Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([NH2:16])[C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:17])[C:5]([C:18]([OH:20])=[O:19])=[CH:4]1)[CH3:2].[C:21]([O:25][C:26]([NH:28][CH:29]1[CH2:33][CH2:32][NH:31][CH2:30]1)=[O:27])([CH3:24])([CH3:23])[CH3:22].C(N(CC)CC)C>C(#N)C>[CH2:1]([N:3]1[C:12]2[C:7](=[C:8]([NH2:16])[C:9]([F:15])=[C:10]([N:31]3[CH2:32][CH2:33][CH:29]([NH:28][C:26]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])[CH2:30]3)[C:11]=2[F:13])[C:6](=[O:17])[C:5]([C:18]([OH:20])=[O:19])=[CH:4]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: CCn1cc(C(=O)O)c(=O)c2c(N)c(F)c(F)c(F)c21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCn1cc(C(=O)O)c(=O)c2c(N)c(F)c(N3CCC(NC(=O)OC(C)(C)C)C3)c(F)c21
Temperature: 25 °C

Procedure:
A suspension of 3.02 g (10 mmole) of 1-ethyl-5-amino-6,7,8-trifluoro-4-oxo-1,4-dihydro quinoline-3-carboxylic acid, 2.79 g (15 mmole) of 3-(t-butoxycarbonylamino)pyrrolidine, 3.0 g (30 mmole) of triethylamine and 100 ml of acetonitrile is refluxed for 18 hours. The reaction mixture is cooled to room temperature and the precipitate is removed by filtration, washed with acetonitrile, ether, and dried in vacuo to give 1-ethyl-5-amino-6,8-difluoro-7-[3-(t-butoxycarbonylamino)-1-pyrrolidinyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid.
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[N:10]=[C:9]([CH:11]=O)[S:8][C:6]=2[N:7]=1.[NH:19]1[CH2:22][CH:21]([N:23]2[CH2:28][CH2:27][NH:26][C:25](=[O:29])[CH2:24]2)[CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[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[N:10]=[C:9]([CH2:11][N:19]3[CH2:20][CH:21]([N:23]4[CH2:28][CH2:27][NH:26][C:25](=[O:29])[CH2:24]4)[CH2:22]3)[S:8][C:6]=2[N:7]=1
Reactant: O=Cc1nc2c(N3CCOCC3)nc(Cl)nc2s1
Reactant: O=C1CN(C2CNC2)CCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: O=C1CN(C2CN(Cc3nc4c(N5CCOCC5)nc(Cl)nc4s3)C2)CCN1
Reaction time: 16 h
Yield: 75.7 %

Procedure:
A mixture of 5-chloro-7-morpholin-4-ylthiazolo[5,4-d]pyrimidine-2-carbaldehyde (285 mg, 1.00 mmol), 4-azetidin-3-ylpiperazin-2-one (190 mg, 1.22 mmol) and 4 Å powdered molecular sieves (1.0 g) in DCE (10 mL) was allowed to stir at r.t. for 5 h before the addition of sodium triacetoxyborohydride (420 mg, 1.98 mmol). The resulting mixture was allowed to stir for 16 h then filtered through Celite® which was washed with DCM. The filtrate was concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, MeOH:DCM, 2-10%) affording the title compound (321 mg, 75%)._LCMS (method A): RT 1.96 and 0.33 min [M+H]+ 424.3
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13](=[O:19])[CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:10]=2)[N:5]=[CH:4][N:3]=1.CO[CH:22]=[C:23]([C:28]([O:30][CH3:31])=[O:29])[C:24]([O:26][CH3:27])=[O:25].CN(C)C=O>O>[CH3:17][C:15]([CH3:16])([CH3:18])[CH2:14][C:13]([NH:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[NH:1][CH:22]=[C:23]([C:28]([O:30][CH3:31])=[O:29])[C:24]([O:26][CH3:27])=[O:25])=[O:19]
Reactant: COC=C(C(=O)OC)C(=O)OC
Reactant: CC(C)(C)CC(=O)Nc1ccc2ncnc(N)c2c1
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(=CNc1ncnc2ccc(NC(=O)CC(C)(C)C)cc12)C(=O)OC
Temperature: 100 °C
Yield: 82.7 %

Procedure:
A mixture of 4-amino-6-(3,3-dimethylbutyramido)quinazoline (8.5 g), dimethyl methoxymethylenepropanedioate (12.75 g) and N,N-dimethylformamide (34 g) was stirred for an hour at 100° C. After cooling to ambient temperature, to the resultant mixture was added water to give precipitates, which were separated by filtration, washed with water and dried to give crystalline dimethyl [{6-(3,3-dimethylbutyramido)-4-quinazolinylamino}methylene]propanedioate (10.9 g).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12]=[C:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[O:10][C:9]=2[CH:20]=1)(=O)C.C([O-])C.[Na+]>C(O)C>[OH:4][C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH:12]=[C:11]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[O:10][C:9]=2[CH:20]=1
Reactant: CCOC(=O)CC1=COc2ccc(OC(C)=O)cc2O1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CC1=COc2ccc(O)cc2O1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
0.84 g (3.78 mmol) of the ester obtained in Step A is dissolved in 20 ml of anhydrous ethanol; the medium is then adjusted to a basic pH using a molar solution of sodium ethanolate (0.5 ml). After 18 hours of stirring under an inert atmosphere and at ambient temperature, the reaction mixture is neutralised with DOWEX X-8 resin (acid form). The solid is then filtered off; the filtrate is then concentrated in vacuo. The residue obtained is purified on a silica column (eluant:AcOEt/PE:50/50) to yield the title compound in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:8][NH2:9])=[CH:6][CH:7]=1.C(O[CH:13]=[C:14]([C:17]#[N:18])[C:15]#[N:16])C>C(O)C>[Cl:1][C:2]1[N:3]=[N:4][C:5]([N:8]2[C:17]([NH2:18])=[C:14]([C:15]#[N:16])[CH:13]=[N:9]2)=[CH:6][CH:7]=1
Reactant: NNc1ccc(Cl)nn1
Reactant: CCOC=C(C#N)C#N
Solvent: CCO
Product: N#Cc1cnn(-c2ccc(Cl)nn2)c1N

Procedure:
A mixture of 4.35 g. (30 mmoles) of 3-chloro-6-pyridazinylhydrazine, 3.96 g. (30 mmoles) of ethoxymethylenemalononitrile and 60 ml. of ethanol is heated and refluxed for 2 hours. After cooling the separated crystals are filtered, washed with ethanol and dried. Yield: 5.85 g. (88.5%); m.p.: 250°-252° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]2[C:4]=1[CH2:5][CH2:6][C:7](=O)[CH2:8]2.[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C1(C)C=CC=CC=1>[CH2:16]([NH:23][C:7]1[CH2:6][CH2:5][C:4]2[C:9](=[C:10]([O:13][CH3:14])[CH:11]=[CH:12][C:3]=2[O:2][CH3:1])[CH:8]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCc1ccccc1
Reactant: COc1ccc(OC)c2c1CCC(=O)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(OC)c2c1C=C(NCc1ccccc1)CC2

Procedure:
A mixture containing 82 mmol of 5,8-dimethoxy-3,4-dihydronaphthalen-2(1H)-one, 82 mmol of benzylamine and 0.20 g of p-toluenesulfonic acid is brought to reflux with azeotropic distillation of the water/toluene mixture. After heating for 2 hours, the mixture is cooled, filtered and the solvent evaporated under vacuum and leads to the expected product in the form of an oil.
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([NH:24][CH2:25][C:26]2([C:32]3[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=3)[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[O:23])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1.Cl[C:39]([O:41][CH3:42])=[O:40]>>[F:1][C:2]1[C:3]([C:22]([NH:24][CH2:25][C:26]2([C:32]3[CH:33]=[CH:34][N:35]=[CH:36][CH:37]=3)[CH2:27][CH2:28][N:29]([C:39]([O:41][CH3:42])=[O:40])[CH2:30][CH2:31]2)=[O:23])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1
Reactant: COC(=O)Cl
Reactant: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccncc5)CCNCC4)c3F)s2)c1
Product: COC(=O)N1CCC(CNC(=O)c2nccc(Sc3cnc(Nc4cc(C)ccn4)s3)c2F)(c2ccncc2)CC1

Procedure:
Following the procedure given for example 81, 3-fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)-N-((4-(pyridin-4-yl)piperidin-4-yl)methyl)picolinamide (compound example 45) was reacted with methyl chloroformate to give the title compound. LC/MS (M+H)+: 594. Ret. time: 1.32 min. (Condition I); analytical HPLC Ret. time: 5.23 min (Condition H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:14](=O)[CH3:15])=[C:4]([F:17])[CH:3]=1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:24].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:14]([NH2:24])[CH3:15])=[C:4]([F:17])[CH:3]=1
Reactant: [BH3-]C#N
Reactant: CC(=O)c1ccccc1-c1ccc(Cl)cc1F
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(N)c1ccccc1-c1ccc(Cl)cc1F
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 1-(4′-chloro-2′-fluoro-1,1′-biphenyl-2-yl)ethanone (3.2 g, 12.9 mmol) in anhydrous methanol (200 mL) was added solid ammonium acetate (19.8 g, 257 mmol). The reaction mixture was heated at 60° C. for one hour, followed by the addition of a methanolic solution of sodium cyanoborohydride (1.62 g, 25.8 mmol). After 16 hours, the methanol was removed in vacuo and aqueous ammonium hydroxide was added. The aqueous phase was extracted with diethyl ether (3×200 mL) until the amine was no longer present in the aqueous phase. The organic phase was then washed with 2 N aqueous hydrochloric acid (3×100 mL) and the aqueous phases combined. The solid formed during the acid wash was determined to be the dialkyated amine and was segregated from the aqueous phase. Aqueous sodium hydroxide was added to the acidic aqueous phase until the solution was neutralized to pH 8 to 9. The basic aqueous phase was extracted with diethyl ether until the primary amine was no longer detected in the aqueous phase. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to afford a clear oil that was used without further purification;
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH:18]3OCCO3)[CH:13]=2)=[N:5][C:4]([NH2:23])=[N:3]1.Cl.[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.[BH4-].[Na+]>O1CCCC1.O>[CH3:1][N:2]1[C:6]([NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:13]=2)=[N:5][C:4]([NH2:23])=[N:3]1
Reactant: Cn1nc(N)nc1NCCCOc1cccc(C2OCCO2)c1
Reactant: C1CCNCC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1nc(N)nc1NCCCOc1cccc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1-methyl-N5 -[3-[3-(1,3-dioxolan-2-yl)phenoxy]propyl]-1H-1,2,4-triazole-3,5-diamine (106 mg) in tetrahydrofuran (2 ml) was stirred with 2N hydrochloric acid (0.2 ml) for 1/2 h at room temperature. The mixture was treated with piperidine (0.5 ml), stirred at room temperature for 1 h, and then treated with sodium borohydride (75 mg). After a further 1 h, the mixture was diluted with water, and extracted with ethyl acetate. The combined extracts were dried and evaporated in vacuo. The resulting oil was crystallised from a mixture of benzene and cyclohexane to yield the title compound (60 mg) m.p. 93°-4°. TLC silica (methanol:ammonia 80:1) Rf 0.5.
Reaction SMILES: [CH2:1]([O:8][C:9]([CH2:11][N:12]1[C:21](=[O:22])[C:20]2[N:19]([CH2:23][C:24]#[C:25][CH3:26])[C:18]([N:27]3[CH2:32][CH2:31][CH2:30][C@@H:29]([NH:33]C(OC(C)(C)C)=O)[CH2:28]3)=[N:17][C:16]=2[N:15]([CH3:41])[C:13]1=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[CH2:1]([O:8][C:9]([CH2:11][N:12]1[C:21](=[O:22])[C:20]2[N:19]([CH2:23][C:24]#[C:25][CH3:26])[C:18]([N:27]3[CH2:32][CH2:31][CH2:30][C@@H:29]([NH2:33])[CH2:28]3)=[N:17][C:16]=2[N:15]([CH3:41])[C:13]1=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC#CCn1c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc2c1c(=O)n(CC(=O)OCc1ccccc1)c(=O)n2C
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC#CCn1c(N2CCC[C@@H](N)C2)nc2c1c(=O)n(CC(=O)OCc1ccccc1)c(=O)n2C
Temperature: 30 °C
Reaction time: 0.33 h

Procedure:
213 mg of 1-[(benzyloxycarbonyl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-3-(tert.-butyloxycarbonylamino)-piperidin-1-yl]-xanthine in 2 ml methylene chloride are combined with 1 ml of trifluoroacetic acid and the reaction mixture is shaken for 20 minutes at 30° C. For working up it is made alkaline with 15 ml of 1 N sodium hydroxide solution and the organic phase is separated off. The aqueous phase is extracted with methylene chloride and the combined organic phases are evaporated down. The flask residue is purified through a silica gel column with methylene chloride/methanol (100:0 to 70:30) as eluant.
Reaction SMILES: [CH:1]1([CH2:7]/[CH:8]=[CH:9]/[CH2:10][OH:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:12](OC(=O)C)(=[O:14])[CH3:13].C(N(CC)CC)C>C(OCC)C.CN(C)C1C=CN=CC=1>[C:12]([O:11][CH2:10]/[CH:9]=[CH:8]/[CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: OC/C=C/CC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(=O)OC/C=C/CC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
A solution of 7.54 g of (E)-4-cyclohexyl-2-butenol in 200 ml of diethyl ether was treated with 9.99 g of acetic anhydride and 7.42 g of triethylamine and stirred overnight at room temperature. The mixture was then treated with 0.005 g of 4-dimethylaminopyridine and stirred for a further 0.5 hours. The mixture was washed with 5% aqueous sodium hydrogen carbonate, water and brine, then dried over anhydrous magnesium sulphate and evaporated. The residue was dried under vacuum to give 9.50 g of (E)-4-cyclohexyl-2-butenol acetate in the form of a pale yellow oil.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:26])=[N+:7]([O-])[C:8]([CH:11]([O:21][C:22](=[O:24])[CH3:23])[CH2:12][N:13]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:14](=[O:16])[CH3:15])=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[C:27]([O:30]C(=O)C)(=[O:29])[CH3:28].C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[C:1]([O:4][C:5]1[C:6]([CH2:26][O:30][C:27](=[O:29])[CH3:28])=[N:7][C:8]([CH:11]([O:21][C:22](=[O:24])[CH3:23])[CH2:12][N:13]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:14](=[O:16])[CH3:15])=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C(CN(C(C)=O)C(C)(C)C)OC(C)=O)[n+]([O-])c1C
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(=O)OCc1nc(C(CN(C(C)=O)C(C)(C)C)OC(C)=O)ccc1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 27 %

Procedure:
A solution of 1.0 g. (0.0027 mole) of 3-acetoxy-2-methyl-6-[1-acetoxy-2-(N-tert-butylacetamido)ethyl]-pyridine N-oxide in 10 ml. of acetic anhydride was heated at the reflux temperature for 2.5 hours, then was allowed to cool to room temperature and stirred at this temperature overnight. The reaction mixture was poured into a two phase mixture of ethyl acetate and aqueous sodium bicarbonate and stirred for 1 hour. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness in vacuo to give a brown oil which was purified by column chromatography on silica gel with ether as the eluant to give 300 mg. (27%) of the desired product; m.p. 60°-64° C.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:30](=[O:38])[NH:31][S:32]([CH:35]4[CH2:37][CH2:36]4)(=[O:34])=[O:33])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([OH:23])=O)=[CH:18][C:17]4[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:39]1([CH2:46][CH2:47][CH2:48][N:49]2[CH2:54][CH2:53][O:52][CH2:51][CH2:50]2)[CH2:45][CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CO>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:30]([NH:31][S:32]([CH:35]4[CH2:36][CH2:37]4)(=[O:34])=[O:33])=[O:38])=[CH:12][C:13]=3[N:14]3[CH2:20][C:19]([C:21]([N:42]4[CH2:43][CH2:44][CH2:45][N:39]([CH2:46][CH2:47][CH2:48][N:49]5[CH2:50][CH2:51][O:52][CH2:53][CH2:54]5)[CH2:40][CH2:41]4)=[O:23])=[CH:18][C:17]4[CH:24]=[C:25]([O:28][CH3:29])[CH:26]=[CH:27][C:16]=4[C:15]=23)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc2c(c1)C=C(C(=O)O)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)C3CC3)cc21
Reactant: C1CNCCN(CCCN2CCOCC2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)C=C(C(=O)N1CCCN(CCCN3CCOCC3)CC1)Cn1c-2c(C2CCCCC2)c2ccc(C(=O)NS(=O)(=O)C3CC3)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 72.6 %

Procedure:
To a stirring solution of 13-cyclohexyl-10-((cyclopropylsulfonyl)carbamoyl)-3-methoxy-7H-indolo[2,1-a][2]benzazepine-6-carboxylic acid (33 mg, 0.062 mmol) and 4-(3-(1,4-diazepan-1-yl)propyl)morpholine (36 mg, 0.158 mmol) in DMF (0.5 ml) and TEA (50 μl, 0.359 mmol) was added HATU (35 mg, 0.092 mmol). The reaction mixture was stirred at room temperature under nitrogen for 4 h. The crude reaction mixture was diluted with MeOH (˜1 mL), filtered and purified by preparative HPLC (H2O/CH3CN with 10 mM NH4OAc) to yield 13-cyclohexyl-N-(cyclopropylsulfonyl)-3-methoxy-6-((4-(3-(4-morpholinyl)propyl)-1,4-diazepan-1-yl)carbonyl)-7H-indolo[2,1-a][2]benzazepine-10-carboxamide (35.1 mg, 0.045 mmol, 72.6% yield) as a yellow solid. 1HNMR (300 MHz, CD3OD) δ 0.91-2.34 (m, 20H), 2.49-3.49 (m, 15H), 3.81-3.96 (m, 7H), 4.03-4.23 (m, 1H), 4.30-4.48 (m, 1H), 5.05-5.23 (m, 1H), 6.90 (s, 1H) 7.04 (d, J=2.6 Hz, 1H), 7.13 (dd, J=8.4, 2.6 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H), 7.42-7.88 (m, 2H), 8.24 (s, 1H). LCMS: m/e 744 (M+H)+, ret time 2.88 min, column B, 4 minute gradient.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)([O-:3])=[O:2].Br[CH:23]([CH3:33])[C:24]([O:31][CH3:32])=[CH:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[N+:1]([C:4]1[CH:17]=[C:16]([C:18]([F:19])([F:20])[F:21])[CH:15]=[CH:14][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:23]([CH3:33])[C:24]([O:31][CH3:32])=[CH:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:9][CH:8]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)C=C(OC)C(C)Br
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C=C(OC)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2[N+](=O)[O-])cc1

Procedure:
A mixture of 4-(2-nitro-4-trifluoromethylphenoxy)phenol (9.36 mm)., ethyl 4-bromo-3-methoxy-2-pentenoate (12 mm.) and K2CO3 (14 mm.) in acetone (20 ml.) is refluxed for 24 hours. After filtration, the filtrate is concentrated and the oily residue chromatographed on silica gel to yield ethyl 4-[4-(2-nitro-4-trifluoromethylphenoxy)phenoxy]-3-methoxy-2-pentenoate.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:6]#[N:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:34]N1C(=O)CCC1=O>C(Cl)Cl>[Br:34][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:6]#[N:7]
Reactant: N#Cc1cc(CO)cc(C(F)(F)F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: N#Cc1cc(CBr)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
3-(Hydroxymethyl)-5-(trifluoromethyl)benzonitrile (0.33 mg, 1.64 mmol) and triphenylphosphine (0.86 g, 3.28 mmol) were combined in methylene chloride (6 mL) and cooled to 0° C. N-Bromosuccinimide (0.61 mg, 3.43 mmol) was introduced in portions and the reaction allowed to warm to room temperature. After 16 h, the reaction mixture was diluted with methylene chloride, washed with concentrated sodium bicarbonate (2×), brine (2×), dried over sodium sulfate, and concentrated. Column chromatography on silica gel (20% ethyl acetate/hexanes) gave 0.36 g (83%). 1H-NMR (CDCl3, 500 MHz) δ 7.97 (s, 2H), 7.84 (s, 1H), 4.50 (s, 2H).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[F:12].[F:13][C:14]1[CH:19]=[C:18]([CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:17]=[C:16]([F:26])[C:15]=1B1OC(C)(C)C(C)(C)O1>>[F:13][C:14]1[CH:19]=[C:18]([CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:17]=[C:16]([F:26])[C:15]=1[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[F:12]
Reactant: CC1(C)OB(c2c(F)cc(C3CCOCC3)cc2F)OC1(C)C
Reactant: COC(=O)c1ccc(F)c(Br)n1
Product: COC(=O)c1ccc(F)c(-c2c(F)cc(C3CCOCC3)cc2F)n1
Yield: 59 %

Procedure:
Method 1 was followed using methyl 6-bromo-5-fluoropicolinate (1.0 equiv.) and 2-(2,6-difluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (3.0 equiv.) at 100° C. for 20 min in microwave to give methyl 6-(2,6-difluoro-4-(tetrahydro-2H-pyran-4-yl)phenyl)-5-fluoropicolinate in 59% yield. LC/MS=352.2 (MH+), Rt=0.92 min.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([C:9]([F:13])=[CH:10][C:11]=1[Cl:12])[NH2:8])[CH:2]=[CH2:3].[CH2:14]1[CH:19]2[C:20]([O:22][C:23](=O)[CH:18]2[CH2:17][CH:16]=[CH:15]1)=[O:21].C(O)(=O)C>O>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([N:8]2[C:20](=[O:21])[C:19]3[CH2:14][CH2:15][CH2:16][CH2:17][C:18]=3[C:23]2=[O:22])[C:9]([F:13])=[CH:10][C:11]=1[Cl:12])[CH:2]=[CH2:3]
Reactant: O=C1OC(=O)C2CC=CCC12
Reactant: C=CCOc1cc(N)c(F)cc1Cl
Solvent: CC(=O)O
Solvent: O
Product: C=CCOc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Temperature: 25 °C

Procedure:
A mixture of 9.0 g of 19A, 6.8 g of THPA and 100 mL of glacial acetic acid was heated at reflux temperature for 4 hours. The resulting mixture was cooled to room temperature, poured into 450 mL of water and extracted with ether. The extract phase was washed with water, dried (Na2SO4), and filtered, and the solvent was evaporated from the filtrate. The residue was flash-chromatographed on silica gel, with a 15:85 v:v mixture of ethyl acetate and hexane as eluent, to give N-(3-(allyloxy)-4-chloro-6-fluorophenyl)-3,4,5,6-tetrahydrophthalimide (19B), as an orange oil.
Reaction SMILES: B(O)(O)[C:2]1[CH:3]=[CH:4][C:5]([CH3:8])=[CH:6][CH:7]=1.Br[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][C:20]([CH3:31])=[C:21]([CH2:23][CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][C@H:26]3[CH3:30])[N:22]=2)=[CH:14][CH:13]=1>>[CH3:31][C:20]1[O:19][C:18]([C:15]2[CH:16]=[CH:17][C:12]([C:2]3[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=3)=[CH:13][CH:14]=2)=[N:22][C:21]=1[CH2:23][CH2:24][N:25]1[CH2:29][CH2:28][CH2:27][C@H:26]1[CH3:30]
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCC[C@H]1C
Reactant: Cc1ccc(B(O)O)cc1
Product: Cc1ccc(-c2ccc(-c3nc(CCN4CCC[C@H]4C)c(C)o3)cc2)cc1

Procedure:
The title compound is prepared in a manner substantially analogous to example 133 starting from tolyl boronic acid (195 mg, 1.43 mmol) and 2-(4-Bromo-phenyl)-5-methyl-4-[2-((R)-2-methyl-pyrrolidin-1-yl)-ethyl]-oxazole (100 mg, 0.287 mmol) to give 33 mg (32%). MS (m/e) 361.3 (M+1)
Reaction SMILES: C[O:2][C:3](=[O:44])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([Cl:24])[C:19]=3[F:25])[C@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[F:35])([C:26]#[N:27])[C@H:15]([CH2:36][C:37]3([CH3:43])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)[NH:14]2)=[O:12])=[CH:6][CH:5]=1.[OH-].[Na+].CO.Cl>O1CCCC1>[Cl:24][C:20]1[C:19]([F:25])=[C:18]([C@@H:17]2[C@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[F:35])([C:26]#[N:27])[C@H:15]([CH2:36][C:37]3([CH3:43])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]3)[NH:14][C@H:13]2[C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:44])=[O:2])=[CH:5][CH:6]=2)=[O:12])[CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC3(C)CCCCC3)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C[C@@H]2N[C@@H](C(=O)Nc3ccc(C(=O)O)cc3)[C@H](c3cccc(Cl)c3F)[C@@]2(C#N)c2ccc(Cl)cc2F)CCCCC1
Temperature: 80 °C
Yield: 93.1 %

Procedure:
To a solution of rac-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-methyl-cyclohexylmethyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid methyl ester prepared in Example 344 (0.16 g, 0.24 mmol) in tetrahydrofuran (3 mL) was added an aqueous solution (1 N) of NaOH (3 mL, 3 mmol) and methanol (1 mL). The reaction mixture was heated at 80° C. for 2 h, and the “pH” of the solution was adjusted to 5 by aqueous HCl solution. The mixture was extracted ethyl acetate twice. The combined organic extracts were washed with water, brine, dried over MgSO4, and concentrated to give rac-4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(1-methyl-cyclohexylmethyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid as a white solid (0.14 g, 90%).