Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][CH:8]=[C:7]([C:15]#[N:16])[C:6]2=O.O=P(Cl)(Cl)[Cl:20].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Cl:20][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][C:7]=1[C:15]#[N:16]
Reactant: COc1cc2[nH]cc(C#N)c(=O)c2cc1OC
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Temperature: 70 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
A mixture of 6,7-dimethoxy-4-oxo-1,4-dihydroquinoline-3-carbonitrile (from Step B, 20 g, 87 mmol) and POCl3 (87 mL) was heated to reflux and allowed to stir for 2 hours. The reaction mixture was cooled to 70° C. and concentrated in vacuo to provide a crude residue. The crude residue was diluted with methylene chloride and the resultant solution was cooled to 0° C. and to the resultant solution was added aqueous K2CO3 until the solution was at pH 8-9. The resultant solution was allowed to stir for 30 minutes at 25° C., then transferred to a separatory funnel. The organic layer was collected, washed with water, dried over sodium sulfate, filtered through celite, and concentrated in vacuo to provide 4-chloro-6,7-dimethoxyquinoline-3-carbonitrile as an off-white solid (19.8 g, 92%). A sample recrystallized from methylene chloride was characterized as follows: mp 220-223° C.; 1H NMR (DMSO-d6)δ 8.98 (s, 1H), 7.54 (s, 1H), 7.42 (s, 1H), 4.02 (s, 3H), 4.01 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:9])[CH:5]=[CH:6][C:7]=1[F:8].[OH-].[Na+].I[CH2:13][CH3:14]>CO>[Br:1][C:2]1[CH:3]=[C:4]([S:9][CH2:13][CH3:14])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Fc1ccc(S)cc1Br
Reactant: CCI
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCSc1ccc(F)c(Br)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 98.4 %

Procedure:
A mixture of 3-bromo-4-fluorobenzenethiol (3.89 g, 18.8 mmol) and 5M sodium hydroxide (3.95 mL, 19.7 mmol) in methanol (40 mL) was stirred at 0° C. for 10 minutes. To this solution was added iodoethane (1.803 mL, 22.54 mmol). The reaction mixture was stirred at ambient temperature for 6 hours. The solvent was removed, and the residue was partitioned between water and ethyl acetate. The aqueous layer was extracted with addition ethyl acetate three times. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated to give the title compound (4.35 g, 98%). It was used directly for the next reaction.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]2=[C:7](C(O)=O)[N:8]=[CH:9][N:4]2[CH:3]=1>C(O)(=O)C>[Br:1][C:2]1[S:6][C:5]2=[CH:7][N:8]=[CH:9][N:4]2[CH:3]=1
Reactant: O=C(O)c1ncn2cc(Br)sc12
Solvent: CC(=O)O
Product: Brc1cn2cncc2s1
Temperature: 25 °C
Yield: 14.1 %

Procedure:
A solution of 2-bromoimidazo[5,1-b]thiazole-7-carboxylic acid (36 mg, 0.14 mmol) in acetic acid (1 ml) was heated under reflux for 2 days. The reaction solution was allowed to cool to room temperature and was then concentrated by removal of the solvent under the reduced pressure, and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=1:1) to give 2-bromoimidazo[5,1-b]thiazole (4 mg, 14%) as a white solid.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=O)[NH:16][N:15]=2)=[CH:10][CH:9]=1>O>[Cl:3][C:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14]([C:11]2[CH:12]=[CH:13][C:8]([O:7][CH3:6])=[CH:9][CH:10]=2)=[N:15][N:16]=1
Reactant: COc1ccc(-c2n[nH]c(=O)c3ccccc23)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Product: COc1ccc(-c2nnc(Cl)c3ccccc23)cc1
Yield: 74 %

Procedure:
With cooling with ice, 25 ml of phosphorus oxychloride was added to 95.05 g (20 mmol) of the obtained 4-(4-methoxyphenyl)-2H-phthalazin-1-on, and the reaction liquid was stirred under reflux for 6 hours. Water was added to the reaction liquid, extracted with chloroform, and the organic layer was washed with saturated saline water. This was dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 4.00 g (yield: 74%) of 1-chloro-4-(4-methoxyphenyl)-phthalazine as a white solid.
Reaction SMILES: [CH3:1][C:2]([NH:5][C:6]([C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N:9]=1)=[O:7])([CH3:4])[CH3:3].C([Li])CCC.[Cl:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[CH2:24]Cl.O>O1CCCC1.[Br-].[Na+].C(OCC)(=O)C>[Cl:20][C:21]1[CH:22]=[C:23]([CH2:24][CH2:14][C:13]2[C:8]([C:6]([NH:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: Cc1cccnc1C(=O)NC(C)(C)C
Reactant: ClCc1cccc(Cl)c1
Agent: [Br-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)NC(=O)c1ncccc1CCc1cccc(Cl)c1
Temperature: -40 °C
Reaction time: 0.17 h
Yield: 105.7 %

Procedure:
To a cold (-40° C.) solution of N-(1,1-dimethylethyl)-3-methyl-2-pyridinecarboxamide (31.5 g; 0.16 mol) in 600 mL of dry tetrahydrofuran was added n-butyllithium in hexanes (2.5 mol; 131 mL) while the temperature was maintained at -40° C. The solution turned deep red after one equivalent was added. Sodium bromide (1.6 g) was added and the mixture was stirred for 10 min. A solution of m-chlorobenzyl-chloride (26.5 g; 0.174 mol) in 125 mL of dry tetrahydrofuran (THF) was added while the temperature was again maintained at -40° C. The reaction mixture was stirred for a further 30 min. after which water was carefully added until the color dissipated. The product was isolated by extraction into ethyl acetate which was washed with water, dried (MgSO4) and concentrated to give 53.6 g (HPLC purity 89%; yield 92%) of 3-[2-(3-chlorophenyl)ethyl]-N-(1,1-dimethylethyl)-2-pyridine carboxamide as an oil. This oil may be used directly in the next step or crystallized from hexanes to give 3-[2-(3-chlorophenyl)ethyl]-N-(1,1-dimethylethyl)-2-pyridine carboxamide as a white solid: m.p. 45°-46° C.; NMR (200 MHz,CDCl3)δ1.50 (s,9H), 2.96 (t,2H,J=8 Hz); 3.40 (t,2H,J=8 Hz); 7.0-7.3 (m,5H); 7.39 (dd,1H,J=8, 2 Hz); 7.98 (br s, 1H); 8.30 (dd,1H, J=4, 1 Hz); mass spectrum, m/e (rel intensity) 316M+ (19). Anal. Calcd for C18H21N2OCl: C,68.22; H,6.68; N,8.88; Cl,11.19. Found: C,68.25; H,6.59; N,8.78; Cl,11.10.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH:13][CH2:14][CH:15]([CH2:17][OH:18])[OH:16].C1C=CC=CC=1.[F:25][C:26]1[CH:27]=[C:28]([N:39]2[CH2:43][C@H:42]([CH2:44][NH:45][C:46](=[O:48])[CH3:47])[O:41][C:40]2=[O:49])[CH:29]=[CH:30][C:31]=1[N:32]1[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1>O>[F:25][C:26]1[CH:27]=[C:28]([N:39]2[CH2:43][C@H:42]([CH2:44][NH:45][C:46](=[O:48])[CH3:47])[O:41][C:40]2=[O:49])[CH:29]=[CH:30][C:31]=1[N:32]1[CH2:33][CH2:34][C:35]2([O:16][CH:15]([CH2:17][OH:18])[CH2:14][O:13]2)[CH2:36][CH2:37]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=O)CC3)c(F)c2)C(=O)O1
Reactant: OCC(O)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)OCC(CO)O4)c(F)c2)C(=O)O1
Temperature: 25 °C
Yield: 84 %

Procedure:
Para-toluenesulfonic acid monohydrate (299 mg) and glycerol (0.21 ml) were added successively to a benzene suspension (10 ml) of 500 mg of the (S)-N-{3-[3-fluoro-4-(4-oxo-piperidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (Compound No. 7) which was synthesized in Example 3, and the mixture was heated under reflux for 4 h, with water being removed continuously by means of a water separator. After the reaction mixture was cooled to room temperature, a saturated aqueous sodium hydrogencarbonate solution was added and the mixture was stirred. Thereafter, the solution was extracted with methylene chloride and the organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The solvent was evaporated under vacuum and the residue was purified by silica gel column chromatography (solvent: chloroform/methanol=50/1-25/1) to afford the title compound (510 mg) in a yield of 84%.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=O)[CH2:8][CH2:7]2)([O-:3])=[O:2].C(C1C(=O)C([Cl:25])=C(Cl)C(=O)C=1C#N)#N.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[Cl:25][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[CH:12][CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:10]=1
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc2nc(Cl)ccc2c1
Temperature: 90 °C
Yield: 50 %

Procedure:
6-Nitro-3,4-dihydro-1H-quinolin-2-one (12.56 g, 65.4 mmol) was suspended in toluene (200 mL), to which DDQ (15.06 g, 66.3 mmol) was added. Phosphoryl trichloride (30.5 mL, 327 mmol) was then added dropwise and the reaction mixture was then heated at 90° C. for 3 hours. It was then observed that the deep red semi-solution had become an orange free flowing suspension, which LC-MS confirmed contained desired product. The reaction mixture was then poured slowly into ice water (1 L), keeping temperature below 10° C. This solution was then neutralized to pH 7 via slow addition of 2.5M aq. sodium hydroxide, keeping temperature below 10° C. This brown suspension was then extracted with ethyl acetate. The aqueous layer was back extracted further with ethyl acetate, and the combined organic layers were washed with brine. The resulting orange/brown solution was dried over MgSO4, filtered and concentrated to afford a brown/orange solid, which was dried under high vacuum overnight. The mass of dry material (2-chloro-6-nitro-quinoline) was 7.2 g (50% yield).
Reaction SMILES: [CH2:1]([C:3]1[S:24][C:6]2=[N:7][C:8]([CH3:23])=[C:9]([CH2:18][C:19]([O:21]C)=[O:20])[C:10]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)=[C:5]2[C:4]=1[CH3:25])[CH3:2].[O-2].[Li+].[Li+].Cl>O1CCOCC1.O>[CH2:1]([C:3]1[S:24][C:6]2=[N:7][C:8]([CH3:23])=[C:9]([CH2:18][C:19]([OH:21])=[O:20])[C:10]([C:11]3[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=3)=[C:5]2[C:4]=1[CH3:25])[CH3:2]
Reactant: CCc1sc2nc(C)c(CC(=O)OC)c(-c3ccc(C)cc3)c2c1C
Agent: Cl
Agent: [Li+]
Agent: [O-2]
Solvent: C1COCCO1
Solvent: O
Product: CCc1sc2nc(C)c(CC(=O)O)c(-c3ccc(C)cc3)c2c1C
Temperature: 65 °C
Yield: 58.1 %

Procedure:
To a solution of methyl 2-(2-ethyl-3,6-dimethyl-4-p-tolylthieno[2,3-b]pyridin-5-yl)acetate (0.077 g; 0.218 mmol) in dioxane (5 mL) and water (1.4 mL) was added a 1N lithium oxide solution (1.4 mL; 1.40 mmol). The reaction mixture was heated at 65° C. for 2 h. After cooling to room temperature, the reaction mixture was acidified with 1N HCl (pH˜2) and partially concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was crystallized from a mixture of ethyl acetate/heptane to afford 0.043 g (58%) of the title compound as a white powder.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[CH:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:10]=2[CH2:9]1)=O)(C)(C)C.C(OC(N1CCC(=O)CC1)=O)(C)(C)C.ClC1C=CC=CC=1CN.[N+](C=CC1C=CC=CC=1)([O-])=O>>[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([CH2:23][N:14]2[C:11]3[CH2:12][CH2:13][NH:8][CH2:9][C:10]=3[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15]2)=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(c(-c3ccccc3)cn2Cc2ccc(Cl)cc2)C1
Agent: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: NCc1ccccc1Cl
Agent: O=[N+]([O-])C=Cc1ccccc1
Product: Clc1ccc(Cn2cc(-c3ccccc3)c3c2CCNC3)cc1

Procedure:
1-(4-Chloro-benzyl)-3-phenyl-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester. The desired compound (405.6 mg) was prepared from 0.53 g of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 334 μL of 2-chlorobenzylamine, and 0.34 g of (2-nitro-vinyl)-benzene as in Example 1, Step A. MS (ESI): exact mass calculated for C25H27ClN2O2, 422.18. found, m/z 423.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[N:13][C:14]([C:16]([OH:18])=O)=[CH:15][C:10]=3[N:9]=[CH:8]2)=[CH:4][CH:3]=1.Cl.[CH2:22]([O:25][NH2:26])[CH:23]=[CH2:24]>>[CH2:22]([O:25][NH:26][C:16]([C:14]1[N:13]=[CH:12][C:11]2[N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:20][CH:19]=3)[CH:8]=[N:9][C:10]=2[CH:15]=1)=[O:18])[CH:23]=[CH2:24]
Reactant: C=CCON
Reactant: O=C(O)c1cc2ncn(Cc3ccc(F)cc3)c2cn1
Agent: Cl
Product: C=CCONC(=O)c1cc2ncn(Cc3ccc(F)cc3)c2cn1

Procedure:
The title compound was prepared by coupling of 3-(4-fluorobenzyl)-3H-imidazo[4,5-c]pyridine-6-carboxylic acid and N-allyloxyamine hydrochloride under the same conditions as those in step (c) of example 1. 1H NMR (300 MHz, MeOH-d4) δ: 8.71 (s, 1H), 8.53 (s, 1H), 8.31 (s, 1H), 7.40-7.33 (m, 2H), 7.09-7.01 (m, 2H), 6.01-5.99 (m, 1H), 5.57 (s, 2H), 5.40-5.20 (m, 2H), 4.41 (d, 2H, J=6.0 Hz). LCMS (API-ES, M+H+): 327.0.1. HRMS calcd for C17H16FN4O2 (M+H) 327.1257, found 327.1248. HPLC: 100% purity.
Reaction SMILES: [CH2:1]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[S:29]1[CH:33]=[N:32][N:31]=[C:30]1[NH2:34].Cl>N1C=CC=CC=1>[CH2:1]([C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:34][C:30]2[S:29][CH:33]=[N:32][N:31]=2)(=[O:27])=[O:26])=[CH:21][CH:20]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1nncs1
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCc1ccc(S(=O)(=O)Nc2nncs2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 51.3 %

Procedure:
To a solution of p-octadecylbenzenesulfonyl chloride (500 mg, 1.17 mmol) in pyridine (8 mL) was added 1,3,4-thiadiazol-2-amine (177 mg, 1.75 mmol). The reaction mixture was stirred at room temperature for 6 hours, then 2 M HCl (40 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (3×50 mL), the organic layer was washed with water (40 mL) and brine (40 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by chromatography over silica gel (70-230 mesh) eluted with methanol:DCM 1:19 to give the product as a solid (296 mg, 0.60 mmol, 51% yield), mp 116-117° C.; 1H NMR (300 MHz, CDCl3) δ 0.86 (t, 3H, J=6.9 Hz), 1.25 (m, 30H), 1.60 (m, 2H), 2.64 (t, 2H, J=7.8 Hz), 7.29 (d, 2H, J=7.8 Hz), 7.82 (d, 2H, J=7.8 Hz), 8.21 (s, 1H); 13C NMR (75 MHz, CDCl3) 14.0, 22.7, 29.2, 29.3, 29.4, 29.5, 29.6, 29.7, 31.1, 31.9, 35.9, 126.5, 128.9, 138.1, 142.6, 148.6, 167.4; MS (LCQ, ESI+) Calcd for C26H44N3O2S2 494.3. found 494.2 (M+H)+. HRMS (ESI+, m/z) Calcd for C26H44N3O2S2 494.2869. found 494.2869 (M+H)+.
Reaction SMILES: C(O[C:4](=[O:15])[C:5](=[CH:11]OCC)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:9]([O:8][C:6]([C:5]1[C:4](=[O:15])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[NH:16][CH:11]=1)=[O:7])[CH3:10]
Reactant: Nc1ccccc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)c1c[nH]c2ccccc2c1=O
Temperature: 260 °C
Yield: 74.2 %

Procedure:
31.7 g (147 mmol) of 2-Ethoxymethylene-malonic acid diethyl ester and 13.7 g (147 mmol) of aniline were stirred neat at 110° C. for 1 h, then 300 mL of diphenyl ether was added and the temperature of the oil bath was raised to 260° C. for 2 h. The solution was then cooled down to rt, diluted with 600 mL of hexanes and filtered. The solids were washed with 200 mL of hexanes and dried to yield 23.7 g of the product as a light brown powder. LC-MSD, m/z for C12H11NO3 [M+H]+=218.2, HPLC retention time: 2.5 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[N:20][N:21]([CH:23]2[CH2:28][CH2:27][CH2:26][N:25]([CH3:29])[CH2:24]2)[CH:22]=1.[Cl:30][C:31]1[CH:36]=[C:35](B2OC(C)(C)C(C)(C)O2)[CH:34]=[C:33]([Cl:46])[C:32]=1[OH:47]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C:18]2[CH:19]=[N:20][N:21]([CH:23]4[CH2:28][CH2:27][CH2:26][N:25]([CH3:29])[CH2:24]4)[CH:22]=2)=[CH:3][C:2]([C:35]2[CH:36]=[C:31]([Cl:30])[C:32]([OH:47])=[C:33]([Cl:46])[CH:34]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:15][CH2:16]1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CN1CCCC(n2cc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Product: CN1CCCC(n2cc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(Cl)c(O)c(Cl)c5)cc34)cn2)C1
Yield: 84.7 %

Procedure:
Following general procedure F, {6-Bromo-4-[1-(1-methylpiperidin-3-yl)-1H-pyrazol-4-ylamino]quinolin-3-yl}(cyclopropyl)methanone (53 mg, 0.110 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (47 mg, 0.165 mmol) to afford the desired product (50 mg, 84%) as a green-yellow solid: 1H NMR (500 MHz, DMSO-d6) δ 10.83 (s, 1H), 9.06 (s, 1H), 8.23 (d, J=2.1 Hz, 1H), 8.04 (dd, J=8.7, 2.1 Hz, 1H), 7.93-7.85 (m, 2H), 7.50 (s, 2H), 7.43 (s, 1H), 4.22-4.12 (m, 1H), 2.94 (d, J=11.4 Hz, 2H), 2.88-2.79 (m, 1H), 2.39 (s, 3H), 2.27-2.20 (m, 2H), 2.02-1.89 (m, 4H), 1.02-0.91 (m, 4H); ESI MS m/z 536 [C28H27Cl2N5O2+H]+; HPLC 98.6% (AUC), tR=10.40 min.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][O:6][C@@H:7]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[CH:29]=1)[C@@H:8]1[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]1)C.[BH4-].[Na+]>CO>[F:27][C:23]1[C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[CH:29]=2)=[C:21]([C@H:7]([O:6][CH2:5][CH2:4][OH:3])[C@@H:8]2[O:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:9]2)[CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)CO[C@@H](c1cccc(F)c1-c1cccc(C)c1)[C@H]1CN(C(=O)OC(C)(C)C)CCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cccc(-c2c(F)cccc2[C@H](OCCO)[C@H]2CN(C(=O)OC(C)(C)C)CCO2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.5 %

Procedure:
To a solution of (R)-tert-butyl 2-((S)-(2-ethoxy-2-oxoethoxy)(6-fluoro-3′-methylbiphenyl-2-yl)methyl)morpholine-4-carboxylate (570 mg, 1.17 mmol) in CH3OH (20 mL) at rt, NaBH4 (355 mg, 9.36 mmol) was added in portions. The mixture was stirred for ˜0.5 h at rt and then evaporated. The residue was partitioned between water and EtOAc. The combined organic layers were washed with brine, dried over anhydrous NaSO4 and evaporated to give semi-crude (R)-tert-butyl 2-((S)-(6-fluoro-3′-methylbiphenyl-2-yl)(2-hydroxyethoxy)methyl)morpholine-4-carboxylate (498 mg, 96%), which was used in the next step reaction without further purification. MS (E/Z): 446 (M+H+)
Reaction SMILES: COC(=O)[CH2:4][C@H:5]([N:9]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:10][CH2:11][C:12](OC)=O)[C:6]([OH:8])=O.C[O-].[Na+].CO.[C:29](N)(C)(C)[CH3:30]>C1COCC1>[CH:6]([CH:5]1[N:9]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:10][CH2:11][C:12]2([CH2:30][CH2:29]2)[CH2:4]1)=[O:8]
Reactant: CC(C)(C)N
Reactant: COC(=O)CCN(C(=O)OC(C)(C)C)[C@@H](CC(=O)OC)C(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC2)CC1C=O
Temperature: 85 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
To a solution of (S)-2-[tert-Butoxycarbonyl-(2-methoxycarbonyl-ethyl)-amino]-succinic acid 4-methyl ester (intermediate 12, 420 g, 1.35 mol) in THF (2 L) under nitrogen cooled to 0° C. was added NaOMe/MeOH (1.5 L, 2.7M) in half an hour. The resulting yellow solution was stirred at 85° C. for 3 hours (after 1 hour a suspension was obtained). THF (1.5 L) was distilled off under the reduced pressure and water (2 L) was added. The resulting mixture was stirred at 110° C. for 20 hours. The mixture was washed with ethyl acetate (2×1 L). The aqueous solution was cooled to 0° C. and the value of pH was adjusted to 2.5 with concentrated HCl. The product was extracted with ethyl acetate (3×1 L) and the organic extracts were combined, washed with saturated NaCl (1 L), dried (Na2SO4) and filtered. The filtrate was cooled to 0° C. and tert-butylamine (145 ml, 1.35 mol) was added with stirring. The yellow solid was collected by filtration and dried, then boiled in isopropyl alcohol (1.5 L). The suspension was cooled to 5° C. and collected by filtration to give 180 g of intermediate 3 (light white solid, yield:45%).
Reaction SMILES: [C:1]1(=[O:43])[N:5]([CH2:6][CH2:7][CH2:8][C:9]([CH2:24][CH2:25][CH2:26][N:27]2[C:31](=[O:32])[C:30]3=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]3[C:28]2=[O:37])(C(OC(C)(C)C)=O)[C:10]([O:12]C(C)(C)C)=[O:11])[C:4](=[O:38])[C:3]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:2]12.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:28]1(=[O:37])[N:27]([CH2:26][CH2:25][CH2:24][CH:9]([CH2:8][CH2:7][CH2:6][N:5]2[C:4](=[O:38])[C:3]3=[CH:39][CH:40]=[CH:41][CH:42]=[C:2]3[C:1]2=[O:43])[C:10]([OH:12])=[O:11])[C:31](=[O:32])[C:30]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]12
Reactant: CC(C)(C)OC(=O)C(CCCN1C(=O)c2ccccc2C1=O)(CCCN1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C(O)C(CCCN1C(=O)c2ccccc2C1=O)CCCN1C(=O)c2ccccc2C1=O
Yield: 86.3 %

Procedure:
A mixture of di-tert-butyl Bis(3-phthalimidopropyl)malonate (Step A) (6 g, 10.16 mmol), a catalytic amount of PTSA in 60 mL of toluene is heated to reflux for 4 hours. The reaction is cooled and a solid is filtered and dried. The solid is heated neat (under a nitrogen atmosphere) for 2 hours. From this procedure 3.81 g of Bis(3-phthalimidopropyl)acetic acid is isolated.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:2]=1.Br[CH2:14][C:15]#[N:16]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH2:8][CH2:9][N:10]([CH2:14][C:15]#[N:16])[CH2:11][CH2:12]2)[CH:2]=1
Reactant: c1cncc(N2CCNCC2)c1
Reactant: N#CCBr
Product: N#CCN1CCN(c2cccnc2)CC1

Procedure:
The title compound is synthesized by coupling of 1-Pyridin-3-yl-piperazine and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a white solid; ES-MS: M+=203.2: AtRet=1.10.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]2[O:22][CH:21]=[C:20]([C:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=3)[C:15]=2[CH:16]=[N:17][C:18]=1[NH2:19])[CH3:11].C[Si]([N:33]=[C:34]=[O:35])(C)C.CN(C=O)C.CCN(C(C)C)C(C)C>>[NH2:19][C:18]1[N:17]=[CH:16][C:15]2[C:20]([C:23]3[CH2:24][CH2:25][N:26]([C:34]([NH2:33])=[O:35])[CH2:27][CH:28]=3)=[CH:21][O:22][C:14]=2[C:13]=1[O:12][C@@H:10]([C:3]1[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[Cl:1])[CH3:11]
Reactant: C[C@@H](Oc1c(N)ncc2c(C3=CCNCC3)coc12)c1c(Cl)ccc(F)c1Cl
Reactant: C[Si](C)(C)N=C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](Oc1c(N)ncc2c(C3=CCN(C(N)=O)CC3)coc12)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 7-[(R)-1-(2,6-dichloro-3-fluorophenyl)-ethoxy]-3-(1,2,3,6-tetrahydropyridin-4-yl)-furo[3,2-c]pyridin-6-ylamine (9.00 mg, 0.0213 mmol), trimethylsilyl isocyanate (5.31 μL, 0.0392 mmol), DMF (0.5 mL, 0.005 mol), and DIPEA (0.03 mL, 0.2 mmol) was stirred at rt for 3 h. The solution was taken directly for HPLC purification. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a yellow solid. 1H NMR (CD3OD, 400 MHz): δ=1.85-1.92 (m, 3H), 2.51 (br, s, 2H), 3.60-3.68 (m, 2H), 4.10 (br, s, 2H), 6.27 (d, J=3.5 Hz, 1H), 6.52 (q, J=6.8 Hz, 1H), 7.18-7.27 (m, 1H), 7.36-7.44 (m, 1H), 7.63-7.70 (m, 1H), 8.13-8.17 (m, 1H). MS (ES+): m/z 465.02 [MH+]. HPLC: tR=2.49 min (ZQ2, polar—5 min). The title compound was also converted to its mesylate and maleic acid salts by precipitation from ethanol.