Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]2[N:17]=[C:18](Br)[S:19][C:13]=2[CH:12]1[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[O:28][CH2:29][C:30]([O:32]CC)=[O:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-].[CH2:36]([Zn+])[CH2:37][CH3:38]>C1COCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]2[N:17]=[C:18]([CH2:36][CH2:37][CH3:38])[S:19][C:13]=2[CH:12]1[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[O:28][CH2:29][C:30]([OH:32])=[O:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC[Zn+]
Reactant: CCOC(=O)COc1ccc(Cl)cc1C1c2sc(Br)nc2CCN1C(=O)OCc1ccccc1
Agent: [Pd]
Agent: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCc1nc2c(s1)C(c1cc(Cl)ccc1OCC(=O)O)N(C(=O)OCc1ccccc1)CC2
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a solution under N2 of (±)-2-bromo-4-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid benzyl ester (50 mg, 0.09 mmol, 1.00 eq.) and 0.5M propylzinc bromide in THF (0.36 mL, 0.18 mmol, 2.00 eq.) in THF (10 mL), tetrakis(triphenylphosphine) palladium (0) (5.1 mg, 4 μmol, 0.05 eq) was added. The mixture was stirred at 50° C. for 18 hours. The mixture was allowed to cool to r.t. and concentrated in vacuo. The residue was taken up in DMF, filtered, and purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo. The resulting ester was dissolved in DMF (0.5 mL), 1M aq. NaOH soln. (0.5 mL) was added. The resulting solution was stirred at r.t. for 18 hours. The solution was neutralized with formic acid (1 mL), filtered, and then purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the desired acid as a white solid.
Reaction SMILES: [F:1][CH:2]([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].[C:12]([C:15]1[S:16][C:17]([Br:20])=[CH:18][CH:19]=1)(=[O:14])[CH3:13].Cl>CCOCC.C1COCC1>[F:8][CH:2]([F:1])[C:3](=[O:5])[CH2:13][C:12]([C:15]1[S:16][C:17]([Br:20])=[CH:18][CH:19]=1)=[O:14]
Reactant: CC(=O)c1ccc(Br)s1
Reactant: CCOC(=O)C(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(CC(=O)C(F)F)c1ccc(Br)s1
Yield: 73.3 %

Procedure:
Ethyl difluoroacetate (2.43 g, 19.6 mmol) was placed in a 100 mL round bottom flask, and dissolved in ether (15 mL). To the stirred solution was added 25 weight % sodium methoxide (4.23 g, 19.5 mmol) followed by 2-acetyl-5-bromothiophene (3.59 g, 17.5 mmol). After two hours a precipitate formed and THF (15 mL) was added to allow stirring to continue. The reaction was stirred at room temperature 6.2 hours, then treated with 3N HCl (20 mL). The organic layer was collected and washed with brine, dried over MgSO4, and concentrated in vacuo to give a yellow oil which was crystallized from methylene chloride/isooctane to give yellow needles (3.63 g, mp 83.5°-85° C., 73% ). 1H NMR (CDCl3) 300 MHz 14.60 (br s, 1H), 7.53 (d, J=4.0 Hz, 1H), 7.15 (d, J=4.0 Hz, 1H), 7.19 (m, 1H), 6.32 (s, 1H), 6.04 (t, J=54.2 Hz, 1H); 19F NMR (CDCl3) 300 MHz: -127.00 (d) ; M+282.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[C:13]([O:14][CH3:15])=[C:12](Cl)[N:11]=[CH:10][N:9]=1>O>[CH3:15][O:14][C:13]1[C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:9][CH:10]=[N:11][CH:12]=1
Reactant: COc1c(Cl)ncnc1Cl
Reactant: C1CNCCN1
Solvent: O
Product: COc1cncnc1N1CCNCC1

Procedure:
Piperazine (20 g) was dissolved in water (100 mL) in a Parr bottle and then solid 4,6-dichloro-5-methoxypyrimidine (5.00 g, 27.9 mmol) was added. The mixture was vigorously stirred for 2 h at room temperature during which the 4,6-dichloro-5-methoxypyrimidine dissolved. The stirring bar was removed, catalyst (10% Pd/C, 1.0 g) was added to the turbid solution, and the mixture was then hydrogenated (60 psi, 3 h) at room temperature. The catalyst was filtered off and the filtrate extracted 3 times with CH2Cl2. The CH2Cl2 extracts were dried over Na2SO4 and concentrated in vacuo to give a clear oil which solidified upon standing (3.34 g, 61.7%). This crude product was Kugelrohr distilled (yield 3.24 g), dissolved in acetonitrile, and concentrated HCl added to precipitate the product as a white powder which was dried in vacuo (4.32 g, 94.0% from crude product, m.p. 219°-221.5° C.).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[O:6][C:7]1[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=1.[CH2:14]([O:21][CH2:22][C@H:23]([NH:27]C(OC(C)(C)C)=O)[C:24](O)=[O:25])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[NH2:27][C@@H:23]([CH2:22][O:21][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:24]([NH:11][C:10]1[CH:12]=[CH:13][C:7]([O:6][C:2]2[S:1][CH:5]=[CH:4][N:3]=2)=[CH:8][CH:9]=1)=[O:25]
Reactant: Nc1ccc(Oc2nccs2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Product: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2nccs2)cc1
Yield: 60 %

Procedure:
Proceeding as in Reference 5, but substituting 4-(thiazol-2-yloxy)aniline and (S)-3-(benzyloxy)-2-(tert-butoxycarbonylamino)propanoic acid, gave (S)-2-amino-3-(benzyloxy)-N-(4-thiazol-2-yloxyphenyl)propanamide (200 mg, 60%).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)[S:4][C:3]=1[C:13]([NH2:15])=[O:14].[CH3:16][C:17](=O)[CH2:18][CH2:19][CH2:20][CH3:21].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>C(O)(=O)C>[CH2:18]([C:17]1([CH3:16])[NH:1][C:2]2[CH:6]=[C:5]([C:7]3[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=3)[S:4][C:3]=2[C:13](=[O:14])[NH:15]1)[CH2:19][CH2:20][CH3:21]
Reactant: NC(=O)c1sc(-c2ccncc2)cc1N
Reactant: CCCCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCCC1(C)NC(=O)c2sc(-c3ccncc3)cc2N1
Temperature: 80 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
A mixture of 3-amino-5-(pyridin-4-yl)thiophene-2-carboxamide (0.108 g, 0.500 mmol), 2-hexanone (2.0 mL), p-toluenesulfonic acid monohydrate (0.0095 g, 0.050 mmol) and acetic acid (2.0 mL) was stirred for 3 h at 80° C. in a sealed tube. The mixture was poured into sat. aqueous sodium hydrogen carbonate (150 mL). Extraction with ethyl acetate (100 mL), drying over magnesium sulfate, filtration and concentration at reduced pressure gave an oil. This oil was purified by column chromatography (Combiflash, 12 g silica gel, dichloromethane to 90:10 dichloromethane/methanol), then triturated with ethyl acetate, and the precipitate was collected by filtration to afford the title compound (0.0747 g, 50%) as a yellow solid:
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH:18][CH2:19][CH2:20][N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:17])[O:18][CH2:19][CH2:20][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: OCCN1CCCC1
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Product: N=C(OCCN1CCCC1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile and N-(2-hydroxyethyl)pyrrolidine, there is obtained 2-pyrrolidino-ethyl 5,7-dihydro-6H-dibenz[c,e]-azepine-6-carboximidate as a resin, mass spectrum m/e: M+ 335 (1), 238 (6), 194 (12), 179 (22), 165 (22), 97 (100), 84 (39), 69 (56);
Reaction SMILES: [CH3:1][C@@H:2]([CH2:6][CH3:7])[CH2:3][CH2:4][OH:5].N1C=CC=NC=1.[CH3:14][S:15](Cl)(=[O:17])=[O:16]>>[CH3:14][S:15]([O:5][CH2:4][CH2:3][C@@H:2]([CH3:1])[CH2:6][CH3:7])(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: CC[C@H](C)CCO
Solvent: c1cncnc1
Product: CC[C@H](C)CCOS(C)(=O)=O
Yield: 43.3 %

Procedure:
In a flask were charged 15.89 g of (S)-3-methylpentanol and 65 ml of pyrimidine. After cooling to 0° to 50° C., 23.63 g of methanesulfonyl chloride was added thereto dropwise, and the mixture was allowed to react at the same temperature for 1 hour. The reaction mixture was extracted with diethyl ether, and the extract was washed with water and concentrated to obtain 12.14 g (46.42%) of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[C:5]2[S:10][C:9]([C:11](=[O:13])[CH3:12])=[CH:8][C:6]=2[N:7]=1.[BrH:20].C(O)(=O)C.BrBr>C(Cl)(Cl)Cl>[Br:20][CH2:12][C:11]([C:9]1[S:10][C:5]2[C:4]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:3][C:2]([Cl:1])=[N:7][C:6]=2[CH:8]=1)=[O:13]
Reactant: Br
Reactant: CC(=O)c1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: BrBr
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: O=C(CBr)c1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 0 °C

Procedure:
To a solution of 1-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)ethanone (1.0 eq) dissolved in a mixture of CHCl3, 33% wt HBr and acetic acid (1:1:1) at −0° C. was added a solution of Br2 in CHCl3 (1.05 eq). Reaction mixture was stirred at −0° C. until completed, then extracted in dichloromethane with saturated bicarbonate solution one time. The organic layer is dried, filtered and concentrated to yield the crude intermediate. This intermediate is purified by flash chromatography to yield 2-bromo-1-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)ethanone.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:10][C:11]([OH:13])=[O:12])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].[Si](C=[N+]=[N-])(C)(C)[CH3:15]>C1COCC1.CO>[C:1]([C:3]1[CH:4]=[C:5]([CH2:10][C:11]([O:13][CH3:15])=[O:12])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: N#Cc1cc(CC(=O)O)ccc1F
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(F)c(C#N)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40.9 %

Procedure:
2-(3-Cyano-4fluorophenyl)acetic acid (4.0 g, 22.3 mmol) was diluted with THF (10 mL) and methanol (2 mL), placed under nitrogen and cooled to 0° C. TMSCHN2 (16.7 mL, 33.5 mmol) was added dropwise and the reaction was stirred for 30 minutes. The reaction was quenched with water and diluted with DCM. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated. The residue was purified using a Biotage 40M cartridge eluting with hexanes ethyl acetate (9.1) to yield methyl 2(3-cyano-4-fluorophenyl)acetate (1.76 g, 9.11 mmol, 41%) as clear oil that solidified to a white solid. 1H NMR (400 MHz, CDCl3) δ 7.48-7.59 (m, 2H), 7.19 (t, J=8.2 Hz, 1H), 3.73 (s, 3H), 3.64 (s, 2H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[C:11](=[O:12])[N:10]([CH3:13])[C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=2[S:7]1.Cl.[C:19]1([C:25]2[CH2:26][CH2:27][NH:28][CH2:29][CH:30]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.Cl>C1(C)C=CC=CC=1>[CH3:13][N:10]1[C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=2[S:7][CH:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:28]2[CH2:27][CH:26]=[C:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:30][CH2:29]2)[C:11]1=[O:12]
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: CN1C(=O)C(CCCCBr)Sc2ccccc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN1C(=O)C(CCCCN2CC=C(c3ccccc3)CC2)Sc2ccccc21
Yield: 70.3 %

Procedure:
2.4 g (=0.0076 m) of 2-(4-bromobutyl)-4-methyl-2H-1,4-benzothiazine-3(4H)-one, 1.49 g (=0.0076 m) of 4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride and 3.09 g of triethylamine were introduced into 20 ml of toluene. The resulting suspension was heated for 10.5 hours with stirring. The mixture was worked up by cooling and introducing the suspension into 30 ml of 20% strength aqueous hydrochloric acid solution. The resulting precipitate was filtered out, and the aqueous phase was rendered alkaline and extracted with 200 ml of dichloromethane. The precipitate was introduced into an aqueous alkaline solution and extracted with 450 ml of dichloromethane. The combined dichloromethane extracts were washed, dried over sodium sulfate, and the solvent was distilled off. 2.1 g of 4-methyl-2-[4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)-butyl]-2H-1,4-benzothiazine-3(4H)-one were obtained as a beige-colored powder.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18]([OH:20])=O)[CH2:16][C:15]2[CH:14]=[C:13]3[O:21][CH2:22][C@H:23]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=5)[CH:26]=4)[O:24][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.Cl.Cl.[CH3:53][O:54][C:55](=[O:73])[C@@H:56]([NH2:72])[CH2:57][C:58]1[CH:63]=[CH:62][C:61]([C:64]2[CH:69]=[CH:68][N:67]=[C:66]([CH3:70])[C:65]=2[CH3:71])=[CH:60][CH:59]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CCN=C=NCCCN(C)C.Cl>[C:1]([O:5][C:6]([N:8]1[C@H:17]([C:18](=[O:20])[NH:72][C@H:56]([C:55]([O:54][CH3:53])=[O:73])[CH2:57][C:58]2[CH:59]=[CH:60][C:61]([C:64]3[CH:69]=[CH:68][N:67]=[C:66]([CH3:70])[C:65]=3[CH3:71])=[CH:62][CH:63]=2)[CH2:16][C:15]2[CH:14]=[C:13]3[O:21][CH2:22][C@H:23]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([O:31][CH2:32][C:33]5[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([Cl:40])[CH:34]=5)[CH:26]=4)[O:24][C:12]3=[CH:11][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@H](c1cccc(OCc2ccc(Cl)c(Cl)c2)c1)O3
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccnc(C)c2C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1cccc(OCc2ccc(Cl)c(Cl)c2)c1)CO3
Temperature: 0 °C
Reaction time: 2 h

Procedure:
(3S,8S)-3-[3-(3,4-Dichloro-benzyloxy)-phenyl]-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7,8-dicarboxylic acid 7-tert-butyl ester (150 mg) was taken in 2 mL of anhydrous DCM and EDCl (64 mg), HOBT (47 mg) and (S)-2-amino-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester dihydrochloride (91 mg) and stirred for 5 minutes. Reaction mixture was cooled to 0° C. and DIEA (164 mg) was added and reaction was stirred at room temperature for 2 hours. After the reaction is complete, it was purified by silica gel column chromatography (1:3 EtOAc/hexanes to 2% MeOH in 1:1 EtOAc/hexanes) (152 mg). LCMS (m/z): 853.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)=[C:10]([CH2:13][CH2:14][CH2:15]OS(C)(=O)=O)[NH:11][CH:12]=2)=[CH:4][CH:3]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:21]3[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=3)=[C:10]([CH2:13][CH2:14][CH2:15][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[NH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCCCc1[nH]cc(-c2ccc(F)cc2)c1-c1ccncc1
Reactant: C1COCCN1
Solvent: ClCCl
Product: Fc1ccc(-c2c[nH]c(CCCN3CCOCC3)c2-c2ccncc2)cc1

Procedure:
4-(4-fluorophenyl)-2-(3-mesyloxypropyl)-3-(4-pyridyl)pyrrole (0.25 g, 0.0007 mol) was refluxed for 16 hours in CH2Cl2 (50 mL) and morpholine (0.25 mL). The solution was cooled and diluted with CH2Cl2 (˜100 mL), then washed with H2O (3×50 mL). The organics were dried over Na2SO4 and evaporated in vacuo to give an oil. This oil was purified on SiO2 eluting with 10% MeOH in CH2Cl2 to give 4-(4-fluorophenyl)-2-(3-morpholinopropyl)-3-(4-pyridyl)pyrrole isolated as a solid (0.088 g, 36% yield). 1HNMR (DMSO-d6) δ 11.12 (1H, s, NH), 8.42 (2H, d), 7.05 (6H, m), 6.95 (1H, d), 3.55 (4H, t), 2.62 (2H, t), 2.29 (6H, m), 1.71 (2H, m).
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7](=O)[CH:8]([CH3:17])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[C:4]=2[CH:3]=1.[H-].[Na+].P(Cl)(OCC)(OCC)=O.[N+:32]([CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])#[C-:33].[H-].[Na+].C1COCC1>C1COCC1>[CH2:38]([O:37][C:35]([C:34]1[N:32]=[CH:33][N:6]2[C:7]=1[CH:8]([CH3:17])[N:9]=[C:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)[C:4]1[CH:3]=[C:2]([Br:1])[CH:20]=[CH:19][C:5]2=1)=[O:36])[CH3:39]
Reactant: CC1N=C(c2ccccn2)c2cc(Br)ccc2NC1=O
Reactant: [C-]#[N+]CC(=O)OCC
Agent: CCOP(=O)(Cl)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ncn2c1C(C)N=C(c1ccccn1)c1cc(Br)ccc1-2
Temperature: -10 °C
Reaction time: 3 h

Procedure:
The 7-bromo-3-methyl-5-pyridin-2-yl-1,3-dihydro-benzo[e][1,4]diazepin-2-one 125 (3.3 g, 10 mmol) was suspended in dry THF (200 mL) and cooled to −10° C. Sodium hydride (60% dispersion in mineral oil, 0.48 g, 12 mmol) was added into the suspension in one portion. The reaction mixture was allowed to stir and warm to rt over a 3 h period. The reaction mixture was again cooled to −10° C. and diethyl chlorophosphate (2.31 mL, 16 mmol) was added. The cooling bath was then removed and stirring continued for 3 h. At this time, sodium hydride (60% dispersion in mineral oil, 0.56 g, 14 mmol) was suspended in dry THF (150 mL) at −10° C. in another flask. Ethyl isocyanoacetate (1.31 mL, 12 mmol) was added to the NaH/THF suspension, the solution which resulted was allowed to stir for 3 h. After 3 h, the first flask was cooled to −30° C. and the solution in the 2nd reaction flask was added to the first flask via a cannula. The reaction mixture was allowed to stir for 24 h, and then cooled with an ice-water bath and slowly quenched with acetic acid (10 mL). Water was added to the reaction mixture after which it was extracted with EtOAc. The EtOAc layers were combined, washed with aq NaHCO3, brine and dried (Na2SO4). After removal of the solvent under reduced pressure, the solid was purified by flash chromatography (silica gel, EtOAc:hexane, gradient elution 1:1, 2:1, 3:1). The ester 126 was a white solid (1.40 g, 33%). mp 193-195° C.; IR (KBr, cm−1) 2962, 1719, 1260, 1021; 1H NMR (CDCl3) δ 7.92 (s, 1 H), 7.72 (dd, J=8.5, 1.5 Hz, 1 H), 7.6 (t, J=6.9 Hz, 1 H), 7.48 (d, J=8.5 Hz, 1 H), 7.42-7.49 (m, 2 H), 7.23-7.29 (m, 1 H), 7.05 (t, J=9.3 Hz, 1 H), 6.71 (q, J=7.3 Hz, 1 H), 4.41 (m, 2 H), 1.42 (t, J=7.1 Hz, 3 H), 1.29 (d, J=7.2, 3 H).
Reaction SMILES: [OH:1][C:2]1C(OCCC)=CC(C=O)=C[C:3]=1[N+]([O-])=O.[OH:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH:21]=[O:22].BrCCO>>[OH:1][CH2:2][CH2:3][O:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH:21]=[O:22]
Reactant: CCCOc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: COc1ccc(C=O)cc1O
Agent: OCCBr
Product: COc1ccc(C=O)cc1OCCO

Procedure:
Followed procedure described in Intermediate 65, step 2 starting from 3-hydroxy-4-methoxybenzaldehyde and 2-bromoethanol, using crude material for next step.
Reaction SMILES: [CH2:1]([N:3]([CH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1B1OC(C)(C)C(C)(C)O1)[C:4]([CH:6]1[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH3:29][O:30][C:31](=[O:51])[CH2:32][C:33]1[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[C:35](OS(C(F)(F)F)(=O)=O)[CH:34]=1>>[CH3:29][O:30][C:31](=[O:51])[CH2:32][C:33]1[CH:34]=[C:35]([C:11]2[CH:12]=[CH:13][C:14]([C:16]([F:17])([F:18])[F:19])=[CH:15][C:10]=2[CH2:9][N:3]([C:4]([CH:6]2[CH2:7][CH2:8]2)=[O:5])[CH2:1][CH3:2])[CH:36]=[C:37]([C:39]([F:41])([F:40])[F:42])[CH:38]=1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)C1CC1
Reactant: COC(=O)Cc1cc(OS(=O)(=O)C(F)(F)F)cc(C(F)(F)F)c1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)cc(C(F)(F)F)c1)C(=O)C1CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 4, using the following starting materials: cyclopropanecarboxylic acid ethyl-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-amide and (3-trifluoromethanesulfonyloxy-5-trifluoromethyl-phenyl)-acetic acid methyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:14]([CH:15]=[CH2:16])[CH2:13][CH2:12][O:11][CH:10]2[OH:17])[CH:5]=[CH:6][C:7]=1[F:8].[F:18][C:19]([F:34])([F:33])[C:20]1[CH:21]=[C:22]([C@H:30](O)[CH3:31])[CH:23]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:25]=1>ClCCl>[F:18][C:19]([F:33])([F:34])[C:20]1[CH:21]=[C:22]([C@H:30]([O:17][C@@H:10]2[C@@H:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Br:1])[CH:3]=3)[C@H:14]([CH:15]=[CH2:16])[CH2:13][CH2:12][O:11]2)[CH3:31])[CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[CH:25]=1
Reactant: C[C@@H](O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C=CC1CCOC(O)C1c1ccc(F)c(Br)c1
Solvent: ClCCl
Product: C=C[C@@H]1CCO[C@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]1c1ccc(F)c(Br)c1
Temperature: 40 °C
Reaction time: 72 h

Procedure:
(±) 3-(3-Bromo-4-fluorophenyl)-4-vinyltetrahydropyran-2-ol (from step f) above; 10.32 g, 0.034 mol), (1R)-3,5-bis(trifluoromethyl)phenylethanol (11 g, 0.042 mol), Amberlyst™ (5 g) and molecular sieves (8 g) were suspended in dichloromethane (20 mL) and the mixture was shaken at 40° C. for 3 days. The resulting yellow solution was filtered, concentrated in vacuo and was purified by chromatography on silica using 1-5% ethyl acetate in hexane as eluant to give a mixture of isomers 1-3 (which were retained) and the desired isomer 4 (3.6 g, 20%) as a colourless oil.
Reaction SMILES: [CH:1]1(ON2C(=O)C3=CC=CC=C3C2=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH2:18].NN.Cl>C(O)C>[CH:1]1([CH:4]2[CH:5]=[CH:1][CH:2]=[CH:3][O:18]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O
Reactant: O=C1c2ccccc2C(=O)N1OC1CCCC1
Agent: Cl
Agent: NN
Solvent: CCO
Product: C1=COC(C2CCCC2)C=C1
Temperature: 25 °C
Yield: 175.8 %

Procedure:
A mixture of N-cyclopentyloxyphthalimide (11 g), 100% hydrazine hydrate (2.6 g), and ethanol (30 ml) was heated under reflux for 5 minutes. Concentrated hydrochloride acid (6 ml) was added to the mixture, which was heated under reflux Water (20 ml) was added to the mixture, which was cooled to room temperature, and filtered. The filtrate was evaporated to dryness, ethanol (50 ml) was added to the residue, and a small amount of insoluble material was filtered off. The filtrate was evaporated to dryness, and the residue was recrystallised from ethanol/ether to give cyclopentyloxamine (6.28 g,) 96%), m.p. 156.9°.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@@:3]1([CH2:10][O:11][Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[C:7]([OH:9])=O.[F:22][C:23]1[CH:24]=[CH:25][C:26]([NH:29][NH2:30])=[N:27][CH:28]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[F:22][C:23]1[CH:24]=[CH:25][C:26]([NH:29][NH:30][C:7]([C@:3]2([CH2:10][O:11][Si:12]([CH:13]([CH3:14])[CH3:15])([CH:16]([CH3:17])[CH3:18])[CH:19]([CH3:20])[CH3:21])[CH2:4][CH2:5][CH2:6][N:2]2[CH3:1])=[O:9])=[N:27][CH:28]=1
Reactant: NNc1ccc(F)cn1
Reactant: CC(C)[Si](OC[C@@]1(C(=O)O)CCCN1C)(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)[Si](OC[C@@]1(C(=O)NNc2ccc(F)cn2)CCCN1C)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
To a solution of Intermediate 85g (1.08 g, 3.58 mmol), (5-fluoro-pyridin-2-yl)-hydrazine (500 mg, 3.93 mmol) and DIPEA (1.38 g, 10.7 mmol) in DCM (120 mL) was added HATU (2.04 g, 5.37 mmol) and the mixture stirred at RT for 2 h. The solution was washed with 10% aq. K2CO3 solution, brine, dried (MgSO4), and concentrated in vacuo. The residue was purified by FCC, using 0-6% [2M NH3 in MeOH] in DCM, to give the title compound as a pale yellow oil (1.37 g, 90%). LCMS (Method 4): Rt 2.74 min, m/z 425 [MH+].
Reaction SMILES: C[O:2][C:3]([C@:5]1([CH3:25])[C@@H:9]([O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH2:8][CH2:7][N:6]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=O.C([BH-](CC)CC)C.[Li+]>C1COCC1>[C:21]([O:20][C:18]([N:6]1[CH2:7][CH2:8][C@@H:9]([O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[C@@:5]1([CH2:3][OH:2])[CH3:25])=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: COC(=O)[C@]1(C)[C@@H](O[Si](C)(C)C(C)(C)C)CCN1C(=O)OC(C)(C)C
Agent: CC[BH-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@@H](O[Si](C)(C)C(C)(C)C)[C@]1(C)CO
Temperature: 25 °C
Reaction time: 4 h
Yield: 68928400 %

Procedure:
To a solution of 4B (206 mg, 0.550 nmol) in THF (5 mL) at −78° C. under nitrogen was added dropwise 1.0 M lithium triethylborohydride in tetrahydrofuran (3.00 mL, 3.00 mmol). The reaction was allowed to warm to rt and was stirred for 4 h. The reaction was quenched by pouring over ice (50 g) and stirring for 30 min. The product was extracted into EtOAc and washed with saturated aqueous NaHCO3 and brine. The organic layer was dried over MgSO4, filtered and concentrated. Purification via silica gel chromatography (0-15% EtOAc in hexane) provided the title compound (131 mg).