Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:25]=[CH:24][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[CH3:26][NH:27][CH3:28]>>[CH3:26][N:27]([CH3:28])[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:25]=[CH:24][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1
Reactant: FC(F)(F)c1ccc(-c2nsc3cc(OCCCCBr)ccc23)cc1
Reactant: CNC
Product: CN(C)CCCCOc1ccc2c(-c3ccc(C(F)(F)F)cc3)nsc2c1

Procedure:
According to the method in example 7, 6-(4-Bromo-butoxy)-3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazole and Dimethylamine were converted to yield Dimethyl-{4-[3-(4-trifluoromethyl-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-amine, MS: 395 (MH+).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:3]1.Cl[CH2:27][C:28]1[CH:29]=[CH:30][C:31]2[O:36][C:35]([CH3:38])([CH3:37])[C:34](=[O:39])[N:33]([CH2:40][CH2:41][CH2:42][O:43][CH3:44])[C:32]=2[CH:45]=1>>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:16]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:17])[CH2:3][CH:2]2[O:1][CH2:27][C:28]2[CH:29]=[CH:30][C:31]3[O:36][C:35]([CH3:38])([CH3:37])[C:34](=[O:39])[N:33]([CH2:40][CH2:41][CH2:42][O:43][CH3:44])[C:32]=3[CH:45]=2)=[CH:13][CH:12]=1
Reactant: COCCCN1C(=O)C(C)(C)Oc2ccc(CCl)cc21
Reactant: COc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2O)cc1
Product: COCCCN1C(=O)C(C)(C)Oc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OC)cc3)cc21

Procedure:
Analogously to Method D, 0.500 g of benzyl 3-hydroxy-4-(4-methoxyphenyl)piperidine-1-carboxylate and 0.505 g of 6-chloromethyl-4-(3-methoxypropyl)-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one are reacted. The title compound is obtained as an orange oil. Rf=0.17 (1:1 EtOAc-heptane); Rt=5.51.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([OH:9])=O)[CH:4]=[N:3][C:2]=1[C:10]1[N:15]=[CH:14][CH:13]=[CH:12][N:11]=1.[Cl-].[F:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([NH3+:27])[CH:22]=[C:21]2[CH3:28].CCN(C(C)C)C(C)C.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>CN(C=O)C>[F:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][CH:26]=1)[N:23]([NH:27][C:7]([C:5]1[CH:4]=[N:3][C:2]([C:10]3[N:15]=[CH:14][CH:13]=[CH:12][N:11]=3)=[N:1][CH:6]=1)=[O:9])[CH:22]=[C:21]2[CH3:28]
Reactant: Cc1cn([NH3+])c2ccc(F)cc12
Reactant: O=C(O)c1cnc(-c2ncccn2)nc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cn(NC(=O)c2cnc(-c3ncccn3)nc2)c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 56 %

Procedure:
A mixture of [2,2′]bipyrimidinyl-5-carboxylic acid (166 mg, 0.82 mmol), 5-fluoro-3-methyl-indol-1-yl-ammonium chloride (164 mg, 0.82 mmol) and DIPEA (106 mg, 0.82 mmol) in DMF (5 mL) is stirred at rt for 5 min. 4-(4,6-Dimethoxy-[1,3,5]triazin-2-yl)-4-methyl-morpholin-4-ium chloride (226 mg, 0.82 mmol) is added. The reaction mixture is heated to 50° C. for 1.5 h and then concentrated in vacuo. The residue is taken up in DMSO-d6 and then purified via reverse phase C18 HPLC chromatography eluting with water and acetonitrile containing 0.1% TFA buffer to afford [2,2]bipyrimidinyl-5-carboxylic acid (5-fluoro-3-methyl-indol-1-yl)-amide (56%). MS: 349 (M+H); 1H NMR (300 MHz, CDCl3): δ=2.27 (s, 3H), 7.05 (dt, 1H), 7.33 (s, 1H), 7.36 (dd, 1H), 7.42-7.46 (m, 1H), 7.72 (t, 1H), 9.07 (d, 2H), 9.51 (s, 2H), 12.17 (s, 1H).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:11]([OH:12])=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH2:13][CH2:14][NH:15][C:16](=[O:18])[CH3:17])=[CH:5][CH:4]=1.[CH:19]1([C:22](Cl)=[O:23])[CH2:21][CH2:20]1.O>N1C=CC=CC=1>[C:16]([NH:15][CH2:14][CH2:13][CH:9]1[C:10]2[C:6](=[CH:5][CH:4]=[C:3]([NH:2][C:22]([CH:19]3[CH2:21][CH2:20]3)=[O:23])[C:11]=2[OH:12])[CH2:7][CH2:8]1)(=[O:18])[CH3:17]
Reactant: CC(=O)NCCC1CCc2ccc(N)c(O)c21
Reactant: O=C(Cl)C1CC1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)NCCC1CCc2ccc(NC(=O)C3CC3)c(O)c21
Reaction time: 3 h
Yield: 106.7 %

Procedure:
N-[2-(6-Amino-7-hydroxy-2,3-dihydro-1H-inden-1-yl)ethyl]acetamide hydrochloride (100 mg, 0.369 mmol) was dissolved in pyridine (4 mL), cyclopropylcarbonyl chloride (36.8 μL, 0.406 mmol) was added under ice-cooling, and the mixture was stirred for 3 hr. Water was added to the reaction solution, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/methanol=100/0→95/5) to give the title compound (119 mg, yield 100%).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[H-].[Na+].I[CH3:15]>CN(C=O)C>[CH3:15][N:6]1[C:7]2[C:3](=[C:2]([CH3:1])[CH:10]=[C:9]([CH3:11])[CH:8]=2)[CH:4]=[CH:5]1
Reactant: CI
Reactant: Cc1cc(C)c2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C)c2ccn(C)c2c1
Yield: 84.5 %

Procedure:
A solution of the 4,6-dimethylindole (750 mg, 5.2 mmol) in DMF (20 mL) is cooled to 0° C. under nitrogen and is treated with 60% sodium hydride in mineral oil (413 mg, 10.3 mmol). After stirring for 15 minutes the iodomethane (0.4 mL, 6.2 mmol) is introduced and the cooling bath is removed. After 30 minutes the solution is quenched with water (5 ml) and then concentrates to reduce the volume of DMF. The reaction is poured into a mixture of water (200 mL) and EtOAc (100 mL). The layers are separated and the aqueous phase is extracted with EtOAc (3×200 mL). The combined organics are washed with water (3×), dried (MgSO4), filtered and concentrated. The residue is purified by flash chromatography with 10% EtOAc in Hexane as the eluent to afford 1,4,6-Trimethyl-1H-indole (700 mg, 80%) as a white solid.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][O:6][N:7]=[C:8]([O:10][CH2:11][CH3:12])[CH3:9].[CH3:14][NH2:15]>CO>[CH2:11]([O:10][C:8](=[N:7][O:6][CH2:5][CH2:4][C:3](=[O:2])[NH:15][CH3:14])[CH3:9])[CH3:12]
Reactant: CN
Reactant: CCOC(C)=NOCCC(=O)OC
Solvent: CO
Product: CCOC(C)=NOCCC(=O)NC
Temperature: 60 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
To a solution of a known compound, 3-(1-ethoxyethylideneaminooxy)-propanoic acid methyl ester (CAS No. 97164-30-2, 41.3 g, 0.218 mol) in methanol (150 ml) was added methylamine (40% solution in methanol, 200 ml) at room temperature, and the mixture was stirred at 60° C. for 12 hours. The reaction mixture was concentrated under reduced pressure to give N-(2-methylcarbamoyl-ethoxy)-acetimidic acid ethyl ester (41.0 g, 100%).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2[CH:33]=[CH:32][C:14]([O:15][C:16]3[CH:25]=[C:24]4[C:19]([CH:20]([C:26]([O:28][CH3:29])=[O:27])[CH2:21][CH2:22][O:23]4)=[CH:18][C:17]=3[C:30]#[N:31])=[CH:13][CH:12]=2)=[O:10])[CH:5]=[CH:4][CH:3]=1.[CH3:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][C:40]=1[CH3:41].C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>O>[C:30]([C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:16]=1[O:15][C:14]1[CH:32]=[CH:33][C:11]([C:9](=[O:10])[NH:8][C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([C:37]4[CH:38]=[CH:39][C:40]([CH3:41])=[C:35]([CH3:34])[CH:36]=4)[N:7]=3)=[CH:12][CH:13]=1)[O:23][CH2:22][CH2:21][CH:20]2[C:26]([O:28][CH3:29])=[O:27])#[N:31]
Reactant: Cc1ccc(B(O)O)cc1C
Reactant: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(Br)n4)cc3)c(C#N)cc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(-c5ccc(C)c(C)c5)n4)cc3)c(C#N)cc21
Temperature: 100 °C
Reaction time: 16 h
Yield: 95.5 %

Procedure:
Methyl 7-(4-(6-bromopyridin-2-ylcarbamoyl)phenoxy)-6-cyanochroman-4-carboxylate (51 mg, 0.1003 mmol), 3,4-dimethylphenylboronic acid (19.562 mg, 0.1304 mmol), sodium carbonate (31.901 mg, 0.301 mmol), toluene (1 mL), and water (0.1 mL) were placed in a vial with a Teflon lined screw cap. Argon was bubbled through the mixture for 10 minutes. Palladium (0) tetrakistriphenylphosphine (5.797 mg, 0.00501 mmol) was added and the vial was sealed. The vial was placed in a preheated sand bath (100° C.) and the mixture was stirred for 16 hours at that temperature. The mixture was cooled to ambient temperature and whole mixture was purified on silica gel (EtOAc-hexanes gradient) to provide 51.1 mg of the title compound as a thin film (95.5%).
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:8]([NH2:13])=[CH:9][N:10]=[N:11][CH:12]=1.[CH3:15]CCCCCC.C(OCC)(=O)C>>[CH3:15][NH:13][C:8]1[C:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:14])=[CH:12][N:11]=[N:10][CH:9]=1
Reactant: Cc1ccccc1-c1cnncc1N
Reactant: CCCCCCC
Solvent: CCOC(C)=O
Product: CNc1cnncc1-c1ccccc1C

Procedure:
The title compound was prepared in analogy to example 8, intermediate a, from 5-o-tolyl-pyridazin-4-ylamine and using a gradient of n-heptane:ethyl acetate (100:0 to 40:60) for the chromatographic purification. Light yellow solid (71%). MS (EI): m/z=199 ([M]).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][C:14](OC)=[C:13]([CH:19]=O)[CH:12]=2)[CH:3]=1.CN.[C:23]([BH3-])#[N:24].[Na+].[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31]>C(O)(=O)C.CO>[C:27]([OH:34])(=[O:33])/[CH:28]=[CH:29]/[C:30]([OH:32])=[O:31].[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:19][NH:24][CH3:23])[CH:12]=2)[CH:3]=1
Reactant: COc1ccc(Oc2cc(Cl)ccc2C#N)cc1C=O
Reactant: [BH3-]C#N
Agent: CN
Agent: O=C(O)/C=C/C(=O)O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CNCc1cccc(Oc2cc(Cl)ccc2C#N)c1
Yield: 67.5 %

Procedure:
4-Chloro-2-(3-formyl-4-methoxy-phenoxy)-benzonitrile (1.00 g, 3.48 mmol), methylamine (2M in methanol, 5.2 ml, 10.4 mmol) and sodium cyanoborohydride (0.24 g, 3.8 mmol) were stirred at ambient temperature in a 1% acetic acid/methanol solution (75 ml) for 18 h. The solvent was removed in vacuo. The residue was treated with 10% aqueous sodium carbonate and extracted with ethyl acetate. The ethyl acetate layer was separated and washed with water, brine and dried over MgSO4. After filtration, fumaric acid (0.40 g, 3.4 mmol) was added to the filtrate and the solvent removed in vacuo. The residue was triturated with ethyl acetate overnight, filtered and dried to give 4-chloro-2-(3-methylaminomethyl-phenoxy)-benzonitrile fumarate (892 mg, 61%) as a white solid.
Reaction SMILES: [C:1]([NH2:4])(=[S:3])[CH3:2].Br.Br[CH2:7][C:8]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=O.[OH-].[NH4+]>CO.O>[CH3:2][C:1]1[S:3][CH:7]=[C:8]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[N:4]=1
Reactant: O=C(CBr)c1cccnc1
Reactant: CC(N)=S
Agent: Br
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1nc(-c2cccnc2)cs1
Reaction time: 1 h
Yield: 77.2 %

Procedure:
A solution of thioacetamide (5 g) in methanol (25 ml) was added dropwise to a stirred suspension of 3-bromoacetylpyridine hydrobromide (17,75 g) in methanol (89 ml) at room temperature over ten minutes. After about one hour, the hydrobromide of the product crystallized out. The mixture was diluted with ether (100 ml) and the product was isolated by filtration. The solid was dissolved in water and the solution was basified with ammonium hydroxide. The product was extracted into ether and the extract was washed with saturated salt solution, then evaporated to give 2-methyl-4-(pyridin-3-yl)-thiazole as a crystalline solid (8,6 g) Mp 81° C.
Reaction SMILES: [Li+].[I-].[CH2:3]([Mg]Br)[CH2:4][CH2:5][CH2:6][CH3:7].Cl[C:11](=[O:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13]>C1COCC1>[O:17]=[C:11]([CH2:3][CH2:4][CH2:5][CH2:6][CH3:7])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(=O)Cl
Reactant: CCCCC[Mg]Br
Agent: [I-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCCC(=O)C(=O)OCC
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 23.7 %

Procedure:
To a suspension of LiI (23.61 g, 176.44 mmol) in THF (200 mL) at rt was slowly added Cu2Br2 (25.30 g, 88.22 mmol). A vigorous exothermic reaction occurred, and the mixture was then cooled to −78° C. Pentylmagnesium bromide (2M, 36.76 mL, 88.22 mmol) was slowly added at −78° C., and followed soon after by ethyl chloro(oxo)acetate (10 g, 73.52 mmol). The resulting solution was stirred 10 minutes at −78° C., then quenched by dropwise addition of water. The mixture was allowed to warm to rt, and then the organic phase was separated, dried (MgSO4), and evaporated. Purification by flash chromatography using 9:1 hexane/EtOAc as eluant gave ethyl 2-oxoheptanoate as a colorless oil (3.0 g, 23%). 1NMR (400 MHz, CDCl3) δ 4.33-4.21 (m, 2 H), 2.82 (m, 2 H), 1.63-1.59 (m, 2 H), 1.63-11.19 (m, p H), 0.9-0.83 (m, 3 H), LC-MS m/z 279.21 (MH+), retention time 2.42 min (method 2).
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:17]=[C:16]([C:18]([Cl:21])([Cl:20])[Cl:19])[N:15]=[C:14]([N:22]4[CH2:27][CH:26]5[CH2:28][CH2:29][CH:23]4[CH2:24][N:25]5C(OC(C)(C)C)=O)[N:13]=3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.O1CCOCC1>C(Cl)(Cl)Cl>[ClH:19].[N:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:12]3[N:17]=[C:16]([C:18]([Cl:20])([Cl:19])[Cl:21])[N:15]=[C:14]([N:22]4[CH2:27][CH:26]5[CH2:28][CH2:29][CH:23]4[CH2:24][NH:25]5)[N:13]=3)=[CH:10][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CC2CCC1CN2c1nc(-c2ccc(N3CCCC3)cc2)nc(C(Cl)(Cl)Cl)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: ClC(Cl)(Cl)c1nc(-c2ccc(N3CCCC3)cc2)nc(N2CC3CCC2CN3)n1
Temperature: 25 °C
Yield: 181.3 %

Procedure:
Deprotected a solution of the product of Step 1 (1.1 g, 1.98 mmol) in anhydrous CHCl3 (18 mL) with 4N HCl in dioxane (18 mL, 71.6 mmol) under N2. Stirred at room temperature for >18 h, then concentrated. Added diethyl ether (60 mL) and CH2Cl2 (5 mL) and stirred for 1 h. Filtered resulting solid, washed with ether and CH2Cl2, and dried to give the title compound (0.88 g) as a yellow solid. MS, calc'd=452.10. Obsv'd m/z: 453.10 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:30](=[CH:31][CH:32]=1)[C:8]1[NH:9][C:10]([C@@H:12]3[C@H:17]4[CH2:18][C@H:14]([CH2:15][CH2:16]4)[N:13]3[C:19](=[O:29])[C@@H:20]([NH:24][C:25](=[O:28])[O:26][CH3:27])[CH:21]([CH3:23])[CH3:22])=[N:11][C:7]=1[CH:6]=[CH:5]2.CC1(C)C(C)(C)OB([C:41]2[CH:42]=[C:43]3[C:63](=[CH:64][CH:65]=2)[C:47]2[NH:48][C:49]([C@@H:51]4[CH2:55][CH2:54][CH2:53][N:52]4[C:56]([O:58][C:59]([CH3:62])([CH3:61])[CH3:60])=[O:57])=[N:50][C:46]=2[CH:45]=[CH:44]3)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.C(OCC)(=O)C>[CH3:27][O:26][C:25]([NH:24][C@@H:20]([CH:21]([CH3:23])[CH3:22])[C:19]([N:13]1[C@H:12]([C:10]2[NH:9][C:8]3[C:30]4[C:4]([CH:5]=[CH:6][C:7]=3[N:11]=2)=[CH:3][C:2]([C:41]2[CH:42]=[C:43]3[C:63](=[CH:64][CH:65]=2)[C:47]2[NH:48][C:49]([C@@H:51]5[CH2:55][CH2:54][CH2:53][N:52]5[C:56]([O:58][C:59]([CH3:61])([CH3:62])[CH3:60])=[O:57])=[N:50][C:46]=2[CH:45]=[CH:44]3)=[CH:32][CH:31]=4)[C@H:17]2[CH2:18][C@@H:14]1[CH2:15][CH2:16]2)=[O:29])=[O:28]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2[nH]1
Reactant: COC(=O)N[C@H](C(=O)N1[C@H]2CC[C@H](C2)[C@H]1c1nc2ccc3cc(Br)ccc3c2[nH]1)C(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)N[C@H](C(=O)N1[C@H]2CC[C@H](C2)[C@H]1c1nc2ccc3cc(-c4ccc5c(ccc6nc([C@@H]7CCCN7C(=O)OC(C)(C)C)[nH]c65)c4)ccc3c2[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 67.1 %

Procedure:
Methyl (S)-1-((1S,3S,4R)-3-(7-bromo-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-3-methyl-1-oxobutan-2-ylcarbamate (0.300 g, 0.601 mmol), (S)-tert-butyl 2-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate (0.334 g, 0.721 mmol), and aqueous potassium phosphate (2M, 0.901 mL, 1.802 mmol) were suspended in 1,2-dimethoxyethane (3.00 mL) and sparged with argon gas for 30 minutes. Palladium tetrakis triphenylphosphine (0.069 g, 0.060 mmol) was added and the reaction mixture was capped and placed in a preheated 80° C. oil bath. The solution was heated for 18 hours and subsequently stirred at room temperature for two days. Upon completion, the reaction was diluted with ethyl acetate and washed with brine. The concentrated organic layer was purified by normal phase chromatography (40-100% ethyl acetate (10% MeOH) in hexanes) to give (S)-tert-butyl 2-(2′-((1S,3S,4R)-2-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)-2-azabicyclo[2.2.1]heptan-3-yl)-1H,1′H-7,7′-binaphtho[1,2-d]imidazol-2-yl)pyrrolidine-1-carboxylate (0.305 g, 67%). LCMS-ESI+: calc'd for C44H49N7O5: 755.38 (M+); Found: 756.8 (M+H+).
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[CH:9][C:10]([F:15])=[C:11](Cl)[CH:12]=2)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]1.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>N1C=CC=CC=1>[F:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[CH:9][C:10]([F:15])=[C:11]([N:24]3[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]3)[CH:12]=2)[C:7](=[O:16])[C:6]([C:17]([OH:19])=[O:18])=[CH:5]1
Reactant: O=C(O)c1cn(CCF)c2cc(Cl)c(F)cc2c1=O
Reactant: CN1CCNCC1
Solvent: c1ccncc1
Product: CN1CCN(c2cc3c(cc2F)c(=O)c(C(=O)O)cn3CCF)CC1
Yield: 56.9 %

Procedure:
A mixture of 1-(2-fluoroethyl)-6-fluoro-7-chloro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (0.72 g) (2.5 millimole), N-methylpiperazine (1.25 g) (12.5 millimole) and 2 ml pyridine was heated at 135°-145° C. for 10 hours. After cooling, the mixture was evaporated under vacuum. The residue was acidified with acetic acid. The undissolved matter was filtered off. The filtrate was neutralized with an aqueous solution of caustic soda. The presipitate was filtered, washed and dried and recrystallized from a mixture of DMF and ethanol. 0.50 g (57%) of 1-(2-fluoroethyl)-6-fluoro-7-(4-methyl-1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid was obtained.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=2)[CH:6]=1.O.O.Cl[Sn]Cl.[OH-].[K+]>C(O)C>[CH3:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=2)[CH:6]=1
Reactant: Cc1cn(-c2ccc([N+](=O)[O-])cc2)cn1
Agent: Cl[Sn]Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cn(-c2ccc(N)cc2)cn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 10152.9 %

Procedure:
4-(4-methyl-1H-imidazol-1-yl)nitrobenzene (22.5 g; 0.87 mmol) is dissolved in abs. ethanol (250 mL), then SnCl2.2H2O (125 g; 0.55 mol) is added portion-wise, on cooling at 0° C. The resulting mixture is stirred at r.t. for 2 hours and heated at reflux overnight. The reaction mixture is then cooled at r.t. and the pH is adjusted to 12, by adding 30% KOH (500 mL), then KOH pellets under stirring. The resulting suspension is filtered and the cake is washed with ethanol, the combined filtrate and washings are concentrated and the residue is extracted with DCM. Concentration of the combined organic extracts afforded the title product as a slight brown solid (15.3 g; 80%), m.p.: 122-125° C. C10H11N3, MW 173.22.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[C:10]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[N:11][C:12]([CH3:29])=[C:13]([CH3:28])[C:14]=1[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24].[CH2:37]([O:39][CH2:40][C:41](Cl)=[O:42])[CH3:38]>ClCCl>[CH2:37]([O:39][CH2:40][C:41]([NH:8][C:9]1[C:10]([O:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[N:11][C:12]([CH3:29])=[C:13]([CH3:28])[C:14]=1[NH:15][CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:42])[CH3:38]
Reactant: CCOCC(=O)Cl
Reactant: Cc1nc(Oc2ccccc2)c(N)c(NCCCCNC(=O)OC(C)(C)C)c1C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOCC(=O)Nc1c(Oc2ccccc2)nc(C)c(C)c1NCCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Triethylamine (3.3 mL, 23.7 mmol) was added to a chilled (0° C.) mixture of tert-butyl 4-[(3-amino-5,6-dimethyl-2-phenoxypyridin-4-yl)amino]butylcarbamate (8.60 g, 21.5 mmol) and anhydrous dichloromethane (200 mL). Ethoxyacetyl chloride (2.76 g, 22.5 mmol) was added. After one hour the reaction mixture was allowed to warm to ambient temperature and stirred for 2 hours. The reaction mixture was concentrated under reduced pressure to provide tert-butyl 4-({3-[(ethoxyacetyl)amino]-5,6-dimethyl-2-phenoxypyridin-4-yl}amino)butylcarbamate as a brown oil. The oil was combined with pyridine (130 mL) and heated at reflux overnight. The reaction mixture was concentrated under reduced pressure to provide a brown oil. The oil was dissolved in dichloromethane and was washed with water. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was dissolved in diethyl ether and then concentrated under reduced pressure to provide 8.21 g of tert-butyl 4-[2-(ethoxymethyl)-6,7-dimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridin-1-yl]butylcarbamate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[CH:7]=[C:8]([C:25]1[S:26][C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[N:29]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[CH2:21][CH2:20][CH2:19][NH:18][C:17]=2[N:16]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO.C(O)C>[C:1]([O:5][C:6](=[O:34])[CH2:7][CH:8]([C:25]1[S:26][C:27]2[CH:33]=[CH:32][CH:31]=[CH:30][C:28]=2[N:29]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[CH2:21][CH2:20][CH2:19][NH:18][C:17]=2[N:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C=C(CCCCCCc1ccc2c(n1)NCCC2)c1nc2ccccc2s1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CO
Product: CC(C)(C)OC(=O)CC(CCCCCCc1ccc2c(n1)NCCC2)c1nc2ccccc2s1

Procedure:
To a stirred suspension of 10% palladium on carbon (50 mg) in methanol (5 mL) was added a solution of 3-(benzothiazol-2-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-non-2-enoic acidtert-butyl ester 29-7c (190 mg) in ethanol (5 mL) and the mixture was subjected to an atmosphere of hydrogen for 48 hours. The reaction mixture was filtered through Celite and concentrated at reduced pressure. The resulting oil was purified by flash column chromatography over silica gel with 4:1 hexanes/acetone to give 29-8c as a colorless oil.
Reaction SMILES: F[C:2]1[N:7]=[C:6]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][C:12]([O:21][CH3:22])=[CH:13][C:14]=3[O:19][CH3:20])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.Cl.Cl.[N:25]1([CH:31]([CH3:34])[CH2:32][OH:33])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.CN(C)C(N(C)C)=N>CS(C)=O.O>[OH:33][CH2:32][CH:31]([N:25]1[CH2:30][CH2:29][N:28]([C:2]2[N:7]=[C:6]([C:8]3[NH:17][C:16](=[O:18])[C:15]4[C:10](=[CH:11][C:12]([O:21][CH3:22])=[CH:13][C:14]=4[O:19][CH3:20])[N:9]=3)[CH:5]=[CH:4][CH:3]=2)[CH2:27][CH2:26]1)[CH3:34]
Reactant: CC(CO)N1CCNCC1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cccc(F)n3)nc2c1
Agent: CN(C)C(=N)N(C)C
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cccc(N4CCN(C(C)CO)CC4)n3)nc2c1
Temperature: 85 °C
Yield: 54.4 %

Procedure:
A mixture of 2-(6-fluoropyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.202 g, 0.67 mmol), 2-(piperazin-1-yl)propan-1-ol dihydrochloride (0.292 g, 1.34 mmol) and 1,1,3,3-tetramethylguanidine (0.310 g, 2.69 mmol) in dry DMSO (1.5 mL) was heated at 85° C. for 6 h. After that time the reaction was cooled to rt, diluted with water (15 mL) and extracted with ethyl acetate (2×30 mL). The combined organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 97:3 dichloromethane/methanol to 95:5 dichloromethane/methanol) to give 2-(6-(4-(1-hydroxypropan-2-yl)piperazin-1-yl)pyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.155 g, 54%) as a yellow solid: mp 202-204° C.; 1H NMR (400 MHz, CDCl3) δ 10.30 (s, 1H), 7.87 (d, J=7.42 Hz, 1H), 7.64-7.72 (m, 1H), 6.79-6.88 (m, 2H) 6.49 (d, J=2.34 Hz, 1H) 3.99 (s, 3H), 3.94 (s, 3H), 3.61-3.72 (m, 4H), 3.38-3.52 (m, 2H), 2.89-2.99 (m, 1H), 2.78-2.88 (m, 2H), 2.54-2.64 (m, 2H), 0.97 (d, J=6.64 Hz, 3H); ESI MS m/z 426 [M+H]+.