Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:5]2[C:6]3[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=3[O:8][CH2:9][CH2:10][C:4]=2[S:3][C:2]=1[NH:15][CH2:16][CH:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:24](=O)[CH2:25][CH3:26])[CH2:19][CH2:18]1.Cl.[OH-].[Na+]>C1COCC1>[CH2:24]([NH:23][CH:20]1[CH2:21][CH2:22][CH:17]([CH2:16][NH:15][C:2]2[S:3][C:4]3[CH2:10][CH2:9][O:8][C:7]4[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=4[C:5]=3[N:1]=2)[CH2:18][CH2:19]1)[CH2:25][CH3:26]
Reactant: CCC(=O)NC1CCC(CNc2nc3c(s2)CCOc2ccccc2-3)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCNC1CCC(CNc2nc3c(s2)CCOc2ccccc2-3)CC1
Temperature: 25 °C
Reaction time: 52 h
Yield: 76.9 %

Procedure:
To a stirred solution of N1-{4-[(4,5-dihydrobenzo[2,3]oxepino[4,5-d][1,3]thiazol-2-ylamino)methyl]cyclohexyl}propanamide (0.405 g, 1.05 mmol) in anhydrous THF (4 ml) was added 1M BH3 in THF (5.5 ml, 5.5 mmol). The solution was stirred at room temperature for 52 hours. 4N HCl (12 ml) was added slowly and stirring continued for 30 minutes thereafter. The solution was poured into 2N NaOH (60 ml) and extracted with EtOAc. The extract was washed with 10% brine, separated and evaporated to yield 77% (300 mg) of the amine as a viscous golden oil: 1H-NMR (CDCl3) δ 0.88 (3H, t), 1.06 (2H, m), 1.38 (2H, m), 1.49 (2H, m), 1.80 (6H, m), 2.40 (1H, m), 2.58 (2H, t), 3.15 (2H, m), 3.63 (2H, t), 4.30 (2H, t), 5.12 (1H, m), 6.98 (1H, d), 7.11 (2H, m), 8.23 (1H, dd); 400 (ESMS, MH+).
Reaction SMILES: [CH2:1]([N:4]([CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][CH:16]=1)[CH:5]1[CH2:13][CH2:12][C:8]2[N:9]=[CH:10][S:11][C:7]=2[CH2:6]1)[CH2:2][CH3:3].[C:24]1([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.OCCCCNC(=O)C1C=CC=CC=1>>[C:24]1([N:30]2[CH2:35][CH2:34][N:33]([C:19]([C:18]3[CH:22]=[CH:23][C:15]([CH2:14][N:4]([CH2:1][CH2:2][CH3:3])[CH:5]4[CH2:13][CH2:12][C:8]5[N:9]=[CH:10][S:11][C:7]=5[CH2:6]4)=[CH:16][CH:17]=3)=[O:20])[CH2:32][CH2:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CCCN(Cc1ccc(C(=O)Cl)cc1)C1CCc2ncsc2C1
Agent: O=C(NCCCCO)c1ccccc1
Product: CCCN(Cc1ccc(C(=O)N2CCN(c3ccccc3)CC2)cc1)C1CCc2ncsc2C1
Yield: 59 %

Procedure:
Compound 43 is prepared from 42C and 1-phenyl-piperazine as described for 1D.
Reaction SMILES: C(NCCCN1C2C(=O)N(C)C(=O)N(C)C=2N=C1)C1C=CC=CC=1.[CH3:25][C:26]1[NH:27][C:28]2[C:33]([CH:34]=1)=[C:32]([O:35]CC1OC1)[CH:31]=[CH:30][CH:29]=2>>[CH3:25][C:26]1[NH:27][C:28]2[C:33]([CH:34]=1)=[C:32]([OH:35])[CH:31]=[CH:30][CH:29]=2
Reactant: Cc1cc2c(OCC3CO3)cccc2[nH]1
Agent: Cn1c(=O)c2c(ncn2CCCNCc2ccccc2)n(C)c1=O
Product: Cc1cc2c(O)cccc2[nH]1

Procedure:
24.8 g of 7-(3-benzylaminopropyl)-theophylline are heated with stirring for 3 hours to 130° C. with crude 2-methyl-4-(2,3-epoxypropoxy)-indole obtained from 5.9 g of 2-methyl-4-hydroxy indole. Following the addition of chloroform and water, stirring is continued, the layers are separated, the chloroform phase is extracted by shaking twice with water, the chloroform extract is dried with sodium sulphate and the solvent is distilled off. The hydrochloride is precipitated from the alcoholic solution of the residue by acidification with alcoholic hydrochloric acid. The salt recrystallised from ethanol is hydrogenated in alcoholic solution at 60° C./6 atmospheres in the presence of 0.5 g of 5% palladium-carbon catalyst. The filtered reaction solution is concentrated by evaporation in vacuo, the residue is taken up in water and the base described in Example 29 is precipitated with 1N NaOH. Yield: 1.8 g; Melting point: 168°-170° C.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([OH:13])=O)=[N:9][CH:10]=1.[NH2:16][C:17]1[CH:18]=[C:19]([C:23]2([CH3:30])[NH:28][C:27](=[S:29])[CH2:26][O:25][CH2:24]2)[CH:20]=[CH:21][CH:22]=1>>[CH3:30][C:23]1([C:19]2[CH:18]=[C:17]([NH:16][C:11]([C:8]3[CH:7]=[CH:6][C:5]([O:4][CH2:3][C:2]([F:1])([F:15])[F:14])=[CH:10][N:9]=3)=[O:13])[CH:22]=[CH:21][CH:20]=2)[CH2:24][O:25][CH2:26][C:27](=[S:29])[NH:28]1
Reactant: CC1(c2cccc(N)c2)COCC(=S)N1
Reactant: O=C(O)c1ccc(OCC(F)(F)F)cn1
Product: CC1(c2cccc(NC(=O)c3ccc(OCC(F)(F)F)cn3)c2)COCC(=S)N1

Procedure:
In a reaction analogous to that described in example 6 (method B), the condensation of 5-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (CAS 881409-53-6) with Building block F, (RS)-5-(3-amino-phenyl)-5-methyl-morpholine-3-thione, yielded the title compound as a as light yellow oil (64% of theory). Mass (calculated) C19H18F3N3O3S [425.43]; (found) [M+H]+=426.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[CH2:15][CH2:16][C:17]([O:19]C)=[O:18])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1>Cl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:21])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCC(=O)c1ccc(-c2cccc(F)c2)cc1
Agent: Cl
Product: O=C(O)CCC(=O)c1ccc(-c2cccc(F)c2)cc1
Yield: 96.6 %

Procedure:
In a manner similar to Example 4, Step (b), 4-(3′-fluoro-biphenyl-4-yl)-4-oxo-butyric acid, methyl ester (1.0968 g, 0.00383 mol) was refluxed in 6 M aqueous hydrochloric acid (20 mL) to give 1.007 g of 4-(3′-fluoro-biphenyl-4-yl)-4-oxo-butyric acid as a pale orange solid; mp 153-155° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:24]=1[C:25]([NH2:27])=[O:26]>>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:23]2[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:24]=2[C:25]([NH2:27])=[O:26])[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1
Reactant: Cc1cccc(N)c1C(N)=O
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)nc(Cl)nc32)cc1
Product: Cc1ccc(S(=O)(=O)n2ccc3c(Nc4cccc(C)c4C(N)=O)nc(Cl)nc32)cc1

Procedure:
Using General Protocol II and starting with 2,4-dichloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (2.79 g, 8.2 mmol) and 2-amino-6-methylbenzamide (0.830 g, 5.46 mmol), 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-methylbenzamide was isolated as a yellow solid (0.960 g, 38% yield); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.32 (s, 3 H), 2.36 (s, 3 H), 6.49 (s, 1 H), 7.18-7.24 (m, 2 H), 7.30 (s, 1 H), 7.44-7.47 (m, 4 H), 7.56 (d, J=4.03 Hz, 1 H), 7.95 (d, J=8.43 Hz, 2 H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]=[C:10]=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:12]1[CH:16]=[C:15]([CH2:17][CH2:18][OH:19])[N:14]=[CH:13]1>>[C:1]1([CH2:7][CH2:8][NH:9][C:10](=[O:11])[O:19][CH2:18][CH2:17][C:15]2[N:14]=[CH:13][NH:12][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCc1c[nH]cn1
Reactant: O=C=NCCc1ccccc1
Product: O=C(NCCc1ccccc1)OCCc1c[nH]cn1

Procedure:
The preparation is carried out as in Example 23 with 2-phenylethyl isocyanate and 2-(1H-imidazol-4-yl)ethanol. The title compound is extracted from water with dichloromethane, purified by chromatography and crystallized in the hydrogenmaleate form from ethanol/diethyl ether.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH2:13][CH3:14])=[N:7]2.[NH2:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[S:23][C:24]1[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=1>>[CH3:22][C:20]1[CH:19]=[CH:18][C:17]([S:23][C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)=[C:16]([NH:15][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:21]=1
Reactant: Cc1ccc(Sc2ccc(O)cc2)c(N)c1
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Product: CCCc1ccc2c(Nc3cc(C)ccc3Sc3ccc(O)cc3)ccnc2n1

Procedure:
The product from Example 2g (275 mg, 0.133 mmol) was reacted with the product from Example 4c (231 mg, 0.133 mol) for 5 h following the procedure from Example 1g giving the title compound after purification of the crude product by HPLC with TFA as the trifluoroacetic acid salt (288 mg, 42%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.98 (t, J=7.35 Hz, 2H) 1.85 (m, 2H) 2.33 (s, 3H) 3.00 (t, J=7.35 Hz 2H) 6.29 (d, J=6.99 Hz, 1H) 6.73 (d, J=8.46 Hz, 2H) 7.00 (m, 2H) 7.19 (d, J=8.46 Hz, 2H) 7.27 (s, 1H) 7.83 (d, J=8.82 Hz, 1H) 8.43 (d, J=7.35 Hz, 1H) 9.04 (d, J=8.46 Hz, 1H) 9.90 (s, 1H) 11.04 (s, 1H) 14.40 (br. s, 1H); MS (ESI+) m/z 402 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:3]([C@@H:15]2[O:21][C@H:20]([CH2:22][O:23]C(=O)C)[C@@H:18]([OH:19])[C@H:16]2[OH:17])[C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][C:7]([Cl:13])=[C:6]([Cl:14])[CH:5]=2.[CH3:27][O-:28].[Na+].CO.C(Cl)(Cl)Cl.CO.O>CO>[Cl:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[Cl:14])[N:3]([C@@H:15]1[O:21][C@H:20]([CH2:22][OH:23])[C@@H:18]([OH:19])[C@H:16]1[OH:17])[C:2]([O:28][CH3:27])=[C:10]2[CH:11]=[O:12]
Reactant: C[O-]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(Cl)c(C=O)c3cc(Cl)c(Cl)cc32)[C@H](O)[C@@H]1O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1c(C=O)c2cc(Cl)c(Cl)cc2n1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 38 %

Procedure:
2,5,6-Trichloro-3-formyl-1-(5-O-acetyl-β-D-ribofuranosyl)indole (see Chen et al.; 4.24, 148 mg, 0.35 mmol) was dissolved in dry MeOH (20 mL) to which was added sodium methoxide (21 mg, 0.39 mmol). The solution was stirred at room temperature for 30 min, then the solvent was removed under vacuum. The residue was suspended in 10% aqueous NaHCO3, and the suspension extracted with EtOAc (2×50 mL). The combined organic extracts were dried over MgSO4, filtered and evaporated to yield a white solid. The solid was dissolved in MeOH (1 mL) and subjected to column chromatography (40×350 mm) on silica gel with 20% MeOH/CHCl3. Fractions containing product were pooled and evaporated to yield a white solid (the balance of recovered material was the deprotected 2-chloro derivative). The crude product was dissolved in MeOH and subjected to column chromatography (40×350 mm) on C18-reverse phase silica gel with 75% MeOH/H2O. Fractions containing product were pooled and evaporated to yield 50 mg (42%) of 4.25 as a white crystalline solid: mp 198-199° C.; Rf 0.2 (10% MeOH/CHCl3); 1H-NMR (500 MHz, DMSO-d6): δ 10.21 (s, 1H), 8.34 (s, 1H), 8.31 (s, 1H), 5.84 (d, 1H), 5.41 (d, 1H, D2O exch.), 5.30 (t, 1H, D2O exch.), 5.23 (d, 1H, D2O exch.), 4.41 (s, 4H), 4.13 (s, 1H), 3.95 (d, 1H), 3.69 (m, 2H). 13C-NMR (125 MHz, DMSO-d6): δ 183.28, 160.04, 129.51, 125.21, 124.83, 124.68, 121.12, 114.73, 100.30, 86.81, 85.93, 71.06, 69.75, 64.78, 61.18. HRMS (EI) m/z calcd. for C15H15Cl2NO6 375.0276, found 375.0278. Anal calcd for C15H15Cl2NO6: C, 47.89; H, 4.02; N, 3.72. Found: C, 47.73; H, 4.12; N, 3.72.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)=[CH:4][CH:3]=1.O1CCCC1.O=[C:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[N:7]1([CH2:6][C:5]2[CH:13]=[CH:14][C:2]([NH:1][CH:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)=[CH:3][CH:4]=2)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Nc1ccc(CN2CCOCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(CN3CCOCC3)cc2)CC1
Reaction time: 72 h

Procedure:
A flask containing 4-(4-aminobenzyl)morpholine from Preparation No. 22 (0.48 g) is treated with tetrahydrofuran (10 mL) and tert-butyl 4-oxo-1-piperidinecarboxylate (0.60 gm) under an argon atmosphere. The solution is treated with acetic acid (0.20 mL) followed by sodium triacetoxyborohydride (0.80 g). After stirring 3 days, the mixture is concentrated under reduced pressure. The residue is partitioned between dichloromethane and dilute aqueous sodium hydroxide. The aqueous is back-extracted with additional portions of dichloromethane. The combined organic layer is washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue is flash column chromatographed on silica gel eluting with 2% to 6% methanol in dichloromethane to afford 0.96 g of tert-butyl 4-[4-(4-morpholinylmethyl)anilino]-1-piperidinecarboxylate as a tan solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:58]=[CH:57][C:45]([C:46]([NH:48][CH2:49][CH2:50][C:51]2[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=2)=[O:47])=[CH:44][C:43]=1[CH3:59]>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:58]=[CH:57][C:45]([C:46]([NH:48][CH2:49][CH2:50][C:51]6[CH:52]=[N:53][CH:54]=[CH:55][CH:56]=6)=[O:47])=[CH:44][C:43]=5[CH3:59])[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: Cc1cc(C(=O)NCCc2cccnc2)ccc1Br
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3ccc(C(=O)NCCc4cccnc4)cc3C)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (70 mg) and 4-bromo-3-methyl-N-(2-pyridin-3-yl-ethyl)-benzamide (62 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product 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)-3-methyl-N-(2-pyridin-3-yl-ethyl)-benzamide was obtained, and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-302) as a pale brown powder (29 mg, 41%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C@H:16]1[CH2:21][CH2:20][C@@H:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]1.[Cl:26][C:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[C:29]([F:42])[C:28]=1[OH:43].C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>>[ClH:1].[ClH:26].[Cl:26][C:27]1[CH:32]=[C:31]([C:2]2[N:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C@H:16]2[CH2:21][CH2:20][C@@H:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]2)[CH:30]=[C:29]([F:42])[C:28]=1[OH:43]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@@H](CN(C)C)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1N[C@H]1CC[C@@H](CN(C)C)CC1

Procedure:
Following general procedure II, 1-(6-chloro-4-{cis-4-[(dimethylamino)methyl]-cyclohexyl amino}-1,5-naphthyridin-3-yl)ethanone (120 mg, 0.30 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (100 mg, 0.30 mmol) followed by formation of the dihydrochloride salt to afford the desired product (150 mg, 81%) as an off-white solid: 1H NMR (500 MHz, CD3OD) δ 9.17 (s, 1H), 8.46 (d, J=9.0 Hz, 1H), 8.45-8.30 (m, 1H), 7.99 (q, J=2.7, 1.7 Hz, 1H), 7.90-7.82 (m, 1H), 5.93 (p, J=4.2 Hz, 1H), 3.20 (d, J=7.1 Hz, 2H), 2.95 (s, 6H), 2.78 (s, 3H), 2.15 (dddt, J=44.4, 14.7, 11.4, 4.1 Hz, 3H), 2.01-1.86 (m, 2H), 1.61 (dtd, J=14.3, 10.8, 3.6 Hz, 3H), 1.20 (s, 1H); ESI MS m/z 471 [M+H]+; HPLC 95.7% (AUC), tR=9.9 min.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:25]=[CH:26][CH:27]=1)[CH2:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([C@@H:19]2[CH2:21][C@H:20]2[C:22]([OH:24])=O)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=[N:43][C:38]2[CH:39]=[CH:40][CH:41]=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.NCC1CC1>ClCCl.CN(C=O)C>[CH:39]1([CH2:38][NH:43][C:22]([CH:20]2[CH2:21][CH:19]2[C:16]2[CH:17]=[CH:18][C:13]([NH:12][CH2:11][C:10]3[CH:25]=[CH:26][CH:27]=[C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH:9]=3)=[CH:14][CH:15]=2)=[O:24])[CH2:41][CH2:40]1
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccc(NCc2cccc(Oc3ccccc3)c2)cc1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NCC1CC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NCC1CC1)C1CC1c1ccc(NCc2cccc(Oc3ccccc3)c2)cc1
Reaction time: 0.25 h
Yield: 9.7 %

Procedure:
To a mixture of (+)-(trans)-2-{4-[(3-phenoxybenzyl)amino]phenyl}cyclopropanecarboxylic acid (III-3b) (0.09 g, 0.25 mmol) in dichloromethane (2 mL) and DMF (1 mL) was added HATU (0.14 g, 0.37 mmol). The mixture was stirred for 15 min followed by addition of aminomethylcyclopropane (0.03 g, 0.37 mmol). The solution stirred for 4 h after which the dichloromethane was removed via rotavap. Sat. NaHCO3 and ethyl acetate were added and the organic layer separated and washed with H2O, dried over MgSO4, filtered and concentrated. The crude material was purified on silica gel eluting with an increasing gradient from hexanes to 30% ethyl acetate/hexanes to give the title compound as a white powder (0.01 g, 11%). 1H NMR (400 MHz, CDCl3) δ 7.34-7.28 (m, 3H), 7.10-7.08 (m, 2H), 7.02-6.98 (m, 3H), 6.92-6.89 (m, 3H), 6.55 (d, J=8.3 Hz, 2H), 5.68 (s, 1H), 4.29 (s, 2H), 4.01 (s, 1H), 3.15-3.12 (m, 2H), 2.39 (s, 1H), 1.57-1.46 (m, 2H), 1.17-1.14 (m, 1H), 0.95 (s, 1H), 0.51 (d, J=7.7 Hz, 2H), 0.20 (d, J=4.6 Hz, 2H). ES-MS m/z 413.3 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([Sn](C)(C)C)[S:10][C:3]=12.Br[C:16]1[N:21]=[CH:20][CH:19]=[CH:18][N:17]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:16]3[N:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[S:10][C:3]=12
Reactant: C[Sn](C)(C)c1cc2nccc(Cl)c2s1
Reactant: Brc1ncccn1
Product: Clc1ccnc2cc(-c3ncccn3)sc12
Yield: 40.4 %

Procedure:
This material was prepared by coupling 7-chloro-2-(trimethylstannyl)thieno[3,2-b]pyridine 39a (0.218 g, 0.66 mmole) with 2-bromopyrimidine (0.104 g, 0.66 mmole) using tereakis(triphenylphosphine) palladium(0) (31 mg) as catalyst in a manner as previously described for example 39b to give a white solid (0.066 g, 40%). 1H NMR (300 MHz, CDCl3) δ8.76 (2H, d, J=4.90 Hz), 8.57 (1H, d, J=5.1 Hz), 8.41 (1H, s), 7.26 (1H, d, J=5.1 Hz), 7.20 (1H, m); ESIMS (MH+): 248.00.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[CH:14][C:5]=1[C:6]([N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=[O:7])([O-])=O.[H][H]>[Pd].CO>[NH2:1][C:4]1[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:5]=1[C:6]([N:8]1[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1)=[O:7]
Reactant: [H][H]
Reactant: O=C(c1ccc([N+](=O)[O-])cc1[N+](=O)[O-])N1CCOCC1
Agent: [Pd]
Solvent: CO
Product: Nc1ccc(C(=O)N2CCOCC2)c(N)c1
Yield: 94.5 %

Procedure:
A two liter autoclave was charged with 130.6 g of N-(2,4-dinitrobenzoyl)morpholine, 1200 ml methanol and 6.2 g of a 5% palladium on carbon/50% water catalyst. The mixture was hydrogenated at 800 psi while maintaining the temperature between 60°-100° C. Hydrogen uptake ceased after 30 min. The mixture was cooled, filtered and methanol removed at reduced pressure. The residue was crystallized from toluene to yield 97.1 g of N-(2,4-diaminobenzoyl)morpholine, mp 114°-115° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:23][C:24]1([CH3:36])[CH:33]=[C:32]([CH3:34])[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([OH:35])[CH:30]=2)[NH:25]1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[N:5]=[CH:4][N:3]=[C:2]2[O:35][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24]([CH3:36])([CH3:23])[CH:33]=[C:32]2[CH3:34]
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Reactant: CC1=CC(C)(C)Nc2ccc(O)cc21
Product: COc1cc2c(Oc3ccc4c(c3)C(C)=CC(C)(C)N4)ncnc2cc1OCC1CCN(C)CC1
Yield: 73.7 %

Procedure:
Using a procedure analogous to that described for Example 9, 4-chloro-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazoline (0.13 g, 0.4 mmol), (prepared as described for the starting material in Example 10), was reacted with 2,2,4-trimethyl-1,2-dihydroquinolin-6-ol (95 mg, 0.5 mmol), (IZV. ACAD. NAVK. SSSR. Ser. Khim. 1981, 9, 2008), to give 6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)-4-(2,2,4-trimethyl-1,2-dihydroquinolin-6-yloxy)quinazoline (140 mg, 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH:15]=[CH:14][CH2:13][O:12]1)[C:5]([OH:7])=O.[Cl:17][C:18]1[CH:29]=[CH:28][C:21]2[NH:22][C:23]([C@@H:25]([NH2:27])[CH3:26])=[N:24][C:20]=2[CH:19]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N:11]1[CH2:16][CH:15]=[CH:14][CH2:13][O:12]1)[C:5]([NH:27][C@H:25]([C:23]1[NH:22][C:21]2[CH:28]=[CH:29][C:18]([Cl:17])=[CH:19][C:20]=2[N:24]=1)[CH3:26])=[O:7]
Reactant: C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: O=C(O)c1ccc(N2CC=CCO2)c(Cl)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)c1ccc(N2CC=CCO2)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 1f from 3-chloro-4-(3,6-dihydro-[1,2]oxazin-2-yl)-benzoic acid, (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-ethylamine, TBTU and NMM in DMF.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3([CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21](=[O:28])[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:14][CH2:13]3)[C:11](=[O:29])[N:10]([CH2:30][C:31]3[CH:32]=[C:33]([CH:41]=[CH:42][CH:43]=3)[C:34]([O:36]C(C)(C)C)=[O:35])[CH2:9]2)=[CH:4][CH:3]=1>Cl.O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]3([CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21](=[O:28])[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:14][CH2:13]3)[C:11](=[O:29])[N:10]([CH2:30][C:31]3[CH:32]=[C:33]([CH:41]=[CH:42][CH:43]=3)[C:34]([OH:36])=[O:35])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccc(F)cc3)C3(CCN(CCCC(=O)c4ccccc4)CC3)C2=O)c1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)c1cccc(CN2CN(c3ccc(F)cc3)C3(CCN(CCCC(=O)c4ccccc4)CC3)C2=O)c1
Yield: 27.6 %

Procedure:
A solution of tert-butyl 3-((1-(4-fluorophenyl)-4-oxo-8-(4-oxo-4-phenylbutyl)-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (100 mg, 0.171 mmol, 1 equiv) in 4M hydrogen chloride solution in dioxane was stirred at ambient temperature for 5 h. The mixture was concentrated in vacuo and purified using preparative thin layer chromatography in 10% methanol in dichloromethane to afford the title compound as white powder (25 mg, 23%); 1H NMR (400 MHz, DMSO-d6): δ 1.62 (d, 2H, J=14 Hz); 1.83 (t, 2H, J=6.8 and 7.2 Hz); 2.19-2.28 (m, 2H); 2.44 (t, 2H, J=6.8 Hz); 2.78 (bs, 4H); 3.03 (t, 2H, J=7.2 and 6.8 Hz); 4.54 (s, 2H); 4.59 (s, 2H); 6.81-6.85 (m, 2H); 6.99 (t, 2H, J=8.8 and 9.6 Hz); 7.49-7.53 (m, 4H); 7.62 (t, 1H, J=7.6 Hz); 7.86 (bs, 2H); 7.95-7.97 (m, 2H); 13.1 (bs, 1H); MS for C31H32FN3O4 m/z 530.4 (M+H)+.