Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].[CH3:11][N:12]1[C:16]([C:17](Cl)=[O:18])=[CH:15][C:14]([CH3:20])=[N:13]1.O>CN(C)C(=O)C>[CH3:11][N:12]1[C:16]([C:17]([NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[O:18])=[CH:15][C:14]([CH3:20])=[N:13]1
Reactant: Cc1cc(C(=O)Cl)n(C)n1
Reactant: Nc1cccc([N+](=O)[O-])c1
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(C(=O)Nc2cccc([N+](=O)[O-])c2)n(C)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
To a solution of 3-nitroaniline (1.0 g, 7.2 mmol) in N,N-dimethylacetamide (6 mL) was added a solution of 1,3-dimethyl-1H-pyrazole-5-carbonylchloride (1260 mg, 8.0 mmol) in N,N-dimethylacetamide (2 mL), and the mixture was stirred at room temperature for 30 min. Water (200 mL) was added to the mixture under ice-cooling, and the mixture was filtrated. The obtained solid was washed with water and diethyl ether to give 1,3-dimethyl-N-(3-nitrophenyl)-1H-pyrazole-5-carboxamide (1850 mg, 7.1 mmol). To a solution of the obtained 1,3-dimethyl-N-(3-nitrophenyl)-1H-pyrazole-5-carboxamide (1850 mg, 7.1 mmol) in ethanol (50 mL) was added 10% palladium/carbon (190 mg). Hydrazine monohydrate (1090 mg, 22 mmol) was slowly added to the mixture at room temperature and the mixture was stirred at 60° C. for 1 hr. The reaction mixture was filtrated, and the filtrate was evaporated under reduced pressure. To the residue were added ethyl acetate and water, and the aqueous layer was extracted with ethyl acetate (×4). Combined organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtrated. The filtrate was concentrated under reduced pressure, and the residue was washed with ethyl acetate/hexane to give the title compound (1650 mg, 99%) as a pale-yellow solid.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[OH:13][C:14]([CH3:52])([CH3:51])[CH2:15][O:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]3[N:48]=[CH:49][CH:50]=[C:24]23)[CH2:19][CH2:18]1>C(OCC)(=O)C.O>[OH:13][C:14]([CH3:51])([CH3:52])[CH2:15][O:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([N:23]2[C:28](=[O:29])[C:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=4[C:43]4[NH:3][C:4](=[O:7])[O:5][N:44]=4)=[CH:33][CH:32]=3)=[C:26]([CH2:45][CH2:46][CH3:47])[N:25]3[N:48]=[CH:49][CH:50]=[C:24]23)[CH2:19][CH2:18]1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ccnn12
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)(C)O)CC2)c2ccnn12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of hydroxylammonium chloride (42 g), sodium hydrogen carbonate (61 g) and dimethyl sulfoxide (240 mL) was stirred at 50° C. for 30 min. 4′-({4-[trans-4-(2-Hydroxy-2-methylpropoxy)cyclohexyl]-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl}methyl)biphenyl-2-carbonitrile (32 g) was added, and the mixture was stirred at 90° C. for 15 hr. The mixture was allowed to cool to room temperature, and the reaction mixture was diluted with ethyl acetate and water. After extraction with ethyl acetate, the organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (300 mL). N,N′-Carbonyldiimidazole (11.5 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (10.6 mL) were successively added to the tetrahydrofuran solution mentioned above, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, and 1 M hydrochloric acid was added. After extraction with ethyl acetate, the organic layer was successively washed with saturated aqueous sodium hydrogen carbonate and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as an amorphous solid. The solid was dissolved in acetone, and crystallized. The resulting solid was collected by filtration, washed with acetone, and dried under reduced pressure to give the title compound as a colorless solid (25.9 g, 73%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][O:12][CH3:13])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[Cl:17][C:18]1[CH:19]=[C:20]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:22][C:23]=1F.[H-].[Na+].O>CN(C=O)C.C(OCC)C>[Cl:17][C:18]1[CH:19]=[C:20]([N+:25]([O-:27])=[O:26])[CH:21]=[CH:22][C:23]=1[N:11]([O:12][CH3:13])[S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:14]([O-:16])=[O:15])[CH:4]=1)(=[O:10])=[O:9]
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: CONS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: CON(c1ccc([N+](=O)[O-])cc1Cl)S(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 12 %

Procedure:
To a solution of 4-chloro-N-methoxy-3-nitrobenzenesulfonamide (0.53 g (1.99 mmol)) and 3-chloro-4-fluoronitrobenzene (1.05 g (5.98 mmol) in 5.0 ml of DMF, sodium hydride (60%, 0.09 g (2.25 mmol)) was added bit by bit with stirring under cooling with ice, and the mixture was stirred under cooling with ice for one hour and at room temperature for 2 hours. Water and diethyl ether were added to the resulting mixture and insolubles were removed by filtration. The filtrate was allowed to stand somewhile and then, the organic layer was separated and washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure The residue was subjected to silica gel column chromatography with ethyl acetate-hexane (1:5) as eluent to give 0.10 g (12%) of the title compound as pale yellow-white crystals.
Reaction SMILES: Br[C:2]1[C:3](=[O:21])[O:4][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][C:7]=1[OH:8].[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[SH:32])([CH2:24][CH3:25])[CH3:23].N1CCCCC1>ClCCl>[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32][C:2]1[C:3](=[O:21])[O:4][C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][C:7]=1[OH:8])([CH2:24][CH3:25])[CH3:23]
Reactant: CCC(C)c1ccccc1S
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)CC(O)=C1Br
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CCC(C)c1ccccc1SC1=C(O)CC(c2ccccc2)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared as described in General Method 6 from 1.6 mmol of 3-bromo-5,6-dihydro-4-hydroxy-6,6-diphenyl-2H-pyran-2-one (prepared in example AAA), 1.7 mmol of 2-sec-butylbenzenethiol, and 1.7 mmol of piperidine in 25 mL of dichloromethane. The product was chromatographed on silica gel, eluting first with chloroform and then with 5% methanol in chloroform, to give the title compound (m.p. 161°-162° C.). 1H NMR (DMSO-d6) δ 0.81 (t, 3 H), 1.15 (d, 3 H), 1.43-1.64 (m, 2 H), 2.98 (m, 1 H), 3.77 (s, 2 H), 5.65 (dd, 1 H), 6.47 (t, 1 H), 6.92 (t, 1 H), 7.07 (d, 1 H), 7.34-7.48 (m, 10 H), 12.4 (bs, 1 H).
Reaction SMILES: [F:1][C:2]1([F:58])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18]CC4C=CC(OC)=CC=4)[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][N:33]([C:36]4[N:41]=[CH:40][C:39]([CH2:42][O:43][CH2:44][CH3:45])=[CH:38][N:37]=4)[CH2:32][CH2:31]3)[C:9]=2[CH:46]([F:57])[C:47]2[CH:52]=[CH:51][C:50]([C:53]([F:56])([F:55])[F:54])=[CH:49][CH:48]=2)[CH2:4][CH2:3]1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[F:58][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([C:8]2[C:17]3[CH:16]([OH:18])[CH2:15][C:14]([CH3:28])([CH3:29])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][N:33]([C:36]4[N:41]=[CH:40][C:39]([CH2:42][O:43][CH2:44][CH3:45])=[CH:38][N:37]=4)[CH2:32][CH2:31]3)[C:9]=2[CH:46]([F:57])[C:47]2[CH:48]=[CH:49][C:50]([C:53]([F:54])([F:56])[F:55])=[CH:51][CH:52]=2)[CH2:6][CH2:7]1
Reactant: CCOCc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3C(F)c3ccc(C(F)(F)F)cc3)C(OCc3ccc(OC)cc3)CC(C)(C)C4)CC2)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCOCc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3C(F)c3ccc(C(F)(F)F)cc3)C(O)CC(C)(C)C4)CC2)nc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 57.9 %

Procedure:
To a solution of 68 mg (0.085 mmol) of 4-(4,4-Difluorocyclohexyl)-2-{1-[5-(ethoxymethyl)pyrimidin-2-yl]piperidin-4-yl}-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 21, in 1 ml of dichloromethane, 46 μl of anisole and 130 μl of trifluoroacetic acid were added, and the reaction solution was stirred at room temperature for 19 hours. Then, 100 μl of trifluoroacetic acid was further added and the reaction solution was stirred at room temperature for 1 hour. After completion of the reaction, the reaction solution was poured into saturated sodium hydrogencarbonate aqueous solution and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=98/2-70/30 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure. n-Hexane was added to the obtained residue and the precipitate was obtained by filtration to provide 34 mg of the title compound as a white solid (yield: 58%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:8]=[C:9]([F:33])[C:10]3[N:11](C(OC(C)(C)C)=O)[C:12]4[C:17]([S:18][C:19]=3[CH:20]=2)=[CH:16][C:15]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[Cl:34]CCl>>[Cl-:34].[O:1]1[CH2:2][CH2:3][N:4]([C:7]2[CH:8]=[C:9]([F:33])[C:10]3[C:19]([CH:20]=2)=[S+:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([N:21]4[CH2:22][CH2:23][CH2:24][CH2:25]4)[CH:16]=2)[N:11]=3)[CH2:5][CH2:6]1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1c2ccc(N3CCCC3)cc2Sc2cc(N3CCOCC3)cc(F)c21
Product: Fc1cc(N2CCOCC2)cc2[s+]c3cc(N4CCCC4)ccc3nc12
Product: [Cl-]
Temperature: 40 °C
Reaction time: 3 h

Procedure:
To a solution 3-morpholino-7-(pyrrolidin-1-yl)-1-fluoro-10-Boc-phenothiazine (150 mg) in dichloromethane (10 mL) HCl (2 mL, 4 M solution in 1,4-dioxane)) was added. The reaction mixture was stirred at 40° C. for 3 h. Solvent was removed under vacuum. Product was purified by flash chromatography.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[N:8]1([CH2:14][C:15]2[CH:29]=[CH:28][C:18]3[O:19][CH:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:21][C:17]=3[CH:16]=2)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:3]1[CH:4]=[CH:5][CH:6]=[N:7][C:2]=1[N:11]1[CH2:10][CH2:9][N:8]([CH2:14][C:15]2[CH:29]=[CH:28][C:18]3[O:19][CH:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[O:21][C:17]=3[CH:16]=2)[CH2:13][CH2:12]1
Reactant: c1ccc(C2Oc3ccc(CN4CCNCC4)cc3O2)cc1
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: c1ccc(C2Oc3ccc(CN4CCN(c5ncccn5)CC4)cc3O2)cc1
Yield: 81.2 %

Procedure:
A solution of 5.7 g (0.05 mole) of 2-chloropyrimidine and 14.7 g (0.05 mole) of 5-(1-piperazinyl methyl)-2-phenyl benzo [d]-1,3-dioxole in 200 ml of dimethylformamide was refluxed for 9 hours in the presence of 13.8 g of dry potassium carbonate. The so-obtained salt was suction-filtered off and the solvent was evaporated off under reduced pressure. The crystallised residue was washed with water, and was then recrystallised from 110 ml of cyclohexane. There was obtained 15.2 g of 5-[4-(2-pyrimidinyl)-1 piperazinyl] methyl-2-phenyl benzo [d]-1,3-dioxole, cream-coloured crystals melting at (K) 106° C.
Reaction SMILES: [H-].[Na+].[C:3]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].Cl.Cl[CH:20]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([C@H:30]2[O:34][N:33]=[C:32]([C:35]3[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=3)[CH2:31]2)=[O:29])=[CH:23][CH:22]=1>CN(C=O)C>[N:37]1[CH:38]=[CH:39][CH:40]=[C:35]([C:32]2[CH2:31][C@@H:30]([C:28]([NH:27][C:24]3[CH:25]=[CH:26][C:21]([CH:20]([N:10]([C:3]([O:5][C:6]([CH3:8])([CH3:9])[CH3:7])=[O:4])[C:11](=[O:12])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[CH:22][CH:23]=3)=[O:29])[O:34][N:33]=2)[CH:36]=1
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Reactant: O=C(Nc1ccc(C(Cl)c2ccccc2)cc1)[C@@H]1CC(c2cccnc2)=NO1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C(c1ccccc1)c1ccc(NC(=O)[C@@H]2CC(c3cccnc3)=NO2)cc1
Temperature: 25 °C

Procedure:
) NaH (0.047 mol) was added portionwise to a solution of bis(1,1-dimethylethyl) imidodicarbonate (0.023 mol) in DMF (250 ml), stirred at RT (H2 gas evolution). The mixture was stirred for 30 minutes at RT. (5S)-N-[4-(chlorophenylmethyl)phenyl]-4,5-dihydro-3-(3-pyridinyl)-5-isoxazolecarboxamide monohydrochloride (0.0233 mol) was added portionwise and the resulting reaction mixture was stirred vigorously for 1 hour at RT (H2 gas evolution). The solvent was evaporated under reduced pressure. The residue was partitioned between water and CH2Cl2. The separated organic layer was dried (MgSO4), filtered and the solvent evaporated under reduced pressure, yielding 1,1-dimethylethyl (5S)-[[4-[[[4,5-dihydro-3-(3-pyridinyl)-5-isoxazolyl]carbonyl]amino]phenyl]phenylmethyl][(1,1-dimethylethoxy)carbonyl]carbamate (compound 501).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]([C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1)([O:8][Si:9]([CH2:14][CH3:15])([CH2:12][CH3:13])[CH2:10][CH3:11])[C:4]([F:7])([F:6])[F:5].[OH-].[Na+].CCOC(C)=O.CCOC(C)=O.CO>CC(O)=O.[Pt]>[F:24][C:2]([F:1])([F:23])[C:3]([C@@H:16]1[CH2:21][CH2:20][C@H:19]([NH2:22])[CH2:18][CH2:17]1)([O:8][Si:9]([CH2:12][CH3:13])([CH2:10][CH3:11])[CH2:14][CH3:15])[C:4]([F:7])([F:6])[F:5].[F:24][C:2]([F:1])([F:23])[C:3]([C@H:16]1[CH2:21][CH2:20][C@H:19]([NH2:22])[CH2:18][CH2:17]1)([O:8][Si:9]([CH2:12][CH3:13])([CH2:10][CH3:11])[CH2:14][CH3:15])[C:4]([F:7])([F:6])[F:5]
Reactant: CC[Si](CC)(CC)OC(c1ccc(N)cc1)(C(F)(F)F)C(F)(F)F
Agent: [Pt]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CO
Product: CC[Si](CC)(CC)OC([C@H]1CC[C@@H](N)CC1)(C(F)(F)F)C(F)(F)F
Product: CC[Si](CC)(CC)OC([C@H]1CC[C@H](N)CC1)(C(F)(F)F)C(F)(F)F

Procedure:
A solution of 5 g (13.4 mmol) of 4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-phenylamine in 150 mL of AcOH was treated with 2.5 g of Pt/C (10%) and hydrogenated for 72 hrs at atmospheric pressure under intense stirring. Filtration and evaporation of the solvent gave a yellow semisolid that was distributed between a 1M aqueous solution of NaOH and EtOAc. The combined organic phases were dried over Na2SO4 and evaporated to yield 4 g of crude product. Chromatography on silica gel with EtOAc and then EtOAc/MeOH 10:1 gave ca. 1.9 g (37%) of cis-4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-cyclohexylamine and ca. 1.9 g (37%) trans-4-(2,2,2-trifluoro-1-triethylsilanyloxy-1-trifluoromethyl-ethyl)-cyclohexylamine as a light yellow oil, MS: 380 (M+H)+.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH2:8])[CH2:4][CH2:3]1.[Cl:9][C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][N:16]2[CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[C:12]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][C:32]#[N:33])=[CH:27][CH:26]=2)[N:11]=1>O>[ClH:9].[ClH:9].[NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:10]2[N:18]=[C:17]3[C:13]([N:14]=[CH:15][N:16]3[CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)=[C:12]([NH:24][C:25]3[CH:26]=[CH:27][C:28]([CH2:31][C:32]#[N:33])=[CH:29][CH:30]=3)[N:11]=2)[CH2:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](N)CC1
Reactant: N#CCc1ccc(Nc2nc(Cl)nc3c2ncn3C2CCCC2)cc1
Solvent: O
Product: Cl
Product: N#CCc1ccc(Nc2nc(N[C@H]3CC[C@H](N)CC3)nc3c2ncn3C2CCCC2)cc1
Temperature: 140 °C

Procedure:
684 mg of trans-1,4-diaminocyclohexane is taken to approximately 140° C. then 211 mg of the product obtained in Stage 1 above is added, the reaction medium is maintained under agitation at 140° C. for 6 hours then left to return to ambient temperature. Then 10 ml of water is added, followed by extracting with dichloromethane, drying and evaporating the solvent. The residue is chromatographed on silica (eluent: MeOH/NH4OH 98/2), followed by taking up in 6 ml of an ethanolic solution of hydrochloric acid, evaporating the solvents, impasting the residue in ether, drying under reduced pressure at 60° C. and 199 mg of expected product is recovered.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])[CH:14]=[CH:15][CH:16]=3)[CH:9]=2)[NH:4][CH:3]=1.[C:25]1([CH3:35])[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=1.[OH-].[K+].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1.O>[I:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([C:17]([N:19]4[CH2:20][CH2:21][O:22][CH2:23][CH2:24]4)=[O:18])[CH:14]=[CH:15][CH:16]=3)[CH:9]=2)[N:4]([S:31]([C:28]2[CH:29]=[CH:30][C:25]([CH3:35])=[CH:26][CH:27]=2)(=[O:33])=[O:32])[CH:3]=1
Reactant: O=C(c1cccc(-c2cnc3[nH]cc(I)c3c2)c1)N1CCOCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4cccc(C(=O)N5CCOCC5)c4)cnc32)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 74 %

Procedure:
A mixture of (3-(3-iodo-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)(morpholino)methanone (600 mg, 1.38 mmol), p-toluenesulfonyl chloride (528 mg, 2.77 mmol), potassium hydroxide (50% w/v in water, 0.387 mL, 3.45 mmol) and tetrabutylammonium hydroxide (40% w/v in water, 0.448 mL, 0.69 mmol) in toluene (5 mL) was stirred at room temperature for 15 hours. Water was added to the mixture and the aqueous mixture was extracted by ethyl acetate (3×). The organic layers were combined, dried over sodium sulfate, filtered and concentrated to dryness. Silica gel chromatography of the crude product afforded (3-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)(morpholino)methanone (600 mg, 74% yield) as yellow solids. MS: m/z 588.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:14]2[C:22]3[C:17](=[C:18]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)([CH2:12][CH3:13])[CH2:9][CH2:10]O)=[CH:4][CH:3]=1.CCN(S(F)(F)[F:34])CC>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:14]2[C:22]3[C:17](=[C:18]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15]2)([CH2:12][CH3:13])[CH2:9][CH2:10][F:34])=[CH:4][CH:3]=1
Reactant: CCC(CCO)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: CCC(CCF)(c1ccc(Cl)cc1)n1ccc2c(NS(C)(=O)=O)cccc21
Reaction time: 1 h

Procedure:
To a solution of N-(1-(3-(4-chlorophenyl)-1-hydroxypentan-3-yl)-1H-indol-4-yl)methanesulfonamide (20 mg, 0.05 mmol), as described in Example 40 Step I, in DCM (5 mL) was added DAST (16 mg, 0.1 mmol) at 0° C. The mixture was stirred for 1 h, then quenched with saturated aqueous ammonium chloride (5 mL) and extracted with ethyl acetate. The combined organics were washed with water (5 mL) and brine (5 mL), dried over MgSO4, filtered and concentrated. The resulting crude product was purified by Pre-HPLC (Mobile phase: acetonitrile/water (0.03% TFA)) to afford the title racemic compound as a white solid. The racemic compound was submitted to chiral SFC separation using IC (30% MeOH (0.1% DEA)/CO2, 4.6×250 mm, 41° C.) to give two separated enantiomers. LC/MS m/z=409.1 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:14][C:15]1[CH:20]=[N:19][CH:18]=[CH:17][N:16]=1.IC1C=C2C(=CC=1)N=CN=C2NC1SC2C(N=1)=CC=CN=2>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[NH:14][C:15]1[CH:20]=[N:19][CH:18]=[CH:17][N:16]=1
Reactant: COc1ccc2ncnc(Cl)c2c1
Reactant: Nc1cnccn1
Agent: Ic1ccc2ncnc(Nc3nc4cccnc4s3)c2c1
Product: COc1ccc2ncnc(Nc3cnccn3)c2c1

Procedure:
The compound of Example 37 was manufactured using 4-chloro-6-methoxy-quinazoline and 2-aminopyrazine by the same method as in Example 1 for the manufacture of (6-iodoquinazolin-4-yl)-thiazolo[5,4-b]pyridin-2-yl-amine, by a similar method thereto or by a combination of such a method with a conventional method.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[OH-].[Na+].[CH2:9]([C:11]1([CH2:15]OS(C)(=O)=O)[CH2:14][O:13][CH2:12]1)[CH3:10]>C(O)(=O)C.O.C1(C)C=CC=CC=1>[CH2:9]([C:11]1([CH2:15][O:5][CH2:4][CH2:3][CH2:2][CH2:1][OH:6])[CH2:14][O:13][CH2:12]1)[CH3:10]
Reactant: OCCCCO
Reactant: CCC1(COS(C)(=O)=O)COC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CCC1(COCCCCO)COC1
Temperature: 60 °C

Procedure:
1,4-Butanediol (721 g (8.0 mol)) and toluene (350 ml) were added to a glass flask having an inner volume of 2,000 ml equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser, and the mixture was warmed to 60° C. with stirring. 96% Sodium hydroxide (184 g (4.4 mol)) was added with stirring, the mixture was warmed to 75° C. Subsequently 3-ethyl-3-methanesulfonyloxymethyloxetane (777 g (3.8 mol)) having purity of 95% synthesized by the same method as in Reference Example 1 was dropwise added while keeping a liquid temperature at 75-85° C., the mixture was reacted at the same temperature for 2 hours. After the completion of the reaction, water (800 ml) was added to the reaction liquid (a bisoxetane ether compound generated in the amount of only 6% (an analysis value by a gas chromatography)), and a liquid separation was performed to give an organic layer. Toluene (800 ml) and water (400 ml) were added to a resultant organic layer, and acetic acid was added with stirring so that pH was adjusted to 9.5. After a liquid separation, an aqueous layer was extracted with toluene (400 ml) twice. An extract (a toluene layer) and an organic layer were combined, and the resultant was concentrated under reduced pressure. A resultant concentrate was distilled under reduced pressure (157-159° C., 1.9 kPa) to give, as a colorless liquid, 3-ethyl-3-(4-hydroxybutyl)oxymethyloxetane having a purity of 96% (an analysis value by a gas chromatography) (477 g) (an isolated yield based on 3-ethyl-3-methanesulfonyloxymethyloxetane: 64%).