Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]3[N:14]=[C:15]([CH3:28])[N:16]=[C:17]([N:18]4[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][C:26]#[N:27])[CH2:20][CH2:19]4)[C:12]=3[C:11]([CH3:29])=[C:10]2[CH3:30])=[C:4]([CH3:31])[CH:3]=1.[OH:32]S(O)(=O)=O.[OH-].[Na+]>>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]3[N:14]=[C:15]([CH3:28])[N:16]=[C:17]([N:18]4[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][C:26]([NH2:27])=[O:32])[CH2:20][CH2:19]4)[C:12]=3[C:11]([CH3:29])=[C:10]2[CH3:30])=[C:4]([CH3:31])[CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: Cc1nc(N2CCC(CCC#N)CC2)c2c(C)c(C)n(-c3c(C)cc(Br)cc3C)c2n1
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc(N2CCC(CCC(N)=O)CC2)c2c(C)c(C)n(-c3c(C)cc(Br)cc3C)c2n1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 3-{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-propionitrile (0.40 g), H2SO4 (4 mL) was added and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into ice, and then was made to alkaline by adding 4 M aqueous NaOH solution. The mixture was extracted with ethyl acetate and the organic phase and the organic phase was dried over Na2SO4. The desiccant was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified with column chromatography (silica gel: Wako gel C200, eluent: CHCl3:methanol=60/1) to obtain an oil. The oily product was crystallized from diethylether to obtain the title compound (0.33 g) as a white crystal.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:17])[CH2:10][C:11]1[N:12]=[N:13][CH:14]=[CH:15][CH:16]=1.I[CH3:19]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:17])[CH:10]([C:11]1[N:12]=[N:13][CH:14]=[CH:15][CH:16]=1)[CH3:19]
Reactant: CI
Reactant: O=C(Cc1cccnn1)c1ccc(F)cc1F
Product: CC(C(=O)c1ccc(F)cc1F)c1cccnn1
Yield: 64.3 %

Procedure:
Methylation of the product of part (i) (3.30 g) with iodomethane (5.0 g) according to the method of Example 11(ii) gave the title compound as a gum (2.25 g) which was used directly in the next stage.
Reaction SMILES: Cl.[NH2:2][CH2:3][C@H:4]([OH:41])[C@@H:5]([NH:13][C:14](=[O:40])[C@@H:15]([NH:22][C:23](=[O:39])[C@@H:24]([CH2:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:16][C:17]1[N:18]=[CH:19][NH:20][CH:21]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[C:42]1(=O)[O:47][C:45](=[O:46])[C:44]2=[CH:48][CH:49]=[CH:50][CH:51]=[C:43]12>C(#N)C>[CH:7]1([CH2:6][C@H:5]([NH:13][C:14](=[O:40])[C@@H:15]([NH:22][C:23](=[O:39])[C@@H:24]([CH2:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:35])[CH3:36])[CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:16][C:17]2[N:18]=[CH:19][NH:20][CH:21]=2)[C@@H:4]([OH:41])[CH2:3][N:2]2[C:45](=[O:46])[C:44]3=[CH:48][CH:49]=[CH:50][CH:51]=[C:43]3[C:42]2=[O:47])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: O=C1OC(=O)c2ccccc21
Reactant: CC(C)(C)C(=O)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)CN
Agent: Cl
Solvent: CC#N
Product: CC(C)(C)C(=O)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)CN1C(=O)c2ccccc2C1=O
Yield: 56.7 %

Procedure:
50 mg (0.08 mmol) of (S)-N-[(1S,2S)-3-amino-1-(cyclohexylmethyl)-2-hydroxypropyl]-α-[(R)-α-(3,3-dimethyl-2-oxobutyl)hydrocinnamamido]imidazole-4-propionamide hydrochloride and 1.5 g (10 mmol) of phthalic anhydride were suspended in 15 ml of acetonitrile and heated to reflux overnight. Thereafter, the reaction mixture was evaporated to dryness under reduced pressure and the residue was chromatographed on 10 g of silica gel with a mixture of methylene chloride, methanol and ammonia as the eluting agent, whereby there were obtained 31 mg of (S)-N[(1S,2S)-1-(cyclohexylmethyl)-2-hydroxy-3-phthalimidopropyl]-α-[(R)-α-(3,3-dimethyl-2-oxobutyl)hydrocinnamamido]imidazole-4-propionamide as a foam, MS: 684 (M+H)+.
Reaction SMILES: [BH4-].[Na+].[Si:3]([O:10][C@@H:11]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12](OCC)=[O:13])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]>CO>[Si:3]([O:10][C@@H:11]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:12][OH:13])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: CCOC(=O)[C@@H](O[Si](C)(C)C(C)(C)C)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@H](CO)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
15.5 g of sodium borohydride were added in portions, whilst ice-cooling, to a solution of 20 g of ethyl (S)-α-t-butyldimethylsilyloxy-α-phenylacetate [prepared as described in step (a) above] in 500 ml of absolute methanol, and the resulting mixture was stirred overnight at room temperature. At the end of this time, 10 g of sodium borohydride were added in portions, whilst ice-cooling. The reaction mixture was then stirred at room temperature for 5 hours, after which it was concentrated by evaporation under reduced pressure, and the concentrate was mixed with water and ethyl acetate. The ethyl acetate layer was separated, washed with water and dried over anhydrous sodium sulfate, and then the solvent was removed by distillation under reduced pressure, to give the title compound as a crude product.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[CH3:10][C:11]1[CH:12]=[C:13]([CH:28]=[CH:29][C:30]=1[CH3:31])[O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:22]([NH2:27])=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:17][CH:16]=1>C1COCC1>[CH3:10][C:11]1[CH:12]=[C:13]([CH:28]=[CH:29][C:30]=1[CH3:31])[O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:22]3=[N:27][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:23]3[CH:24]=[CH:25][CH:26]=2)=[CH:17][CH:16]=1
Reactant: O=S(=O)(Cl)CCCl
Reactant: Cc1ccc(Oc2ccc(-c3cccnc3N)cc2)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(Oc2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)cc1C
Reaction time: 0.17 h

Procedure:
To a suspension of NaH (60%, 99 mg) in THF (dry) (10 mL) was added 2-chloroethanesulfonyl chloride (0.156 mL) at 0° C. and the mixture was stirred for 10 min at the same temperature. A solution of 3-(4-(3,4-dimethylphenoxy)phenyl)pyridin-2-amine (144 mg) in THF (dry) (10 mL) was added at 0° C. and the mixture was stirred at room temperature under nitrogen overnight. The mixture was quenched with water at 0° C. and extracted with EtOAc/THF. Silica-gel was added to the organic phase and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (silica gel, eluted with MeOH in EtOAc) to give the title compound (119.7 mg). A part of product was recrystallized from MeCN/IPE.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH2:2][CH3:3].N1C=CC=CC=1.[NH2:20][C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]=[C:26]([CH3:31])[CH:25]=[N:24]2.C([O-])(O)=O.[Na+]>ClCCl>[CH3:31][C:26]1[CH:25]=[N:24][C:23]2[C:28](=[CH:29][CH:30]=[C:21]([NH:20][S:10]([C:7]3[CH:8]=[CH:9][C:4]([CH2:1][CH2:2][CH3:3])=[CH:5][CH:6]=3)(=[O:12])=[O:11])[CH:22]=2)[N:27]=1
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cnc2cc(N)ccc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCc1ccc(S(=O)(=O)Nc2ccc3nc(C)cnc3c2)cc1
Reaction time: 0.08 h
Yield: 98.4 %

Procedure:
To a solution of 4n-propylbenzenesulphonyl chloride (115 mg, 0.528 mmol) in dichloromethane (3 mL) was added pyridine (100 μL, 1.26 mmol) and the mixture was stirred under N2 for 5 min, after which time 6-amino-2-methylquinoxaline (80 mg, 0.50 mmol) was added. The resulting mixture was stirred for 2 h at room temperature, then saturated NaHCO3 solution (8 mL) was added and the mixture was extracted into ethyl acetate (15 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and evaporated to give a residue that was purified using flash chromatography to afford a white solid (168 mg, 95%), single spot at Rf 0.72 (ethyl acetate). mp 135.6-136.2° C., HPLC purity 99+% (tR 2.23 min in 10% water-acetonitrile). 1H NMR (CDCl3): δ 8.66 (1H, s), 7.89 (1H, di-J=9.2 Hz), 7.77 (2H, d, J=8.4 Hz), 7.67 (1H, d, J=2.5 Hz), 7.54 (1H, dd, J=8.9, 2.5 Hz), 7.22 (2H, d, J=8.4 Hz), 2.71 (3H, s), 2.56 (2H, t, J=7.7 Hz), 1.58 (2H, sextet, J=7.7 Hz), 0.87 (3H, t, J=7.4 Hz). LCMS: 340.25 (M−). FAB-MS (MH+, C18H19N3O2S): calcd 342.1276, found 342.1290.
Reaction SMILES: [CH:1]1([C:9]([OH:11])=O)[C:3]2([CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(OCC)(=O)C.Cl.[NH2:31][C@@H:32]([CH3:36])[C:33]([NH2:35])=[O:34]>O>[NH2:35][C:33](=[O:34])[C@@H:32]([NH:31][C:9]([C@@H:1]1[C:3]2([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:2]1)=[O:11])[CH3:36]
Reactant: C[C@H](N)C(N)=O
Reactant: O=C(O)C1CC12CCCCC2
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CCOC(C)=O
Product: C[C@H](NC(=O)[C@H]1CC12CCCCC2)C(N)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 1000 mL flask was charged with the product from Example 1B (47.8 g, 0.31 mol), 1,1′-carbonyldiimidazole (60.8 g, 0.37 mol) and 500 mL of ethyl acetate. The mixture was stirred at ambient temperature for 2 hours then (2S)-2-aminopropanamide hydrochloride (46.7 g, 0.70 mol, commercially available from Aldrich) and 30 mL of water were charged to the flask. The reaction mixture was heated at 65° C. for 19 hours. After cooling to ambient temperature, the reaction flask was charged with 500 mL of water and stirred for 4 hours resulting in formation of a crystalline solid. The solid was filtered, rinsed with 100 mL of ethyl acetate, and dried to provide the title compound in 97% diastereomeric excess (de) as determined by HPLC: Zobax RX-C8 column, 5 μm, 4.6×250 mm; detector λ=205 nm, eluted with 15% CH3CN/0.03 M KH2PO4 for 10 minutes then 35% CH3CN/0.03 M KH2PO4 over 15 minutes; retention time 20.01 minutes. Stereochemistry was determined by x-ray crystallography. X-ray data: MW=224.30, C12H20N2O2, crystal dimensions 0.40X0.40X0.40 mm, primitive orthorhombic, P212121 (#19), a=6.9845(9) Å, b=8.642(1) Å, c=22.081(3) Å, V=1332.8(3) Å3, Z=4, Dcalc=1.118 g/cm3. Crystallographic data were collected using MoKα graphite monochromated radiation (λ=0.71069 Å). Refinement of the structure using full matrix least squares refinement of 2049 observed reflections (I>3.00σ(I)) and 145 variable parameters and converged with unweighted and weighted agreement factors of R=0.068 and Rw=0.075. 1H NMR (DMSO-d6, 300 MHz) δ 8.00 (d, 1H), 7.19 (s, 1H), 6.91 (s, 1H), 4.22 (p, 1H), 1.50 (dd), 1.3-1.6 (m, 10H), 1.19 (d, 3H), 0.85 (dd), 0.59 (dd, 1H); 13C NMR (DMSO-d6, 100 MHz) δ 174.1, 169.8, 47.9, 37.0, 28.3, 28.1, 26.7, 25.9, 25.2, 25.2, 18.5, 18.1; MS m/z 225 (M+H)+.
Reaction SMILES: [CH:1]([N:4]1[C:9]2[N:10]=[C:11](S(C)=O)[N:12]=[CH:13][C:8]=2[CH:7]=[CH:6][C:5]1=[O:17])([CH3:3])[CH3:2].[CH2:18]([N:20]([CH2:31][CH3:32])[CH2:21][CH2:22][O:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1)[CH3:19]>>[CH2:31]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([NH:28][C:11]2[N:12]=[CH:13][C:8]3[CH:7]=[CH:6][C:5](=[O:17])[N:4]([CH:1]([CH3:3])[CH3:2])[C:9]=3[N:10]=2)=[CH:29][CH:30]=1)[CH3:32]
Reactant: CC(C)n1c(=O)ccc2cnc(S(C)=O)nc21
Reactant: CCN(CC)CCOc1ccc(N)cc1
Product: CCN(CC)CCOc1ccc(Nc2ncc3ccc(=O)n(C(C)C)c3n2)cc1
Temperature: 175 °C
Yield: 47.5 %

Procedure:
To 8-isopropyl-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (126 mg, 0.50 mmol) was added 4-(2-diethylaminoethoxy)aniline (313 mg, 1.51 mmol). The reaction mixture was heated at 175° C. for 10 minutes then cooled to room temperature and partitioned between saturated sodium bicarbonate and ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography eluting with 10% methanol in ethyl acetate. The fractions containing product were concentrated, and hexane was added. The resultant solid was collected by filtration to give 94 mg (47%) of 2-[4-(2-diethylaminoethoxy)-phenylamino]-8-isopropyl-8H-pyrido[2,3-d]pyrimidin-7-one, mp 84-85° C.
Reaction SMILES: [Si:1]([O:18][CH2:19][CH2:20][O:21][CH2:22][C@H:23]([OH:34])[C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][N:28]=1)=[O:25])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:35][C:36]1[C:37]([N:44]2[C:48]3=[N:49][CH:50]=[N:51][C:52](Cl)=[C:47]3[CH:46]=[N:45]2)=[C:38]([CH:41]=[CH:42][CH:43]=1)[C:39]#[N:40]>>[Si:1]([O:18][CH2:19][CH2:20][O:21][CH2:22][C@H:23]([O:34][C:52]1[N:51]=[CH:50][N:49]=[C:48]2[N:44]([C:37]3[C:38]([C:39]#[N:40])=[CH:41][CH:42]=[CH:43][C:36]=3[Cl:35])[N:45]=[CH:46][C:47]=12)[C:24]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][N:28]=1)=[O:25])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(NC(=O)[C@@H](O)COCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)nc1
Reactant: N#Cc1cccc(Cl)c1-n1ncc2c(Cl)ncnc21
Product: Cc1ccc(NC(=O)[C@H](COCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)Oc2ncnc3c2cnn3-c2c(Cl)cccc2C#N)nc1

Procedure:
Prepared using a procedure analogous to that described with Intermediate AH7 using (S)-3-(2-(tert-butyldiphenylsilyloxy)ethoxy)-N-(5-methylpyridin-2-yl)-2-hydroxypropanamide (Intermediate AU2) and 3-chloro-2-(4-chloro-1H-pyrazolo[3,4-d]pyrimidin-1-yl)benzonitrile (Intermediate AH6). m/z (ES+) (M+H)+=732; HPLC tR=3.76 min
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=O)=[CH:5][CH:4]=1.[C:19]1(C)C=CC=CC=1.C[Mg]Br.[Cl-].[NH4+]>O.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([C:7]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH2:19])=[CH:5][CH:4]=1
Reactant: Cc1ccccc1
Reactant: COc1ccc(C(=O)c2ccc(OC)cc2)cc1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: O
Product: C=C(c1ccc(OC)cc1)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 258 g 4,4'-dimethoxybenzophenone in 3000 ml warm toluene was added to 1600 ml 1.4M methylmagnesium bromide under nitrogen with stirring, over a one-hour period. The reaction temperature was kept below 40° C. After addition was complete, stirring was continued for one hour at 30°-40° C. and two hours at 50° C. The mixture was cooled to room temperature and poured into a stirred mixture of 400 ml acetic acid and 624 g ammonium chloride in 7200 ml deionized water. After gas evolution and exotherm had subsided, the organic (toluene) phase was separated and the aqueous phase was washed with 2×600 ml toluene. The combined toluene phases were washed with 1×2400 ml water, then placed in a flask and treated with a solution of 1470 ml deionized water and 1470 ml acetic acid at 50° C. for three hours to effect dehydration of the intermediate hydroxy compound. On cooling, the phases were separated and the toluene phase was washed with 2×1000 ml deionized water, then dried over magnesium sulfate. Filtration and removal of toluene gave a slightly wet cake which was triturated with 1400 ml diethyl ether, filtered and dried to give 222 g 1,1-di(p-methoxyphenyl)-ethene, m.p. 141°-143° C. whose structure was also confirmed by NMR.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:8]2[CH:9]=[C:10]([OH:13])[CH:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].C(N(CC)CC)C.[C:21](Cl)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[C:8]2[CH:9]=[C:10]([O:13][C:21](=[O:28])[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)C1=Cc2ccc(O)cc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)C1=Cc2ccc(OC(=O)c3ccccc3)cc21
Reaction time: 0.08 h

Procedure:
27 g of 5-hydroxybenzocyclobutene-1-carboxylic acid methyl ester are dissolved in 2000 ml of dichloromethane and then 18 g of triethylamine are added. Over a period of 5 minutes, while stirring at 10°-20°, 25 g of benzoyl chloride are added in portions, stirring is carried out for 5 hours at room temperature, 200 ml of water are added and the organic phase is separated off, dried over magnesium sulphate and concentrated to dryness by evaporation. 5-benzoyloxybenzocyclobutene-1-carboxylic acid methyl ester is obtained in the form of a colourless, viscous oil.
Reaction SMILES: [Br:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:16]O>C(Cl)Cl.CN(C=O)C>[CH3:16][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][CH:9]=[C:10]([Cl:11])[C:2]=1[Br:1]
Reactant: O=C(O)c1cccc(Cl)c1Br
Reactant: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(Cl)c1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-bromo-3-chlorobenzoic acid (7.29 mmol) in 20 mL DCM and 1 mL DMF was added 1.06 mL thionyl chloride. After stirring at RT overnight, 5 mL MeOH were added and stirring was continued at RT for 1 h. The reaction mixture was cooled in an ice bath, quenched by adding a sat. aq. NaHCO3 solution and extracted twice with DCM. The combined organic layers were dried over MgSO4 and concentrated in vacuo to give the desired product as colorless oil.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:33][C:34]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:35]=1[F:42])[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:18]([C:29]([F:32])([F:31])[F:30])=[N:19][C:20]([C:21]([N:23]3[CH2:27][CH2:26][C@H:25]([F:28])[CH2:24]3)=[O:22])=[C:14]2[CH2:13]1)=[O:11])(C)(C)C.[ClH:44]>C(OCC)(=O)C>[ClH:44].[NH2:7][C@H:8]([CH2:33][C:34]1[CH:39]=[C:38]([F:40])[C:37]([F:41])=[CH:36][C:35]=1[F:42])[CH2:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]2[C:18]([C:29]([F:32])([F:31])[F:30])=[N:19][C:20]([C:21]([N:23]3[CH2:27][CH2:26][C@H:25]([F:28])[CH2:24]3)=[O:22])=[C:14]2[CH2:13]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CC[C@H](F)C3)c2C1)Cc1cc(F)c(F)cc1F
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)N3CC[C@H](F)C3)c2C1)Cc1cc(F)c(F)cc1F
Yield: 94 %

Procedure:
(R)-[3-[1-((S)-3-Fluoro-pyrrolidine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 26a (0.15 g, 0.24 mmol) and 2 mL of ethyl acetate were added into the reaction flask. A solution of 2.7 N hydrochloric acid in 5 mL of ethyl acetate was then added to the flask. The reaction mixture was reacted at room temperature for 3 hours and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure to obtain the title compound (R)-3-amino-1-[1-((S)-3-fluoropyrrolidine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-4-(2,4,5-trifluoro-phenyl)-butan-1-one hydrochloride 26 (140 mg, yield 94%) as a white solid.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[NH2:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:29]/[O:30][C:31]([C:34]([O:36]C(C)(C)C)=[O:35])([CH3:33])[CH3:32])/[C:15]([NH:17][C@H:18]2[C@H:21]([CH2:22][CH3:23])[N:20]([S:24]([OH:27])(=[O:26])=[O:25])[C:19]2=[O:28])=[O:16])[N:13]=1.FC(F)(F)C(O)=O>>[CH2:1]([N:3]([CH2:6][CH3:7])[CH2:4][CH3:5])[CH3:2].[NH2:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:29]/[O:30][C:31]([C:34]([OH:36])=[O:35])([CH3:32])[CH3:33])/[C:15]([NH:17][C@H:18]2[C@H:21]([CH2:22][CH3:23])[N:20]([S:24]([OH:27])(=[O:26])=[O:25])[C:19]2=[O:28])=[O:16])[N:13]=1
Reactant: CC[C@H]1[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c2csc(N)n2)C(=O)N1S(=O)(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC[C@H]1[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)O)c2csc(N)n2)C(=O)N1S(=O)(=O)O
Reaction time: 20 h
Yield: 25.6 %

Procedure:
250 mg of (3S, 4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[[1-(t-butoxycarbonyl)-1-methylethoxy]imino]acetamido]-4-ethyl-2-oxo-1-azetidinesulphonic acid triethylamine salt are added at -10° C. to 3 ml of trifluoroacetic acid. After 20 hours at -10° C., the mixture is evaporated and the residue is purified by DCCC [droplet counter current chromatography; rising droplets in the mixture chloroform/methanol/water (7:13:8)]. 58 mg of amorphous (3S, 4S)-3-[(Z)-2-(2-amino-4-thiazolyl)-2-[(1-carboxy-1-methylethoxy)imino]acetamido]-4-ethyl-2-oxo-1-azetidinesulphonic acid triethylamine salt are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1[C:8]([O:10]CC)=O.[CH3:13][O:14][C:15]([NH:17][C:18](=[N:21]C(OC)=O)SC)=[O:16].CC(O)=O.C[O-].[Na+]>CO>[CH3:7][C:5]1[NH:4][C:3]2[C:8](=[O:10])[NH:21][C:18]([NH:17][C:15](=[O:16])[O:14][CH3:13])=[N:1][C:2]=2[CH:6]=1
Reactant: CCOC(=O)c1[nH]c(C)cc1N
Reactant: COC(=O)N=C(NC(=O)OC)SC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)Nc1nc2cc(C)[nH]c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.6 %

Procedure:
The pyrrole 6 (2.68 g, 16 mmol) was dissolved in MeOH (40 mL), and 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (3.74 g, 18 mmol) was added followed by AcOH (4.6 mL). The mixture was stirred at room temperature overnight and became a thick paste. To the reaction mixture NaOMe in MeOH (25%) 45 mL was added, and stirring was continued at room temperature for 2 h. The mixture was neutralized with AcOH and the solid collected by filtration and washed well with water. After drying, 7 (2.44 g, 69%) was obtained as an off-white powder: mp 234-236° C.; TLC Rf0.22 (MeOH/CHCl3, 1:5); 1H NMR (DMSO-d6) δ 2.28 (s, 3 H, CH3), 3.73 (s, 3 H, OCH3), 5.95 (s, 1 H), 10.90 (s, 1 H), 11.10 (s, 1 H), 11.76 (1 H). Anal. (C9H10N4O3.0.79C6H6.0.55C7H8O3S) C, H, N.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([N:14]([C@@H:22]([CH2:33][CH2:34][CH3:35])[C:23](OCC1C=CC=CC=1)=[O:24])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[CH2:15]([N:14]([C@@H:22]([CH2:33][CH2:34][CH3:35])[CH2:23][OH:24])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCC[C@@H](C(=O)OCc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC[C@@H](CO)N(Cc1ccccc1)Cc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 61.8 %

Procedure:
To a cold (0° C.) suspension of LiAlH4 (184 mg, 4.84 mmol) in THF (10 mL), a solution of ester 9 (375 mg, 0.97 mmol) in THF (2.5 mL) was added. The mixture was stirred at 0° C. for 2 h, and then quenched by dropwise addition of EtOH (3 ml). Na—K tartrate solution (10% aq, 30 mL) was added, and the crude was extracted with EtOAc (3×30 mL), dried over Na2SO4, concentrated in vacuo and purified by column chromatography on silica (hexane/EtOAc 5:1) to obtain alcohol 10 as a colorless oil (170 mg, 62% yield).
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][CH2:5][C:4]([CH3:14])([CH3:13])[C:3]1=[O:15].[Br:16]Br>C(Cl)Cl.[Fe]>[Br:16][C:11]1[CH:10]=[CH:9][C:8]2[N:2]([CH3:1])[C:3](=[O:15])[C:4]([CH3:13])([CH3:14])[CH2:5][CH2:6][C:7]=2[CH:12]=1
Reactant: BrBr
Reactant: CN1C(=O)C(C)(C)CCc2ccccc21
Agent: [Fe]
Solvent: ClCCl
Product: CN1C(=O)C(C)(C)CCc2cc(Br)ccc21

Procedure:
A solution of 18.0 g of 2,3,4,5-tetrahydro-1,3,3-trimethyl-2-oxo-1H-1-benzazepine in 250 ml of methylene chloride was treated with 2.0 g of iron powder and thereafter dropwise with 5.83 ml of bromine in 30 ml of methylene chloride. The reaction mixture was heated to reflux overnight, thereafter poured on to ice, extracted with diethyl ether, washed with sodium pyro- sulphite solution, water and saturated sodium chloride solution, dried and evaporated. Crystallization from ethyl acetate/n-hexane yielded 21.4 g of pure 7-bromo-2,3,4,5-tetrahydro-1,3,3-trimethyl-2-oxo-1H-1-benzazepine.