Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:20][CH:21]2[CH2:24][CH:23]([C:25]#[N:26])[CH2:22]2)[C:5]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1.[CH3:27][NH:28][C:29](=[O:45])[C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+].ClCCl>O1CCOCC1.O.Cl[Pd]Cl>[Cl:1][C:2]1[N:3]=[C:4]([O:20][CH:21]2[CH2:24][CH:23]([C:25]#[N:26])[CH2:22]2)[C:5]2[C:10]([C:33]3[CH:34]=[CH:35][C:30]([C:29]([NH:28][CH3:27])=[O:45])=[CH:31][CH:32]=3)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(OC3CC(C#N)C3)nc(Cl)nc21
Reactant: CNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: ClCCl
Product: CNC(=O)c1ccc(-c2cn(COCC[Si](C)(C)C)c3nc(Cl)nc(OC4CC(C#N)C4)c23)cc1
Temperature: 85 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
3-((2-Chloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)cyclobutanecarbonitrile (1 equiv), N-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (1.15 equiv), sodium carbonate (3 equiv) and [1,1′-bisdiphenylphosphino)ferrocene]-dichloropalladium(II), complex with dichloromethane (0.1 equiv) suspended in 1,4-dioxane/water, and flushed with nitrogen, were stirred at 85° C. for 2 h. The reaction mixture was purified using silica gel chromatography (0 to 100% ethyl acetate in hexane) to give the title compound (50% yield). MS (ESI) m/z 512.3 [M+H]+.
Reaction SMILES: N[C:2]([C:9]1C=CC2C(=CC=C(OCCCCCCC)C=2)N=1)([CH3:8])[C:3]([O:5]CC)=[O:4].[CH3:27][OH:28].[CH3:29][O-:30].[Na+]>O>[CH3:27][O:28][CH2:29][O:30][CH2:9][C@@H:2]([CH3:8])[C:3]([OH:5])=[O:4]
Reactant: C[O-]
Reactant: CCCCCCCOc1ccc2nc(C(C)(N)C(=O)OCC)ccc2c1
Reactant: CO
Agent: [Na+]
Solvent: O
Product: COCOC[C@@H](C)C(=O)O
Temperature: -78 °C
Reaction time: 12 h
Yield: 95.8 %

Procedure:
(R)-Methyl 3-(methoxymethoxy)-2-methylpropanoate (7, 5.00 g, 0.0308 mol) was is dissolved in methanol (50 mL, 1 mol). The solution was then cooled to −78° C. Sodium methoxide (5.26 g, 0.0925 mol), was added gradually (in very small portions) followed by water (1.11 mL, 0.0616 mol) at −78° C. The reaction mixture was then stirred at 23° C. for 12 hours. An additional portion of NaOMe (95%, 1.0 g) was added to the reaction mixture followed by H2O (0.8 mL). The reaction mixture was allowed to stir at 23° C. for 4 hours. All the solvents were removed under vacuum, and before quenched with concentrated HCl to pH ˜5. Excess of solvents were removed under vacuum. The residue was extracted with DCM (50×3 mL). The combined organic layers were treated with water, brine and dried over Na2SO4. Removal of solvent gave a liquid product (4.37 g, 96%). 1H NMR (CHLOROFORM-d) δ: 4.64 (s, 2H), 3.69-3.82 (m, 1H), 3.56-3.68 (m, 1H), 3.37 (s, 3H), 2.80 (m, 1H), 1.23 (d, J=7.3 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:15]([O:17]CC)=[O:16])[C:5]2[CH:6]=[CH:7][N:8]([CH:11]3[CH2:14][CH2:13][CH2:12]3)[C:9]=2[CH:10]=1.[OH-].[Na+]>CO.C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:15]([OH:17])=[O:16])[C:5]2[CH:6]=[CH:7][N:8]([CH:11]3[CH2:12][CH2:13][CH2:14]3)[C:9]=2[CH:10]=1
Reactant: CCOC(=O)c1cc(Br)cc2c1ccn2C1CCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc(Br)cc2c1ccn2C1CCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 55 %

Procedure:
To a solution of ethyl 6-bromo-1-cyclobutyl-1H-indole-4-carboxylate (0.3 g, 0.973 mmol) (crude residue from above) in MeOH (8 mL) and THF (2 mL) was added 3 M NaOH (1.298 mL, 3.89 mmol). The reaction was stirred at RT for 16 h, at which time the volatiles were removed in vacuo. The residue was diluted with water and slowly acidified with 1 N HCl to pH 3-4. The solids were filtered and dried on hivac for 16 h to give 6-bromo-1-cyclobutyl-1H-indole-4-carboxylic acid (0.21 g, 0.535 mmol, 55.0% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.79-1.89 (m, 2 H) 2.34-2.46 (m, 2 H) 3.84 (s, 1 H) 5.08 (t, J=8.21 Hz, 1 H) 6.99 (d, J=3.03 Hz, 1 H) 7.75-7.79 (m, 1 H) 7.81 (d, J=3.03 Hz, 1 H) 8.01-8.05 (m, 1 H) 13.03 (br. s., 1 H). MS(ES) [M+H]+ 294.1.
Reaction SMILES: [CH3:1][C:2]([NH:4][CH2:5][CH2:6][C:7]1[C:11]2[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][C:10]=2[NH:9][CH:8]=1)=[O:3].S(OC)(O[CH3:21])(=O)=O.[OH-].[Na+]>>[CH3:1][C:2]([NH:4][CH2:5][CH2:6][C:7]1[C:11]2[CH:12]=[C:13]([O:16][CH3:21])[CH:14]=[CH:15][C:10]=2[NH:9][CH:8]=1)=[O:3]
Reactant: CC(=O)NCCc1c[nH]c2ccc(O)cc12
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc2[nH]cc(CCNC(C)=O)c2c1

Procedure:
To the aqueous alcoholic solution containing N-acetyl serotonine prepared in Example 2, there were added slowly and simultaneously 36 g of dimethyl sulphate and 20 g of 30% sodium hydroxide so that the pH was maintained at 12.5, while ensuring that the temperature did not exceed 40° C. During this operation, a part of the melatonine formed crystallised and this was filtered after neutralisation. The mother-liquor of crystallisation was decolourised with activated carbon, concentrated to eliminate the ethanol, then extracted with dichloromethane. After separation of the aqueous phase, the organic phase was concentrated to dryness which allowed the recuperation of a further 28 g of crude melatonine. The two fractions, which totalled 42 g, were mixed and purified by recrystallisation in a mixture containing water and ethanol in a 75:25 ratio. 30 g of white crystals of melatonine were obtained having a purity of 98.6%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[CH:26][C:25]=2[O:32][CH3:33])=[CH:20][CH:19]=1)[NH:5][C:6](=[O:16])[C:7]1[C:12]([Cl:13])=[CH:11][C:10](Br)=[CH:9][C:8]=1[Cl:15].[CH3:35][Si:36]([CH3:50])([CH3:49])[CH2:37][CH2:38][O:39][CH2:40][N:41]1[C:45](B(O)O)=[CH:44][CH:43]=[N:42]1>C1COCC1>[CH3:1][O:2][C:3](=[O:34])[C@H:4]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:29]([O:30][CH3:31])=[CH:28][CH:27]=[CH:26][C:25]=2[O:32][CH3:33])=[CH:20][CH:19]=1)[NH:5][C:6](=[O:16])[C:7]1[C:12]([Cl:13])=[CH:11][C:10]([C:45]2[N:41]([CH2:40][O:39][CH2:38][CH2:37][Si:36]([CH3:50])([CH3:49])[CH3:35])[N:42]=[CH:43][CH:44]=2)=[CH:9][C:8]=1[Cl:15]
Reactant: COC(=O)[C@H](Cc1ccc(-c2c(OC)cccc2OC)cc1)NC(=O)c1c(Cl)cc(Br)cc1Cl
Reactant: C[Si](C)(C)CCOCn1nccc1B(O)O
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1ccc(-c2c(OC)cccc2OC)cc1)NC(=O)c1c(Cl)cc(-c2ccnn2COCC[Si](C)(C)C)cc1Cl
Yield: 95.6 %

Procedure:
N-(4-Bromo-2,6-dichlorobenzoyl)-4-(2,6-dimethoxyphenyl)-L-phenylalanine methyl ester (0.240 g) was coupled with 1-[[2-(trimethylsilyl)ethoxy]methyl]-5-pyrazoleboronic acid (0.343 g) in THF (10 mL) as described in Example 7-2) to give N-[4-[1-[[2-(trimethylsilyl)ethoxy]methyl ]-5-pyrazolyl]-2,6-dichlorobenzoyl]-4-(2,6-dimethoxyphenyl)-L-phenylalanine methyl ester (0.277 g). ESMS: m/z 684 (MH+) and 682 (M−H)−.
Reaction SMILES: [C:1]([NH2:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)Br.[P:14]([OH:17])([OH:16])[OH:15]>O1CCOCC1.O>[C:2]1([C:1]([NH2:9])([P:14]([OH:17])(=[O:15])[OH:16])[P:14]([OH:17])(=[O:16])[OH:15])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OP(O)O
Reactant: NC(=O)c1ccccc1
Agent: BrP(Br)Br
Solvent: C1COCCO1
Solvent: O
Product: NC(c1ccccc1)(P(=O)(O)O)P(=O)(O)O

Procedure:
120 parts of benzamide were suspended in 300 parts of dioxan and reacted with 541 parts of phosphorus tribromide. Then 82 parts of phosphorous acid dissolved in dioxan were added at about 20°C, and the mixture was heated at 60° to 70° C for 3 to 4 hours. The reaction mixture was poured on ice and then concentrated. Subsequently, the mixture was extracted with acetone and then with ether. The residue was isolated, dissolved in water and precipitated again with ethyl acetate/acetone. The precipitate, the trihydrate of 1-phenyl-1-aminomethane-1,1-diphosphonic acid was isolated and dried in air. The yield amounts to 18%, based on PBr3.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5](=O)[CH2:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:8]=1[Cl:15])[CH3:2].[CH2:18]([O:20][CH:21](OCC)OCC)[CH3:19].C(OC(=O)C)(=[O:30])C>>[CH2:1]([O:3][C:4](=[O:17])[C:5]([C:6](=[O:30])[C:7]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:8]=1[Cl:15])=[CH:21][O:20][CH2:18][CH3:19])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)C(=O)Cc1cc(F)c(F)cc1Cl
Reactant: CCOC(OCC)OCC
Product: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)cc1Cl

Procedure:
2-Chloro-4,5-difluoro-α-oxo-benzenepropanoic acid ethyl ester (20 g, 76 mmol), triethylorthoformate (17.0 g, 115 mmol) and acetic anhydride (19.5 g, 191 mmol) were combined and heated to reflux for 3 hours. Excess solvent was removed in vacuo to provide the crude title product, which was used without purification.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:10]=[N:11][CH:12]=[C:13](Br)[CH:14]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C.C([Li])CCC.CCCCCC>O1CCCC1.O>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[C:13]([B:16]([OH:21])[OH:17])[CH:12]=[N:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NS(=O)(=O)c1cncc(Br)c1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CC(C)(C)NS(=O)(=O)c1cncc(B(O)O)c1
Temperature: -78 °C
Reaction time: 3.5 h
Yield: 50.3 %

Procedure:
A solution of 5-bromo-pyridine-3-sulfonic acid tert-butylamide (CAS 911111-80-3; WO2010007) (11.4 g, 39 mmol) in tetrahydrofuran (200 ml) was treated with triisopropyl borate (33 ml, 144 mmol) and cooled to −78° C. A solution of n-butyl lithium in hexane (1.6M, 90 ml, 144 mmol) was added cautiously whereby the reaction temperature was kept below −60° C. The reaction mixture was stirred for 3.5 hours at −78° C. For the workup, the reaction mixture was treated with water (300 ml), stirred at room temperature for 15 minutes, and then extracted with ethyl acetate. The aqueous layer was separated and acidified with hydrochloric acid (3M) to pH 4. Thereafter, solid sodium chloride was added, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, dried over magnesium sulphate, filtered, and the solvent evaporated to give a light yellow amorphous product. For purification, the residue was dissolved at room temperature in a 3:1-mixture of water and isopropanol (100 ml). More water was added (total volume: 200 ml), then the solution cooled to 0° C., stirred for 30 minutes. The precipitate was filtrated, the solid washed with water and dried at high vacuum to give the 5-(N-tert-butylsulfamoyl)pyridin-3-ylboronic acid (5.06 g, 50% yield) as an off-white solid. MS (ISN): m/z=257.1 [M−H]−.
Reaction SMILES: O.O.Cl[Sn]Cl.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([N+:27]([O-])=O)[CH:20]=2)=[CH:17][CH3:18])[CH:11]=[C:12]([O:14][CH3:15])[CH:13]=1.[OH-].[Na+]>C(O)C.C(OCC)(=O)C>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([NH2:27])[CH:20]=2)=[CH:17][CH3:18])[CH:11]=[C:12]([O:14][CH3:15])[CH:13]=1
Reactant: CC=C(c1cc(OC)cc(OC)c1)c1ccc(OC)c([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CC=C(c1cc(OC)cc(OC)c1)c1ccc(OC)c(N)c1
Temperature: 70 °C
Yield: 66.8 %

Procedure:
SnCl2.2H2O (5.20 g, 23.0 mmol) was added to a stirred solution of (E/Z) 4-[1-(3,5-dimethoxy-phenyl)-propenyl]-1-methoxy-2-nitro-benzene (1.10 g, 3.2 mmol) in ethanol (200 proof, 20 mL) and ethyl acetate (10 mL). The reaction mixture was heated at 70° C. for 1 h. The solution was cooled down to room temperature, poured into ice water (100 mL), and basified with 10 N NaOH (20 mL) to pH ˜12. The aqueous layer was extracted with ethyl acetate (5×35 mL). The combined organic layers were washed with water (60 mL), brine (50 mL) and dried (MgSO4). Removal of solvent and chromatography (Silica Gel) gave a mixture of (E/Z) 5-[1-(3,5-dimethoxy-phenyl)-propenyl]-2-methoxy-phenylamine as an oil (0.64 g, 51% yield): 1H NMR (CDCl3) δ 1.70-1.78 (2d, J=7.0 Hz, 6H, 2CH3), 3.74-3.87 (4s+m, 22H, 6OCH3+2NH2), 6.02-6.10 (m, 2H, 2CH), 6.33-6.79 (m, 12H, Ar); 13C NMR (CDCl3) δ 15.60, 15.73, 55.30, 55.45, 55.52, 98.70, 98.92, 105.72, 107.99, 109.95, 109.99, 113.91, 116.77, 117.30, 120.32, 122.05, 123.83, 132.49, 135.56, 135.61, 142.09, 142.33, 142.50, 145.66, 146.32, 146.56, 160.36, 160.51; Anal. Calcd for C18H21NO3: C, 72.22; H, 7.07; N, 4.68. Found: C, 71.94; H, 7.37; N, 4.54.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:11]([O:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([CH:26]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:22][CH2:21]1)(=[O:16])[CH2:12][C:13]([CH3:15])=O.[NH2:39]/[C:40](/[CH3:46])=[CH:41]\[C:42]([O:44][CH3:45])=[O:43]>C(O)(C)C>[Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]1[C:41]([C:42]([O:44][CH3:45])=[O:43])=[C:40]([CH3:46])[NH:39][C:13]([CH3:15])=[C:12]1[C:11]([O:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][N:23]([CH:26]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:22][CH2:21]1)=[O:16]
Reactant: COC(=O)/C=C(/C)N
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: CC(=O)CC(=O)OCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Solvent: CC(C)O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)C1c1cccc(Cl)c1Cl
Yield: 31.6 %

Procedure:
A mixture of 2,3-dichlorobenzaldehyde, 2-(4-benzhydryl-1-piperazinyl)ethyl acetoacetate and methyl 3-aminocrotonate was worked up in isopropyl alcohol in the same manner as Example 1 to give 2-(4-benzhydryl-1-piperazinyl)ethyl methyl 4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate as a light yellow powder, m.p. 84°-88° C. (sintering). Yield 31.6%. IR(Nujol)cm-1 : 3320, 1730, 1690. NMR(CDCl3) δ: 2.28(6H, s, ##STR17## 3.58(3H,s,COOCH3), 4.15(2H,t,J=6,--COOCH2CH2 --), 4.19(1H,s,>N--CH<), 5.45(1H,s,C(4) --H), 5.61(1H,s,NH).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([C:17]([NH:19][C:20]4[S:21][CH:22]=[CH:23][N:24]=4)=[O:18])[C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[N:25]1([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>CS(C)=O.O>[S:21]1[CH:22]=[CH:23][N:24]=[C:20]1[NH:19][C:17]([C:16]1[C:10]2[N:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:28]4[CH2:27][CH2:26][N:25]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:30][CH2:29]4)=[N:7][CH:6]=3)[NH:12][C:11]=2[CH:13]=[CH:14][CH:15]=1)=[O:18]
Reactant: O=C(Nc1nccs1)c1cccc2[nH]c(-c3ccc(Cl)nc3)nc12
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3nc4c(C(=O)Nc5nccs5)cccc4[nH]3)cn2)CC1
Temperature: 140 °C
Reaction time: 0.42 h
Yield: 47.1 %

Procedure:
A mixture containing 2-(6-chloropyridin-3-yl)-N-(thiazol-2-yl)-1H-benzo[d]imidazole-4-carboxamide (7; 30 mg, 0.084 mmol) and tert-butyl piperazine-1-carboxylate (170; 156.5 mg, 0.84 mmol) in DMSO (1.2 mL) was stirred at 140° C. in a microwave reactor for 25 min. The reaction mixture was cooled to room temperature and diluted with water. The resulting solids were collected by filtration, washed with water and dried under vacuum to afford tert-butyl 4-(5-(4-(thiazol-2-ylcarbamoyl)-1H-benzo[d]imidazol-2-yl)pyridin-2-yl)piperazine-1-carboxylate 8 as a pale yellow solid (20 mg, 71%). MS (ESI) calcd for C25H27N7O3S: 505.19; found: 506 [M+H].
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[N:5]=[C:6]([NH:11][C:12]3[CH:13]=[C:14]([NH:19][C:20](=[O:32])[C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:30]#[N:31])([CH3:29])[CH3:28])[CH:22]=4)[CH:15]=[CH:16][C:17]=3[CH3:18])[N:7]=[CH:8][C:9]=2[N:10]=1.[Cl:33][CH2:34][C:35](Cl)=[O:36].O>CN(C)C(=O)C>[Cl:33][CH2:34][C:35]([NH:1][C:2]1[S:3][C:4]2[N:5]=[C:6]([NH:11][C:12]3[CH:13]=[C:14]([NH:19][C:20](=[O:32])[C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([C:30]#[N:31])([CH3:29])[CH3:28])[CH:22]=4)[CH:15]=[CH:16][C:17]=3[CH3:18])[N:7]=[CH:8][C:9]=2[N:10]=1)=[O:36]
Reactant: O=C(Cl)CCl
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Nc1ncc2nc(N)sc2n1
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1Nc1ncc2nc(NC(=O)CCl)sc2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.9 %

Procedure:
To a solution of N-{3-[(2-amino[1,3]thiazolo[5,4-d]pyrimidin-5-yl)amino]-4-methylphenyl}-3-(1-cyano-1-methylethyl)benzamide (948 mg, 2.14 mmol) produced in Example D25(iii) in N,N-dimethylacetamide (20 mL) was added chloroacetyl chloride (425 μL, 5.34 mmol), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added water (60 mL), and the mixture was extracted with ethyl acetate (30 mL, 15 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=60/40→30/70), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was washed with ethyl acetate to give the title compound (778 mg, 71%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([O:19]CC)=O)=[C:4]2[CH2:3]1.[Cl-].[NH4+:23].N>CO>[CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]2[CH:14]=[N:15][C:16]([C:17]([NH2:23])=[O:19])=[C:4]2[CH2:3]1
Reactant: [NH4+]
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1ccccc1-2
Agent: N
Agent: [Cl-]
Solvent: CO
Product: CN1Cc2c(C(N)=O)ncn2-c2ccccc2C1=O
Temperature: 120 °C
Reaction time: 12 h

Procedure:
A mixture of 10.0 g of ethyl 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate, 200 ml of methanol, 0.5 g of ammonium chloride and 30 g of ammonia (100%) is stirred in an autoclave under nitrogen (40 bar) at a temperature of 120° C. for 12 hours. After cooling and discharging the over-pressure, the mixture is evaporated to dryness. After partition of the residue between methylene chloride and water, the organic phase is dried and evaporated. The residue is recrystallised from ethyl acetate, there being obtained 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxamide in the form of white crystals of melting point 274°-275° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)=[C:9]([N:23]2[C:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:26][N:25]=[N:24]2)[CH:10]=[CH:11][CH:12]([OH:22])[CH2:13][C:14](=[O:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:4][CH:3]=1.C(B(CC)CC)C.[BH4-].[Na+]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)=[C:9]([N:23]2[C:27]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[N:26][N:25]=[N:24]2)[CH:10]=[CH:11][CH:12]([OH:22])[CH2:13][CH:14]([OH:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(=O)CC(O)C=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)n1nnnc1-c1ccccc1
Agent: CCB(CC)CC
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(O)CC(O)C=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)n1nnnc1-c1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 96.9 %

Procedure:
A solution containing 0.9 g (1.7 mmoles) of ethyl 9,9-bis(4-fluorophenyl)-5-hydroxy-8-(5-phenyl-1 H-tetrazol-1-yl)-3-oxo-6,8-nonadienoate in 20 mL of dry tetrahydrofuran at 0° C. under argon was treated with triethylborane (1.74 mL, 1.0 M in THF, 1.74 mmoles). The colorless solution was allowed to stir at 0° C. for 1.5 hours then cooled to -80° C. under argon. To this stirring solution was added sodium borohydride (130 mg, 3.4 mmoles) in one portion and the suspension was stirred for one hour. The crude reaction was quenched with 4.0 mL of 2 M HCl followed by 20 mL of half saturated aqueous NH4Cl solution. The mixture was extracted twice with ethyl acetate (40 mL) and the organic layers were combined and evaporated. The concentrated crude product was diluted with 250 mL of methanol and the solution was allowed to stand at room temperature for 45 minutes then concentrated under reduced pressure at room temperature. Analytical TLC showed only one spot for the product. A solution of the crude product was filtered through silica gel and the filtrate was then concentrated under reduced pressure. Recrystallization from a mixture of ethyl acetate-hexanes gave 0.9 g of the title compound; m.p.=160.5°-161.5° C.
Reaction SMILES: [Br-].[CH2:2]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH2:3][CH3:4].C([Li])CCC.[CH2:29]([O:36][C:37]1[CH:44]=[CH:43][C:40]([CH:41]=O)=[C:39]([OH:45])[CH:38]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.ClCCl>C1COCC1>[CH2:29]([O:36][C:37]1[CH:44]=[CH:43][C:40]([CH:41]=[CH:2][CH2:3][CH3:4])=[C:39]([OH:45])[CH:38]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1O
Agent: [Br-]
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCC=Cc1ccc(OCc2ccccc2)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
To a flame dried 500 mL 3-neck flask under an atmosphere of argon, was charged n-propyltriphenylphosphonium bromide (12.66 g, 32.85 mmol) dissolved in anhydrous THF (85 mL), followed by the dropwise addition of n-butyllithium 16.4 mL, 26.28 mmol). The dark red mixture was stirred at ambient temperature for 1 h. 15 min. Next 4-benzyloxy-2-hydroxybenzaldehyde (1.5 g, 6.57 mmol) (Synth. Commun., 26(3), 593-601, (1996) was added followed by the addition of anhydrous dichloromethane (27 mL). The mixture was stirred at ambient temperature for 18 h. The solvents were removed in vacuo, and the residue was partitioned between ethyl acetate and water (500 mL each). The organic layer was washed with brine (500 mL), dried (Na2SO4), and concentrated in vacuo. The crude product was purified using the Biotage FlashElute chromatography system using a 65M normal phase cartridge, eluting with 15% ethyl acetate/Hex to give a yellow solid (1.50 g, 90%). 1H NMR (400 MHz, CDCl3) δ7.43-7.30 (m, 5H), 7.19 (d, J=8.3 Hz, 1H), 6.52 (dd, J=8.8, 2.4 Hz, 1H), 6.46 (d, J=2.4 Hz, 1H), 6.43 (s, 1H), 6.14-6.07 (m, 1H), 5.03 (s, 2H), 4.98 (s, 1H), 2.25 (quintet, J=7.6 Hz, 2H), 1.09 (t, J=7.3 Hz, 3H), MS (ES) m/e 255 (M+1).
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[C:12](=O)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:14])[CH:10]=2)[C:5]21[CH2:18][CH2:17][CH2:16][CH2:15]2.O.[NH2:20][CH2:21][C@H:22]([OH:24])[CH3:23]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:14][C:9]1[CH:10]=[C:11]2[C:6]([C:5]3([CH2:18][CH2:17][CH2:16][CH2:15]3)[C:4]3[CH:3]=[CH:2][N:20]([CH2:21][C@H:22]([OH:24])[CH3:23])[C:12]=32)=[CH:7][CH:8]=1
Reactant: Cc1ccc2c(c1)C(=O)C(CC=O)C21CCCC1
Reactant: C[C@@H](O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc2c(c1)-c1c(ccn1C[C@@H](C)O)C21CCCC1
Reaction time: 0.75 h
Yield: 73.3 %

Procedure:
A solution of 2.42 g of (RS)-2'-(2-oxoethyl)-5'-methyl-2',3'-dihydro-spiro[cyclopentane-1,1'-[1H]indene]-3'-one and 80 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 3.0 g of (R)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (diethyl ether/hexane 3:2). 2.06 g (73%) of (R)-1-[7'-methyl-1',4'-dihydro-spiro[cyclopentane-1,4'-indeno[1,2-b]pyrrole]-1'-yl]-propan-2-ol were obtained as a red oil.