Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C@H:9]1[C@H:15]([O:16]CC2C=CC=CC=2)[C@@H:14]([O:24]CC2C=CC=CC=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([F:49])[C:42]=4[F:50])[CH:34]=3)[O:32][C@@:10]1([CH:51]([OH:53])[CH3:52])[CH2:11][O:12]2)C1C=CC=CC=1.ClC1C=CC=CC=1Cl>[Pd].CO.O1CCCC1>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@@:13]23[O:32][C@@:10]([CH:51]([OH:53])[CH3:52])([CH2:11][O:12]2)[C@@H:9]([OH:8])[C@H:15]([OH:16])[C@H:14]3[OH:24])=[CH:34][C:35]=1[CH2:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([F:49])[C:42]=1[F:50]
Reactant: COc1ccc(Cc2cc([C@]34OC[C@](C(C)O)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)c(F)c1F
Agent: [Pd]
Solvent: Clc1ccccc1Cl
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(Cc2cc([C@]34OC[C@](C(C)O)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)c(F)c1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 39.9 %

Procedure:
To a solution of 1-[(1R,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(2,3-difluoro-4-methoxy-phenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]ethanol 21q (136 mg, 0.18 mmol) in a methanol/tetrahydrofuran mixture (v/v=4/1, 10 mL) were added o-dichlorobenzene (0.1 mL, 0.87 mmol) and 10% Pd/C (20 mg, 0.02 mmol) in turn at room temperature. The mixture was stirred at room temperature for 4 hours under H2 and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=10/1 to give the title compound 21 as colourless oil (34 mg, 39.3%, HPLC: 97.27%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 517.2 [M+HCOO]−; and 1H NMR (400 MHz, DMSO-d6) δ(ppm): 7.43 (d, 1H), 7.40-7.23 (m, 2H), 6.96 (m 1H), 6.87 (m, 1H), 5.33 (s, 1H), 4.93 (s, 2H), 4.58 (s, 1H), 4.05 (s, 2H), 3.98 (d, 1H), 3.84 (s, 3H), 3.76 (d, 1H), 3.53 (d, 1H), 3.42 (m, 3H), 1.18-1.13 (d, 3H).
Reaction SMILES: C(O[C:6](=[O:33])[N:7]([CH2:9][CH2:10][NH:11][C:12]([C:14]1[N:15]=[CH:16][C:17]2[C:18](=[O:32])[N:19]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:20]=[CH:21][C:22]=2[C:23]=1[OH:24])=[O:13])[CH3:8])(C)(C)C.[F:34][C:35]([F:40])([F:39])C(O)=O.C(N(CC)CC)C.FC(F)(F)C(OCC)=O>C(Cl)Cl.C1COCC1>[CH3:8][N:7]([C:6](=[O:33])[C:35]([F:40])([F:39])[F:34])[CH2:9][CH2:10][NH:11][C:12]([C:14]1[N:15]=[CH:16][C:17]2[C:18](=[O:32])[N:19]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:20]=[CH:21][C:22]=2[C:23]=1[OH:24])=[O:13]
Reactant: O=C(O)C(F)(F)F
Reactant: CN(CCNC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O)C(=O)OC(C)(C)C
Agent: CCOC(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(CCNC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
{2-[(7-Benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carbonyl)-amino]-ethyl}-methyl-carbamic acid tert-butyl ester (25 mg, 0.055 mmol) was dissolved in CH2Cl2 (1.5 mL). Trifluoroacetic acid (1 mL) was added, and the mixture was stirred at r.t. for 2 h. Solvent and excess TFA were removed in vacuo. To the residue were added THF (3 mL), triethylamine (0.040 mL, 0.28 mmol), and ethyl trifluoroacetate (2 mL), and the resulting mixture was refluxed for 16 h. The mixture was concentrated to dryness, and the residue was dissolved in EtOAc and washed with 1 M HCl. The organic layers were dried over MgSO4 and concentrated. The crude product was purified by silica gel chromatography (0-5% MeOH/CH2Cl2) to give 5.4 mg of the title compound as a white solid. MS: (+) m/z 449.29 (M+1).
Reaction SMILES: Cl.N=[C:3]1[NH:7][C@@H:6]([CH2:8][CH2:9][CH2:10][C:11]2[O:12][CH:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:15]=2)[C@@H:5]([C:21]([F:24])([F:23])[F:22])[CH2:4]1.[SiH](CC)(CC)CC.C(O)(C(F)(F)F)=[O:33].C(Cl)Cl>>[O:33]=[C:3]1[NH:7][CH:6]([CH2:8][CH2:9][CH2:10][C:11]2[O:12][CH:13]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:15]=2)[CH:5]([C:21]([F:24])([F:23])[F:22])[CH2:4]1
Reactant: CCOC(=O)c1coc(CCC[C@@H]2NC(=N)C[C@@H]2C(F)(F)F)n1
Reactant: O=C(O)C(F)(F)F
Agent: CC[SiH](CC)CC
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)c1coc(CCCC2NC(=O)CC2C(F)(F)F)n1
Reaction time: 0.5 h

Procedure:
Isomer B: (±)ethyl (cis) 2-[3-[5-imino-3-(trifluoromethyl)pyrrolidin-2-yl]propyl]oxazole-4-carboxylate, monohydrochloride ##STR230## 225A) To a stirring solution of the product of Example 224 B (5 mmol) in 10 mL of 10% TFA/DCM is added Et3SiH (7.5 mmol). After stirring for 30 min, the solvent is removed under vacuum and the residue is purified by column chromatography to provide ethyl 2-[3-[5-oxo-3-(trifluoromethyl)pyrrolidin-2-yl]propyl]oxazole-4-carboxylate.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+:11]([O-])([OH:13])=[O:12]>S(=O)(=O)(O)O>[I:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1ccccc1I
Agent: O=S(=O)(O)O
Product: O=C(O)c1cc([N+](=O)[O-])ccc1I
Temperature: 80 °C

Procedure:
2-Iodobenzoic acid (100 g) was dissolved in 400 mL of concentrated sulphuric acid and placed in a 2 liter 3 necked flask. The flask was fitted with reflux condenser, a thermometer and an addition funnel. Fuming nitric acid (400 ml) was added drop by drop. The addition was adjusted in such a way that the temperature was allowed to raise to 80° C. over a period of 2 hours. During the addition, the reaction mixture was stirred vigorously and maintained the temperature at 80° C. for an additional 2 hours. After the completion of the reaction, the reaction mixture was poured slowly into crushed ice (3 Kg). The contents were allowed to settle and were filtered. The yellow precipitate was collected and dried at 30° C. The yield was 90 grams.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11].[H-].[Na+].Br[CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>CN(C=O)C>[C:27]([O:26][C:24]([CH2:23][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: O=C(OCc1ccccc1)c1cc2ccccc2[nH]1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Cn1c(C(=O)OCc2ccccc2)cc2ccccc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
50.25 g of benzyl 2-indolecarboxylate (Preparation 2.1, step A) are dissolved in 140 ml of anhydrous DMF, followed by addition over 30 minutes, under a stream of dry nitrogen, of a solution of 6.6 g of NaH at 80% in oil, in 100 ml of DMF. The reaction medium is stirred for 90 minutes at RT and is then cooled on an ice bath and 42.91 ml of tert-butyl bromoacetate are added dropwise. After stirring at RT overnight, the DMF is evaporated off and the residue is taken up in DCM and then in water. After stirring, the phases are separated by settling and the aqueous phase is then extracted twice-with DCM; the combined organic phases are washed with saturated NaCl solution and then dried over MgSO4. After filtration and evaporation, the residue is taken up in a mixture of 100 ml of ethyl ether and 100 ml of heptane. After stirring for 2 hours, the crystals formed are filtered off and then washed with 50 ml of a heptane/ethyl ether mixture (70/30; v/v) and dried in an oven. 58 g of the expected product are obtained: m.p. 95-96° C.
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].CC(C)([O-])C.[K+].[CH2:18]([N:20]1[C:24]2=[N:25][C:26]([CH:43]=O)=[C:27]([CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:28]([C:29]3[CH:30]=[N:31][CH:32]=[C:33]([CH3:35])[CH:34]=3)=[C:23]2[CH:22]=[N:21]1)[CH3:19]>C1COCC1.O>[C:1](/[CH:3]=[CH:43]/[C:26]1[N:25]=[C:24]2[N:20]([CH2:18][CH3:19])[N:21]=[CH:22][C:23]2=[C:28]([C:29]2[CH:30]=[N:31][CH:32]=[C:33]([CH3:35])[CH:34]=2)[C:27]=1[CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])#[N:2]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CCOC(=O)CCc1c(C=O)nc2c(cnn2CC)c1-c1cncc(C)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CCc1c(/C=C/C#N)nc2c(cnn2CC)c1-c1cncc(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a suspension of diethyl (cyanomethyl)phosphonate (17.4 mg) in THF (0.5 ml) was added potassium tert-butoxide (11.3 mg) at 0° C. and the mixture was stirred at room temperature for 30 minutes. A solution of ethyl 3-[1-ethyl-6-formyl-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]propanoate (20 mg) in THF (0.5 ml) was added at 0° C. and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, brine, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by preparative thin layer chromatography eluting with a mixture of EtOAc and n-hexane (1:1) to give ethyl 3-[6-[(E)-2-cyanovinyl]-1-ethyl-4-(5-methyl-3-pyridyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]propanoate (17 mg) as a colorless crystal.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.C(Cl)(Cl)(Cl)Cl.CCN(C(C)C)C(C)C.[P:27]([O-:44])([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C(#N)C.CN(C1C=CN=CC=1)C>[CH2:29]([O:28][P:27]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1)([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:44])[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Reactant: COC(=O)Cc1ccc(O)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Product: COC(=O)Cc1ccc(OP(=O)(OCc2ccccc2)OCc2ccccc2)cc1
Reaction time: 0.17 h
Yield: 88.5 %

Procedure:
To a solution of methyl 2-(4-hydroxyphenyl)acetate (1.89 g, 11.4 mmol) in acetonitrile (90 mL) at −10° C. was added CCl4 (5.5 mL, 57 mmol), DIPEA (4.16 mL, 23.9 mmol) and DMAP (139 mg, 1.14 mmol). After stirring for 10 mins, the mixture was added dibenzyl phosphite (3.7 mL, 16.5 mmol) slowly to keep the temperature below −10° C. The reaction was stirred at −10° C. for 1 h. The reaction was quenched with aqueous K2HPO4 (0.5 M) in acetonitrile (60 mL) and allowed to stirred at rt. The mixture was extracted by ethyl acetate (150 mL×3). The combined organic layers was washed with water and brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was subjected to ISCO (30-50% AcOEt/hexanes) to give the title compound (4.3 g, 88.5% yield) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5](O)=[O:6].C(Cl)(=O)C(Cl)=O.[CH3:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:18]=1>ClCCl.CN(C=O)C.C(OCC)(=O)C>[F:1][C:2]([F:9])([F:8])/[CH:3]=[CH:4]/[C:5]([N:26]1[CH2:27][CH2:28][N:23]([C:19]2[CH:18]=[C:17]([CH3:16])[CH:22]=[CH:21][N:20]=2)[CH2:24][CH2:25]1)=[O:6]
Reactant: O=C(O)/C=C/C(F)(F)F
Reactant: Cc1ccnc(N2CCNCC2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccnc(N2CCN(C(=O)/C=C/C(F)(F)F)CC2)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
(E)-4,4,4-Trifluorobut-2-enoic acid (28 mg, 0.2 mmol) was dissolved in dichloromethane (1 ml), oxalyl chloride (20 μl, 0.2 mmol) was added and the resulting solution was stirred at room temperature for 5 minutes. This solution was added to a solution of 1-(4-methyl-2-pyridyl)piperazine (36 mg, 0.2 mmol) and TEA (42 μl, 0.3 mmol) in anhydrous DMF (0.5 ml) and the resulting mixture was stirred at room temperature for one hour. The mixture was diluted with ethyl acetate, washed with sat. sodium bicarbonate solution, brine, dried (magnesium sulfate) and concentrated under reduced pressure. The residue was used directly in the next step. MS (multi-mode) m/z=300.1 [M+1]+.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[N:13]=[C:14]([CH2:37][O:38][CH2:39][CH3:40])[N:15]([CH2:16][C:17]3([O:30][CH2:31][CH2:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]3)[C:11]=2[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:4]=1>C(O)C>[CH2:39]([O:38][CH2:37][C:14]1[N:15]([CH2:16][C:17]2([O:30][CH2:31][CH2:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[C:3]([NH2:2])[C:12]=2[N:13]=1)[CH3:40]
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CC1(OCCS(C)(=O)=O)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCO
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CC1(OCCS(C)(=O)=O)CCNCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 76.3 %

Procedure:
A solution of HCl in ethanol (4.2 M, 0.8 mL, 3.56 mmol) was added to a suspension of tert-butyl 4-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}-4-[2-(methylsulfonyl)ethoxy]piperidine-1-carboxylate (0.40 g, 0.71 mmol) in ethanol (4 mL) at rt. The resulting yellow solution was heated at reflux for 1.5 h. The reaction was stirred at rt for 16 h, then was concentrated under reduced pressure. The resulting solid was dissolved in water (20 mL) and 20% aqueous NaOH was added until the pH=13. The solution was extracted with dichloromethane (3×50 mL). The organic layers were combined, washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to provide a solid that was crystallized from acetonitrile. The crystals were dried under vacuum at 65° C. to provide 2-(ethoxymethyl)-1-({4-[2-(methylsulfonyl)ethoxy]piperidin-4-yl}methyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.25 g, 76%) as crystalline plates, mp 212-214° C. 1H NMR (300 MHz, DMSO-d6) δ 8.26 (d, J=8.1 Hz, 1H), 7.61 (d, J=8.1 Hz, 1H), 7.44 (t, J=8.1 Hz, 1H), 7.26 (t, J=8.1 Hz, 1H), 6.61 (bs, 2H), 4.85 (s, 2H), 4.81 (s, 2H), 3.70 (t, J=5.6 Hz, 2H), 3.55 (q, J=7.5 Hz, 2H), 3.19 (t, J=5.6 Hz, 2H), 2.92 (s, 3H) 2.66-2.58 (m, 4H), 1.84 (bs, 1H), 1.70-1.66 (m, 2H), 1.48-1.38 (m, 2H), 1.16 (t, J=7.5 Hz, 3H); MS (APCI) m/z 462 (M+H)+; Anal. Cacld for C22H31N5O4S: C, 57.25; H, 6.77: N, 15.17. Found: C, 57.48; H, 7.05; N, 15.57.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10](OC)[CH:9]=[CH:8][C:3]=1[C:4](OC)=O.[C:14]1([CH3:20])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N#N>CCN(CC)CC.CCOC(C)=O.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:3]1([C:4]#[C:20][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:2]=1
Reactant: Cc1ccccc1
Reactant: COC(=O)c1ccc(OC)cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: N#N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C(#Cc1ccccc1)c1ccccc1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
Compound 11 (106 mg, 0.43 mmol) and copper (I) iodide (1.6 mg, 2 mol %) were added to an oven-dried reaction flask containing toluene (2 mL) and Et3N (2 mL). The reaction mixture was stirred at room temperature for 5 min with N2 (g) bubbling. Bis(triphenylphosphine)palladium(II) dichloride (3 mg, 1 mol %) and a solution of compound 8 (63 mg, 0.43 mmol) in Et3N (1 mL) were added. The reaction mixture was stirred at 100° C. for 24 h. The reaction was cooled to room temperature, then diluted with EtOAc (50 mL) and washed with brine (3×20 mL). The organic layer was collected, dried over anhydrous Na2SO4, filtered, concentrated and purified by silica column chromatography (20% EtOAc in hexanes) to afford compound 12 in 62.8% (84 mg) yield as a brown solid. 1H-NMR (CDCl3, 400 MHz) δ 8.00 (1H, d, J=8.4 Hz, Ar), 7.14 (1H, s, Ar), 6.93 (1H, d, J=1.6 Hz, Ar), 6.88 (1H, dd, J=8.4 Hz, 1.6 Hz, Ar), 6.81 (1H, dd, J=8.4 Hz, 1.6 Hz, Ar), 6.68 (1H, d, J=8.4 Hz, Ar), 4.79 (2H, s, NH2), 3.89 (6H, s, 2×OCH3), 3.76 (3H, s, OCH3); 13C-NMR (CDCl3, 100 MHz) δ 165.9, 162.3, 151.4, 144.5, 132.8, 126.6, 122.9, 118.5, 117.9, 115.8, 115.6, 114.4, 107.6, 93.9, 92.6, 56.0, 55.7, 52.2; MS (ESI) m/z Calcd for C18H17NO4 (M+): 311.1, Found: 312.0 (M+H+).
Reaction SMILES: Cl[S:2]([N:5]=C=O)(=[O:4])=[O:3].C(O)=O.[NH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([Br:22])[CH:18]=2)[CH:13]=1.C(OCC)(=O)C>C1C=CC=CC=1>[Br:22][C:17]1[CH:16]=[CH:15][C:14]2[C:19](=[CH:20][CH:21]=[C:12]([NH:11][S:2](=[O:4])(=[O:3])[NH2:5])[CH:13]=2)[CH:18]=1
Reactant: Nc1ccc2cc(Br)ccc2c1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: O=CO
Solvent: c1ccccc1
Product: NS(=O)(=O)Nc1ccc2cc(Br)ccc2c1
Temperature: 25 °C
Reaction time: 19.5 h

Procedure:
A solution of chlorosulfonyl isocyanate (870 μl, WAKO) in benzene (10 ml) was added dropwise with formic acid (377 μl, WAKO) under ice cooling, warmed to room temperature, stirred and for 19.5 hours, then warmed to 40° C., and further stirred for 4 hours. The reaction mixture was added dropwise with a solution of 2-amino-6-bromonaphthalene (443 mg) in benzene (5 ml) under ice cooling, warmed to room temperature, and stirred 21.5 hours. The reaction mixture was filtered to obtain solid, and the solid was added with ethyl acetate, mixed and filtered again. The solvent of the filtrate was evaporated under reduced pressure. The residue was purified by column chromatography (Quad, hexane:ethyl acetate=2:1) to obtain the title compound (Intermediate 66, 158 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:10][C:11]1[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=1.[F:17][C:18]([F:28])([F:27])[C:19](=O)[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:19]([C:18]([F:17])([F:27])[F:28])[NH:10][C:11]2=[N:12][NH:13][C:14]([CH3:16])=[C:15]12
Reactant: Cc1cc(N)n[nH]1
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: O=Cc1ccccc1Cl
Product: CCOC(=O)C1=C(C(F)(F)F)Nc2n[nH]c(C)c2C1c1ccccc1Cl

Procedure:
The title compound was prepared from 2-chlorobenzaldehyde, 3-amino-5-methylpyrazole and ethyl trifluoroacetoacetate in the same manner as in Example 1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[NH:12][C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].C1(C)C=CC(S(O[CH2:34][C:35]([F:38])([F:37])[F:36])(=O)=O)=CC=1.O1CCCC1>CN(C)C=O.O>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:15]3[N:16]=[CH:17][CH:18]=[CH:19][C:14]=3[C:13](=[O:20])[N:12]([CH2:34][C:35]([F:38])([F:37])[F:36])[C:11]2=[O:21])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=c1[nH]c(=O)n(-c2cccc([N+](=O)[O-])c2)c2ncccc12
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: O=c1c2cccnc2n(-c2cccc([N+](=O)[O-])c2)c(=O)n1CC(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 88.7 %

Procedure:
2.8 g of 1-(m-nitrophenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione was dissolved in 30 ml of dimethylformamide. To the solution was added 0.6 g of about 50 % sodium hydride and the whole was stirred for 20 minutes at room temperature, and then heated up to 90°C. To this was added dropwise a solution of 7.5 g of 2,2,2-trifluoroethyl p-toluenesulfonate and 20 ml of tetrahydrofuran and the mixture was reacted for 2 hours. After the reaction was complete, the solvent was removed from the resulting mixture by distillation, and to the residue obtained was added water to precipitate a crude product. This product was recrystallized from methanol to yield 3.2 g of 1-(m-nitrophenyl)-3-(2,2,2-trifluoroethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione as pale yellow prisms, melting at 228-229°C.
Reaction SMILES: [C:1]([C:4]1[S:5]C(Br)=C[CH:8]=1)(=O)[CH3:2].[Br:10][C:11]1[S:15][C:14]([C:16]([CH2:18][C:19]#[N:20])=[O:17])=[CH:13][CH:12]=1.N1CCOCC1.[S]>CC(=O)CC>[NH2:20][C:19]1[S:5][C:4]([CH3:8])=[C:1]([CH3:2])[C:18]=1[C:16]([C:14]1[S:15][C:11]([Br:10])=[CH:12][CH:13]=1)=[O:17]
Reactant: N#CCC(=O)c1ccc(Br)s1
Reactant: CC(=O)c1ccc(Br)s1
Agent: [S]
Solvent: CCC(C)=O
Solvent: C1COCCN1
Product: Cc1sc(N)c(C(=O)c2ccc(Br)s2)c1C
Yield: 51 %

Procedure:
The procedure of Example 1 was followed except that 2-acetyl-5-bromothiophene (Aldrich) was used in place of acetophenone to prepare the corresponding 2-(5-bromothiophene-2-carbonyl)acetonitrile (Steps A and B). 2-Butanone (Aldrich), 2-(5-bromothiophene-2-carbonyl)acetonitrile, morpholine, and sulfur were reacted according to the procedure of Step C, Example 1, to afford the desired compound. Yield: 51%; IR (KBr) cm−1: 3348, 1559, 1448, 1413, 1388, 1318, 1263, 974, 769; 1H NMR (CDCl3):δ 2.16 (s, 6H), 5.90 (bs, 2H), 7.02 (d, J=4 Hz, 1H), 7.11 (d, 1H, J=4 Hz); orange solid, mp: 128–130° C. (petroleum ether).
Reaction SMILES: [CH3:1][CH:2]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:13]1([CH2:19][CH2:20][CH2:21]Br)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H-].[Na+]>>[CH3:1][C:2]([CH2:21][CH2:20][CH2:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: BrCCCc1ccccc1
Reactant: CCOC(=O)C(C)C(=O)OCC
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C(C)(CCCc1ccccc1)C(=O)OCC
Yield: 79.3 %

Procedure:
In a similar manner to that described in Reference example 2(a), a reaction was carried out using diethyl 2-methylmalonate (3.48 g), 3-phenylpropyl bromide (3.98 g) and sodium hydride (55% suspension in oil, 0.96 g) and the reaction mixture was treated to afford the desired compound (4.63 g) as a syrup.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[C:12]([C:15]4[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:22][CH2:23][CH2:24]O)[CH:16]=4)[CH:11]=[C:10]([C:26]([NH:28][CH2:29][C:30]4[C:31](=[O:38])[NH:32][C:33]([CH3:37])=[CH:34][C:35]=4[CH3:36])=[O:27])[C:9]=3[CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:59].O>C(Cl)Cl>[Br:59][CH2:24][CH2:23][CH2:22][O:21][C:17]1[CH:16]=[C:15]([C:12]2[CH:11]=[C:10]([C:26]([NH:28][CH2:29][C:30]3[C:31](=[O:38])[NH:32][C:33]([CH3:37])=[CH:34][C:35]=3[CH3:36])=[O:27])[C:9]3[CH:8]=[N:7][N:6]([CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[C:14]=3[CH:13]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3cccc(OCCCO)c3)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cccc(OCCCBr)c3)cc3c2cnn3C2CCCC2)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 71.3 %

Procedure:
To a stirred solution of 1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(3-(3-hydroxypropoxy)phenyl)-1H-indazole-4-carboxamide (0.35 g, 0.68 mmol) in DCM (5 mL), triphenyl phosphine (0.285 g, 1.08 mmol) was added and the reaction mixture stirred at room temperature for 10 min Finally CBr4 (0.36 g, 1.08 mmol) was added portion wise and resulting solution was stirred at room temperature for 4 h. On completion, water was added to the reaction mixture and extracted with 5% MeOH/DCM. The combined organic layer was dried over sodium sulfate and concentrated to give crude material which was purified by column chromatography over silica gel to afford 6-(3-(3-bromopropoxy) phenyl)-1-cyclopentyl-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-indazole-4-carboxamide (0.28 g, 71%).