Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][O:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18]>>[CH3:10][O:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]([NH:18][C:2]2[N:7]=[C:6]([NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[C:15]([O:14][CH2:13][CH2:12][O:11][CH3:10])[CH:16]=3)[C:5]([F:9])=[CH:4][N:3]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: COCCOc1cccc(N)c1
Product: COCCOc1cccc(Nc2ncc(F)c(Nc3cccc(OCCOC)c3)n2)c1

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, 2,4-dichloro-5-fluoropyrimidine and 3-(2-methoxyethoxy)aniline were reacted to produce N2,N4-bis[3-(2-methoxyethyl)oxyphenyl]-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.96 (d, 1H, J=2.9 Hz), 7.36 (t, 1H, J=1.7 Hz), 7.28 (t, 1H J=1.7 Hz), 7.25-7.06 (m, 4H), 6.98 (br s, 1H), 6.75 (d, 1H, J=2.3 Hz), 6.70 (dd, 1H, J=1.7 and 8.2 Hz), 6.58 (dd, 1H, J=1.7 and 8.2 Hz), 4.08-4.03 (m, 4H), 3.74-3.69 (m, 4H), 3.44 (s, 3H), 3.43 (s, 3H); LCMS: ret. time: 21.01 min.; purity: 97%; MS (m/e): 429 (MH+).
Reaction SMILES: [CH2:1]([S:3]([NH:6][C@@H:7]([CH:11]([CH3:13])[CH3:12])[C:8]([OH:10])=O)(=[O:5])=[O:4])[CH3:2].[OH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][NH2:23])=[CH:17][C:16]=1[O:24][CH3:25].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.O>[OH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][NH:23][C:8](=[O:10])[C@@H:7]([NH:6][S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH:11]([CH3:13])[CH3:12])=[CH:17][C:16]=1[O:24][CH3:25]
Reactant: COc1cc(CCN)ccc1O
Reactant: CCS(=O)(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCS(=O)(=O)N[C@H](C(=O)NCCc1ccc(O)c(OC)c1)C(C)C

Procedure:
A mixture of 2.1 g of (S)-2-(ethylsulfonylamino)-3-methyl-butyric acid, 1.7 g of 2-(4-hydroxy-3-methoxyphenyl)-ethylamine, 4.6 g of (benzotriazol-1-yloxy)-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) and 4.5 ml of N,N-diisopropylethylamine is stirred in 40 ml of N,N-dimethylformamide at room temperature for 2 hours. The reaction mixture is introduced into 500 ml of water and extracted twice with 400 ml of ethyl acetate each time. The organic phases are washed once with 300 ml of water and once with 200 ml of saturated sodium chloride solution, dried over magnesium sulfate and concentrated. (S)-2-(Ethylsulfonylamino)-3-methyl-butyric acid N-[2-(4-hydroxy-3-methoxyphenyl)-ethyl]-amide is obtained in the form of an oil, which can be purified by flash-chromatography on silica gel using a mixture of ethyl acetate/n-hexane=3:1.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12]/[C:11](=[N:13]/[O:14][CH3:15])/[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[N:19]([CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=C=O.[CH2:27]([N:29]1[C:41]2[CH:40]=[CH:39][C:38]([NH2:42])=[CH:37][C:36]=2[C:35]2[C:30]1=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH3:28]>>[CH2:27]([N:29]1[C:41]2[CH:40]=[CH:39][C:38]([NH:42][C:16]([C@@H:9]3[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]3[C:6]([NH:19][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])=[O:7])=[O:18])=[CH:37][C:36]=2[C:35]2[C:30]1=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH3:28]
Reactant: CO/N=C1\C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: CCCCCN=C=O
Product: CCCCCNC(=O)N1CC(=NOC)C[C@H]1C(=O)Nc1ccc2c(c1)c1ccccc1n2CC

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4E)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 1-isocyanatopentane, and 9-ethyl-9H-carbazol-3-amine the title compound was obtained in 81% purity by LC/MS. MS(ESI+): m/z=464.2.
Reaction SMILES: C[C:2]1[CH2:6][CH2:5][CH2:4][Si:3]=1Cl.[Na].[CH3:9][NH:10][C:11](=[O:13])[CH3:12].[Cl-].[C:15]1(C)C=CC=CC=1>>[CH3:15][CH:12]([Si:3]1[CH2:4][CH2:5][CH2:6][CH:2]=1)[C:11]([NH:10][CH3:9])=[O:13]
Reactant: Cc1ccccc1
Reactant: CC1=[Si](Cl)CCC1
Reactant: CNC(C)=O
Agent: [Cl-]
Agent: [Na]
Product: CNC(=O)C(C)[Si]1=CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methylsilacyclopentenyl chloride, 5 mols, was added to a slurry of 5.5 mols of the sodium salt of N-methylacetamide in 1500 ml. of dry toluene in a flask at such a rate as to keep the reaction mixture at a temperature below 60° C. After the addition of the chloride had been completed, the reaction mixture was stirred for 2 hours at room temperature, filtered to remove NaCl and the filtrate was fractionally distilled to give a moderate yield of methylsilacyclopentenyl-N-methylacetamide, b.p.=76° to 87° C. at approximately 0.1 kilopascals of pressure. Infra-red spectroscopy indicated that the bonding in this silylamide, between the methylsilacyclopentenyl radical and the N-methylacetamido radical, is predominently silicon-nitrogen bonding.
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][C:9]([N:12]3[CH2:16][CH2:15][N:14]([C:17]4[CH:18]=[N:19][CH:20]=[CH:21][C:22]=4[CH3:23])[C:13]3=[O:24])=[CH:8][C:7]=2F)=O)[CH2:3][CH2:2]1.CO.O.[NH2:29][NH2:30]>C(Cl)(Cl)Cl>[CH:1]1([C:4]2[C:6]3[C:7](=[CH:8][C:9]([N:12]4[CH2:16][CH2:15][N:14]([C:17]5[CH:18]=[N:19][CH:20]=[CH:21][C:22]=5[CH3:23])[C:13]4=[O:24])=[CH:10][CH:11]=3)[NH:30][N:29]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccncc1N1CCN(c2ccc(C(=O)C3CC3)c(F)c2)C1=O
Reactant: NN
Solvent: CO
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1ccncc1N1CCN(c2ccc3c(C4CC4)n[nH]c3c2)C1=O
Temperature: 120 °C
Yield: 31.97 %

Procedure:
1-(4-Cyclopropanecarbonyl-3-fluoro-phenyl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-161b: 175 mg, 0.516 mmol) in hydrazine hydrate solution (10 mL) was taken in a reaction flask. The flask was refluxed at 120° C. overnight. The reaction was monitored by TLC (5% MeOH in CHCl3). The reaction mixture was cooled to room temperature and partitioned between ice water and chloroform. The organic layer was dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (4% MeOH in CHCl3), followed by hexane and ether wash, afforded 55 mg of the product (31.97% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:15]3[C:16]([Br:32])=[CH:17][C:18]([F:31])=[C:19]([NH:21][C:22]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[O:23])[CH:20]=3)[C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][N:3]=1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>>[C:33]([NH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:15]3[C:16]([Br:32])=[CH:17][C:18]([F:31])=[C:19]([NH:21][C:22]([NH:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[O:23])[CH:20]=3)[C:8](=[O:14])[N:9]2[CH2:12][CH3:13])=[CH:4][N:3]=1)(=[O:35])[CH3:34]
Reactant: CC(=O)OC(C)=O
Reactant: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2Br)cc2cnc(N)cc21
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2Br)cc2cnc(NC(C)=O)cc21
Temperature: 110 °C
Reaction time: 8 h
Yield: 57.5 %

Procedure:
1-(5-(7-amino-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-bromo-2-fluorophenyl)-3-phenylurea (90 mg, 0.181 mmol) was suspended in acetic anhydride (5 mL, 52.9 mmol) and heated at 110° C. for 4 h. The reaction was cooled to RT, poured onto ice (15 g), and stirred overnight. The solids were collected, rinsed well with H2O, air dried, then suspended in MeCN (2-3 mL) and heated at 80° C. overnight. The solids were collected by filtration, rinsed with MeCN and dried under vacuum to afford 1-(5-(7-acetamido-1-ethyl-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-4-bromo-2-fluorophenyl)-3-phenylurea (56 mg, 57% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.84 (s, 1H), 9.10 (s, 1H), 8.73 (d, J=2.4 Hz, 1H), 8.71 (s, 1H), 8.26 (s, 1H), 8.22 (d, J=8.4 Hz, 1H), 7.95 (s, 1H), 7.7 (d, J=6.8 Hz, 1H), 7.42-7.40 (m, 2H), 7.28-7.24 (m, 2H), 6.98-6.95 (m, 1H), 4.19 (q, J=6.8 Hz, 2H), 2.15 (s, 3H), 1.25 (t, J=6.8 Hz, 3H); MS (ESI) m/z: 538.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]SC1SCC(=O)N=1.[CH2:24]([C:26]1[NH:27][CH:28]=[CH:29][N:30]=1)[CH3:25].[OH-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:27]1[CH:28]=[CH:29][N:30]=[C:26]1[CH2:24][CH3:25]
Reactant: CCc1ncc[nH]1
Reactant: COc1ccc(OCCCCCCSC2=NC(=O)CS2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCc1nccn1CCCCCCOc1ccc(OC)cc1Cl
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Stir at room temperature for four days 2 gms. of the iodide prepared in Examples 2 or 3, 2 gms. of 2-ethylimidazole, 2.5 ml. DMF and 0.4 gm sodium hydroxide in a reaction flask. Remove the solvent and partition with water/methylene chloride. Elute on a silica column with 100% methylene chloride and then 10% methanol to yield the title compound. MS:m/z 337 (M+) H1 -NMR-200 mHz, εH (CDCl3), 1.34 (3H,t,J 7.5 Hz), 1.3-1.65 (4H,m), 1.70-1.90 (4H,m) 2.66 (2H,q,J 7.5Hz), 3.75 (3H,s), 3.83 (2H,t,J 7Hz), 3.95 (2H,t,J 6Hz), 6.7-7.0 (5H,m).
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:9]=[CH:10][C:11]([C:14]#[N:15])=[N:12][CH:13]=2)[CH2:3]1.[C:16]([C:19]1[CH:20]=[C:21]([S:25](Cl)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1)(=[O:18])[CH3:17].C(N(C(C)C)CC)(C)C>ClCCl>[C:16]([C:19]1[CH:20]=[C:21]([S:25]([N:7]2[CH2:6][CH2:5][N:4]([C:8]3[CH:9]=[CH:10][C:11]([C:14]#[N:15])=[N:12][CH:13]=3)[CH2:3][C@H:2]2[CH3:1])(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)c1cccc(S(=O)(=O)Cl)c1
Reactant: C[C@@H]1CN(c2ccc(C#N)nc2)CCN1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)c1cccc(S(=O)(=O)N2CCN(c3ccc(C#N)nc3)C[C@H]2C)c1
Temperature: 25 °C
Yield: 80.3 %

Procedure:
To a stirred solution of 5-[(3R)-3-methylpiperazin-1-yl]pyridine-2-carbonitrile (250 mg, 1.24 mmol) and 3-acetylbenzenesulfonyl chloride (270.3 mg, 1.24 mmol) in anhydrous dichloromethane (4 mL) was added diisopropylethylamine (0.43 mL, 2.48 mmol). The mixture was stirred at room temperature for over night. Reaction was complete as determined by TLC. The reaction mixture was purified via flash column chromatography to yield 5-{(3R)-4-[(3-acetylphenyl)sulfonyl]-3-methylpiperazin-1-yl}pyridine-2-carbonitrile in 80.3% yield (383 mg) as a light yellow solid.
Reaction SMILES: C([O:4][CH2:5][C:6]([N:8]=[C:9]([NH:20][CH2:21][CH2:22][S:23][CH2:24][C:25]1[O:26][C:27]([CH2:30][N:31]([CH3:33])[CH3:32])=[CH:28][CH:29]=1)[N:10]([CH3:19])[N:11]=CC1C=CC=CC=1)=O)(=O)C.O>Cl>[NH3:8].[CH3:32][N:31]([CH2:30][C:27]1[O:26][C:25]([CH2:24][S:23][CH2:22][CH2:21][NH:20][C:9]2[N:10]([CH3:19])[N:11]=[C:6]([CH2:5][OH:4])[N:8]=2)=[CH:29][CH:28]=1)[CH3:33]
Reactant: CC(=O)OCC(=O)N=C(NCCSCc1ccc(CN(C)C)o1)N(C)N=Cc1ccccc1
Agent: Cl
Solvent: O
Product: CN(C)Cc1ccc(CSCCNc2nc(CO)nn2C)o1
Product: N
Reaction time: 0.17 h
Yield: 137.7 %

Procedure:
A solution of 2-(acetyloxy)-N-[[[2-[[[5-[(dimethylamino)methyl]-2-furanyl]methyl]thio]ethyl]amino][1-methyl-2-(phenylmethylene)hydrazino]methylene]acetamide (0.74 g) in 2N hydrochloric acid was heated at 98°-100° for 1 h. Water (5 ml) was added to the cooled solution which was washed with ethyl acetate. The aqueous fraction was made alkaline with sodium carbonate and the solution was evaporated to dryness in vacuo. The residue was suspended in ethyl acetate (20 ml), excess anhydrous sodium carbonate and decolourising charcoal were added. The suspension was boiled for 10 mins, cooled, filtered and the filtrate was evaporated in vacuo. The residual oil was chromatographed on silica using methanol:0.88 ammonia, (79:1) to give the title compound (0.35 g) as a pale brown oil.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C@H:8]([NH:13][C@H:14]([C:19]([NH:21][C:22]2([C:25]#[N:26])[CH2:24][CH2:23]2)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[C:27]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)(=[O:29])[CH3:28].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)CC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:27]([C:30]1[CH:35]=[CH:34][C:33]([C:2]2[N:7]=[CH:6][C:5]([C@H:8]([NH:13][C@H:14]([C:19]([NH:21][C:22]3([C:25]#[N:26])[CH2:24][CH2:23]3)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=2)=[CH:32][CH:31]=1)(=[O:29])[CH3:28]
Reactant: CC(=O)c1ccc(B(O)O)cc1
Reactant: CC(C)C[C@H](N[C@@H](c1ccc(Cl)nc1)C(F)(F)F)C(=O)NC1(C#N)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCCO
Product: CC(=O)c1ccc(-c2ccc([C@H](N[C@@H](CC(C)C)C(=O)NC3(C#N)CC3)C(F)(F)F)cn2)cc1
Temperature: 150 °C

Procedure:
To a solution of N2-[(1S)-1-(6-chloropyridin-3-yl)-2,2,2-trifluoroethyl]-N1-(1-cyanocyclopropyl)-L-leucinamide (100 mg, 0.26 mmol) in toluene (1.5 mL) and n-propanol (0.4 mL) was added under a stream of nitrogen, 4-(acetyl)phenylboronic acid (55 mg, 0.33 mmol), Pd(PPh3)4 (15 mg, 0.013 mmol) and Na2CO3 (2 M, 0.5 mL). The mixture was degassed with a rapid stream of nitrogen bubbling through the mixture and the mixture was heated to 150° C. in a Smith Creator microwave reactor (Personal Chemistry AB, Uppsala, Sweden) for 800 sec. The mixture was cooled, diluted with EtOAc and washed with water. Chromatography (50% EtOAc/Hexane) gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][N:24]1[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]=[C:25]1[CH2:33][NH:34][CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38]>ClCCl>[Cl:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([O:13][CH3:14])[CH:8]=[CH:7][C:3]=1[C:4]([N:34]([CH2:33][C:25]1[N:24]([CH2:23][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[O:16][CH3:15])[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=2[N:26]=1)[CH2:35][CH2:36][CH:37]([CH3:39])[CH3:38])=[O:5]
Reactant: COc1ccc(C(=O)Cl)c(Cl)c1OC
Reactant: COc1ccccc1Cn1c(CNCCC(C)C)nc2ccccc21
Solvent: ClCCl
Product: COc1ccccc1Cn1c(CN(CCC(C)C)C(=O)c2ccc(OC)c(OC)c2Cl)nc2ccccc21
Yield: 95 %

Procedure:
A solution of 5.4 mmole 1-{[2-(chloromethyl)-benzimidazolyl]methyl}-2-methoxybenzene in 20 mL of dryacetonitrile is treated with 10 mL of isoamylamine for 16 hours at room temperature. The solvent is removed in vacuo and the residue is partitioned between 30 mL of ethyl acetate and 10 mL of 1 N NaOH. The ethyl acetate layer is dried over anhydrous Na2SO4 and solvent removed in vacuo to afford 1.7 g 97% ({1-[(2-methoxyphenyl)methyl]benzimidazol-2-yl}methyl)(3-methylbutyl) amine. 2-Chloro-3,4-dimethoxybenzoylchloride (1.5 equ.) is treated with 1.0 equivalent of ({1-[(2-methoxyphenyl)methyl]benzimidazol-2-yl}methyl)(3-methylbutyl) amine in dichloromethane at room temperature for 1 hour. The reaction is quenched with 1 N NaOH and partitioned between dichloromethane and water. The organic layer is dried with Na2SO4 and the solvent removed in vacuo. The residue is chromatographed (SiO2) with ethyl acetate to afford 95% of (2-chloro-3,4-dimethoxyphenyl)-N-({1-[(2-methoxyphenyl)methyl]benzimidazol-2-yl}methyl)-N-(3-methylbutyl)carboxamide (Compound 1). Mass Spec M+ 537.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:22])[CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>>[Cl:1][C:2]1[CH:11]=[C:10]([C:12](=[O:22])[CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccc(C(=O)CCc2cccc(O)c2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(CCc1cccc(O)c1)c1ccc(C(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.1 %

Procedure:
A mixture of 2-chloro-4-[1-oxo-3-(3-hydroxyphenyl)propyl]benzoic acid, methyl ester (Example 19; 2.1 g, 6.6 mmol) and 1 M sodium hydroxide solution was stirred for 4 h at room temperature. The solution was filtered through Celite and the filter cake was washed with water (5 mL). 1 M HCl (22 mL) was added to the stirred filtrate and the resulting mixture was stirred for 2 h and then filtered. The solid was washed with water, dried and recrystallized from ether/hexane to give 2-chloro-4-[1-oxo-3-(3-hydroxyphenyl)propyl]benzoic acid (1.59 g, 79%) as an off-white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:32])[C:22]3[CH:27]=[CH:26][C:25]([CH:28]=[CH:29][C:30]#[N:31])=[CH:24][CH:23]=3)[CH2:17][CH2:16]1)(=[O:14])=[O:13])[CH:6]=[CH:5]2.[BH4-].[Na+]>N1C=CC=CC=1.CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([N:15]1[CH2:16][CH2:17][N:18]([C:21](=[O:32])[C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]#[N:31])=[CH:24][CH:23]=3)[CH2:19][CH2:20]1)(=[O:13])=[O:14])[CH:6]=[CH:5]2
Reactant: N#CC=Cc1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccncc1
Product: N#CCCc1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 64.1 %

Procedure:
4-(6-Chloronaphthalene-2-sulfonyl)-1-[4-(2-cyano-1-ethenyl)benzoyl]piperazine (699 mg) was dissolved in pyridine (15 ml) and methanol (5 ml), and to the mixture was added sodium borohydride (68 mg). The mixture was stirred at 60° C. for 2 hours and concentrated. To the residue was added diluted hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated sodium bicarbonate aqueous solution and brine in this order, dried and concentrated. The residue was purified with silica gel column chromatography (hexane: ethyl acetate=2:3) to give colorless crystals of the title compound (450 mg).
Reaction SMILES: [C:1]([NH:20][C@H:21]([CH2:24][CH3:25])[CH:22]=[O:23])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([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.[CH2:26]([Mg]Br)[CH3:27].O>CCOCC>[C:1]([NH:20][C@H:21]([CH2:24][CH3:25])[CH:22]([OH:23])[CH2:26][CH3:27])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[Mg]Br
Reactant: CC[C@H](C=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCOCC
Product: CCC(O)[C@@H](CC)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of (R)-2-(trityl-amino)-butyraldehyde (1.5 g, 1 eq, 4.53 mmol) in ether (150 mL) under an argon atmosphere at −78° C., was added ethylmagnesium bromide (3 M in ether, 1.51 mL, 1 eq, 4.53 mmol) dropwise. The solution was sired at −78° C. for 2 h, then allowed to warm to room temperature over 16 h. The mixture was re-cooled to 0° C., H2O (150 mL) added, and the organic phase separated. The aqueous phase was extracted with more ether (2×50 mL), and the combined organic phase washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by silica gel column chromatography, eluted with hexane:ether (90:10) to afford the title compound as a light yellow oil; Yield: 1.13 g (69%): (57% A de 3S,4R: 43% de 3R,4R). 1H-NMR (d6-DMSO, 250 MHz): δ 0.45+0.69 (t+m, 6H, J=7.43 Hz, —NHCH(CH2CH3)CH(CH2CH3)OH), 1.12-1.29 (m, 4H, —NHCH(CH2CH3)CH(CH2CH3)OH), 2.16 (m, 1H, —NHCH(CH2CH3)CH(CH2CH3)OH), 2.54 (m, 1H, —NHCH(CH2CH3)CH(CH2CH3)OH), 3.21-3.40 (m, 1H, —NHCH(CH2CH3)CH(CH2CH3)OH), 4.29+4.39 (2×d, 1H, J=4.42+5.37 Hz, —NHCH(CH2CH3)CH(CH2CH3)OH), 7.15-7.52 (m, 15H, 3×Bz).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=4)=[CH:13][CH:14]=3)[CH2:9]2)[N:5]=[C:4]([NH2:25])[N:3]=1.[NH:26]1[CH2:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.C(N(CC)C(C)C)(C)C.C(O)(C)(C)C>CO>[N:26]1([C:2]2[CH:7]=[C:6]([N:8]3[CH:17]([CH3:18])[CH2:16][C:15]4[C:10](=[CH:11][C:12]([C:19]5[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=5)=[CH:13][CH:14]=4)[CH2:9]3)[N:5]=[C:4]([NH2:25])[N:3]=2)[CH2:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1
Reactant: C1CNCCNC1
Reactant: CC1Cc2ccc(-c3cnn(C)c3)cc2CN1c1cc(Cl)nc(N)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: CC(C)(C)O
Product: CC1Cc2ccc(-c3cnn(C)c3)cc2CN1c1cc(N2CCCNCC2)nc(N)n1

Procedure:
A mixture of 4-chloro-6-[3-methyl-7-(1-methyl-1H-pyrazol-4-yl)-3,4-dihydroisoquinolin-2(1H)-yl]pyrimidin-2-amine (18 mg, 0.050 mmol), 1,4-diazepane (15.0 mg, 0.150 mmol, Aldrich, Cat. No. H16604)) and N,N-diisopropylethylamine (20.0 uL, 0.115 mmol) in tert-butyl alcohol (0.5 mL, 5 mmol) was heated at 120° C. overnight. After cooling, the mixture was diluted with methanol, and purified by RP-HPLC (pH=10) to afford the desired product. (M+H)+: m/z=419.2.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17]N)=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:8]=2[CH:25]=1)([O-:3])=[O:2].C=O.[C:28]([BH3-])#[N:29].[Na+].[C:32](O)(=O)C>C(#N)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[C:14]([CH2:17][N:29]([CH3:28])[CH3:32])=[N:15][N:16]=[C:12]3[CH2:11][N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:8]=2[CH:25]=1)([O-:3])=[O:2]
Reactant: [BH3-]C#N
Reactant: CC(=O)O
Reactant: NCc1nnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1)=NC2
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Product: CN(C)Cc1nnc2n1-c1ccc([N+](=O)[O-])cc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Example 23, a solution of 8-nitro-1-(aminomethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine in acetonitrile is treated with formalin, sodium cyanoborohydride and acetic acid to give 8-nitro-1-[(dimethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([C:5]([F:8])([F:7])[F:6])=[CH2:4].[C:11]([O:15]O)([CH3:14])(C)[CH3:12].[C:17](O)(C)(C)[CH3:18]>C1(C)C=CC=CC=1>[O:15]1[CH:12]2[CH:11]1[CH:14]1[CH2:18][CH:17]2[C:3]([C:5]([F:8])([F:7])[F:6])([C:2]([F:10])([F:9])[F:1])[CH2:4]1
Reactant: CC(C)(C)O
Reactant: C=C(C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OO
Solvent: Cc1ccccc1
Product: FC(F)(F)C1(C(F)(F)F)CC2CC1C1OC21
Temperature: 60 °C

Procedure:
11.5 g (50 mmol) of the Diels-Alder reaction product of 3,3,3-trifluoro-2-trifluoromethyl-1-propene andcyclopentadiene are mixed in 10 ml of dry toluene with 326 mg (1 mmol) of molybdenum acetylacetonate, and 21 ml of a 2.9 molar solution of t-butyl hydroperoxide in toluene (61 mmol) is added dropwise at 22° C. within 30 minutes. During this period, the temperature rises to 45°C. The solution is then heated to 60° C., and after two and a half hours 3 g of molecular sieve 4 A and another 5 ml of the 2.9 molar solution of t-butyl hydroperoxide in toluene are added. After 20 hours of reaction time, the solvent, t-butanol and any remaining t-butyl hydroperoxide are carefully stripped off under reduced pressure. The residue is chromatographed on 160 g of silica gel. The mobile solvent usedis a mixture of hexane/methylene chloride/diethyl ether (10:10:0.5 parts byvolume). The product-containing fractions are combined and subjected to fractional distillation under reduced pressure. The product distils at a pressure of 150 to 190 mbar and a temperature of 100° to 124° C.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][C:8]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)=[N:9]2)=[CH:4][CH:3]=1.S(Cl)([Cl:21])=O>>[ClH:21].[Cl:21][C:6]1[C:5]2[C:10](=[CH:11][C:2]([F:1])=[CH:3][CH:4]=2)[N:9]=[C:8]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=c1[nH]c(-c2cccnc2)nc2cc(F)ccc12
Product: Cl
Product: Fc1ccc2c(Cl)nc(-c3cccnc3)nc2c1

Procedure:
A suspension of the quinazolinone compound (1.2 g, prepared in Reference example 4) in 20 mL of thionyl chloride was heated to reflux for three hours. The excess of thionyl chloride was removed by distillation. The residue was distilled azeotropically with benzene (5 mL×3) and then reduced the total volume to about 5 mL. After cooling in refrigerator, precipitate was collected by filtration and washed with benzene twice to give the title compound (1.38 g) as a crystalline solid having the following physical data.