Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([P+:3]([CH2:8]O)([CH2:6]O)[CH2:4]O)O.[Cl-:10].[NH2:11][C:12]([NH2:14])=[O:13]>C1(C)C=CC=CC=1>[Cl-:10].[NH:11]([CH2:8][P+:3]([CH2:1][NH:11][C:12]([NH2:14])=[O:13])([CH2:4][NH:11][C:12]([NH2:14])=[O:13])[CH2:6][NH:11][C:12]([NH2:14])=[O:13])[C:12]([NH2:14])=[O:13]
Reactant: NC(N)=O
Reactant: OC[P+](CO)(CO)CO
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: NC(=O)NC[P+](CNC(N)=O)(CNC(N)=O)CNC(N)=O
Yield: 101.1 %

Procedure:
Reaction of THPC (9.53 g, 0.05 mol) with urea (12.01 g, 0.2 mol) in toluene (75 ml), following Example 1, gave 18.14 g (101%) of tetrakis(ureidomethyl)phosphonium chloride (I, R=R'=R"=H, X=Cl) as a colorless, brittle glass.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH2:11][NH2:12])=[CH:8][C:6]=2[N:7]=1.CCN(CC)CC.C([O:28][C:29](=O)[CH2:30][N:31]([CH3:33])[CH3:32])C>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[C:5]2[S:10][C:9]([CH2:11][NH:12][C:29](=[O:28])[CH2:30][N:31]([CH3:33])[CH3:32])=[CH:8][C:6]=2[N:7]=1
Reactant: CCOC(=O)CN(C)C
Reactant: NCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)CC(=O)NCc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 25 °C
Reaction time: 33 h

Procedure:
To a solution of (2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methanamine 27 from Example 11 (50 mg, 0.2 mmol) in CH2Cl2 (4 mL) was added Et3N (84 μL, 0.6 mmol) and dimethylglycine ethyl ester (0.3 mmol). The reaction stirred 18-48 h at room temperature before being quenched with water. The aqueous layer was extracted with EtOAc. The combined organics were dried over Na2SO4 and concentrated in vacuo to give N-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)-2-(dimethylamino)acetamide which was utilized in a Suzuki coupling according to General Procedure A. The crude material was purified by reversed phase HPLC to give 350 (10 mg). MS (Q1) 452 (M)+
Reaction SMILES: C(O[C:4](=[O:9])[CH2:5][C:6]([CH3:8])=[O:7])C.[F:10][C:11]([F:20])([F:19])[C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>C1(C)C(C)=CC=CC=1>[O:7]=[C:6]([CH3:8])[CH2:5][C:4]([NH:16][C:15]1[CH:17]=[CH:18][C:12]([C:11]([F:10])([F:19])[F:20])=[CH:13][CH:14]=1)=[O:9]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)CC(C)=O
Solvent: Cc1ccccc1C
Product: CC(=O)CC(=O)Nc1ccc(C(F)(F)F)cc1

Procedure:
Ethylacetoacetate (10 g) and 4-(trifluoromethyl) aniline (12.38 g) in xylene (250 ml) was refluxed for 48 hours. Reaction mixture was concentrated and purified by column chromatography to give pure (9.7 g).
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([C:16]#[C:17][C:18]3[CH:19]=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=3)=[C:14]([CH2:25][CH3:26])[N:13]=[CH:12][N:11]=2)=[CH:6][C:5]=1[Cl:27].[Li+].[OH-]>O.C1COCC1>[NH2:24][C:21]1[N:20]=[CH:19][C:18]([C:17]#[C:16][C:15]2[C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3]([OH:28])=[O:2])=[C:5]([Cl:27])[CH:6]=3)=[N:11][CH:12]=[N:13][C:14]=2[CH2:25][CH3:26])=[CH:23][CH:22]=1
Reactant: CCc1ncnc(-c2ccc(C(=O)OC)c(Cl)c2)c1C#Cc1ccc(N)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCc1ncnc(-c2ccc(C(=O)O)c(Cl)c2)c1C#Cc1ccc(N)nc1
Temperature: 50 °C

Procedure:
The title compound is synthesized according to general procedure GP8 starting from 3.3 g (8.4 mmol) 4-[5-(6-amino-pyridin-3-ylethynyl)-6-ethyl-pyrimidin-4-yl]-2-chloro-benzoic acid methyl ester using 1.06 g (25.2 mmoL) LiOH in 20 mL water and 100 mL THF. The reaction mixture is stirred over night at 50° C. The solvent is removed under reduced pressure and the residue is taken up in water. Aqueous 1 M HCl is added until pH 5-6 is reached. The precipitated product is filtered off and washed with water and MeOH. After drying 2.5 g (89%) of the desired product are obtained as solid material.
Reaction SMILES: [Li][CH2:2]CCC.[OH:6][C:7]1[CH:8]=[C:9]([CH:27]=O)[C:10]2[CH2:11][CH:12]([C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=3)[CH:13]3[CH2:19][CH2:18][CH2:17][CH:14]3[C:15]=2[CH:16]=1.C(OCC)(=O)C>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[OH:26][C:23]1[CH:24]=[CH:25][C:20]([CH:12]2[CH2:11][C:10]3[C:15](=[CH:16][C:7]([OH:6])=[CH:8][C:9]=3[CH:27]=[CH2:2])[CH:14]3[CH2:17][CH2:18][CH2:19][CH:13]23)=[CH:21][CH:22]=1
Reactant: [Li]CCCC
Reactant: O=Cc1cc(O)cc2c1CC(c1ccc(O)cc1)C1CCCC21
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=Cc1cc(O)cc2c1CC(c1ccc(O)cc1)C1CCCC21

Procedure:
Combine BuLi (0.1 ml, 1.6M, 0.16 mmol), methyltriphenylphosphonium bromide (0.063 g, 0.175 mmol) and tetrahydrofuran (1.0 ml) and stir 15 minutes. Add 8-Hydroxy-4-(4-hydroxy-phenyl)-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[a]naphthalene-6-carbaldehyde (0.012 g, 0.04 mmol) in tetrahydrofuran (1.0 ml) and stir 30 minutes. Take into ethyl acetate and wash with ammonium chloride solution solution, then brine. Dry over anhydrous sodium sulfate and concentrate to a residue which yields after separation on silica gel with 33% EtOAC/hexanes, the titled compound (0.006 g, 50%). 1H NMR (CD3OD) 7.15 (d, J=8.4, Hz, 2H), 7.04 (dd, J=11 and 6 Hz, 1H), 6.75 (m, 3H), 3.4 (m, 1H), 3.0 (m, 1H), 2.85 (m, 2H), 2.55(m, 1H) 2.2 (m, 1H), 1.6-1.2. MS m/z 305 (M−1).
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH3:7])[CH2:5][OH:6])[CH3:2].[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1>>[C:8]1([CH3:18])[CH:13]=[CH:12][C:11]([S:14]([O:6][CH2:5][CH:4]([O:3][CH2:1][CH3:2])[CH3:7])(=[O:16])=[O:15])=[CH:10][CH:9]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(C)CO
Product: CCOC(C)COS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
20.8 g (0.20 mol) of 2-ethoxypropanol are added slowly during 20 minutes with stirring to a mixture of 43.3 g (0.227 mol) of toluene-p-sulphonylchloride and 20 ml of dry pryridine. The temperature of the reaction mixture is kept at 20° with external cooling. After stirring for 2 hours at 20°, the mixture is poured into ice-water and extracted with ether. The ether layer is washed with 2N sulphuric acid, with water and with saturated sodium hydrogencarbonate solution. After drying over sodium sulphate, filtration and evaporation in vacuo, 2-ethoxypropyl toluene-p-sulphonate is obtained as a yellow oil.
Reaction SMILES: ClC1N=C2C(C=[CH:7][C:8]([N:12]3[CH:20](OC(OC4C=CC=CC=4)=O)[C:19]4[C:14](=CC=[CH:17][CH:18]=4)[C:13]3=O)=N2)=CC=1.C(#[N:34])C>>[CH2:20]([N:12]1[CH2:8][CH2:7][NH:34][CH2:14][CH2:13]1)[CH2:19][CH:18]=[CH2:17]
Reactant: CC#N
Reactant: O=C(Oc1ccccc1)OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Product: C=CCCN1CCNCC1

Procedure:
Following the procedure of Example 36 but starting from 2-(7-chloro-1,8-naphthyridin-2-yl)-3-phenoxycarbonyloxy-1-isoindolinone (4.32 g.) and 1-(but-3-en-1-yl)-piperazine (7 g.) in acetonitrile (25 cc.), 3-[4-(but-3-en-1-yl)-1-piperazinyl]-carbonyloxy-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone (1.4 g.) melting at 142° C is obtained.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])[C:11]([Cl:19])=[CH:10][C:9]=1[NH:20][C:21](=[O:45])[CH2:22][C:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:35]=[CH:34][N:33]=[C:32]([CH2:36][O:37]C3CCCCO3)[CH:31]=2)[CH:25]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:19][C:11]1[C:12]([N:14]([CH:16]([CH3:18])[CH3:17])[CH3:15])=[CH:13][C:8]2[N:7]=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[CH:35]=[CH:34][N:33]=[C:32]([CH2:36][OH:37])[CH:31]=4)[CH:25]=3)[CH2:22][C:21](=[O:45])[NH:20][C:9]=2[CH:10]=1
Reactant: CC(C)N(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(COC4CCCCO4)c3)c2)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)N(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-c3ccnc(CO)c3)c1)=N2

Procedure:
The title compound was prepared from (RS)-[4-chloro-5-(isopropyl-methyl-amino)-2-(3-oxo-3-{3-[2-(tetrahydro-pyran-2-yloxymethyl)-pyridin-4-yl]-phenyl}-propionylamino)-phenyl]-carbamic acid tert-butyl ester (Example M280) (0.35 g, 0.54 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (162 mg, 67%).
Reaction SMILES: [N:1]([O-:3])=[O:2].[Na+].Br[CH2:6][CH2:7][CH2:8][CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11].O>CS(C)=O>[N+:1]([CH2:6][CH2:7][CH2:8][CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11])([O-:3])=[O:2]
Reactant: C[Si](C)(C)CCCCBr
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C[Si](C)(C)CCCC[N+](=O)[O-]
Reaction time: 3 h
Yield: 44.8 %

Procedure:
4-Nitrobutyltrimethylsilane was prepared as follows: To a solution of 1.9 g (0.028 mol) of sodium nitrite in 30 ml of dimethyl sulfoxide was added 2.92 g (0.014 mol) of 4-bromobutyltrimethylsilane. After 3 hrs, 30 ml of water was added and the mixture was extracted with three 15 ml portions of carbon tetrachloride. The carbon tetrachloride solution was washed with 10 ml of water and dried over magnesium sulfate. The NMR spectrum showed 30% nitrite ester (CH2ONOδ4.57), and 70% nitro compound. Distillation gave 1.1 g (45%) of 4-nitrobutyltrimethylsilane, bp 54°-6° (0.9 mm).
Reaction SMILES: C(NC(C)C)(C)C.[C:8]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])=[CH:10][CH:9]=1.Br[CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].[NH4+].[Cl-]>C1COCC1.[Li]CCCC>[C:8]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:16]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17])=[CH:10][CH:9]=1
Reactant: O=C(CCc1ccc(-c2ccccc2)cc1)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)CC(Cc1ccc(-c2ccccc2)cc1)C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 43.7 %

Procedure:
To a solution of diisopropylamine (2.70 ml, 18.96 mmol) in THF (20 ml), BuLi in hexanes (11.85 ml, 18.96 mmol) was added under nitrogen at 0° C. After stirred for 0.5 hour at the same temperature, the solution was cooled to −78° C. and then a solution of benzyl 3-(biphenyl-4-yl)propanoate (5 g, 15.80 mmol) in THF (20 ml) was added. After stirred for 1.5 hour at the same temperature, tert-butyl bromoacetate (3.33 ml, 22.12 mmol) was added, and then the mixture was warmed up to 0° C. The reaction mixture was allowed to stir at 0° C. for 2 hours, and then stirred at room temperature for 14 hours. The reaction mixture was poured into 150 ml of saturated aq. NH4Cl. The product was extracted twice with EtOAc. The combined organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue was purified by flash column chromatography on silica gel (eluent: heptane/EtOAc=100:0 to 10:1) to give the 1-benzyl 4-tert-butyl 2-(biphenyl-4-ylmethyl)succinate (2.97 g); Retention time=1.00 minutes (condition G); MS (m+1)=431.2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]([C:12]1[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][NH2:25])=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:11].N1C=CC=CC=1CCNC(C1C(C2C=CC=CC=2)=CC=CC=1CN[C:45]([O:47][CH:48]([CH3:55])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:46])=O>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8][NH:9][C:10]([C:12]1[C:13]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:24][NH:25][C:45]([O:47][C@H:48]([CH3:55])[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[O:46])=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:11]
Reactant: CC(OC(=O)NCc1cccc(-c2ccccc2)c1C(=O)NCCc1ccccn1)c1ccccc1
Reactant: NCc1ccccc1-c1ccccc1C(=O)NCCc1ccccn1
Product: C[C@@H](OC(=O)NCc1ccccc1-c1ccccc1C(=O)NCCc1ccccn1)c1ccccc1

Procedure:
From 0.3 mmol of 2′-aminomethylbiphenyl-2-carboxylic acid 2-(2-pyridyl)-ethylamide (precursor 5d) and (R)-α-methylbenzyl N-succinimido-carbonate (precursor 4i), according to the general working procedure 60 mg of (R)-2′-(α-methylbenzyloxycarbonylaminomethylbiphenyl-2-carboxylic acid 2-(2-pyridyl)ethylamide were obtained. MS (ES+): m/e=480 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[C:3]=1[NH2:9].[C:10]([O-])(O)=O.[Na+]>C(O)=O.O>[CH3:1][C:2]1[C:3]2[N:9]=[CH:10][NH:8][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(N)c1N
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: Cc1cccc2[nH]cnc12

Procedure:
A solution of 3-methylbenzene-1,2-diamine (170 mg) in formic acid (2 mL) was heated at 140° C. for 5 min in a microwave reactor. The mixture was diluted with water, neutralized with sat. NaHCO3, then extracted with EtOAc. The organic phase was washed with water and brine, dried (Na2SO4), filtered through a 1″ pad of silica gel and concentrated to afford 122 mg of Intermediate 171.1 as a tan solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Br[CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH2:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:10]=2)[O:3]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (400 mg, 0.002 mol, Aldrich, Cat. No. 525057) in acetonitrile (10 mL) was added tert-butyl 2-bromoacetate (0.36 mL, 0.0025 mol, Aldrich, Cat. No. 124230) and cesium carbonate (1.0 g, 0.0031 mol). The suspension was stirred at r.t. overnight. The reaction mixture was partitioned with AcOEt and water. The organic layer was separated, washed with water and brine, dried over MgSO4. After filtration, the filtrate was concentrated to afford the desired compound which was directly used in the next step reaction without further purification. LCMS (M+H)+: m/z=309.1.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH2:26])[O:22][C:21]3=[O:27])=[CH:16][C:15]=2[F:28])[CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].N1C=CC=CC=1.[C:35](OC(=O)C)(=[O:37])[CH3:36]>C(Cl)Cl>[CH3:4][C:2]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][NH:26][C:35](=[O:37])[CH3:36])[O:22][C:21]3=[O:27])=[CH:16][C:15]=2[F:28])[CH2:12][CH2:13]1)=[O:7])([CH3:1])[CH3:3]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N3C[C@H](CN)OC3=O)cc2F)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of (S)4-)-4-[4-[5-(aminomethyl)-2-oxo-3-oxazolidinyl]-2-fluorophenyl]-1-piperidinecarboxylic acid 1,1-dimethylethyl ester (EXAMPLE 20, Step 8, 9.45 g) in dry methylene chloride (96 mL) under N2 is treated with pyridine (5.82 mL) and acetic anhydride (3.40 mL), and the resulting mixture is stirred at ambient temperature for four hours, diluted with methylene chloride (25 mL), washed with water (25 mL), saturated aqueous sodium bicarbonate (25 mL) and saline (25 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product which is then chromatographed on silica gel (230-400 mesh, 350 g), eluting with a gradient of methanol/chloroform (2.5/97.5-7.5/92.5). Pooling and concentration of those fractions with an Rf=0.51 by TLC (methanol/chloroform, 10/90) gives the title compound, mp 144-146° C.
Reaction SMILES: [Br:1][CH:2]=[CH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.ClC1C=CC=C(C(OO)=[O:19])C=1>C(Cl)(Cl)Cl>[Br:1][CH:2]=[CH:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]2[O:19][CH:7]2[CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: BrC=CCc1ccccc1
Solvent: ClC(Cl)Cl
Product: BrC=CCC1=CC2OC2C=C1
Reaction time: 168 h
Yield: 87.1 %

Procedure:
The mixture of 5.1 g of p-bromoallylbenzene, 8.5 g of m-chloroperbenzoic acid and 200 ml of chloroform was allowed to stand at about 5° C for 7 days. The resulting mixture was washed with 10% sodium hydroxide solution, water, Mohr's salt solution, then water, and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain 4.8 g (yield 85%) of p-bromoallylbenzene oxide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH:12]2[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C[Si](C)(C)N[Si](C)(C)C.[Na].[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]#[C:37][CH2:38][CH2:39][CH2:40]I)=[CH:32][CH:31]=1>CN(C=O)C>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]#[C:37][CH2:38][CH2:39][CH2:40][C:12]2([S:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)(=[O:10])=[O:11])[S:16][C:15](=[O:17])[NH:14][C:13]2=[O:18])=[CH:32][CH:31]=1
Reactant: Clc1ccc(C#CCCCI)cc1
Reactant: COc1ccc(S(=O)(=O)C2SC(=O)NC2=O)cc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)C2(CCCC#Cc3ccc(Cl)cc3)SC(=O)NC2=O)cc1
Reaction time: 0.25 h

Procedure:
To a solution of 5-(4-methoxyphenylsulfonyl)-thiazolidine-2,4-dione [U.S. Pat. No. 5,605,918; February 1997; Wrobel, et al.]((2.74 g, 9.5 mMol) in DMF (50 ml) was added sodium hexamethyldisilazane (1.0 M solution in THF-19.0 ml, 19.0 mmol) at room temperature, under nitrogen, and this was stirred for 15 minutes. To this was added 1-(4-chlorophenyl)-5-iodo-1-pentyne (2.70 g, 9.5 mmol) over 5 minutes, and this solution was stirred overnight at room temperature. The reaction mixture was quenched in water, and the solid that was obtained was recrystallized from methanol to give 1.59 g of the title compound as colorless crystals, m.p. 172-174°; NMR (CDCl3) δ1.59 (m, 1H); 2.0(m, 1H); 2.36 (dq (doublet of quartets?), 1H); 2.5 (t, 2H); 2.67 (dq, 1H); 3.88 (s, 3H); 7.0 (d, 2H); 7.26 (s, 4H) 7.86 (d, 2H) In a manner essentially that of Example 100, the following products of Examples 101-171 were obtained by alkylation of an arylthiazolidine-2,4-dione with the appropriate iodo or bromo compound. All structures were verified by NMR and gave spectra consistent with that shown in Example 100:
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([CH3:12])[C:9]=2[CH3:11])[CH:4]([CH3:18])[CH:3]1[CH2:19][CH3:20].[Cl:21]Cl>Cl.C(O)(=O)C>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([CH3:12])[C:9]=2[CH3:11])[CH:4]([CH3:18])[C:3]1([CH2:19][CH3:20])[Cl:21]
Reactant: ClCl
Reactant: CCC1C(=O)c2c(cc(OCC(=O)O)c(C)c2C)C1C
Agent: Cl
Solvent: CC(=O)O
Product: CCC1(Cl)C(=O)c2c(cc(OCC(=O)O)c(C)c2C)C1C

Procedure:
By following substantially the procedure described in Example 12, Step B, using as the reactants (1-oxo-2-ethyl-3,6,7-trimethyl-5-indanyloxy)acetic acid (2.76 g., 0.01 mole), glacial acetic acid (50 ml.), chlorine (710 mg., 0.01 mole) and concentrated hydrochloric acid (1 drop) there is obtained (1-oxo-2-ethyl-2-chloro-3,6,7-trimethyl-5-indanyloxy)acetic acid.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:4]=[C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[CH:15][CH:14]=[C:13]([CH3:24])[N:12]=2)=[O:10])[S:6][CH:7]=1.Br[C:28]1C=NC=CC=1C>>[F:26][C:2]([F:1])([F:25])[C:3]1[N:4]=[C:5]([NH:8][C:9]([C:11]2[C:16]([NH:17][C:18]3[CH:19]=[N:20][CH:21]=[CH:22][C:23]=3[CH3:28])=[CH:15][CH:14]=[C:13]([CH3:24])[N:12]=2)=[O:10])[S:6][CH:7]=1
Reactant: Cc1ccncc1Br
Reactant: Cc1ccc(Nc2cccnc2)c(C(=O)Nc2nc(C(F)(F)F)cs2)n1
Product: Cc1ccc(Nc2cnccc2C)c(C(=O)Nc2nc(C(F)(F)F)cs2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (4-trifluoromethyl-thiazol-2-yl)-amide (example 18) and 3-Bromo-4-methylpyridine in accordance with the general method of example 20 to yield the final compound as a orange solid, MS (ISP): m/e=394.0 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C1C(=O)N([Br:36])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:36][CH2:1][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2ccsc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cccc2ccsc12
Yield: 38.6 %

Procedure:
To a solution of intermediate 137, 7-methylbenzo[b]thiophene (1.0 g, 6.5 mmol) in CCl4 (20 mL) was added benzoyl peroxide (1.1 g, 4.54 mmol) followed by portionwise addition of NBS (1.15 g, 6.5 mmol). The reaction mixture stirred at reflux while irradiating with a 250 W lamp. The reaction mixture was stirred at reflux for 3 h. The solution was cooled, filtered and the solvent evaporated in vacuo. The residue was subjected to column chromatography on silica gel with hexanes as the eluent to afford the title compound (0.570 g, 33% yield): 1H NMR (400 MHz, CDCl3) δ: 7.80 (1H, dd, J=7.8, 1.7 Hz), 7.49 (1H, d, J=5.4 Hz), 7.40-7.33 (3H, m), 4.78 (2H, s). LCMS (M+H)+ m/z 209.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([C:13]([F:16])([F:15])[F:14])([OH:12])[CH2:4][C:5]1[CH:6]2[CH2:11][CH:9]([CH:10]=1)[CH2:8][CH2:7]2.[C:19](Cl)(=[O:21])[CH3:20]>C(N(CC)CC)C>[F:1][C:2]([F:17])([F:18])[C:3]([C:13]([F:15])([F:14])[F:16])([O:12][C:19](=[O:21])[CH3:20])[CH2:4][C:5]1[CH:6]2[CH2:11][CH:9]([CH:10]=1)[CH2:8][CH2:7]2
Reactant: CC(=O)Cl
Reactant: OC(CC1=CC2CCC1C2)(C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(=O)OC(CC1=CC2CCC1C2)(C(F)(F)F)C(F)(F)F

Procedure:
Notes: 2-(1′,1′-bis(trifluoromethyl)-1′-acetoxyethyl)norbornene was prepared from 2-(1′,1′-bis(trifluoromethyl)-1′-hydroxyethyl)norbornene (Central Glass, Japan), using a standard procedure (acetylchloride and triethyl amine).
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.[OH:15][CH2:16][C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>>[C:6]([C:5]1[C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=[CH:11][C:4]=1[O:15][CH2:16][C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])#[N:7]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cccc([N+](=O)[O-])c1C#N
Yield: 89 %

Procedure:
Prepared as in Example 166d from 2,6-dinitrobenzonitrile and (S)-tert-butyl 2-(hydroxymethyl)pyrrolidine-1-carboxylate in 89% yield as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ 1.40 (s, 9H), 1.81 (m, 1H), 2.03 (m, 3H), 3.32 (m, 2H), 4.08 (m, 1H), 4.33 (m, 2H), 7.79 (d, J=7.8 Hz, 1H), 7.93 (m, 2H).
Reaction SMILES: [CH:1]1([NH:7][C:8]([NH2:10])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:11]1(N)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.NC(N)=O>>[C:8]([NH:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([NH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:9]
Reactant: NC(=O)NC1CCCCC1
Reactant: NC1CCCCC1
Agent: NC(N)=O
Product: O=C(NC1CCCCC1)NC1CCCCC1

Procedure:
U.S. Pat. Nos. 2,253,528 and 2,257,717 disclose a preparation of monocyclohexylurea by reacting cyclohexylamine with an excess of urea and under an overpressure in an autoclave within a temperature range from 100° C. to the decomposition point of the monocyclohexylurea. During this reaction considerable proportions of dicyclohexylurea are produced which have to be separated off in an expensive manner.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13][N:12]=[C:11]([CH3:14])[N:10]=2)[C:5]([OH:8])=[N:6][CH:7]=1.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1C=CC=CC=1.C(=O)([O-])[O-].[Ag+2]>[CH2:15]([O:8][C:5]1[C:4]([C:9]2[O:13][N:12]=[C:11]([CH3:14])[N:10]=2)=[CH:3][C:2]([Br:1])=[CH:7][N:6]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: Cc1noc(-c2cc(Br)cnc2O)n1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: c1ccccc1
Product: Cc1noc(-c2cc(Br)cnc2OCc2ccccc2)n1
Temperature: 20 °C
Reaction time: 6 h

Procedure:
A solution 5-bromo-3-(3-methyl-1,2,4-oxadiazol-5-yl)pyridin-2-ol (1 eq) in benzene (0.05M) was added silver carbonate (1 eq) and benzyl bromide (1.2 eq). The reaction mixture was stirred 6 h at 20° C. and then concentrated. The residue was purified by flash chromatography (Hexane:EtOAc, 90:10) to afforded the title compound.