Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[C:6]([O:14][CH3:15])[CH:5]=1)=[O:3].[Br:16]Br>COC.C(Cl)(Cl)Cl>[Br:16][CH2:1][C:2]([C:4]1[CH:5]=[C:6]([O:14][CH3:15])[C:7]([O:12][CH3:13])=[C:8]([O:10][CH3:11])[CH:9]=1)=[O:3]
Reactant: BrBr
Reactant: COc1cc(C(C)=O)cc(OC)c1OC
Agent: COC
Solvent: ClC(Cl)Cl
Product: COc1cc(C(=O)CBr)cc(OC)c1OC
Reaction time: 1 h

Procedure:
A mixture of 3.0 g of 3,4,5-trimethoxyacetophenone in 70 ml of dimethyl ether and 30 ml of chloroform is cooled to 0° and then treated with a mixture containing 0.73 ml of bromine in 15 ml of chloroform in a dropwise manner. The reaction mixture is allowed to warm to 20°- 25° and stirred for 1 hr. The reaction mixture is partitioned between chloroform and water. The organic layer is separated, washed with dilute sodium bicarbonate, washed with saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product (4.31 g) is recrystallized from ethanol/water. The solid is isolated and dried (18 hours, 0.01 mm, 40°) to give the title compound, mp 61°-62°; IR (mineral oil) 3010, 2995, 2952, 2926, 2868, 2855, 1695, 1687, 1586, 1505, 1466, 1455, 1428, 1417, 1389, 1335, 1255, 1229, 1190, 1151, 1128, 1004, 820, 636, and 602 cm-1 ; NMR (CDCl3, TMS) 7.24, 4.43 and 3.93δ; CMR (CDCl3) 190.2, 153.1, 149.9, 143.3, 128.9, 106.5, 60.9, 56.3 and 30.4δ; MS (m/z) M+ =288, other ions at m/z 259, 228, 195, 181, 167, 152, 137, 122, 109, 77, 66 and 53.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([O:11][CH3:12])[C:3]=1[CH:4]=O.CC([O-])=O.[Na+].Cl.[NH2:19][OH:20]>CN(C=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([O:11][CH3:12])[C:3]=1[CH:4]=[N:19][OH:20]
Reactant: COc1cc(Cl)cc(Cl)c1C=O
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(Cl)cc(Cl)c1C=NO
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of 2,4-dichloro-6-methoxybenzaldehyde (2.39 mmol) in 5 mL DMF was cooled to 0° C. and NaOAc (2.63 mmol) followed by hydroxylamine HCl (2.63 mmol) were added. The ice bath was removed and the reaction mixture was stirred at RT for 10 min. The mixture was diluted with EtOAc and washed once with water and brine. The combined organic layers were dried over MgSO4 and concentrated in vacuo to give the desired compound as white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][C:12]([NH2:16])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1.Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([OH:34])([C:30]([F:33])([F:32])[F:31])[C:26]([F:29])([F:28])[F:27])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[NH2:16][C:12]1[CH:11]=[C:10]2[C:15](=[CH:14][CH:13]=1)[N:7]([CH:4]1[CH2:3][CH2:2][N:1]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]([OH:34])([C:26]([F:27])([F:28])[F:29])[C:30]([F:31])([F:32])[F:33])=[CH:23][CH:24]=3)[CH2:6][CH2:5]1)[N:8]=[CH:9]2
Reactant: Nc1ccc2c(cnn2C2CCNCC2)c1
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Nc1ccc2c(cnn2C2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)c1
Yield: 14.5 %

Procedure:
1-(Piperidin-4-yl)-1H-indazol-5-amine (4.85 mmol, 1.05 g), 2-(4-(bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (4.85 mmol, 1.636 g) and potassium carbonate (9.71 mmol, 1.342 g) were combined and stirred in acetonitrile (15 mL) at room temperature for 3 days. The reaction mixture was concentrated under vacuum. The resulting residue was purified by silica chromatography (eluting with a solvent gradient from dichloromethane to 5% methanol/dichloromethane) to afford the title compound (332 mg). MS (ESI) m/z 473.0 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:5]([OH:13])=[CH:4][CH:3]=1.Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][C:15]2[C:24]3[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=3)[N:18]=[CH:17][CH:16]=2)=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: CCOC(=O)c1cc(Cl)ccc1O
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Product: CCOC(=O)c1cc(Cl)ccc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 120 °C
Reaction time: 8 h
Yield: 14.4 %

Procedure:
Ethyl 5-chlorosalicylate (147 mg), 4-chloro-6,7-dimethoxyquinoline (165 mg), and 4-dimethylaminopyridine (270 mg) were suspended in o-dichlorobenzene (1 ml), and the suspension was stirred at 120° C. overnight. The reaction solution was cooled to room temperature, and the solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (41 mg, yield 15%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:17][CH2:16][NH:15][C@@H:14]([CH3:18])[CH2:13]2)=[N:4][N:3]=1.C(N(CC)CC)C.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])(O)=O.[Na+]>ClCCl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:17][CH2:16][N:15]([C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:33])[C@@H:14]([CH3:18])[CH2:13]2)=[N:4][N:3]=1
Reactant: C[C@H]1CN(c2nnc(Cl)c3ccccc23)CCN1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H]1CN(c2nnc(Cl)c3ccccc23)CCN1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-1-chloro-4-(3-methylpiperazin-1-yl)phthalazine (3.64 g, 13.9 mmol) was dissolved in dry dichloromethane (30 mL) and triethylamine (4.26 mL, 30.6 mmol). Benzoyl chloride (1.77 mL, 15.3 mmol) was added and stirred at rt for 1 hour. The reaction was added to saturated NaHCO3 (150 mL) and the aqueous layer was extracted with 3× dichloromethane. The combined organics were dried (MgSO4) and evaporated to give a yellow oil. Chromatography over silica gel with a gradient of hexanes/30-100% ethyl acetate gave an off-white solid. MS (M+H)+=367.1.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][CH2:10][O:11]C(=O)C)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].OS(O)(=O)=O>C(O)C>[CH2:6]([O:5][P:4]([CH2:9][CH2:10][OH:11])(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCOP(=O)(CCOC(C)=O)OCC
Agent: O=S(=O)(O)O
Solvent: CCO
Product: CCOP(=O)(CCO)OCC
Yield: 78.8 %

Procedure:
100 g of 2-acetoxyethane phosphonic acid diethyl ester are heated to 80°C jointly with 200 ml of ethanol. To this solution are added dropwise within 5 hours 20 ml of ethanol containing 1 wt.% of H2SO4 while simultaneously removing by continuous distillation a mixture of ethylacetate and ethanol. The residue is submitted to distillation under reduced pressure. 64 g of 2-hydroxyethane-phosphonic acid diethyl ester are obtained, corresponding to a yield of 80% of the theoretical.
Reaction SMILES: [CH:1]1([C:4]([NH:6][NH2:7])=[O:5])[CH2:3][CH2:2]1.[Cl:8][C:9]1[C:10]([Cl:18])=[N:11][CH:12]=[C:13]([CH:17]=1)[C:14](Cl)=[O:15].Cl>[OH-].[Na+].C(COC)OC>[CH:1]1([C:4]([NH:6][NH:7][C:14]([C:13]2[CH:12]=[N:11][C:10]([Cl:18])=[C:9]([Cl:8])[CH:17]=2)=[O:15])=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(Cl)c1cnc(Cl)c(Cl)c1
Reactant: NNC(=O)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: O=C(NNC(=O)C1CC1)c1cnc(Cl)c(Cl)c1
Temperature: 0 °C
Yield: 34.5 %

Procedure:
A mixture of cyclopropanecarboxylic acid hydrazide (1.6 g, 16 mmol) in 5% aqueous sodium hydroxide (50 mL) was cooled to 0° C. with stirring and a solution of 5,6-dichloronicotinoyl chloride (3.1 g, 14.8 mmol) in dimethoxyethane (10 mL) added over 20 minutes. This was stirred at room temperature overnight, acidified to pH 3-4 with 1N hydrochloric acid and filtered. The resulting tan solid was dried to give the desired product (1.4 g, 35%).
Reaction SMILES: [CH3:1][N:2]([CH3:23])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([C:14]2[NH:22][C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[CH:15]=2)=[CH:10][CH:11]([CH3:13])[CH3:12])[CH:4]=1.[H][H]>CO.O1CCCC1.[Pd]>[CH3:23][N:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]([C:14]2[NH:22][C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[CH:15]=2)[CH2:10][CH:11]([CH3:13])[CH3:12])[CH:4]=1
Reactant: CC(C)C=C(c1cccc(N(C)C)c1)c1cc2cccnc2[nH]1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)CC(c1cccc(N(C)C)c1)c1cc2cccnc2[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.1 %

Procedure:
A solution of N,N-dimethyl-3-(3-methyl-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)but-1-enyl)benzenamine (1.6 g, 5.2 mmol) in methanol (40 mL) and tetrahydrofuran (40 mL) was treated with 10% palladium on carbon (320 mg). The reaction was stirred for 16 h at 25° C. under a balloon filled with hydrogen gas. At this time, the reaction mixture was filtered through a pad of celite and washed with tetrahydrofuran (2×20 mL). The filtrate was concentrated in vacuo. Silica gel column chromatography (30 g, petroleum ether/ethyl acetate 8:1) afforded N,N-dimethyl-3-(3-methyl-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)butyl)benzeneamine (1.2 g, 75%) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ ppm 9.54 (br. s., 1H), 8.14 (d, 1H, J=4.5 Hz), 7.78 (d, 1H, J=7.8 Hz), 7.15 (t, 1H, J=7.2 Hz), 7.03 (dd, 1H, J1=7.8 Hz, J2=4.8 Hz), 6.64-6.57 (m, 3H), 6.30 (s, 1H), 4.12 (t, 1H, J=8.1 Hz), 2.89 (s, 6H), 2.09-1.81 (m, 2H), 1.61-1.52 (m, 1H), 0.96 (s, 3H), 0.93 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:12]3[CH:17]=[CH:16][N+:15]([O-:18])=[CH:14][CH:13]=3)[N:9]=[C:10](I)[C:3]=12.[CH3:19][O:20][C:21]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:23][C:22]=1[NH:36][C:37]([C:39]1[N:40]([CH3:48])[C:41]2[C:46]([CH:47]=1)=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:38].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:12]3[CH:17]=[CH:16][N+:15]([O-:18])=[CH:14][CH:13]=3)[N:9]=[C:10]([C:25]3[CH:24]=[CH:23][C:22]([NH:36][C:37]([C:39]4[N:40]([CH3:48])[C:41]5[C:46]([CH:47]=4)=[CH:45][CH:44]=[CH:43][CH:42]=5)=[O:38])=[C:21]([O:20][CH3:19])[CH:26]=3)[C:3]=12
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: Nc1ncnc2c1c(I)nn2-c1cc[n+]([O-])cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cc(-c2nn(-c3cc[n+]([O-])cc3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reaction time: 18 h
Yield: 71.4 %

Procedure:
A suspension of 4-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-pyridiniumolate (0.500 g, 0.0014 mol) in dimethoxyethane (15 mL) and water (30 mL) was reacted with N2-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-methyl-1H-2-indolecarboxamide (0.631 g, 0.00155 mol), sodium carbonate (0.374 g, 0.0035 mol) and tetrakis(triphenylphosphine)palladium (0) (0.163 g, 0.00014 mol) at 80° C. for 18 hours. The solid was filtered and washed with water. The solid was slurried in ethyl acetate for 18 hours and filtered, washing with ethyl acetate. The solid was dried in vacuo to give crude 4-[4-amino-3-(3-methoxy-4-[(1-methyl-1H-2-indolyl)-carbonyl]aminophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-pyridiniumolate (0.523 g, 0.0010 mol) as a brown solid:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][F:29])=[CH:22][N:21]=1)[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:42]>ClCCl>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:10][C@H:11]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][F:29])=[CH:22][N+:21]=1[O-:42])[C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(OCCF)cn1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](C[C@H](Cc1ccc(OCCF)c[n+]1[O-])C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
To a solution of 350 mg di-tert-butyl (4R)—N-(tert-butoxycarbonyl)-4-{[5-(2-fluoroethoxy)pyridin-2-yl]methyl}-L-glutamate (0.68 mmol; see Example 17d) in dichloromethane (5 mL) was added 185 mg meta-chloro peroxybenzoic acid (70%), and the mixture was stirred for 1 h at room temperature. The mixture was extracted with aqueous sodium bicarbonate, followed by re-extraction of the aqueous layer with dichloromethane. The combined organic layers were concentrated in vacuo, and the residue was purified by preparative HPLC (Method D) to give 340 mg of the target compound (93% yield).
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[C:45]([O:49][C:50]([NH:52][C@H:53]1[CH2:57][CH2:56][CH2:55][C@H:54]1[C:58](O)=[O:59])=[O:51])([CH3:48])([CH3:47])[CH3:46]>C(Cl)Cl.C(Cl)(Cl)Cl>[C:45]([O:49][C:50](=[O:51])[NH:52][C@@H:53]1[CH2:57][CH2:56][CH2:55][C@@H:54]1[C:58]([N:21]1[CH2:22][CH2:23][CH:18]([N:4]([CH:1]2[CH2:3][CH2:2]2)[S:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)(=[O:6])=[O:7])[CH2:19][CH2:20]1)=[O:59])([CH3:48])([CH3:46])[CH3:47]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@H]1C(=O)O
Reactant: O=S(=O)(c1cccc(C(F)(F)F)c1)N(C1CCNCC1)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N[C@@H]1CCC[C@@H]1C(=O)N1CCC(N(C2CC2)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.2 %

Procedure:
N-Cyclopropyl-N-piperidin-4-yl-3-trifluoromethyl-benzenesulfonamide (0.372 g, 1.1 mmol), HOBt (0.145 g, 1.1 mmol), EDCI (0.246 g, 1.32 mmol) and rac-cis-2-(tert-butoxycarbonylamino)-cyclopentanecarboxylic acid (0.275 g, 1.2 mmol) were dissolved in 5 ml of dry CH2Cl2. The mixture allowed to stir at room temperature for 12 hours. The reaction mixture was diluted with 30 ml of CHCl3 and washed with 10 ml of H2O. The organic layer was dried over MgSO4 and concentrated to dryness. The crude product was purified through a column of silica gel with a gradient of 30% to 70% EtOAc in hexane to afford the rac-((1R,2S)-2-{4-[cyclopropyl-(3-trifluoromethyl-benzenesulfonyl)-amino]-piperidine-1-carbonyl}-cyclopentyl)-carbamic acid tert-butyl ester (592 mg, 99%).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Li:10]CCCC>>[CH:1]1([Li:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: C1=Cc2ccccc2C1
Reactant: [Li]CCCC
Product: [Li]C1C=Cc2ccccc21

Procedure:
Indene was reacted with BuLi to form indenyl lithium, which compound was reacted with methyl iodide to form 1-methylindene. Use was made of: 18.2 grams of indene, 100 ml of n-Buli solution, 22.0 grams of methyl iodide.
Reaction SMILES: [NH2:1][C:2]1[CH2:7][CH:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:5][C:4](=[O:14])[CH:3]=1.[C:15](O)(=[O:18])[CH:16]=[CH2:17]>C(Cl)(Cl)Cl>[CH2:8]([CH:6]1[CH2:7][C:2]2[NH:1][C:15](=[O:18])[CH2:16][CH2:17][C:3]=2[C:4](=[O:14])[CH2:5]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: C=CC(=O)O
Reactant: CCCCCCC1CC(=O)C=C(N)C1
Solvent: ClC(Cl)Cl
Product: CCCCCCC1CC(=O)C2=C(C1)NC(=O)CC2
Temperature: 140 °C
Reaction time: 2 h
Yield: 52.2 %

Procedure:
The obtained 3-amino-5-n-hexyl-2-cyclohexene-1-one (16.8 g) and acrylic acid (12.4 g) were mixed, and the mixture was stirred at 140° C. for 2 hours. After completion of the reaction, chloroform was added, and the mixture was washed with sodium bicarbonate water, water and aqueous NaCl solution in this order, followed by drying over sodium sulfate. A crude product was obtained when the solvent was evaporated. The crude was purified by silica gel column chromatography (eluent=chloroform:methanol (50:1)). as a result, 11.2 g of 7-n-hexyl-1,2,3,4,5,6,7,8-octahydroquinoline-2,5-dione was obtained as colorless needles having a melting point of 142°-144° C. (52.0%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[OH:10][CH:11]([CH3:27])[CH:12]([NH:17][CH2:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:13]([O:15][CH3:16])=[O:14].FC(F)(F)S(O[Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])(=O)=O.C(OCC)C>C(Cl)Cl>[Si:34]([O:10][CH:11]([CH3:27])[CH:12]([NH:17][CH2:18][C:19](=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:13]([O:15][CH3:16])=[O:14])([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: COC(=O)C(NCC(=O)c1ccccc1)C(C)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: COC(=O)C(NCC(=O)c1ccccc1)C(C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diisopropylethylamine (3.1 ml) is added to a solution of methyl (2RS,3RS)-3-hydroxy-2-(2-oxo-2-phenylethyl)aminobutyrate (3.70 g, Reference compound No. 46-10) in methylene chloride (35 ml). The mixture is cooled with ice, and tert-butyldimethylsilyl trifluoromethanesulfonate (4.06 ml) is added to the mixture. Then, the temperature is raised to room temperature, and the whole is stirred overnight. Diethyl ether is added to the reaction mixture, and the whole is washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine successively, and the organic layer is dried over anhydrous magnesium sulfate. The organic layer is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography to give the titled reference compound (4.21 g).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:21]=[CH:20][C:7]([CH:8]=[C:9]2[CH2:13][CH2:12][C:11](C)([C:14](OC)=O)[C:10]2=[O:19])=[CH:6][CH:5]=1.Cl>O>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH:8]=[C:9]2[CH2:13][CH2:12][CH:11]([CH3:14])[C:10]2=[O:19])=[CH:20][CH:21]=1
Reactant: COC(=O)C1(C)CCC(=Cc2ccc(Cl)cc2)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1CCC(=Cc2ccc(Cl)cc2)C1=O
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A solution of 12 g of sodium hydroxide in 20 ml of water was added to 10 g of methyl 3-(4-chloro-benzylidene)-1-methyl-2-oxocylopentanecarboxylate (I-1) (prepared in Example 1). The mixture was stirred for 2 hours at 80° C. The reaction mixture was poured into 10% aqueous solution of hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain 4.1 g of an oily matter (yield, 51.8%).
Reaction SMILES: NC(N)=O.[Cl:5][C:6]1[CH:12]=[CH:11][C:9]([NH2:10])=[C:8]([OH:13])[C:7]=1[S:14]([N:17]1[CH2:22][CH2:21][S:20](=[O:24])(=[O:23])[CH2:19][CH2:18]1)(=[O:16])=[O:15].[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[N:32]=[C:33]=[O:34]>>[Cl:5][C:6]1[CH:12]=[CH:11][C:9]([NH:10][C:33]([NH:32][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[Cl:25])=[O:34])=[C:8]([OH:13])[C:7]=1[S:14]([N:17]1[CH2:22][CH2:21][S:20](=[O:24])(=[O:23])[CH2:19][CH2:18]1)(=[O:16])=[O:15]
Reactant: O=C=Nc1ccccc1Cl
Reactant: Nc1ccc(Cl)c(S(=O)(=O)N2CCS(=O)(=O)CC2)c1O
Agent: NC(N)=O
Product: O=C(Nc1ccccc1Cl)Nc1ccc(Cl)c(S(=O)(=O)N2CCS(=O)(=O)CC2)c1O
Yield: 325.9 %

Procedure:
Following the general procedure for urea formation outlined in example 15, 4-chloro-3-(1,1-dioxidothiomorpholinosulfonyl)-2-hydroxyaniline (62 mg, 0.018 mmol) and 2-chlorophenylisocyanate (34 mg, 0.22 mmol) were coupled to form the desired urea (29 mg, 32%). LC-MS (m/z) 496.0 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[N:11]([CH3:15])[C:10]([CH3:16])=[C:9]2[C:17]([OH:19])=O)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][N:25]=[C:24]2[Cl:30]>>[Cl:30][C:24]1[C:23]2[C:27](=[CH:28][CH:29]=[C:21]([NH:20][C:17]([C:9]3[CH:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[CH2:13][C:12](=[O:14])[N:11]([CH3:15])[C:10]=3[CH3:16])=[O:19])[CH:22]=2)[NH:26][N:25]=1
Reactant: Nc1ccc2[nH]nc(Cl)c2c1
Reactant: CC1=C(C(=O)O)C(c2ccc(Cl)cc2)CC(=O)N1C
Product: CC1=C(C(=O)Nc2ccc3[nH]nc(Cl)c3c2)C(c2ccc(Cl)cc2)CC(=O)N1C

Procedure:
The title compound was prepared from the product of Example 56, Step 2 and 5-amino-3-chloroindazole using the method described in Example 56, Step 3. MS (ES+) m/e 430 [M+H]+
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][C:15]2[C:14]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)=[N:13][CH:12]=[CH:11][C:10]=2[CH2:9]1)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[F:28][C:25]([F:26])([F:27])[C:22]1[CH:21]=[CH:20][C:19]([NH:18][C:14]2[C:15]3[CH2:16][CH2:17][NH:8][CH2:9][C:10]=3[CH:11]=[CH:12][N:13]=2)=[CH:24][CH:23]=1
Reactant: FC(F)(F)c1ccc(Nc2nccc3c2CCN(Cc2ccccc2)C3)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: FC(F)(F)c1ccc(Nc2nccc3c2CCNC3)cc1
Reaction time: 24 h
Yield: 98.1 %

Procedure:
6-Benzyl-N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydro-2,6-naphthyridin-1-amine (280 mg, 0.73 mmol) was dissolved in methanol (25 mL) and palladium hydroxide was added (0.2 g, 20% wt). The mixture was shaken on a Parr Shaker under H2 (g) atmosphere (60 PSI) for 1 day. The mixture was filtered through celite and evaporated to give 0.21 g of material as grey crystals (quant.), which was used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16](Cl)[CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=[O:12])=[C:4]([F:19])[CH:3]=1.C[Si](C=[N+]=[N-])(C)C.C[OH:28].C1C=CC=CC=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[NH:17][C:16](=[O:28])[CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=[O:12])=[C:4]([F:19])[CH:3]=1
Reactant: O=C(O)c1ccc(Cl)nc1Nc1ccc(Br)cc1F
Reactant: CO
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: c1ccccc1
Product: O=C(O)c1ccc(=O)[nH]c1Nc1ccc(Br)cc1F
Reaction time: 1 h
Yield: 93 %

Procedure:
Preparation of 2-(4-bromo-2-fluorophenylamine)-6-chloro-nicotinic acid methyl ester: To a suspension of 2-(4-bromo-2-fluorophenylamino)-6-chloro-nicotinic acid (5.00 g, 14.5 mmol) in methanol/benzene (1:1, 100 mL) under N2 was added (trimethylsilyl)diazomethane (2.0 M solution in hexanes) dropwise until the bubbling caused by gas evolution ceased. Solids precipitated out of solution. The reaction was allowed to stir for 1 hour. Excess (trimethylsilyl)diazomethane was quenched by the dropwise addition of glacial acetic acid. The precipitated solids were filtered and washed with methanol. The filtrate was concentrated to a smaller volume and additional solids precipitated out of solution that were filtered and washed with methanol. The solids were combined and dried under vacuum to yield 4.82 g (93%) of pure desired product as a dark pink solid.