Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([O:14]C)[C:5]2[CH:6]=[C:7]([C:9](=[O:11])[CH3:10])[O:8][C:4]=2[CH:3]=1.ClC1C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-]>>[Cl:1][C:2]1[CH:13]=[C:12]([OH:14])[C:5]2[CH:6]=[C:7]([C:9](=[O:11])[CH3:10])[O:8][C:4]=2[CH:3]=1
Reactant: COc1cc(Cl)cc2oc(C(C)=O)cc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: CC(=O)c1cc2c(O)cc(Cl)cc2o1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
To a stirred solution of 1-(6-chloro-4-methoxybenzofuran-2-yl)ethanone (Example 37C, 1.43 g, 6.37 mmol) in chlorobenzene (15 mL, 148 mmol) was added aluminum chloride (3.40 g, 25.5 mmol) in portions over a period of 10 minutes. The reaction vessel was then sealed and heated at 100° C. for 40 minutes, then cool to r.t. and poured onto crushed ice (rinsed stirring bar with EtOAc). This was stirred for 30 minutes, then extracted with ethyl acetate. The organic phase was dried (MgSO4), filtered and concentrated to dryness. The residue was purified by ISCO using hexanes/EtOAc as eluent. Fractions containing the desired product were concentrated to give the title material (1.18 g, 5.60 mmol, 88% yield) as a light brown solid. LC (Method A): 1.783 min. LCMS (APCI) calcd for C10H8ClO3 [M+H]+ m/z 211.02. found 211.0. 1H NMR (CDCl3, 400 MHz) δ ppm: 11.01 (s, 1H), 7.89 (s, 1H), 6.72 (s, 1H), 2.52 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:32])=[C:6]([CH:31]=1)[O:7][CH2:8][C:9]1[C:18]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][C:20]=2[O:26][CH3:27])=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([CH3:30])=[CH:12][C:13]([CH3:29])([CH3:28])[NH:14]2.[C:33](N1C=CN=C1)(N1C=CN=C1)=[O:34].[CH3:45][N:46]([CH3:51])[CH2:47][CH2:48][NH:49][CH3:50]>CN(C)C1C=CN=CC=1.O1CCCC1>[CH3:45][N:46]([CH3:51])[CH2:47][CH2:48][N:49]([C:33]([O:25][C:22]1[CH:23]=[CH:24][C:19]([C:18]2[C:9]([CH2:8][O:7][C:6]3[CH:31]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[CH3:32])=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:28])([CH3:29])[CH:12]=[C:11]3[CH3:30])=[C:20]([O:26][CH3:27])[CH:21]=1)=[O:34])[CH3:50]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CNCCN(C)C
Reactant: COc1cc(O)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)C(C)=CC(C)(C)N2
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc(OC(=O)N(C)CCN(C)C)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)C(C)=CC(C)(C)N2
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.7 %

Procedure:
A mixture of 5-(5-fluoro-2-methylphenoxymethyl)-6-(4-hydroxy-2-methoxyphenyl)-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 3-1, 26.0 mg, 0.0600 mmol), 1,1′-carbonyldiimidazole (31.4 mg, 0.194 mmol) and 4-dimethylaminopyridine (1.1 mg, 0.0090 mmol) was dissolved in anhydrous tetrahydrofuran (0.6 mL), and then the mixture was stirred at room temperature for 1 hour. N,N,N′-trimethylethylenediamine (15 μL, 0.12 mmol) was added thereto, the mixture was stirred at room temperature for 1 hour, and then the mixture was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (10.0 mg) as a colorless amorphous product. (Yield 30%)
Reaction SMILES: [CH3:1][S:2]([O:5]S(C)(=O)=O)(=O)=[O:3].[NH2:10][C:11]1[C:20]2=[N:21][N:22]([CH2:32][CH3:33])[C:23]([CH2:24][C:25]3([OH:31])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[C:19]2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[NH2:10][C:11]1[C:20]2=[N:21][N:22]([CH2:32][CH3:33])[C:23]([CH2:24][C:25]3([OH:31])[CH2:30][CH2:29][N:28]([S:2]([CH3:1])(=[O:5])=[O:3])[CH2:27][CH2:26]3)=[C:19]2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: CS(=O)(=O)OS(C)(=O)=O
Reactant: CCn1nc2c(N)nc3ccccc3c2c1CC1(O)CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCn1nc2c(N)nc3ccccc3c2c1CC1(O)CCN(S(C)(=O)=O)CC1
Reaction time: 16 h
Yield: 44.4 %

Procedure:
Methanesulfonic anhydride (0.160 g, 0.922 mmol) was added to a slurry of 4-[(4-amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-1-yl)methyl]piperidin-4-ol (0.300 g, 0.922 mmol) in chloroform (10 mL). After 16 hours, 2M aqueous sodium carbonate was added and the biphasic mixture was stirred for 30 minutes resulting in a white precipitate. The mixture was extracted with 10% methanol in dichloromethane. The solution was concentrated. The residue was purified via automated flash chromatography and recrystallized from acetonitrile to provide 0.165 g of 4-[(4-amino-2-ethyl-2H-pyrazolo[3,4-c]quinolin-1-yl)methyl]-1-(methylsulfonyl)piperidin-4-ol as a white solid, mp 268-270° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][C:33]=1[NH:34][C:35]([C:37]1([C:40](=[O:49])[NH:41][C:42]2[CH:47]=[CH:46][C:45]([F:48])=[CH:44][CH:43]=2)[CH2:39][CH2:38]1)=[O:36])[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([N:12](C(OC2C=CC=CC=2)=O)C(=O)OC2C=CC=CC=2)[CH:7]=1.[CH3:50][N:51]1[CH2:56][CH2:55]C(NC)[CH2:53][CH2:52]1.[CH3:59][N:60]([CH3:63])[CH:61]=[O:62]>>[F:1][C:2]1[CH:3]=[C:4]([O:5][C:6]2[CH:11]=[CH:10][N:9]=[C:8]([NH:12][C:61]([N:60]([CH3:63])[CH:59]3[CH2:55][CH2:56][N:51]([CH3:50])[CH2:52][CH2:53]3)=[O:62])[CH:7]=2)[CH:31]=[CH:32][C:33]=1[NH:34][C:35]([C:37]1([C:40]([NH:41][C:42]2[CH:43]=[CH:44][C:45]([F:48])=[CH:46][CH:47]=2)=[O:49])[CH2:38][CH2:39]1)=[O:36]
Reactant: O=C(Oc1ccccc1)N(C(=O)Oc1ccccc1)c1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)c(F)c2)ccn1
Reactant: CNC1CCN(C)CC1
Reactant: CN(C)C=O
Product: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)c(F)c3)ccn2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.1 %

Procedure:
To a solution of phenyl N-[4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate (50.0 mg) in N,N-dimethylformamide (1.0 ml) was added 1-methyl-4-(methylamino)piperidine (0.0436 ml), followed by stirring at room temperature for 16 hr. The reaction mixture was partitioned between ethyl acetate and a 1N aqueous solution of sodium hydroxide. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Fuji Silysia NH, heptane:ethyl acetate=1:2, ethyl acetate, then ethyl acetate:methanol=50:1). Fractions containing the target compound were concentrated. To the residue was added diethyl ether:hexane=1:3, and the precipitate was collected by filtration. This was washed with diethyl ether:hexane=1:3 and dried under aeration to provide the titled compound as white powder (26.1 mg, 60.1%).
Reaction SMILES: [CH2:1]([NH:8][C:9]([CH:11]1[CH2:23][N:21]2[C:22]3[CH:14]([CH:15]([NH:24][C:25](=[O:38])[CH:26]([CH2:34][CH:35]([CH3:37])[CH3:36])[CH:27]([CH2:31][CH2:32][CH3:33])[C:28]([NH2:30])=[O:29])[CH2:16][CH2:17][C:18]=3[CH:19]=[CH:20]2)[C:13](=[O:39])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(CN)CCCCC1>>[CH:2]1([CH2:1][NH:8][C:9]([CH:11]2[CH2:23][N:21]3[C:22]4[CH:14]([CH:15]([NH:24][C:25](=[O:38])[CH:26]([CH2:34][CH:35]([CH3:36])[CH3:37])[CH:27]([CH2:31][CH2:32][CH3:33])[C:28]([NH2:30])=[O:29])[CH2:16][CH2:17][C:18]=4[CH:19]=[CH:20]3)[C:13](=[O:39])[CH2:12]2)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CCCC(C(N)=O)C(CC(C)C)C(=O)NC1CCc2ccn3c2C1C(=O)CC(C(=O)NCc1ccccc1)C3
Agent: NCC1CCCCC1
Product: CCCC(C(N)=O)C(CC(C)C)C(=O)NC1CCc2ccn3c2C1C(=O)CC(C(=O)NCC1CCCCC1)C3
Yield: 32 %

Procedure:
The compound of Example 3f was synthesized in a manner similar to the synthesis of the compound of Example 3a, but using cyclohexylmethylamine as the amine in the last step. Cleavage of 100 mg of functionalized resin (0.53 mmol/g) and purification by RP-HPLC provided 9.0 mg (32%) of the title compound as a white powder. MS (M+H)+=539.5.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([OH:9])=[C:4]([CH3:10])[C:3]=1[CH3:11].[CH2:12]=O.[C:14]([O:19][CH3:20])(=[O:18])[C:15]([CH3:17])=[CH2:16].O>CO>[OH:1][C:2]1[C:7]([CH3:12])=[C:6]2[C:5](=[C:4]([CH3:10])[C:3]=1[CH3:11])[O:9][C:15]([CH3:17])([C:14]([O:19][CH3:20])=[O:18])[CH2:16][CH2:8]2
Reactant: Cc1cc(O)c(C)c(C)c1O
Reactant: C=O
Reactant: C=C(C)C(=O)OC
Solvent: CO
Solvent: O
Product: COC(=O)C1(C)CCc2c(C)c(O)c(C)c(C)c2O1
Temperature: 25 °C

Procedure:
Into a 30-mL stainless-steel pressure reactor equipped with a stirrer, 1,4-dihydroxy-2,3,5-trimethylbenzene (1.0 g, 6.6. mmol), paraformaldehyde (0.4 g, 13.2 mmol), methyl methacrylate (3.3 g, 32.9 mmol), and water (0.29 g, 16.1 mmol) were placed. The mixture was allowed to react at 180° C. for three hours under stirring, while the reactor was tightly closed. After completion of reaction, the reaction mixture was cooled to room temperature, and methanol was added to the mixture, whereby crystals were precipitated. The crystals were collected through filtration, to thereby yield methyl 6-hydroxy-2,5,7,8-tetramethyl-chroman-2-carboxylate in the form of white powder (1.3 g, 4.9 mmol). Reaction scores on the basis of 1,4-dihydroxy-2,3,5-trimethylbenzene and chemical purity which was determined through HPLC were found to be as follows:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:22])/[CH:5]=[CH:6]/[C:7]1[CH:8]=[C:9]2[C:18](=[CH:19][CH:20]=1)[O:17][C:12]1([CH2:16][CH2:15][NH:14][CH2:13]1)[CH2:11][C:10]2=[O:21].CCN(C(C)C)C(C)C.[CH2:32](Br)[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:22])/[CH:5]=[CH:6]/[C:7]1[CH:8]=[C:9]2[C:18](=[CH:19][CH:20]=1)[O:17][C:12]1([CH2:16][CH2:15][N:14]([CH2:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:13]1)[CH2:11][C:10]2=[O:21]
Reactant: BrCCc1ccccc1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCNC1)O2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(CCc3ccccc3)C1)O2
Temperature: 25 °C
Reaction time: 192 h

Procedure:
A suspension of (E)-3-[4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-acrylic acid methyl ester (500 mg, 1.55 mmol, Intermediate 1) in DCM (15 ml) was treated with DIPEA (0.33 ml, 1.86 mmol) and phenethyl bromide (0.251 ml, 1.86 mmol), and stirred at RT for 8 days. The mixture was concentrated and the crude residue was purified by column chromatography (eluent: petroleum ether/EtOAc 7:3) to give (±)-(E)-3-[1′-(2-phenyl-ethyl)-4-oxo-spiro(chromane-2,3′-pyrrolidine)-6-yl]-acrylic acid methyl ester a yellow solid (280 mg).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([OH:16])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(=O)(O)[O-].[Na+].[CH3:22][C:23]1[C:24]2[CH:33]=[CH:32][CH:31]=[CH:30][C:25]=2[S:26][C:27]=1[CH:28]=O.F[C:35](F)(F)C(O)=O>>[CH3:35][O:15][C:14]([C@@H:3]1[CH2:4][C:5]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[C@H:28]([C:27]2[S:26][C:25]3[CH:30]=[CH:31][CH:32]=[CH:33][C:24]=3[C:23]=2[CH3:22])[NH:2]1)=[O:16]
Reactant: O=C(O)C(F)(F)F
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: Cc1c(C=O)sc2ccccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COC(=O)[C@@H]1Cc2c([nH]c3ccccc23)[C@H](c2sc3ccccc3c2C)N1
Temperature: 25 °C
Yield: 32.6 %

Procedure:
An aqueous solution of (S)-(−)-tryptophan hydrochloride (1.45 g, 5.7 mmol) was made alkaline with a saturated sodium bicarbonate solution and extracted with ethyl acetate. The extract was washed once with aqueous sodium chloride solution, dried (sodium sulfate), filtered, and concentrated in vacuo. The free base-was dissolved in chloroform (50 mL) and treated with 3-methylbenzo[b]thiophene-2-carbaldehyde (1.0 g, 5.7 mmol) and trifluoroacetic acid (21.2 mmol, 1.32 g). The resulting mixture then was heated to reflux for 3 hours. The solution was cooled to room temperature, washed once with saturated sodium bicarbonate solution, dried (sodium sulfate), filtered, and concentrated in vacuo to provide a mixture of two diastereomers. The isomers were separated by chromatography (silica gel, 30% ethyl acetate:hexanes) to give 700 mg (38%) of (1R,3S)-1-(3-methylbenzo[b]thiophen-2-yl)-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic acid methyl ester (Intermediate 5) and 400 mg (19%) of (1S;3S)-1-(3-methylbenzo[b]thiophen-2-yl)-2,3,4,9-tetra-hydro-1H-β-carboline-3-carboxylic acid methyl ester (Intermediate 6).
Reaction SMILES: [F:1][CH:2]([F:12])[C:3]1[CH:10]=[C:9](F)[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.O>[F:1][CH:2]([F:12])[C:3]1[CH:10]=[C:9]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6]
Reactant: O=Cc1ccc(F)cc1C(F)F
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=Cc1ccc(N2CCOCC2)cc1C(F)F
Temperature: 100 °C
Reaction time: 4 h
Yield: 51.6 %

Procedure:
A mixture containing 2-(difluoromethyl)-4-fluorobenzaldehyde (47; 3.50 g, 20.1 mmol), morpholine (48; 1.9 g, 22.1 mmol) and K2CO3 (5.5 g, 40.2 mmol) in 50 mL of DMSO was stirred at 100° C. for 4 h. The resulting reaction mixture was cooled to room temperature and diluted with water (200 mL). The precipitated solids were collected by filtration and dried to afford 2-(difluoromethyl)-4-morpholinobenzaldehyde 49 (2.5 g, 52%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:34][C:35]1[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1.O>ClCCl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([S:41]([C:38]4[CH:39]=[CH:40][C:35]([CH3:34])=[CH:36][CH:37]=4)(=[O:43])=[O:42])[C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:25])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2c(=O)n(-c3ccc(C(C)(C)C#N)cc3)c3c4cc(Br)ccc4ncc32)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 1, 50 mg, 0.12 mmol) and triethylamine (24.4 mg, 0.36 mmol) in dichloromethane (6 ml) was added 4-methylbenzene-1-sulfonyl chloride (35.02 mg, 0.18 mmol) at 0° C. The reaction was stirred at RT for 3 hours. The reaction mixture was poured into cold water and organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound. Yield: 17 mg (25.37%); 1H NMR (CDCl3, 300 MHz): δ 9.59 (s, 1H), 8.085-8.113 (d, 2H, J=8.4 Hz), 7.97-8.001 (d, 1H, J=9 Hz), 7.707-7.735 (d, 2H, J=8.4 Hz), 7.621-7.659 (dd, 1H, J=9.3, 2.1 Hz), 7.422-7.450 (d, 2H, J=8.4 Hz), 7.351-7.378 (d, 2H, J=8.1 Hz), 6.989-6.996 (d, 1H, J=2.1 Hz), 2.43 (s, 3H), 1.81 (s, 6H); MS: ink 561 (M+).
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH2:6][CH2:5]1)(=O)C.[C:22](=[O:25])([O-:24])[O-].[K+].[K+].C([OH:30])C>O.Cl>[C:11]([OH:30])(=[O:10])/[CH:12]=[CH:13]/[C:22]([OH:24])=[O:25].[N:17]1([C:14]2[CH:13]=[CH:12][C:11]([O:10][CH:7]3[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]3)=[CH:16][CH:15]=2)[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: O=C([O-])[O-]
Reactant: CC(=O)N1CCC(Oc2ccc(N3CCCC3)cc2)CC1
Reactant: CCO
Agent: Cl
Agent: [K+]
Solvent: O
Product: O=C(O)/C=C/C(=O)O
Product: c1cc(N2CCCC2)ccc1OC1CCNCC1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
1-Acetyl-4-(4-pyrrolidinopheyloxy)piperidine (1.5 g) obtained in Example 1 was dissolved in a mixed solvent of ethanol (5 ml), water (5 ml) and conc. hydrochloric acid (5 ml), followed by heating with stirring at 100° C. for 15 hours. The solution was made basic with potassium carbonate and then extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off. The residual oily compound (1.22 g) was dissolved in methanol (30 ml). After fumaric acid (0.52 g) was dissolved in the solution, the solvent was distilled off to leave a solid which was recrystallized from ethanol to obtain colorless crystals (1.4 g), m.p. 199°-201° C.
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:21]=[CH:20][C:10]([O:11][CH:12]([CH3:19])[C:13]([O:17]C)=[CH:14][CH2:15]O)=[CH:9][CH:8]=2)=[C:4]([F:24])[CH:3]=1.O>C(Cl)Cl>[Br:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:21]=[CH:20][C:10]([O:11][CH:12]([CH3:19])[C:13](=[O:17])[CH:14]=[CH2:15])=[CH:9][CH:8]=2)=[C:4]([F:24])[CH:3]=1
Reactant: COC(=CCO)C(C)Oc1ccc(Oc2ccc(Br)cc2F)cc1
Solvent: O
Solvent: ClCCl
Product: C=CC(=O)C(C)Oc1ccc(Oc2ccc(Br)cc2F)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 68.9 %

Procedure:
To a solution of 30 ml of 35% HClO4 and 15 ml CH2Cl2 at 0° C. was added 3.0 g (7.55 mmol) 4-(4-(4-bromo-2-fluorophenoxy)phenoxy)-3-methoxy-2-penten-1-ol in 15 ml CH2Cl2. The mixture was stirred at 0° C. for 45 min, then poured into water and extracted with ether. The combined ether extracts were washed with water, dried over MgSO4 and the solvent was removed by rotary evaporation. The residue was purified by HPLC, eluting with 95:5 hexane:acetone, to give 1.9 g (69%) of the product as a clear, colorless oil. Structure was established on the basis of IR and NMR analysis. Calc: C, 55.91; H, 3.86. Found: C, 56.84, H, 4.00.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]2[O:16][C:13]([CH3:15])([CH3:14])[C:10]([CH3:12])([CH3:11])[O:9]2)=[C:4]([F:17])[CH:3]=1.[N:18]([CH:21]1[CH2:23][CH2:22]1)=[C:19]=[O:20]>C(Cl)Cl>[CH:21]1([NH:18][C:19]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([B:8]3[O:9][C:10]([CH3:12])([CH3:11])[C:13]([CH3:15])([CH3:14])[O:16]3)=[C:4]([F:17])[CH:3]=2)=[O:20])[CH2:23][CH2:22]1
Reactant: O=C=NC1CC1
Reactant: CC1(C)OB(c2ccc(N)cc2F)OC1(C)C
Solvent: ClCCl
Product: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2F)OC1(C)C
Temperature: 37 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
To a stirred solution of 4-amino-2-fluorophenyl boronic acid pinacol ester (1.185 g, 5.0 mmol) in DCM (17 ml) was added isocyanato cyclopropane (830 mg, 10.0 mmol) and stirred overnight at 37° C. The reaction mixture was washed with water (20 mL), passed through a PTFE hydrophobic frit and the solvent removed in vacuo to yield a white solid (1.56 g) used without further purification.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[OH:13][C:14]([CH3:41])([CH3:40])[CH2:15][N:16]1[C:24]2[C:19](=[CH:20][C:21]([CH2:25][NH:26][S:27]([C:30]3[CH:39]=[CH:38][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:32][CH:31]=3)(=[O:29])=[O:28])=[CH:22][CH:23]=2)[CH:18]=[N:17]1>>[Cl:8][C:7]1[C:2]([N:26]([CH2:25][C:21]2[CH:20]=[C:19]3[C:24](=[CH:23][CH:22]=2)[N:16]([CH2:15][C:14]([OH:13])([CH3:40])[CH3:41])[N:17]=[CH:18]3)[S:27]([C:30]2[CH:31]=[CH:32][C:33]([C:34]([O:36][CH3:37])=[O:35])=[CH:38][CH:39]=2)(=[O:29])=[O:28])=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)NCc2ccc3c(cnn3CC(C)(C)O)c2)cc1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Product: COC(=O)c1ccc(S(=O)(=O)N(Cc2ccc3c(cnn3CC(C)(C)O)c2)c2ncc(C(F)(F)F)cc2Cl)cc1

Procedure:
The titled compound was prepared according to the procedure described in step-2 of Example 1 from 2,3-dichloro-5-(trifluoromethyl)pyridine and methyl 4-(N-((1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yl)methyl)sulfamoyl)benzoate (step-3 of Example 22).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[C:16]([C:17]([NH:19][CH2:20][C:21]4[CH:32]=[CH:31][C:24]([O:25][C@H:26]([CH3:30])[C:27]([OH:29])=O)=[CH:23][C:22]=4[F:33])=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.C[N:35]1CCOCC1.ClC(OCC(C)C)=O.CO.ClCCl>COCCOC>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([O:10][C:11]3[N:12]=[CH:13][CH:14]=[CH:15][C:16]=3[C:17]([NH:19][CH2:20][C:21]3[CH:32]=[CH:31][C:24]([O:25][C@@H:26]([C:27](=[O:29])[NH2:35])[CH3:30])=[CH:23][C:22]=3[F:33])=[O:18])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: C[C@@H](Oc1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCO3)c(F)c1)C(=O)O
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Solvent: CO
Solvent: ClCCl
Solvent: COCCOC
Product: C[C@@H](Oc1ccc(CNC(=O)c2cccnc2Oc2ccc3c(c2)OCO3)c(F)c1)C(N)=O
Temperature: -10 °C
Yield: 60.1 %

Procedure:
To a stirred solution of (R)-2-[4-({[2-(benzo[1,3]dioxol-5-yloxy)-pyridine-3-carbonyl]-amino}-methyl)-3-fluoro-phenoxy]-propionic acid (0.25 g, 0.55 mmol) in ethylene glycol dimethyl ether (20 mL) at −10° C. was added N-methyl morpholine (0.06 mL, 0.55 mmol) followed by dropwise addition of isobutyl chloroformate (0.071 mL, 0.55 mmol). The turbid solution was stirred at −10° C. 10 min. Ammonia gas was bubbled through the reaction mixture 10 min, which was then warmed to room temperature and stirred a further 15 min. The reaction mixture was partitioned between chloroform and water. The organic layer was dried over sodium sulfate and concentrated in vacuo to afford a white solid. Flash column chromatography (1% methanol/dichloromethane) yielded 0.15 g of a white solid (60% yield).
Reaction SMILES: [CH3:1][CH:2]1[C:6](=[O:7])[C:5]([OH:8])=[C:4]([CH3:9])[O:3]1.[CH:10](=[O:12])[CH3:11].C(O)(=O)C(O)=O>O>[OH:12][CH:10]([C:4]1([CH3:9])[C:5](=[O:8])[C:6]([OH:7])=[C:2]([CH3:1])[O:3]1)[CH3:11]
Reactant: CC=O
Reactant: CC1=C(O)C(=O)C(C)O1
Agent: O=C(O)C(=O)O
Solvent: O
Product: CC1=C(O)C(=O)C(C)(C(C)O)O1
Yield: 54.6 %

Procedure:
In a round-bottomed flask equipped with a stirrer and a condensor, 12.8 g (0.1 mole) of 2,5-dimethyl-4-hydroxy-3-(2H)-furanone and 44 g (1.0 mole) of acetaldehyde were introduced into a solution of 3.0 g of oxalic acid in 100 ml of water. The mixture was stirred and refluxed for 1 hour. After cooling, the mixture was extracted 5 times with 25 ml portions of chloroform and the organic solvent was evaporated off. The residue was purified by chromatography on 50 g of polyamide. After elution by means of a 50/50 mixture of ether and petroleum ether, 9.4 g of the title compound was obtained (which corresponds to a yield of 54%). Recrystallization from ether gave the pure product with m.p. 112-114°C).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[NH2:9].[C:10]([CH2:12][C:13](O)=[O:14])#[N:11].Cl.C(N=C=NCCCN(C)C)C>C1COCC1.CN(C1C=CN=CC=1)C>[C:10]([CH2:12][C:13]([NH:9][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])=[O:14])#[N:11]
Reactant: N#CCC(=O)O
Reactant: COc1ccncc1N
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccncc1NC(=O)CC#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
4-Methoxypyridin-3-amine (22 g, 177.2 mmol) and 2-cyanoacetic acid (19.60 g, 230.4 mmol) were slurried in THF (1 L). The mixture was cooled in an ice bath and DMAP (28.15 g, 230.4 mmol) was added followed by 3-(ethyliminomethyleneamino)-N,N-dimethyl-propan-1-amine hydrochloride (50.95 g, 265.8 mmol). The mixture was allowed to warm to ambient temperature and stirred overnight. The mixture was partially concentrated, then diluted with ethyl acetate/water. The organic phase was isolated and washed with saturated NaHCO3, then brine, dried (MgSO4), filtered and concentrated. The residue was slurried in ether/petrol to give 2-cyano-N-(4-methoxypyridin-3-yl)acetamide 8 as a yellow solid (26.4 g, 78%). LC-MS (M+H)+ 192.0; 1H NMR (500 MHz, DMSO-d6) δ 9.81 (s, 1H), 8.86 (s, 1H), 8.28 (d, 1H), 7.15 (d, 1H), 4.00 (s, 2H), 3.92 (s, 3H).