Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[CH2:63]([CH:70]1[CH2:74][CH2:73][CH2:72][NH:71]1)[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:71]1[CH2:72][CH2:73][CH2:74][CH:70]1[CH2:63][C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1)=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: c1ccc(CC2CCCN2)cc1
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(Nc1ncnc2cc(C(=O)N3CCCC3Cc3ccccc3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 2-benzyl-pyrrolidine in DMSO at ambient temperature.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][S:7]([C:10]1[CH:28]=[CH:27][C:13]([C:14]([NH:16][N:17]=[CH:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)=[NH:15])=[CH:12][CH:11]=1)(=[O:9])=[O:8].[BH3-]C#N.[Na+].Cl>C1COCC1>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][S:7]([C:10]1[CH:11]=[CH:12][C:13]([C:14]([NH:16][NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[C:21]([Cl:26])[CH:20]=2)=[NH:15])=[CH:27][CH:28]=1)(=[O:9])=[O:8]
Reactant: N=C(NN=Cc1ccc(Cl)c(Cl)c1)c1ccc(S(=O)(=O)Nc2nccs2)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Product: N=C(NNCc1ccc(Cl)c(Cl)c1)c1ccc(S(=O)(=O)Nc2nccs2)cc1
Yield: 23.3 %

Procedure:
A solution of 4-(thiazol-2-ylsulfamoyl)-N-(3,4-dichloro-benzylideneamino)-benzamidine (0.387 mmol) and NaCNBH3 (large excess) was stirred in THF (5 mL) at room temperature. To the solution was added 6 N HCl drop wise until all starting material is consumed. The solution was quenched with sat NaHCO3 and extracted with ethyl acetate. The organic phase was collected and concentrated in vacuo. The crude product was purification by reverse phase chromatography to yield 4-(thiazol-2-ylsulfamoyl)-N-(3,4-dichlorobenzylamino)-benzamidine (0.09 mmol).
Reaction SMILES: [ClH:1].CN1CCCC(C(O)=O)C1.Cl.[CH3:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH:16]([CH3:20])[N:15]1[CH2:21][CH2:22][C:23]([O:25]CC)=[O:24].Cl>>[ClH:1].[CH3:20][CH:16]1[CH2:17][CH2:18][CH2:19][CH:14]([CH3:13])[N:15]1[CH2:21][CH2:22][C:23]([OH:25])=[O:24]
Reactant: CCOC(=O)CCN1C(C)CCCC1C
Agent: CN1CCCC(C(=O)O)C1
Agent: Cl
Product: CC1CCCC(C)N1CCC(=O)O

Procedure:
3-(2,6-Dimethylpiperdino)propionic acid hydrochloride may be obtained by working according to the method described in Example 4 for the preparation of 1-methyl-3-piperidinecarboxylic acid hydrochloride, but starting with ethyl 3-(2,6-dimethylpiperidino)propionate hydrochloride (12.5 g) and 6N aqueous hydrochloric acid solution (35 cc). 3-(2,6-Dimethylpiperidino)propionic acid hydrochloride, m.p. 215° C., is thereby obtained.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])=[CH:6][C:7]([C:10]([NH:12][C:13]([C:18]3[N:22]=[C:21]([CH3:23])[O:20][N:19]=3)([CH3:17])[C:14]([OH:16])=O)=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[F:30][C:31]1([F:35])[CH2:34][NH:33][CH2:32]1.Cl>>[CH:1]1([C:4]2[C:5]([O:24][CH2:25][C:26]([F:29])([F:27])[F:28])=[CH:6][C:7]([C:10]([NH:12][C:13]([C:18]3[N:22]=[C:21]([CH3:23])[O:20][N:19]=3)([CH3:17])[C:14]([N:33]3[CH2:34][C:31]([F:35])([F:30])[CH2:32]3)=[O:16])=[O:11])=[N:8][CH:9]=2)[CH2:3][CH2:2]1
Reactant: FC1(F)CNC1
Reactant: Cc1nc(C(C)(NC(=O)c2cc(OCC(F)(F)F)c(C3CC3)cn2)C(=O)O)no1
Agent: Cl
Product: Cc1nc(C(C)(NC(=O)c2cc(OCC(F)(F)F)c(C3CC3)cn2)C(=O)N2CC(F)(F)C2)no1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 2-[[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridine-2-carbonyl]amino]-2-(5-methyl-1,2,4-oxadiazol-3-yl)propanoic acid (Example 147c) and 3,3-Difluoro-azetidine; hydrochloride (CAN 288315-03-7) as starting materials and isolated (18 mg, 24%); MS (ESI, m/z): 490.5 (M+H+).
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Na+].[Br-].[Cl:12][C:13]1[CH:14]=[N:15][C:16]2[C:21]([C:22]=1[CH2:23][CH2:24][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[CH:20][C:19]([O:44][CH3:45])=[CH:18][CH:17]=2.[C:46]([O:50][C:51](=[O:61])[NH:52][C@H:53]1[CH2:58][CH2:57][C@H:56]([CH:59]=O)[CH2:55][CH2:54]1)([CH3:49])([CH3:48])[CH3:47].C(OCC)(=O)C>O1CCCC1>[C:46]([O:50][C:51](=[O:61])[NH:52][C@H:53]1[CH2:54][CH2:55][C@H:56]([CH:59]=[CH:24][CH2:23][C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:44][CH3:45])[CH:20]=3)[N:15]=[CH:14][C:13]=2[Cl:12])[CH2:57][CH2:58]1)([CH3:49])([CH3:47])[CH3:48]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](C=O)CC1
Reactant: COc1ccc2ncc(Cl)c(CC[P+](c3ccccc3)(c3ccccc3)c3ccccc3)c2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc2ncc(Cl)c(CC=C[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c2c1
Temperature: -10 °C
Reaction time: 0.75 h

Procedure:
Sodium hexamethyldisilazide (1.0 M in tetrahydrofuran, 3.27 mL, 3.27 mmol, 2.3 eq) is added dropwise at −78° C. to a stirred solution of [2-(3-chloro-6-methoxy-quinolin-4-yl)-ethyl]-triphenyl-phosphonium bromide (800 g, 1.42 mmol, 1.0 eq) in tetrahydrofuran (25 mL). The reaction mixture is then stirred for 45 minutes at −10° C. before lowering down the temperature to −78° C. followed by the addition of (trans-4-formyl-cyclohexyl)-carbamic acid tert-butyl ester (420 mg, 1.85 mmol, 1.3 eq). The reaction mixture is then stirred at 0° C. for 1 hour, extracted with ethyl acetate (3×30 mL) and a saturated ammonium chloride aqueous solution (30 mL). The combined organic layers are washed with brine, dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 8:1, v/v) to afford {trans-4-[3-(3-chloro-6-methoxy-quinolin-4-yl)-propenyl]-cyclohexyl}-carbamic acid tert-butyl ester as an off-white solid (374 mg, 61% yield).
Reaction SMILES: Cl.[CH:2]([N:5]1[C:9]([C:10]2[N:19]=[C:18]3[N:12]([CH2:13][CH2:14][O:15][C:16]4[CH:23]=[C:22]([C@@H:24]5[CH2:29][CH2:28][NH:27][CH2:26][C@H:25]5[OH:30])[CH:21]=[CH:20][C:17]=43)[CH:11]=2)=[N:8][CH:7]=[N:6]1)([CH3:4])[CH3:3].Br[C:32]([CH3:38])([CH3:37])[C:33]([NH:35][CH3:36])=[O:34].[OH-].[Na+]>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].C(Cl)Cl>[OH:30][C@H:25]1[C@H:24]([C:22]2[CH:21]=[CH:20][C:17]3[C:18]4[N:12]([CH:11]=[C:10]([C:9]5[N:5]([CH:2]([CH3:4])[CH3:3])[N:6]=[CH:7][N:8]=5)[N:19]=4)[CH2:13][CH2:14][O:15][C:16]=3[CH:23]=2)[CH2:29][CH2:28][N:27]([C:32]([CH3:38])([CH3:37])[C:33]([NH:35][CH3:36])=[O:34])[CH2:26]1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc([C@@H]3CCNC[C@H]3O)cc1OCC2
Reactant: CNC(=O)C(C)(C)Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: ClCCl
Product: CNC(=O)C(C)(C)N1CC[C@@H](c2ccc3c(c2)OCCn2cc(-c4ncnn4C(C)C)nc2-3)[C@H](O)C1
Temperature: 25 °C
Reaction time: 7.5 h
Yield: 37 %

Procedure:
A mixture of trans-racemic-4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidin-3-ol hydrochloride (199 mg, 0.46 mmol), 2-bromo-2-methyl-N-methyl propionamide (83 mg, 0.46 mmol), NaOH (2 mL, 50% aqueous solution), TBAB (16 mg, 0.05 mmol) and DCM (2.5 mL) was stirred vigorously at RT for 7.5 h. The phases were separated and the aqueous layer extracted three times with 10% methanol in DCM, the combined organic extracts washed with brine then dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 0 to 10% methanol in DCM) to give 330 (84 mg, 37%). LCMS: RT=2.54 min, [M+H]+=494. 1H NMR 400 MHz (CDCl3) δ: 8.44 (1H, d, J=8.23 Hz), 7.87 (1H, s), 7.48 (1H, s), 7.17 (1H, br), 7.08 (1H, m), 6.86 (1H, s), 6.03-6.01 (1H, m), 4.77-4.07 (4H, m), 3.82 (1H, br), 3.17 (1H, m), 2.86 (3H, d, J=4.98 Hz), 2.85 (2H, m), 2.46 (1H, m), 2.27 (1H, m), 2.18 (1H, m), 1.90 (1H, m), 1.70 (1H, m), 1.61 (6H, m), 1.27 (6H, d, J=10.69 Hz)
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N:18]3[CH2:22][CH2:21][CH2:20][CH:19]3[CH3:23])[N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[C:34]3[C:38](=[CH:39][CH:40]=2)[NH:37][N:36]=[CH:35]3)O1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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]>[NH:37]1[C:38]2[C:34](=[CH:33][C:32]([C:2]3[CH:3]=[C:4]([NH:11][C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([N:18]5[CH2:22][CH2:21][CH2:20][CH:19]5[CH3:23])[N:13]=4)[C:5]4[N:6]([CH:8]=[CH:9][N:10]=4)[N:7]=3)=[CH:40][CH:39]=2)[CH:35]=[N:36]1
Reactant: CC1(C)OB(c2ccc3[nH]ncc3c2)OC1(C)C
Reactant: CC1CCCN1c1cccc(Nc2cc(Cl)nn3ccnc23)n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CC1CCCN1c1cccc(Nc2cc(-c3ccc4[nH]ncc4c3)nn3ccnc23)n1
Temperature: 100 °C
Yield: 38.5 %

Procedure:
A mixture of 6-chloro-N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (0.1 g, 0.304 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (0.082 g, 0.33 mmol), Pd2(dba)3 (0.035 g, 0.061 mmol), X-phos (0.058 g, 0.122 mmol) and Na2CO3 (0.097 g, 0.912 mmol) in dioxane (20 mL) and water (10 mL) was heated to 100° C. for 16 h in a sealed tube under N2 atmosphere then concentrated in vacuo. The residue was purified by chromatography (silica gel, 10 g, 200˜300 mesh, methanol:dichloromethane=1:30) to afford 6-(1H-indazol-5-yl)-N-(6-(2-methylpyrrolidin-1-yl)pyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine (48 mg, 38%) as a yellow solid. 1H NMR (300 MHz, DMSO): δ 13.25 (s, 1H), 9.59 (s, 1H), 8.87 (s, 1H), 8.29-8.17 (m, 3H), 7.96 (dd, 1H, J1=8.7 Hz, J2=1.8 Hz), 7.67-7.62 (m, 2H), 7.43 (t, 1H, J=7.8 Hz), 6.73 (d, 1H, J=7.5 Hz), 6.06 (d, 1H, J=8.1 Hz), 4.25-4.21 (m, 1H), 3.63-3.58 (m, 1H), 3.44-3.39 (m, 1H), 2.10-2.05 (m, 3H), 1.70 (s, 1H), 1.12 (d, 3H, J=6.0 Hz). LC-MS: [M+H]+, 411, tR=1.619 min, HPLC: 98.4% at 214 nm, 97.91% at 254 nm, tR=5.848 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([CH:8]=1)[NH2:7].CO[CH:12]1[CH2:16][CH2:15][CH:14](OC)O1>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([N:7]2[CH:12]=[CH:16][CH:15]=[CH:14]2)[CH:8]=1
Reactant: Nc1cc(Br)ccc1F
Reactant: COC1CCC(OC)O1
Solvent: CC(=O)O
Product: Fc1ccc(Br)cc1-n1cccc1
Yield: 99 %

Procedure:
A mixture of 5-bromo-2-fluoroaniline (prepared according to the procedure of Roe et al. in J. Org. Chem., 1956, 21, 28-29) (200 mg, 1.05 mmol) and 2,5-dimethoxytetrahydrofuran (171 μl, 1.32 mmol) in glacial acetic acid (1.5 ml) was heated at 130° C. for 20 min and then concentrated under reduced pressure. The residue was dissolved in dichloromethane and pre-adsorbed onto silica. Purification by chromatography on silica gel eluting with 10% diethyl ether in isohexane yielded 1-(5-bromo-2-fluorophenyl)-1H-pyrrole (335 mg, 99%): δH (360 MHz, CDCl3) 7.53 (1H, dd, J 7 and 3), 7.33 (1H, ddd, J 9, 4 and 3), 7.10 (1H, dd, J 11 and 9), 7.04-6.95 (2H, m), 6.36 (2H, t, J 2).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].Cl[C:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[S:21](=[O:29])(=[O:28])[N:20]=1>O1CCOCC1>[O:28]=[S:21]1(=[O:29])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:19]([NH:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:20]1
Reactant: CCOC(=O)CCCN
Reactant: O=S1(=O)N=C(Cl)c2ccccc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCOC(=O)CCCNC1=NS(=O)(=O)c2ccccc21
Reaction time: 0.08 h

Procedure:
4.07 ml (29.2 mM) of triethylamine is added to 5.0 g. (29.2 mM) of ethyl 4-aminobutyrate hydrochloride, suspended in 75 ml of dioxane. After stirring for 5 minutes, 5.88 g. (29.2 mM) of 3-chloro-1,2-benzisothiazole 1,1-dioxide is added and the mixture is refluxed for one hour. The solvent is evaporated in vacuo and the residue is taken up in chloroform, washed with water, and evaporated to dryness. The residual 4-[(1,1-dioxo-1,2-benzisothiazol-3-yl)amino]-butanoic acid, ethyl ester is recrystallized from 40 ml. of methanol/water, yield 3.72 g., m.p. 125°-127°.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:5]2[C:10]([CH3:11])=[N:9][N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:15][CH:14]=3)[C:6]=2[N:7]=1.[C:31]1([C:37]#[CH:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CCN(CC)CC.C1COCC1.CCOC(C)=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.[Cu]I>[CH3:11][C:10]1[C:5]2[C:4]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:3][C:2]([C:38]#[C:37][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[N:7][C:6]=2[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)[N:9]=1
Reactant: CCOC(=O)c1cc(Cl)nc2c1c(C)nn2Cc1ccc(Oc2ccccc2)cc1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(C#Cc2ccccc2)nc2c1c(C)nn2Cc1ccc(Oc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 30.8 %

Procedure:
(see, e.g., Dai, W., et al., Org Lett 2006, 8, 4665-7). A mixture of 50 (95 mg, 0.22 mmol), Pd(PPh3)2Cl2 (16 mg, 0.02 mmol), and CuI (8.6 mg, 0.04 mmol) in Et3N (0.5 mL) and dry THF (1 mL) was added dropwise to a solution of phenylacetylene (40 μL, 0.36 mmol) in Et3N (0.5 mL) under nitrogen at room temperature. Reaction mixture was heated to 60° C. and stirred overnight then diluted with EtOAc (10 mL) and washed with saturated aqueous NH4Cl (15 mL×2) and brine (15 mL). The organic layer was dried (Na2SO4), filtered, concentrated under reduced pressure. The crude was purified by flash column chromatography on silica gel to give the title compound (33 mg, 31%) as an orange oil. 1H NMR (500 MHz, CDCl3) δ 7.81 (s, 1H), 7.68-7.63 (m, 2H), 7.42-7.37 (m, 3H), 7.35-7.29 (m, 4H), 7.08 (t, J=7.6 Hz, 1H), 6.97 (d, J=8.4 Hz, 2H), 6.93 (d, J=8.4 Hz, 2H), 5.68 (s, 2H), 4.50 (q, J=7.1 Hz, 2H), 2.72 (s, 3H), 1.47 (t, J=7.1 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 165.08, 157.02, 156.83, 152.00, 141.84, 141.44, 133.56, 132.20, 131.77, 129.69, 129.47, 129.36, 128.45, 123.28, 121.86, 121.06, 118.94, 118.81, 110.56, 90.88, 88.87, 62.09, 49.81, 16.24, 14.26.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][N:5]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:6][CH2:7]Cl.[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][C:23]#[N:24])[CH:17]=1>[Br-].C([P+](CCCC)(CCCC)CCCC)CCCCCCCCCCCCCCC.[OH-].[Na+]>[ClH:2].[CH2:9]([N:5]1[CH2:6][CH2:7][C:22]([C:18]2[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=2)([C:23]#[N:24])[CH2:3][CH2:4]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: ClCCN(CCCl)Cc1ccccc1
Reactant: N#CCc1cccnc1
Agent: CCCCCCCCCCCCCCCC[P+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Product: N#CC1(c2cccnc2)CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Combine N,N-bis-(2-chloroethyl)benzylamine hydrochloric acid salt (72.0 g, 269 mmol) and pyrid-3-ylacetonitrile (31.8 g, 269 mmol) and hexadecyltributylphosphonium bromide (6 g) in aqueous solution of sodium hydroxide (50% by weight, 400 mL). Heat on a steam bath and stir vigorously. After 1.5 hours, cool the reaction mixture to ambient temperature. Extract the reaction mixture three times with dichloromethane. Combine the organic layers and extract twice with an aqueous 10% hydrochloric acid solution. Combine the aqueous layers and make basic with an aqueous solution of sodium hydroxide (50% by weight). Extract the basified aqueous layer three times with diethyl ether. Dry the combined ether layers over MgSO4 and filter to give a filtrate. Purge the filtrate with hydrogen chloride (gas) to give a solid. Collect the solid by filtration and dry in vacuo at 65° C. to give 1-benzyl-4-(pyrid-3-yl)-4-cyanopiperidine hydrochloric acid salt.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]([F:15])([F:14])[F:13])[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.C(=O)(O)[O-].[Na+].[CH2:25](O)[CH3:26]>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]([F:13])([F:14])[F:15])[C:5]([O:7][CH2:25][CH3:26])=[O:6]
Reactant: CCO
Reactant: O=C(O)c1ccc(OC(F)(F)F)c(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(OC(F)(F)F)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
To a solution of 3-fluoro-4-(trifluoromethoxy)benzoic acid (1.00 g, 4.46 mmol) in ethanol (10 ml) was added thionyl chloride (1.33 g, 11.2 mmol) at 0° C. The reaction solution was slowly warmed to room temperature, and stirred at the same temperature overnight. The reaction solution was poured into saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate twice. The organic layer was combined, washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:0→9:1) to give ethyl 3-fluoro-4-(trifluoromethoxy)benzoate (0.72 g, 64%) as a colorless and clear oil.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][N:11]([CH3:44])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([N:35]3[C:39]4=[N:40][CH:41]=[CH:42][CH:43]=[C:38]4[CH:37]=[CH:36]3)[CH2:34][CH2:33][CH2:32][CH2:31]2)[N:15]=1)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:45](OC1C(C(O)=O)=NC(CC2(N3C4=NC=CC=C4C=C3)CCCC2)=NC=1O)[C:46]1[CH:51]=CC=CC=1.[Si](OCCNCC1CC1)(C(C)(C)C)(C)C>>[Si:1]([O:8][CH2:9][CH2:10][N:11]([CH2:44][CH:51]1[CH2:46][CH2:45]1)[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([N:35]3[C:39]4=[N:40][CH:41]=[CH:42][CH:43]=[C:38]4[CH:37]=[CH:36]3)[CH2:31][CH2:32][CH2:33][CH2:34]2)[N:15]=1)=[O:13])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: O=C(O)c1nc(CC2(n3ccc4cccnc43)CCCC2)nc(O)c1OCc1ccccc1
Reactant: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(n3ccc4cccnc43)CCCC2)nc(O)c1OCc1ccccc1
Agent: CC(C)(C)[Si](C)(C)OCCNCC1CC1
Product: CC(C)(C)[Si](C)(C)OCCN(CC1CC1)C(=O)c1nc(CC2(n3ccc4cccnc43)CCCC2)nc(O)c1OCc1ccccc1

Procedure:
5-Benzyloxy-6-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-cyclopropylmethyl-amide (413) was prepared following the same method as described for 5-benzyloxy-6-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-methyl-amide (405) from 5-benzyloxy-6-hydroxy-2-(1-pyrrolo[2,3-b]pyridin-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (404) (200 mg, 0.45 mmol) and [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-cyclopropylmethyl-amine (134 mg, 0.58 mmol) (8i) to get an off-white sticky solid (180 mg, 61%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[C:26]([C:28]1[N:33]=[C:32]2[NH:34][CH:35]=[C:36]([CH:37]=O)[C:31]2=[CH:30][CH:29]=1)#[CH:27]>CO.N1CCCCC1>[C:26]([C:28]1[N:33]=[C:32]2[NH:34][CH:35]=[C:36](/[CH:37]=[C:7]3\[O:8][C:4]4[C:3]([CH2:12][N:13]5[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]5)=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=4[C:6]\3=[O:9])[C:31]2=[CH:30][CH:29]=1)#[CH:27]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Reactant: C#Cc1ccc2c(C=O)c[nH]c2n1
Solvent: C1CCNCC1
Solvent: CO
Product: C#Cc1ccc2c(/C=C3\Oc4c(ccc(O)c4CN4CCN(C(=O)OC(C)(C)C)CC4)C3=O)c[nH]c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.017 g, 0.049 mmol) obtained in Example A16, Step 1 in methanol (2.0 mL) was added with 6-ethynyl-1H-pyrrolo[2,3-b]pyridine-3-carboxaldehyde (0.007 g, 0.041 mmol). Then, the mixture was added with 5 drops of piperidine, and then the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and then the residue was washed with methylene chloride to obtain tert-butyl (Z)-4-({2-[(6-ethynyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.015 g, 60%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:12]3([F:16])[CH2:15][O:14][CH2:13]3)[N:8]2[CH3:11])=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][C@@H:18]2[CH3:23])[N:3]=1.Cl[C:25]1N=C2C(N=C(C3(O)COC3)N2CC)=C(N2CCOC[C@@H]2C)N=1.CCCCCCC>C(OCC)(=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:12]3([F:16])[CH2:15][O:14][CH2:13]3)[N:8]2[CH2:11][CH3:25])=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][C@@H:18]2[CH3:23])[N:3]=1
Reactant: CCn1c(C2(O)COC2)nc2c(N3CCOC[C@@H]3C)nc(Cl)nc21
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1nc(C1(F)COC1)n2C
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CCn1c(C2(F)COC2)nc2c(N3CCOC[C@@H]3C)nc(Cl)nc21

Procedure:
This compound was prepared in an analogous fashion to (S)-4-(2-chloro-8-(3-fluorooxetan-3-yl)-9-methyl-9H-pur-in-6-yl)-3-methylmorpholine, using (S)-3-(2-chloro-9-ethyl-6-(3-methylmorpholino)-9H-purin-8-yl)oxetan-3-ol as the starting material. LC-MS m/z (method C)=356/358 [M+H]+, RT=2.62 min; TLC (1:1 heptane:ethyl acetate): Rf=0.58.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([C:23](O)=O)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>N1C=CC=CC=1.CCOC(C)=O>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([C:23]2[NH:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=3[N:9]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: Nc1ccc(F)cc1N
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2nc3cc(F)ccc3[nH]2)CC1
Temperature: 25 °C
Yield: 32 %

Procedure:
This compound is synthesized as described by adaptation of the following reference: Lin et al, Tetrahedron Lett., 2006, 47, 17, 2883. To a stirred mixture of 4-fluorobenzene-1,2-diamine (1.0 g, 7.93 mmol) and 1-[(tert-butoxy)carbonyl]piperidine-4-carboxylic acid (1.82 g, 7.93 mmol) in pyridine (4 mL) is added triphenyl phosphite (2.49 mL, 9.51 mmol). The reaction mixture is heated under reflux for 18 h. The reaction mixture is cooled to room temperature and diluted with EtOAc (40 mL). The solution is washed with 1M aqueous HCl (8 mL) followed by saturated aqueous NaHCO3 (8 mL) and water (5 mL) to give an oily residue. The crude product is purified by column chromatography (Isolute column, eluent: DCM, 3% MeOH) to afford 0.81 g of tert-butyl-4-(5-fluoro-1H-1,3-benzodiazol-2-yl)piperidine-1-carboxylate.