Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([NH:8][CH3:9])[CH:7]=1.[CH3:13][C:14]1[CH:15]=[C:16]([OH:24])[CH:17]=[C:18]([CH3:23])[C:19]=1[N+:20]([O-:22])=[O:21].CC(C)([O-])C.[K+].Cl>CN(C)C(=O)C>[CH3:23][C:18]1[CH:17]=[C:16]([CH:15]=[C:14]([CH3:13])[C:19]=1[N+:20]([O-:22])=[O:21])[O:24][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([NH:8][CH3:9])[CH:7]=1
Reactant: Cc1cc(O)cc(C)c1[N+](=O)[O-]
Reactant: CNc1cc(Cl)ccc1[N+](=O)[O-]
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CNc1cc(Oc2cc(C)c([N+](=O)[O-])c(C)c2)ccc1[N+](=O)[O-]
Temperature: 125 °C
Reaction time: 0.75 h
Yield: 80.4 %

Procedure:
To a solution of N-(5-chloro-2-nitrophenyl)-N-methylamine (0.86 g) and 3,5-dimethyl-4-nitrophenol (0.76 g) in N,N-dimethylacetamide (12 ml) was added potassium t-butoxide (0.554 g) at room temperature, and the resulting mixture was stirred successively at the same temperature for 20 minutes, at 100° C. for 10 minutes, at 125° C. for 45 minutes, and at 140° C. for 1 hour. After cooling the reaction mixture to 0° C., the reaction mixture was adjusted to a pH of about 3 with 3N hydrochloric acid. The crystalline solid precipitated was collected by filtration, washed successively with 3N hydrochloric acid and water and air-dried for 3 days to afford the title compound (1.16 g, yield: 80%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:38]=[CH:37][S:36][C:14]=3[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH:20]([NH:23][C:24]([C:26]4[CH:35]=[CH:34][C:29]([C:30]([O:32]C)=[O:31])=[CH:28][CH:27]=4)=[O:25])[CH2:19]3)[N:17]=2)=[N:7][C:8]=1[O:9][CH3:10].O[Li].O.Cl>CO.C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:38]=[CH:37][S:36][C:14]=3[N:15]=[C:16]([N:18]3[CH2:22][CH2:21][CH:20]([NH:23][C:24]([C:26]4[CH:35]=[CH:34][C:29]([C:30]([OH:32])=[O:31])=[CH:28][CH:27]=4)=[O:25])[CH2:19]3)[N:17]=2)=[N:7][C:8]=1[O:9][CH3:10]
Reactant: COC(=O)c1ccc(C(=O)NC2CCN(c3nc(Nc4ccc(OC)c(OC)n4)c4ncsc4n3)C2)cc1
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc(Nc2nc(N3CCC(NC(=O)c4ccc(C(=O)O)cc4)C3)nc3scnc23)nc1OC
Temperature: 25 °C
Reaction time: 24 h
Yield: 20.6 %

Procedure:
To a stirred solution of methyl 4-(1-(7-(5,6-dimethoxypyridin-2-ylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidin-3-ylcarbamoyl)benzoate (350 mg, 0.65 mmol) in 20 mL of methanol and 40 mL of THF was added a solution of LiOH.H2O (274 mg, 6.5 mmol) in one portion at room temperature. Then the solution was stirred at room temperature for 24 hours. The solution was acidified with 1N HCl to pH=4. The solvent was evaporated and the residue was purified by preparative HPLC (Gemini 5u C18 150×21.2 mm; inject volume: 3 ml/inj, flow rate: 20 ml/min; wavelength: 214 nm and 254 nm; the gradient conditions are: 30% acetonitrile/70% water (0.1% TFA V/V) initially, and then proceed to 55% acetonitrile/45% water (0.1% TFA V/V) in a linear fashion after just 9 min.) to give 4-(1-(7-(5,6-dimethoxypyridin-2-ylamino)thiazolo[5,4-d]pyrimidin-5-yl)pyrrolidin-3-ylcarbamoyl)benzoic acid (70 mg, 20.5%) as a pale yellow solid. 1H NMR (300 MHz, DMSO): δ 8.87-8.18 (m, 2H), 8.67 (s, 1H), 8.03-7.96 (m, 5H), 7.44 (d, 1H, J=8.7 Hz), 4.66 (brs, 1H), 4.11 (brs, 2H), 3.90 (s, 3H), 3.78 (s, 3H), 3.68 (brs, 2H), 2.27 (brs, 1H), 2.08 (brs, 1H). LC-MS: 522 [M+H]+, tR=1.44 min. HPLC: 99.68% at 214 nm, 99.31% at 254 nm, tR=6.98 min.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[C:32]([N:35]1[CH:39]([C:40]2[CH:41]=[CH:42][C:43]([O:51][CH3:52])=[C:44]([CH:50]=2)[O:45][CH2:46][C:47](O)=[O:48])[CH2:38][C:37]([C:53]2[CH:58]=[C:57]([O:59][CH3:60])[C:56]([O:61][CH3:62])=[C:55]([O:63][CH3:64])[CH:54]=2)=[N:36]1)(=[O:34])[CH3:33]>ClCCl.O>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:1][C:47](=[O:48])[CH2:46][O:45][C:44]1[CH:50]=[C:40]([CH:39]2[N:35]([C:32](=[O:34])[CH3:33])[N:36]=[C:37]([C:53]3[CH:58]=[C:57]([O:59][CH3:60])[C:56]([O:61][CH3:62])=[C:55]([O:63][CH3:64])[CH:54]=3)[CH2:38]2)[CH:41]=[CH:42][C:43]=1[O:51][CH3:52]
Reactant: Nc1nc2ccccc2s1
Reactant: COc1ccc(C2CC(c3cc(OC)c(OC)c(OC)c3)=NN2C(C)=O)cc1OCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C2CC(c3cc(OC)c(OC)c(OC)c3)=NN2C(C)=O)cc1OCC(=O)Nc1nc2ccccc2s1
Yield: 799.1 %

Procedure:
To a solution of 2-aminobenzothiazole (359.37 ma, 1.0 mmol) in dichloromethane (20 mL) was added 1-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide (EDC) (191 mg, 1.0 mmol) and 1-hydroxy-1,2,3-benzotriazole (HOBt) (13.5 ma, 0.1 mmol). Then added 2-{5-[1-acetyl-3-(3,4,5-trimethoxyphenyl)-4,5-dihydro-1H-5-pyrazolyl]-2-methoxyphenoxy}acetic acid (3) (458 mg, 0.1 mmol) and the reaction mixture was stirred at a temperature of 25° C. for 24 h and the reaction was monitored by TLC. Then to this water is added and extracted with dichloromethane. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate and hexane as solvent system to obtain the pure product (10a) (472 mg, 80% yield)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][O:39][CH2:40][CH2:41][NH:42][CH3:43]>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:42]([CH2:41][CH2:40][O:39][CH3:38])[CH3:43])[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CNCCOC
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1
Product: COCCN(C)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCOCC4)c3)c3ccccc23)n1

Procedure:
Compound is prepared from 3-fluoro-N-(4-{[2-(methylsulfonyl)pyrimidin-4-yl]oxy}-1-naphthyl)-5-morpholin-4-ylbenzamide and (2-methoxy-ethyl)-methylamine according to conditions described in general procedure C. Mp: 96-98° C.; 1H NMR (400 MHz, DMSO-d6) δ 2.90-3.15 (m, 4 H), 3.27 (t, J=4.8 Hz, 4 H), 3.20-3.40 (m, 6 H), 3.77 (t, J=4.8 Hz, 4 H), 6.28 (s, 1H), 7.05 (d, J=12.4 Hz, 1H), 7.27 (d, J=8.7 Hz, 1H), 7.43-7.62 (m, 5 H), 7.82 (s, 1H), 8.00 (d, J=7.7 Hz, 1H), 8.26 (d, J=5.1Hz, 1H), 10.47 (s, 1H).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]#[N:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:12][OH:13].[OH-].[Na+]>CCO.O>[NH2:10][C:9]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:13][N:12]=1
Reactant: NO
Reactant: N#CC#Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1cc(-c2ccccc2)on1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 3-phenyl-2-propyne-nitrile (1.27 g, 0.01 mol, Step A) in EtOH (20 mL) was added at RT hydroxylamine hydrochloride (3.5 g, 0.05 mol) followed by 10% NaOH (28 mL). The exothermic reaction was stirred at RT 24 h, then diluted with H2O. The resulting precipitate was filtered off, washed with H2O and dried over P2O5 to afford 3-amino-5-phenylisoxazole as a white crystalline solid.
Reaction SMILES: [O-:1][CH2:2][CH3:3].[Na+].[Cl:5][C:6]1[C:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([CH:23]=O)[CH:17]=2)=[N:8][CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1.[CH2:25]([OH:27])[CH3:26]>C1(C)C=CC=CC=1>[Cl:5][C:6]1[C:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18](/[CH:23]=[CH:3]/[C:2]([O:27][CH2:25][CH3:26])=[O:1])[CH:17]=2)=[N:8][CH:9]=[C:10]([C:12]([F:14])([F:15])[F:13])[CH:11]=1
Reactant: O=Cc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Reactant: CCO
Reactant: CC[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)/C=C/c1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Temperature: 20 °C
Reaction time: 44 h
Yield: 71 %

Procedure:
A solution of 1.35 g of sodium ethoxide in 20 ml of anhydrous ethanol was added dropwise to 4.0 g of 3-chloro-2-(4-chloro-3-formylphenyl)-5-trifluoromethylpyridine and 2.9 g of triethyl phosphonatoacetate in 70 ml of anhydrous toluene. After stirring at about 20° C. for 44 hours, the solvent was removed. The residue was taken up in 100 ml of 10% strength hydrochloric acid and extracted three times with 100 ml of ethyl acetate each time. The combined organic phases were washed with 100 concentrated. Chromatography on silica gel with cyclohexane/ethyl acetate (10:1) resulted in 3.4 g (71%) of colorless crystals; melting point: 118°-120° C.
Reaction SMILES: [C:1]([NH:4][CH:5]([S:16][CH3:17])[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])(=[O:3])[CH3:2].[C:18](NC(OCC)C(NCC1C=CC=CC=1)=O)(=O)C.CCS>>[C:1]([NH:4][CH:5]([S:16][CH2:17][CH3:18])[C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(NC(C)=O)C(=O)NCc1ccccc1
Reactant: CSC(NC(C)=O)C(=O)NCc1ccccc1
Solvent: CCS
Product: CCSC(NC(C)=O)C(=O)NCc1ccccc1
Yield: 38 %

Procedure:
Using the procedure described for the synthesis of 2-acetamido-N-benzyl-2-(methylmercapto)acetamide, 2-acetamido-N-benzyl-2-ethoxyacetamide (2.00 g, 8.0 mmol) and EtSH (0.65 g, 10.4 mmol) were converted to 0.80 g (38%) of the desired product. The compound was further purified by recrystallization from chloroform/hexane to give a beige solid. Rf 0.60 (4% MeOH/CHCl3). mp 146°-148° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH:10]([N:12]3[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][OH:20])[CH2:14][CH2:13]3)[C:9]3[CH:21]=[C:22]([CH:25]([CH3:27])[CH3:26])[CH:23]=[CH:24][C:8]=3[S:7][C:6]=2[CH:28]=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33]([CH:37]=[C:38]([O:42][CH3:43])[C:39]=1[O:40][CH3:41])[C:34](Cl)=[O:35].O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH:10]([N:12]3[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][O:20][C:34](=[O:35])[C:33]4[CH:32]=[C:31]([O:30][CH3:29])[C:39]([O:40][CH3:41])=[C:38]([O:42][CH3:43])[CH:37]=4)[CH2:16][CH2:17]3)[C:9]3[CH:21]=[C:22]([CH:25]([CH3:26])[CH3:27])[CH:23]=[CH:24][C:8]=3[S:7][C:6]=2[CH:28]=1
Reactant: CC(C)c1ccc2c(c1)C(N1CCN(CCO)CC1)Cc1ccc(F)cc1S2
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Solvent: ClC(Cl)Cl
Solvent: O
Product: COc1cc(C(=O)OCCN2CCN(C3Cc4ccc(F)cc4Sc4ccc(C(C)C)cc43)CC2)cc(OC)c1OC
Reaction time: 8 h

Procedure:
A solution of 5.7 g of 3-fluoro-10-[4-(2-hydroxyethyl)piperazino]-8-isopropyl-10,11-dihydrodibenzo(b,f)thiepin (Example 2) in 20 ml of chloroform was treated with 5.2 g of 3,4,5-trimethoxybenzoyl chloride and after its dissolution, the mixture left overnight at room temperature. It was then decomposed with water and then diluted with chloroform and washed with an ice-cold 5% sodium hydroxide solution, dried with potassium carbonate and the chloroform evaporated. The remaining oil (8.4 g, 100%) was the crude ester which was neutralized with oxalic acid in ethanol to yield an oxalate crystallizing from aqueous ethanol and melting at 188°-192° C. with decomposition. The compound is identical with the product obtained by a different way according to Example 16.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[C:7]([CH3:12])=[N:8][NH:9][C:10]=1[CH3:11])[CH3:2].[Cl:14][C:15]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:16]=1[CH2:17]Br.C([O-])([O-])=O.[K+].[K+]>C(#N)C.CO>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[C:7]([CH3:12])=[N:8][N:9]([CH2:17][C:16]2[CH:19]=[CH:20][C:21]([N+:23]([O-:25])=[O:24])=[CH:22][C:15]=2[Cl:14])[C:10]=1[CH3:11])[CH3:2]
Reactant: CCOC(=O)Cc1c(C)n[nH]c1C
Reactant: O=[N+]([O-])c1ccc(CBr)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Product: CCOC(=O)Cc1c(C)nn(Cc2ccc([N+](=O)[O-])cc2Cl)c1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 88.3 %

Procedure:
To a solution of (3,5-dimethyl-1H-pyrazol-4-yl)acetic acid ethyl ester (1.40 g, 7.7 mmol) and 2-chloro-4-nitrobenzyl bromide (4.60 g, 20.7 mmol) in 20 mL acetonitrile is added K2CO3 (1.59 g, 11.5 mmol) and the mixture is stirred for 48 hours at room temperature. The solvent is removed by evaporation and the residue is dissolved in dichloromethane/water. After extraction with dichloromethane the organic layer is dried over Na2SO4 and evaporated under reduced pressure to yield 2.79 g of [3,5-dimethyl-1-(2-chloro-4-nitro-benzyl)-1H-pyrazol-4-yl]-acetic acid ethyl ester (ESI mass spectrum: [M+H]+=352; Retention time: 1.95 min (method A). b) To a solution [3,5-dimethyl-1-(2-chloro-4-nitrobenzyl)-1H-pyrazol-4-yl]acetic acid ethyl ester (2.39 g, 6.8 mmol) in methanol (40 mL) is added Raney nickel (250 mg) and the mixture is hydrogenated. The catalyst is filtered off and the filtrate is concentrated under reduced pressure to yield 1.18 g of the title compound (ESI mass spectrum: [M+H]+=322; Retention time HPLC: 1.76 min (method A)).
Reaction SMILES: [Ge:1](Cl)([Cl:4])([Cl:3])[Cl:2].C([SiH2]O[Si](CC)(CC)CC)C.[C:17]([OH:21])(=[O:20])[CH:18]=[CH2:19].Cl>CCCCCC>[C:17]([OH:21])(=[O:20])[CH2:18][CH3:19].[Cl:2][GeH:1]([Cl:4])[Cl:3]
Reactant: Cl[Ge](Cl)(Cl)Cl
Reactant: C=CC(=O)O
Agent: CC[SiH2]O[Si](CC)(CC)CC
Agent: Cl
Solvent: CCCCCC
Product: CCC(=O)O
Product: Cl[GeH](Cl)Cl
Temperature: 25 °C
Reaction time: 168 h

Procedure:
To a 2 L round bottom flask purged with argon was added successively: germanium tetrachloride (200 g [0.9346 mol]), tetraethyl disiloxane (125 g[0.93 mol]), and acrylic acid (70.0 g[0.97 mol]). The reaction flask was purged with argon then sealed by placement of a ground glass stopper with a teflon sleeve and secured via teflon tape. The slightly cloudy mixture changed to a clear, colorless homogeneous solution within about 2 hours, and this was stirred for seven days at ambient temperature. The volatile components were removed via vacuum (0.5 to 5 mmHg) while the product mixture was heated to an internal temperature of 70°-C.-80° C., where it was a homogeneous, clear and colorless viscous solution (melt). Evacuation was continued until no more distillate was observed (ca. 2 hours). This was cooled to an ambient temperature to yield a white amorphous solid. To this was added 950 mL of concentrated HCl. The resulting heterogeneous mixture was warmed to an internal temperature of 60° C.-70° C., and stirred for four hours. The cooled mixture was extracted 3 times with 500 mL of dichloromethane. The combined extracts were evaporated under reduced pressure via rotary evaporator to give a white amorphous solid. This was dissolved in ca. 1 L boiling hexane (until a clear colorless homogeneous hot solution was obtained), and let cool gently to ambient temperature. The product, trichlorogermane propionic acid, was isolated via suction filtration, washed once with hexane to give fine prisms, mp 75° C.-79° C. (a range of mp 75° C.-90° C. would be acceptable). This was immediately taken up (vigorous reaction), with careful addition of 850 mL of ammonium hydroxide (29% ammonia). The resulting turbid mixture was stirred for 4 days at ambient temperature (the mixture changes to a clear, colorless homogeneous solution within 3 hours). To this homogeneous solution was added dropwise over two hours through a reflux condenser 400 mL of concentrated sulfuric acid. NOTE: This is a very vigorous reaction and should be handled with extreme care. A white precipitate formed after addition of ca. 375 mL of acid. The pot was stirred for 48 hours, and then the white solid was isolated via suction filtration, washed successively with 2×150 mL water, 1×150 mL acetone, and 1×200 mL of dimethyl ether, then this brilliant white solid was air dried overnight, and then taken up with 150 mL hot water (~80° C.), when it was stirred for about 1 hour, then cooled to ambient temperature and filtered to give a white solid. This was washed successively with 2×150 mL of water, 1×150 mL acetone and 1×150 diethyl ether to yield 78.84 g (50%) of analytically pure carboxyethyl germanium sesquioxide.
Reaction SMILES: C[O:2][C:3]([C:5]1([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Br:18])(=[O:11])=[O:10])[CH2:7][CH2:6]1)=[O:4].C1COCC1.CO.O[Li].O>O>[Br:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[S:9]([NH:8][C:5]1([C:3]([OH:4])=[O:2])[CH2:7][CH2:6]1)(=[O:10])=[O:11]
Reactant: COC(=O)C1(NS(=O)(=O)c2ccccc2Br)CC1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)C1(NS(=O)(=O)c2ccccc2Br)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 98 %

Procedure:
methyl-1-(2-bromophenylsulfonamido)cyclopropanecarboxylate (500 mg, 1.49 mmol) was charged, and dissolved through addition of THF (3 ml), and methanol (3 ml). LiOH.H2O dissolved in H2O (3 ml) was added thereto, followed by stirring for 12 hours at room temperature. After stirring for 12 hours, the resultant solution was vacuum-evaporated, acidified with 2N—HCl to pH 2-3, and extracted with EA (×2). The organic layer was dried with MgSO4, and filtered. Through vacuum distillation, the solvent was removed so as to obtain 1-(2-bromophenylsulfonamido)cyclopropanecarboxylic acid (469 mg, 1.46 mmol, 98%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:18]=[C:17]([NH2:19])[CH:16]=[C:6]([C:7]([N:9]([CH2:13][CH2:14][CH3:15])[CH2:10][CH2:11][CH3:12])=[O:8])[CH:5]=1.N1C=CC=CC=1.[Cl:27][CH2:28][CH2:29][CH2:30][S:31](Cl)(=[O:33])=[O:32]>CN(C1C=CN=CC=1)C.C(Cl)Cl.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:18]=[C:17]([NH:19][S:31]([CH2:30][CH2:29][CH2:28][Cl:27])(=[O:33])=[O:32])[CH:16]=[C:6]([C:7]([N:9]([CH2:10][CH2:11][CH3:12])[CH2:13][CH2:14][CH3:15])=[O:8])[CH:5]=1
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CCCN(CCC)C(=O)c1cc(N)cc(C(=O)OC)c1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCN(CCC)C(=O)c1cc(NS(=O)(=O)CCCCl)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.9 %

Procedure:
A solution of 5-amino-N,N-dipropyl-isophthalamic acid methyl ester (D88) (1.4 g, 5.0 mmol, 1 equiv), DMAP (100 mg) and pyridine (392 mg, 5.0 mmol, 1.1 equiv) in CH2Cl2 (20 ml) was treated dropwise with 3-chloropropane-1-sulfonyl chloride (946 mg, 5.3 mmol, 1.1 equiv). The resulting mixture was stirred for 16 h at room temperature and then diluted with AcOEt (100 ml). The resulting solution was washed with 2N aqueous HCl solution (50 ml) followed by saturated aqueous NaHCO3 solution (50 ml), dried over MgSO4 and concentrated in vacuo. The residue was triturated with Et2O to give 5-(3-chloro-propane-1-sulfonylamino)-N,N-dipropyl-isophthalamic acid methyl ester (D91) (1.8 g, 86%) as a pink solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10]C(OCCOS(C3C=CC(C)=CC=3)(=O)=O)=C[CH:13]=2)[C:8]([S:29]([C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=[CH:34][CH:33]=2)(=[O:31])=[O:30])=[N:7]1.[CH2:45]1[CH2:49][O:48][CH2:47][CH2:46]1.[CH3:50][NH:51][CH3:52]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:47]([O:48][CH2:49][CH2:45][N:51]([CH3:52])[CH3:50])=[CH:46][CH:13]=2)[C:8]([S:29]([C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:35]=[CH:34][CH:33]=2)(=[O:31])=[O:30])=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)OCCOc2ccc3c(c2)c(S(=O)(=O)c2cccc4ccccc24)nn3Cc2cccc(Cl)c2)cc1
Reactant: C1CCOC1
Reactant: CNC
Product: CN(C)CCOc1ccc2c(c1)c(S(=O)(=O)c1cccc3ccccc13)nn2Cc1cccc(Cl)c1
Temperature: 25 °C
Yield: 94.6 %

Procedure:
A solution of toluene-4-sulfonic acid 2-[1-(3-chloro-benzyl)-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl ester (0.344 g, 0.532 mmol) in 2.0 M dimethylamine in THF (8.0 mL, 16.0 mmol) was stirred at 70° C. in a sealed tube for 2 hours. After cooling to ambient temperature, the reaction mixture was solvent evaporated. It was partitioned with ethyl acetate and aqueous sodium bicarbonate. The organic phase was washed with brine, dried with anhydrous magnesium sulfate, filtered and concentrated. Drying at 80° C. in vacuo for 20 minutes gave {2-[1-(3-chloro-benzyl)-3-(naphthalene-1-sulfonyl)-1H-indazol-5-yloxy]-ethyl}-dimethyl-amine as a dark yellow gum (0.261 g, 94.6%). This was dissolved in chloroform, and ethereal hydrochloride was added. The mixture was concentrated and dried in vacuo at 82° C. for 14 hours. The result was the hydrochloride as a light orange foam (0.252 g); Mass Spectrum (+EI, [M+H]+) m/z 520. 1HNMR (500 MHz, DMSO-d6): δ9.92-9.94 (br, s, 1H), 8.73-8.75 (m, 1H), 8.56 (dd, 1H, J=7.32 Hz and 1.10 Hz), 8.27 (d, 1H, J=8.29 Hz), 8.02-8.05 (m, 1H), 7.82 (d, 1H, J=9.15 Hz), 7.70-7.74 (m, 1H), 7.58-7.64 (m, 2H), 7.31 (d, 1H, J=2.32 Hz), 7.15-7.27 (m, 3H), 7.04 (d, 1H, J=7.68 Hz), 5.73 (s, 2H), 4.34-4.37 (m, 2H), 3.47-3.49 (m, 2H), 2.81 ppm (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:36])=[C:6]([CH:35]=1)[O:7][CH2:8][C:9]1[C:10]([C:23]2[CH:28]=[C:27]([C:29](OC)=[O:30])[CH:26]=[CH:25][C:24]=2[O:33][CH3:34])=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]([CH3:19])[C:16](=[O:20])[C:15]([CH3:22])([CH3:21])[NH:14]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C.O>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:36])=[C:6]([CH:35]=1)[O:7][CH2:8][C:9]1[C:10]([C:23]2[CH:28]=[C:27]([CH2:29][OH:30])[CH:26]=[CH:25][C:24]=2[O:33][CH3:34])=[CH:11][CH:12]=[C:13]2[C:18]=1[N:17]([CH3:19])[C:16](=[O:20])[C:15]([CH3:22])([CH3:21])[NH:14]2
Reactant: COC(=O)c1ccc(OC)c(-c2ccc3c(c2COc2cc(F)ccc2C)N(C)C(=O)C(C)(C)N3)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(CO)cc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Reaction time: 0.5 h
Yield: 47 %

Procedure:
8-(5-Fluoro-2-methylphenoxymethyl)-7-(2-methoxy-5-methoxycarbonylphenyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Compound No. 6-37, 50.2 mg, 0.102 mmol) was dissolved in anhydrous tetrahydrofuran (0.5 ml), and lithium aluminum hydride (6.8 mg, 0.18 mmol) was added thereto at 0° C. After the reaction mixture was stirred at same temperature for 30 minutes, ethyl acetate (1 mL) and water (1 mL) were added thereto successively. Moreover ethyl acetate (10 mL) and water (10 mL) were added and partitioned. The organic layer was washed with saturated brine (10 mL), dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (29.8 mg) as a pale yellow solid. (Yield 47%)
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=O)[CH:9]=2)[NH:4][N:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21](=O)[CH2:22][C:23]#[N:24])=[CH:17][CH:16]=1.[NH2:26][C:27]([CH3:31])=[CH:28][C:29]#[N:30]>C(O)CCCC.C(#N)C>[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[NH:26][C:27]([CH3:31])=[C:28]([C:29]#[N:30])[CH:11]([C:8]3[CH:9]=[C:10]4[C:5](=[CH:6][CH:7]=3)[NH:4][N:3]=[C:2]4[CH3:1])[C:22]=2[C:23]#[N:24])=[CH:17][CH:16]=1
Reactant: Cc1n[nH]c2ccc(C=O)cc12
Reactant: CC(N)=CC#N
Reactant: COc1ccc(C(=O)CC#N)cc1
Solvent: CCCCCO
Solvent: CC#N
Product: COc1ccc(C2=C(C#N)C(c3ccc4[nH]nc(C)c4c3)C(C#N)=C(C)N2)cc1
Temperature: 105 °C

Procedure:
A mixture of 250 mg (1.56 mmol) 3-methyl-1H-indazole-5-carbaldehyde (Example 1A), 328 mg (1.88 mmol) 3-(4-methoxyphenyl)-3-oxopropanenitrile and 128 mg (1.56 mmol) 3-aminobut-2-enenitrile in 1-pentanol (1.55 ml) containing powdered 4 Å molecular sieve was heated to 105° C. overnight. After cooling, the reaction mixture was diluted with acetonitrile and directly purified by preparative RP-HPLC (acetonitrile/water+0.1% TFA gradient) to afford 180 mg (30% of th.) of the racemic title compound.