Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:7]=[CH:6][S:5][N:4]=1)=[CH2:2].C([Li])CCC.[CH2:13]([Sn:17]([CH2:23][CH2:24][CH2:25][CH3:26])([CH2:19][CH2:20][CH2:21][CH3:22])Cl)[CH2:14][CH2:15][CH3:16].C(=O)(O)[O-].[Na+]>C1COCC1>[CH2:23]([Sn:17]([CH2:13][CH2:14][CH2:15][CH3:16])([CH2:19][CH2:20][CH2:21][CH3:22])[C:6]1[S:5][N:4]=[C:3]([CH:1]=[CH2:2])[CH:7]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: C=Cc1ccsn1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: C=Cc1cc([Sn](CCCC)(CCCC)CCCC)sn1
Temperature: -78 °C
Reaction time: 1 h
Yield: 43.8 %

Procedure:
To a cold (−78° C.) solution of 3-vinylisothiazole (300 mg, 2.70 mmol) in anhydrous THF (6.0 mL) was added n-butyllithium (1.855 mL, 2.97 mmol) dropwise. After stirring the reaction mixture for 60 minutes at −78° C., a solution of tributylchlorostannane (0.873 mL, 3.24 mmol) in anhydrous THF (1.5 mL) was added. The reaction mixture was stirred for 30 minutes at −78° C. and then allowed to warm to room temperature over a 1 hour period. Saturated aqueous sodium bicarbonate was added and the aqueous phase was extracted with EtOAc. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and evaporated in vacuo. The residue was purified by silica gel chromatography (Flash 60 column) eluting with hexane/EtOAc (19:1) to give the title compound as a pale yellow oil (472.8 mg, 44%). 1H NMR (500 MHz, CDCl3) δ ppm 0.90 (t, J=7.32 Hz, 9H), 1.13-1.18 (m, 6H), 1.34 (sextet, J=7.42 Hz, 6H), 1.52-1.61 (m, 6H), 5.50 (dd, J=11.23, 0.98 Hz, 1H), 6.00 (dd, J=17.60, 0.98 Hz, 1H), 6.96 (dd, J=17.57, 11.23 Hz, 1H), 7.33 (s, 1H).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[NH:18][N:17]=[N:16][N:15]=2)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.C(Cl)(=O)C.Cl>CO>[NH:18]1[C:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[N:15][N:16]=[N:17]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nnn[nH]2)CC1
Agent: Cl
Solvent: CO
Solvent: CC(=O)Cl
Product: C1CC(c2nnn[nH]2)CCN1
Reaction time: 2.5 h

Procedure:
To 100 mg of the solid from Step A was added a solution of 0.30 mL of acetyl chloride in 5 mL of methanol (generates a methanol solution of hydrochloric acid). After 2.5 hours at room temperature, the reaction was evaporated to dryness, triturated twice with ether and vacuum dried to give the title compound as a tan solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][CH:12]([CH3:14])[CH3:13])[NH:6][C:5]2=[O:15].[F:16][C:17]([F:29])([F:28])[C:18]1[CH:19]=[C:20]([S:24](Cl)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1>N1C=CC=CC=1>[CH2:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][S:24]([C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([C:17]([F:16])([F:28])[F:29])[CH:19]=3)(=[O:26])=[O:25])=[CH:10][CH:9]=2)[C:5](=[O:15])[NH:6]1)[CH:12]([CH3:13])[CH3:14]
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: CC(C)Cn1[nH]c(=O)c2cc(N)ccc21
Solvent: c1ccncc1
Product: CC(C)Cn1[nH]c(=O)c2cc(NS(=O)(=O)c3cccc(C(F)(F)F)c3)ccc21
Temperature: 60 °C
Reaction time: 24 h
Yield: 21.6 %

Procedure:
To a solution of 5-amino-1-isobutyl-1,2-dihydro-indazol-3-one (0.04 g) in pyridine (1 mL) was added 3-trifluoromethylbenzenesulfonylchoride (0.041 g) in one go. The solution was stirred at 60° C. for 24 hours. The pyridine was then removed in vacuo and the residue was dissolved in EtOAc/water and separated. The aqueous phase was extracted a further two times with EtOAc and the combined organic phases were washed with brine and dried over sodium sulfate. The drying agent was removed by filtration and the volatiles were removed in vacuo to afford a crude residue. The crude material was purified via flash column chromatography eluting with EtOAc/nHeptane/1% AcOH) to afford the desired N-(1-isobutyl-3-oxo-2,3-dihydro-1H-indazol-5-yl)-3-trifluoromethyl-benzenesulfonamide (0.015 g) as a pale yellow powder. MS (ESI+): 414.4[M+H]+).
Reaction SMILES: C(OC([N:8]1[C:12]([CH2:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([S:22]([C:25]3[S:29][C:28]4[CH:30]=[C:31]([Cl:34])[CH:32]=[CH:33][C:27]=4[CH:26]=3)(=[O:24])=[O:23])[CH2:18][C:17]2=[O:35])=[CH:11][N:10]=[CH:9]1)=O)(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>C(Cl)Cl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[Cl:34][C:31]1[CH:32]=[CH:33][C:27]2[CH:26]=[C:25]([S:22]([N:19]3[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][CH2:13][C:12]4[NH:8][CH:9]=[N:10][CH:11]=4)[C:17](=[O:35])[CH2:18]3)(=[O:24])=[O:23])[S:29][C:28]=2[CH:30]=1
Reactant: CC(C)(C)OC(=O)n1cncc1CCCN1CCN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CCN1CCCc1cnc[nH]1
Reaction time: 3 h

Procedure:
5-{3-[4-(6-Chloro-benzo[b]thiophene-2-sulfonyl)-2-oxo-piperazin-1-yl]-propyl}-imidazol-1carboxylic acid tert-butyl ester (30 mg, 0.055 mmol) is stirred vigorously in a 30% solution of trifluoroacetic acid and methylene chloride (2 mL). The reaction is complete after stirring for three hours. The volatile solvents are removed on the rotovap, and the gummy solid is titurated with ether several times to afford 4-(6-chloro-benzo[b]thiophene-2-sulfonyl)-1-[3-(3H-imidazol-4-yl)-propyl]-piperazin-2-one trifluoroacetic acid salt (30 mg) as a yellow solid. C18H19ClN4O3S2 (m/z)+: 439, 441. Anal cald. for C18H19ClN4O3S2.C2HF3O2: C, 43.44; H, 3.65; N, 10.13. Found C, 42.03; H, 3.55; N, 8.26.
Reaction SMILES: OC1C=C(C[C@@H](C)C(OC)=O)C=CC=1.OC1C=C(C[C@H](C)C(OC)=O)C=CC=1.[OH:29][C:30]1[CH:31]=[C:32]([CH2:36][C@@H:37]([CH3:43])[C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH:33]=[CH:34][CH:35]=1.OC1C=C(C[C@H](C)C(OCC)=O)C=CC=1>>[OH:29][C:30]1[CH:31]=[C:32]([CH2:36][CH:37]([CH3:43])[C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH:33]=[CH:34][CH:35]=1
Reactant: CCOC(=O)[C@H](C)Cc1cccc(O)c1
Agent: CCOC(=O)[C@@H](C)Cc1cccc(O)c1
Agent: COC(=O)[C@@H](C)Cc1cccc(O)c1
Agent: COC(=O)[C@H](C)Cc1cccc(O)c1
Product: CCOC(=O)C(C)Cc1cccc(O)c1

Procedure:
Methyl (2R)-3-(3-hydroxyphenyl)-2-methylpropanoate (62) and methyl (2S)-3-(3-hydroxyphenyl)-2-methylpropanoate (63). Racemic ethyl 3-(3-hydroxyphenyl)-2-methylpropanoate 62.C (0.40 g) was separated by ChiralPak OJ-H column, eluted with 10% isopropanol in hexane to give the separated enantiomers; (R)-ethyl 3-(3-hydroxyphenyl)-2-methylpropanoate and (S)-ethyl 3-(3-hydroxyphenyl)-2-methylpropanoate 62 and 63. MS ESI (pos.) m/e: 209.1 (M+H)+.
Reaction SMILES: C([BH3-])#N.[Na+].[CH2:5]([O:12][C:13]1[CH:21]=[CH:20][C:16]([CH:17]=[N:18][OH:19])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+]>C(O)(=O)C.CO.C(OCC)(=O)C.O>[CH2:5]([O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][N:18]([C:22](=[O:24])[CH3:23])[OH:19])=[CH:20][CH:21]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: ON=Cc1ccc(OCc2ccccc2)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [BH3-]C#N
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CC(=O)N(O)Cc1ccc(OCc2ccccc2)cc1
Reaction time: 1 h

Procedure:
Sodium cyanoborohydride (21.3 g) was added in portions to a solution of 4-benzyloxybenzaldehyde oxime (51 g) in acetic acid (250 ml) at ca 50° (cooling). After the reduction was complete, acetic anhydride (22.5 ml) was added in one portion, and the mixture was stirred for 1 hour. The mixture was then poured into water, and the neutral product was isolated with ethyl acetate. The residue was treated with potassium carbonate (2 g) in methanol (400 ml) to hydrolyse the O-acetyl material, then the solvent was evaporated. Addition of 20% citric acid solution (400 ml) and isolation with ethyl acetate furnished N-(4-Benzyloxybenzyl) acetohydroxamic acid (32 g), m.pt. 119°-120° [from ethyl acetate-light petroleum (b.pt. 60°-80°)].
Reaction SMILES: C(N1CCN(C2SC(C(O)=O)=C(C)N=2)C1=O)C1C=CC=CC=1.[CH3:23][C:24]1[N:25]=[C:26]([N:32]2[CH2:36][CH2:35][N:34]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:46])[F:45])=[CH:40][CH:39]=3)[C:33]2=[O:48])[S:27][C:28]=1[C:29](O)=[O:30].[NH2:49][CH2:50][C:51]1[CH:56]=[N:55][C:54]([CH3:57])=[CH:53][N:52]=1>>[CH3:23][C:24]1[N:25]=[C:26]([N:32]2[CH2:36][CH2:35][N:34]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([C:44]([F:47])([F:45])[F:46])=[CH:40][CH:39]=3)[C:33]2=[O:48])[S:27][C:28]=1[C:29]([NH:49][CH2:50][C:51]1[CH:56]=[N:55][C:54]([CH3:57])=[CH:53][N:52]=1)=[O:30]
Reactant: Cc1cnc(CN)cn1
Reactant: Cc1nc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)O
Agent: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Product: Cc1cnc(CNC(=O)c2sc(N3CCN(Cc4ccc(C(F)(F)F)cc4)C3=O)nc2C)cn1
Yield: 42 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 4-methyl-2-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiazole-5-carboxylic acid to react with 2-(aminomethyl)-5-methylpyrazine, the title compound was obtained as a white powder in 42% yield: mp 172-173° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.49 (s, 1H), 8.36 (s, 1H), 7.63 (d, J=7.8 Hz, 2H), 7.42 (d, J=7.8 Hz, 2H), 6.77 (t, J=4.8 Hz, 1H), 4.68 (d, J=4.8 Hz, 2H), 4.59 (s, 2H), 4.11-4.05 (m, 2H), 3.49-3.43 (m, 2H), 2.59 (s, 3H), 2.47 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.5, 157.5, 155.5, 153.0, 152.6, 148.7, 143.4, 142.7, 139.7, 130.6, 130.2, 128.5, 125.9, 125.8, 122.1, 117.7, 47.6, 42.3, 42.0, 41.9, 21.2, 17.3; MS (ES+) m/z 491.2 (M+1).
Reaction SMILES: Cl.C(OC([N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[N:18]1[CH:24]2[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]2)[CH2:20][CH2:19]1)=O)(C)(C)C>>[NH:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[N:18]1[CH:24]2[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]2)[CH2:20][CH2:19]1
Reactant: CC(C)(C)OC(=O)n1c(N2CCN3CCC2CC3)nc2ccccc21
Agent: Cl
Product: c1ccc2[nH]c(N3CCN4CCC3CC4)nc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.9 %

Procedure:
1 N Hydrochloric acid (3 mL, in methanol) was added to of 2-(1,4-diaza-bicyclo[3.2.2]non-4-yl)-benzoimidazole-1-carboxylic acid tert-butyl ester (104 mg, 0.304 mmol). The mixture was stirred at RT for 18 h and concentrated. The residue was diluted with 1 N hydrochloric acid (3 mL, aq.) and extracted with ethyl acetate (3×). The aqueous layer was treated with 6 N sodium hydroxide (3 mL, aq.) and extracted with chloroform (6×). The combined organic layers were dried (Na2SO4), filtered and concentrated to afford 50 mg (68%) of the title compound: 1H NMR (CD3OD, 400 MHz) δ 7.19 (dd, 2H, J=5.8 Hz, 3.3 Hz), 6.95 (dd, 2H, J=5.8, 2.9 Hz), 4.98 (br s, 1H), 4.27-4.24 (m, 1H), 3.83 (t, 2H, J=5.8 Hz), 3.09-2.91 (m, 6H), 2.16-2.08 (m, 2H), 1.87-1.78 (m, 2H); MS (Cl) m/z 243.3 (M+1). The hydrochloride salt was prepared by diluting in ethyl acetate and adding a 2.5 N HCl solution in ethyl acetate: mp>300° C.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[C:8]([C@@H:11]([O:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[N:27]([C:31]3[CH:32]=[C:33]([CH:41]=[CH:42][CH:43]=3)[C:34]([O:36]CC(C)C)=[O:35])[N:26]=[CH:25]4)[C@@H:12]([NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[CH3:17])[CH3:13])[CH:9]=[CH:10][C:5]=2[CH2:4][O:3][CH2:2]1.[OH-].[Li+].C(OCC)(=O)C.Cl>CO.C1COCC1.O>[O:1]1[C:6]2[CH:7]=[C:8]([C@@H:11]([O:21][C:22]3[CH:23]=[C:24]4[C:28](=[CH:29][CH:30]=3)[N:27]([C:31]3[CH:32]=[C:33]([CH:41]=[CH:42][CH:43]=3)[C:34]([OH:36])=[O:35])[N:26]=[CH:25]4)[C@@H:12]([NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[CH3:17])[CH3:13])[CH:9]=[CH:10][C:5]=2[CH2:4][O:3][CH2:2]1
Reactant: CC(C)COC(=O)c1cccc(-n2ncc3cc(O[C@H](c4ccc5c(c4)OCOC5)[C@H](C)NC(=O)C(C)(F)F)ccc32)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@H](NC(=O)C(C)(F)F)[C@H](Oc1ccc2c(cnn2-c2cccc(C(=O)O)c2)c1)c1ccc2c(c1)OCOC2
Reaction time: 2 h
Yield: 100.5 %

Procedure:
Isobutyl 3-(5-((1R,2S)-1-(4H-benzo[d][1,3]dioxin-7-yl)-2-(2,2-difluoropropanamido)propoxy)-1H-indazol-1-yl)benzoate (I5a) (398 mg, 0.67 mmol) was dissolved in methanol (3 mL) and THF (3.0 mL). Lithium hydroxide (0.032 mL, 2.01 mmol) dissolved in water (2.5 mL) was added. A clear slightly pink solution was obtained. After 2 h the solution was ice-cold. Ethyl acetate was added and then hydrochloric acid (1M) to acidic pH. The water phase was once more extracted with ethyl acetate. The collected organic phases were dried over magnesium sulfate and evaporated. It was dissolved in methanol and the solution was applied onto a 1 g SCX column. The methanol eluate (ca 15 mL) was concentrated. Freeze-drying from acetonitrile/water gave the title compound (362 mg, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=[CH:12][C:13]([O:15]C)=[O:14])[CH:6]=[CH:7][CH:8]=1.O.[OH-].[Li+]>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=[CH:12][C:13]([OH:15])=[O:14])[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)C=CC=Cc1cccc(OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cccc(C=CC=CC(=O)O)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of the product from step (i) (53.2 g) and lithium hydroxide monohydrate (52 g) in methanol (250 ml) and water (100 ml) was stirred at room temperature for 24 hours and partitioned between ethyl acetate and 2M HCl. The organic phase was washed with brine, dried (MgSO4), and evaporated under reduced pressure to afford an orange oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[BH3-]C#N.[Na+]>C(O)(=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2
Reactant: Brc1ccc2[nH]ccc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Brc1ccc2c(c1)CCN2
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.9 %

Procedure:
To 5-Bromo-1H-indole (2.5 g, 12.82 mmol) in acetic acid (10.0 mL), NaCNBH3 (2.38 g, 38.46 mmol) was added portion wise at 10° C. over the period of 20 min. After that the reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was diluted with water and extracted with diethyl ether. The organic layer was washed with saturated NaHCO3, water and brine solution. The combined ether layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford title compound as a pale yellow semi-solid (1.8 g, 71%).
Reaction SMILES: C([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22](=S)[NH:23][CH3:24])C1C=CC=CC=1.CI.[F:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][C:36]([NH:38][NH2:39])=O)=[CH:31][CH:30]=1.CN(C=O)C>C(#N)C>[F:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][C:36]2[N:23]([CH3:24])[C:22]([C:10]3[N:11]=[C:12]4[N:17]([C:18](=[O:19])[C:9]=3[OH:8])[CH2:16][CH2:15][O:14][C:13]4([CH3:20])[CH3:21])=[N:39][N:38]=2)=[CH:33][CH:34]=1
Reactant: CNC(=S)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(C)C
Reactant: NNC(=O)Cc1ccc(F)cc1
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c(Cc2ccc(F)cc2)nnc1-c1nc2n(c(=O)c1O)CCOC2(C)C
Temperature: 50 °C
Reaction time: 16 h
Yield: 22.4 %

Procedure:
To a solution of 3-(benzyloxy)-N,9,9-trimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carbothioamide (0.1 g, 0.278 mmol, 1.0 equiv) in acetonitrile (0.9 mL) under a nitrogen atmosphere, was added MeI (0.070 mL, 1.11 mmol, 4 equiv). The reaction was heated at 50° C. (oil bath) for 45 min. The reaction was then cooled to ambient temperature and concentrated in vacuo. 2-(4-Fluorophenyl)acetohydrazide (0.14 g, 0.84 mmol, 3 equiv) was then added to the residue followed by DMF (2 mL) and the slurry was heated at 140° C. (oil bath). After stirring 16 h, the reaction was cooled to ambient temperature and concentrated in vacuo. The residue was added to a saturated aqueous solution of NaHCO3 and extracted with CH2Cl2 (×3). The combined CH2Cl2 extracts were dried (Na2SO4) and then concentrated in vacuo. The crude product was treated with DMF (˜1.5 mL). After trying to dissolve material, the insoluble portion was filtered and washed with methanol to provide the title compound (0.024 g, 22% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.21 (dd, J=8.81, 5.29 Hz, 2H), 7.03 (t, J=8.69 Hz, 2H), 4.24 (s, 2H), 4.04 (q, J=2.77 Hz, 4H), 3.93 (s, 3H), 1.57 (s, 6H); LCMS (ES+, (M+H)+) m/z 386.22.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:22])[NH:6][C:7]2[C:12]([C:13]=1C)=[C:11](OS(O)(=O)=O)[C:10]([CH3:20])=[CH:9][C:8]=2[Cl:21])(=[O:3])[CH3:2].[CH2:23]([NH2:26])[CH:24]=[CH2:25]>>[C:1]([C:4]1[C:5](=[O:22])[NH:6][C:7]2[C:12]([C:13]=1[NH:26][CH2:23][CH:24]=[CH2:25])=[CH:11][C:10]([CH3:20])=[CH:9][C:8]=2[Cl:21])(=[O:3])[CH3:2]
Reactant: C=CCN
Reactant: CC(=O)c1c(C)c2c(OS(=O)(=O)O)c(C)cc(Cl)c2[nH]c1=O
Product: C=CCNc1c(C(C)=O)c(=O)[nH]c2c(Cl)cc(C)cc12
Yield: 81.9 %

Procedure:
3-Acetyl-8-chloro-6-methyl-4 -methylsulfoxy -2-quinolinone (2.97 g, 0.01 mol) and allylamine (0.57g, 0.01 mol) were used, but the reaction was carried out as the above process of example 37 to obtain the desired product (2.38g, yield: 82%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.[F:10][C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:12]=1[S:18](Cl)(=[O:20])=[O:19]>>[Br:8][C:6]1[CH:7]=[C:2]([NH:1][S:18]([C:12]2[CH:13]=[CH:14][C:15]([F:17])=[CH:16][C:11]=2[F:10])(=[O:20])=[O:19])[CH:3]=[C:4]([OH:9])[CH:5]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Reactant: Nc1cc(O)cc(Br)c1
Product: O=S(=O)(Nc1cc(O)cc(Br)c1)c1ccc(F)cc1F
Yield: 121.5 %

Procedure:
3-Amino-5-bromophenol (600 mg, 2.87 mmol, prepared according to WO 2011119704 A1 20110929) was treated with 2,4-difluorobenzene-1-sulfonyl chloride (386 μl, 2.87 mmol) according to the method described in Preparation 15b to give 1.27 g (99% yield) of the title compound as an oil. Purity 70%.
Reaction SMILES: C(Cl)=C.Cl[CH:5]=[CH:6][C:7]#[C:8][CH2:9][O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1.C(N)CCC.[CH3:22][Si:23]([C:26]#[CH:27])([CH3:25])[CH3:24]>O1CCCC1.[Al].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[O:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[O:10][CH2:9][C:8]#[C:7][CH:6]=[CH:5][C:27]#[C:26][Si:23]([CH3:25])([CH3:24])[CH3:22]
Reactant: C#C[Si](C)(C)C
Reactant: ClC=CC#CCOC1CCCCO1
Agent: [Cu]I
Agent: [Pd]
Agent: C=CCl
Solvent: C1CCOC1
Solvent: CCCCN
Product: C[Si](C)(C)C#CC=CC#CCOC1CCCCO1
Yield: 89.1 %

Procedure:
Degassed anhydrous tetrahydrofuran (500 mL) was added to 5.86 g (4.32 mmol) solid tetrakis(triphenylphosphine) palladium(0) and copper (I) iodide (5.17 g, 27.1 mmol) stirring under argon. A solution of the vinyl chloride (compound M of step (a) 45.38 g, 226.1 mmol) in 100 mL of dry tetrahydrofuran was added via cannula followed immediately by the addition of 45 mL (455 mmol) neat butylamine. The flask was wrapped in aluminum foil to exclude light and then 41.6 mL (294 mmol) of trimethylsilyl acetylene was added via syringe over 4 min. After about 10 min the reaction became very warm and was cooled in an ice water bath for 3 min. The cooling bath was then removed and the reaction allowed to stir for 4 h at ambient temperature. Air was bubbled through the reaction for 15 min and then the reaction was filtered by suction through a glass frit using pentane then ether washes for transfer. The reaction was diluted with ether and washed with five 500 ml portions of water. The aqueous washes were reextracted with a small amount of diethyl ether and the combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated on a rotary evaporator. Flash chromatography over SiO2 using 2.5% to 4% ethyl acetate/hexane as eluent provided 52.86 g (89%) of liquid as the desired product:
Reaction SMILES: CO[C:3](=[NH:18])[CH2:4][CH2:5][S:6][CH2:7][C:8]1[CH:13]=[C:12]([CH2:14][N:15]([CH3:17])[CH3:16])[CH:11]=[CH:10][N:9]=1.[N:19]#[C:20][NH2:21]>CO>[C:20]([NH:21][C:3](=[NH:18])[CH2:4][CH2:5][S:6][CH2:7][C:8]1[CH:13]=[C:12]([CH2:14][N:15]([CH3:17])[CH3:16])[CH:11]=[CH:10][N:9]=1)#[N:19]
Reactant: N#CN
Reactant: COC(=N)CCSCc1cc(CN(C)C)ccn1
Solvent: CO
Product: CN(C)Cc1ccnc(CSCCC(=N)NC#N)c1
Reaction time: 8 h

Procedure:
Methyl-3-(4-dimethylaminomethyl-2-pyridylmethylthio)propionimidate is added to a methanol solution of cyanamide. After standing overnight N-cyano-3-(4-dimethylaminomethyl-2-pyridylmethylthio)propionamidine is obtained.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:19]3[C:27]4[C:22](=[N:23][CH:24]=[C:25]([C:28]#[N:29])[CH:26]=4)[C:21]([CH3:31])([CH3:30])[CH2:20]3)=[C:7]([CH3:18])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[OH-:32].[Na+]>CCO.O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:19]3[C:27]4[C:22](=[N:23][CH:24]=[C:25]([C:28]([NH2:29])=[O:32])[CH:26]=4)[C:21]([CH3:31])([CH3:30])[CH2:20]3)=[C:7]([CH3:18])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC(C)(C)c2ncc(C#N)cc21
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1c(-c2ccccn2)nc2cc(F)ccc2c1N1CC(C)(C)c2ncc(C(N)=O)cc21

Procedure:
1-(7-Fluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-yl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-6-carbonitrile (80 mg, 0.195 mmol) in EtOH (3 mL) was treated with sodium hydroxide (156 mg, 3.91 mmol) in water (1.0 mL). The reaction was heated at reflux for 3 h. After this time the reaction was evaporated in vacuo. Reverse phase HPLC (10% to 60% acetonitrile in water) gave 1-(7-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinyl)-3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridine-6-carboxamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.72 (1H, ddd, J=4.8, 1.8, 1.1 Hz), 8.34 (1H, d, J=1.8 Hz), 7.99-8.06 (1H, m), 7.80-7.96 (4H, m), 7.48-7.61 (2H, m), 7.31 (1H, br. s.), 6.61 (1H, d, J=1.8 Hz), 3.90-3.99 (1H, m), 3.85 (1H, d, J=9.4 Hz), 2.27 (3H, s), 1.53 (3H, s), 1.45 (3H, s). Mass Spectrum (ESI) m/e=428 (M+1).
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[CH2:6][NH:7][C:8](=[O:38])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH:27][C:28](=[O:37])[C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:35]Br)[CH:30]=2)[CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].[N:52]1([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:58][CH2:57][CH2:56][NH:55][CH2:54][CH2:53]1>CN(C)C=O.O>[F:1][C:2]([F:43])([F:42])[C:3]1[CH:4]=[C:5]([CH:39]=[CH:40][CH:41]=1)[CH2:6][NH:7][C:8]([C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:18]=[CH:17][C:16]=2[NH:27][C:28]([C:29]2[CH:30]=[C:31]([CH:32]=[CH:33][CH:34]=2)[CH2:35][N:55]2[CH2:56][CH2:57][CH2:58][N:52]([C:59]([O:61][C:62]([CH3:65])([CH3:64])[CH3:63])=[O:60])[CH2:53][CH2:54]2)=[O:37])[CH:10]=1)=[O:38]
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCCC3)ccc2NC(=O)c2cccc(CBr)c2)c1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCN(Cc2cccc(C(=O)Nc3ccc(N4CCCCC4)cc3-c3cc(C(=O)NCc4cccc(C(F)(F)F)c4)ccn3)c2)CC1
Temperature: 70 °C
Reaction time: 3 h
Yield: 85.1 %

Procedure:
Into a 100-mL round-bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(2-(3-(bromomethyl)benzamido)-5-(piperidin-1-yl)phenyl)isonicotinamide (400 mg, 0.61 mmol, 1.00 equiv) in N,N-dimethylformamide (20 mL), potassium carbonate (248 mg, 1.79 mmol, 2.92 equiv), potassium iodide (20 mg, 0.12 mmol, 0.20 equiv), and tert-butyl 1,4-diazepane-1-carboxylate (240 mg, 1.20 mmol, 1.95 equiv). The resulting solution was stirred for 3 h at 70° C. in an oil bath. The resulting solution was diluted with 300 mL of water. The resulting solution was extracted with 4×200 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 2×200 mL of brine. The mixture was dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane:methanol (20:1˜10:1). The product was obtained as 400 mg (85%) of a yellow solid. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.875-8.887 (d, J=3.6 Hz, 1H), 8.287-8.298 (d, J=3.3 Hz, 1H), 8.253 (s, 1H), 7.936 (s, 1H), 7.772-7.936 (m, 2H), 7.433-7.711 (m, 7H), 7.106-7.146 (dd, J=2.7 Hz, J′=9.0 Hz, 1H), 4.689 (s, 2H), 3.740 (s, 2H), 3.482 (m, 4H), 3.197-3.232 (m, 4H), 2.656-2.693 (m, 4H), 1.720-1.847 (m, 6H), 1.614-1.649 (m, 2H), 1.420-1.459 (m, 9H). MS (ES, m/z): 771 [M+H]+; 793 [M+Na]+.