Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]([N:5]1[C:14]2[C:9](=[C:10]([O:28][CH2:29][CH2:30][CH3:31])[C:11]([CH:15]3[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)=[CH:12][CH:13]=2)[CH2:8][CH2:7][C@@H:6]1[CH3:32])(=[O:4])[CH3:3]>O1CCOCC1.C(OCC)C>[CH3:32][C@H:6]1[CH2:7][CH2:8][C:9]2[C:14](=[CH:13][CH:12]=[C:11]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:10]=2[O:28][CH2:29][CH2:30][CH3:31])[N:5]1[C:2](=[O:4])[CH3:3]
Reactant: CCCOc1c(C2CCN(C(=O)OC(C)(C)C)CC2)ccc2c1CC[C@H](C)N2C(C)=O
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCCOc1c(C2CCNCC2)ccc2c1CC[C@H](C)N2C(C)=O
Reaction time: 3 h

Procedure:
A solution of hydrogen chloride (4.0 N in 1,4-dioxane, 1.4 mL, 5.6 mmol) was added to a solution of (S)-tert-butyl 4-(1-acetyl-2-methyl-5-propoxy-1,2,3,4-tetrahydroquinolin-6-yl)piperidine-1-carboxylate (480 mg, 1.1 mmol) in 1,4-dioxane (3 mL). The reaction was stirred for 3 hours resulting in a white precipitate. The reaction solution was diluted with diethyl ether (10 mL) and the precipitate was collected by filtration. The filtrate was further washed with diethyl ether (10 mL), collected and dried in vacuo affording the hydrochloride salt of the title compound as a white powder. The salt was free based via neutralization in ethyl acetate with saturated aqueous sodium carbonate solution until a pH=7.5 was achieved. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo affording (S)-1-(2-methyl-6-(piperidin-4-yl)-5-propoxy-3,4-dihydroquinolin-1(2H)-yl)ethan-1-one (356 mg, 97%) as a colorless solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.96-1.06 (m, 6H), 1.11-1.26 (m, 1H), 1.38-1.61 (m, 4H), 1.66-1.89 (m, 2H), 2.20 (s, 3H), 2.16-2.28 (m, 2H), 2.52 (m, 2H), 2.67-2.80 (m, 2H), 2.83-2.94 (m, 1H), 2.99 (br d, J=12.02 Hz, 2H), 3.58-3.72 (m, 2H), 4.40-4.63 (br d, J=6.75 Hz, 1H), 7.03 (br s, 2H). MS (ESI, pos. ion) m/z 331 [M+H]+.
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[C:40]1[C:48]2[C:43](=[C:44]([CH3:49])[CH:45]=[CH:46][CH:47]=2)[N:42]([CH2:50][C:51]2[CH:56]=[CH:55][C:54](I)=[CH:53][CH:52]=2)[CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:58]([OH:62])(=[O:61])[CH:59]=[CH2:60].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C>[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[C:40]1[C:48]2[C:43](=[C:44]([CH3:49])[CH:45]=[CH:46][CH:47]=2)[N:42]([CH2:50][C:51]2[CH:56]=[CH:55][C:54](/[CH:60]=[CH:59]/[C:58]([OH:62])=[O:61])=[CH:53][CH:52]=2)[CH:41]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2c([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)cn(Cc3ccc(I)cc3)c12
Reactant: C=CC(=O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOCC
Product: Cc1cccc2c([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)cn(Cc3ccc(/C=C/C(=O)O)cc3)c12
Temperature: 80 °C
Reaction time: 8 h
Yield: 85.7 %

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-7-methyl-1H-indole (1.18 g) in N,N-dimethylformamide (10 mL) was added 55% sodium hydride (87 mg) under ice-cooling, and the mixture was stirred at the same temperature for 15 minutes. To this mixture was added 4-iodobenzyl bromide (0.62 g) at the same temperature, and the mixture was stirred at the same temperature for 15 minutes, and stirred at room temperature for 1 hour. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=5/1-3/1) to give 3-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-1-(4-iodo-benzyl)-7-methyl-1H-indole (1.48 g). A mixture of 3-(2,3,4,6-tetra-O-benzyl-β-D-glucopyranosyl)-1-(4-iodobenzyl)-7-methyl-1H-indole (1.06 g), acrylic acid (0.18 g), palladium(II) acetate (14 mg), tris(2-methylphenyl)phosphine (37 mg), triethylamine (2 mL) and acetonitrile (2 mL) was stirred at 80° C. under an argon atmosphere overnight. The reaction mixture was diluted with diethyl ether, and the mixture was stirred at room temperature for 10 minutes. The insoluble material was removed by filtration, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1-1/3) to give the title compound (0.85 g).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.[OH:19][CH2:20][CH2:21][CH2:22][CH:23]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:24][C@@H:25]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[NH:26][C:27]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>ClCCl>[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([O:19][CH2:20][CH2:21][CH2:22][CH:23]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:24][C@@H:25]([C:46]([O:48][C:49]([CH3:51])([CH3:52])[CH3:50])=[O:47])[NH:26][C:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)C(CCCO)C[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCC(C[C@H](NC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 0.1 %

Procedure:
At 0° C. triethylamine (0.31 mL, 2.2 mmol) and 4-methylbenzenesulfonyl chloride (0.141 g, 0.74 mmol) were added to a solution of di-tert-butyl 4-(3-hydroxypropyl)-N-trityl-L-glutamate (0.239 g, 0.427 mmol) in dichloromethane (10 mL). The resulting mixture was stirred at 0° C. for 2 h and for 16 h at room temperature. The solution was concentrated and the crude product was purified by flash chromatography (silica, ethyl acetate/hexane) to afford di-tert-butyl 4-{3-{[(4-methylphenyl)sulfonyl)oxy]propyl}-N-trityl-L-glutamate (0.255 mg, 67%) as a mixture of (4S,4S)/(2S,4R) diastereoisomers. The isomers were separated by chiral HPLC (Chiralpak AD-H 5 μm 250×20 mm, hexane/2-propanol 9:1, 25 mL/min):
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[CH:21]=[CH:20][CH:19]=[CH:18][C:6]=2[C:7]=1[S:8]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)(=[O:10])=[O:9])[CH3:2].[CH2:22]([N:24]([CH2:28][CH3:29])[CH2:25][CH2:26]Cl)[CH3:23]>>[CH2:1]([C:3]1[O:4][C:5]2[CH:21]=[CH:20][CH:19]=[CH:18][C:6]=2[C:7]=1[S:8]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:23][CH2:22][N:24]([CH2:28][CH3:29])[CH2:25][CH3:26])=[CH:13][CH:12]=1)(=[O:10])=[O:9])[CH3:2]
Reactant: CCN(CC)CCCl
Reactant: CCc1oc2ccccc2c1S(=O)(=O)c1ccc(O)cc1
Product: CCc1oc2ccccc2c1S(=O)(=O)c1ccc(OCCN(CC)CC)cc1

Procedure:
Reaction of 2-ethyl-3-(4-hydroxyphenylsulfonyl)benzofuran with 2-diethylaminoethyl chloride by the procedure described in Example 1 gives the title compound.
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:21])([F:20])[S:9]([O:12]S(C(F)(F)F)(=O)=O)(=[O:11])=[O:10].O[C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH2:25][CH2:26][C:27](=[O:33])[NH:28]2>ClCCl>[F:7][C:8]([F:21])([F:20])[S:9]([O:12][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH2:25][CH2:26][C:27](=[O:33])[NH:28]2)(=[O:11])=[O:10]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C1CCc2c(O)cccc2N1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C1CCc2c(cccc2OS(=O)(=O)C(F)(F)F)N1
Reaction time: 2 h
Yield: 107 %

Procedure:
Pyridine (30 ml) and trifluoromethanesulfonic anhydride (25 g) were added with stirring at 0° C. to an anhydrous dichloromethane solution (200 ml) of 5-hydroxy-3,4-dihydro-1H-quinolin-2-one (15.9 g), followed by stirring for 2 hours. The resulting mixture was concentrated under reduced pressure, water was added to the residue, and extraction with dichloromethane was performed. The extract was washed with water, an aqueous potassium hydrogensulfate solution and water in this order, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was recrystallized from an ethyl acetate-diisopropyl ether mixed solvent to thereby obtain 28 g (yield: 97%) of 5-trifluoromethanesulfonyloxy-3,4-dihydro-1H-quinolin-2-one as a light brown powder.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]#[N:19])[CH:16]=3)[N:11]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][O:21]3)[N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(OCC)(=O)C>[O:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH:20]1[N:11]1[C:12]2[C:17](=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)[C:9]([CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:10]1
Reactant: N#Cc1ccc2c(c1)c(/C=C/c1ccccc1)nn2C1CCCCO1
Solvent: CCOC(C)=O
Product: N#Cc1ccc2c(c1)c(CCc1ccccc1)nn2C1CCCCO1
Reaction time: 5 h
Yield: 42.5 %

Procedure:
3-((1 E)-2-Phenylvinyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (0.275 g, 0.83 mmol) was dissolved in ethyl acetate (20 mL). The flask was purged with nitrogen, then hydrogen. To this solution was added palladium on carbon (10 weight %, 14 mg). The mixture was stirred under an atmosphere of hydrogen for 5 hours. The catalyst was filtered and washed with small portions of ethyl acetate (5 mL). The filtrate was concentrated under reduced pressure resulting in the title compound (oil solidified under vacuum) (0.117 g, 84% yield): ES-MS (m/z) 332 [M+1]+.
Reaction SMILES: Cl[C:2]1[C:3]2[C:17]([I:18])=[CH:16][N:15]([C@@H:19]3[O:25][C@H:24]([CH2:26][OH:27])[C@@H:22]([OH:23])[C@@:20]3([CH3:28])[OH:21])[C:4]=2[N:5]=[C:6]([NH:8]C(=O)C(C)(C)C)[N:7]=1.[NH3:29]>>[NH2:8][C:6]1[N:7]=[C:2]([NH2:29])[C:3]2[C:17]([I:18])=[CH:16][N:15]([C@@H:19]3[O:25][C@H:24]([CH2:26][OH:27])[C@@H:22]([OH:23])[C@@:20]3([CH3:28])[OH:21])[C:4]=2[N:5]=1
Reactant: N
Reactant: CC(C)(C)C(=O)Nc1nc(Cl)c2c(I)cn([C@@H]3O[C@H](CO)[C@@H](O)[C@@]3(C)O)c2n1
Product: C[C@@]1(O)[C@H](O)[C@@H](CO)O[C@H]1n1cc(I)c2c(N)nc(N)nc21

Procedure:
A mixture of the compound from Step B (2.92 g, 5.6 mmol) and anhydrous liquid ammonia (50 mL) was heated in a stainless steel autoclave at 110° C. for 1d, then cooled and the solvent evaporated. The residue was treated with MeOH to yield 0.30 g of 15.4. The filtrate was evaporated and purified on silica gel column with CH2Cl2/MeOH (20/1) to furnish additional 1.52 g of the target compound (total yield 77%).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[CH:5][NH:4][N:3]=1.F[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[F:17].C(=O)(O)[O-].[Na+].O>CS(C)=O>[F:17][C:9]1[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:8]=1[N:4]1[CH:5]=[N:6][C:2]([CH3:1])=[N:3]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: Cc1nc[nH]n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ncn(-c2ccc([N+](=O)[O-])cc2F)n1
Temperature: 80 °C
Yield: 17 %

Procedure:
A mixture of 3-methyl-1H-1,2,4-triazole (15.0 g, 181 mmol), 1,2-difluoro-4-nitrobenzene (28.7 g, 181 mmol), and sodium bicarbonate (15.2 g, 181 mmol) in DMSO (100 mL) was heated at 80° C. for 48 h. The reaction mixture was allowed to cool to rt and was poured into water (800 mL). The aqueous mixture was extracted with EtOAc (3×200 mL). The combined organic extracts were sequentially washed with water (500 mL) and brine solution (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude reaction mixture was purified using silica gel chromatography (30-80% EtOAc/hexane, linear gradient) to afford two regioisomeric products. Pure fractions of the less polar regioisomer were combined and concentrated to afford 1-(2-fluoro-4-nitrophenyl)-3-methyl-1H-1,2,4-triazole (7.2 g, 30.8 mmol, 17% yield) as an off-white solid. Pure fractions of the more polar regioisomer were combined and concentrated to afford 1-(2-fluoro-4-nitrophenyl)-5-methyl-1H-1,2,4-triazole (6.23 g, 28.0 mmol, 15% yield) as an off-white solid. Data for 1-(2-fluoro-4-nitrophenyl)-5-methyl-1H-1,2,4-triazole: LC-MS (M+H)+=223.1. 1H NMR (500 MHz, CDCl3) δ ppm 8.18-8.24 (m, 2H) 8.04 (s, 1H) 7.69-7.78 (m, 1H) 2.47-2.53 (m, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7](I)=[CH:6][C:3]=1[C:4]#[N:5].[Cl-].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:17][Zn+].NC1C=CC(CC2C=CC=CC=2)=CC=1C#N>>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:17][C:16]2[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:14]([O:13][CH3:12])[CH:15]=2)=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(I)ccc1N
Reactant: COc1ccc(C[Zn+])cc1OC
Agent: N#Cc1cc(Cc2ccccc2)ccc1N
Agent: [Cl-]
Product: COc1ccc(Cc2ccc(N)c(C#N)c2)cc1OC

Procedure:
From 9 (488 mg, 2 mmol) and 3,4-dimethoxybenzylzinc chloride (0.5 M in THF, 10 mL, 5.0 mmol) by the same method as 10a; yellow oil (247 mg, 46%): 1H NMR (CDCl3) δ 3.79 (s, 2H, CH2), 3.83 (s, 3H, OMe), 3.86 (s, 3H, OMe), 4.21 (br s, NH2), 6.65-6.82 (m, 4H, H-3, H-2′, H-5′, and H-6′), 7.15 (d, J=8.4 Hz, 1H, H-4),7.17 (s, 1H, H-6).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]3[N:24]([C:25](=[O:35])[C:26]4[C:31]([F:32])=[CH:30][C:29]([F:33])=[CH:28][C:27]=4[F:34])[N:23]=[C:22]([C:36]4[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=4)[S:21]3)[C:15]=2[O:43][CH2:44][C:45]#N)[N:7]=1)=[O:5])C.[Li+].[OH-:48].C1[CH2:53][O:52]CC1>CO>[F:42][C:39]1[CH:40]=[CH:41][C:36]([C:22]2[S:21][CH:20]([C:16]3[C:15]([O:43][CH2:44][C:45]([O:52][CH3:53])=[O:48])=[C:14]([CH:19]=[CH:18][CH:17]=3)[O:13][CH2:12][C:8]3[N:7]=[C:6]([C:4]([OH:3])=[O:5])[CH:11]=[CH:10][CH:9]=3)[N:24]([C:25](=[O:35])[C:26]3[C:27]([F:34])=[CH:28][C:29]([F:33])=[CH:30][C:31]=3[F:32])[N:23]=2)=[CH:37][CH:38]=1
Reactant: C1CCOC1
Reactant: CCOC(=O)c1cccc(COc2cccc(C3SC(c4ccc(F)cc4)=NN3C(=O)c3c(F)cc(F)cc3F)c2OCC#N)n1
Reactant: [OH-]
Agent: [Li+]
Solvent: CO
Product: COC(=O)COc1c(OCc2cccc(C(=O)O)n2)cccc1C1SC(c2ccc(F)cc2)=NN1C(=O)c1c(F)cc(F)cc1F
Reaction time: 1 h

Procedure:
6-{2-Cyanomethoxy-3-[5-(4-fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-phenoxymethyl}-pyridine-2-carboxylic acid ethyl ester is dissolved in THF (1.5 mL) and MeOH (1.0 mL), LiOH (1 M) (0.5 mL) is added. After stirring for 1 hour, the solvent is removed from the reaction mixture. A mixture of MeOH/DMSO is added to the residue and resultant solution is filtered. The clear solution is purified by preparative LC/MS (20-100% MeCN/H2O) to give 6-{3-[5-(4-fluoro-phenyl)-3-(2,4,6-trifluoro-benzoyl)-2,3-dihydro-[1,3,4]thiadiazol-2-yl]-2-methoxycarbonylmethoxy-phenoxymethyl}-pyridine-2-carboxylic acid as white solid after removal of solvent: 1H NMR (400 MHz, CDCl3) δ 8.21 (d, J=7.9 Hz, 1H), 8.03 (t, J=7.3 Hz, 1H), 7.81 (d, 10.1 Hz, 1H), 7.8 (s, 1H), 7.55 (dd, J=8.9, 5.3 Hz, 2H), 7.0-7.1 (m, 4H), 6.92 (d, J=8 Hz, 1H), 6.76 (t, J=7.5 Hz, 2H), 5.31 (s, 2H), 4.94 (d, J=7.8 Hz, 2H), 4.8 (bs, 1H), 3.8 (s, 3H); LC/MS (ES+): (M+1) 656.3.
Reaction SMILES: [F:1][C:2]1([F:26])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([C:15]3[CH2:16][CH:17]4[CH2:21][NH:20][CH2:19][CH:18]4[CH:22]=3)=[CH:12][CH:13]=2)[N:8]([CH3:23])[S:7]1(=[O:25])=[O:24].CCN(C(C)C)C(C)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>C(#N)C>[F:26][C:2]1([F:1])[CH2:4][CH:3]1[CH2:5][N:6]1[C:14]2[C:9](=[N:10][C:11]([C:15]3[CH2:16][CH:17]4[CH2:21][N:20]([S:37]([CH3:36])(=[O:39])=[O:38])[CH2:19][CH:18]4[CH:22]=3)=[CH:12][CH:13]=2)[N:8]([CH3:23])[S:7]1(=[O:25])=[O:24]
Reactant: CN1c2nc(C3=CC4CNCC4C3)ccc2N(CC2CC2(F)F)S1(=O)=O
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CN1c2nc(C3=CC4CN(S(C)(=O)=O)CC4C3)ccc2N(CC2CC2(F)F)S1(=O)=O
Reaction time: 0.17 h

Procedure:
1-[(2,2-Difluorocyclopropyl)methyl]-5-(1,2,3,3a,4,6a-hexahydrocyclo-penta-[c]pyrrol-5-yl)-3-methyl-1,3-dihydro[1,2,5]thiadiazolo[3,4-b]pyridine 2,2-dioxide (24-2, 40 mg, 0.11 mmol, 1.0 equiv) was added to anhydrous acetonitrile (1.0 mL) followed by the sequential addition of DIPEA (55 μL, 0.31 mmol, 3.0 equiv) and methanesulfonyl chloride (12 μL, 0.16 mmol, 1.5 equiv). After 10 min at RT, LCMS showed complete consumption of starting material. Purification by reverse-phase HPLC (10-100% CH3CN:0.1% TFA in H2O) afforded 26-1 as a white solid. MS ink (M+H): calculated=461.1123; observed=461.1129.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:18]=[CH:17][C:12]([CH2:13][O:14][CH2:15]Cl)=[CH:11][CH:10]=1.[Cl:19][C:20]1[CH:21]=[N:22][C:23](=[O:26])[NH:24][CH:25]=1.C(N(CC)CC)C>ClCCl>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[CH:18]=[CH:17][C:12]([CH2:13][O:14][CH2:15][N:24]2[CH:25]=[C:20]([Cl:19])[CH:21]=[N:22][C:23]2=[O:26])=[CH:11][CH:10]=1
Reactant: ClCOCc1ccc(COC2CCCCO2)cc1
Reactant: O=c1ncc(Cl)c[nH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1ncc(Cl)cn1COCc1ccc(COC2CCCCO2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
Chloromethyl 4-(tetrahydropyran-2-yloxymethyl)benzyl ether (see Preparation 12) (4.7 mmol) in dichloromethane (40 ml) was added dropwise with stirring to a solution of 5-chloropyrimidin-2-one (4.7 mmol) and triethylamine (4.7 mmol) in dichloromethane (10 ml). The mixture was stirred at room temperature for 2 hours and was then washed with water, the organic solution dried (MgSO4) and the solvent distilled off to yield a crude product in 89% yield (1.53 g), which was extracted with ether and the residual material purified on neutral alumina eluting with dichloromethane and subsequently with 10% MeOH in dichloromethane; yield 0.42 g (26%) of the non-crystalline title compound. 1H NMR (CDCl3): δ1.4-2.0 (6H, m, THP), 3.3-4.3 (2H, m), 4.5-4.9 (2CH2, CH), 5.37 (NCH2), 7.38 (Ph), 7.88 and 8.53 (H-4, H-6, J 4 Hz).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1([C:11]2O[C:13]([C:16]3[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=3)=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].BrN1C(=O)CCC1=O.[NH2:31][NH2:32]>C1COCC1.O>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1([C:11]2[N:31]=[N:32][C:13]([C:16]3[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=3)=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: Cn1cc(-c2ccc(C3(NC(=O)OC(C)(C)C)CC3)o2)cn1
Agent: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(-c2ccc(C3(NC(=O)OC(C)(C)C)CC3)nn2)cn1
Temperature: -35 °C
Reaction time: 20 h
Yield: 21.7 %

Procedure:
In a round bottom flask, {1-[5-(1-methyl-1H-pyrazol-4-yl)-furan-2-yl]-cyclopropyl}-carbamic acid tert-butyl ester (226 mg, 0.745 mmol) was dissolved in a mixture of THF (12.4 mL) and water (1.3 mL). The flask was cooled to −35° C. in a dry ice/acetone bath (the mixture becomes a thick slurry) and then N-bromosuccinimide (146 mg, 0.819 mmol) was added as a solid in one portion. The reaction immediately turned a bright yellow color. The reaction was stirred for 15 min at this temperature after which time anhydrous hydrazine (0.21 mL, 6.7 mmol) was added in one portion via syringe. The ice bath was removed and the reaction was allowed to stir at room temperature for 20 h. The volatiles were removed at 50° C. under a stream of N2. The resulting residue was purified by flash chromatography (silica, 90→100% EtOAc/hexanes) to give 51 mg of {1-[6-(1-methyl-1H-pyrazol-4-yl)-pyridazin-3-yl]-cyclopropyl}-carbamic acid tert-butyl ester as a bright yellow solid, m/z 316.6 [M+H]+.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([O:23]C3C=CC=CC=3)=O)=[CH:16][CH:15]=2)[N:11]=[C:10]([C:30]([O:32][CH3:33])=[O:31])[CH:9]=1.C(N(CC)CC)C.[CH:41]1([NH2:44])[CH2:43][CH2:42]1>CN(C=O)C>[CH:41]1([NH:44][C:21]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([C:12]3[N:11]=[C:10]([C:30]([O:32][CH3:33])=[O:31])[CH:9]=[C:8]([N:3]4[CH2:4][CH2:5][O:6][CH2:7][C@@H:2]4[CH3:1])[N:13]=3)=[CH:15][CH:16]=2)=[O:23])[CH2:43][CH2:42]1
Reactant: NC1CC1
Reactant: COC(=O)c1cc(N2CCOC[C@@H]2C)nc(-c2ccc(NC(=O)Oc3ccccc3)cc2)n1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(N2CCOC[C@@H]2C)nc(-c2ccc(NC(=O)NC3CC3)cc2)n1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
Methyl 6-[(3S)-3-methylmorpholin-4-yl]-2-[4-(phenoxycarbonylamino)phenyl]pyrimidine-4-carboxylate (547 mg) was dissolved in DMF (8 mL) and triethylamine (0.59 mL) followed by cyclopropylamine (0.491 mL) added. The reaction was stirred at 40° C. for 2 hours then the mixture was vacuumed to dryness and partitioned between DCM (50 mL) and water (50 mL). The organic layer was dried over magnesium sulphate and vacuumed to dryness then chromatographed on silica, eluting with 5% methanol in DCM, to give the desired material (351 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]2[CH:8]=[N:7][CH:6]=[CH:5][C:4]=2[C:3]=1[NH2:12].[F:13][C:14]([F:26])([F:25])[C:15]1[CH:24]=[CH:23][C:18]([CH2:19][N:20]=[C:21]=[O:22])=[CH:17][CH:16]=1>>[F:1][C:2]1[C:3]([NH:12][C:21]([NH:20][CH2:19][C:18]2[CH:17]=[CH:16][C:15]([C:14]([F:13])([F:26])[F:25])=[CH:24][CH:23]=2)=[O:22])=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2
Reactant: Nc1c(F)ccc2cnccc12
Reactant: O=C=NCc1ccc(C(F)(F)F)cc1
Product: O=C(NCc1ccc(C(F)(F)F)cc1)Nc1c(F)ccc2cnccc12

Procedure:
Prepared from 6-fluoroisoquinolin-5-amine (Description 89) and [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to Description 61. m/z (ES+) 364 (M+H)+.
Reaction SMILES: [C:1]1([N:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][N:15]=3)[CH:10]=[C:9]([C:17](OC3CCCC(=O)C=3)=[O:18])[C:8]2=[O:27])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C[C:36]([CH3:40])([OH:39])[C:37]#N.[C:41](O)(=O)[CH2:42][C:43](CC(O)=O)(C(O)=O)[OH:44]>ClCCl>[OH:44][C:43]1[CH2:42][CH2:41][CH2:40][C:36](=[O:39])[C:37]=1[C:17]([C:9]1[C:8](=[O:27])[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:16]2[C:11]([CH:10]=1)=[CH:12][CH:13]=[CH:14][N:15]=2)=[O:18]
Reactant: O=C1C=C(OC(=O)c2cc3cccnc3n(-c3ccccc3)c2=O)CCC1
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Reactant: CC(C)(O)C#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCCC(O)=C1C(=O)c1cc2cccnc2n(-c2ccccc2)c1=O
Temperature: 25 °C
Yield: 47 %

Procedure:
2.16 g (6.0 mmol) of 3-oxo-1-cyclohexenyl 1-phenyl-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate was dissolved in dichloromethane (50 mL), and 1.01 mL (7.2 mmol) of triethylamine and 0.56 g (6.6 mmol) of acetone cyanohydrin were added to the above solution. The resulting mixture was stirred for one whole day and night at room temperature. The reaction mixture was poured into an aqueous solution of citric acid, and the mixture was extracted with dichloromethane. The organic phase was washed with water, dried, and concentrated. The residue was washed with methanol, and thus 1.01 g (yield: 47%) of the title compound was obtained as pale brown crystals.