Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@@H:3]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)=[CH:7][CH:6]=1)#[N:2].[N-:26]=[N+:27]=[N-:28].[Na+].O>C(O)(C)C.CCOC(C)=O.[Br-].[Zn+2].[Br-]>[C:21]([O:20][C:19](=[O:25])[NH:18][C@H:3]([C:1]1[NH:28][N:27]=[N:26][N:2]=1)[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)=[CH:9][CH:10]=1)([CH3:22])([CH3:24])[CH3:23]
Reactant: Cc1cccc(-c2ccc(C[C@@H](C#N)NC(=O)OC(C)(C)C)cc2)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Br-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: O
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: Cc1cccc(-c2ccc(C[C@H](NC(=O)OC(C)(C)C)c3nnn[nH]3)cc2)c1
Temperature: 25 °C

Procedure:
(S)-tert-butyl 1-cyano-2-(3′-methylbiphenyl-4-yl)ethylcarbamate (0.81 g, 2.408 mmol), sodium azide (0.344 g, 5.30 mmol) and zinc bromide (0.325 g, 1.445 mmol) were refluxed in i-propanol (15 mL) and H2O (30 mL) for 6 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc, and washed with 1M HCl and brine. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was purified by silica gel flash column chromatography (EtOAc/heptane->10% MeOH in DCM/DCM) to give [(S)-2-(3′-methyl-biphenyl-4-yl)-1-(1H-tetrazol-5-yl)-ethyl]-carbamic acid tert-butyl ester. 1H NMR (400 MHz, DMSO-d6) δ 1.30 (s, 9H), 2.36 (s, 3H), 3.10-3.21 (m, 1H), 3.24-3.31 (m, 1H), 4.96-5.15 (m, 1H), 7.15 (d, J=7.33 Hz, 1H), 7.27-7.35 (m, 3H), 7.39-7.46 (m, 2H), 7.55 (d, J=8.08 Hz, 2H), 7.65 (d, J=8.34 Hz, 1H); MS: m/z (MH+) 380; Retention time=1.51 min. (condition A)
Reaction SMILES: [OH-].[Na+].[C:3]([CH2:8][C:9]([O:11]C)=[O:10])(=[O:7])[CH:4]([CH3:6])[CH3:5]>O>[C:3]([CH2:8][C:9]([OH:11])=[O:10])(=[O:7])[CH:4]([CH3:6])[CH3:5]
Reactant: COC(=O)CC(=O)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)C(=O)CC(=O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Sodium hydroxide (0.4 g) was dissolved in water (10 ml) and methyl isobutyrylacetate (manufactured by Fluka Corp., 1.44 g) was added thereto and stirred for 6 hours at room temperature. The reaction product was washed with ether and ether extraction was performed by adding a 10%-dilute sulfuric acid (4.9 g). An excess of anhydrous sodium sulfate was added to the ether extract, drying was performed thereon, and the anhydrous sodium sulfate was removed by filtering. In addition, the ether was removed using a rotary evaporator and an isobutyrylacetic acid was obtained (yield: 1 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[CH:10]=[C:11]([C:15](=[O:17])[CH:16]=2)[C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:29]O>>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)[CH:10]=[C:11]([C:15](=[O:17])[CH:16]=2)[C:12]([O:14][CH3:29])=[O:13])=[CH:6][CH:7]=1
Reactant: CO
Reactant: Nc1ccc(-c2cc(=O)c(C(=O)O)cn2-c2ccc(F)cc2)cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cn(-c2ccc(F)cc2)c(-c2ccc(N)cc2)cc1=O
Temperature: 5 °C
Reaction time: 0.17 h

Procedure:
In 50 ml of methanol was suspended 6.5 g of 6-(4-aminophenyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydronicotinic acid, and the suspension was cooled to 5° C., after which 3.9 g of thionyl chloride was added dropwise thereto over 10 minutes. After completion of the dropwise addition, the resulting mixture was refluxed for 6 hours, and then cooled to room temperature, after which the solvent was removed by distillation under reduced pressure. To the residue were added 30 ml of water and 30 ml of chloroform, and the resulting mixture was adjusted to a pH of 7 with sodium hydrogencarbonate, after which the aqueous layer was separated, washed with 30 ml of a saturated aqueous solution of sodium chloride, and then dried with anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. The resulting crystalline substance was washed with 50 ml of diethyl ether to obtain 6.7 g of methyl 6-(4-aminophenyl)-1-(4-fluorophenyl)-4-oxo-1,4-dihydronicotinate having a melting point of 250° C. or more.
Reaction SMILES: [CH3:1][Si:2]([CH3:39])([CH3:38])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([C:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]=2)[CH:9]=1>CCOC(C)=O.[Pd]>[CH3:37][Si:34]([CH3:35])([CH3:36])[CH2:33][CH2:32][O:31][CH2:30][N:7]([CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:1])([CH3:39])[CH3:38])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1
Temperature: 45 °C
Reaction time: 3 h
Yield: 100.5 %

Procedure:
A mixture of tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate (5.05 g, 8.78 mmol) and 10% Pd/C (100 mg) in EtOAc was stirred at 45° C. under hydrogen (balloon pressure) for three hours. After filtration, washing with EtOAc (3×) and concentration, tert-butyl 4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)piperidine-1-carboxylate (5.1 g, 99.5%) was obtained as oil.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[C:19]3[C:14](=[CH:15][C:16]([C:20]([N:22]4[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]4)=[O:21])=[CH:17][CH:18]=3)[N:13]([CH3:31])[CH:12]=2)[CH2:7][CH2:6]1)[CH:2]([CH3:4])[CH3:3].Cl.[CH2:33](N1CCC(C2C3C(=CC(C(N4CCN(C(C)C)CC4)=O)=CC=3)NC=2)CC1)[CH:34](C)[CH3:35].ICC(C)C>>[CH2:31]([N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[C:16]([C:20]([N:22]3[CH2:27][CH2:26][N:25]([CH:28]([CH3:30])[CH3:29])[CH2:24][CH2:23]3)=[O:21])[CH:15]=2)[C:11]([CH:8]2[CH2:7][CH2:6][N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH2:10][CH2:9]2)=[CH:12]1)[CH:34]([CH3:35])[CH3:33]
Reactant: CC(C)CN1CCC(c2c[nH]c3cc(C(=O)N4CCN(C(C)C)CC4)ccc23)CC1
Reactant: CC(C)CN1CC=C(c2cn(C)c3cc(C(=O)N4CCN(C(C)C)CC4)ccc23)CC1
Agent: CC(C)CI
Agent: Cl
Product: CC(C)CN1CCC(c2cn(CC(C)C)c3cc(C(=O)N4CCN(C(C)C)CC4)ccc23)CC1

Procedure:
According to the procedure described for the synthesis of [3-(1-isobutyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1-methyl-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone; hydrochloride (example 42) the title compound was prepared from [3-(1-isobutyl-piperidin-4-yl)-1H-indol-6-yl]-(4-isopropyl-piperazin-1-yl)-methanone (example 2, free base) and 1-iodo-2-methylpropane (commercially available). MS (m/e): 467.5 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[C:5]([NH:7][CH2:8][CH:9]([OH:21])[CH2:10][N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)=[O:6].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:19][CH2:20][N:11]1[CH2:10][CH:9]([OH:21])[CH2:8][NH:7][C:5](=[O:6])[C:4]1[CH:22]=[CH:23][CH:24]=[C:2]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH:3]=1
Reactant: C1COCCN1
Reactant: O=C(NCC(O)CN1CCc2ccccc2C1)c1cccc(Br)c1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: O=C(NCC(O)CN1CCc2ccccc2C1)c1cccc(N2CCOCC2)c1
Yield: 7.4 %

Procedure:
A mixture of 3-bromo-N-(3-(3,4-dihydroisoquinolin-2(1H)-yl)-2-hydroxypropyl)benzamide (200 mg, 0.51 mmol), morpholine (44 mg, 0.51 mmol), Pd2(dba)3 (46 mg, 0.05 mmol), BINAP (62 mg, 0.1 mmol) and NaOtBu (73 mg, 0.77 mmol) in toluene (6 mL) was stirred at reflux for 16 h under N2. The reaction solution was concentrated, and the residue was dissolved in EA and filtered. The filtrate was concentrated, and the residue was purified by prep-HPLC to give the title compound (15 mg, Yield 7.5%). 1H NMR (CD3OD, 400 MHz): δ 8.48 (brs, 1H), 7.42 (s, 1H), 7.37-7.28 (m, 2H), 7.27-7.19 (m, 3H), 7.18-7.11 (m, 2H), 4.31-4.23 (m, 1H), 4.19 (s, 2H), 3.86 (dd, J=5.1, 4.8 Hz, 4H), 3.61-3.44 (m, 2H), 3.32-3.29 (m, 2H), 3.25-3.16 (m, 4H), 3.14-2.97 (m, 4H). LCMS (m/z): 396.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13](=[O:19])[CH2:12][CH2:11]3)=[CH:6][N:5]=[CH:4][C:3]=1[CH2:20][NH:21][C:22]([C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][N:25]=1)=[O:23].[H-].[Na+].[CH3:33]I>>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]([CH3:18])[C:13](=[O:19])[CH2:12][CH2:11]3)=[CH:6][N:5]=[CH:4][C:3]=1[CH2:20][N:21]([CH3:33])[C:22]([C:24]1[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][N:25]=1)=[O:23]
Reactant: CI
Reactant: CN1C(=O)CCc2cc(-c3cncc(CNC(=O)c4ncccc4Cl)c3Cl)ccc21
Agent: [H-]
Agent: [Na+]
Product: CN(Cc1cncc(-c2ccc3c(c2)CCC(=O)N3C)c1Cl)C(=O)c1ncccc1Cl

Procedure:
In analogy to the procedure described for the preparation of example 195, 3-chloro-pyridine-2-carboxylic acid [4-chloro-5-(1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-6-yl)-pyridin-3-ylmethyl]-amide (example 220) has been reacted with sodium hydride and methyl iodide to give the title compound as off-white solid. MS: 455.1 (M+H+).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]([Cl:15])([F:14])[F:13])[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].[F:25][C:26]([F:33])([C:29]([F:32])([F:31])[F:30])[CH2:27][NH2:28].C(N(CC)CC)C>CN(C=O)C>[Cl:15][C:12]([F:14])([F:13])[C:6]1[N:5]=[C:4]([C:16]([F:19])([F:17])[F:18])[C:3]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:2]([NH:28][CH2:27][C:26]([F:33])([F:25])[C:29]([F:32])([F:31])[F:30])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1Cl
Reactant: NCC(F)(F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1NCC(F)(F)C(F)(F)F
Yield: 81.1 %

Procedure:
This compound was prepared as described in Example 37: 5.0 g (0.013 mol) of product of Example 28, 1.94 g (0.013 mol) of 2,2,3,3,3-pentafluoropropylamine, 1.81 ml (0.013 mol) of triethylamine in 30 ml of DMF were reacted at 50° C. for 64 hours, affording 5.36 g of oil. This oil was purified by HPLC using 1% ethyl acetate/cyclohexane as eluting solvent to give 1.82 g of oil which was kugelrohr distilled at 41 Pa, pot temperature 95° C., to give 1.55 g (23.4%) of product as a clear oil, nD25 1.4351.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([F:25])([F:24])[F:23])[C:16]=4[C:15](=[O:26])[N:14]([CH3:27])[CH2:13][C:12]=23)[N:4]=1.[CH2:28]([NH2:31])[CH2:29][CH3:30]>CN(C)C=O>[CH3:27][N:14]1[C:15](=[O:26])[C:16]2[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][C:17]=2[N:11]2[CH:10]=[N:9][C:8]([C:5]3[N:4]=[C:3]([CH2:2][NH:31][CH2:28][CH2:29][CH3:30])[O:7][N:6]=3)=[C:12]2[CH2:13]1
Reactant: CN1Cc2c(-c3noc(CCl)n3)ncn2-c2cccc(C(F)(F)F)c2C1=O
Reactant: CCCN
Solvent: CN(C)C=O
Product: CCCNCc1nc(-c2ncn3c2CN(C)C(=O)c2c-3cccc2C(F)(F)F)no1
Yield: 66.6 %

Procedure:
1.19 g (3 mmol) of 3-(5-chloromethyl-1,2,4-oxa-diazol-3-yl)-5-methyl-7-trifluoromethyl-5,6-dihydro-4H-imidazo [1,5-a ][1,4]benzodiazepine-6-one were stirred at room temperature overnight with 5.3 g (90 mmol) of propylamine and 10 ml of N,N-dimethylformamide. After evaporating the reaction mixture the residue was dissolved in methylene chloride and the solution was washed with water. By drying the organic phase over magnesium sulfate and evaporating the solvent there was obtained 0.84 g (67%) of 5-methyl-3-(5-propylaminomethyl-1,2,4-oxadiazol-3-yl)-7-trifluoromethyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one, which was converted into the hydrochloride of m.p. 234°-237°.
Reaction SMILES: [Br:1]Br.[CH2:3]([N:5]([CH2:8][C:9]1[N:14]=[C:13]([NH:15][C:16]([NH:18][C:19]2[N:20]=[C:21]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)[S:22][CH:23]=2)=[O:17])[CH:12]=[CH:11][CH:10]=1)[CH2:6][CH3:7])[CH3:4]>CO>[Br:1][C:23]1[S:22][C:21]([C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[N:20][C:19]=1[NH:18][C:16]([NH:15][C:13]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:8][N:5]([CH2:6][CH3:7])[CH2:3][CH3:4])[N:14]=1)=[O:17]
Reactant: BrBr
Reactant: CCN(CC)Cc1cccc(NC(=O)Nc2csc(-c3ccncc3)n2)n1
Solvent: CO
Product: CCN(CC)Cc1cccc(NC(=O)Nc2nc(-c3ccncc3)sc2Br)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Bromine (46 μL, 0.90 mmol) was added to a solution of 1-(6-diethylaminomethyl-pyridin-2-yl)-3-(2-pyridin-4-yl-thiazol-4-yl)urea (190 mg, 0.45 mmol, Example 117) in MeOH (8 mL) and the resulting solution was stirred at RT for 1 h. The reaction was quenched with saturated sodium bisulfite solution and concentrated in vacuo. The residue was dissolved in CHCl3/IpOH (3/1, 10 mL) and washed with H2O (3×10 mL) followed by 1N NaOH solution (10 mL). (The organics were combined, dried over Na2SO4, and concentrated in vacuo to give a yellow solid. MS m/z: 461.1 (M+H). Calc'd for C19H21BrN6OS-461.39.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1)#[N:2].CN(C(OC)OC)C.[N:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][C:26]=1[NH:35][CH2:36][CH2:37][NH:38][C:39]1[N:44]=C(C2C=CC(C(N)=O)=CC=2)C=[CH:41][N:40]=1.[O-]CC.[Na+]>C(O)C.C1COCC1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:41][N:40]=[C:39]([NH:38][CH2:37][CH2:36][NH:35][C:26]3[CH:27]=[CH:28][C:29]4[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:25]=3)[N:44]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: NC(=O)c1ccc(-c2ccnc(NCCNc3ccc4ccccc4n3)n2)cc1
Reactant: CCOC(=O)CC(=O)c1ccc(C#N)cc1
Agent: CC[O-]
Agent: COC(OC)N(C)C
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(NCCNc2ccc3ccccc3n2)nc1-c1ccc(C#N)cc1
Temperature: 80 °C

Procedure:
Ethyl 3-(4-cyanophenyl)3-oxopropanoate (64 mg, 0.3 mmol) was heated with DMFDMA (50 μl) and dry THF (1 ml) at 70° C. for 3 hours. The cooled mixture was then added to a suspension of amino[2-(2-quinolylamino)ethyl]carboxamidinium 4-methylbenzenesulfonate (prepared according to Example 12), (120 mg, 0.3 mmol) in ethanol (2 ml) containing 0.35 mmol of sodium ethoxide. The reaction was then heated at 80° C. overnight and then concentrated in vacuo. The residue was taken up in dichloromethane and washed with saturated aqueous sodium bicarbonate. The organic layer was concentrated in vacuo. The residue was taken up in acetonitrile. Addition of water gave a precipitate which was filtered off and dried to give the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][OH:25])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.Br[C:28]1[N:33]([CH3:34])[C:32](=[O:35])[CH:31]=[CH:30][CH:29]=1>>[OH:25][CH2:24][CH2:23][CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:26])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:28]3[N:33]([CH3:34])[C:32](=[O:35])[CH:31]=[CH:30][CH:29]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1
Reactant: Cn1c(Br)cccc1=O
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2cccc(=O)n2C)cc1)N1CC[C@](CCCO)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (R)-3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-phenyl-1,3-oxazinan-2-one following procedures analogous to those described in Example 313 Steps 3 and 4 using 6-bromo-1-methylpyridin-2(1H)-one in Step 4. LC-MS Method 2 tR=1.088, m/z=447; 1H NMR (CDCl3) 1.38 (m, 1H), 1.56 (d, 3H), 1.70 (m, 1H), 1.95-2.08 (m, 2H), 2.23 (m, 1H), 2.37 (s, 2H), 3.05 (m, 1H), 3.33 (s, 3H), 3.58 (m, 2H), 5.73 (m, 1H), 6.29 (d, 1H), 6.89 (d, 1H), 7.01-7.09 (m, 4H), 7.21-7.39 (m, 5H), 7.53 (t, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=O)=[C:6]([S:10][CH3:11])[CH:5]=[CH:4][CH:3]=1.Cl.[NH2:13][OH:14].C([N-]CC)C>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([S:10][CH3:11])[C:7]=1/[CH:8]=[N:13]/[OH:14]
Reactant: NO
Reactant: CSc1cccc(Cl)c1C=O
Agent: CC[N-]CC
Agent: Cl
Solvent: CCO
Product: CSc1cccc(Cl)c1/C=N/O
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
6-Chloro-2-(methythio)benzaldehyde (11.6 g, 75.16 mmol), and hydroxylamine hydrochloride (5.75 g, 82.86 mmol) were combined in ethanol (100 ml). Diethylamide (11.5 ml, 82.86 mmol) was slowly added to the solution and it was allowed to stir at room temperature overnight. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate and then washed successively with water and saturated aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to yield (E)-2-chloro-6-(methylthio)benzaldehyde oxime (12.37 g) as a white solid. (This method is general for other 2-(methythio)benzaldehydes). 1H NMR (300 MHz, DMSO-d6): 11.62 (s, 1H), 8.22 (s, 1H), 7.20-7.40 (m, 3H), 2.41 ppm (s, 3H). MW=202 confirmed by LC-MS, tr=3.58 min (Method B) MH+=203.
Reaction SMILES: [N:1]#[N:2].C(OC([NH:13][C@@H:14]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C@H:15]([OH:30])[CH2:16][C@@:17]1([C:27]([NH2:29])=[O:28])[CH2:21][C@H:20]([OH:22])[CH2:19][N:18]1[C:23]([CH3:26])([CH3:25])[CH3:24])=O)C1C=CC=CC=1>C(O)C.[Pd]>[N:1]#[N:2].[NH2:13][C@@H:14]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C@H:15]([OH:30])[CH2:16][C@@:17]1([C:27]([NH2:29])=[O:28])[CH2:21][C@H:20]([OH:22])[CH2:19][N:18]1[C:23]([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)N1C[C@@H](O)C[C@@]1(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(N)=O
Agent: [Pd]
Agent: N#N
Solvent: CCO
Product: CC(C)(C)N1C[C@@H](O)C[C@@]1(C[C@@H](O)[C@@H](N)Cc1ccccc1)C(N)=O
Yield: 98.6 %

Procedure:
0.11 g of N2 -[3(S)-(benzyloxyformamido)-2(R)-hydroxy-4-phenylbutyl]-N1 -tert.butyl-4(S)-hydroxy-L-prolinamide was dissolved in 10 ml of ethanol and hydrogenated over 20 mg of 10% palladium-on-carbon at room temperature and under atmospheric pressure for 2 hours. The catalyst was filtered off and the filtrate was evaporated to give 0.08 g of N2 -[3(S)-amino-2(R)-hydroxy-4-phenylbutyl]-N1 -tert.butyl-4(S)-hydroxy-L-prolinamide as a gum which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[CH:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[Cl-].[Cl-].[Al+3].Cl>CN(C=O)C>[Br:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:6])=[C:2]([F:1])[CH:10]=1
Reactant: c1ccccc1
Reactant: O=C(O)c1ccc(Br)cc1F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: O=C(c1ccccc1)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In an oven dried flask was added 2-fluoro-4-bromobenzoic acid (1.0 g, 0.0046 mol), thionyl chloride (0.77 mL, 0.010 mol) and a drop of DMF and the reaction was refluxed for 2 h. The excess thionyl chloride was then distilled off and the residual thionyl chloride was removed on the high vacuum pump. Benzene (20 mL, 0.2 mol) and aluminum trichloride (0.676 g, 0.00507 mol) were added to the reaction mixture. The reaction mixture was stirred at room temp for 1 h. The crude reaction mixture was poured onto ice and conc. HCl (15 mL). The organic layer was separated and the aqueous layer extracted with EtOAc. The combined organic phases were washed with 5% aq NaOH solution, water and dried (Na2SO4). The organic phase was concentrated in vacuo to give a residue which was purified by silica gel chromatography, eluting with 2% EtOAc in hexane. 1H NMR (400 MHz, CDCl3): δ=7.32-7:41 (m, 1H), 7.42-7.53 (m, 4H), 7.56-7.67 (m, 1H), 7.77-7.88 (m, 2H). MS (ES+): m/z 280.78 (40) [MH+]. HPLC: tR=3.8 min(Open Lynx polar—5 min).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]([NH:11][C:12]2[N:17]=[C:16]([N:18]3[C@@H:22]([CH:23]([CH3:25])[CH3:24])[CH2:21][O:20][C:19]3=[O:26])[CH:15]=[CH:14][N:13]=2)[CH3:10])=[CH:5][CH:4]=1.[N:27]1[CH:28]=[CH:29][N:30]2[CH2:35][CH2:34][NH:33][CH2:32][C:31]=12>CS(C)=O.CCOC(C)=O>[N:27]1[CH:28]=[CH:29][N:30]2[CH2:35][CH2:34][N:33]([CH2:2][C:3]3[CH:8]=[CH:7][C:6]([C@@H:9]([NH:11][C:12]4[N:17]=[C:16]([N:18]5[C@@H:22]([CH:23]([CH3:25])[CH3:24])[CH2:21][O:20][C:19]5=[O:26])[CH:15]=[CH:14][N:13]=4)[CH3:10])=[CH:5][CH:4]=3)[CH2:32][C:31]=12
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)c2ccc(CCl)cc2)n1
Reactant: c1cn2c(n1)CNCC2
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)[C@H]1COC(=O)N1c1ccnc(N[C@@H](C)c2ccc(CN3CCn4ccnc4C3)cc2)n1
Yield: 62.8 %

Procedure:
A solution of (S)-3-(2-((S)-1-(4-(chloromethyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one (75 mg, 0.2 mmol) and 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (25 mg, 0.2 mmol) in DMSO (2 mL) was heated at 80° C. for 16 h. The reaction mixture was diluted with EtOAc (20 mL) and washed with water (20 mL). After separation, the aqueous phase was washed with EtOAc (2×15 mL). Combined organics were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (MeOH in CH2Cl2 0 to 10%) provided (S)-3-(2-((S)-1-(4-((5,6-dihydroimidazo[1,2-a]pyrazin-7(8H)-yl)methyl)phenyl)ethylamino)pyrimidin-4-yl)-4-isopropyloxazolidin-2-one (58 mg, white solid) in 62.8% yield.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]([O:12]C)[CH:8]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1C(O)=O.Cl.N1C=CC=CC=1>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([OH:12])[C:10]=1[Cl:11])[C:5]([OH:7])=[O:6]
Reactant: COc1cc(C(=O)O)c(C(=O)O)c(Cl)c1Cl
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C(O)c1cc(O)c(Cl)c(Cl)c1
Temperature: 180 °C

Procedure:
3,4-Dichloro-5-methoxyphthalic acid (17.5 g., 0.066 mole) is mixed with pyridine hydrochloride (120 g.). The mixture is heated at 180° C. for one hour and then poured into water (1 l.). The solid that separates melts at 211°-212..5° C. and is used without purification in the next step.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.[NH2:15][CH2:16][C:17]1[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[C:19]([CH3:30])[CH:18]=1>>[Cl:14][C:13]1[C:3]2[CH2:2][N:15]([CH2:16][C:17]3[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:26])([CH3:27])[CH3:25])=[O:22])=[C:19]([CH3:30])[CH:18]=3)[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Reactant: Cc1cc(CN)ccc1C(=O)OC(C)(C)C
Product: Cc1cc(CN2Cc3c(ccnc3Cl)C2=O)ccc1C(=O)OC(C)(C)C
Yield: 83 %

Procedure:
The title compound is prepared in 83% yield (560 mg, colorless oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (500 mg, 1.8 mmol, Step-1 of Intermediate-1) and tert-butyl 4-(aminomethyl)-2-methylbenzoate (400 mg, 1.8 mmol) in a similar manner to Intermediate-2.
Reaction SMILES: [C:1]([N:4]1[CH:10]([CH3:11])[CH2:9][C:8]2[CH:12]=[C:13]([Br:18])[C:14]([O:16][CH3:17])=[CH:15][C:7]=2[C:6]([C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[C:21]([Cl:28])[CH:20]=2)=[N:5]1)(=[O:3])[CH3:2].O.NN>CO.ClCCl.[Ni]>[C:1]([N:4]1[CH:10]([CH3:11])[CH2:9][C:8]2[CH:12]=[C:13]([Br:18])[C:14]([O:16][CH3:17])=[CH:15][C:7]=2[C:6]([C:19]2[CH:24]=[CH:23][C:22]([NH2:25])=[C:21]([Cl:28])[CH:20]=2)=[N:5]1)(=[O:3])[CH3:2]
Reactant: COc1cc2c(cc1Br)CC(C)N(C(C)=O)N=C2c1ccc([N+](=O)[O-])c(Cl)c1
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COc1cc2c(cc1Br)CC(C)N(C(C)=O)N=C2c1ccc(N)c(Cl)c1
Reaction time: 0.75 h
Yield: 80.6 %

Procedure:
4.66 g (10 mmoles) of (±)-3-acetyl-7-bromo-4,5-dihydro-1-(3-chloro-4-nitrophenyl)-4-methyl-8-methoxy-3H-2,3-benzodiazepine are dissolved in a mixture of 45 cm3 of methanol and 45 cm3 of dichloromethane, then 3.0 g of wet Raney nickel catalyst and, under vigorous stirring, 1.7 cm3 (35 mmoles) of 98% hydrazine hydrate are added. The reaction mixture is stirred for further 45 minutes, the catalyst is filtered, washed with dichloromethane, the filtrate is evaporated, and the residue is rubbed with 50 cm3 of water to obtain solid matter. The crude product is purified by boiling in 50 ml of acetonitrile. Thus, 3.52 g (81%) of the title compound are obtained in the form of white solids melting at 235–237° C.