Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](N(OC)C)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O1CCC[CH2:21]1.O1CCCC1.C[Mg]Cl>CCOCC>[C:14]([CH:11]1[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]1)(=[O:15])[CH3:21]
Reactant: C1CCOC1
Reactant: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: C[Mg]Cl
Solvent: CCOCC
Product: CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 500 ml round bottom flask was added tert-butyl-4-{[methoxy(methyl)amino]carbonyl}piperidine-1-carboxylate (29 g, 106 mmol) and 150 ml tetrahydrofuran. The resulting solution was cooled with ice bath and methylmagnesium chloride tetrahydrofuran solution (42.6 ml, 3M, 128 mmol) was added by a syringe. The mixture was stirred at 0° C. for 30 minutes. It was diluted with 200 ml of ether and the resulting mixture was washed twice with 150 ml saturated ammonium chloride solution. The organics were dried over sodium sulfate, filtered and concentrated. The crude product was used for next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:20][CH2:19][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[N:34]2[CH:38]=[CH:37][C:36]([CH3:39])=N2)[C:23]([F:26])([F:25])[F:24])[N:3]=1.ClC1C=CC([C@@H](O)C(F)(F)F)=C(N2CCCC2=[O:52])C=1>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:9][CH2:10][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:19][CH2:20]2)[CH:5]=[C:4]([O:21][C@H:22]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=2[N:34]2[CH2:38][CH2:37][CH2:36][C:39]2=[O:52])[C:23]([F:24])([F:26])[F:25])[N:3]=1
Reactant: O=C1CCCN1c1cc(Cl)ccc1[C@@H](O)C(F)(F)F
Reactant: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)n1
Product: Nc1nc(O[C@H](c2ccc(Cl)cc2N2CCCC2=O)C(F)(F)F)cc(N2CCC3(CC2)CN[C@H](C(=O)O)C3)n1

Procedure:
The title compound was prepared as described for (S)-8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 10d) starting with (R)-1-(5-chloro-2-(2,2,2-trifluoro-1-hydroxyethyl)phenyl)pyrrolidin-2-one.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:19][O:20][C:21]1[CH:59]=[CH:58][C:24]([CH2:25][N:26]2[CH:30]=[C:29]([C:31](OCC)=[O:32])[C:28]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]4[N:47]=[C:48]([C:52]5[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=5)[O:49][C:50]=4[CH3:51])=[CH:40][CH:39]=3)=[N:27]2)=[CH:23][CH:22]=1.O>O1CCCC1>[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:10][C:9]=1[CH2:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:25][N:26]2[CH:30]=[C:29]([CH2:31][OH:32])[C:28]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][CH2:45][C:46]4[N:47]=[C:48]([C:52]5[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=5)[O:49][C:50]=4[CH3:51])=[CH:40][CH:39]=3)=[N:27]2)=[CH:58][CH:59]=1
Reactant: CCOC(=O)c1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2nn(Cc3ccc(OCc4nc(-c5ccccc5)oc4C)cc3)cc2CO)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.4 %

Procedure:
Lithium aluminium hydride (2.03 g) was added to a solution of ethyl 1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1H-pyrazole-4-carboxylate (40.00 g) in tetrahydrofuran (150 ml) at 0° C., and the mixture was stirred at room temperature for 30 minutes. After water was added to the reaction mixture, the precipitate was removed by filtration and the filtrate was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and then concentrated. The crystals obtained were collected by filtration to yield [1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1H-pyrazol-4-yl]methanol (35.91 g, yield: 95%). This was recrystallized from tetrahydrofuran-hexane. Melting point: 157–158° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([OH:40])[CH2:11][S:12][C@H:13]3[C:16](=[O:17])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[C@@H:14]3[C:25]3[CH:39]=[CH:38][C:28]([O:29][CH2:30][C:31]([NH:33][CH2:34][C:35](O)=[O:36])=[O:32])=[CH:27][CH:26]=3)=[CH:9][C:4]=2[O:3][CH2:2]1.CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH2:70][C@@H:71]([C:75]([OH:77])=[O:76])[CH:72]([CH3:74])[CH3:73]>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]([OH:40])[CH2:11][S:12][C@H:13]3[C:16](=[O:17])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[C@@H:14]3[C:25]3[CH:39]=[CH:38][C:28]([O:29][CH2:30][C:31]([NH:33][CH2:34][C:35]([NH:70][C@@H:71]([C:75]([OH:77])=[O:76])[CH:72]([CH3:74])[CH3:73])=[O:36])=[O:32])=[CH:27][CH:26]=3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc4c(c3)OCO4)C(=O)N2c2ccc(F)cc2)cc1
Reactant: CC(C)[C@@H](N)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)[C@@H](NC(=O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc4c(c3)OCO4)C(=O)N2c2ccc(F)cc2)cc1)C(=O)O
Temperature: 30 °C
Reaction time: 1 h

Procedure:
To a stirred solution of N-({4-[(2R,3R)-3-{[2-(1,3-benzodioxol-5-yl)-2-hydroxyethyl]thio}-1-(4-fluorophenyl)-4-oxoazetidin-2-yl]phenoxy}acetyl)glycine (12.8 mg, 0.023 mmol) in DMF (2 ml) was added N-methylmorpholine (15 μl, 0.091 mmol). TBTU (8.8 mg, 0.027 mmol) was added and the reaction mixture was stirred at 30° C. for 1 hour. D-valine (4.5 mg, 0.038 mmol) was added and the mixture was stirred at ambient temperature overnight. The solution was purified with preparative HPLC on a C8 column, UV 240/260 nm. A gradient from 20 to 45% MeCN in 0.1M NH4OAc buffer was used as eluent. The pure fractions were collected and the MeCN was removed under reduced pressure. The remaining water solution was acidified to pH 1 with HCl (1M) and extracted with DCM. The organic phase was passed through a phase separator and concentrated under reduced pressure. The residue was dissolved in MeCN and water. After lyophilisation, the title compound was obtained. H-NMR (400 MHz, DMSO-d6): 0.80 (bs, 6H), 1.92-2.04 (m, 1H), 2.77-2.90 (m, 2H), 3.77 (bs, 2H), 3.94-4.10 (b, 1H), 4.22-4.30 (m, 1H), 4.49 (s, 2H), 4.56-4.64 (m, 1H), 4.99-5.03 (m, 1H), 5.90-5.94 (m, 2H), 6.70-6.79 (m, 2H), 6.82 (s, 1H), 6.96 (d, 2H), 7.09-7.15 (m, 2H), 7.18-7.24 (m, 2H), 7.34 (d, 2H), 8.23 (bs, 1H). M/z: 666.67 (M−1).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([F:9])=[C:5]([F:10])[C:4]=1[F:11])#[CH:2].C[Mg]Br.[CH:15](=[O:20])[CH2:16][CH2:17][CH2:18][CH3:19].Cl>C1COCC1>[OH:20][CH:15]([CH2:16][CH2:17][CH2:18][CH3:19])[C:2]#[C:1][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[C:5]([F:10])[C:4]=1[F:11]
Reactant: CCCCC=O
Reactant: C#Cc1ccc(F)c(F)c1F
Agent: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CCCCC(O)C#Cc1ccc(F)c(F)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 107.2 %

Procedure:
Under nitrogen replacement, 110 g of 1-ethynyl-2,3,4-trifluorobenzene was dissolved in 440 mL of THF. To this, 846 mL of methylmagnesium bromide (1.0 M in Toluene/THF=4/1) was added dropwise for 1 hour while ice-cooling, and stirred for 30 minutes. To this, 72.8 g of pentanal was added dropwise for 1 hour, warmed to room temperature, and stirred for 1 hour. After the reaction solution was poured into 300 g of ice/300 mL of concentrated hydrochloric acid, and stirred for a while, an organic layer was separated and an aqueous layer was extracted with toluene. After the extract and the organic layer were mixed together, washed using water and a saturated saline solution in that order, and dried using anhydrous magnesium sulfate, the solvent was evaporated under a reduced pressure to obtain a brown oily material. This was purified by column chromatography (silica gel, toluene) to obtain 183 g of 1-(3-hydroxy-1-heptynyl)-2,3,4-trifluorobenzene as a reddish brown oily material.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH:6]([NH:14]C(=O)OC(C)(C)C)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1)(=[O:3])[CH3:2].FC(F)(F)C(O)=O>>[NH2:14][CH:6]([C:7]1[CH:8]=[CH:9][C:10]([Cl:13])=[CH:11][CH:12]=1)[CH2:5][NH:4][C:1](=[O:3])[CH3:2]
Reactant: CC(=O)NCC(NC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)NCC(N)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
Tert-butyl 2-acetamido-1-(4-chlorophenyl)ethylcarbamate (Intermediate 82) (148 mg, 0.47 mmol) was treated with trifluoroacetic acid (2 mL). The solution was stirred for 1 hours at room temperature. The mixture was concentrated under reduced pressure. The crude product was purified by ion exchange chromatography, using an SCX column. The residue was loaded onto the column in methanol and washed with methanol. The desired product was eluted from the column using 2M ammonia in methanol and pure fractions were evaporated to dryness to afford N-(2-amino-2-(4-chlorophenyl)ethyl)acetamide (98 mg, 97%) as a pale yellow crystalline solid.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]([CH2:8][C:9]([CH3:20])([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:5]=1)([O-])=O.O.C(OCC)(=O)C.C(N(CC)CC)C>CCO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]([CH3:20])([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:21][CH:22]=1
Reactant: CCOC(=O)C(C)(Cc1ccc([N+](=O)[O-])cc1)C(=O)OCC
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)C(C)(Cc1ccc(N)cc1)C(=O)OCC
Yield: 81.2 %

Procedure:
Stannous chloride dihydrate (4.39 g, 19.4 mmol) was added to a solution of diethyl 2-(4-nitrobenzyl)-2-methylmalonate (3.00 g, 9.70 mmol) in EtOH (30 ml) and stirred at reflux for 3 h. Water and ethyl acetate were added and the solution was basified with triethyl amine adjusted an pH˜9. The salts were filtered and washed with ethyl acetate. The organic layer was separated from the filtrate and washed with water, brine solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 2.20 g (81.4%) of diethyl 2-(4-aminobenzyl)-2-methylmalonate as brown oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:25])=[C:19]([NH2:24])[CH:20]=[CH:21][C:22]=2[F:23])[CH:5]=[CH:4][N:3]=1.[F:26][C:27]1[CH:28]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:25])=[C:19]([NH:24][S:33]([C:29]3[CH:30]=[CH:31][CH:32]=[C:27]([F:26])[CH:28]=3)(=[O:35])=[O:34])[CH:20]=[CH:21][C:22]=2[F:23])[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)c1nc(-c2c(F)ccc(N)c2F)c(-c2ccnc(Cl)n2)s1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Product: CC(C)(C)c1nc(-c2c(F)ccc(NS(=O)(=O)c3cccc(F)c3)c2F)c(-c2ccnc(Cl)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using {3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}amine (500 mg, 1.313 mmol) and 3-fluorobenzenesulfonyl chloride (0.210 mL, 1.575 mmol), the title compound was obtained as an yellow foam (690 mg, 98% yield).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:34]=[CH:33][C:14]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][Br:32])=[CH:19][CH:18]=2)=O)=[CH:13][CH:12]=1>C1COCC1.Cl[Ti](Cl)(Cl)Cl.[Zn]>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:34]=[CH:33][C:14]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][Br:32])=[CH:19][CH:18]=2)=[C:15]([C:14]2[CH:33]=[CH:34][C:11]([O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])=[CH:12][CH:13]=2)[C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][Br:32])=[CH:21][CH:22]=2)=[CH:13][CH:12]=1
Reactant: O=C(c1ccc(OCCCCCCCCBr)cc1)c1ccc(OCCCCCCCCBr)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: BrCCCCCCCCOc1ccc(C(=C(c2ccc(OCCCCCCCCBr)cc2)c2ccc(OCCCCCCCCBr)cc2)c2ccc(OCCCCCCCCBr)cc2)cc1
Temperature: 25 °C
Yield: 62 %

Procedure:
In a suspension of 4,4′-bis(8-bromooctyloxy)benzophenone (1.0 g, 1.7 mmol) in 50 mL of THF were added TiCl4 (0.19 mL, 1.7 mmol) and Zn dust (0.22 g, 3.4 mmol). After refluxing for 20 h, the reaction mixture was cooled to room temperature and filtered. The solvent was evaporated under vacuum and the crude product was purified by a silica gel column using a chloroform/hexane (1:1 v/v) mixture as eluent. 1,1,2,2-tetrakis[4-(8-bromooctyloxy)phenyl]-ethene was obtained as yellow viscous liquid in 62% yield (0.6 g). Rf=0.5 (chloroform/hexane=1:1). 1H NMR (400 MHz, CDCl3), δ (ppm): 6.99-6.90 (m, 8H), 6.63-6.60 (m, 8H), 3.87-3.80 (m, 8H), 3.41-3.39 (m, 8H), 1.86-1.70 (m, 16H), 1.34-1.26 (m, 32H). 13C NMR (100 MHz, CDCl3), δ (ppm): 157.9, 137.5, 133.2, 129.9, 114.2, 68.3, 55.6, 34.7, 33.4, 29.9, 29.3, 28.7, 26.6.
Reaction SMILES: [OH2:1].CO.[OH:4][CH2:5][C:6]([CH2:19][OH:20])([CH2:9][O:10][CH2:11][C:12]([CH2:17][OH:18])([CH2:15][OH:16])[CH2:13][OH:14])[CH2:7][OH:8]>C(OC)(=O)C=C.OC1C=C(S(O)(=O)=O)C=CC=1C.C1(C)C=CC(S(O)(=O)=O)=CC=1.S([O-])([O-])(=O)=O.[Cu+2].C1(C)C=CC=CC=1>[C:17]([O-:18])(=[O:1])[CH:12]=[CH2:15].[OH:14][CH2:13][C:12]([CH2:17][OH:18])([CH2:11][O:10][CH2:9][C:6]([CH2:19][OH:20])([CH2:7][OH:8])[CH2:5][OH:4])[CH2:15][OH:16]
Reactant: O
Agent: [Cu+2]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1O
Solvent: C=CC(=O)OC
Solvent: CO
Solvent: Cc1ccccc1
Product: C=CC(=O)[O-]
Temperature: 100 °C
Reaction time: 6 h

Procedure:
In a four-neck glass flask of 3 L in volume to which a reflux cooler, a water separator, an air introducing tube, a thermometer and a stirrer were attached, 203 g of methyl acrylate, 100 g of dipentaerythritol (purity: 95% or higher, made by Tokyo Chemical Industry Co., Ltd.), 6.3 g of 3-hydroxy-4-methyl-benzenesulfonic acid, 12.6 g of p-toluenesulfonic acid, 0.16 g of copper sulfate, and further 140 g of toluene as a solvent were charged. The mixture was stirred while nitrogen gas was blown in the flask, and heated at 100° C. for 2 hours. Thereafter, while the system interior was gradually depressurized and methanol produced by the transesterification and toluene as a solvent were distilled out, the reaction was performed finally at 200 mmHg for 6 hours. After the finish of the reaction, cleaning with an alkali aqueous solution and a neutralization operation were repeated to obtain an acrylate of dipentaerythritol as a reaction product.
Reaction SMILES: [F:1][C:2]1([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH2:8][CH2:7][CH:6]=[CH:5][CH2:4][CH2:3]1.ClC1C=C(C=CC=1)C(OO)=[O:23]>C(Cl)Cl>[F:1][C:2]1([C:9]2[N:13]([CH3:14])[N:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])[CH2:3][CH2:4][CH:5]2[CH:6]([O:23]2)[CH2:7][CH2:8]1
Reactant: Cn1ncc([N+](=O)[O-])c1C1(F)CCC=CCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cn1ncc([N+](=O)[O-])c1C1(F)CCC2OC2CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of (Z)-5-(1-fluorocyclohept-4-enyl)-1-methyl-4-nitro-1H-pyrazole (900 mg, 3.77 mmol) in DCM (30 mL) at 0° C. was added portionwise meta-chloroperoxybenzoic acid (1.0 g, 4.14 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 90 min before being quenched with a saturated solution of sodium hydrogencarbonate (30 mL). The mixture was extracted with DCM (100 mL), washed with aqueous 2 M NaOH (2×50 mL) and brine (30 mL). The organic layer was separated, dried over MgSO4 and concentrated under reduced pressure to give 5-(4-fluoro-8-oxabicyclo[5.1.0]octan-4-yl)-1-methyl-4-nitro-1H-pyrazole as a colourless solid (982 mg, quantitative) as a 2:5 ratio of diastereomers.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([OH:8])[CH:7]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10].C(N(CC)CC)C>C1COCC1.C(OCC)C>[C:9]([O:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Br:1])[CH:7]=1)(=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: Oc1cncc(Br)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(=O)Oc1cncc(Br)c1
Temperature: 25 °C
Yield: 84 %

Procedure:
A mixture of 3-bromo-5-hydroxypyridine (9.00 g, 51.7 mmol), acetic anhydride (6.0 mL) and triethylamine (12.0 mL) in THF (50 mL) was heated to reflux overnight, cooled to room temperature, diluted with diethyl ether, washed with water, 5% NaHCO3, water, and brine, dried (MgSO4), filtered, and concentrated to provide the desired product (9.37 g, 84%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:19]=[CH:18][C:17]([CH2:20][C:21]([NH2:23])=[O:22])=[C:16]([NH:24][CH2:25][CH:26]4[CH2:30][CH2:29][CH2:28][NH:27]4)[CH:15]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[C:31](OC(=O)C)(=[O:33])[CH3:32].N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.O>[C:31]([N:27]1[CH2:28][CH2:29][CH2:30][CH:26]1[CH2:25][NH:24][C:16]1[CH:15]=[C:14]([NH:13][C:10]2[CH:11]=[CH:12][C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[CH:8][CH:9]=2)[N:19]=[CH:18][C:17]=1[CH2:20][C:21]([NH2:23])=[O:22])(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)Cc1cnc(Nc2ccc(N3CCOCC3)cc2)cc1NCC1CCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)N1CCCC1CNc1cc(Nc2ccc(N3CCOCC3)cc2)ncc1CC(N)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.7 %

Procedure:
30.3 mg of 6-[(4-morpholinophenyl)amino]-4-[(pyrrolidin-2-ylmethyl)amino]pyridine-3-carboxyamide (the compound of Example 358) was dissolved in 2 mL of methylene chloride, to which 9.4 mg of acetic anhydride and 9.1 mg of pyridine were sequentially added, and stirred at room temperature for 2 hours. To the reaction mixture saturated sodium bicarbonate in water was added, extracted with chloroform:methanol=10:1, the extract was washed with saturated saline, and dried on anhydrous sodium sulfate. The solvent was evaporated, and the residue was purified by silica gel thin layer chromatography (chloroform:ammonia methanol=8:1), recrystallized from chloroform-ether to obtain the title compound (29.3 mg, 87%) as a light yellow crystalline powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:18]=[CH:17][O:16][C:15]=2[C:19](OC)=[O:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:18]=[CH:17][O:16][C:15]=2[CH2:19][OH:20])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1occc1C1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccoc2CO)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 60.2 %

Procedure:
A solution of 4-(2-methoxycarbonylfuran-3-yl)piperidine-1-carboxylic acid t-butyl ester (2.0 g, 6.5 mmol, 1.0 eq.) in THF (60 mL) was added to a solution of LiAlH4 (490 mg, 13 mmol, 2.0 eq.) in THF (100 mL) at −30° C. The resulting solution was stirred for 1 hour and allowed to warm to 0° C., then stirred for 1 hour at 0° C. Water (0.5 mL) was added dropwise to quench the reaction. The mixture was allowed to warm to room temperature, and 15% NaOH (0.5 mL) and water (1.5 mL) was added. The solids were filtered and the filter cake was washed with EtOAc (50 mL). The filtrate was concentrated and the residue was applied onto a silica gel column and purified by chromatography with PE/EtOAc (10:1˜5:1), then by preparative HPLC to yield 4-(2-hydroxymethylfuran-3-yl)piperidine-1-carboxylic acid t-butyl ester (1.1 g) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:21](I)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.O1CCCCC1[N:29]1[C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=[N:30]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(O)(C(F)(F)F)=O>C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:21]([C:31]2[NH:30][N:29]=[CH:33][CH:32]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(-c2ccn[nH]2)c1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A mixture of 6-chloro-5-iodo-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 56.1, 4.0 g, 8.95 mmol), 1-(tetrahydro-2H-pyran-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (3.73 g, 13.42 mmol), Pd(PPh3)4 (0.517 g, 0.447 mmol), K3PO4 (5.70 g, 26.8 mmol) and toluene (45 mL) was stirred at 80° C. for 5 h under an argon atmosphere. The RM was filtered through Hyflo®, washed with EtOAc (100 mL) and the combined filtrates were evaporated to dryness under reduced pressure. The residue was purified by flash chromatography (Silica gel column, 80 g, n-hexane/EtOAc from 9:1 to 1:1) to give the protected intermediate, of which 1.5 g (3.02 mmol) was dissolved in DCM (20 mL), treated with TFA (2.32 mL, 30.2 mmol) and stirred for at RT for 76 h. The solvent was evaporated off under reduced pressure and the residue was treated with sat. aq. Na2CO3 (80 mL) and extracted with EtOAc. The combined extracts were washed with brine (50 mL), dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (Silica gel column, 40 g, n-hexane/EtOAc from 9:1 to 1:1) to give the title compound as beige crystals. UPLC-MS (Condition 2) tR=1.02 min, m/z=382.9 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 6.91 (s, 1H) 7.38 (d, J=8.99 Hz, 2H) 7.80-8.00 (m, 3H) 8.73 (d, J=2.35 Hz, 1H) 8.88 (d, J=2.74 Hz, 1H) 10.73 (s, 1H) 13.29-13.42 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH3:15])[C:13]([CH2:16]O)=[N:12][C:11]=2[CH:18]([CH3:20])[CH3:19])[CH:5]=[C:6]([Cl:8])[CH:7]=1.S(Cl)([Cl:23])=O>CN(C)C=O>[Cl:23][CH2:16][C:13]1[N:14]([CH3:15])[C:10]([S:9][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)=[C:11]([CH:18]([CH3:20])[CH3:19])[N:12]=1
Reactant: CC(C)c1nc(CO)n(C)c1Sc1cc(Cl)cc(Cl)c1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)c1nc(CCl)n(C)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To dry dimethylformamide (50 ml)solution of 22.5 g (67.9 mmol)of [5-(3,5-dichlorophenylthio)-4-isopropyl-1-methyl-1H-imidazol-2-yl]methanol (Compound I-8)was added 25.0 ml of thionyl chloride, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and to the residue, ethyl acetate was added and extracted. The extract was neutralized with a saturated aqueous sodium hydrogen carbonate solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give 23.7 g of 2-chloromethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1-methylimidazole (28a)(yield about 100%). mp 110-111° C.