Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([OH:18])=[C:16]([S:19][C:20]([F:23])([F:22])[F:21])[C:15]([C:24]#[N:25])=[N:14]1.ClC1C=CC=C(C(OO)=[O:34])C=1.C(=O)(O)[O-].[Na+]>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([OH:18])=[C:16]([S:19]([C:20]([F:23])([F:21])[F:22])=[O:34])[C:15]([C:24]#[N:25])=[N:14]1
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(O)c1SC(F)(F)F
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(O)c1S(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of 15 g (35.5 mmol) of 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulfenyl-5-hydroxypyrazole in 125 ml of dichloromethane at room temperature was added a solution of m-chloroperbenzoic acid (8.76 g, 70%, 35.5 mmol) in 375 ml of dichloromethane. The resulting solution was stirred at room temperature for 17 hr. It was then concentrated and triturated with ethyl acetate and heptane(1:2). Upon filtration a solid was obtained. This solid was dissolved in ethyl acetate and stirred with saturated sodium bicarbonate solution. The layers were separated and the aqueous layer was extracted three times with ethyl acetate. The combined organic layer was dried (magnesium sulfate) and concentrated. Upon chromatographic purification via silica gel column, a solid (5.7 g, 13.01 mol, 37%) was obtained as the desired product, mp 185–187d.
Reaction SMILES: [CH3:1][C:2]1[C@@H:3]2[C@@H:19]([C@:20]3([CH3:28])[C:25]([CH:26]=1)=[CH:24][C:23](=[O:27])[CH2:22][CH2:21]3)[CH2:18][CH2:17][C@@:16]1([CH3:29])[C@H:4]2[CH2:5][CH2:6][C@@H:7]1[C@H:8]([CH3:15])[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12].C1CCCCC=1.N#N>[Pd].C(O)C>[CH3:1][C@H:2]1[CH2:26][C:25]2[C@:20]([CH3:28])([CH2:21][CH2:22][C:23](=[O:27])[CH:24]=2)[C@@H:19]2[C@@H:3]1[C@H:4]1[C@:16]([CH3:29])([CH2:17][CH2:18]2)[C@@H:7]([C@H:8]([CH3:15])[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[CH2:6][CH2:5]1
Reactant: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C(C)=CC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [Pd]
Agent: N#N
Solvent: CCO
Solvent: C1=CCCCC1
Product: COC(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3[C@@H](C)CC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
A mixture of methyl 7-methyl-3-oxochola-4,6-dien-24-oate (9) (0.62 g, 1.56 mmoles), 5% palladium on carbon (72 mg), 1, 8-diazobicyclo[5.4.0]undec-7-ene (15 ml), cyclohexene (4.9 ml) and ethanol (3.6 ml) was heated under reflux in an N2 for 6 hrs. The cooled mixture was filtered, and the catalyst washed with ethanol (4 times). The combined filtrate and washes were evaporated in vacuo . The residue was dissolved in EtOAc (30 ml), washed with 0.5M HCl, H2O, saturated brine and dried (MgSO4). Evaporation in vacuo gave 0.62 g of pure 10 as a pale yellow syrup. NMR (CDCl3): δ 0.71 (s, 3H, 18-Me); 0.94 (d, 3H, 20-Me); 1.05 (d, 3H, 7-Me); 1.15 (s, 3H, 19-Me); 3.66 (s, 3H, CO2Me); 5.70 (s, 1H, 4-H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)C(=C1SCCCS1)[CH2:6][CH2:5]2.Cl.[C:18]([OH:21])(=[O:20])[CH3:19]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:19]([C:18]([OH:21])=[O:20])[CH2:6][CH2:5]2
Reactant: CC(=O)O
Reactant: Brc1ccc2c(c1)CCC2=C1SCCCS1
Agent: Cl
Product: O=C(O)C1CCc2cc(Br)ccc21
Temperature: 25 °C
Yield: 86 %

Procedure:
To a mixture of 2-(5-bromo-indan-1-ylidene)-[1,3]dithiane (2.02 g, 6.45 mmol) in acetic acid (34 ml) was added 37% HCl (11 ml). After the addition, the brown mixture was heated to reflux for 3 h; then, the reaction mixture was allowed to cool to room temperature and was concentrated to dryness, using toluene as co-evaporating solvent to remove acetic acid and water. This process was repeated four times. The remaining brown oil was purified by chromatography (silica gel; CH2Cl2/EtOAc 100:0-0:100) to obtain the title compound as light brown solid (1.335 g, 86%). MS: 238.6 [M−H]−.
Reaction SMILES: Cl.[C:2]1([CH3:10])[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[C:11]([CH2:17][C:18]#[N:19])(=O)[C:12]([CH3:15])([CH3:14])[CH3:13]>CO>[C:12]([C:11]1[CH:17]=[C:18]([NH2:19])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:10])=[CH:3][CH:4]=2)[N:9]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Solvent: CO
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Temperature: 25 °C
Yield: 116 %

Procedure:
A solution of p-tolyl-hydrazine hydrochloride (15.86 g, 100 mmol) and pivaloylacetonitrile (17.9 g, 143 mmol) dissolved in MeOH (65 mL) was heated to reflux for 18 hours under N2 atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was triturated with ether and collected by filtration. The solid was dried under high vacuum to provide 26.6 g of white solid (99% yield).
Reaction SMILES: [C:1]([O:8][C:9]([C:12]([CH2:15][CH2:16]I)([F:14])[F:13])([F:11])[F:10])([C:4]([F:7])([F:6])[F:5])([F:3])[F:2].CN1CCCC1=[O:24]>O>[C:1]([O:8][C:9]([C:12]([CH2:15][CH2:16][OH:24])([F:14])[F:13])([F:11])[F:10])([C:4]([F:7])([F:6])[F:5])([F:3])[F:2]
Reactant: FC(F)(F)C(F)(F)OC(F)(F)C(F)(F)CCI
Reactant: CN1CCCC1=O
Solvent: O
Product: OCCC(F)(F)C(F)(F)OC(F)(F)C(F)(F)F
Yield: 52 %

Procedure:
The flask was charged with 130 g of C2F5OCF2CF2CH2CH2I, 643 mL of the N-methyl pyrrolidone and 48 mL of deionized (DI) water. The reaction mixture was heated to 132 C for 20 hours. DI water was added and the lower layer was separated. The lower layer was dissolved in ether, washed with saturated sodium sulfite, and dried over anhydrous sodium sulfate. After rotary vaporization, 48 g of C2F5OCF2CF2CH2CH2OH (compound B3) was obtained by distillation in 52% yield. The boiling point was 70˜72° C. at 60 mm Hg pressure (7980 Pa).
Reaction SMILES: [F:1][C:2]1([F:35])[CH2:8][N:7]([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]2[N:17]=[C:18]([NH:21][C:22]3[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][C:23]=3[O:31][CH3:32])[N:19]=[CH:20][C:5]=2[N:4]([CH3:33])[C:3]1=[O:34].C(N(C(C)C)C(C)C)C.[O:45]1[CH2:50][CH2:49][CH:48]([NH2:51])[CH2:47][CH2:46]1>CN(C)C=O>[F:35][C:2]1([F:1])[CH2:8][N:7]([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:6]2[N:17]=[C:18]([NH:21][C:22]3[CH:30]=[CH:29][C:25]([C:26]([NH:51][CH:48]4[CH2:49][CH2:50][O:45][CH2:46][CH2:47]4)=[O:28])=[CH:24][C:23]=3[O:31][CH3:32])[N:19]=[CH:20][C:5]=2[N:4]([CH3:33])[C:3]1=[O:34]
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(CCc1ccccc1)CC(F)(F)C(=O)N2C
Reactant: NC1CCOCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)NC2CCOCC2)ccc1Nc1ncc2c(n1)N(CCc1ccccc1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
To a mixture of 0.08 g (0.17 mmole) of 4-(7,7-difluoro-5-methyl-6-oxo-9-phenethyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-275), 0.12 mL (0.64 mmole) of ethyldiisopropyl amine and 0.018 g (0.19 mmole) of tetrahydro-pyran-4-ylamine in 2.0 mL of dimethylformamide was added 0.079 g (0.19 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The mixture was extracted with dichloromethane 3 times. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-95:5) gave 0.070 g of 4-(7,7-difluoro-5-methyl-6-oxo-9-phenethyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-(tetrahydro-pyran-4-yl)-benzamide (I-280) as a white solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:9][CH2:10][C:11]2[N:12]=[C:13]([C:17]3[O:18][CH:19]=[CH:20][CH:21]=3)[O:14][C:15]=2[CH3:16])=[N:7][CH:8]=1.[CH2:22]([N:29]1[CH:33]=[C:32]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:31]([OH:39])=[N:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:22]([N:29]1[CH:33]=[C:32]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:31]([O:39][CH2:2][C:3]2[CH:8]=[N:7][C:6]([O:9][CH2:10][C:11]3[N:12]=[C:13]([C:17]4[O:18][CH:19]=[CH:20][CH:21]=4)[O:14][C:15]=3[CH3:16])=[CH:5][CH:4]=2)=[N:30]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(CCl)cn1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)nc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
A mixture of 5-chloromethyl-2-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}pyridine (1.30 g), ethyl 1-benzyl-3-hydroxy-1H-pyrazole-4-carboxylate (1.06 g), potassium carbonate (0.59 g) and N,N-dimethylformamide (50 mL) was stirred at 90° C. for 2 hrs. Water was poured into the reaction mixture, and the precipitated crystals were collected by filtration to give ethyl 1-benzyl-3-[(6-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-pyridinyl)methoxy]-1H-pyrazole-4-carboxylate as colorless crystals (2.00 g, yield 90%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 140-141° C.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[NH:9]1[CH:13]=[CH:12][CH:11]=[N:10]1.Br[C:15]1[CH:16]=[CH:17][C:18]2[C:19]3[N:28]([CH2:29][CH2:30][CH2:31][O:32][CH3:33])[C:27]([CH2:34][O:35][CH2:36][CH3:37])=[N:26][C:20]=3[C:21]([NH2:25])=[N:22][C:23]=2[CH:24]=1>[Cu]I.O1CCOCC1>[CH2:36]([O:35][CH2:34][C:27]1[N:28]([CH2:29][CH2:30][CH2:31][O:32][CH3:33])[C:19]2[C:18]3[CH:17]=[CH:16][C:15]([N:9]4[CH:13]=[CH:12][CH:11]=[N:10]4)=[CH:24][C:23]=3[N:22]=[C:21]([NH2:25])[C:20]=2[N:26]=1)[CH3:37]
Reactant: c1cn[nH]c1
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCOC
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOCc1nc2c(N)nc3cc(-n4cccn4)ccc3c2n1CCCOC
Temperature: 25 °C
Reaction time: 15.5 h
Yield: 25 %

Procedure:
A 4 dram vial containing a stir bar was charged sequentially with copper(I) iodide (0.003 g), potassium phosphate (0.890 g), pyrazole (0.164 g), 7-bromo-2-ethoxymethyl-1-(3-methoxypropyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.786 g), (1)-trans-1,2-diaminocyclohexane (0.030 mL), and anhydrous 1,4-dioxane (2 mL). The vial was flushed with nitrogen, capped, and placed in an oil bath at 110° C. After 15.5 hours, the reaction was cooled to room temperature and purified by flash column chromatography using a gradient of CMA/chloroform as the eluent. Subsequent recrystallization from acetonitrile yielded 0.190 g of 2-ethoxymethyl-1-(3-methoxypropyl)-7-(pyrazol-1-yl)-1H-imidazo[4,5-c]quinolin-4-amine as a white solid, mp 159.0-160.0° C.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:20])[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[C:6]2[N:5]=[C:4]([CH3:21])[C:3]=1[CH2:22][CH2:23]Cl.NC(N)=[S:27].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[C:16]1([CH3:17])[CH:15]=[C:14]([CH3:18])[CH:13]=[C:12]([CH3:19])[C:11]=1[C:10]1[C:9]([CH3:20])=[N:8][N:7]2[C:2]3[S:27][CH2:23][CH2:22][C:3]=3[C:4]([CH3:21])=[N:5][C:6]=12
Reactant: NC(N)=S
Reactant: Cc1cc(C)c(-c2c(C)nn3c(Cl)c(CCCl)c(C)nc23)c(C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(C)c(-c2c(C)nn3c4c(c(C)nc23)CCS4)c(C)c1
Yield: 97.7 %

Procedure:
A solution of 7-chloro-6-(2-chloroethyl)-3-mesityl-2,5-dimethylpyrazolo[1,5-a]pyrimidine (500 mg,1.38 mmol), thiourea (105 mg, 1.38 mmol)and sodium carbonate (180 mg, 1.73 mmol) in ethanol (10 mL) was heated under reflux for one hour. After evaporating, water was added and the resulting crystals were collected by filtration. The crystals were washed with water, to give the title compound (436 mg) as white crystals.
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1.[CH3:28][O:29][CH2:30][CH2:31][C:32](O)=[O:33]>>[O:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:32](=[O:33])[CH2:31][CH2:30][O:29][CH3:28])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[O:6][CH2:5]1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1
Reactant: COCCC(=O)O
Agent: Cl
Product: COCCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, off-white solid (36 mg, 64%), MS (ISP) m/z=418.4 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine hydrochloride (Intermediate A) (50 mg, 0.136 mmol) and 3-methoxypropionic acid.
Reaction SMILES: Br[CH2:2][CH:3]=[CH:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[CH:11]=[CH:10]2.[CH2:23]([NH:25][CH2:26][CH2:27][OH:28])[CH3:24]>>[CH2:23]([N:25]([CH2:2][CH:3]=[CH:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[CH:11]=[CH:10]2)[CH2:26][CH2:27][OH:28])[CH3:24]
Reactant: Fc1ccc(-n2ccc3cc(OCC=CCBr)ccc32)cc1
Reactant: CCNCCO
Product: CCN(CC=CCOc1ccc2c(ccn2-c2ccc(F)cc2)c1)CCO

Procedure:
In analogy to example 3.3, 5-(4-Bromo-but-2-enyloxy)-1-(4-fluoro-phenyl)-1H-indole and 2-ethylaminoethanol were converted to yield 2-(Ethyl-{4-[1-(4-fluoro-phenyl)-1H-indol-5-yloxy]-but-2-enyl}-amino)-ethanol as colorless viscous oil, MS: 369 (MH+).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)=[CH:13][CH:12]=2)[CH2:6]1)=[O:4].[OH-].[Na+].Cl>C1COCC1>[F:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[CH2:18][O:17][C:14]1[CH:13]=[CH:12][C:11]([N:7]2[C:8](=[O:10])[CH2:9][CH:5]([C:3]([OH:4])=[O:2])[CH2:6]2)=[CH:16][CH:15]=1
Reactant: COC(=O)C1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)C1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Temperature: 50 °C

Procedure:
3.5 g (10.2 mmol) of [Rac] 1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methyl ester (Example 1d) are dispersed in 11.2 ml of a 1N solution of sodium hydroxide, and tetrahydrofuran is added to such an extent that a clear solution is obtained. Thereupon, the reaction mixture is heated to 50° C. during 1 h. For the working-up, the cooled solution is treated with 11.2 ml of 1N hydrochloric acid and THF evaporated under reduced pressure while the product starts to precipitate. The product is filtered and dried under vacuum to yield 2.39 g (71% of theory) of a white solid which is used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[CH3:19][C:20]([CH3:24])([C:22]#[CH:23])[OH:21]>>[OH:21][C:20]([CH3:24])([CH3:19])[C:22]#[C:23][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)ccc1OCC2
Reactant: C#CC(C)(C)O
Product: CC(C)(O)C#Cc1ccc2c(c1)-c1nc(C(N)=O)cn1CCO2

Procedure:
10-Bromo-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide (0.1 g) was reacted with dimethyl ethynyl carbinol similar to as described in Procedure E to afford 52.2 mg of 10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide following reverse phase hplc purification. MS (Q1) 338 (M)+. 1H NMR (400 MHz, DMSO) δ 8.50 (d, J=2.1 Hz, 1H), 7.79 (s, 1H), 7.51 (s, 1H), 7.29 (dd, J=8.5, 2.2 Hz, 1H), 7.11 (s, 1H), 7.01 (d, J=8.5 Hz, 1H), 5.42 (s, 1H), 4.48 (s, 4H), 1.48 (s, 7H).
Reaction SMILES: Cl.C[O:3][C:4](=[O:16])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Br:15])[CH:9]=1)[NH2:6].[N:17]1[S:21][N:20]=[C:19]2[C:22]([S:26]([NH:29][C:30]3[CH:38]=[C:37]([Br:39])[CH:36]=[CH:35][C:31]=3[C:32](O)=[O:33])(=[O:28])=[O:27])=[CH:23][CH:24]=[CH:25][C:18]=12>>[N:17]1[S:21][N:20]=[C:19]2[C:22]([S:26]([NH:29][C:30]3[CH:38]=[C:37]([Br:39])[CH:36]=[CH:35][C:31]=3[C:32]([NH:6][C@@H:5]([CH2:7][C:8]3[CH:13]=[CH:12][C:11]([F:14])=[C:10]([Br:15])[CH:9]=3)[C:4]([OH:3])=[O:16])=[O:33])(=[O:28])=[O:27])=[CH:23][CH:24]=[CH:25][C:18]=12
Reactant: COC(=O)[C@@H](N)Cc1ccc(F)c(Br)c1
Reactant: O=C(O)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nsnc12
Agent: Cl
Product: O=C(N[C@@H](Cc1ccc(F)c(Br)c1)C(=O)O)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nsnc12

Procedure:
The title compound was prepared from 3-bromo-4-fluoro-L-phenylalanine methyl ester hydrochloride and 2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-bromo-benzoic acid as in Example 1, Part C, followed by hydrolysis of the resulting methyl ester as in EXAMPLE 2, Part E. HPLC: RT=9.75 min. MS (ESI−): mass calcd. for C22H15Br2FN4O5S2, 658.32; m/z found, 655/657/659 [M−H]−. 1H NMR (400 MHz, acetone-d6): 11.76 (s, 1H), 8.46-8.41 (m, 1H), 8.32-8.27 (m, 1H), 8.16-8.09 (m, 1H), 7.93-7.82 (m, 2H), 7.66-7.60 (m, 1H), 7.53-7.47 (m, 1H), 7.41-7.34 (m, 1H), 7.24-7.11 (m, 2H), 4.95-4.86 (m, 1H), 3.39-3.31 (m, 1H), 3.21-3.12 (m, 1H).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N:23]([CH3:34])[C:24]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:25])[CH:18]=2)[CH:7]=[C:8]([F:16])[C:9]=1/[CH:10]=[CH:11]/[C:12]([O:14]C)=[O:13]>O1CCCC1.CO>[F:3][C:4]1[CH:5]=[C:6]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N:23]([CH3:34])[C:24]([NH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:25])[CH:18]=2)[CH:7]=[C:8]([F:16])[C:9]=1/[CH:10]=[CH:11]/[C:12]([OH:14])=[O:13]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2cc(F)c(/C=C/C(=O)OC)c(F)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2cc(F)c(/C=C/C(=O)O)c(F)c2)c1
Yield: 74 %

Procedure:
In a manner similar to that of Example (19g), by reaction of 400 mg (10 mmol, 7.0 eq) of sodium hydroxide and 630 mg (1.41 mmol, 1 eq) of methyl (E)-3-[3,5-difluoro-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]acrylate in 15 ml of a tetrahydrofuran/methanol mixture (8/2), and after crystallization from dichloromethane/heptane, 450 mg of (E)-3-[3,5-difluoro-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]acrylic acid are obtained in the form of a white powder (m.p.=136° C.). Yield=74%
Reaction SMILES: [F:1][CH:2]([F:21])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([C:10]([F:13])([F:12])[F:11])[C:5]=1[CH2:14][S:15][C:16]1[O:17][CH:18]=[CH:19][N:20]=1.[Br:22]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:22][C:18]1[O:17][C:16]([S:15][CH2:14][C:5]2[C:6]([C:10]([F:12])([F:13])[F:11])=[N:7][N:8]([CH3:9])[C:4]=2[O:3][CH:2]([F:1])[F:21])=[N:20][CH:19]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1nc(C(F)(F)F)c(CSc2ncco2)c1OC(F)F
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(C(F)(F)F)c(CSc2ncc(Br)o2)c1OC(F)F

Procedure:
2-({[5-(Difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]methyl}sulfanyl)-1,3-oxazole (1.24 g, 4 mmol) is initially charged in 20 ml of dimethylformamide. N-Bromosuccinimide (0.892 g, 5 mmol) is then added a little at a time with stirring. The mixture is stirred at 40° C. for a further 6 hours. For work-up, the reaction mixture is added to water and extracted twice with dichloromethane, and the extracts are then washed with water and finally with saturated NaCl solution. The combined organic phases are dried over magnesium sulfate, filtered off and concentrated. The crude product is purified chromatographically (heptane:ethyl acetate, gradient 10:0 to 7:3). This gives 0.70 g of product (43.2% of theory).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[C:14]([Cl:15])=[CH:13][C:12]([N+:16]([O-])=O)=[CH:11][C:10]=1[Cl:19])([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+]>C(O)C.O.[Fe]>[C:1]([O:5][C:6](=[O:20])[CH2:7][O:8][C:9]1[C:14]([Cl:15])=[CH:13][C:12]([NH2:16])=[CH:11][C:10]=1[Cl:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1c(Cl)cc([N+](=O)[O-])cc1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)COc1c(Cl)cc(N)cc1Cl

Procedure:
A solution of (4-nitro-2,6-dichloro-phenoxy)-acetic acid tert-butyl ester (1 g) in ethanol (17 mL) and water (8.6 mL) is treated with iron powder (0.861 g) and ammonium chloride (86 mg) and the mixture is heated to reflux for approximately 1 hour. The mixture is then filtered and concentrated under reduced pressure. The resulting oil is partitioned between water and ethyl acetate, and the organic phase is then washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to provide the desired compound as a pale yellow solid.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([NH:15][CH2:16][C:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=1[CH2:23][C:24]([NH:26][CH:27]1[C:45](=[O:46])[N:29]2[C:30]([C:42]([OH:44])=[O:43])=[C:31]([CH2:34][S:35][C:36]3[S:37][C:38]([CH3:41])=[N:39][N:40]=3)[CH2:32][S:33][C@H:28]12)=[O:25])=O)(C)(C)C>CCOCC>[NH2:15][CH2:16][C:17]1[CH2:22][CH2:21][CH2:20][CH2:19][C:18]=1[CH2:23][C:24]([NH:26][CH:27]1[C:45](=[O:46])[N:29]2[C:30]([C:42]([OH:44])=[O:43])=[C:31]([CH2:34][S:35][C:36]3[S:37][C:38]([CH3:41])=[N:39][N:40]=3)[CH2:32][S:33][C@H:28]12)=[O:25]
Reactant: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)CC4=C(CNC(=O)OC(C)(C)C)CCCC4)[C@H]3SC2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(NC(=O)CC4=C(CN)CCCC4)[C@H]3SC2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of trifluoroacetic acid (2 ml.) and 5d (1.20 g., 2 mmoles) was stirred for 30 min at room temperature and diluted with ether (50 ml.) to precipitate the trifluoroacetate of 6d. The trifluoroacetate was slurried in water (2 ml.), adjusted at pH 6 with ammonium hydroxide and diluted with acetonitrile (200 ml.) to precipitate 6d. Yield 0.75 g. (76%). M.p. 215° - 220° C. (dec.).
Reaction SMILES: [Sn].[CH3:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]2[CH2:12][CH2:13][CH2:14][C:15](=[O:16])[C:4]=12.[Br-:17].[Br-].[Br-].C[N+](C)(C)C1C=CC=CC=1.C[N+](C1C=CC=CC=1)(C)C.C[N+](C1C=CC=CC=1)(C)C>C(Cl)Cl>[Br:17][CH:14]1[CH2:13][CH2:12][N:5]2[C:6]3[C:11]([C:3]([CH3:2])=[C:4]2[C:15]1=[O:16])=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: Cc1c2n(c3ccccc13)CCCC2=O
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Agent: [Sn]
Solvent: ClCCl
Product: Cc1c2n(c3ccccc13)CCC(Br)C2=O
Temperature: 10 °C
Reaction time: 30 h
Yield: 86.8 %

Procedure:
The reaction was performed in the dark (the flask wrapped in a tin-foil), and with the provision for maintaining a nitrogen atmosphere. To a solution of 10-methyl-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-one (described in Example 7, 49.75 g) in methylene chloride (250 mL) was added a solution of trimethylphenylammonium tribromide (94 g) in methylene chloride (1200 mL) as fast as possible (over 2 min); the inside temperature was maintained at 10° C. The reaction mixture was stirred at room temperature for 30 hr, evaporated in vacuo, and the solid residue was partitioned between water (600 mL) and benzene-diethyl ether 1:1 (800 mL, v/v). The separated organic layer was dried (MgSO4), filtered, and the filtrate was evaporated. The crude product was dissolved in chloroform (55 mL), and diethyl ether (600 mL) was added at once, whereby a voluminous, dark-green material precipitated. It was quickly removed by filtration (without suction), and the filtrate was chilled to 0° C. The crystals which formed were collected by filtration; 38 g, mp 126°-128° C. This material was recrystallized from chloroform-diethyl ether (1:8, v/v) to give 35 g of the title compound, mp 131°-133° C.; IR (CHCl3) 1665-1660, and 1535 cm-1 ; UV max (MeOH) 246 and 327 nm, (ε 16000) and (18200) respectively; NMR (CDCl3) δ 2.67 (br s, 3H), overlapping with 2.65 (m, 2H), 4.29 (dd, J1 =7.5 Hz, J2 =4.5 Hz, 2H), 4.67 (t, J=4 Hz, 1H), 7.25-7.7 (m, 4H); Anal. Calcd for C13H12BrNO: C, 56.12% H, 4.35% N, 5.03% and Found: C, 56.20% H, 4.32% N, 5.05%.