Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:20]([NH2:21])=[C:19]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[N:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:33](OCC)(OCC)OCC>C(OC(=O)C)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[N:16]=[CH:17][N:18]=[C:19]3[C:20]=2[N:21]=[CH:33][N:22]3[C:23]2[CH:24]=[CH:25][C:26]([S:29]([CH3:32])(=[O:31])=[O:30])=[CH:27][CH:28]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ncnc(Nc3ccc(S(C)(=O)=O)cc3)c2N)CC1
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ncnc3c2ncn3-c2ccc(S(C)(=O)=O)cc2)CC1
Temperature: 140 °C

Procedure:
4-[5-Amino-6-(4-methanesulfonyl-phenylamino)-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (300 mg, 0.6 mmol) was dissolved in mixture of triethyl orthoformate (4 mL) and acetic anhydride (4 mL), and then the mixture was refluxed at 140° C. for 15 hours. The crude product was quenched with saturated sodium bicarbonate and extracted with ethyl acetate, then dried in vacuo. Solid was precipitated out in acetonitrile/water and provided Compound B4 as a peach solid (205 mg, 67%). 1H NMR (CDCl3, 400MHz) δ 1.48 (s, 9H), 1.95-1.91 (m, 2H), 2.14-2.11 (m, 2H), 3.12 (s, 3H), 3.34-3.27 (m, 2H), 3.94-3.91 (m, 2H), 5.61 (m, 1H), 8.06 (d, 2H), 8.19 (d, 2H), 8.29 (s, 1H), 8.61 (s, 1H). Exact mass calculated for C22H27N5O5S 473.17, found 474.3 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]#[CH:5])[CH3:2].C([Li])CCC.CN(P(N(C)C)(N(C)C)=O)C.[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1COCC1>[CH2:4]([O:3][C:1]#[C:2][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:5]
Reactant: C#COCC
Reactant: BrCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC#CCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
To a solution of ethoxy acetylene (9.95 g of 50% w/w. solution in hexanes, 70 mmol) in THF (100 ml) at −78° was added n-butyl lithium (31 ml of 2.5M solution in hexanes, 78 mmol). The mixture was stirred at this temperature for 2 h. prior to the addition of HMPA (20 ml), stirring was continued for a further 15 min. before the addition of benzyl bromide (9.2 ml). The reaction mixture was allowed to warm to room temperature overnight before partitioning between EtOAc (300 ml) and water (200 ml). The organics were separated, washed with water (5×200 ml), brine (200 ml), dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as a mobile brown oil (11.1 g, 99%). δH (300 MHz, CDCl3) 7.15-7.57 (5H, m), 4.12 (2H, q, J 7.1 Hz), 3.60 (2H, s), 1.41 (3H, t, J 7.1 Hz); m/z (ES+, 70V) MH+161.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](OCCCCCCC)=[C:6]([CH:38]=1)[C:7]([NH:9][C@@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2OC2C=CC(C(F)(F)F)=CC=2)=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:8].[C:47]([C:51]1[CH:56]=[CH:55][C:54](B(O)O)=[CH:53][CH:52]=1)([CH3:50])([CH3:49])[CH3:48]>>[C:18]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:20][C:15]([CH2:14][C@H:10]([NH:9][C:7]([C:6]2[CH:38]=[C:2]([C:54]3[CH:55]=[CH:56][C:51]([C:47]([CH3:50])([CH3:49])[CH3:48])=[CH:52][CH:53]=3)[CH:3]=[CH:4][CH:5]=2)=[O:8])[C:11]([OH:13])=[O:12])=[CH:16][CH:17]=1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: CCCCCCCOc1ccc(Br)cc1C(=O)N[C@@H](Cc1ccc(-c2ccccc2Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)O
Product: CC(C)(C)c1ccc(-c2cccc(C(=O)N[C@@H](Cc3ccc(-c4ccccc4)cc3)C(=O)O)c2)cc1
Yield: 86.5 %

Procedure:
3-Biphenyl-4-yl-(2S)-[(3-bromo-benzoyl-amino)-propionic acid (100 mg, 0.23 mmol) was reacted with 4-tert-butyl phenyl boronic acid (0.125 mg, 0.69 mmol) by following general procedure D yielding the title compound (95 mg, 85%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[CH:3]=1.[Br:10][CH2:11][C:12](Br)=[O:13].[Cl-].[Al+3].[Cl-].[Cl-].O>C(OCC)(=O)C>[Br:10][CH2:11][C:12]([C:7]1[C:2]([Cl:1])=[CH:3][C:4]([Cl:9])=[CH:5][C:6]=1[Cl:8])=[O:13]
Reactant: Clc1cc(Cl)cc(Cl)c1
Reactant: O=C(Br)CBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(CBr)c1c(Cl)cc(Cl)cc1Cl
Temperature: 80 °C
Yield: 69 %

Procedure:
A mixture of 1,3,5-trichlorobenzene (10.0 g, 55.1 mmol), 2-bromoacetyl bromide (5.0 mL, 57.8 mmol, 1.05 eq), and aluminum chloride (7.7 g, 57.8 mmol, 1.05 eq) was heated neat at 80° C. under argon for 17 h until a black precipitate is formed. The reaction was cooled to room temperature, and the resultant black mass was dissolved in ethyl acetate (500 mL). Water (200 mL) was added slowly at 0° C. to quench the reaction, and the biphasic layers were separated. The organic layer was then washed with water (2×150 mL) and brine (1×150 mL), dried (MgSO4), filtered, and evaporated in vacuo. Recrystallization from hexane gave 11.5 g (69.3%) of 2-bromo-1-(2,4,6-trichlorophenyl)ethanone as a fluffy white solid. 1H-NMR (DMSO-d6) δ 7.86 (s, 2H), 4.78 (s, 2H); Rf=0.28, 2% ethyl acetate-hexane.
Reaction SMILES: C(OC(=O)C)C.[ClH:7].[CH3:8][O:9][C:10]([C:12]1[N:13]([CH2:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][N:32]2C(OC(C)(C)C)=O)[C:14](=[O:29])[C:15]2[C:20]([C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:19][C:18]([Br:28])=[CH:17][CH:16]=2)=[O:11]>>[ClH:7].[CH3:8][O:9][C:10]([C:12]1[N:13]([CH2:30][CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][NH:32]2)[C:14](=[O:29])[C:15]2[C:20]([C:21]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[CH:19][C:18]([Br:28])=[CH:17][CH:16]=2)=[O:11]
Reactant: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1CC1CCCCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1CC1CCCCN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
4N Hydrogen chloride ethyl acetate solution (5 ml) was added to 6-bromo-2-(1-tert-butoxycarbonylpiperidin-2-ylmethyl)-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (44 mg), and the mixture was stirred at room temperature for 2 hrs. The solvent was evaporated under reduced pressure, and the obtained residue was crystallized from isopropyl ether to give the title compound (21 mg, 53%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[CH:11]=[C:12]([C:16]1[S:17][C:18]([CH3:21])=[N:19][N:20]=1)[C:13](=O)[CH3:14])[C:6]#[N:7].[NH2:22]/[C:23](/[CH3:27])=[CH:24]\[C:25]#[N:26]>C(O)(C)C>[C:6]([C:5]1[CH:8]=[CH:9][C:10]([CH:11]2[C:12]([C:16]3[S:17][C:18]([CH3:21])=[N:19][N:20]=3)=[C:13]([CH3:14])[NH:22][C:23]([CH3:27])=[C:24]2[C:25]#[N:26])=[C:3]([O:2][CH3:1])[CH:4]=1)#[N:7]
Reactant: COc1cc(C#N)ccc1C=C(C(C)=O)c1nnc(C)s1
Reactant: C/C(N)=C/C#N
Solvent: CC(C)O
Product: COc1cc(C#N)ccc1C1C(C#N)=C(C)NC(C)=C1c1nnc(C)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
150 mg (0.501 mmol) of the compound from example 25A and 41 mg (0.501 mmol) of 3-amino-crotononitrile are dissolved in 5 ml of isopropanol and stirred at the reflux temperature overnight. After cooling to room temperature, the volatile components are removed in a rotary evaporator, and the crude product is purified by preparative HPLC (eluent: acetonitrile/water with 0.1% formic acid, gradient 20:80→95:5). Crystallization from ethyl acetate/diethyl ether results in 30 mg (16% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[Cl:24])[C@H:12]([CH3:16])[CH2:13][CH2:14]O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:49]I>C(OCC)C.CC#N>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:17]2[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=2[Cl:24])[C@H:12]([CH3:16])[CH2:13][CH2:14][I:49])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: II
Reactant: C[C@H](CCO)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOCC
Product: C[C@H](CCI)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Reaction time: 12 h
Yield: 96 %

Procedure:
To a solution of 4-chloro-N-(2,5-dichlorophenyl)-N-[1(R)-methyl-(3-hydroxy)-propyl]benzene-sulfonamide (1.40 g, 3.40 mmol), triphenylphosphine (0.900 g, 3.40 mmol) and imidazole (0.230 g, 3.40 mmol) in diethyl ether/CH3CN (2:1, 7.0 mL) was added iodine (0.860 g, 3.40 mmol) at 0° C. under nitrogen and stirred for 12 h. The solvent was removed, the residue was taken into CH2Cl2, washed with water, dried over Na2SO4 and filtered. The organic solution was concentrated to afford the title compound as a light yellow oil in 96% yield.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH:27]([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][C@H:4]1[F:36].[C:37](Cl)(=[O:39])[CH3:38]>>[C:37]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([CH:27]([F:29])[F:28])[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:33][CH2:34]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][C@H:4]1[F:36])(=[O:39])[CH3:38]
Reactant: CC(=O)Cl
Reactant: Cc1[nH]c2c(-c3cc(C(F)F)ccc3OCC3CC3)ncnc2c1C(=O)N[C@H]1CC[C@H](N)[C@H](F)C1
Agent: Cl
Product: CC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(C(F)F)ccc4OCC4CC4)ncnc23)C[C@H]1F

Procedure:
Starting from N-[(1S*,3R*,4S*)-4-amino-3-fluorocyclohexyl]-4-[2-(cyclopropylmethoxy)-5-(difluoromethyl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f72) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@@H:10]1[CH2:40][P:41](=[O:44])([O-:43])[O-:42])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.C[Si](Br)(C)C>C(#N)C>[CH2:1]([O:8][C@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C@@H:10]1[CH2:40][P:41](=[O:42])([OH:43])[OH:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=P([O-])([O-])C[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: C[Si](C)(C)Br
Solvent: c1ccncc1
Solvent: CC#N
Product: O=P(O)(O)C[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90.8 %

Procedure:
To a solution of (((2S,3S,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)methyl)phosphonate (0.6 g, 0.89 mmol, 1.0 equiv) in dry acetonitrile (60 mL) was added pyridine (1.1 mL, 10.2 mmol, 11.5 equiv) at 0° C. under argon atmosphere. TMSBr (2.5 mL, 17.7 mmol, 20 equiv) dissolved in dry acetonitrile (25 mL) was added dropwise to the reaction mixture at 0° C. which was stirred for 10 minutes and then warmed to room temperature and stirred for 3 hours. The volatiles were removed in vacuo (bath temperature <15° C.) to give an oil. Ice cold water (20 mL) was added, and the organic material was extracted into DCM (2×80 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo (bath temp <15° C.) to give ((((2S,3S,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl)tetrahydro-2H-pyran-2-yl)methyl)phosphonic acid as a pale green solid (0.50 g). The material thus obtained was used without further purification. ESI (M+1) m/z: 619.0; calc for C35H39O8P 618.2.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]([C:9]1[CH:29]=[CH:28][C:12]([CH2:13][N:14]2[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][C:15]2=[O:27])=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].FC(F)(F)C(O)=O>ClCCl>[F:30][C:2]([F:1])([F:31])[C:3]([C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]2[CH2:19][CH2:18][NH:17][CH2:16][C:15]2=[O:27])=[CH:28][CH:29]=1)([OH:8])[C:4]([F:7])([F:6])[F:5]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)C(=O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CNCCN1Cc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.8 %

Procedure:
To a stirring solution of tert-butyl 4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)-3-oxopiperazine-1-carboxylate (3.05 mmol, 1.39 g) in dichloromethane (15 mL) was added trifluoroacetic acid (30.5 mmol, 3.47 g) and the mixture allowed to stir at room temperature for 5 hours. The reaction mixture was concentrated and the resulting residue purified by strong cation exchange column chromatography to afford the title compound (932 mg). MS (ESI) m/z 357.0 [M+H]+
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:22]2[C:21]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N:15]=[C:14]([NH2:23])[C:13]=2[N:12]=[C:11]1[CH2:24][CH2:25][CH2:26][CH3:27].C(N(CC)CC)C.[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>ClCCl>[NH2:23][C:14]1[C:13]2[N:12]=[C:11]([CH2:24][CH2:25][CH2:26][CH3:27])[N:10]([CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:35](=[O:42])[C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:22]=2[C:21]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[N:15]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCCCCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCCCCCCNC(=O)c1ccccc1
Temperature: 25 °C
Yield: 46.8 %

Procedure:
A solution of 1-(8-aminooctyl)-2-butyl-1H-imidazo[4,5-c]quinolin-4-amine (1.2 g, 3.26 mmol) and triethylamine (500 μL, 3.59 mmol) in dichloromethane (30 mL) was cooled to 0° C. Benzoyl chloride (380 μL, 3.26 mmol) was slowly added dropwise. The reaction mixture was allowed to slowly warm to ambient temperature. After several hours the reaction mixture was washed with distilled water (1×50 mL) and brine (2×50 mL), dried over sodium sulfate and then concentrated under reduced pressure to provide 1.5 g of crude orange gooey material. This material was purified by column chromatography (65 g of silica gel, eluting with 7.5% methanol in dichloromethane). The purified material was dissolved in a small amount of dichloromethane and the solution was diluted with hexane to precipitate a white powder. This material was isolated by filtration, washed with hexanes and then dried in a vacuum oven at 60° C. overnight to provide 0.72 g of N-[8-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)octyl]benzamide as a white powder, m.p. 149.5-151.3° C. Analysis: Calculated for C29H37N5O: % C, 73.85; % H, 7.91; % N, 14.85;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[CH:10][C:9](=[O:12])[NH:8][C:7]=2[N:13]=1.I[CH2:15][CH2:16][C@@H:17]1[CH2:21][O:20][C:19]([CH3:23])([CH3:22])[O:18]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH3:22][C:19]1([CH3:23])[O:18][C@H:17]([CH2:16][CH2:15][N:8]2[C:9](=[O:12])[CH:10]=[N:11][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[N:13][C:7]2=3)[CH2:21][O:20]1
Reactant: CC1(C)OC[C@@H](CCI)O1
Reactant: COc1ccc2ncc(=O)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc2ncc(=O)n(CC[C@@H]3COC(C)(C)O3)c2n1
Temperature: 50 °C
Reaction time: 13 h
Yield: 100.1 %

Procedure:
In N,N-dimethylformamide (40 ml) were dissolved 6-methoxypyrido[2,3-b]pyrazin-3(4H)-one (1.48 g, 8.34 mmol) and (4R)-4-(2-iodoethyl)-2,2-dimethyl-1,3-dioxolane (3.20 g, 12.51 mmol). Cesium carbonate (3.81 g, 11.68 mmol) was added to the solution and the mixture was stirred at 50° C. for 13 hours. After cooling in the air, water was added to the reaction solution and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to yield 2.55 g (100%) of the title compound in the form of a light yellow oily product.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]([OH:23])=O)=[CH:17][C:16]=1[CH3:24].O[N:26]=[C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:35][C:36]([F:39])([F:38])[F:37])[NH2:28].CCN(C(C)C)C(C)C>>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[O:23][N:28]=[C:27]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][C:36]([F:37])([F:38])[F:39])[N:26]=2)=[CH:17][C:16]=1[CH3:24]
Reactant: COc1ccccc1-c1ccc(C(=O)O)cc1C
Reactant: NC(=NO)c1ccccc1OC(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1ccc(-c2nc(-c3ccccc3OC(F)(F)F)no2)cc1C

Procedure:
Oxalyl chloride (126 μL; 1.49 mmol; 3 eq.), Intermediate 26 (120 mg; 0.5 mmol; 1 eq.), Intermediate 2 (109 mg; 0.5 mmol, 1 eq.) and DIEA (256 μL; 1.49 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography c-hexane/ethyl acetate, 95/5) afforded the title compound as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][N:5]2[C:16]([CH:18]1[CH2:20][CH2:19]1)=[O:17].C1(C(N2C3C(=CC([C:36]4[CH:37]=[N:38][NH:39][CH:40]=4)=CC=3)N(C(OC(C)C)=O)C[C@@H]2C)=O)CC1>>[CH:18]1([C:16]([N:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([C:36]4[CH:37]=[N:38][NH:39][CH:40]=4)[CH:3]=3)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6]2)=[O:17])[CH2:20][CH2:19]1
Reactant: CC(C)OC(=O)N1C[C@H](C)N(C(=O)C2CC2)c2ccc(-c3cn[nH]c3)cc21
Reactant: CC(=O)N1c2ccc(Br)cc2N(C(=O)C2CC2)C[C@@H]1C
Product: CC(=O)N1c2ccc(-c3cn[nH]c3)cc2N(C(=O)C2CC2)C[C@@H]1C

Procedure:
(S)-1-(4-(Cyclopropanecarbonyl)-2-methyl-6-(1H-pyrazol-4-yl)-3,4-dihydroquinoxalin-1 (2H)-yl)ethan-1-one was synthesized from (S)-1-(6-bromo-4-(cyclopropanecarbonyl)-2-methyl-3,4-dihydroquinoxalin-1 (2H)-yl)ethan-1-one according to the procedure outlined above for (S)-isopropyl 4-(cyclopropanecarbonyl)-3-methyl-7-(1H-pyrazol-4-yl)-3,4-dihydroquinoxaline-1(2H)-carboxylate. MS (ESI, pos. ion) m/z 359 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([C:35]2[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=2)[CH2:38]Cl)[CH:28]=[C:29]([O:33][CH3:34])[C:30]=1[O:31][CH3:32]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=2)[CH2:38][C:37]2[CH:40]=[CH:41][CH:42]=[C:35]([C:27]3[CH:28]=[C:29]([O:33][CH3:34])[C:30]([O:31][CH3:32])=[C:25]([O:24][CH3:23])[CH:26]=3)[CH:36]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc(-c2cccc(CCl)c2)cc(OC)c1OC
Reactant: CSc1ccc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Product: COc1cc(-c2cccc(CN(c3ccc(SC)cc3)C3CCN(C(=O)OC(C)(C)C)CC3)c2)cc(OC)c1OC

Procedure:
1-(tert-Butoxycarbonyl)-4-[[4-(methylthio)phenyl]amino]piperidine (645 mg) and 3-(3,4,5-trimethoxyphenyl)benzyl chloride (586 mg) was treated in the same manner as described in Example 9 to give light yellow amorphous of the title compound.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[N:11]([C:17]1[CH:22]=[CH:21][C:20]([N:23]3[CH2:27][CH2:26][C@@H:25]([NH:28][CH3:29])[CH2:24]3)=[C:19]([F:30])[CH:18]=1)[CH2:10][CH2:9]2)[CH2:2][CH2:3][CH3:4].[CH3:31][S:32]([CH:35]=[CH2:36])(=[O:34])=[O:33]>>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](=[O:16])[N:11]([C:17]1[CH:22]=[CH:21][C:20]([N:23]3[CH2:27][CH2:26][C@@H:25]([N:28]([CH2:36][CH2:35][S:32]([CH3:31])(=[O:34])=[O:33])[CH3:29])[CH2:24]3)=[C:19]([F:30])[CH:18]=1)[CH2:10][CH2:9]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1ccc2c(c1)CCN(c1ccc(N3CC[C@@H](NC)C3)c(F)c1)C2=O
Reactant: C=CS(C)(=O)=O
Product: CCCCOc1ccc2c(c1)CCN(c1ccc(N3CC[C@@H](N(C)CCS(C)(=O)=O)C3)c(F)c1)C2=O

Procedure:
6-Butoxy-2-[3-fluoro-4-((R)-3-methylaminopyrrolidin-1-yl)phenyl]-3,4-dihydro-2H-isoquinolin-1-one was reacted with methanesulfonylethene by method G. The product with the molecular weight of 517.67 (C27H36FN3O4S) was obtained in this way; MS (ESI): 518 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](Br)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C([Li])CCC.[CH:18]12[O:24][CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23]2.B(F)(F)F.CCOCC>CCOCC.CCCCCC>[F:1][C:2]1[CH:3]=[C:4]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]2[OH:24])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: C1CCC2OC2C1
Reactant: Fc1cc(Br)cc(C(F)(F)F)c1
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: OC1CCCCC1c1cc(F)cc(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of 8.00 g (32.9 mmol) 3-fluoro-5-trifluoromethyl-bromo-benzene in 40 ml Et2O under nitrogen was cooled to −78° C. and drop-wise 20.56 ml (32.9 mmol) of a 1.6 M butyl lithium solution in hexane were added. The reaction was strongly exothermic and the temperature was kept below −70° C. Then after 30 min. at −78° C. 2.66 ml (2.58 g, 26.3 mmol) cyclohexene oxide were added followed by 3.75 ml (4.2 g, 29.6 mmol) boron trifluoride diethyl etherate. The latter has to be added drop-wise to keep the temperature below −70° C. The reaction mixture was stirred for 2 h at −78° C. and then quenched with 40 ml saturated aqueous KHSO4 solution, warmed up to ambient temperature and extracted with tert.-butyl methyl ether. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated. The crude product, 7.53 g light yellow crystals, was purified by re-crystallisation from n-heptane: 4.90 g rac-2-(3-fluoro-5-trifluoromethyl-phenyl)-cyclohexanol as colorless crystalls: m.p. 76.5–77.4° C., MS (EI): 262.1 M+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])(=[O:12])=[O:11].[CH3:18][C:19]1[C:20]([CH:26]=O)=[N:21][CH:22]=[C:23]([CH3:25])[CH:24]=1.[BH4-].[Na+].C([O-])(O)=O.[Na+]>CO.C(Cl)Cl>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][CH2:26][C:20]1[C:19]([CH3:18])=[CH:24][C:23]([CH3:25])=[CH:22][N:21]=1)(=[O:12])=[O:11]
Reactant: NCCCCS(=O)(=O)c1nc2ccccc2[nH]1
Reactant: Cc1cnc(C=O)c(C)c1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1cnc(CNCCCCS(=O)(=O)c2nc3ccccc3[nH]2)c(C)c1
Reaction time: 1 h
Yield: 13.4 %

Procedure:
A solution of 4-(1H-benzoimidazole-2-sulfonyl)-butylamine (350 mg, 1.4 mmol) and 3,5-dimethylpyridine-2-carbaldehyde (187 mg, 1.4 mmol) in dry MeOH (10 mL) was stirred for 3 h. At this time, solid NaBH4 (116 mg, 4.2 mmol) was added in one portion. Stirring was continued for 1 h, then saturated aqueous NaHCO3 (10 mL) and CH2Cl2 (20 mL) was added. The biphasic mixture was extracted with CH2Cl2 (3×20 mL), then the combined organic fractions were dried (MgSO4), and concentrated. Purification of the crude material by flash chromatography (silica gel, CH2Cl2/MeOH/NH4OH; 20:2:1) afforded 70 mg of [4-(1H-benzoimidazole-2-sulfonyl)-butyl]-(3,5-dimethyl-pyridin-2-ylmethyl)-amine (14% yield). 1H NMR (CDCl3) δ 184-1.86 (m, 4H), 2.26 (s, 3H), 2.29 (s, 3H), 2.95-3.00 (m, 2H), 3.34-3.56 (m, 2H), 4.12 (s, 2H), 7.34-7.37 (m, 2H), 7.44 (s, 1H), 7.67-7.71 (m, 2H), 8.19 (s, 1H).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][C:5]1[CH:6]=[CH:7][C:8]([I:15])=[C:9]([CH2:11][C:12](Cl)=[O:13])[CH:10]=1.CCOC(C)=O>CCOCC>[CH3:1][N:2]([CH3:3])[C:12](=[O:13])[CH2:11][C:9]1[CH:10]=[C:5]([CH3:4])[CH:6]=[CH:7][C:8]=1[I:15]
Reactant: CNC
Reactant: Cc1ccc(I)c(CC(=O)Cl)c1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: Cc1ccc(I)c(CC(=O)N(C)C)c1

Procedure:
Dimethylamine (200 ml of 2 M solution in THF) is added dropwise to a solution of 5-methyl-2-iodophenylacetyl chloride in Et2O (500 ml) which is cooled in an ice bath. After the addition is complete, EtOAc (350 ml) is added and the solution is washed with water (350 ml), brine (250 ml) and dried (MgSO4). Evaporation on a rotovap and trituration with 1:1 Et2O/hexanes gives N,N-dimethyl-5-methyl-2-iodophenylacetamide as a light tan solid, m.p. 47–49°.