Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]1[C@@H:6]([OH:7])[C@H:5]([N:8]2[CH:16]=[N:15][C:14]3[C:9]2=[N:10][C:11]([N:29]2[CH2:33][CH2:32][C@@H:31]([NH:34][C:35]([NH:37][C:38]4C=NC=CC=4)=[O:36])[CH2:30]2)=[N:12][C:13]=3[NH:17][C@H:18]([CH2:27][OH:28])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[CH2:4][C@@H:3]1[NH:44][C:45](=[O:48])[CH2:46][OH:47].[C:49]1([O:55]C(=O)NC2C=NC=CC=2)[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>>[OH:1][C@H:2]1[C@@H:6]([OH:7])[C@H:5]([N:8]2[CH:16]=[N:15][C:14]3[C:9]2=[N:10][C:11]([N:29]2[CH2:33][CH2:32][C@@H:31]([NH:34][C:35]([NH:37][CH2:38][C:53]4[CH:52]=[CH:51][CH:50]=[C:49]([OH:55])[CH:54]=4)=[O:36])[CH2:30]2)=[N:12][C:13]=3[NH:17][C@H:18]([CH2:27][OH:28])[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=2)[CH2:4][C@@H:3]1[NH:44][C:45](=[O:48])[CH2:46][OH:47]
Reactant: O=C(Nc1cccnc1)Oc1ccccc1
Reactant: O=C(CO)N[C@H]1C[C@@H](n2cnc3c(N[C@H](CO)Cc4ccc(O)cc4)nc(N4CC[C@@H](NC(=O)Nc5cccnc5)C4)nc32)[C@H](O)[C@@H]1O
Product: O=C(CO)N[C@H]1C[C@@H](n2cnc3c(N[C@H](CO)Cc4ccc(O)cc4)nc(N4CC[C@@H](NC(=O)NCc5cccc(O)c5)C4)nc32)[C@H](O)[C@@H]1O

Procedure:
The title compound is prepared analogously to N-((1S,2R,3S,4R)-2,3-Dihydroxy-4-{6-[(S)-1-hydroxymethyl-2-(4-hydroxy-phenyl)-ethylamino]-2-[(R)-3-(3-pyridin-3-yl-ureido)-pyrrolidin-1-yl]-purin-9-yl}-cyclopentyl)-2-hydroxy-acetamide (Example 195), by substituting (3-hydroxy-benzyl)-carbamic acid phenyl ester (Intermediate ZD) for pyridin-3-yl-carbamic acid phenyl ester (Intermediate ZB).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([CH:9]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[CH2:10][C:11]([O:13]CC)=[O:12])[NH:8][C:4]=2[CH:3]=1>C(O)(=O)C.Cl>[ClH:1].[Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([CH:9]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)[CH2:10][C:11]([OH:13])=[O:12])[NH:8][C:4]=2[CH:3]=1
Reactant: CCOC(=O)CC(c1ccc(Cl)cc1)c1nc2ccc(Cl)cc2[nH]1
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)CC(c1ccc(Cl)cc1)c1nc2ccc(Cl)cc2[nH]1
Yield: 188.2 %

Procedure:
The ester (135 mg) was dissolved in a mixture of acetic acid (2 ml) and conc. HCl (1 ml) and heated under reflux for 1 h. All volatiles are removed at the water aspirator and the residue was precipitated from acetone solution with ethyl acetate to give 3-(5-chloro-2-benzimidazolyl)-3-(4-chlorophenyl)propanoic acid HCl (130 mg) as colourless solid.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].[S:5](=[O:9])(=[O:8])([OH:7])[OH:6].C(=O)=O.[NH2:13][C:14]([NH2:16])=[O:15].S(=O)(=O)(O)O>O>[C:2]1([NH:4][NH:16][C:14](=[O:15])[NH:13][NH:1]1)=[O:3].[S:5](=[O:7])(=[O:6])([OH:9])[OH:8]
Reactant: NC(N)=O
Agent: O=C=O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C1NNC(=O)NN1
Temperature: 100 °C

Procedure:
One kilogram of anhydrous diurea-sulfuric acid adduct is prepared by reacting anhydrous solid urea with chilled fuming sulfuric acid in a flask emersed in a dry ice bath. Four hundred and fifty grams of fuming sulfuric acid are placed in the flask suspended in the dry ice bath and are allowed to cool. 550 grams of anhydrous urea prills are then gradually added over a period of approximately 30 minutes while constantly monitoring the temperature of the reaction phase. The rate of urea addition is controlled to maintain a reaction-phase temperature of approximately 100° C. and the reaction phase is continuously stirred during the reaction. The resulting product contains less than 0.5 weight percent water, has a urea/sulfuric acid molar ratio of 2.0, contains approximately 55 weight percent urea and 45 weight percent sulfuric acid, and has a melting point of approximately 85° C.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([C:12]1[C:13]([CH3:24])=[N:14][O:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:32][CH2:31]1)=[O:29])[CH3:26]>>[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36]([C:20]3[CH:21]=[CH:22][C:17]([C:16]4[O:15][N:14]=[C:13]([CH3:24])[C:12]=4[C@H:10]([OH:11])[CH2:9][O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:18][CH:19]=3)=[CH:35][CH:34]=2)[CH2:31][CH2:32]1)=[O:29])[CH3:26]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1[C@H](O)COCc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4[C@H](O)COCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using (S)-2-benzyloxy-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-ethanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [C:1]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(/C(OC(C)C)=O)=N\C(OC(C)C)=O.COC1C(OC)=C(OC)C=C(/[CH:46]=[CH:47]/[C:48]([N:50]2[C:55](=[O:56])[CH:54]=[CH:53][CH2:52]C2)=[O:49])C=1.CN(C)CCO>C1(C)C=CC=CC=1.C1COCC1>[C:48]([NH:50][C:55](=[O:56])/[CH:54]=[CH:53]/[CH3:52])(=[O:49])[C:47]([CH3:46])=[CH2:1]
Reactant: COc1cc(/C=C/C(=O)N2CCC=CC2=O)cc(OC)c1OC
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: CN(C)CCO
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)NC(=O)/C=C/C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
Experimental Procedure: Triphenylphosphine (92.0 mg, 0.35 mmol) and (E)-diisopropyl diazene-1,2-dicarboxylate (DIAD, 71.0 mg, 0.35 mmol) were dissolved to a 1:1 mixture of THF and toluene (4 mL); then mono-demethylated piperlongumine (50.0 mg, 0.18 mmol) was added. After 10 min, 2-(dimethylamino) ethanol (31.0 mg, 0.35 mmol) was added to the mixture. The reaction was stirred at room temperature for 3 h. At the end, the solvent was evaporated under vacuum, and the crude product was subjected to flash chromatography (hexane/ethyl acetate=100/0 to 50:50), to afford the desired product in 90% yield.
Reaction SMILES: C1C=C[NH+]=CC=1.[O-:7][Cr](Cl)(=O)=O.[CH3:12][C:13]1([CH3:35])[C:17]([C:19]2[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=2)(O)[C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:15][CH2:14]1>C(Cl)Cl>[CH3:12][C:13]1([CH3:35])[CH2:14][C:15](=[O:7])[C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:17]1[C:19]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: O=[Cr](=O)([O-])Cl
Reactant: CC1(C)CC=C(c2ccccc2)C1(O)c1ccc(S(C)(=O)=O)cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC1(C)CC(=O)C(c2ccccc2)=C1c1ccc(S(C)(=O)=O)cc1
Yield: 16.8 %

Procedure:
To a suspension of PCC (4 g) and 10 g of 4 Å molecular seives in 100 mL of CH2Cl2 was added a solution of the product of Step 5 (1.2 g) in 10 mL CH2Cl2. The reaction mixture was stirred for 12 hand then diluted with 200 mL of 1:1 hexanes/EtOAc, and filtered through a pad of silica gel. The filtrate was concentrated and the residue was purified by chromatography eluting with 3:2 hexanes/EtOAc to give 200 mg of the title compound as a white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][O:6][C:7]1[C:8]([CH3:29])=[C:9]2[C:14](=[C:15]([CH3:18])[C:16]=1[CH3:17])[O:13][C:12]([CH2:27][OH:28])([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:11][CH2:10]2.CN(C)C=O.Cl[C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1>C1C=CC=CC=1>[CH3:3][O:4][CH2:5][O:6][C:7]1[C:8]([CH3:29])=[C:9]2[C:14](=[C:15]([CH3:18])[C:16]=1[CH3:17])[O:13][C:12]([CH2:27][O:28][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][CH:37]=1)([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:11][CH2:10]2
Reactant: CCCCCCCCC1(CO)CCc2c(C)c(OCOC)c(C)c(C)c2O1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CCCCCCCCC1(COc2ccc([N+](=O)[O-])cc2)CCc2c(C)c(OCOC)c(C)c(C)c2O1
Temperature: 50 °C

Procedure:
0.38 g of a 55% w/w suspension of sodium hydride in mineral oil was added to a mixture of 3 g of 6-methoxymethoxy-5,7,8-trimethyl-2-octylchroman-2-ylmethanol (prepared as described in Preparation 13) and 25 ml of dimethylformamide under a nitrogen stream at room temperature, and the resulting mixture was heated for 2 hours at 50° C. A mixture of 1.4 g of p-chloronitrobenzene and 2 ml of benzene was then added dropwise, whilst ice-cooling, and the resulting mixture was heated for 2 hours at 50° C. The reaction mixture was then poured into ice-water and extracted with benzene. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography eluted with benzene, to give the title compound.
Reaction SMILES: CO.C[O:4][C:5]([C:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9][CH:8]=1)=[O:6].[OH-].[Li+].Cl>O.O1CCCC1>[S:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:7]([C:5]([OH:6])=[O:4])=[CH:8]1
Reactant: COC(=O)c1csc2ccccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1csc2ccccc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 100.2 %

Procedure:
To a methanol (100 mL) solution of 1-benzothiophene-3-carboxylic acid methyl ester (20.6 g, 107 mmol), tetrahydrofuran (200 mL), water (100 mL) and lithium hydroxide (9.00 g, 214 mmol) were added at room temperature, and the mixture was stirred for 15 hours at room temperature. 1N-hydrochloric acid (214 mL, 214 mmol) was added to the reaction liquor, and then methanol was distilled off under reduced pressure. To the obtained aqueous layer, 1N-hydrochloric acid (50 mL, 50 mmol) was added, and the solids generated therefrom were collected by filtration, washed with water, and then dried for two days at 50° C. using a vacuum pump, to obtain the title compound (19.1 g, 100%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([I:21])[CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([O:18]CC)=[O:17])=[CH:7]2.O[Li].O.Cl>C1COCC1.CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([I:21])[CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:14])([F:13])[F:15])[C:8]([C:16]([OH:18])=[O:17])=[CH:7]2
Reactant: CCOC(=O)C1=Cc2cc(I)cc(Cl)c2OC1C(F)(F)F
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)C1=Cc2cc(I)cc(Cl)c2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
To 180 mg (0.42 mmole) of ethyl 8-chloro-6-iodo-2-(trifluoromethyl)-2H-chromene-3-carboxylate was added 100 mgs of LiOH—H2O and 5 mL of a solvent mixture of THF/MeOH/H2O (7:2:1). The mixture was heated to reflux for 30 min. and allowed to cool to rt. After standing overnight, the mixture was concd in vacuo, treated with 20 mL 1N HCl and allowed to stir. The mixture was extracted three times with Et2O, the combined extracts dried and concd in vacuo to give 150 mgs (88.3%) of an off-white solid: 1H NMR (CDCl3/d6-acetone/400 MHz) 5.86 (q, 1H, J=6.7 Hz), 7.60 (s, 1H), 7.70 (s, 1H), 7.75 (s, 1H); 19F NMR (CDCl3/d6-acetone/400 MHz) −79.2 (d, 3F, J=6.8 Hz); MS(ESI+) 405 (M+1, 100, one Cl pattern); HRMS (ES-) m/z calcd for (C11H4O3IClF3) 402.8840, found 402.8850.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[OH-].[Na+].[CH3:20]O>>[OH:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:8]=[C:9]([OH:11])[CH:10]=1)[C:5]([O:7][CH3:20])=[O:6]
Reactant: Cc1c(O)cc(O)cc1C(=O)O
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)c1cc(O)cc(O)c1C
Temperature: 25 °C

Procedure:
To 168.2 g of 3,5-dihydroxy-2-methylbenzoic acid in 0.6 l of methanol were added 10 ml of 98% sulfuric acid, and the mixture was heated at reflux for 18 hours. The solution was cooled to room temperature and neutralized by the addition of about 30 ml of 28% sodium hydroxide solution. The solvent was evaporated in vacuo, and the residue was taken up in 0.7 l of ethyl acetate. The solution was washed successively with saturated sodium carbonate solution and brine, dried over sodium sulfate, and the solvent was evaporated in vacuo. The residue was crystallized from ethyl acetate/hexane to yield 162.9 g of methyl 3,5-dihydroxy-2-methylbenzoate, m.p. 136°-138° C.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:11][CH2:12][CH3:13])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:18]O>>[OH:1][C:2]1[C:3]([CH2:11][CH2:12][CH3:13])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:18])=[O:6]
Reactant: CCCc1c(O)cccc1C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: CCCc1c(O)cccc1C(=O)OC
Temperature: 25 °C
Reaction time: 35 h
Yield: 87 %

Procedure:
Cool a solution of 3-hydroxy-2-propyl-benzoic acid (59.79 g, 332 mmol) in MeOH (598 mL) to −10° C. and add thionyl chloride (36.26 mL, 497.1 mmol) using a syringe pump over 35 min. Allow the mixture to warm to ambient temperature while stirring over 35 h. Concentrate the mixture in vacuo and dilute the residue with methyl-tert-butylether (360 mL). Concentrate the resultant mixture in vacuo to dryness to yield the title compound (64.4 g, 87%) as a tan solid. 1H NMR (300 MHz, CDCl3) δ 7.38 (dd, J=8.0, 0.8 Hz, 1H); 7.10 (t, J=8.0 Hz, 1H); 6.93 (dd, J=8.0, 0.8 Hz, 1H); 5.1 (bs, 1 H); 3.89 (s, 3H); 2.98 (m, 2H), 1.61 (m, 2H); 1.00 (t, J=7.4 Hz, 3H).
Reaction SMILES: [C:1]([C:7]1[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=1[C:9](N(C)OC)=[O:10])#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:19][O:20][C:21]1[CH:29]=[CH:28][C:24]([CH2:25][Mg]Cl)=[CH:23][CH:22]=1>C1COCC1>[C:1]([C:7]1[CH:18]=[CH:17][CH:16]=[CH:15][C:8]=1[C:9](=[O:10])[CH2:25][C:24]1[CH:28]=[CH:29][C:21]([O:20][CH3:19])=[CH:22][CH:23]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCC#Cc1ccccc1C(=O)N(C)OC
Reactant: COc1ccc(C[Mg]Cl)cc1
Solvent: C1CCOC1
Product: CCCCC#Cc1ccccc1C(=O)Cc1ccc(OC)cc1
Yield: 69 %

Procedure:
2-(1-Hexyn-1-yl)-N-methyl-N-(methyloxy)benzamide (158) (0.50 g, 2.04 mmol) was treated with 4-methoxy benzylmagnesium chloride in THF at 40° C. to give 0.43 g (69%) of the title compound (159) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 0.93 (t, J=7.2 Hz, 3H), 1.40-1.53 (m, 2H), 1.56-1.65 (m, 2H), 2.45 (t, J=7.0 Hz, 2H), 3.78 (s, 3H), 4.36 (s, 2H), 6.83 (d, J=8.5 Hz, 2H), 7.14 (d, J=8.5 Hz, 2H), 7.26-7.30 (m, 1H), 7.33-7.39 (m, 1H), 7.44-7.50 (m, 2H). LCMS (ESI): m/z 307 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].Cl.O>[OH-].[Na+]>[CH2:16]([O:15][C:13]([NH:2][CH:3]1[CH2:8][CH2:7][CH:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1)=[O:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N[C@H]1CC[C@H](C(=O)O)CC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(NC1CCC(C(=O)O)CC1)OCc1ccccc1
Reaction time: 1.5 h
Yield: 84.7 %

Procedure:
To a solution of trans-4-aminocyclohexane carboxylic acid hydrochloride (5.0 g, 34.92 mmol) in aqueous 2.0N NaOH (35 mL) is added benzyl chloroformate (5.0 mL, 34.92 mmol). The mixture stirs for 1.5 h. Then the suspension is acidified with 12N HCl (aq) to pH=1. H2O is added (100 mL) and the precipitate is filtered off. The filter cake is dried to afford 8.2 g of 4-benzyloxycarbonylamino-cyclohexanecarboxylic acid. LC/MS: [M+H]+=278, Rt=0.85 min (method 6)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:31])[C:10]([NH:12][CH2:13][C:14]2[C:15]([C:24]3[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=3)=[N:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=2)=[O:11])=[CH:5][CH:4]=1.[C:32]([O:36][C:37]([NH:39][S:40](N1C=CC(=[N+](C)C)C=C1)(=[O:42])=[O:41])=[O:38])([CH3:35])([CH3:34])[CH3:33].C(N(CC)CC)C>ClCCl>[O:11]=[C:10]([NH:12][CH2:13][C:14]1[C:15]([C:24]2[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=2)=[N:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=1)[CH:9]([C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][S:40]([NH:39][C:37](=[O:38])[O:36][C:32]([CH3:34])([CH3:33])[CH3:35])(=[O:41])=[O:42])=[CH:8][CH:7]=1)[CH3:31]
Reactant: C[N+](C)=c1ccn(S(=O)(=O)NC(=O)OC(C)(C)C)cc1
Reactant: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)C(C)c2ccc(CN)cc2)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)C(C)c2ccc(CNS(=O)(=O)NC(=O)OC(C)(C)C)cc2)c1
Reaction time: 8 h
Yield: 49.9 %

Procedure:
To a stirred solution of 2-(4-(aminomethyl)phenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (167 mg, 0.39 mmol) in dichloromethane the intermediate (A) (117 mg, 0.39 mmol) and triethylamine (0.20 mL, 0.56 mmol) was added was stirred for overnight. The reaction mixture was stirred for overnight at room temperature. The mixture was diluted with dichloromethane and washed with water, brine, dried over magnesium sulfate and filtered. The filtrate was evaporated and the residue was purified by column chromatography. Tert-butyl N-(4-(1-oxo-1-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methylamino)propan-2-yl)benzyl)sulfamoylcarbamate (118 mg) was obtained as 50% yield.
Reaction SMILES: C1(O)C=CC=CC=1.[OH:8][C@@H:9]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([OH:26])[CH:21]=1)[CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].CC1C=CC(S(O[CH2:38][CH:39]2[CH2:48][C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[O:41][CH2:40]2)(=O)=O)=CC=1>>[O:41]1[C:42]2[C:47](=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:48][CH:39]([CH2:38][O:26][C:22]2[CH:21]=[C:20]([C@H:9]([OH:8])[CH2:10][CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:25]=[CH:24][CH:23]=2)[CH2:40]1
Reactant: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(O)c1
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3ccccc3C2)cc1
Solvent: Oc1ccccc1
Product: CC(C)(C)OC(=O)NCC[C@@H](O)c1cccc(OCC2COc3ccccc3C2)c1

Procedure:
Alkylation of phenol (7, Intermediate I) with chroman-3-ylmethyl 4-methylbenzenesulfonate following the method used in Example 12 gave tert-butyl ((3R)-3-(3-(chroman-3-ylmethoxy)phenyl)-3-hydroxypropyl)carbamate as a colorless oil. Yield (71%); 1H NMR (400 MHz, DMSO-d6) δ 7.21 (t, J=7.6 Hz, 1H), 7.10-7.05 (m, 2H), 6.91 (s, 1H), 6.88 (d, J=7.6 Hz, 1H), 6.85-6.83 (m, 1H), 6.81-6.79 (m, 1H), 6.75 (d, J=8.4 Hz, 1H), 5.19 (d, J=4.8 Hz, 1H), 4.53-4.48 (m, 1H), 4.31-4.28 (m, 1H), 3.99-3.91 (m, 2H), 2.98-2.93 (m, 2H), 2.92-2.90 (m, 1H), 2.71-2.69 (m, 2H), 1.66 (q, J=6.8 Hz, 2H), 1.36 (s, 9H).
Reaction SMILES: O1CCCC1.[NH2:6][C:7]1[C:12]([C:13]2[O:17][N:16]=[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[CH:14]=2)=[CH:11][CH:10]=[C:9]([NH2:26])[N:8]=1.[OH-].[Na+].Cl[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[N:32]=1>CN(C)C=O>[CH3:38][O:37][C:33]1[N:32]=[C:31]([CH2:30][O:25][C:22]2[CH:23]=[CH:24][C:19]([CH2:18][C:15]3[CH:14]=[C:13]([C:12]4[C:7]([NH2:6])=[N:8][C:9]([NH2:26])=[CH:10][CH:11]=4)[O:17][N:16]=3)=[CH:20][CH:21]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: Nc1ccc(-c2cc(Cc3ccc(O)cc3)no2)c(N)n1
Reactant: COc1cccc(CCl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cccc(COc2ccc(Cc3cc(-c4ccc(N)nc4N)on3)cc2)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 58.8 %

Procedure:
To a tetrahydrofuran (3 mL) solution of 4-(5-(2,6-diamino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (30 mg, 0.11 mmol) described in Manufacturing Example 18-1-1 was added a 5 N sodium hydroxide aqueous solution (21.2 μL, 0.11 mmol), which was dissolved by irradiating ultrasonic wave for 1 minute. The reaction solution was concentrated under a reduced pressure, which gave a white solid. To a mixture of this solid and N,N-dimethylformamide (1 mL) was added an N,N-dimethylformamide (1 mL) solution of 2-chloromethyl-6-methoxypyridine (20.0 mg, 0.13 mmol) described in Manufacturing Example 99-1-2, which was stirred for 1 hour at 60° C. This reaction mixture was cooled to room temperature, and then partitioned into water and ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound (26.1 mg, 61%).
Reaction SMILES: O[CH2:2][CH2:3][CH:4]1[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[O:6][CH2:5]1.C(Br)(Br)(Br)[Br:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>CN(C)C=O.C(=O)(O)[O-].[Na+]>[Br:13][CH2:2][CH2:3][CH:4]1[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[O:6][CH2:5]1
Reactant: CC1(C)OCC(CCO)CO1
Reactant: BrC(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OCC(CCBr)CO1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
To an ice-cooled solution of 5-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxan (6.08 g, 38 mmol) and carbon tetrabromide (18.90 g, 57 mmol) in N,N-dimethylformamide (110 ml), triphenyl-phosphine (14.95 g, 57 mmol) was added. The solution was stirred for 0.5 hour at 0° C. The solution was then diluted with saturated aqueous sodium bicarbonate (55 ml) followed by water (55 ml), and was extracted with hexane (2×150 ml). The combined organic layers were dried (magnesium sulphate) and the solvent removed. The residue was placed under high vacuum for 2 hours to remove bromoform. The residue was taken up in a small amount of hexane, filtered and the solvent removed to afford 5-(2-bromoethyl)-2,2-dimethyl-1,3-dioxan (7.40 g, 87%) as a colourless oil which crystallised on cooling, m.p. ca. 18° C.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:21][C:22]2[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=2)=[N:4][C:5]([NH:11][C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH3:13])=[C:6]([N+:8]([O-])=O)[CH:7]=1.[NH4+].[Cl-].CCOC(C)=O>CO.C1COCC1.[Zn]>[F:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([NH:11][C@H:12]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH3:13])=[N:4][C:3]=1[NH:21][C:22]1[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=1
Reactant: Cc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cc3)c([N+](=O)[O-])cc2F)n[nH]1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(Nc2nc(N[C@@H](C)c3ccc(F)cc3)c(N)cc2F)n[nH]1
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
To a solution of (S)-3-fluoro-N6-(1′-(4-fluorophenyl)ethyl)-N2-(5-methyl-1H-pyrazol-3-yl)-5-nitropyridine-2,6-diamine (Method 47, 0.6 g, 1.6 mmol) in a mixture of MeOH-THF (1:1, 40 ml) under nitrogen was added zinc dust (0.52 g, 8.0 mmol). A saturated aqueous solution of NH4Cl (4.0 ml) was then added slowly from an addition funnel over 20 minutes. Upon completion of the addition, the reaction was allowed to stir for an additional 30 minutes, at which point a saturated aqueous solution of NH4OAc (5.0 ml) was added, and the reaction was stirred for 30 minutes. EtOAc (15 ml) was then added, and the reaction was stirred vigorously. The remaining solids were then filtered through celite, and the organic fraction was separated from the remaining filtrate, dried over Na2SO4, filtered and concentrated to give to give crude (S)-5-fluoro-N2-(1′-(4-fluorophenyl)ethyl)-N6-(5-methyl-1H-pyrazol-3-yl)pyridine-2,3,6-triamine (0.50 g, 90%) which was used without further purification. The above amine was immediately placed in EtOH (30 ml) and formamidine acetate (0.36 g, 3.4 mmol) was added. The reaction was flushed with nitrogen and heated to 95° C. for 12 hours. The reaction was cooled to room temperature, and a saturated aqueous NaHCO3 solution (5 ml) was added, along with EtOAc (15 ml). The resulting mixture was stirred vigorously for 10 minutes. The layers were then allowed to separate, and the organic fraction was isolated, washed with brine (15 ml), dried over Na2SO4, filtered and concentrated. The resulting dark residue was purified by column chromatography (hexanes-EtOAc=1:30) to give the title compound (0.30 g, 48%). 1H NMR (400 MHz, CD3OD) δ 8.29 (s, 1H), 7.57 (d, J=11.1 Hz, 1H), 7.46-7.42 (m, 2H), 7.04-7.00 (m, 2H), 6.29 (s, 1H), 5.15-5.10 (m, 1H), 2.37 (s, 3H), 1.58 (d, J=7.0 Hz, 3H). MS: Calcd.: 354. Found: [M+H]+ 355.