Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[C:16]2[C:15](=[O:17])[CH:14]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[O:12][C:11]=2[C:10]([CH2:22][CH2:23][CH3:24])=[C:9]2[C:4]=1[C:5](=[O:25])[CH2:6][CH2:7][CH2:8]2.[I-].[K+].O>C(O)=O>[OH:2][C:3]1[C:16]2[C:15](=[O:17])[CH:14]=[C:13]([C:18]([O:20][CH3:21])=[O:19])[O:12][C:11]=2[C:10]([CH2:22][CH2:23][CH3:24])=[C:9]2[C:4]=1[C:5](=[O:25])[CH2:6][CH2:7][CH2:8]2
Reactant: CCCc1c2c(c(OC)c3c(=O)cc(C(=O)OC)oc13)C(=O)CCC2
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: O=CO
Product: CCCc1c2c(c(O)c3c(=O)cc(C(=O)OC)oc13)C(=O)CCC2
Yield: 109 %

Procedure:
Methyl 6,7,8,9-tetrahydro-5-methoxy-4,6-dioxo-10-propyl-4H-naphtho[2,3-b]pyran-2-carboxylate (172 mg; 0.5 mmole) in formic acid (5 ml) was heated on a steam bath with ground potassium iodide (800 mg; 4.8 mmole) for 1 hour. The mixture was poured into water and extracted with ethylacetate (3×). The organic fractions were washed with water and dried (sodium sulphate) to yield a brown oil (180 mg) which crystallised on trituration with ethanol. The solid was filtered off and washed with a little ether to give the title compound as a yellow powder (110 mg; 67%) mp 200° (decomposition).
Reaction SMILES: [O-2].[Eu+3:2].[O-2].[O-2].[Eu+3].[N+:6]([O-:9])([OH:8])=[O:7]>>[N+:6]([O-:9])([O-:8])=[O:7].[Eu+3:2].[N+:6]([O-:9])([O-:8])=[O:7].[N+:6]([O-:9])([O-:8])=[O:7]
Reactant: O=[N+]([O-])O
Agent: [Eu+3]
Agent: [O-2]
Product: O=[N+]([O-])[O-]
Reaction time: 1 h
Yield: 65 %

Procedure:
Slightly excess europium oxide was dissolved in concentrated nitric acid under heating to effect the reaction. After 1 hour, the reaction liquid was filtered and the filtrate was cooled to precipitate crystalline europium nitrate. Yield: 65%.
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][CH:10]([O:12][C:13]3[C:18]4[CH:19]=[C:20]([CH3:22])[O:21][C:17]=4[CH:16]=[C:15]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:14]=3)[CH2:9]2)C=CC=CC=1>CCOC(C)=O.CO.[Pd]>[NH:8]1[CH2:11][CH:10]([O:12][C:13]2[C:18]3[CH:19]=[C:20]([CH3:22])[O:21][C:17]=3[CH:16]=[C:15]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:14]=2)[CH2:9]1
Reactant: CCOC(=O)c1cc(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2cc(C)oc2c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(OC2CNC2)c2cc(C)oc2c1
Reaction time: 14 h

Procedure:
A mixture of ethyl 4-{[1-(diphenylmethyl)azetidin-3-yl]oxy}-2-methyl-1-benzofuran-6-carboxylate (2.1 g, 4.77 mmol) in EtOAc/MeOH (10 mL/20 mL) and Pd/C (0.060 g, 10%, 0.048 mmol) was stirred for 14 hours under a hydrogen atmosphere (balloon). The mixture was filtered through a bed of Celite washing with methanol. The sample was concentrated to give a pale white solid (quantitative yield), which was used without further purification. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.35-1.52 (m, 3 H) 2.18 (s, 1 H) 2.47 (s, 3 H) 3.78-3.94 (m, 2 H) 4.00-4.13 (m, J=7.16 Hz, 2 H) 4.29-4.49 (m, 2 H) 5.11-5.27 (m, 1 H) 6.52 (s, 1 H) 7.05 (s, 1 H) 7.78 (s, 1 H); MS (ESI, pos): 276.
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[N:13]=[N:14][C:15](Cl)=[CH:16][CH:17]=2)[CH:7]=1)[C:3](=[O:5])[CH3:4].[NH2:19][NH:20][C:21]([NH2:23])=S>C(O)C>[CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]3[N:14]([C:21]([NH2:23])=[N:20][N:19]=3)[N:13]=2)[CH:7]=1)[C:3](=[O:5])[CH3:4]
Reactant: CC(=O)N(C)c1cccc(-c2ccc(Cl)nn2)c1
Reactant: NNC(N)=S
Solvent: CCO
Product: CC(=O)N(C)c1cccc(-c2ccc3nnc(N)n3n2)c1
Yield: 34 %

Procedure:
A solution of 3.0 g N-methyl-N-[3-(6-chloro-3-pyridazinyl)phenyl]acetamide and 2.0 g thiosemicarbazide in 100 ml ethanol was heated at reflux for 5.5 hours. The ethanol was removed in vacuo, 100 ml glacial acetic acid added and the mixture was refluxed for 18 hours. The acetic acid was removed in vacuo and the yellow residue added to 300 ml water. This mixture was brought to pH~7 with aqueous sodium bicarbonate and extracted with 100 ml portions of dichloromethane and dichloromethane-ethyl acetate. The combined extracts were dried, the solvent removed in vacuo, and the product mixture chromatographed on silica gel using dichloromethane-methanol (95.5) as solvent. Recombining the pure fractions and recrystalizing from ether-methanol-hexane afforded 1.10 g yellow crystals, mp 206°-207° C.
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH2:4][OH:5].[CH3:7][C:8]([CH3:12])=[CH:9][CH:10]=O.COCCO.OO>O>[CH3:7][C:8](=[CH:9][CH2:10][CH2:1][C:2](=[CH:3][CH:4]=[O:5])[CH3:6])[CH3:12]
Reactant: CC(C)=CCO
Reactant: CC(C)=CC=O
Agent: OO
Solvent: O
Solvent: COCCO
Product: CC(C)=CCCC(C)=CC=O
Yield: 88 %

Procedure:
A mixture of 100 parts of 3-methyl-2-buten-1-ol, 100 parts of 3,3-dimethylacrolein, 200 parts of ethylene glycol monomethyl ether and 3 parts of 30% aqueous hydrogen peroxide solution is heated under reflux for six hours while stirring and the water formed is removed continuously using pentane as entrainer. Fractional distillation of the reaction product gives 84.5 parts of citral, equivalent to a yield of 88% of theory, at a conversion of 53% (based on 3,3-dimethylacrolein).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][C@H:10]2[CH2:14][N:13]([CH2:15][C:16](=[O:32])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]4=[O:30])=[CH:20][C:19]=3[F:31])[CH2:12][C@@H:11]2[O:33][CH2:34][C:35]([OH:37])=O)=[O:8])=[CH:4][CH:3]=1.[CH:38]1([NH2:41])[CH2:40][CH2:39]1>>[CH:38]1([NH:41][C:35]([CH2:34][O:33][C@H:11]2[CH2:12][N:13]([CH2:15][C:16](=[O:32])[NH:17][C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]4=[O:30])=[CH:20][C:19]=3[F:31])[CH2:14][C@@H:10]2[NH:9][C:7]([C:5]2[S:6][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:8])=[O:37])[CH2:40][CH2:39]1
Reactant: O=C(O)CO[C@H]1CN(CC(=O)Nc2ccc(-n3ccccc3=O)cc2F)C[C@@H]1NC(=O)c1ccc(Cl)s1
Reactant: NC1CC1
Product: O=C(CN1C[C@H](NC(=O)c2ccc(Cl)s2)[C@@H](OCC(=O)NC2CC2)C1)Nc1ccc(-n2ccccc2=O)cc1F

Procedure:
According to general procedure D ((3S,4S)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-1-{[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenylcarbamoyl]-methyl}-pyrrolidin-3-yloxy)-acetic acid (example 97) was reacted with cyclopropylamine to give 5-chloro-thiophene-2-carboxylic acid ((3S,4S)-4-cyclopropylcarbamoylmethoxy-1-{[2-fluoro-4-(2-oxo-pyridin-1-yl)-phenylcarbamoyl]-methyl}-pyrrolidin-3-yl)-amide. White solid. MS588.5 ([M+H]+)
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][CH2:6][CH2:7][N:8]1[C:12]2[CH:13]=[CH:14][C:15]([C:17](=[O:26])[N:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH3:19])=[CH:16][C:11]=2[N:10]=[C:9]1[NH:27][C:28]([C:30]1[S:31][CH:32]=[CH:33][CH:34]=1)=[O:29])C.[OH-].[Na+].Cl>CO.O.C(Cl)Cl>[CH:20]1([N:18]([CH3:19])[C:17]([C:15]2[CH:14]=[CH:13][C:12]3[N:8]([CH2:7][CH2:6][CH2:5][C:4]([OH:35])=[O:3])[C:9]([NH:27][C:28]([C:30]4[S:31][CH:32]=[CH:33][CH:34]=4)=[O:29])=[N:10][C:11]=3[CH:16]=2)=[O:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CCOC(=O)CCCn1c(NC(=O)c2cccs2)nc2cc(C(=O)N(C)C3CCCCC3)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CN(C(=O)c1ccc2c(c1)nc(NC(=O)c1cccs1)n2CCCC(=O)O)C1CCCCC1
Reaction time: 4 h
Yield: 91.8 %

Procedure:
To a stirred solution of 4-{5-(N-cyclohexyl-N-methyl-carbamoyl)-2-[(thiophene-2-carbonyl)-amino]-benzoimidazol-1-yl}-butyric acid ethyl ester (Example 1) (0.5 g, 1.0 mmol) in MeOH (10 mL) and water (10 mL) was added solid NaOH (0.12 g, 3 mmol). The reaction was complete in 4 h. The mixture was acidified with 1N HCl, and was diluted with CH2Cl2 (20 mL). The organic layer was dried over magnesium sulfate, the solvent evaporated and the residue purified by flash chromatography with 10% MeOH/dichloromethane to give the title compound (0.43 g, 92%), m.p. 256-258° C.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]2[CH2:21][CH2:22][N:23]=[C:13]12)[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].[ClH:24]>CO>[ClH:24].[OH:5][CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][N:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]2[CH2:21][CH2:22][N:23]=[C:13]12
Reactant: O=C(CN1C2=NCCN2c2ccccc21)c1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC(CN1C2=NCCN2c2ccccc21)c1ccccc1
Reaction time: 4 h

Procedure:
Add bit by bit 0.3 g (7.5 mmol) of sodium borohydride to a suspension of 1.94 g (7 mmol) of 9-phenacyl-2,3-dihydroimidazo[1,2-a]benzimidazole in 15 ml of methanol over a period of thirty minutes at room temperature. Continue stirring for a further four hours and leave until the next day. Add 10 ml of 10% hydrochloric acid until a pH of 2-3 is obtained and evaporate the methanol. Treat the residue with a solution of ammonium hydroxide and extract with chloroform. Recrystallise from ethanol the residue from extraction.
Reaction SMILES: [CH2:1]([N:5]([C:34](=[O:41])[CH2:35][C:36]([O:38]CC)=[O:37])[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH2:19][C@H:20]([OH:33])[C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:22]=3)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].C(O)(=O)C>O.C(O)C>[CH2:1]([N:5]([C:34](=[O:41])[CH2:35][C:36]([OH:38])=[O:37])[C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH2:19][C@H:20]([OH:33])[C:21]3[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([NH:28][S:29]([CH3:32])(=[O:31])=[O:30])[CH:22]=3)[CH2:14][CH2:13]2)=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(C(=O)CC(=O)OCC)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CCCCN(C(=O)CC(=O)O)c1ccc(N2CCC(NC[C@H](O)c3ccc(O)c(NS(C)(=O)=O)c3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.2 %

Procedure:
To a stirred solution of ethyl 3-(butyl-4-{4-[((2R)-2-hydroxy-2-{4-hydroxy-3-l}ethyl)amino]-1-piperidineyl}anilino)-3-oxopropanoate (which was obtained in Example 373) (0.23 g, 0.39 mmol) in distilled water (3 mL) and ethanol (2 mL) was added 1 N sodium hydroxide (2 mL). The reaction was stirred at room temperature for 1 hour. The mixture was acidified (pH 6) with glacial acetic acid, concentrated, triturated with water, ethyl acetate, ether, and dried under vacuum to give the titled compound as a tan solid (0.04 g, 19%); 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.50 (m, 6H), 1.70-1.95 (m, 2H), 2.60-2.80 (m, 5H), 2.83 (s, 2H), 2.91 (s, 3H), 3.45-3.70 (m, 4H), 4.55-4.65 (m, 1H), 6.81 (d, J=8.0 Hz, 1H), 6.90 (d, J=8.7 Hz, 2H), 7.09 (d, J=8.7 Hz, 2H), 7.07 (s, 1H); MS (ES) m/z: 563.2 (MH+); HRMS Calcd. for C27H39N4O7S(MH+): 563.2461. Found: 563.2526.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([O:15][N:16]=[C:17]3[CH2:22][CH2:21][N:20]([C:23]4[C:28]([F:29])=[CH:27][C:26]([CH2:30][C:31]([OH:33])=O)=[C:25]([F:34])[CH:24]=4)[CH2:19][CH2:18]3)[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].[NH2:35][CH:36]1[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]1.C1C=CC2N(O)N=NC=2C=1.CO>ClCCCl>[CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:10][CH2:11][CH:12]([O:15][N:16]=[C:17]3[CH2:22][CH2:21][N:20]([C:23]4[C:28]([F:29])=[CH:27][C:26]([CH2:30][C:31]([NH:35][CH:36]5[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]5)=[O:33])=[C:25]([F:34])[CH:24]=4)[CH2:19][CH2:18]3)[CH2:13][CH2:14]2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CN1CCC(N)CC1
Reactant: CCc1cnc(N2CCC(ON=C3CCN(c4cc(F)c(CC(=O)O)cc4F)CC3)CC2)nc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CO
Product: CCc1cnc(N2CCC(ON=C3CCN(c4cc(F)c(CC(=O)NC5CCN(C)CC5)cc4F)CC3)CC2)nc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Compound 77e (9 mg, 0.019 mmol) was dissolved in DCE (0.5 mL) and 4-amino-1-methylpiperidine (0.01 mL) was added followed by HOBt (4 mg, 0.03 mmol) and EDC (12 mg, 0.06 mmol) and stirred at r.t. for 16 h. MeOH was added and the mixture purified by HPLC to give 2-(4-{4-[1-(5-ethyl-pyrimidin-2-yl)-piperidin-4-yloxyimino]-piperidin-1-yl}-2,5-difluoro-phenyl)-N-(1-methyl-piperidin-4-yl)-acetamide 77-1. LC-MS 570.2 (MFE).
Reaction SMILES: C1(CCN2C3C(=CC=CC=3)C(O)(C3C(O)=CC4OCOC=4C=3)C2=O)CC1.[C:27]1([CH:33]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[N:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:36](O)([C:43]3[CH:48]=[CH:47][C:46]([O:49][C:50]([F:53])([F:52])[F:51])=[CH:45][C:44]=3[OH:54])[C:35]2=[O:56])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:27]1([CH:33]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[N:34]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH:36]([C:43]3[CH:48]=[CH:47][C:46]([O:49][C:50]([F:52])([F:53])[F:51])=[CH:45][C:44]=3[OH:54])[C:35]2=[O:56])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1ccc(OC(F)(F)F)cc1O
Agent: O=C1N(CCC2CC2)c2ccccc2C1(O)c1cc2c(cc1O)OCO2
Product: O=C1C(c2ccc(OC(F)(F)F)cc2O)c2ccccc2N1C(c1ccccc1)c1ccccc1

Procedure:
Following the procedure as described in PREPARATION 2C, and making non-critical variations to replace 1-(2-cyclopropylethyl)-3-hydroxy-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1,3-dihydro-2H-indol-2-one with 1-(diphenylmethyl)-3-hydroxy-3-[2-hydroxy-4-(trifluoromethoxy)phenyl]-1,3-dihydro-2H-indol-2-one, the title compound was obtained (82%): MS (ES+) m/z 498.4 (M+23).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][CH2:9][N:10]2[CH2:14][CH:13]([CH2:15][CH2:16][CH3:17])[CH2:12][C:11]2=[O:18])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:19]1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+].CCOC(C)=O>C(OC)(OC)OC>[N:1]1[C:2]2[C:3](=[N:4][CH:5]=[CH:6][CH:7]=2)[N:8]([CH2:9][N:10]2[CH2:14][CH:13]([CH2:15][CH2:16][CH3:17])[CH2:12][C:11]2=[O:18])[CH:19]=1
Reactant: CCCC1CC(=O)N(CNc2ncccc2N)C1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COC(OC)OC
Product: CCCC1CC(=O)N(Cn2cnc3cccnc32)C1
Yield: 302.4 %

Procedure:
A solution of 1-{[(3-aminopyridin-2-yl)amino]methyl}-4-propylpyrrolidin-2-one x78 (1 eq, 1.6 mmol, 300 mg), and para-toluenesulfonic acid (0.32 mmol, 0.2 eq, 42 mg) in trimethyl orthoformate (15 ml) is allowed to react at room temperature for 3 days. After hydrolysis (20 ml of saturated NaHCO3), extraction with AcOEt (2×10 ml), drying of the cumulated organic layers over MgSO4, and filtration, the volatiles are removed under reduced pressure and the crude material is purified by preparative chromatography affording 250 mg of 1-(3H-imidazo[4,5-b]pyridin-3-ylmethyl)-4-propylpyrrolidin-2-one 268.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23]([C:25]2[C:26](=[O:52])[N:27]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[N:28]([CH2:31][C@H:32]([O:34][C:35](=[O:45])[CH2:36][NH:37]C(OC(C)(C)C)=O)[CH3:33])[C:29]=2[CH3:30])=[O:24])=[CH:18][C:17]=1[F:53].[ClH:54]>CCOC(C)=O>[ClH:54].[NH2:37][CH2:36][C:35]([O:34][C@H:32]([CH3:33])[CH2:31][N:28]1[C:29]([CH3:30])=[C:25]([C:23](=[O:24])[NH:22][C:19]2[CH:20]=[CH:21][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[C:17]([F:53])[CH:18]=2)[C:26](=[O:52])[N:27]1[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1)=[O:45]
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)c4c(C)n(C[C@@H](C)OC(=O)CNC(=O)OC(C)(C)C)n(-c5ccccc5)c4=O)cc3F)c2cc1OC
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4c(C)n(C[C@@H](C)OC(=O)CN)n(-c5ccccc5)c4=O)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
To a solution of (R)-1-(4-(4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorophenylcarbamoyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydropyrazol-1-yl)propan-2-yl-2-(tert-butoxycarbonyl amino)acetate (100 mg, 0.137 mmol) in EtOAc (15 mL) was added 3 mL of saturated HCl in EtOAc (3 mL). The reaction mixture was stirred at rt overnight. The solid formed was collected and was crystallized in MeOH/EtOAc (20 mL, v/v=1:5). The product was further washed with EtOAc (5 mL×3) and dried under vacuum overnight to afford the title compound as a white solid (88 mg, 83%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][OH:19])[CH:13]=1)=O.B.CSC>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][NH:11][C:12]1[CH:13]=[C:14]([CH2:18][OH:19])[CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Cc1ccccc1Br)Nc1cccc(CO)c1
Agent: B
Solvent: CSC
Solvent: C1CCOC1
Product: OCc1cccc(NCCc2ccccc2Br)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(2-bromophenyl)-N-[3-(hydroxymethyl)phenyl]acetamide was dissolved THF (0.2 M), followed by addition of BH3·DMS (3 eq), and the reaction was heated to reflux with stirring. After 2 hrs, the mixture was cooled to room temperature, and quenched with excess 10% HCl. The mixture was heated to reflux for 1 hr, and then cooled to room temperature. After washing with EtOAc, the aqueous phase was made alkaline with 10% sodium carbonate, and extracted with EtOAc. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was triturated with EtOAc to afford a colorless solid. EI-MS m/z 307/309 (M+H)+
Reaction SMILES: C1(C2C=CC=CC=2)C=CC=CC=1.IC1C=CC2OCOC=2C=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][C:34](OC)=[CH:33][CH:32]=2)=[CH:27][CH:26]=1>>[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[CH:27][CH:26]=1
Reactant: COc1ccc(-c2ccc(OC)cc2)cc1
Agent: Ic1ccc2c(c1)OCO2
Solvent: c1ccc(-c2ccccc2)cc1
Product: COc1ccc(-c2ccccc2)cc1
Temperature: 60 °C

Procedure:
This reaction can also be conveniently carried out without removal of excess bis(pinacolato)diboron when this reagent is used in near stoichiometric molar ratio for the synthesis of the arylboronic acid ester. Thus, reacting 267 mgs (1.05 mmol) of bis(pinacolato)diboron, 25 mg of PdCl2(dppf).CH2Cl2, 416 mg (3.0 mmol) K2CO3 and 234 mg (1.0 mmol) 4-iodoanisole in 5 ml methanol at 25° C. for 16 h gave (by gc analysis) a 94% yield of the required ester (with 1.4% dimer) which was converted to the biphenyl by addition of 1-iodo-3,4-methylenedioxybenzene (excess, 315 mg, 1.27 mmol) and warming the mixture to 60° C. for 12 h. The ratio of 4,4′-dimethoxybiphenyl:4,4′-30 bis(1,3-benzodioxole) to asymmetric biaryl was 1:1.2:19. Some 4-methoxybiphenyl is also formed in the coupling reaction, presumably from the coupling of phenyl groups stemming from the catalyst phosphine ligand and the 4-methoxyphenyl from the boronic acid ester.
Reaction SMILES: [OH:1][CH:2]([C:7]([O:20][CH3:21])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([O:5][CH3:6])=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH3:28][O:29][C:30]1[N:35]=[C:34](Cl)[CH:33]=[C:32]([O:37][CH3:38])[N:31]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O.O>[CH3:28][O:29][C:30]1[N:35]=[C:34]([O:1][CH:2]([C:7]([O:20][CH3:21])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]([O:5][CH3:6])=[O:4])[CH:33]=[C:32]([O:37][CH3:38])[N:31]=1
Reactant: COc1cc(Cl)nc(OC)n1
Reactant: COC(=O)C(O)C(OC)(c1ccccc1)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(Oc1cc(OC)nc(OC)n1)C(OC)(c1ccccc1)c1ccccc1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
1.15 g (4 mmol) of methyl 2-hydroxy-3-methoxy-3,3-diphenyl-propionate were dissolved in 10 ml of dimethylformamide, and 276 mg (2 mmol) of potassium carbonate were added. Then 524 mg (3 mmol) of 2,6-dimethoxy-4-chloropyrimidine were added, and the mixture was stirred at 100° C. for 6 hours. It was then cautiously hydrolyzed with 10 ml of water, the pH was adjusted to 5 with citric acid and, after extraction with ethyl acetate, the organic phase was washed with water then dried over magnesium sulfate, and the solvent was removed by distillation. The oily residue (1.9 g) was chromatographed on silica gel, resulting in 617 mg of a slightly impure oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH3:14][N:15]1[CH2:20][CH2:19][CH:18]([NH2:21])[CH2:17][CH2:16]1>CCO>[N+:11]([C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[NH:21][CH:18]1[CH2:19][CH2:20][N:15]([CH3:14])[CH2:16][CH2:17]1)([O-:13])=[O:12]
Reactant: CN1CCC(N)CC1
Reactant: O=[N+]([O-])c1ccc(Cl)c([N+](=O)[O-])c1
Solvent: CCO
Product: CN1CCC(Nc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])CC1
Temperature: 40 °C
Yield: 54.2 %

Procedure:
Chloro-2,4-dinitrobenzene 1 (2.0 g, 9.874 mmol) was dissolved in anhydrous EtOH (40 mL) in a small argon purged flask and warmed in an oil bath to 40° C. Addition of 1-Methyl-piperidin-4-ylamine 50 (1.24 g, 10.862 mmol) occurred dropwise. The solution was heated to reflux in an oil bath for 48 hours. After cooling to room temperature the solvent was removed under reduced pressure and the resulting residue partitioned between H2O and ethyl acetate and IM ammonium hydroxide solution added to adjust pH to 9. The mixture was transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with ethyl acetate and the combined organic layers were washed with H2O, brine (twice), dried over magnesium sulphate, filtered and then concentrated. Recrystallization of the crude solid from EtOH yielded a yellow solid 51 (2,4-Dinitro-phenyl)-(1-methyl-piperidin-4-yl)-amine Yield: 1.50 grams (54.2%). 1H NMR (DMSO) δ: 1.59-1.75 (m, 2H), 1.86-1.98 (m, 2H), 2.06-2.17 (m, 2H), 2.18 (s, 3H), 2.62-2.77 (m, 2H), 3.71-3.84 (m, 1H), 7.31 (d, 1H, J=9.7), 8.24 (dd, 1H, J=9.7, 2.7), 8.45 (d, 1H, J=7.7), 8.85 (d, 1H, J=2.6); MS (ESI): 281 (MH+, 100%).
Reaction SMILES: Cl[C:2]1(O)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]1[S:12]([C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13].[Cl:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[S:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])=[CH:26][CH:25]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: Cc1ccc(S(=O)(=O)C2C=Nc3ccccc3C2(O)Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)c2cnc3ccccc3c2-c2ccc(Cl)cc2)cc1
Yield: 79.6 %

Procedure:
A mixture of 4-chloro-3-(4-methyl-benzenesulfonyl)-quinolin-4-ol (0.2 g, 0.67 mmol) and 4-chlorophenylboronic acid (0.16 g, 1.0 mmol) in 8 ml dioxane was stirred for 20 hours at 90° C. with potassium carbonate (0.5 g, 3.6 mmol) and tetrakis-(triphenylphosphin)palladium(0) (0.04 g, 0.035 mmol). After cooling the mixture was concentrated in vacuo. The crude residue was purified by column chromatography on silica gel (Kieselgel 60, eluent: chloroform) to obtain 0.21 g of the title compound in 80% yield.