Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[CH:20][C:6]1=2)=[O:4].[N:21]1([CH2:26][C@@H:27]2[CH2:31][CH2:30][CH2:29][NH:28]2)[CH2:25][CH2:24][CH2:23][CH2:22]1.C(OCC)(=O)C.CO>C(O)C>[N:21]1([CH2:26][C@@H:27]2[CH2:31][CH2:30][CH2:29][N:28]2[CH2:2][C:3]([N:5]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[C:9](=[O:16])[NH:8][C:7]3[CH:17]=[CH:18][CH:19]=[CH:20][C:6]2=3)=[O:4])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=C1Nc2ccccc2N(C(=O)CCl)c2ccccc21
Reactant: C1CN[C@H](CN2CCCC2)C1
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C1Nc2ccccc2N(C(=O)CN2CCC[C@H]2CN2CCCC2)c2ccccc21

Procedure:
The title compound is prepared analogously to Example 31 from 5-(chloroacetyl)-5,10-dihydro-11H-dibenzo[b,e][1,4]diazepin-11-one and (S)-(+)-2-[(1-pyrrolidinyl)methyl]pyrrolidine to give colorless crystals, mp. 142°-144° C. (ethyl acetate/methanol 99:1 v/v); [α]D20 =-18.5° (ethanol).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[C:7](=[CH2:11])[CH2:6][CH2:5][C:4]=2[C:3]=1[C:12]#[N:13].B.C1C[O:18]CC1.[OH-].[Na+].OO>C1COCC1.O>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[CH:7]([CH2:11][OH:18])[CH2:6][CH2:5][C:4]=2[C:3]=1[C:12]#[N:13]
Reactant: C1CCOC1
Reactant: C=C1CCc2c1ccc(F)c2C#N
Agent: B
Agent: OO
Agent: [Na+]
Solvent: O
Product: N#Cc1c(F)ccc2c1CCC2CO
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-Fluoro-1-methylidene-2,3-dihydro-1H-indene-4-carbonitrile (30 mg, 0.173 mmol) in THF was added BH3.THF (0.173 ml, 0.173 mmol) at 0° C. The mixture was allowed to stir at 0° C. for 15 minutes, and then warm up to RT for 30 minutes. TLC showed little SM left at that point. To this reaction was then added Sodium Hydroxide (2M, 0.173 ml, 0.346 mmol) and Hydrogen peroxide (39.3 mg, 0.346 mmol). The mixture was stirred for another hour at RT. TLC and LC showed good reaction. The reaction was diluted with water, extracted with EtOAc, washed with water and brine, dried over Na2SO4, and concentrated. The resulting oil was used directly in the next step. LC-MS (IE, m/z): 192 [M+1]+.
Reaction SMILES: O[CH:2]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH3:18])[CH3:17])=[CH:11][CH:10]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].S(Cl)([Cl:29])=O.N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>CCOCC>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([Cl:29])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16]([C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH3:18])[CH3:17])=[CH:11][CH:10]=1)[CH3:7]
Reactant: CCOC(=O)C(O)Cc1ccc(OC(C)(C)C(=O)c2ccccc2)cc1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCOC(=O)C(Cl)Cc1ccc(OC(C)(C)C(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In 10 ml of ether, 350 mg of ethyl 2-hydroxy-3-[4-(2-benzoyl-2-propyloxy)phenyl]propionate, 360 mg of thionyl chloride, and catalytic amount of pyridine are added and stirred at room temperature overnight. Then, saturated aqueous sodium bicarbonate solution is added and the ether layer separated is dried, evaporated, and purified with column chromatography. Ethyl-2-chloro-3-[4-(2-benzoyl-2-propyloxy)phenyl]propionate is obtained with the yield of 300 mg. In IR and NMR, this product is in good agreement with the compound No. 1 in Example 7.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:9]1[C:10]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:11]2[C:16](=[CH:17][C:18]=1[CH3:19])[N:15]=[C:14]([NH:20][NH2:21])[CH:13]=[CH:12]2)[CH2:7][OH:8])([CH3:4])([CH3:3])[CH3:2].[CH:29](OCC)(OCC)OCC>C(O)CCC.C(OCC)(=O)C>[C:1]([O:5][C@@H:6]([C:9]1[C:10]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[C:11]2[C:16](=[CH:17][C:18]=1[CH3:19])[N:15]1[CH:29]=[N:21][N:20]=[C:14]1[CH:13]=[CH:12]2)[CH2:7][OH:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(OCC)OCC
Reactant: Cc1cc2nc(NN)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: CCCCO
Product: Cc1cc2c(ccc3nncn32)c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Temperature: 100 °C

Procedure:
The mixture of (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-2-hydrazinyl-7-methylquinolin-6-yl)ethanol and triethyl orthoformate (0.5 mL) in butanol (5 mL) was heated at 100° C. for 12 hours. The solution was diluted with ethyl acetate, and was washed with 1.0 N sodium hydroxide solution and brine, and dried with sodium sulfate. Concentration and purification by flash column chromatography (hexanes/EtOAc) gave (S)-2-tert-butoxy-2-(6-(4-chlorophenyl)-8-methyl-[1,2,4]triazolo[4,3-a]quinolin-7-yl)ethanol (3.3 mg). LCMS-ESI+ (m/z): [M+H]+ calcd for C23H25ClN3O2: 410.2. Found: 410.2.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([CH2:7][CH2:8][CH2:9][N:10]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:5][N:6]=1.[OH-].[Na+].C(O)(=O)CCC(O)=O>Cl.C(OCC)(=O)C.CO>[CH3:1][C:2]1[S:3][C:4]([CH2:7][CH2:8][CH2:9][NH2:10])=[CH:5][N:6]=1
Reactant: Cc1ncc(CCCN2C(=O)c3ccccc3C2=O)s1
Agent: Cl
Agent: O=C(O)CCC(=O)O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ncc(CCCN)s1

Procedure:
A solution of 19 g of the product of Step F in 100 ml of concentrated hydrochloric acid was refluxed for 16 hours and was then iced. Concentrated sodium hydroxide solution was slowly added thereto to adjust the pH to 12-13 and the mixture was extracted with ethyl acetate. The extracts were dried and evaporated to dryness under reduced pressure to obtain 11 g of raw product which was dissolved in ethyl acetate. A solution of 10% succinic acid in methanol was added thereto until the pH was 7 and the mixture was iced and vacuum filtered. The recovered product was dried and was crystallized from isopropanol to obtain 11.8 g of the hemisuccinate of 2-methyl-5-thiazole-propanamine melting at 170° C.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[N:28]1([CH2:33][C:34]2[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1>>[N:28]1([CH2:33][C:34]2[CH:40]=[CH:39][C:37]([NH:38]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:12]4[C:7]\3=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=4)/[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21)c1ccccc1
Reactant: Nc1ccc(CN2CCCC2)cc1
Product: COc1cc2c(cc1OC)/C(=C(/Nc1ccc(CN3CCCC3)cc1)c1ccccc1)C(=O)N2

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone and 4-(pyrrolidin-1-yl-methyl)-aniline
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[OH:15].[CH2:16]([O:18][C:19](=[O:24])[CH:20]=[C:21](Cl)[CH3:22])[CH3:17]>O1CCCC1>[CH2:16]([O:18][C:19](=[O:24])/[CH:20]=[C:21](/[O:15][C:9]1[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:8]=1[Cl:7])\[CH3:22])[CH3:17]
Reactant: CCOC(=O)C=C(C)Cl
Reactant: Oc1ccc(Cl)cc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)Oc1ccc(Cl)cc1Cl
Temperature: 23 °C
Yield: 38.5 %

Procedure:
Potassium t-butoxide (7.50 g, 0.067 mol) was added to a stirred solution of 2,4-dichloro-phenol (5.46 g, 0.033 mol) in tetrahydrofuran (35 mL) at 23° C. under nitrogen and the reaction mixture was heated to reflux for 0.75 h. The reaction mixture was cooled to 23° C. and a solution of 3-chloro-but-2-enoic acid ethyl ester (prepared as in Example 191, 5.00 g, 0.034 mol) in tetrahydrofuran (40 mL) was added to the reaction mixture. The reaction mixture was refluxed for an additional 3 h. After this time, the mixture was concentrated in vacuo and the residue was diluted with water and extracted with diethyl ether. The organic layer was then washed with 5% aqueous sodium hydroxide solution followed by a saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo to afford (E)-3-(2,4-dichloro-phenoxy)-but-2-enoic acid ethyl ester (3.50 g, 38%) as a yellow oil.
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C@H:10]([NH:16][S@](C(C)(C)C)=O)[CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:6][CH:5]=1.[ClH:24].O1CCOCC1>CO.C(Cl)Cl>[ClH:24].[NH2:16][C@@H:10]([C:7]1[CH:8]=[CH:9][C:4]([O:3][CH:2]([F:1])[F:23])=[CH:5][CH:6]=1)[CH2:11][C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)C[C@@H](N[S@@](=O)C(C)(C)C)c1ccc(OC(F)F)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C[C@@H](N)c1ccc(OC(F)F)cc1
Reaction time: 1 h
Yield: 100 %

Procedure:
To a stirred solution of 380 (8.98 g, 25.7 mmol) in MeOH (60 mL) and DCM (30 mL) was added 4M HCl in dioxane (12.9 mL, 51.4 mmol) and stirring was continued for 60 min at RT. HCl was removed with a stream of dry N2 and most of the solvent was removed on in a rotary evaporator. Ether was added to the residue and the precipitated white solid was filtered to afford 7.23 g (100%) of (R)-methyl 3-amino-3-(4-(difluoromethoxy)phenyl)propanoate hydrochloride (382) which was ca. 95% ee by chiral hplc.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11](Cl)=[O:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]1=[O:14].Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=1[Cl:25].C([O-])(O)=O.[Na+]>COCCOC.[Zn].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>[Cl:25][C:18]1[CH:19]=[C:20]([O:23][CH3:24])[CH:21]=[CH:22][C:17]=1[CH2:16][C:11]([C:8]1[CH:9]=[CH:10][C:5]2[O:4][C:3](=[O:14])[N:2]([CH3:1])[C:6]=2[CH:7]=1)=[O:12]
Reactant: COc1ccc(CBr)c(Cl)c1
Reactant: Cn1c(=O)oc2ccc(C(=O)Cl)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(CC(=O)c2ccc3oc(=O)n(C)c3c2)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 55 %

Procedure:
To a suspension of zinc powder (1.67 g) in 1,2-dimethoxyethane (60 mL) was added tetrakis(triphenylphosphine)palladium(0) (295 mg). A suspension of the 3-methyl-2-oxo-2,3-dihydro-benzooxazole-5-carbonyl chloride (2.71 g) in 1,2-dimethoxyethane (60 mL) was slowly added over a period of 20 minutes. The mixture was cooled in an ice bath and a solution of 1-bromomethyl-2-chloro-4-methoxy-benzene (3.01 g, [CAS Reg. No. 54788-17-9]) in 1,2-dimethoxyethane (20 mL) was slowly added over a period of 30 minutes. The mixture was stirred for 30 minutes at 0° C. and then for 2 hours at r.t. The reaction mixture was poured into ice and basified with sat. NaHCO3. The aqueous phase was then extracted two times with ethyl acetate and the organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, CH2Cl2) to give the title compound as a light yellow solid (2.45 g, 55%). MS (neg. ion, m/e)=330.3 [(M−H)−].
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([O:9][CH3:10])[C:6]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH3:27])(=[N:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:20])[CH:14]=2)=[CH:5][C:4]=1[N:28]=[CH:29]N(C)C)#[N:2].[NH2:33][C:34]1[S:35][CH:36]=[N:37][N:38]=1.CCCCCC.ClCCl.CO>CO>[CH2:25]([O:24][C:22]([N:21]=[S:19]([CH3:27])([C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][O:11][C:6]2[CH:5]=[C:4]3[C:3]([C:1]([NH:33][C:34]4[S:35][CH:36]=[N:37][N:38]=4)=[N:2][CH:29]=[N:28]3)=[CH:8][C:7]=2[O:9][CH3:10])[CH:14]=1)=[O:20])=[O:23])[CH3:26]
Reactant: Nc1nncs1
Reactant: CCOC(=O)N=S(C)(=O)c1cccc(COc2cc(N=CN(C)C)c(C#N)cc2OC)c1
Solvent: ClCCl
Solvent: CO
Solvent: CCCCCC
Product: CCOC(=O)N=S(C)(=O)c1cccc(COc2cc3ncnc(Nc4nncs4)c3cc2OC)c1
Yield: 47 %

Procedure:
According to GWP 5, the reaction of N′-(2-cyano-5-{3-[(RS)-N-(ethoxycarbonyl)-S-methylsulphonimidoyl]benzyloxy}-4-methoxyphenyl)-N,N-dimethylformimidamide (76 mg, 0.17 mmol) with 2-amino-1,3,4-thiadiazole (20 mg, 0.20 mmol) and chromatographic purification (silica gel, amino column, hexane, dichloromethane/methanol: 0→5% methanol) gives the desired product in 47% yield (40 mg).
Reaction SMILES: [NH2:1][C@H:2]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[CH:10][CH:11]=2)[CH:6]=1)[CH2:3][OH:4].[F:17][C:18]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:19]=1[CH:20]=[CH:21][C:22](O)=[O:23].CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[F:17][C:18]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:19]=1[CH:20]=[CH:21][C:22]([NH:1][C@H:2]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[CH:10][CH:11]=2)[CH:6]=1)[CH2:3][OH:4])=[O:23]
Reactant: O=C(O)C=Cc1c(F)cccc1F
Reactant: COc1ccc2ccc([C@@H](N)CO)cc2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2ccc([C@H](CO)NC(=O)C=Cc3c(F)cccc3F)cc2c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 65.2 %

Procedure:
A mixture of (R)-2-Amino-2-(7-methoxy-naphthalen-2-yl)-ethanol (0.1 mmol), 2,6-difluorocinnamic acid (0.1 mmol), EDC·HCl (0.2 mmol), DMAP 0.1 mmol), triethyl amine (0.3 mmol) in dichloromethane (2 mL) was stirred at room temperature for 14 h. The reaction mixture was purified by flash chromatography eluting with 5% methnol in ethyl acetate to provide the title compound as a solid (25 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:17]([CH3:19])[CH3:18])[C:7]([N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([OH:16])=O)=[O:8])=[O:4].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CN1CCOCC1.[Br:48][C:49]1[CH:54]=[CH:53][C:52]([CH:55]2[N:59]([C:60]3[CH:65]=[CH:64][C:63]([C:66]([CH3:69])([CH3:68])[CH3:67])=[CH:62][CH:61]=3)[CH:58]([C:70]3[CH:71]=[C:72]([NH2:88])[C:73]([NH:76][CH2:77][C:78]4[CH:83]=[CH:82][C:81]([O:84][CH3:85])=[CH:80][C:79]=4[O:86][CH3:87])=[CH:74][CH:75]=3)[CH2:57][CH2:56]2)=[CH:51][CH:50]=1>CN(C=O)C.CCOC(C)=O>[Br:48][C:49]1[CH:54]=[CH:53][C:52]([CH:55]2[N:59]([C:60]3[CH:61]=[CH:62][C:63]([C:66]([CH3:69])([CH3:68])[CH3:67])=[CH:64][CH:65]=3)[CH:58]([C:70]3[CH:75]=[CH:74][C:73]([NH:76][CH2:77][C:78]4[CH:83]=[CH:82][C:81]([O:84][CH3:85])=[CH:80][C:79]=4[O:86][CH3:87])=[C:72]([NH:88][C:14]([C@@H:10]4[CH2:11][CH2:12][CH2:13][N:9]4[C:7](=[O:8])[C@@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[CH:17]([CH3:19])[CH3:18])=[O:16])[CH:71]=3)[CH2:57][CH2:56]2)=[CH:51][CH:50]=1
Reactant: COc1ccc(CNc2ccc(C3CCC(c4ccc(Br)cc4)N3c3ccc(C(C)(C)C)cc3)cc2N)c(OC)c1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)O)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)Nc1cc(C2CCC(c3ccc(Br)cc3)N2c2ccc(C(C)(C)C)cc2)ccc1NCc1ccc(OC)cc1OC)C(C)C
Temperature: 0 °C
Reaction time: 18 h

Procedure:
(S)-1-((S)-2-(methoxycarbonylamino)-3-methylbutanoyl)pyrrolidine-2-carboxylic acid (0.339 g, 1.245 mmole) and HOBt (0.191 g, 1.245 mmole) were dissolved in DMF (4 mL) cooled in an ice bath and treated with EDAC (0.245 g, 1.245 mmole) and N-Methylmorpholine (NMM) (0.55 mL, 4.98 mmole). The resulting solution was stirred 5 minutes in the ice bath, treated dropwise with the product from Example 191F in DMF (4 mL) and the resulting dark mixture was stirred in the ice bath for 1 hr then at room temperature for 18 hr. The next day, the reaction mixture was diluted with EtOAc (50 mL) and the organic layer was washed with 10% NaHCO3 and 10% NaCl, dried over anhydrous Na2SO4(s), filtered and the solvent was removed in vacuo leaving an oily residue as the title compound as a mixture of isomers (0.65 g). ESI+(m/z): 868.2.
Reaction SMILES: Br.[NH2:2][C:3]1[N:4]=[C:5]([Br:9])[S:6][C:7]=1[CH3:8].N1C=CC=CC=1.[C:16]([O-])(=[O:18])[CH3:17].[Na+]>C(OC(=O)C)(=O)C>[C:16]([NH:2][C:3]1[N:4]=[C:5]([Br:9])[S:6][C:7]=1[CH3:8])(=[O:18])[CH3:17]
Reactant: Cc1sc(Br)nc1N
Reactant: CC(=O)[O-]
Agent: Br
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1nc(Br)sc1C
Reaction time: 1 h
Yield: 50 %

Procedure:
A suspension of 4-amino-2-bromo-5-methylthiazole hydrobromide (50 mM, 13.7 g) in acetic anhydride (100 ml) was treated dropwise with pyridine (10 ml) while cooling in an ice bath. After stirring for 1 hour the reaction mixture was poured onto 20% aqueous sodium acetate (1 l) and the aqueous solution extracted with dichloromethane (3 × 500 ml.). The combined organic layers were dried and evaporated under reduced pressure to give an oil which crystallised on trituration with ether. The crude product was recrystallised from ethanol to give the 4-acetamido-2-bromo-5-methylthiazole (11.7 g, 50%). mp 129°. (Found: C, 31.15; H, 3.15; N, 12.3. C6H7BrN2OS requires: C, 30.6; H, 3.0; N, 11.9%).
Reaction SMILES: C1(C)C=CC=CC=1.[CH:8]12[O:17][CH:14]([CH2:15][CH2:16]1)[CH:13]1[CH:9]2[C:10](=[O:19])[CH2:11][C:12]1=[O:18].C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Br:32][C:33]1[CH:38]=[CH:37][C:36]([Pb+3])=[C:35]([CH2:40][CH3:41])[CH:34]=1.Cl>CN(C)C1C=CN=CC=1.C(Cl)(Cl)Cl>[Br:32][C:33]1[CH:38]=[CH:37][C:36]([CH:11]2[C:10](=[O:19])[CH:9]3[CH:13]([CH:14]4[O:17][CH:8]3[CH2:16][CH2:15]4)[C:12]2=[O:18])=[C:35]([CH2:40][CH3:41])[CH:34]=1
Reactant: O=C1CC(=O)C2C3CCC(O3)C12
Reactant: CCc1cc(Br)ccc1[Pb+3]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CCc1cc(Br)ccc1C1C(=O)C2C3CCC(O3)C2C1=O
Temperature: 80 °C
Reaction time: 4 h

Procedure:
4-Dimethylaminopyridine (3.67 g, 30.0 mmol) and toluene (10 ml) are added to a solution of (1RS,2SR,6RS,7SR)-10-oxatricyclo[5.2.1.02,6]decane-3,5-dione (1.0 g, 6.0 mmol) in chloroform (40 ml) and the reaction mixture is heated to 80° C. 4-Bromo-2-ethylphenyllead triacetate (5.13 g, 9.04 mmol) is added portionwise over 20 minutes, and once the addition is complete the reaction mixture is stirred at 80° C. for a further 4 hours. The mixture is cooled to room temperature, 2 M aqueous hydrochloric acid (40 ml) is added, and the mixture is stirred vigorously for 15 minutes, then filtered through a small plug of diatomaceous earth, washing with 40 ml dichloromethane. The organic phase is separated, and the aqueous phase is extracted with dichloromethane (2×20 ml). The organic solutions are combined, dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel to give (1RS,2SR,6RS,7SR)-4-(4-bromo-2-ethylphenyl)-10-oxatricyclo-[5.2.1.02,6]decane-3,5-dione.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([O:12][CH2:13][C:14]([OH:16])=O)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+]([O-])(O)=O.[O:21]([CH2:25][CH2:26][NH2:27])[N+:22]([O-:24])=[O:23].C(OC(C)C)(C)C>>[O:21]([CH2:25][CH2:26][NH:27][C:14](=[O:16])[CH2:13][O:12][C:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:11][N:10]=1)[N+:22]([O-:24])=[O:23]
Reactant: NCCO[N+](=O)[O-]
Reactant: O=C(O)COc1cc(-c2ccccc2)on1
Solvent: O=[N+]([O-])O
Solvent: CC(C)OC(C)C
Product: O=C(COc1cc(-c2ccccc2)on1)NCCO[N+](=O)[O-]
Yield: 53.2 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.78 g of 5-phenyl-3-isoxazolyloxyacetic acid and 0.60 g of nitroxyethylamine nitrate, 0.58 g of the title compound was obtained as colorless needles (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: C1COCC1.O.[CH3:7][O:8][C:9](=[O:32])[C:10]1[CH:15]=[C:14](OS(C(F)(F)F)(=O)=O)[CH:13]=[C:12]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:11]=1.[C:33]1(B(O)O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)C.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>[CH3:7][O:8][C:9]([C:10]1[CH:15]=[C:14]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:13]=[C:12]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:11]=1)=[O:32]
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(OS(=O)(=O)C(F)(F)F)c1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(OCc2ccccc2)cc(-c2ccccc2)c1
Temperature: 130 °C
Yield: 90.8 %

Procedure:
To a mixture of THF/H2O (5 mL, v/v=4:1) in a microwave vial was added 3-benzyloxy-5-trifluoromethanesulfonyloxy-benzoic acid methyl ester (100 mg, 0.256 mmol), phenylboronic acid (34 mg, 0.281 mmol), potassium carbonate (71 mg, 0.512 mmol), and Pd(PPh3)4 (15 mg, 0.02 mmol). The reaction vessel was sealed and subjected to microwave heating for 5 min at 130° C. After cooling, it was diluted with diethyl ether and washed with brine, dried (MgSO4), and evaporated. The residue was subjected to chromatography on silica gel using an ethyl acetate-hexane gradient to afford 74 mg (90%) of 5-benzyloxybiphenyl-3-carboxylic acid methyl ester: LCMS m/z=319.4 [C21H18O3+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.[Cl:19][CH2:20][C:21](Cl)=[O:22]>C(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:21]([CH2:20][Cl:19])=[O:22])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCNCC1
Reactant: O=C(Cl)CCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1CCN(C(=O)CCl)CC1
Reaction time: 2 h
Yield: 383.5 %

Procedure:
To a solution of 1-ethoxycarbonylpiperazine (1.5 mL, 10 mmol) in 40 mL CH2Cl2, was added triethylamine (2 mL, 14 mmol) and chloroacetyl chloride (0.8 mL, 5.0 mmol) at 0° C. The resulting reaction mixture was stirred at amibent temperature for 2 hours. The reaction mixture was washed with water, 2N NaHSO4 and brine, and dried over sodium sulfate. The solvent was evaporated in vacuo to afford 1-ethoxycarbonyl-4-chloromethylcarbonylpiperazine (4.5 g) as an yellow oil, which was used without further purification.
Reaction SMILES: S([O-])([O-])(=O)=O.[Na+].[Na+].[N+:8]([C:11]1[CH:12]=[N:13][C:14]2[C:19]([C:20]=1[NH:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[CH:18][CH:17]=[CH:16][CH:15]=2)([O-])=O>[Pt].C1(C)C=CC=CC=1>[NH2:8][C:11]1[CH:12]=[N:13][C:14]2[C:19]([C:20]=1[NH:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[CH:18][CH:17]=[CH:16][CH:15]=2
Reactant: CC(C)(C)OC(=O)NCCNc1c([N+](=O)[O-])cnc2ccccc12
Agent: [Pt]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCNc1c(N)cnc2ccccc12
Reaction time: 8 h
Yield: 80.5 %

Procedure:
Platinum on carbon (1 g of 10%) and sodium sulfate (2 g) were added to a slurry of tert-butyl N-[2-(3-nitroquinolin-4-yl)aminoethyl]carbamate (100 g, 0.30 mol) in toluene (500 mL). The mixture was placed under a hydrogen atmosphere at 50 psi (3.4×104 pascals) on a Parr apparatus at ambient temperature overnight. The reaction mixture was filtered. The filtrate was concentrated to provide 73 g of tert-butyl N-[2-(3-aminoquinolin-4-yl)aminoethyl]carbamate as a dark gold oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:21])=[CH:5][C:6]2[CH2:12][CH2:11][N:10]([CH:13]([CH2:17][O:18][CH3:19])[CH2:14][O:15][CH3:16])[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:23]1[N:28]=[C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([N:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])[C:26]([Cl:42])=[CH:25][N:24]=1>>[Cl:42][C:26]1[C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[S:36]([N:39]([CH3:41])[CH3:40])(=[O:38])=[O:37])=[N:28][C:23]([NH:21][C:4]2[C:3]([O:2][CH3:1])=[CH:20][C:7]3[CH2:8][CH2:9][N:10]([CH:13]([CH2:14][O:15][CH3:16])[CH2:17][O:18][CH3:19])[CH2:11][CH2:12][C:6]=3[CH:5]=2)=[N:24][CH:25]=1
Reactant: CN(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: COCC(COC)N1CCc2cc(N)c(OC)cc2CC1
Product: COCC(COC)N1CCc2cc(Nc3ncc(Cl)c(Nc4ccccc4S(=O)(=O)N(C)C)n3)c(OC)cc2CC1

Procedure:
The title compound was prepared from 8-Methoxy-3-(2-methoxy-1-methoxymethyl-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N,N-dimethyl-benzenesulfonamide in an analogous manner to Example 61e. Product isolated as an off-white solid (0.025 g, 35%). MP: 54-76° C. 1HNMR (400 MHz, CDCl3, δ, ppm): 9.34 (s, 1H), 8.53 (d, 1H, J=8.6 Hz), 8.13 (s, 1H), 7.97 (s, 1H), 7.88 (d, 1H, J=7.8 Hz), 7.59-7.53 (m, 1H), 7.48 (s, 1H), 7.26-7.20 (m, 1H), 6.65 (s, 1H), 3.87 (s, 3H), 3.57-3.51 (m, 2H), 3.48-3.42 (m, 2H), 3.33 (s, 6H), 3.06-2.98 (m, 1H), 2.87-2.67 (m, 14H). MS: 605.50 (MH)+.