54), 95 (89), 68 (68); 1H NMR (DMSO, 400 MHz): δ 7.70 (br s, NH2), 5.84-5.77 (m, 1H), 5.26 (d, J=17 Hz, 1H), 5.19 (d, J=10 Hz, 1H), 4.3-4.0 (br m, 4H), 1.39 (s, 9H).
Reaction SMILES: N[C@@](C)(CC(C)CC)CC(O)=O.[NH2:13][C@@:14]([CH3:26])([CH2:19][CH:20]([CH3:25])[CH2:21][CH2:22][CH2:23]C)[CH2:15][C:16]([OH:18])=[O:17]>>[NH2:13][C@@:14]([CH3:26])([CH2:19][CH:20]([CH3:25])[CH2:21][CH2:22][CH3:23])[CH2:15][C:16]([OH:18])=[O:17]
Reactant: CCCCC(C)C[C@](C)(N)CC(=O)O
Agent: CCC(C)C[C@](C)(N)CC(=O)O
Product: CCCC(C)C[C@](C)(N)CC(=O)O

Procedure:
A procedure similar to that of 3(S)-Amino-3,5-dimethyl-heptanoic acid was used to prepare 3(S)-Amino-3,5-dimethyl-nonanoic acid. m/z 188.1 (C10H21 NO2+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:36](=[O:41])[C:37]([O:39][CH3:40])=[O:38].CCN(CC)CC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:40][O:39][C:37](=[O:38])[C:36]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1)=[O:41]
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(N)c4)nc4ccccc34)ccc21
Reactant: COC(=O)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(=O)Nc1cccc(-c2nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of tert-butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (85 mg, 0.19 mmol) and methyl 2-chloro-2-oxoacetate (35 μL, 0.38 mmol) in CH2Cl2 (1 mL) was added Et3N (53 uL, 0.38 mmol), and catalytic amount of DMAP. The reaction mixture was stirred at RT for 3 h. The reaction was concentrated in vacuo and the residue was purified by flash chromatography on silica (10:1 CH2Cl2:MeOH). The product tert-butyl 5-(2-(3-(2-methoxy-2-oxoacetamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate was isolate. (18 mg, 18%)
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].[OH-].[Na+].CO.Cl[CH2:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=1)[CH:14]=[CH2:15]>COC1C=CC(O)=CC=1.O>[CH:14]([C:13]1[CH:12]=[C:11]([CH:18]=[CH:17][CH:16]=1)[CH2:10][S:1][CH2:2][CH2:3][OH:4])=[CH2:15]
Reactant: C=Cc1cccc(CCl)c1
Reactant: OCCS
Agent: COc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=Cc1cccc(CSCCO)c1
Reaction time: 3 h
Yield: 54 %

Procedure:
A polymerization inhibitor, p-methoxyphenol (1.24 g; 0.01 mole), was added to a mixture of 78 g (1.0 mole) of 2-mercaptoethanol, 133 g (1.0 mole) of a 30 % aqueous solution of sodium hydroxide and 0.15 liter of methanol. While the mixture was cooled to below 10° C., 152 g (1.0 mole) of m-(chloromethyl)styrene was added dropwise over 3 hours. Then, the reaction mixture was continuously stirred for an additional 3 hours to complete the reaction. Water (1 liter) was added to the reaction mixture to separate it into an oil layer and an aqueous layer. The oil layer was washed with water and distilled under reduced pressure (140°-150 ° C./1-2 mmHg) to give 105 g of 2-(3-vinylbenzylthio)ethanol as a colorless transparent liquid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:4][C:5]([O:12]C)=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:7]=1.C(=O)(O)[O-].[Na+]>Br.O>[Cl:1][C:2]1[C:3]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[CH:4][C:5]([OH:12])=[C:6]([CH2:8][C:9]([OH:11])=[O:10])[CH:7]=1
Reactant: COc1cc(N2CCCCC2)c(Cl)cc1CC(=O)O
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=C(O)Cc1cc(Cl)c(N2CCCCC2)cc1O

Procedure:
A solution of 8.5 g (30 mmole) of 5-chloro-2-methoxy-4-(piperidin-1-yl)-phenylacetic acid in 150 ml of 48% hydrobromic acid is boiled under reflux for 15 hours. The reaction mixture is cooled, diluted with water and adjusted to pH 3-4 with saturated sodium bicarbonate solution. The whole is subsequently extracted with ethyl acetate and the combined organic phases are washed with water, dried over sodium sulphate and concentrated by evaporation in a vacuum rotary evaporator. In that manner a dark grey foam of 5-chloro-2-hydroxy-4-(piperidin-1-yl)-phenylacetic acid is obtained which is reacted, without purification, to form 5-chloro-6-(piperidin-1-yl)-benzofuran-2(3H)-one.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:10])([CH3:9])[CH2:7][OH:8].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>C1(C)C=CC(S(O)(=O)=O)=CC=1.ClCCl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:10])([CH3:9])[CH2:7][O:8][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1
Reactant: CC(C)(CO)CCCCBr
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC(C)(CCCCBr)COC1CCCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
In a 500 ml three-neck flask fitted with a condenser and magnetic stirrer was placed under argon a mixture of 6-bromo-2,2-dimethyl-1-hydroxyhexane (25 g, 0.119 mol), dichloromethane (300 ml) and p-toluenesulfonic acid (0.15 g, 0.78 mmol). 3,4-Dihydro-2H-pyran (12.57 g, 0.1495 mol) was added slowly to the mixture at 0° C. The reaction mixture was stirred at room temperature for one hour, and then the mixture was filtered through aluminum oxide, which was further washed with dichloromethane (200 ml). The combined fractions were evaporated under vacuum to provide 33.73 g (97%) of the above-titled compound as a pale-yellow residue, ca. 90%: 1H NMR CDCl3, δ (ppm): 4.48-4.52 (m, 1H), 3.90-3.75 (m, 1H), 3.50-3.35 (m, 4H), 2.95 (d, J=12 Hz, 1H), 1.90-1.20 (m, 12H), 0.90 (s, 6H); 13C NMR CDCl3, δ (ppm): 99.0, 76.2, 61.8, 38.2, 34.0, 33.8, 33.6, 30.5, 25.5, 24.5, 24.4, 22.5, 19.3.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[CH:25]1([N:28]2[CH2:33][CH2:32][CH:31]([NH2:34])[CH2:30][CH2:29]2)[CH2:27][CH2:26]1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([NH:34][CH:31]4[CH2:32][CH2:33][N:28]([CH:25]5[CH2:27][CH2:26]5)[CH2:29][CH2:30]4)=[O:21])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2]
Reactant: NC1CCN(C2CC2)CC1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NC3CCN(C4CC4)CC3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 1-cyclopropylpiperidin-4-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.69 (d, J=6.06 Hz, 2H) 0.82 (br. s., 2H) 1.79 (d, J=10.86 Hz, 2H) 1.97 (d, J=10.86 Hz, 2H) 2.43 (s, 4H) 2.88-3.14 (m, 2H) 3.35-3.34 (m, 2H) 4.00 (d, J=6.57 Hz, 1H) 7.65 (dd, J=8.08, 1.52 Hz, 1H) 7.72 (s, 1H) 7.79 (d, J=8.08 Hz, 1H) 8.16 (s, 1H) 8.35-8.50 (m, 2H) 8.66 (d, J=7.07 Hz, 1H) 8.92 (t, J=1.52 Hz, 1H) 11.41-12.67 (m, 1H). MS m/z [M+H]+ 443.2.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH2:3][CH2:4]I.O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.C([Sn](CCCC)(CCCC)[C:29]#[C:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)CCC>CN(C)C=O.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Cu]I>[F:1][C:2]([F:7])([F:6])[CH2:3][CH2:4][C:29]#[C:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: FC(F)(F)CCI
Reactant: CCCC[Sn](C#Cc1ccccc1)(CCCC)CCCC
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: FC(F)(F)CCC#Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 57.6 %

Procedure:
To a solution of 1,1,1-trifluoro-3-iodopropane (0.052 mL, 0.438 mmol), Pd2(dba)3 (24.0 mg, 0.026 mmol), Tri-2-furylphosphine (10.2 mg, 0.044 mmol) and copper(I) iodide (8.33 mg, 0.044 mmol) in N,N-dimethylformamide (2.5 mL) was added tributyl(phenylethynyl)stannane (0.178 mL, 0.481 mmol) under nitrogen. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water (10 mL), washed with brine (10 mL), and dried over anhydrous sodium sulfate. Concentration followed by purification by silica gel chromatography with hexanes yielded (5,5,5-trifluoropent-1-ynyl)benzene (50 mg). The compound had an HPLC ret. time=4.08 min.−Column: YMC S5 COMBISCREEN® 4.6×50 mm; Gradient time: 4 min; Flow rate=4 ml/min; Solvent A=10% MeOH−90% Water−0.2% H3PO4; Solvent B=90% MeOH−10% water−0.2% H3PO4; Start % B=0; Final % B=100.
Reaction SMILES: [Cl-].[NH4+:2].[NH2-].[Na+:4].[CH3:5][Si:6]([NH:9][Si:10]([CH3:13])([CH3:12])[CH3:11])([CH3:8])[CH3:7]>C1C=CC=CC=1>[CH3:5][Si:6]([N-:9][Si:10]([CH3:13])([CH3:12])[CH3:11])([CH3:8])[CH3:7].[Na+:4].[NH2-:2].[Na+:4].[CH3:5][Si:6]([NH:9][Si:10]([CH3:13])([CH3:12])[CH3:11])([CH3:8])[CH3:7]
Reactant: [NH4+]
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Cl-]
Agent: [NH2-]
Solvent: c1ccccc1
Product: C[Si](C)(C)[N-][Si](C)(C)C

Procedure:
The chemistry of the final HMDS filtrate treatment step is complex. The reactions occurring in the final amide treatment and distillation steps are, however, not fully understood. Thus, the following description should be understood as presently incomplete and partly hypothetical. In liquid anhydrous ammonia, sodium amide reacts rapidly with ammonium chloride to form ammonia and sodium chloride according to the formula: ##STR1## This reaction proceeds slowly, if at all, in HMDS. The ammonium chloride appears to react with a reaction product formed when crude HMDS is "treated" with sodium amide. In this regard, literature reports that sodium bis(trimethylsilyl)amide is formed from the reaction of sodium amide and HMDS in benzene as follows: ##STR2## This reaction proceeds moderately at 25°-30° C. with evolution of ammonia without benzene as a solvent.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20](O)=[O:21])=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.Cl.[NH2:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][C:32]#[N:33].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:32]([CH2:31][CH2:30][O:29][CH2:28][CH2:27][NH:26][C:20]([C:18]1[CH:17]=[CH:16][C:13]2[N:14]([CH3:15])[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:24]=[CH:23][C:5]=4[N:6]=3)=[N:11][C:12]=2[CH:19]=1)=[O:21])#[N:33]
Reactant: N#CCCOCCN
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCCOCCC#N)ccc21
Yield: 67.6 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid [2-(2-cyano-ethoxy)-ethyl]-amide (60 mg) was prepared by following General Procedure F starting 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (70 mg), 3-(2-amino-ethoxy)-propionitrile hydrochloride (100 mg), HBTU (85 mg), and DIEA (100 uL) in DMF (1 mL). LC/MS: m/z 456.0.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C([N:26]1[CH:30]=[CH:29][CH:28]=[C:27]1B(O)O)(OC(C)(C)C)=O.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe].C(#N)C>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:27]3[NH:26][CH:30]=[CH:29][CH:28]=3)[CH:3]=2)[NH:8][CH:9]=1
Reactant: COc1ccccc1-c1c[nH]c2ncc(Br)cc12
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CC#N
Product: COc1ccccc1-c1c[nH]c2ncc(-c3ccc[nH]3)cc12
Yield: 30.4 %

Procedure:
To a Personal Chemistry® microwave vial (2-5 ml size) were added 5-bromo-3-(2-methoxy-phenyl)-1H-pyrrolo[2,3-b]pyridine (96 mg, 0.32 mmol), 1-N-(BOC)pyrrole-2-boronic acid (103 mg, 0.487 mmol) and 12 mg (5 mol %) of dichloro[1,1′-bis(diphenylphoshino)ferrocene]palladium(II) dichloromethane adduct, 1 ml of acetonitrile and 1 ml of a 2 M aqueous solution of sodium carbonate. The vial was sealed, evacuated and purged three times with nitrogen, then irradiated in a Personal Chemistry® microwave reactor with a temperature setting of 150° C. for 15 minutes. Ethyl acetate (50 ml) was added, and the layers were separated. The aqueous fraction was extracted three times with ethyl acetate, and the combined organic fractions were washed with brine, dried (Na2SO4), filtered and concentrated. Purification by flash chromatography on silica gel using a gradient of ethyl acetate in hexanes gave 28.1 mg (30%) of 3-(2-methoxy-phenyl)-5-(1H-pyrrol-2-yl)-1H-pyrrolo[2,3-b]pyridine as a tan solid. 1H-NMR (d6-DMSO) δ=11.78 (br.s, 1H), 11.32 (br. s, 1H), 8.56 (d, 1H), 8.20 (d, 1H), 7.66 (d, 1H), 7.59 (dd, 1H), 7.29 (dd, 1H), 7.12 (d, 1H), 7.07 (t, 1H), 6.83 (m, 1H), 6.49 (m, 1H), 6.10 (m, 1H), 3.82 (s, 3H); MS m/z: 290 [MH]+.
Reaction SMILES: [CH2:1]([C:8]1[C:13]([Br:14])=[CH:12][CH:11]=[C:10]([OH:15])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:22][O:23][CH2:24][CH2:25]Br>CN(C)C=O>[CH2:1]([C:8]1[C:13]([Br:14])=[CH:12][CH:11]=[C:10]([O:15][CH2:25][CH2:24][O:23][CH3:22])[N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(Br)c(Cc2ccccc2)n1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1ccc(Br)c(Cc2ccccc2)n1
Reaction time: 1 h

Procedure:
A mixture of 5 g of 2-benzyl-3-bromo-6-hydroxypyridine, 3.9 g of anhydrous potassium carbonate, 2.7 ml of 2-bromoethyl methyl ether and 20 ml of N,N-dimethylformamide was heated under stirring in an oil bat kept at 80° C. for one hour. After cooling as it was, the mixture was extracted with ethyl acetate-water. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was subjected to silica gel column chromatography and eluted with 1-3% ethyl acetate/hexane, to give 4.2 g of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:3]=1[C:4]([NH:6][C:7]1[C:15]([CH3:16])=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][C:8]=1[CH3:17])=[O:5].C([N:26]([CH2:30][CH3:31])[CH:27]([CH3:29])[CH3:28])(C)C>S(Cl)(Cl)=O.C(Cl)Cl>[CH:8]1[C:28]2[CH2:19][C:18]3[CH:3]=[CH:2][CH:21]=[CH:20][C:31]=3[CH2:30][N:26]([C:11]([C:10]3[CH:14]=[C:15]([CH3:16])[C:7]([NH:6][C:4](=[O:5])[C:3]4[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:2]=4[Cl:1])=[C:8]([CH3:17])[CH:9]=3)=[O:13])[C:27]=2[CH:29]=[CH:15][CH:7]=1
Reactant: Cc1cc(C(=O)O)cc(C)c1NC(=O)c1ccc(Cl)cc1Cl
Reactant: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc(C)c1NC(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 146.8 %

Procedure:
A mixture of 1.69 g of 4-[(2,4-dichlorobenzoyl)amino]-3,5-dimethylbenzoic acid in 2.0 ml of thionyl chloride is heated on a steam bath under argon for 1 hour. The volatiles are evaporated and the residue evaporated in vacuo from toluene to give a residue. A solution of the residue in 25 ml of methylene chloride is treated with 0.75 g of N,N-diisopropylethylamine and 0.98 g of 10,11-dihydro-5H-dibenz[b,e]azepine is stirred at room temperature for 18 hours. The reaction mixture is washed with saturated NaHCO3, dried (Na2SO4) and passed through a pad of hydrous magnesium silicate. The filtrate is evaporated to a glass which is dissolved in methylene chloride dried (Na2SO4) and passed through a short pad of hydrous magnesium silicate. The filtrate is evaporated to give 1.89 g of the desired product as an amorphorous solid.
Reaction SMILES: [S:1]1[C:5]([C:6]2[CH:10]=[C:9]([CH:11](OCC)[O:12]CC)[N:8]([CH3:18])[N:7]=2)=[CH:4][C:3]2[CH2:19][CH2:20][CH2:21][C:2]1=2.[Br:22]N1C(=O)CCC1=O>C(#N)C>[Br:22][C:10]1[C:6]([C:5]2[S:1][C:2]3[CH2:21][CH2:20][CH2:19][C:3]=3[CH:4]=2)=[N:7][N:8]([CH3:18])[C:9]=1[CH:11]=[O:12]
Reactant: CCOC(OCC)c1cc(-c2cc3c(s2)CCC3)nn1C
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: Cn1nc(-c2cc3c(s2)CCC3)c(Br)c1C=O
Yield: 37.9 %

Procedure:
A solution of 3-{4H,5H,6H-cyclopenta[b]thiophen-2-yl}-5-(diethoxymethyl)-1-methyl-1H-pyrazole (37a) (1.69 g, 5.51 mmol) and N-bromosuccinimide (0.88 g, 4.96 mmol) in acetonitrile (10 mL) was stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo. Water (10 mL) was added and the aqueous layer was extracted with ethyl acetate (2×10 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100/0 to 95/5) to provide 4-bromo-3-{4H,5H,6H-cyclopenta[b]thiophen-2-yl}-1-methyl-1H-pyrazole-5-carbaldehyde (37b) (586 mg, 1.88 mmol, 34%).
Reaction SMILES: [F:1][CH:2]([F:41])[C:3]1[N:7]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([NH:20][CH2:21][CH:22]3[CH2:27][CH2:26][N:25]([CH:28]4[CH2:32][CH2:31][CH2:30][CH:29]4[C:33](OC)=[O:34])[CH2:24][CH2:23]3)[N:9]=2)[C:6]2[CH:37]=[CH:38][CH:39]=[CH:40][C:5]=2[N:4]=1.O1CCCC1.C([Al]CC(C)C)C(C)C.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CO>[F:41][CH:2]([F:1])[C:3]1[N:7]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([NH:20][CH2:21][CH:22]3[CH2:27][CH2:26][N:25]([CH:28]4[CH2:32][CH2:31][CH2:30][CH:29]4[CH2:33][OH:34])[CH2:24][CH2:23]3)[N:9]=2)[C:6]2[CH:37]=[CH:38][CH:39]=[CH:40][C:5]=2[N:4]=1
Reactant: COC(=O)C1CCCC1N1CCC(CNc2nc(N3CCOCC3)cc(-n3c(C(F)F)nc4ccccc43)n2)CC1
Agent: CC(C)C[Al]CC(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OCC1CCCC1N1CCC(CNc2nc(N3CCOCC3)cc(-n3c(C(F)F)nc4ccccc43)n2)CC1
Reaction time: 6 h
Yield: 69.4 %

Procedure:
To a mixture of methyl 2-{-4-[({4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(morpholin-4-yl)pyrimidin-2-yl}amino)methyl]piperidin-1-yl}cyclopentane carboxylate (50 mg) and tetrahydrofuran (1 mL) were added a 1.01 M solution of (240 μL) diisobutylaluminum in toluene at 0° C., followed by stirring at the same temperature for 6 hours. To the reaction mixture were added methanol and sodium sulfate decahydrate, followed by stirring at room temperature for 1 hour. The insoluble matter was removed by filtration and then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:50-0:100) to obtain desired (2-{4-[({4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(morpholin-4-yl)pyrimidin-2-yl}amino)methyl]piperidin-1-yl}cyclopentyl)methanol (33 mg).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]([CH3:45])([CH2:43][CH3:44])[CH2:10][C:11]1[N:12]=[C:13]([CH:23]([NH:38][C:39]([O:41][CH3:42])=[O:40])[CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][N:32]=3)=[CH:27][CH:26]=2)[N:14](C(OC(C)(C)C)=O)[CH:15]=1>>[CH3:42][O:41][C:39](=[O:40])[NH:38][CH:23]([C:13]1[NH:14][CH:15]=[C:11]([CH2:10][C:9]([CH3:45])([CH3:8])[CH2:43][CH3:44])[N:12]=1)[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][N:32]=2)=[CH:29][CH:30]=1
Reactant: CCC(C)(C)Cc1cn(C(=O)OC(C)(C)C)c(C(Cc2ccc(-c3ccc(F)cn3)cc2)NC(=O)OC)n1
Solvent: O=C(O)C(F)(F)F
Product: CCC(C)(C)Cc1c[nH]c(C(Cc2ccc(-c3ccc(F)cn3)cc2)NC(=O)OC)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (1 mL) was added to neat tert-butyl 4-(2,2-dimethylbutyl)-2-{2-[4-(5-fluoropyridin-2-yl)phenyl]-1-[(methoxy carbonyl)amino]ethyl}-1H-imidazole-1-carboxylate. After stirring at ambient temperature for 1 h, the reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and 10% aqueous sodium hydroxide. The aqueous phase was extracted with ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Preparatory plate chromatography eluting with 100% ethyl acetate afforded the title compound. (M+H) found: 425.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[NH:22][C:20]3[C:21]4[C:12](=[N:13][NH:14][C:15](=[O:23])[C:16]=4[CH:17]=[CH:18][CH:19]=3)[CH:11]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:6][CH:5]=1>Cl>[O:23]=[C:15]1[C:16]2[CH:17]=[CH:18][CH:19]=[C:20]3[NH:22][CH:10]([C:7]4[CH:6]=[CH:5][C:4]([CH:3]=[O:2])=[CH:9][CH:8]=4)[CH:11]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:12]([C:21]=23)=[N:13][NH:14]1
Reactant: COC(OC)c1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccccc2)cc1
Agent: Cl
Product: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73 %

Procedure:
To 8-(4-(dimethoxymethyl)phenyl)-9-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (89 mg, 0.22 mmol) was added 20 ml of hydrochloric acid (3 mol/L) and the mixture was stirred at room temperature for 2 h. The resulting mixture was evaporated under reduced pressure to 10 ml and then filtered, 59 mg of solid of 4-(3-oxo-9-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde was obtained; yield: 73%. LC-MS (ESI) m/z: 368 (M+1)+.