Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[N:14][CH:15]=[C:16]([C:17]([OH:19])=O)[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.FC(F)(F)C(O)=O.[Br:60][C:61]1[CH:66]=[C:65]([C:67]2([NH2:70])[CH2:69][CH2:68]2)[CH:64]=[CH:63][N:62]=1>CN(C=O)C>[Br:60][C:61]1[CH:66]=[C:65]([C:67]2([NH:70][C:17]([C:16]3[C:11]4[CH:10]=[N:9][N:8]([C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=5)[C:12]=4[CH:13]=[N:14][CH:15]=3)=[O:19])[CH2:68][CH2:69]2)[CH:64]=[CH:63][N:62]=1
Reactant: O=C(O)c1cncc2c1cnn2-c1ccc(F)cc1
Reactant: NC1(c2ccnc(Br)c2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1(c2ccnc(Br)c2)CC1)c1cncc2c1cnn2-c1ccc(F)cc1
Reaction time: 0.5 h

Procedure:
To a mixture of 1-(4-fluoro-phenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid (0.120 g, 0.467 mmol) in DMF (2 mL) is added HATU (186 mg, 0.490 mmol). After 30 minutes, N,N-diisopropylethylamine (325 μL, 1.87 mmol) and 1-(2-bromo-pyridin-4-yl)-cyclopropylamine-trifluoroacetic acid salt (223 mg, 0.507 mmol) are added, and the reaction mixture became homogeneous. After 18 hours, the mixture is concentrated in vacuo, reconstituted in ethyl acetate (50 mL) and washed with 1N sodium hydroxide (3×50 mL). The organic layer is washed with saturated aqueous ammonium chloride (2×50 mL), saturated aqueous sodium bicarbonate (50 mL), brine (50 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue is twice purified by silica gel chromatography eluting with a gradient of 0-10% methanol in methylene chloride to afford the title compound as a solid.
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:38])[C:17]2[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH2:32][C:33]3[NH:34][CH:35]=[CH:36][N:37]=3)[CH2:25][C:26]3[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=3)=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].[CH2:39](N(CC)CC)C.Cl[C:47]([O:49][CH3:50])=[O:48]>C(Cl)(Cl)Cl>[CH2:50]([O:49][C:47]([N:37]1[CH:36]=[CH:35][N:34]=[C:33]1[CH2:32][N:24]([CH2:23][C:20]1[CH:21]=[CH:22][C:17]([C:16](=[O:38])[NH:15][C:12]2[CH:11]=[CH:10][C:9]([CH2:8][N:4]([CH2:5][CH2:6][CH3:7])[CH2:1][CH2:2][CH3:3])=[CH:14][CH:13]=2)=[CH:18][CH:19]=1)[CH2:25][C:26]1[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=1)=[O:48])[CH3:39]
Reactant: COC(=O)Cl
Reactant: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CN(Cc3ncc[nH]3)Cc3nccn3C)cc2)cc1
Reactant: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CN(Cc3nccn3C)Cc3nccn3C(=O)OCC)cc2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
The compound (66.2 mg) obtained in Example 49-1 was dissolved in anhydrous chloroform (2.7 ml). Then, the solution was added with triethylamine (0.028 ml) and then added with methyl chloroformate (manufactured by Kanto Kagaku) (0.015 ml), followed by stirring at room temperature for 6 hours. After completion of the reaction, the solution was added with chloroform (3.0 ml), followed by washing with water and a saturated aqueous sodium bicarbonate solution. The organic layer was dried with anhydrous magnesium sulfate and the solvent was then distilled off, thereby obtaining the subject compound (65.2 mg) as a yellow viscous solid.
Reaction SMILES: [C:1]([C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])#[N:2].Cl.[NH2:17][OH:18].C(=O)([O-])[O-].[Na+].[Na+]>CO.O>[NH2:2]/[C:1](=[N:17]\[OH:18])/[C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C#N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1/C(N)=N/O
Yield: 93 %

Procedure:
A solution of tert-butyl (2S)-2-cyano-1-piperidinecarboxylate (13.10 g) [see Preparation 3] in methanol (500 ml) was added to a solution of hydroxylamine hydrochloride (21.6 g) and sodium carbonate (33.0 g) in water (600 ml). The reaction mixture was warmed to the reflux temperature and stirred for 8 hours after which time the methanol was removed under reduced pressure and the product extracted from the aqueous layer with ethyl acetate (3×500 ml). The combined organic layers were washed with water (500 ml), dried over magnesium sulphate and the solvent removed under reduced pressure to afford tert-butyl (Z)-(2S)-2-[amino(hydroxyimino)methyl]-1-piperidinecarboxylate (14.1 g) as a white solid.
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4](=[O:12])[CH2:5][C:6](=O)[CH2:7][CH2:8][O:9][CH3:10].[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[S:19])=[CH:16][CH:15]=1.CO>ClCCl>[CH3:2][O:3][C:4]([C:5]1[S:19][C:18]([C:17]2[CH:21]=[CH:22][C:14]([Cl:13])=[CH:15][CH:16]=2)=[N:20][C:6]=1[CH2:7][CH2:8][O:9][CH3:10])=[O:12]
Reactant: NC(=S)c1ccc(Cl)cc1
Reactant: COCCC(=O)CC(=O)OC
Agent: [Cl-]
Solvent: CO
Solvent: ClCCl
Product: COCCc1nc(-c2ccc(Cl)cc2)sc1C(=O)OC
Temperature: 0 °C
Reaction time: 2 h
Yield: 56.3 %

Procedure:
Add a 1.0 M solution of sufuryl chloride in dichloromethane (20.0 mL, 20.0 mmol) dropwise to a solution of 5-methoxy-3-oxo-pentanoic acid methyl ester (3.0 g, 18.8 mmol) in dichloromethane (20.0 mL) at 0° C. and stir under nitrogen at 0° C. for 2 h. Concentrate the reaction mixture on a rotavap (rotary evaporator), keeping the bath temperature at RT. Add 4-chlorothiobenz-amide (3.67 g, 21.5 mmol) to the residue, followed by methanol (30.0 mL) and heat to 60° C. for 18 h. Quench the reaction with water and extract with EtOAc (2×). Combine the organic portions, wash with brine, dry over MgSO4, filter, and concentrate under vacuum. Purify by flash chromatography on silica gel, using a gradient of EtOAc/Hexane (0-60%) to give the title compound (3.3 g, 57%). Exact mass=311.0, MS (ES+) 312.0 (M+1). 1H NMR (CDCl3): δ 7.89 (d, 2H, J=8.8 Hz), 7.40 (d, 2H, J=8.8 Hz), 3.88 (s, 3H), 3.82 (t, 2H, J=6.8 Hz), 3.47 (t, 2H, J=6.8 Hz), 3.38 (s, 3H).
Reaction SMILES: CCN(C(C)C)C(C)C.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2([NH:42][C:43]3[N:48]=[C:47]([O:49][CH2:50][C:51]([F:54])([F:53])[F:52])[N:46]=[C:45]([NH:55][C:56]4[CH:64]=[CH:63][C:59]([C:60](O)=[O:61])=[CH:58][CH:57]=4)[N:44]=3)[CH2:41][CH2:40]2)=[CH:35][CH:34]=1.[NH2:65][CH2:66][C:67]([CH3:78])([CH3:77])[CH2:68][NH:69][C:70](=[O:76])[O:71][C:72]([CH3:75])([CH3:74])[CH3:73]>CN(C=O)C.CCOC(C)=O>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]2([NH:42][C:43]3[N:48]=[C:47]([O:49][CH2:50][C:51]([F:54])([F:53])[F:52])[N:46]=[C:45]([NH:55][C:56]4[CH:57]=[CH:58][C:59]([C:60]([NH:65][CH2:66][C:67]([CH3:78])([CH3:77])[CH2:68][NH:69][C:70](=[O:76])[O:71][C:72]([CH3:74])([CH3:73])[CH3:75])=[O:61])=[CH:63][CH:64]=4)[N:44]=3)[CH2:40][CH2:41]2)=[CH:35][CH:34]=1
Reactant: O=C(O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Reactant: CC(C)(CN)CNC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(CNC(=O)OC(C)(C)C)CNC(=O)c1ccc(Nc2nc(NC3(c4ccc(Cl)cc4)CC3)nc(OCC(F)(F)F)n2)cc1
Yield: 71.3 %

Procedure:
iPr2NEt (0.266 g) and O-benzotriazol-1-yl-N,N,N′,N′-tetra-methyluronium tetrafluoroborate (0.610 g) were added into a solution of 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (0.760 g) and tert-butyl 3-amino-2,2-dimethylpropylcarbamate (0.352 g) were dissolved in DMF (3 mL). The reaction was stirred at room temperature for 16 hrs before 200 mL of EtOAc was added. The organic phase was washed with water (2×25 mL) and brine (20 mL), dried over MgSO4, and concentrated to give crude product tert-butyl 3-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-2,2-dimethylpropylcarbamate (0.75 g) which was dissolved in CH2Cl2 (3 mL) and TFA (1.3 mL). After being stirred at room temperature for 16 hours, the mixture was concentrated to give a crude product, N-(3-amino-2,2-dimethylpropyl)-4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamide (0.63 g).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[O:10][CH3:11].Br[CH2:13][CH2:14][CH3:15].[CH3:16][C:17]1([CH3:30])[C@@H:19]2[CH2:20][C:21]3[C:25]([C@H:18]12)=[C:24]([CH3:26])[S:23][C:22]=3[C:27]([OH:29])=O>>[CH3:11][O:10][C:4]1[CH:5]=[C:6]([O:9][CH2:13][CH2:14][CH3:15])[CH:7]=[CH:8][C:3]=1[CH2:2][NH:1][C:27]([C:22]1[S:23][C:24]([CH3:26])=[C:25]2[C:21]=1[CH2:20][C@H:19]1[C:17]([CH3:16])([CH3:30])[C@H:18]12)=[O:29]
Reactant: CCCBr
Reactant: Cc1sc(C(=O)O)c2c1[C@H]1[C@@H](C2)C1(C)C
Reactant: COc1cc(O)ccc1CN
Product: CCCOc1ccc(CNC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)c(OC)c1

Procedure:
(1aS,5aR)-1,1,2-Trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid 2-methoxy-4-propoxy-benzylamide is prepared starting from 4-aminomethyl-3-methoxy-phenol, bromopropane and (1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalene-4-carboxylic acid in analogy to the procedures given in Example 36. LC-MS: tR=1.13 min, [M+1]+=400.19.
Reaction SMILES: [CH:1]1([C:5]#[N:6])[CH2:4][CH2:3][CH2:2]1.C([N-]C(C)C)(C)C.[Li+].[O:15]=[C:16]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17]1.CCOC(C)=O>C1COCC1>[C:5]([C:1]1([C:16]2([OH:15])[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:17]2)[CH2:4][CH2:3][CH2:2]1)#[N:6]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: N#CC1CCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(C2(C#N)CCC2)C1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 15.7 %

Procedure:
To a solution of cyclobutanecarbonitrile (1.75 g, 21.5 mmol) in THF (15 mL) was added 2.0M lithium diisopropylamide (11 mL, 22.5 mmol) dropwise and the solution was stirred at −78° C. for 45 minutes. Then a solution of tert-butyl 3-oxopyrrolidine-1-carboxylate (4.0 g, 21.5 mmol) in THF (2 mL) was added to the solution and the mixture was stirred at −78° C. for 2 hours. The reaction mixture was quenched with saturated NH4Cl solution and extracted with EtOAc (25 mL×3). The organic phase was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography eluted with petroleum ether:EtOAc=2:1 to obtain the title compound (0.9 g, 38.2% yield) as a white solid. 1H NMR: (400 MHz, CDCl3): δ 3.64-3.40 (m, 4H), 2.44 (t, J=7.8 Hz, 2H), 2.33-2.23 (m, 2H), 2.13-1.88 (m, 4H), 1.47 (s, 9H)
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]2[O:13][N:12]=[C:11]([CH2:14][O:15][CH2:16][CH2:17][CH3:18])[N:10]=2)[C:6]2[CH:19]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[S:21][C:5]=2[C:4](=[O:28])[N:3]1[CH:29]1[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30]1.[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45]>C(Cl)Cl>[F:42][C:43]([F:48])([F:47])[C:44]([OH:46])=[O:45].[C:22]1([C:20]2[S:21][C:5]3[C:4](=[O:28])[N:3]([CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)[C:2](=[O:1])[N:7]([CH2:8][C:9]4[O:13][N:12]=[C:11]([CH2:14][O:15][CH2:16][CH2:17][CH3:18])[N:10]=4)[C:6]=3[CH:19]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CCCOCc1noc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccccc4)cc32)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCOCc1noc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccccc4)cc32)n1

Procedure:
To a solution of tert-butyl 4-[2,4-dioxo-6-phenyl-1-{[3-(propoxymethyl)-1,2,4-oxadiazol-5-yl]methyl]-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl}piperidine-1-carboxylate (500 mg, compound B69) in DCM (10 ml) is added trifluoroacetic acid (10 ml). After 1 h at RT all volatile materials are removed in vacuo. The residue is taken up in diethyl ether, the resulting precipitate is filtered off, washed with diethyl ether and dried in vacuo to afford the title compound as a solid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([C:10]1[CH:15]=[CH:14][C:13]([CH:16]2[CH2:21][N:20]([C:22]([N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:23])[CH2:19][CH:18]([NH2:29])[CH2:17]2)=[CH:12][CH:11]=1)[CH3:9].[C:30]1([N:36]2[CH2:41][CH2:40][N:39]([C:42](Cl)=[O:43])[CH2:38][CH2:37]2)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:8]([C:10]1[CH:11]=[CH:12][C:13]([CH:16]2[CH2:21][N:20]([C:22]([N:24]3[CH2:25][CH2:26][CH2:27][CH2:28]3)=[O:23])[CH2:19][CH:18]([NH:29][C:42]([N:39]3[CH2:40][CH2:41][N:36]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH2:37][CH2:38]3)=[O:43])[CH2:17]2)=[CH:14][CH:15]=1)[CH3:9]
Reactant: CCc1ccc(C2CC(N)CN(C(=O)N3CCCC3)C2)cc1
Reactant: O=C(Cl)N1CCN(c2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCc1ccc(C2CC(NC(=O)N3CCN(c4ccccc4)CC3)CN(C(=O)N3CCCC3)C2)cc1

Procedure:
125 mg (50% pure, 0.15 mmol) of 5-(4-ethylphenyl)-1-(pyrrolidin-1-ylcarbonyl)piperidine-3-amine trifluoroacetate (Example 12A) and 40 mg (0.18 mmol, 1.2 eq.) of 4-phenylpiperazine-1-carbonyl chloride were reacted according to General Method 3. Yield: 13 mg (18% of theory)
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][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C1(C)C=CC=CC=1.[CH2:30]([N:32]([CH2:35]C)[CH2:33]C)[CH3:31].ClC(Cl)([O:40][C:41](=O)[O:42]C(Cl)(Cl)Cl)Cl.CN(C)CCO>C(Cl)Cl>[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][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:41](=[O:40])[O:42][CH2:31][CH2:30][N:32]([CH3:35])[CH3:33])=[CH:18][CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: CCN(CC)CC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: CN(C)CCO
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OCCN(C)C)cc3)c2cc1OC
Temperature: 25 °C
Yield: 12 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (74 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (112 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 2-dimethylaminoethanol (32 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (13 mg, yield 12%).
Reaction SMILES: CN([CH2:4][C:5]1OC(CSCCN)=CC=1)C.[CH2:15]([S:17]([NH:20][C:21]1[CH:22]=[C:23]([CH:36]=[CH:37][CH:38]=1)[C:24]([O:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:25])(=[O:19])=[O:18])[CH3:16]>>[CH2:15]([S:17]([NH:20][C:21]1[CH:22]=[C:23]([CH:36]=[CH:37][CH:38]=1)[C:24]([O:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:25])(=[O:19])=[O:18])[CH2:16][CH2:4][CH3:5]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: CCS(=O)(=O)Nc1cccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Product: CCCCS(=O)(=O)Nc1cccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Yield: 100 %

Procedure:
In the same manner, by reacting 0.02 mole of 2-(5-dimethylaminomethylfuran-2-ylmethylthio)ethylamine with 0.02 mole of 4-nitrophenyl 3-ethanesulfonamidobenzoate and, respectively, with 0.02 mole of 4-nitrophenyl 3-butanesulfonamidobenzoate, there is obtained
Reaction SMILES: [C:1]([OH:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Pb:21]=O>C(O)(=O)C>[C:1]([O-:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[Pb+2:21].[C:1]([O-:20])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: O=[Pb]
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCCCC(=O)[O-]
Product: [Pb+2]
Reaction time: 0.02 h

Procedure:
100.4 g of stearic acid and 83.0 g of lead oxide were stirred at 45° C. and 0.3% of acetic acid added. After stirring for 1 minute, slight clumping occurred. After cooling for 5 minutes, stirring was continued. A pale yellowish powder having a lead content of 40.9%, a melting temperature of 114° C., and an acid value of 2.0 was obtained after 20 minutes.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>O1CCCC1>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: C1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccc(Br)cc1)N1CCCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Diisopropylethylamine (2.09 mL, 11.7 mmol) was added at 0° C. to a stirred solution of piperidine (0.40 g, 4.7 mmol) in tetrahydrofuran (10 mL) and the reaction mixture was stirred at room temperature for 15 minutes. A 0.1 M solution of 4-bromo-benzenesulfonyl chloride (1.20 g, 4.7 mmol) in tetrahydrofuran was added at room temperature and the reaction mixture was stirred at room temperature for 2 hours. The solvent was evaporated off under reduced pressure. The residue was diluted with ethyl acetate, and the inorganic salts were filtered through a celite bed. The filtrate was washed with 2 N aqueous HCl, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford 1-(4-bromobenzenesulfonyl)-piperidine, which was used in subsequent reactions without further purification. MS cald. for C11H14BrNO2S [M+] 304, obsd. 304.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:13][C:12]([CH:14]=O)=[CH:11][CH:10]=1.C([O-])(=O)C.[Na+].Cl.[NH2:22][OH:23]>O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[O:13][C:12]([CH:14]=[N:22][OH:23])=[CH:11][CH:10]=1
Reactant: O=Cc1ccc(-c2ccc(Cl)cc2Cl)o1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: ON=Cc1ccc(-c2ccc(Cl)cc2Cl)o1
Reaction time: 8 h

Procedure:
A mixture of 5-(2,4-dichlorophenyl)-2-furancarboxaldehyde (635 g, 2.63 moles), anhydrous sodium acetate (432 g, 5.26 moles), hydroxylamine hydrochloride (366 g, 5.26 moles), SDA #30 (9184 ml) and water (918 ml), was refluxed for 51/3 hours and allowed to stand overnight. The mixture was added to ice/H2O (42 liters), stirred 1 hour and filtered. The grayish-tan solid was washed with water (10 liters), filtered and dried at 65° to 660 g (98%).
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[CH:5]=[C:6]([C:23]([O:25]C)=[O:24])[C:7]2[CH:8]=[N:9][N:10]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[C:11]=2[CH:12]=1.Cl>O1CCCC1.O>[Br:3][C:4]1[CH:5]=[C:6]([C:23]([OH:25])=[O:24])[C:7]2[CH:8]=[N:9][N:10]([S:13]([C:16]3[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)(=[O:15])=[O:14])[C:11]=2[CH:12]=1
Reactant: COC(=O)c1cc(Br)cc2c1cnn2S(=O)(=O)c1ccc(C)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2ncc3c(C(=O)O)cc(Br)cc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.8 %

Procedure:
Lithium hydroxide (0.774 g, 32.3 mmol) was added to a stirred suspension of methyl 6-bromo-1-[(4-methylphenyl)sulfonyl]-1H-indazole-4-carboxylate (5.51 g, 13.46 mmol) in tetrahydrofuran (50 ml) and water (15 ml) and the reaction mixture was stirred at RT for 1 h. The reaction mixture was poured onto 2N HCl (800 ml) with stirring. The precipitate formed was filtered off under vacuum and dried at 50° C. in a vacuum oven for 18 h to give the title compound as a yellow solid (3.5 g).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:15]2[N:20]=[C:19]([NH:21][S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][N:26]=3)(=[O:24])=[O:23])[C:18]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[O:39][CH3:40])=[C:17]([O:41][CH3:42])[N:16]=2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.C(O)C.C1CCC=CC=1>O1CCOCC1.[Pd]>[OH:8][C:9]1[CH:10]=[C:11]([C:15]2[N:20]=[C:19]([NH:21][S:22]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][N:26]=3)(=[O:24])=[O:23])[C:18]([O:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[O:39][CH3:40])=[C:17]([O:41][CH3:42])[N:16]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2cccc(OCc3ccccc3)c2)nc1OC
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCC=C1
Solvent: C1COCCO1
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2cccc(O)c2)nc1OC

Procedure:
1.46 g of 5-methyl-pyridine-2-sulfonic acid [2-(3-benzyloxy-phenyl)-6-methoxy-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-amide were dissolved in dioxane (25 ml) by gentle warming than ethanol (50 ml) was added followed by cyclohexadiene (6 g) and palladium on charcoal, 10%, (1.46 g). The solution was refluxed for 20 h, the catalyst removed by filtration and the solution concentrated on a rotary evaporator. The yellow crystalline solid that precipitated was collected, washed with ether and dried in a vacuum to give the desired 5-methyl-pyridine-2-sulfonic acid [2-(3-hydroxy-phenyl)-6-methoxy-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-amide as off-white crystals. ISP mass spectrum, m/e 495.2 (M+1 calculated for C24H22N4O6S1: 495). Melting point 211°-216° C.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1>C(#N)C>[Cl:8][C:7]1[C:2]([N:13]2[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]2)=[N:3][CH:4]=[CH:5][N:6]=1
Reactant: Clc1nccnc1Cl
Reactant: CN1CCNCC1
Solvent: CC#N
Product: CN1CCN(c2nccnc2Cl)CC1
Temperature: 25 °C
Reaction time: 60 h
Yield: 74 %

Procedure:
A mixture of 2,3-dichloropyrazine (10.1 g, 68 mmol) and N-methylpiperazine (10.15 g, 100 mmol) in acetonitrile (250 mL) was stirred at room temperature for 60 h. The solvent was removed under reduced pressure and the residue was taken up in CHCl3/brine. The dried (MgSO4) organic layer was concentrated and the remaining oil was purified by chromatography on silica gel using CHCl3/MeOH (95:5) as eluent to give 10.7 g (75%) of the title compound as an oil that crystallized upon standing: mp 34-36° C. Anal. (C9H13ClN4) C, H, N.
Reaction SMILES: CO[CH:3]([O:6][CH3:7])[O:4][CH3:5].Cl.[C:9]1([C:15](=[O:19])C(=O)C)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:20]O>>[CH3:7][O:6][C:3]([O:4][CH3:5])([CH3:20])[C:15]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:19]
Reactant: COC(OC)OC
Reactant: CC(=O)C(=O)c1ccccc1
Reactant: CO
Agent: Cl
Product: COC(C)(OC)C(=O)c1ccccc1
Temperature: 22.5 °C
Reaction time: 2 h

Procedure:
1.2 g of trimethoxymethane and 8.7 ml of 25% strength by weight ethanolic HCl solution were added to 14.8 g of 1-phenylpropane-1,2-dione dissolved in 27.5 ml of methanol. The reaction mixture was stirred at 20 to 25° C. for 2 hours, and the solvent was then removed by distillation. The residue was taken up in methyl tert-butyl ether (MTBE) and the solution was washed with water. The organic phases were dried and the solvent removed by distillation. 18.2 g of product were obtained as a clear oil.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]([CH3:11])[CH3:10])[C:4]=1[OH:12].O.C(=O)(O)[O-].[Na+].[Br:19][C@H:20]([CH:24]([CH3:26])[CH3:25])[C:21](Cl)=[O:22]>C(OCC)(=O)C>[Br:19][C@H:20]([CH:24]([CH3:26])[CH3:25])[C:21]([NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH:9]([CH3:10])[CH3:11])[C:4]=1[OH:12])=[O:22]
Reactant: CC(C)[C@@H](Br)C(=O)Cl
Reactant: CC(C)c1cccc(N)c1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)c1cccc(NC(=O)[C@H](Br)C(C)C)c1O
Reaction time: 0.5 h
Yield: 76 %

Procedure:
To a stirred, ice-cooled mixture of 2-amino-6-isopropylphenol hydrochloride (15.0 g), ethyl acetate (200 ml), water (100 ml), and sodium bicarbonate (20.0 g), was added dropwise a solution of (R)-2-bromo-3methylbutyryl chloride (16.0 g) in ethyl acetate (30 ml). The whole was stirred for 30 minutes, and the ethyl acetate layer was separated, washed with water and dried over MgSO4. Removal of the solvent gave (R)-2-(2-bromo-3-methylbutyryl)amino-6-isopropylphenol as crystals (19.1 g, 76.1%). Recrystallization from isopropyl ether afforded colorless needles, mp 108°-109° C. [α]D23 +44.8° (c=0.82, MeOH).