Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=O.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]#[N:21]>C(O)C.N1CCCCC1>[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19](=[CH:6][C:5]1[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:20]#[N:21]
Reactant: COc1ccc(C=O)cc1OC
Reactant: N#CCc1ccccn1
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccc(C=C(C#N)c2ccccn2)cc1OC
Temperature: 25 °C

Procedure:
To a stirred solution of 2.0 g (12.0 mmole) 3,4-dimethoxybenzaldehyde in 75 ml absolute ethanol are added 1.56 g (13.3 mmole) 2-pyridylacetonitrile and 12 drops piperidine. The reaction flask is equipped with a condenser and a drying tube (using anhydrous CaSO4), and the reaction is stirred and heated. After refluxing for 6 hours, the reaction is allowed to cool to room temperature and stirred overnight for 16 hours. The solvent is removed by rotary evaporation, and the residue purified by flash chromatography on silica gel, eluting with hexane-ethyl acetate, 4:1. The yellow solid is recrystallized from acetone-hexane to give 2-(2-pyridyl)-3-(3,4-dimethoxy-phenyl)-2-propenenitrile, m.p. 112°-14 114° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][NH:17][O:18][CH3:19].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1([C:13](=[O:15])[N:17]([O:18][CH3:19])[CH3:16])[CH2:10][CH2:11][CH2:12]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CON(C)C(=O)C1(NC(=O)OC(C)(C)C)CCC1
Yield: 87 %

Procedure:
To a solution of 1-tert-butoxycarbonylamino-cyclobutanecarboxylic acid (3 g, 13.94 mmol) in dry DMF (50 mL) was added N,O-dimethylhydroxylamine x HCl (1.36 g, 13.94 mmol) and DIEA (9.21 mL, 55.75 mmol). The reaction flask was cooled to 0° C. and after 10 minutes HATU (5.30 g, 13.94 mmol) was added to the solution (which turned yellow on addition). After 2 hrs the DMF was removed by rotary evaporation at reduced pressure. The residue was dissolved in EtOAc (100 mL) and washed twice with 10% citric acid (aq) and saturated NaHCO3(aq) solution. The organic phase was dried with Na2SO4, filtered and evaporated on silica. The product was purified by flash chromatography (heptane: ethyl acetate (1:1) to give the product as a colourless oil that slowly crystallizes (3.13 g) in 87% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[NH:14][C:13]4[N:21]=[CH:22][CH:23]=[CH:24][C:12]=4[N:11]3[C:25]=2[C:26]2[CH:31]=[CH:30][C:29]([C:32]3([NH:36]C(=O)OC(C)(C)C)[CH2:35][CH2:34][CH2:33]3)=[CH:28][CH:27]=2)=[CH:4][CH:3]=1.[ClH:44].O1CCOCC1>C(Cl)Cl>[ClH:44].[ClH:44].[ClH:44].[ClH:44].[NH2:36][C:32]1([C:29]2[CH:28]=[CH:27][C:26]([C:25]3[N:11]4[C:12]5[CH:24]=[CH:23][CH:22]=[N:21][C:13]=5[NH:14][C:15]5[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=5[C:10]4=[N:9][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([NH2:1])=[CH:7][CH:6]=3)=[CH:31][CH:30]=2)[CH2:33][CH2:34][CH2:35]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc(N)cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: Nc1ccc(-c2nc3n(c2-c2ccc(C4(N)CCC4)cc2)-c2cccnc2Nc2ccccc2-3)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 82.3 %

Procedure:
tert-Butyl (1-{4-[2-(4-aminophenyl)-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl]phenyl}cyclobutyl)carbamate (32.0 mg, 0.0561 mmol) was dissolved in DCM (1 mL). 4M HCl/dioxane (1 mL) was added to the mixture and stirred at room temperature for 6 hours. The mixture was concentrated and solidified with ether. The precipitated solids were collected by filtration and washed with ether to afford desired product (28.4 mg, 82.3%) as a pale red solid. 1HNMR (DMSO-d6) 400 MHz δ: 8.78 (br s, 3H), 8.66 (br s, 1H), 8.12 (dd, J=4.8, 1.6 Hz, 1H), 7.95 (dd, J=7.8, 1.4 Hz, 1H), 7.59-7.53 (m, 2H), 7.52-7.46 (m, 2H), 7.43-7.36 (m, 1H), 7.35-7.28 (m, 3H), 7.22-7.09 (m, 3H), 6.90 (dd, J=8.0, 1.6 Hz, 1H), 6.76 (dd, J=8.0, 4.8 Hz, 1H), 2.61-2.53 (m, 4H), 2.27-2.13 (m, 1H), 1.89-1.75 (m, 1H); LCMS: 471 [M+H].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=[O:10].[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>>[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[C:9](=[O:10])[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccc(F)cc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously desribed using 125 mg of (2-Amino-5-chloro-phenyl)-(4-fluoro-phenyl)-methanone and 116 mg of 4-tert-butyl-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 1.21 (s, 9H), 7.09 (t, 2H, J=8.8 Hz), 7.29 (m, 3H), 7.43–7.50 (m, 3H), 7.59 (m, 2H), 7.77 (d, 1H, J=8.8 Hz), 9.72 (s, 1H). MS: m/z 446.0 (M++1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[N:11][C:10]([O:13][CH:14]([C:16]([O:18]CC)=[O:17])[CH3:15])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[K+]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH:12]=[N:11][C:10]([O:13][CH:14]([C:16]([OH:18])=[O:17])[CH3:15])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)Oc1ncn(-c2cccc(Br)c2)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CC(Oc1ncn(-c2cccc(Br)c2)n1)C(=O)O

Procedure:
A 28.8 g portion of the compound of Example 20 was refluxed for 10 minutes with 9.5 g of potassium hydroxide in 100 ml of ethanol, and the product was collected as shown in Example 22 and recrystallized from ethanol to obtain 21.6 g of the desired product, m.p. 198°-200°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14](S(C)(=O)=O)=[N:15][CH:16]=2)[N:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]1=[O:29].[CH2:30]([O:32][C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1)[CH3:31]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([NH:37][C:36]3[CH:38]=[CH:39][C:33]([O:32][CH2:30][CH3:31])=[CH:34][CH:35]=3)=[N:15][CH:16]=2)[N:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]1=[O:29]
Reactant: CCOc1ccc(N)cc1
Reactant: CS(=O)(=O)c1ncc2c(n1)N(c1ccccc1)C(=O)N(c1c(Cl)cccc1Cl)C2
Product: CCOc1ccc(Nc2ncc3c(n2)N(c2ccccc2)C(=O)N(c2c(Cl)cccc2Cl)C3)cc1
Temperature: 90 °C
Yield: 71.1 %

Procedure:
A mixture of 158 mg (0.35 mmol) of 3-(2,6-dichlorophenyl)-7-methanesulfonyl-3,4-dihydro-1-phenylpyrimido[4,5-d]pyrimidin-2(1H)-one (prepared in Example 7) and 250 μl (1.9 mmol) of 4-ethoxyaniline were heated at 90° C. for 2 hours. The reaction mixture was partitioned between dichloromethane (10 ml) and 2M hydrochloric acid (10 ml) and the dichloromethane layer separated, washed with saturated aqueous sodium bicarbonate (10 ml), dried over magnesium sulfate, filtered and evaporated. The crude material was purified by flash chromatography on silica gel, eluting with 1:1 ethyl acetate/hexane. Product containing fractions were combined and evaporated to give 126 mg (71%) of 3-(2,6-dichlorophenyl)-7-(4-ethoxyanilino)-3,4-dihydro-1-phenylpyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 224-226° C. [Mass spectrum (ESI) MH+ =506].
Reaction SMILES: [CH3:1][C:2]1([CH3:38])[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]3[C:21]4[C:16](=[C:17]([C:23]5[CH:24]=[C:25]6[C:30](=[CH:31][CH:32]=5)[N:29]=[C:28]([NH:33][CH3:34])[N:27]=[CH:26]6)[C:18]([CH3:22])=[CH:19][CH:20]=4)[CH:15]=[CH:14][N:13]=3)=[CH:8][CH:9]=2)[N:4](C(=O)C)[CH2:3]1.Cl>CCO>[CH3:1][C:2]1([CH3:38])[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]3[C:21]4[C:16](=[C:17]([C:23]5[CH:24]=[C:25]6[C:30](=[CH:31][CH:32]=5)[N:29]=[C:28]([NH:33][CH3:34])[N:27]=[CH:26]6)[C:18]([CH3:22])=[CH:19][CH:20]=4)[CH:15]=[CH:14][N:13]=3)=[CH:8][CH:9]=2)[NH:4][CH2:3]1
Reactant: CNc1ncc2cc(-c3c(C)ccc4c(Nc5ccc6c(c5)N(C(C)=O)CC6(C)C)nccc34)ccc2n1
Agent: Cl
Solvent: CCO
Product: CNc1ncc2cc(-c3c(C)ccc4c(Nc5ccc6c(c5)NCC6(C)C)nccc34)ccc2n1
Temperature: 50 °C
Yield: 72.4 %

Procedure:
1-(3,3-Dimethyl-6-(6-methyl-5-(2-(methylamino)quinazolin-6-yl)isoquinolin-1-ylamino)indolin-1-yl)ethanone (180 mg, 0.36 mmol) was dissolved in 5 mL of EtOH and treated with 2 mL of concentrated aqueous HCl. The mixture was heated to 50° C. for 6 h. The mixture was concentrated and the residue was taken up in DCM and neutralized with 2 M ammonia in MeOH. The solution was pre-adsorbed onto silica gel and purified by column chromatography on silica gel using a gradient of 3 to 12% of MeOH in DCM. The clean fraction were concentrated under vacuum and the residue triturated with 1:1 diethyl ether/hexane to give 120 mg of 6-(1-(3,3-dimethylindolin-6-ylamino)-6-methylisoquinolin-5-yl)-N-methylquinazolin-2-amine as a pale yellow solid. MS (M+H)+ 461.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]#[CH:6])[CH3:3].[F:7][C:8]1[C:9](I)=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH3:24]>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.CN(C=O)C.CCN(CC)CC>[CH3:1][N:2]([CH2:4][C:5]#[C:6][C:9]1[C:8]([F:7])=[CH:16][CH:15]=[C:14]2[C:10]=1/[C:11](=[CH:18]/[C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH3:24])/[C:12](=[O:17])[NH:13]2)[CH3:3]
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#CCN(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CCN(C)C)c21

Procedure:
Using Method C above, N,N-dimethyl propargylamine (42.2 mg, 0.51 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (75 mg, 0.203 mmol) (Starting Material 3 supra) using (Ph3P)4Pd (23.5 mg) and Cul (4 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 6 h to give (Z)-1,3-dihydro-4-[3-(N,N-dimethylamino)-1-propynyl]-5-fluoro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one. (Yield 40 mg, 61%).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH:15]([C:17]3[CH:26]=[CH:25][C:20]4[NH:21][C:22](=[O:24])[O:23][C:19]=4[CH:18]=3)O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.Cl.C([O-])(O)=O.[Na+].O>O1CCOCC1.ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH:14]=[CH:15][C:17]3[CH:26]=[CH:25][C:20]4[NH:21][C:22](=[O:24])[O:23][C:19]=4[CH:18]=3)[CH2:9][CH2:8]2)=[CH:27][CH:28]=1
Reactant: O=c1[nH]c2ccc(C(O)CCN3CCC(Cc4ccc(F)cc4)CC3)cc2o1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=c1[nH]c2ccc(C=CCN3CCC(Cc4ccc(F)cc4)CC3)cc2o1
Reaction time: 0.5 h
Yield: 89.3 %

Procedure:
A solution of 6.7 g of 6-{3-[4-(4-fluorobenzyl)piperid-1-yl]-1-hydroxypropyl}-3H-benzoxazol-2-one [obtainable by hydrogenation of 6-{3-[4-(4-fluorobenzyl)piperid-1-yl]-1-oxopropyl}-3H-benzoxazol-2-one, which can be obtained by reacting 4-(4-fluorobenzyl)piperidine and 6-(3-chloropropionyl)-3H-benzoxazol-2-one] in 70 ml of dioxane is heated under reflux with 7 ml of concentrated HCl for 1.5 h. The mixture is cooled and 8.5 g of NaHCO3 and 70 ml of water are added. 30 ml of dichloromethane are added and the mixture is stirred for 30 minutes. The precipitate is separated off, washed with acetone and ether and dried to give 5.7 g of 6-{3-[4-(4-fluorobenzyl)piperid-1-yl]propenyl}-3H-benzoxazol-2-one (“A”), m.p. 202-203.5°; hydrochloride: m.p. 220-223°.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:18](=[O:20])[CH3:19])=[CH:9][C:10]([Cl:17])=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)(=O)=O.[CH2:23]1[CH:28]([CH2:29][CH2:30][OH:31])[CH2:27][CH2:26][NH:25][CH2:24]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1.ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:17][C:10]1[CH:9]=[C:8]([C:18](=[O:20])[CH3:19])[C:7]([N:25]2[CH2:26][CH2:27][CH:28]([CH2:29][CH2:30][OH:31])[CH2:23][CH2:24]2)=[C:16]2[C:11]=1[CH:12]=[CH:13][CH:14]=[N:15]2
Reactant: CC(=O)c1cc(Cl)c2cccnc2c1OS(=O)(=O)C(F)(F)F
Reactant: OCCC1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)c1cc(Cl)c2cccnc2c1N1CCC(CCO)CC1
Temperature: 65 °C
Yield: 83.8 %

Procedure:
A stirred mixture of 7-acetyl-5-chloroquinolin-8-yl trifluoromethanesulfonate (0.12 g, 0.34 mmol, from Example 47, Step 2), 4-ethanolpiperidine (0.052 g, 0.41 mmol), palladium acetate (1.5 mg, 0.0067 mmol), (S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (6.3 mg, 0.010 mmol), and cesium carbonate (0.31 g, 0.95 mmol) in tetrahydrofuran (3 mL) was heated at 65° C. overnight. The mixture was cooled, diluted with dichloromethane and filtered. The filtrate was washed with brine, dried over MgSO4 and then evaporated to dryness. The residue was purified on silica gel (eluting with 0 to 5% methanol in dichloromethane) to give the desired product (94.8 mg, 84%). LCMS calculated for C18H22ClN2O2 (M+H)+: m/z=333.1; Found: 333.1.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=3)([CH:12]3[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[N:33]([C:36]1[CH:37]=[CH:38][C:39]([CH3:42])=[N:40][CH:41]=1)=[C:34]=[O:35]>ClCCl.C1(C)C=CC=CC=1>[CH3:42][C:39]1[N:40]=[CH:41][C:36]([NH:33][C:34]([N:14]2[CH2:15][CH2:16][CH2:17][CH:12]([C:6]3([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=4)[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[CH2:13]2)=[O:35])=[CH:37][CH:38]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1(Cc1cccc(Cl)c1)C1CCCNC1
Reactant: Cc1ccc(N=C=O)cn1
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(NC(=O)N2CCCC(C3(Cc4cccc(Cl)c4)C(=O)Nc4cc(Cl)ccc43)C2)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of rac-6-chloro-3-(3-chloro-benzyl)-3-piperidin-3-yl-1,3-dihydro-indol-2-one (80 mg, 0.21 mmol) (from Example 25a supra) in dichloromethane (3 mL) was added triethylamine (74.3 ul, 0.53 mmol) (Aldrich), followed by the addition of solution of 5-Isocyanato-2-methyl-pyridine (1.26 mL, 0.25 mmol) in toluene (from Example 71a supra). The mixture was stirred at room temperature for 30 minutes. The mixture was partitioned between dichlormethane and water. The aqueous layer was extracted with dichlormethane. The combined organic layer was washed with water, brine, dried over MgSO4 and concentrated. The residue was purified by chromatography to give rac-3-[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-piperidine-1-carboxylic acid (6-methyl-pyridine-3-yl)-amide as a white solid. (Yield 52 mg, 48.1%).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([I:9])=[CH:5][C:4]=1[Cl:10].[C:11]1(=[O:21])[NH:15][C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.[K]>CN(C)C=O.C(OCC)(=O)C>[Cl:10][C:4]1[CH:5]=[C:6]([I:9])[CH:7]=[CH:8][C:3]=1[CH2:2][N:15]1[C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]2[C:11]1=[O:21]
Reactant: Clc1cc(I)ccc1CBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(I)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.2 %

Procedure:
In a solution of 7.6 g of 1-bromomethyl-2-chloro-4-iodobenzene in 50 mL of N,N-dimethylformamide, 3.7 g of potassium phthalimide was added, and stirred at room temperature for 1 hour. After the completion of the reaction, the reaction mixture was diluted with 80 mL of ethyl acetate, washed with water (30 mL×2), and then dehydrated with and dried over saturated sodium chloride aqueous solution and anhydrous sodium sulfate in that order, and the solvent was distilled off under reduced pressure to obtain 5.7 g of the aimed product as white crystal.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11](O)(=[O:13])[CH3:12]>S(=O)(=O)(O)O.O>[C:11]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)(=[O:13])[CH3:12]
Reactant: O=C(O)c1ccc(O)cc1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)Oc1ccc(C(=O)O)cc1
Temperature: 80 °C

Procedure:
6 Grams of 4-hydroxybenzoic acid and 8.2 g of anhydrous acetic acid were placed in a two-necked flask and mixed. While the mixture was cooled with water, 5 drops of sulfuric acid was added. After termination of heat generation, the mixture was heated at 80° C. for 30 minutes. Then, the reaction mixture was poured into cold water, and a precipitated crystal was filtered.
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([CH2:6][NH:7][C:8]2[C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]([S:17]([NH2:20])(=[O:19])=[O:18])=[C:10]([Cl:21])[CH:9]=2)[O:4][CH:5]=1.[OH-].[CH2:23]([N+:30]([CH3:33])([CH3:32])[CH3:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[NH2:20][S:17]([C:11]1[C:10]([Cl:21])=[CH:9][C:8]([NH:7][CH2:6][C:3]2[O:4][CH:5]=[CH:1][CH:2]=2)=[C:13]([CH:12]=1)[C:14]([O-:16])=[O:15])(=[O:18])=[O:19].[CH2:23]([N+:30]([CH3:33])([CH3:32])[CH3:31])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NS(=O)(=O)c1cc(C(=O)O)c(NCc2ccco2)cc1Cl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Product: NS(=O)(=O)c1cc(C(=O)[O-])c(NCc2ccco2)cc1Cl

Procedure:
In similar manner to Example 9, furosemide can be reacted with benzyltrimethylammonium hydroxide to yield benzyltrimethylammonium 5-aminosulfonyl-4-chloro-2-[(2-furanylmethyl)amino]benzoate.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[CH3:9]I>CO>[CH3:9][NH:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[NH2:8]
Reactant: CI
Reactant: Nc1ccccc1N
Solvent: CO
Product: CNc1ccccc1N

Procedure:
To one liter of methanol were added 89 grams (0.82 mole) of o-phenylenediamine and 25.7 ml. (0.41 mole) of methyl iodide. The mixture was refluxed for 2 hours, and an additional 25.7 ml. (0.41 mole) of methyl iodide then were added. The total mixture was refluxed for 12 hours. The major portion of the methanol then was removed in vacuo. The residual brown oil was poured into two liters of crushed ice, and the pH of the mixture was raised to 9.0 by addition of potassium hydroxide. The resulting mixture then was extracted with ethyl ether, and the extract was dried over potassium carbonate. The ether was removed in vacuo, and the residue was distilled at about 120° C./8 mm. to obtain N-methyl-o-phenylenediamine as a yellow oil which turned brown upon standing.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[O:8][C:7](=[O:9])[N:6]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[CH2:5]1.[C:17]1([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[Cl:16][C:12]1[CH:11]=[C:10]([N:6]2[CH2:5][CH:4]([CH2:3][CH2:2][N:26]3[CH2:27][CH2:28][N:23]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH2:24][CH2:25]3)[O:8][C:7]2=[O:9])[CH:15]=[CH:14][CH:13]=1
Reactant: O=C1OC(CCCl)CN1c1cccc(Cl)c1
Reactant: c1ccc(N2CCNCC2)cc1
Product: O=C1OC(CCN2CCN(c3ccccc3)CC2)CN1c1cccc(Cl)c1

Procedure:
Following the procedure of Example 2, the title compound is prepared from 5-(2-chloroethyl)-3-(3-chlorophenyl)-2-oxazolidinone and 1-phenylpiperazine.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:6](=[CH:7][N:8]([CH3:11])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.C([N-]C(C)C)(C)C.[Li+].[O:20]1CCC[CH2:21]1.CCCCCCC.C(C1C=CC=CC=1)C.C=O>C1COCC1>[Br:1][C:2]1[C:10]2[C:6](=[C:7]([CH2:21][OH:20])[N:8]([CH3:11])[N:9]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Cn1cc2cccc(Br)c2n1
Reactant: C1CCOC1
Agent: C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCc1ccccc1
Solvent: CCCCCCC
Product: Cn1nc2c(Br)cccc2c1CO
Temperature: 2.5 °C
Yield: 93.7 %

Procedure:
To a solution of 7-bromo-2-methyl-2H-indazole (6: R=Me; 0.578 g, 2.93 mmol) in 15 mL of THF at −78° C. was added a 2.0 M solution of lithium diisopropylamide in tetrahydrofuran/heptane/ethylbenzene (1.8 mL, 3.6 mmol). The yellow-orange solution was stirred at 0-5° C. for 15 m, then rechilled to −78° C. for 15 m. Paraformaldehyde (0.92 g) was added, and the orange mixture was rapidly stirred at −78° C. for 75 m then at room temperature for 100 m. The mixture was loaded onto silica gel and concentrated. Column chromatography (0→66% EtOAc/hexanes) afforded 0.662 g of impure (7-bromo-2-methyl-2H-indazol-3-yl)-methanol (14a).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2]/[CH:3]=[CH:4]/[CH3:5].[C:9]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([N:22]=[N+:23]=[N-:24])(=[O:21])=[O:20])=[CH:15][CH:14]=1)(=[O:11])[CH3:10].C1CCN2C(=NCCC2)CC1>CC#N>[C:9]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([S:19]([N:22]=[N+:23]=[N-:24])(=[O:21])=[O:20])=[CH:17][CH:18]=1)(=[O:11])[CH3:10].[N+:22](=[C:2](/[CH:3]=[CH:4]/[CH3:5])[C:1]([O:7][CH3:8])=[O:6])=[N-:23]
Reactant: C/C=C/CC(=O)OC
Agent: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C/C=C/C(=[N+]=[N-])C(=O)OC
Temperature: 25 °C
Yield: 87.2 %

Procedure:
Methyl (E)-2-diazo-3-pentenoate (5) was prepared using the scheme set forth in FIG. 7A. To a stirred solution of trans-pent-3-enoic acid (3.0 g, 30.0 mmol) in methanol (20 mL) was added concentrated H2SO4 (1 mL). The reaction mixture was stirred for 12 h at room temperature and then slowly neutralized with saturated sodium bicarbonate (NaHCO3). The aqueous layer was extracted with dichloromethane, and the combined organic layers were washed with brine and dried (Na2SO4). The solvent was removed under reduced pressure, and the remaining clear oil (3.30 g, 96% yield) was used for the next step, without further purification. To a stirred solution of methyl trans-pent-3-enoate (1.0 g, 8.77 mmol) and p-ABSA (3.15 g, 13.1 mmol) in CH3CN (20 mL) cooled to 0° C., was added DBU (2.66 g, 17.5 mmol) in one portion. p-ABSA (p-acetamidobenzenesulfonyl azide) was prepared using the procedure outlined in Baum et al., Synth. Commun., 17:1709ff (1987), which is hereby incorporated by reference. The reaction mixture was allowed to warm to room temperature over 7 h then quenched with saturated ammonium chloride (NH4Cl). The aqueous layer was extracted with diethyl ether, and the combined organic layers were washed with brine and dried (Na2SO4). The solvent was removed under reduced pressure and the residue was purified by flash chromatography (SiO2, pentane) to give methyl (E)-2-diazo-3-pentenoate (5) (0.80 g, 65% yield) as an orange oil, which was stored in pentane below −10° C. until ready for use. The spectroscopic data are consistent with previously reported data (Davies et al., J. Org. Chem., 57:3186ff (1992), which is hereby incorporated by reference).