Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:9][CH:8]=[CH:7][CH:6]=2.[C:21](OC)(OC)(OC)[CH2:22][CH2:23][CH3:24]>C1(C)C=CC=CC=1.Cl.N1C=CC=CC=1>[CH2:22]([C:21]1[N:12]([CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:11]2[C:10]3[N:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH2:23][CH3:24]
Reactant: CCOC(=O)CCCNc1c(N)cnc2cccnc12
Reactant: CCCC(OC)(OC)OC
Agent: Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCc1nc2cnc3cccnc3c2n1CCCC(=O)OCC
Temperature: 25 °C

Procedure:
The preparation of ethyl 4-[(3-amino[1,5]naphthyridine-4-yl)amino]butyrate is described in Parts A-B of Example 4. Trimethyl orthobutyrate (9.1 mL, 57.2 mmol) and pyridine hydrochloride (110 mg, 0.95 mmol) were added to a solution of ethyl 4-[(3-amino-[1,5]naphthyridine-4-yl)amino]butyrate (13.08 g, 47.7 mmol) in toluene (190 mL) and heated at reflux for 3 hours. The reaction mixture was cooled to ambient temperature and concentrated under reduced pressure. The residue was dissolved in dichloromethane (200 mL) and washed with saturated aqueous sodium bicarbonate (150 mL). The aqueous layer was extracted with dichloromethane (2×50 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to afford 14.9 g of ethyl 4-(2-propyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)-butyrate as a yellow solid.
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.[CH2:7]([O:9][C:10](=[O:13])[CH2:11][NH2:12])[CH3:8].[CH3:14][C:15]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[C:16](Cl)=[O:17]>O.CCOCC>[CH2:7]([O:9][C:10](=[O:13])[CH2:11][NH:12][C:16](=[O:17])[C:15]([CH3:14])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])[CH3:8]
Reactant: CC(C)C(C)(C(=O)Cl)C(C)C
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)CNC(=O)C(C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sodium bicarbonate (1.7 g, 0.02 mole) and glycine ethyl ester hydrochloride (1.4 g, 0.01 mole) were dissolved in water (10 ml) and a solution of 2,3-dimethyl-2-isopropylbutanoyl chloride (1.6 g, 0.009 mole) in ether (10 ml) was added. The mixture was stirred vigorously at room temperature for 2 hours. After 16 hours at room temperature the ether layer was separated and dried (MgSO4). Removal of the solvent left a white solid which was recrystallized from ether/petroleum ether to give N-(2,3-dimethyl-2-isopropylbutanoyl)glycine ethyl ester, mp. 74.5°-75.5°.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1.[CH3:14][N:15]([CH3:31])[C:16]1[CH:21]=[C:20]([N:22]([CH3:24])[CH3:23])[N:19]=[C:18]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[N:17]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:23][N:22]([CH3:24])[C:20]1[CH:21]=[C:16]([N:15]([CH3:14])[CH3:31])[N:17]=[C:18]([N:25]2[CH2:30][CH2:29][N:28]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=3)[CH2:27][CH2:26]2)[N:19]=1
Reactant: CN(C)c1cc(N(C)C)nc(N2CCNCC2)n1
Reactant: CC(=O)NCc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)NCc1ccc(CN2CCN(c3nc(N(C)C)cc(N(C)C)n3)CC2)cc1
Yield: 109.8 %

Procedure:
A solution of N-(4-chloromethylphenylmethyl)acetamide (0.7 g), 1-(4,6-bis(dimethylamino)pyrimidin-2-yl)piperazine (0.9 g) and potassium carbonate (0.7 g) in dimethylformamide (10 ml) was stirred at 80° C. for 6 hr. The reaction mixture was poured into water (100 ml) and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a brown solid (1.6 g). The obtained brown solid was crystallized from ethyl acetate/ethanol (2:1, 30 ml) to give the title compound (0.9 g) as pale-yellow crystals.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[N:13][C:14]([C:16](O)=[O:17])=[CH:15][C:10]=3[N:9]=[CH:8]2)=[CH:4][CH:3]=1.Cl.[CH3:22][O:23][NH2:24]>>[F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]2[C:11]3[CH:12]=[N:13][C:14]([C:16]([NH:24][O:23][CH3:22])=[O:17])=[CH:15][C:10]=3[N:9]=[CH:8]2)=[CH:4][CH:3]=1
Reactant: CON
Reactant: O=C(O)c1cc2ncn(Cc3ccc(F)cc3)c2cn1
Agent: Cl
Product: CONC(=O)c1cc2ncn(Cc3ccc(F)cc3)c2cn1

Procedure:
The title compound was prepared by coupling of 3-(4-fluorobenzyl)-3H-imidazo[4,5-c]pyridine-6-carboxylic acid and N-methoxyamine hydrochloride under the same conditions as those in step (c) of example 1. 1H NMR (300 MHz, MeOH-d4) δ: 8.71 (s, 1H), 8.53 (s, 1H), 8.32 (s, 1H), 7.36-7.33 (m, 2H), 7.07-7.05 (m, 2H), 5.57 (s, 2H), 3.75 (s, 3H). LCMS (API-ES, M+H+): 301.1. HRMS calcd for C15H14FN4O2 (M+H) 301.1 101, found 301.1105. HPLC: >84% purity.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:21]3[C:20]4[CH:19]=[C:18]([O:22][CH:23]([C:27]5[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=5)[C:24](O)=[O:25])[C:17]([O:34][CH3:35])=[CH:16][C:15]=4[N:14]=[CH:13][C:12]=3[N:11]([CH3:36])[N:10]=2)=[CH:5][CH:4]=1)#[N:2].C1(C)C=CC=CC=1.S(Cl)([Cl:46])=O>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:21]3[C:20]4[CH:19]=[C:18]([O:22][CH:23]([C:27]5[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=5)[C:24]([Cl:46])=[O:25])[C:17]([O:34][CH3:35])=[CH:16][C:15]=4[N:14]=[CH:13][C:12]=3[N:11]([CH3:36])[N:10]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: O=S(Cl)Cl
Reactant: COc1cc2ncc3c(c(-c4ccc(C#N)cc4)nn3C)c2cc1OC(C(=O)O)c1ccc(F)cc1
Solvent: Cc1ccccc1
Product: COc1cc2ncc3c(c(-c4ccc(C#N)cc4)nn3C)c2cc1OC(C(=O)Cl)c1ccc(F)cc1

Procedure:
[1-(4-Cyanophenyl)-7-methoxy-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yloxy]-(4-fluorophenyl)acetic acid (190 mg, 394 μmol) is dissolved in thionyl chloride (2.0 ml) and heated under reflux for 2 h. The mixture is then evaporated to dryness in vacuo and co-evaporated twice with distilled, anhydrous toluene, giving [1-(4-cyanophenyl)-7-methoxy-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yloxy]-(4-fluorophenyl)acetyl chloride (195 mg, 389 μmol). 35 mg (69.9 μmol) of the acid chloride obtained are subsequently dissolved in anhydrous N,N-dimethylformamide (2.0 ml) in a dry nitrogen atmosphere, and 2-(4-ethylpiperazin-1-yl)-ethylamine (22 mg, 140 μmol) is added with ice-bath cooling. The reaction solution is stirred at room temperature for 2 h. The mixture is then poured into water (30 ml) and extracted four times with ethyl acetate (30 ml each time). The combined organic phases are washed twice with water (20 ml each time), subsequently dried using Na2SO4, filtered with suction, and the filtrate is evaporated to dryness in vacuo. The residue is dissolved in dimethyl sulfoxide and chromatographed (pHPLC, solvent gradient water/1-30% by vol. of acetonitrile, 0.1% by vol. of formic acid), giving, after freeze-drying, the title compound 2-[1-(4-cyanophenyl)-7-methoxy-3-methyl-3H-pyrazolo[3,4-c]quinolin-8-yloxy]-N-[2-(4-ethylpiperazin-1-yl)ethyl]-2-(4-fluorophenyl)acetamide (21 mg, 33.8 μmol) as lyophilisate having a melting range of 110-112° C. MS: 622.3 (M+H+), TLC (HPTLC): Rf=0.40 (methanol/Hünig's base 99:1, parts by volume).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:9][CH2:8][N:7]1[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:5])C.COC(C)(C)C>O>[CH2:10]([N:7]1[CH2:8][CH2:9][CH:6]1[C:4]([OH:5])=[O:3])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)C1CCN1Cc1ccccc1
Solvent: COC(C)(C)C
Solvent: O
Product: O=C(O)C1CCN1Cc1ccccc1
Temperature: 40 °C
Reaction time: 7 h

Procedure:
10.0 g of N-Benzylazetidine-2-carboxylic acid ethyl ester, 29.6 g of t-butyl methyl ether and 26.7 g of water are mixed at 20 to 25° C. and then 0.333 g of Enzyme (Chirazyme L-2) was added thereto and the resulting solution was heated to 40° C. and stirred for 7 hours. Settled solution was separated into an aqueous phase and an organic phase. The aqueous phase was washed twice with t-butyl methyl ether to yield an aqueous solution of optically active N-benzylazetidine-2-carboxylic acid and a combined organic phase of N-benzylazetidine-2-carboxylic acid ethyl ester. Results of the same analysis as in the Example 1 is shown in Table 8.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[N:24]=[C:23]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:22]3[C:17](=[CH:18][C:19]([O:33][CH3:34])=[C:20]([O:31][CH3:32])[CH:21]=3)[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:35]>C(O)C.O1CCOCC1>[ClH:35].[ClH:35].[CH3:32][O:31][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][C:19]=1[O:33][CH3:34])[N:16]=[C:15]([NH:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)[N:24]=[C:23]2[N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: COc1cc2nc(NC3CCN(C(=O)OC(C)(C)C)CC3)nc(N3CCCCC3)c2cc1OC
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: COc1cc2nc(NC3CCNCC3)nc(N3CCCCC3)c2cc1OC

Procedure:
A solution of 4-(6,7-dimethoxy-4-piperidin-1-yl-quinazolin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.90 g, 4.03 mmol) in ethanol (10 mL) and 4 M HCl in dioxane (40 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 372.1 [M+H]+.
Reaction SMILES: C[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]2[NH:8][C:7](=S)[CH:6]3[CH2:16][CH2:17][CH2:18][CH:5]3[C:4]=2[CH:3]=1.[NH3:19]>>[NH2:19][C:7]1[CH:6]2[CH2:16][CH2:17][CH2:18][CH:5]2[C:4]2[CH:3]=[CH:2][C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]=2[N:8]=1
Reactant: Cc1cc2c(cc1[N+](=O)[O-])NC(=S)C1CCCC21
Reactant: N
Product: NC1=Nc2cc([N+](=O)[O-])ccc2C2CCCC12
Yield: 77 %

Procedure:
As described for Example 4, 8-methyl-7-nitro-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinoline-4-thione (42 mg, 0.16 mmol) is reacted with 7N methanolic ammonia solution (10 ml) to form 30 mg (77%) of product.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][O:19][CH3:20])=[CH:14][CH:15]=2)[C:10]([CH:21]=O)=[C:9]1[CH:23]([CH3:25])[CH3:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:26][C:27]1[CH:28]=[C:29]([CH:32]=[C:33]([F:35])[CH:34]=1)[CH2:30][NH2:31].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][O:19][CH3:20])=[CH:14][CH:15]=2)[C:10]([CH2:21][NH:31][CH2:30][C:29]2[CH:28]=[C:27]([F:26])[CH:34]=[C:33]([F:35])[CH:32]=2)=[C:9]1[CH:23]([CH3:25])[CH3:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1cc(F)cc(F)c1
Reactant: COCOc1ccc2c(c1)c(C=O)c(C(C)C)n2Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COCOc1ccc2c(c1)c(CNCc1cc(F)cc(F)c1)c(C(C)C)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-benzyl-2-isopropyl-5-(methoxymethoxy)-1H-indole-3-carboxaldehyde (Compound 4, 103 mg, 0.31 mmol) in methanol (5.0 ml) was added 3,5-difluorobenzylamine (49 μl, 0.40 mmol), and acetic acid (2 drops). After stirring at room temperature for 1 h, sodium cyanoborohydride (29 mg, 0.47 mmol) was added and the reaction was stirred for 5 h. More 3,5-difluorobenzylamine (50 μl, 0.40 mmol) was added, and the reaction was stirred for 64 h. The solvent was removed and the crude reaction mixture was purified by flash chromatography on silica gel eluting with 10-50% EtOAc-hexanes to yield 1-(1-benzyl-2-isopropyl-5-(methoxymethoxy)-1H-indol-3-yl)-N-(3,5-difluorobenzyl)methanamine (Compound 5) as a light greenish yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:5][CH:4]=1.[CH3:20][C:21]1[S:25][C:24]([C:26](Cl)=[O:27])=[CH:23][CH:22]=1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:26]([C:24]3[S:25][C:21]([CH3:20])=[CH:22][CH:23]=3)=[O:27])[S:11][C:7]=2[C:6]([CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CN2CCOCC2)c2sc(N)nc12
Reactant: Cc1ccc(C(=O)Cl)s1
Solvent: c1ccncc1
Product: COc1ccc(CN2CCOCC2)c2sc(NC(=O)c3ccc(C)s3)nc12

Procedure:
Using 4-methoxy-7-morpholin-4-ylmethyl-benzothiazol-2-ylamine and 5-methyl-thiophene-2-carboxylic acid chloride in pyridine the title compound was obtained as a yellow solid (53% yield), MS: m/e=404.4 (M+H+).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5](Cl)=[N:6][N:7]=1.[Na].[NH2:10][C:11]1[NH:15][N:14]=[N:13][N:12]=1>C(#N)C>[NH:12]1[C:11]([NH:10][C:2]2[N:3]=[N:4][C:5]([NH:10][C:11]3[NH:15][N:14]=[N:13][N:12]=3)=[N:6][N:7]=2)=[N:15][N:14]=[N:13]1
Reactant: Nc1nnn[nH]1
Reactant: Clc1nnc(Cl)nn1
Agent: [Na]
Solvent: CC#N
Product: n1n[nH]c(Nc2nnc(Nc3nnn[nH]3)nn2)n1
Temperature: 25 °C

Procedure:
To a solution of 3,6-dichloro-1,2,4,5-tetrazine (1.51 g, 10 mmol) in acetonitrile (70 ml) was added the sodium salt of 5-amino-1H-tetrazole (2.14 g, 10 mmol). The mixture was refluxed for 24 hours then allowed to cool to room temperature. The suspension was centrifuged until the supernatant liquid was clear. The liquid was decanted and the brown solid washed successively with acetonitrile and water. With each wash the solid was separated from the solvent by centrifugation followed by decantation. The isolated crude yield was 1.5 g (60%), this material was recrystallized from DMSO/methanol yielding an orange brown powder mp 264° C. dec; 1H NMR (deuteriomethylsulfoxide) ∂ 12.5 (br s, 4H); 13C NMR (deuteriomethylsulfoxide) ∂ 151.74, 158.25; IR (KBr) 3421, 3000, 1615, 1436, 1127 cm−1. A gas pycnometer density of 1.76 g/cm3 was also determined and a drop height of 195 cm was measured (Type 12, HMX=24-27 cm).
Reaction SMILES: [Br-:1].[Li+].[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([O:13][C@@H:14]2[CH2:18][O:17][C@@H:16]3[C@@H:19](OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:20][O:21][C@H:15]23)(=[O:12])=[O:11])=[CH:6][CH:5]=1>CS(C)=O.O>[CH3:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([O:13][C@H:14]2[CH2:18][O:17][C@@H:16]3[C@@H:19]([Br:1])[CH2:20][O:21][C@H:15]23)(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CO[C@H]3[C@@H]2OC[C@H]3OS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: [Br-]
Agent: [Li+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc(S(=O)(=O)O[C@H]2CO[C@H]3[C@@H]2OC[C@@H]3Br)cc1
Temperature: 110 °C
Reaction time: 1.75 h
Yield: 54.6 %

Procedure:
Lithium bromide (19.2 g, 220.2 mmol) was added to a stirred solution of ditosylate (42) (40.0 g, 88.1 mmol) in dimethyl sulfoxide (200 mL) under an atmosphere of argon. The mixture was heated at 110° C. for 8 hours then at 120° C. for 1.75 hours. The mixture was diluted with water (500 mL) then extracted with tert-butyl methyl ether (4×250 mL). The organic phase was washed with water (3×250 mL) then brine (250 mL), dried (MgSO4), filtered and reduced in vacuo to leave an orange solid. Recrystallisation from methanol (100 mL) gave bromotosylate (47) (17.47 g, 55%) as a pale yellow solid. [α]D15+49.5° (c=11.7, CHCl3).
Reaction SMILES: [OH:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22])[C:3]1[CH:4]=[N:5][O:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1.[C:24](Cl)(=[O:26])[CH3:25].N1C=CC=CC=1>ClCCl>[C:24]([O:1][CH:2]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:18])([F:20])[F:19])=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22])[C:3]1[CH:4]=[N:5][O:6][C:7]=1[CH:8]1[CH2:10][CH2:9]1)(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1C(O)c1cnoc1C1CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)OC(c1ccc(C(F)(F)F)cc1[N+](=O)[O-])c1cnoc1C1CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 59.1 %

Procedure:
A mixture of 4-[hydroxy-(2-nitro4-trifluoromethylphenyl)methyl]-5-cyclopropylisoxazole (0.69 g), acetyl chloride (0.27 g) and pyridine (0.10 g) in dichloromethane (40 ml) was stirred at 0° C. for 4 hours. The mixture was quenched with water and extracted with dichloromethane. The organic extracts were dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness. The residue was triturated with ether/petroleum ether to give 4-[acetoxy-(2-nitro4-trifluoromethylphenyl)methyl]-5-cyclopropylisoxazole (compound 297, 0.46 g) as a yellow solid: m.p. 82° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[N:12]([CH3:15])[C:11]3[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:10]=3[S:9]2(=[O:22])=[O:21])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:30]([CH3:32])[CH3:31]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[N:12]([CH3:15])[C:11]3[CH:16]=[C:17]([O:20][CH:30]([CH3:32])[CH3:31])[CH:18]=[CH:19][C:10]=3[S:9]2(=[O:21])=[O:22])=[CH:4][CH:3]=1
Reactant: CC(C)I
Reactant: CN1C(=O)N(c2ccc(Cl)cc2)S(=O)(=O)c2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc2c(c1)N(C)C(=O)N(c1ccc(Cl)cc1)S2(=O)=O
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A suspension of 2-(4-chlorophenyl)-6-hydroxy-4-methyl-2H-1,2,4-benzothiadiazine-3(4H)-one 1,1-dioxide (15.33 g), potassium carbonate (7.50 g) and 2-iodopropane (5.43 ml) in N,N-dimethylformamide (150 ml) was stirred for 2 hours at 60° C. The mixture was poured into ice water. The separated solid was collected by filtration, dried, and recrystallized from ethanol to yield 2-(4-chlorophenyl)-6-isopropoxy-4-methyl-2H-1,2,4-benzothiadiazine-3(4H)-one 1,1-dioxide (13.54 g) as a white crystal.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>O1CCCC1>[C:31]([O:23][C:20]1[CH:19]=[CH:18][C:17]([C:15]2[O:14][N:13]=[C:12]([O:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:16]=2)=[CH:22][CH:21]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCOc1cc(-c2ccc(O)cc2)on1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Oc1ccc(-c2cc(OCCNC(=O)OC(C)(C)C)no2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(4-hydroxyphenyl)isoxazole (0.15 g) was dissolved in tetrahydrofuran (1.5 ml), and triethylamine (0.07 ml) and acetyl chloride (0.04 ml) were added dropwise thereto at 5° C. under a nitrogen atmosphere, followed by stirring of the resulting mixture at room temperature for 30 minutes. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous NaCl solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=2/1) to obtain the title compound (0.12 g, 71%) as a colorless powder.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:37]=[CH:36][C:18]([CH2:19][N:20]([CH2:32][C:33]([OH:35])=[O:34])[CH2:21][CH2:22][CH2:23][CH2:24][N:25]([CH2:29][CH2:30][CH3:31])[CH2:26][CH2:27][CH3:28])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.[CH2:38](O)[CH3:39]>>[CH2:38]([O:34][C:33](=[O:35])[CH2:32][N:20]([CH2:19][C:18]1[CH:36]=[CH:37][C:15]([CH2:14][N:7]([CH2:8][C:9]2[NH:13][CH:12]=[CH:11][N:10]=2)[CH2:6][C:2]2[NH:1][CH:5]=[CH:4][N:3]=2)=[CH:16][CH:17]=1)[CH2:21][CH2:22][CH2:23][CH2:24][N:25]([CH2:29][CH2:30][CH3:31])[CH2:26][CH2:27][CH3:28])[CH3:39]
Reactant: CCCN(CCC)CCCCN(CC(=O)O)Cc1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Reactant: CCO
Product: CCCN(CCC)CCCCN(CC(=O)OCC)Cc1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1

Procedure:
The compound (275.6 mg) obtained in Example 69-1 was dissolved in ethanol (11 ml) and the whole was refluxed under heating for 21 hours.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([OH:19])([C:15]([F:18])([F:17])[F:16])[C:11]([F:14])([F:13])[F:12])=[CH:6][CH:5]=1)[CH3:2].Cl[CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)[O:25][C:26]=1[CH3:27]>CN(C=O)C>[CH2:1]([N:3]([CH2:21][C:22]1[N:23]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)[O:25][C:26]=1[CH3:27])[C:4]1[CH:5]=[CH:6][C:7]([C:10]([OH:19])([C:11]([F:13])([F:14])[F:12])[C:15]([F:16])([F:18])[F:17])=[CH:8][CH:9]=1)[CH3:2]
Reactant: Cc1oc(-c2cccc(C(F)(F)F)c2)nc1CCl
Reactant: CCNc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Solvent: CN(C)C=O
Product: CCN(Cc1nc(-c2cccc(C(F)(F)F)c2)oc1C)c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Yield: 49.4 %

Procedure:
A solution of 100 mg (0.35 mmol) of 2-(4-ethylamino-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol and 96 mg (0.35 mmol) of 4-chloromethyl-5-methyl-2-(3-trifluoromethyl-phenyl)-oxazole (example 22.1) in 0.5 mL of DMF was stirred overnight at 80° C. After distribution of the crude mixture between a saturated aqueous solution of NH4Cl and Et2O, the combined organic phases were dried over Na2SO4 and the solvent was evaporated. Column chromatography on silica gel with toluene/EtOAc gave 91 mg (53%) of 2-(4-{ethyl-[5-methyl-2-(3-trifluoromethyl-phenyl)-oxazol-4-ylmethyl]-amino}-phenyl)-1,1,1,3,3,3-hexafluoro-propan-2-ol, yellow solid, MS: 527 (MH+).
Reaction SMILES: [CH2:1]1[NH:5][CH2:4][CH:3]2[CH2:6][O:7][CH2:8][CH2:9][CH:2]12.C([O-])([O-])=O.[K+].[K+].[Cl:16][CH2:17][CH2:18][CH2:19]Br>CC(C)=O>[Cl:16][CH2:17][CH2:18][CH2:19][N:5]1[CH2:1][CH:2]2[CH2:9][CH2:8][O:7][CH2:6][CH:3]2[CH2:4]1
Reactant: ClCCCBr
Reactant: C1CC2CNCC2CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: ClCCCN1CC2CCOCC2C1
Yield: 16.9 %

Procedure:
To a solution of octahydropyrano[3,4-c]pyrrole (0.14 g) in acetone (30 mL) was added K2CO3 (0.76 g) followed by 1-chloro-3-bromopropane (0.57 g, 2.0 eq). The reaction mixture was heated to reflux for 12 h and filtered. The filtrate was concentrated in vacuo, and the residue was dissolved in EtOAc (100 mL). The solution was washed with water (100 mL×2) followed by brine (100 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) EA/CH3OH) to give the title compound (38 mg, 16.96%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 204.7 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20](OC1C=CC=CC=1)=[O:21].[CH3:29][C:30]1[O:34][N:33]=[C:32](C(Cl)=O)[CH:31]=1>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20]([C:32]1[CH:31]=[C:30]([CH3:29])[O:34][N:33]=1)=[O:21]
Reactant: Cc1cc(C(=O)Cl)no1
Reactant: Cn1c(Nc2ccc(I)cc2F)c(C(=O)Oc2ccccc2)c(=O)n(C)c1=O
Product: Cc1cc(C(=O)c2c(Nc3ccc(I)cc3F)n(C)c(=O)n(C)c2=O)no1

Procedure:
The title compound was synthesized following a similar procedure described in the synthesis of compound 2A by reaction of Example 1 and 5-methylisoxazole-3-carbonyl chloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.42 (s, 2H) 3.13 (s, 2H) 3.19 (s, 2H) 6.13-6.29 (m, 1H) 7.08 (t, J=8.59 Hz, 1H) 7.47 (dd, J=8.46, 1.89 Hz, 1H) 7.68 (dd, J=9.98, 1.89 Hz, 1H) 10.47 (s, 1H) [M+H] calc'd for C17H14FIN4O4, 485. found, 485.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[O:15][CH:14]([CH2:17][NH2:18])[CH2:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.Cl[C:29]([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:30]>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[O:15][CH:14]([CH2:17][NH:18][C:29](=[O:30])[O:31][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NCC1Cc2cccc(-c3cccc(F)c3)c2O1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1Cc2cccc(-c3cccc(F)c3)c2O1)OCc1ccccc1
Yield: 85.2 %

Procedure:
Treatment of (±)-1-[7-(3-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methanamine (798 g, 6.382.86 mmol) with diisopropylethylamine (0.554 g, 4.29 mmol) followed by benzyl chloroformate (0.536 g, 3.14 mmol) generally according to the procedure described for Intermediate 12 provided 1.01 g (94%) of (±)-benzyl {[7-(3-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate as a white solid. Rf=0.41 (silica, ethyl acetate:hexanes 2:8); Anal. calcd. for C23H20FNO3: C, 73.2; H, 5.34; N, 3.71. Found: C, 72.96H, 5.38; N, 3.59. Chiral HPLC separation of (±)-benzyl {[7-(3-fluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl}carbamate (Chiralpak OD, isopropanol:hexane 2:8) provided two fractions. Fraction 1 (Rt=7.675 min, Chiralpak OD, isopropanol:hexane 2:8); Fraction 2 (Rt=9.182 min, Chiralpak OD, isopropanol:hexane 2:8).