Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([NH2:15])=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:4][C:3]=1[F:16].[CH:17]1([NH:20][C:21](=[O:25])[C:22](O)=O)[CH2:19][CH2:18]1.CC1C=CC=C(C)N=1.C(P1(=O)OP(=O)(CCC)OP(=O)(CCC)O1)CC>CC1CCCO1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9]3=[N:10][CH:11]=[CH:12][CH:13]=[C:14]3[N:15]=[C:22]2[C:21]([NH:20][CH:17]2[CH2:19][CH2:18]2)=[O:25])=[CH:4][C:3]=1[F:16]
Reactant: Nc1cccnc1Nc1ccc(Cl)c(F)c1
Reactant: O=C(O)C(=O)NC1CC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CC1CCCO1
Solvent: Cc1cccc(C)n1
Product: O=C(NC1CC1)c1nc2cccnc2n1-c1ccc(Cl)c(F)c1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A mixture of the mono-tosylate salt of N2-(4-chloro-3-fluorophenyl)pyridine-2,3-diamine (C12) [prepared via treatment of C12 with p-toluenesulfonic acid monohydrate (1.5 equivalents) in ethanol at 80° C., followed by cooling to room temperature and isolation via filtration] (1.003 g, 2.447 mmol), (cyclopropylamino)(oxo)acetic acid (P2) (0.304 g, 2.35 mmol), 2,6-dimethylpyridine (0.91 mL, 0.84 g, 7.8 mmol), and 2-methyltetrahydrofuran (10 mL) was cooled to −10° C. and treated with 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50 weight % solution in ethyl acetate, 4.3 mL, 4.6 g, 7.2 mmol). The reaction mixture was warmed to 0° C. and held for 1 hour, heated at reflux for 20 hours, and then cooled to 0° C. and filtered, rinsing with 2-methyltetrahydrofuran. The filtrate was sequentially washed with water (10 mL, 5 mL), with aqueous ammonium hydroxide solution (15%, 3×5 mL), with aqueous hydrochloric acid (0.1 M, 10 mL, 5 mL), and with water (10 mL). The organic layer was distilled to a volume of approximately 4 mL, diluted with 2-nnethyltetrahydrofuran (13 mL), and again distilled to approximately 4 mL, whereupon it was cooled to 50° C. and treated with heptane (3 mL). The resulting slurry was stirred at 50° C. for 2 hours, cooled to 20° C., and stirred for 12 hours. The solid was collected via filtration and washed with a mixture of heptane and 2-methyltetrahydrofuran (2:1, 5 mL). The resulting material (0.488 g) was reslurried in a mixture of 2-propanol and ethyl acetate (9:1, 4.9 mL), warmed to 40° C., cooled to 20° C., and stirred for 16 hours. Filtration and washing with 2-propanol (3 mL) afforded the product as an off-white solid. Yield: 410 mg, 1.24 mmol, 53%. LCMS m/z 330.9, 332.9 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.17 (d, J=4.8 Hz, 1H), 8.45 (d, J=4.5 Hz, 1H), 8.27 (d, J=8.0 Hz, 1H), 7.71-7.80 (m, 2H), 7.47 (dd, J=8.0, 4.8 Hz, 1H), 7.40 (br d, J=8.5 Hz, 1H), 2.77-2.86 (m, 1H), 0.65-0.69 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1.[Cl:24][C:25]1[C:26]([CH3:34])=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>>[Cl:24][C:25]1[C:26]([CH3:34])=[C:27]([C:2]2[CH:3]=[C:4]3[C:8]4=[C:9]([CH2:11][CH2:12][N:7]4[C@H:6]4[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[CH2:16][C@@H:5]34)[CH:10]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CC3
Reactant: Cc1c(Cl)cccc1B(O)O
Product: Cc1c(Cl)cccc1-c1cc2c3c(c1)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N3CC2

Procedure:
The title compound was prepared by the method of Example 89 step C from tert-butyl(6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)carboxylate (189 mg, 0.5 mmol) and 3-chloro-2-methylphenylboronic acid (140 mg, 1.0 mmol) to afford after chromatographic purification the title compound (99 mg, 47%). 1H NMR (CDCl3, 300 MHz) δ 7.28–7.31 (m, 1H), 7.10 (d, 2H, J=4.4 Hz), 6.85 (s, 1H), 6.81 (s, 1H), 3.82–4.24 (m, 2H), 3.64–3.74 (m, 1H), 3.24–3.54 (m, 4H), 2.86–3.26 (m, 3H), 1.86 (s, 3H),1.84–1.89 (m, 2H), 1.48 (s, 9H) ppm. MS-ApCI: 425 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:15](=[O:18])[NH:16][N:17]=2)[N:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:26][C:27]1[CH:32]=[N:31][CH:30]=[CH:29][N:28]=1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[C:3]2[N:4]([C:15](=[O:18])[N:16]([CH2:26][C:27]3[CH:32]=[N:31][CH:30]=[CH:29][N:28]=3)[N:17]=2)[N:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1
Reactant: ClCc1cnccn1
Reactant: O=c1[nH]nc2c(Cl)c(-c3ccc(Cl)cc3)cnn12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1n(Cc2cnccn2)nc2c(Cl)c(-c3ccc(Cl)cc3)cnn12
Temperature: 50 °C
Yield: 74 %

Procedure:
To a solution of 8-chloro-7-(4-chlorophenyl)-2H-[1,2,4]triazolo[4,3-b]pyridazin-3-one (0.62 g, 2.21 mmol), prepared as described in Example 354, in DMF (10 mL) at RT was added K2CO3 (0.61 g, 4.4 mmol) and 2-(chloromethyl)pyrazine (0.83 g). The reaction mixture was heated at 50° C. for 2 h. After this time, the mixture was diluted with EtOAc (150 mL). The resultant solution was washed with water and saturated aqueous NaCl. The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with hexanes:EtOAc 1:2 to afford 0.61 g of the title compound, 8-chloro-7-(4-chlorophenyl)-2-(pyrazin-2-ylmethyl)-2H-[1,2,4]triazolo[4,3-b]pyridazin-3-one as a yellow solid. HPLC RT: 2.86 min; MS, M+H=373; 1H NMR (CDCl3): δ 8.64 (d, 1H), 8.54 (m, 2H), 8.11 (s, 1H), 7.54-7.49 (m, 4H), 5.48 (s, 2H).
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH2:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2].[CH:57](OC)=[O:58]>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([NH:50][CH:57]=[O:58])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(N)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reactant: COC=O
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(NC=O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The compound 17-ethyl-1,14-dihydroxy-12-[2'-(4"-amino-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (30 mg) was mixed with methyl formate (0.5 ml) and stirred at 0° C. for 1 hr. The reaction mixture was allowed to warm to room temperature and then stirred overnight. The excess methylformate was removed with nitrogen flow and the crude mixture was purified by preparative tlc on silica gel (1000 microns, 5% i-PrOH/CH2Cl2) to give 25 mg of the title compound. (Mass, 1H and 13C data were consistent with the proposed structure).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[O:12][C:11]([CH:13]=[O:14])=[CH:10][CH:9]=2)[CH:3]=1.[CH:15]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1)=[O:16]>>[CH:15]([C:17]1[CH:22]=[CH:21][C:20]([C:7]2[CH:2]=[CH:3][C:4]([C:8]3[O:12][C:11]([CH:13]=[O:14])=[CH:10][CH:9]=3)=[N:5][CH:6]=2)=[CH:19][CH:18]=1)=[O:16]
Reactant: O=Cc1ccc(-c2cc(Br)ccn2)o1
Reactant: O=Cc1ccc(B(O)O)cc1
Product: O=Cc1ccc(-c2ccc(-c3ccc(C=O)o3)nc2)cc1
Yield: 91 %

Procedure:
The same procedure described for 12 was used by employing compound 41 (1 equiv.) and 4-formylphenyl boronic acid (1 equiv.). Yield 91%, mp 217-219° C. 1H NMR (DMSO-d6); δ 7.46 (d, J=3.6 Hz, 1H), 7.71 (d, J=3.6 Hz, 1H), 8.03-8.05 (m, 5H), 8.37 (dd, J=1.8, 8.4 Hz, 1H), 9.11 (d, J=1.8 Hz, 1H), 9.69 (s, 1H), 10.07 (s, 1H). Anal. Calc. for C17H11NO3: C %, 73.63; H %, 3.99. Found C %, 73.51; H %, 4.23.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C=O>[CH2:23]([O:1][C:2]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(OCc2ccc(Cl)cc2)cc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCc2ccc(Cl)cc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 75 %

Procedure:
A solution of methyl 2-hydroxy-4-(4-chlorobenzyloxy)benzoate (5.2 g) in dry dimethylformamide (DMF) (50 mL) is treated with NaH (60% dispersion, 0.71 g) and stirred at 25° C. for 20 minutes. Benzyl bromide (2.12 mL) is added and the solution heated at 60° C. for 2 hours. The solution is evaporated. The residue is dissolved in ethyl acetate, washed with water, dried, and evaporated. The residue is recrystallized from ethyl acetate to yield methyl 2-benzyloxy-4-(4-chlorobenzyloxy)benzoate as colourless crystals (5.1 g, 75%), m.p. 99-101° C. 1H NMR (DMSO) 3.8(3H,s),5.18 (2H,s), 5.21(2H,s), 6.7(1H,d), 6.85(1H,s), 7.3-7.5(9H,m), 7.75(1H,d).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][N:15]=[C:14](OS(C(F)(F)F)(=O)=O)[C:13]=1[N+:26]([O-:28])=[O:27].Cl.[CH3:30][O:31][CH2:32][CH:33]([NH2:36])[CH2:34][CH3:35]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:36][CH:33]([CH2:32][O:31][CH3:30])[CH2:34][CH3:35])[C:13]=1[N+:26]([O-:28])=[O:27]
Reactant: CCC(N)COC
Reactant: O=[N+]([O-])c1c(-c2ccc(C(F)(F)F)cc2Cl)ccnc1OS(=O)(=O)C(F)(F)F
Agent: Cl
Product: CCC(COC)Nc1nccc(-c2ccc(C(F)(F)F)cc2Cl)c1[N+](=O)[O-]
Yield: 89.2 %

Procedure:
Trifluoro-methanesulfonic acid 4-(2-chloro-4-trifluoromethyl-phenyl)-3-nitro-pyridin-2-yl-ester (0.50 g, 1.11 mmol), prepared substantially as described in Part C of Example 19a, and 1-methoxymethyl-propylamine HCl (0.31 g, 2.22 mmol) were treated substantially as described in Part C of Example 19a to produce 0.40 g (89%) of [4-(2-chloro-4-trifluoromethyl-phenyl)-3-nitro-pyridin-2-yl]-(1-methoxymethyl-propyl)-amine: MS (AP) m/z 403.8 [(M+H)+, 98].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][CH:7]1[NH2:18].Br[CH2:23][CH2:24][CH2:25][CH2:26]Br.C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][CH:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[CH2:9][CH2:8][CH:7]1[N:18]1[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: COc1ccc2c(c1)C(Cc1cccc(Cl)c1)C(N)CC2
Reactant: BrCCCCBr
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc2c(c1)C(Cc1cccc(Cl)c1)C(N1CCCC1)CC2

Procedure:
1-(3-Chlorobenzyl)-7-methoxy-1,2,3,4-tetrahydronaphthalen-2-amine (6 g, 19.88 mmol) was dissolved in acetonitrile (150 mL). 1,4-Dibromobutane (2.61 mL, 21.87 mmol) and triethylamine (6.1 mL, 43.7 mmol) were added and the reaction mixture heated under reflux for 3 h. The reaction mixture was poured on ice and extracted with dichloromethane. The combined organic extracts were successively washed with water and brine, dried (MgSO4) and the solvent was evaporated in vacuo. The crude product (6.6 g) was used for the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:22])[N:4]([CH3:21])[C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[Cl:23]N1C(=O)CCC1=O>C(Cl)Cl>[Cl:23][C:7]1[N:6]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:12][CH:13]=2)[N:4]([CH3:21])[C:3](=[O:22])[C:2]=1[OH:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cn1c(-c2ccc(Oc3ccccc3)cc2)ncc(O)c1=O
Solvent: ClCCl
Product: Cn1c(-c2ccc(Oc3ccccc3)cc2)nc(Cl)c(O)c1=O
Temperature: 50 °C
Yield: 17.9 %

Procedure:
To a solution of 50 mg (0.170 mmol) 5-hydroxy-3-methyl-2-(4-phenoxyphenyl)pyrimidin-4(3H)-one in 850 μl CH2Cl2 was added 23.8 mg (0.178 mmol)N-chlorosuccinimide. The reaction mixture was heated to 50° C. for 12 h, then cooled to rt, and concentrated in vacuo. Purification by HPLC gave 10.0 mg (18% yield) of 6-chloro-5-hydroxy-3-methyl-2-(4-phenoxyphenyl)pyrimidin-4(3H)-one. 1H NMR δ (ppm)(CDC3): 7.48-7.46 (2 H, m), 7.41-7.38 (2 H, m), 7.19 (1 H, d, 3=7.56 Hz), 7.09-7.05 (4 H, m), 6.43 (1 H, bs), 3.56 (3 H, s). FIRMS (ESI positive) calc (M+H)+=329.0687. Found 329.0693.
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].[H-].[Na+].Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([S:19]([NH2:22])(=[O:21])=[O:20])[CH:17]=2)[CH:12]=[CH:11][N:10]=1>CS(C)=O>[NH:4]([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([S:19](=[O:21])(=[O:20])[NH2:22])[CH:17]=2)[CH:12]=[CH:11][N:10]=1)[C:3]([NH2:5])=[NH:2]
Reactant: N=C(N)N
Reactant: NS(=O)(=O)c1ccc2ccnc(Cl)c2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: N=C(N)Nc1nccc2ccc(S(N)(=O)=O)cc12
Temperature: 60 °C
Yield: 85.5 %

Procedure:
Guanidine hydrochloride (42 mg, 0.44 mmol) was added in one portion to a suspension of NaH (13 mg, 80% dispersion by wt in mineral oil, 0.43 mmol) in DMSO (1.5 mL) and the mixture was heated at 60° C. under N2 for 30 min. 1-Chloro-7-isoquinolinesulphonamide (37 mg, 0.152 mmol) was added and the mixture heated at 100° C. for 24 h. The solvents were evaporated in vacuo and the residue was purified by column chromatography upon silica gel using CH2Cl2—MeOH-0.880NH3 (97:3:0.3 to 90:10:1) as eluant to give the title compound (34 mg, 0.13 mmol) as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@H:4]([CH2:25][OH:26])[NH:5][C:6]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:47]([O:54][C:55](=[O:68])[NH:56][CH2:57][CH2:58][CH2:59][CH2:60][C:61]1[CH:66]=[CH:65][C:64](O)=[CH:63][CH:62]=1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:27])[CH:4]([NH:5][C:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:25][O:26][C:64]1[CH:63]=[CH:62][C:61]([CH2:60][CH2:59][CH2:58][CH2:57][NH:56][C:55]([O:54][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)=[O:68])=[CH:66][CH:65]=1
Reactant: O=C(NCCCCc1ccc(O)cc1)OCc1ccccc1
Reactant: COC(=O)[C@H](CO)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: COC(=O)C(COc1ccc(CCCCNC(=O)OCc2ccccc2)cc1)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 336 h
Yield: 64.7 %

Procedure:
Commercially available N-trityl-L-serine methyl ester (1.60 g, 5.34 mmol) was combined with triphenylphosphine (1.28 g, 4.88 mmol) and [4-(4-hydroxyphenyl)butyl]carbamic acid benzyl ester (2.0 g, 6.68 mmol) in benzene (40 mL) at room temperature. Diisopropyl azodicarboxylate (0.958 mL, 4.86 mmol) was added dropwise and the reaction was stirred for 14 days. The solvent was removed under reduced pressure and the residue was purified by column chromatography (silica gel, eluent: 6:1, v/v dichloromethane/ethyl acetate) to provide compound 10 (2.22 g, 51%). 1H NMR (300 MHz, CDCl3) δ 7.52 (m, 6H), 7.39-7.14 (m, 14H), 7.06 (d, 2H), 6.79 (d, 2H), 5.09 (s, 2H), 4.72 (m, 1H), 4.24 (m, 1H), 4.01 (m, 1H), 3.72 (m, 1H), 3.22 (s, 3H), 3.18 (m, 2H), 2.88 (d, 1H), 2.57 (m, 2H), 1.66-1.48 (m, 4H). Rf=0.91 (5:1 v/v dichloromethane/ethyl acetate).
Reaction SMILES: [CH2:1]([N:3]([CH2:36][CH3:37])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30](O)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[F:69][C:70]1[CH:76]=[CH:75][C:73]([NH2:74])=[CH:72][CH:71]=1>CN(C=O)C>[CH2:36]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([NH:74][C:73]2[CH:75]=[CH:76][C:70]([F:69])=[CH:71][CH:72]=2)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:37]
Reactant: CCN(CC)CCCNc1nc(-c2cccc(C(=O)O)c2)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: Nc1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)CCCNc1nc(-c2cccc(C(=O)Nc3ccc(F)cc3)c2)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.5 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]benzoic acid (30 mg, 0.06 mmol) in DMF (0.5 mL) were added HBTU (27 mg, 0.072 mmol), triethylamine (16.9 uL, 0.12 mmol) and 4-fluoroaniline (8.64 uL, 0.09 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (20 mg, 55.5%). LC-MS m/z 601 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=3)=[CH:9][N:8]([CH:20]([CH3:22])[CH3:21])[C:4]=2[N:5]=[CH:6][N:7]=1.[Cl-].[NH4+]>[Fe].O>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:3]3[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=3[N:8]([CH:20]([CH3:22])[CH3:21])[CH:9]=2)=[CH:12][CH:13]=1
Reactant: CC(C)n1cc(-c2ccc([N+](=O)[O-])cc2)c2c(Cl)ncnc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: CC(C)n1cc(-c2ccc(N)cc2)c2c(Cl)ncnc21

Procedure:
A mixture of 4-chloro-7-isopropyl-5-(4-nitrophenyl)pyrrolo[2,3-d]pyrimidine (1.0 g), iron powder (1.76 g), ammonium chloride (86 mg), water (8 ml) and industrial methylated spirit (40 ml) was boiled under reflux for one hour. The mixture was filtered and the solvent evaporated. The residue was taken up in ethyl acetate and washed with water. The ethyl acetate extract was dried, filtered and evaporated to give 5-(4-aminophenyl)-4-chloro-7-isopropylpyrrolo[2,3-d]pyrimidine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([OH:11])[NH:8][N:7]=1)=[O:5])[CH3:2].[C:12](=O)([O-])[O-].[Cs+].[Cs+].IC>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([O:11][CH3:12])[NH:8][N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(O)[nH]n1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CI
Product: CCOC(=O)c1cc(OC)[nH]n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 38 %

Procedure:
5-Hydroxy-1H-pyrazole-3-carboxylic acid ethyl ester (300 mg, 1.92 mmol) was dissolved in anhydrous N,N-dimethylformamide (DMF) (35 ml) and cesium carbonate (626 mg, 1.92 mmol) was added. The resulting suspension was treated with iodomethane (120 μl, 273 mg, 1.92 mmol) and stirred for 12 h at room temperature. The reaction mixture was quenched with saturated potassium hydrogen sulfate solution and extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with water (50 ml) and brine (50 ml). The extract was dried over sodium sulfate, evaporated and the crude product was purified by column chromatography on silica gel. Elution with ethyl acetate/n-heptane (1:3) yielded 124 mg (38%) of a white solid.
Reaction SMILES: C([N:3]1[CH2:18][CH2:17][CH2:16][C:6]2=[N:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:14]([Cl:15])=[C:5]2[CH2:4]1)C.Cl[C:20]([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21]>>[C:23]1([O:22][C:20]([N:3]2[CH2:18][CH2:17][CH2:16][C:6]3=[N:7][C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=4[C:14]([Cl:15])=[C:5]3[CH2:4]2)=[O:21])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCN1CCCc2nc3ccccc3c(Cl)c2C1
Product: O=C(Oc1ccccc1)N1CCCc2nc3ccccc3c(Cl)c2C1
Yield: 18.5 %

Procedure:
11-Chloro-2,3,4,5-tetrahydro-1H-2-azepino[4,3-b]quinoline-carboxylic acid phenyl ester was prepared analogous to Example 98 from 2-ethyl-11-chloro-2,3,4,5-tetrahydro-1H-azepino[4,3-b]quinoline and phenyl chloroformate.
Reaction SMILES: [Na+].[F:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([O-])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.S(Cl)([Cl:23])=O>CN(C)C=O>[F:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([Cl:23])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: O=S(=O)([O-])c1ccc(OCc2ccc(F)cc2)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1ccc(OCc2ccc(F)cc2)cc1

Procedure:
To a stirred solution of 4-hydroxybenzenesulfonic acid sodium salt dihydrate (5.13 g, 22.1 mmol) in 23 mL of 1 N sodium hydroxide was added a solution of 4-fluorobenzyl bromide (3.3 mL, 26.5 mmol) in 20 mL of ethanol. The mixture was heated at reflux for two days, then cooled to ambient temperature (22° C.), whereupon a white precipitate formed. The flaky white solids were collected by filtration, rinsed with ethyl acetate and diethyl ether, and dried to give 4.95 g of 4-(4-fluoro-benzyloxy)-benzenesulfonic acid sodium salt. A stirred solution of 4-(4-fluoro-benzyloxy)-benzenesulfonic acid sodium salt (13.0 g, 42.7 mmol) in 50 mL of thionyl chloride and two drops of dimethylformamide was heated at a gentle reflux for 8 hours. The mixture was concentrated to a yellow solid which was suspended in ethyl acetate and filtered. The filtrate was concentrated to 11.2 g of 4-(4-fluorobenzyloxy)benzenesulfonyl chloride as a light yellow solid: 1H NMR (400 MHz, CDCl3) δ 7.95-7.98 (m, 2 H), 7.38-7.41 (m, 2 H), 7.06-7.12 (m, 4 H), 5.12 (s, 2 H).
Reaction SMILES: [CH3:1][C:2]1[C:11]([N+]([O-])=O)=[CH:10][C:9]([CH3:15])=[C:8]2[C:3]=1[C:4]([O:16][CH3:17])=[CH:5][CH:6]=[N:7]2.C(O)C.[OH-].[NH4+:22]>O>[NH2:22][C:4]1([O:16][CH3:17])[C:3]2[C:8](=[C:9]([CH3:15])[CH:10]=[CH:11][C:2]=2[CH3:1])[N:7]=[CH:6][CH2:5]1
Reactant: [NH4+]
Reactant: COc1ccnc2c(C)cc([N+](=O)[O-])c(C)c12
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COC1(N)CC=Nc2c(C)ccc(C)c21

Procedure:
In a flask is placed 5,8-dimethyl-4-methoxy-6-nitroquinoline (1.16 g, 5.0 mmol) with stannous chloride dihydrate (5.64 g, 25 mmol) and ethanol (50 mL). The mixture is refluxed for 1 hour, diluted with water (100 mL) and concentrated ammonium hydroxide (30 mL), and extracted with chloroform (2×200 mL). The organic portion is dried over potassium carbonate, filtered and the solvents removed by rotary evaporation, yielding 4-amino-5,8-dimethyl-4-methoxyquinoline.