Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[C:6]([O:11][CH3:12])[CH:5]=1.C1COCC1.CO.[OH-].[Li+].Cl>O>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:13])=[O:2])=[CH:5][C:6]=1[O:11][CH3:12]
Reactant: COC(=O)c1ccc(Br)c(OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1cc(C(=O)O)ccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
To a solution of 4-bromo-3-methoxy-benzoic acid methyl ester (6.875 mmol, 1.676 mL) in a mixture 1:1 of THF/MeOH (15 mL), lithium hydroxide (7.553 mmol, 0.180 g) was added, and the reaction was stirred at RT overnight before distillation of volatiles. The residue was diluted with water, acidified with a solution of HCl (1N), and stirred for 1 hour. The formed precipitate was filtered off, and washed with water and petroleum ether to give 4-bromo-3-methoxy-benzoic acid. Yield: 56%.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:18]([N:20]([CH2:22][C:23]([NH:25][CH2:26][C:27](O)=[O:28])=[O:24])[CH3:21])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:30]([O:37][C:38](=[O:56])[C@H:39]([CH2:52][CH2:53][S:54][CH3:55])[NH:40][C:41](=[O:51])[C@H:42]([CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[NH2:43])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH2:30]([O:37][C:38](=[O:56])[C@H:39]([CH2:52][CH2:53][S:54][CH3:55])[NH:40][C:41](=[O:51])[C@H:42]([CH2:44][C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1)[NH:43][C:27](=[O:28])[CH2:26][NH:25][C:23](=[O:24])[CH2:22][N:20]([C:18](=[O:19])[C@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH3:21])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CSCC[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)OCc1ccccc1
Reactant: CN(CC(=O)NCC(=O)O)C(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Product: CSCC[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)CN(C)C(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1

Procedure:
When equivalent quantities of N-t-butoxycarbonyl-L-tyrosylsarcosylglycine and L-phenylalanyl-L-methionine benzyl ester are reacted according to the procedure detailed in Example 12, there is obtained N-t-butoxycarbonyl-L-tyrosylsarcosylglycyl-L-phenylalanyl-L-methionine benzyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[C:7]([Cl:20])[C:8](OS(C(F)(F)F)(=O)=O)=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1OS(C(F)(F)F)(=O)=O.[CH2:29]([C:33]1[CH:37]=[CH:36][S:35][C:34]=1[C:38]#[CH:39])[CH2:30][CH2:31][CH3:32].O.Cl>C(N(CC)CC)C.C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH2:29]([C:33]1[CH:37]=[CH:36][S:35][C:34]=1[C:38]#[C:39][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[CH:10][CH:9]=[C:8]([C:39]#[C:38][C:34]3[S:35][CH:36]=[CH:37][C:33]=3[CH2:29][CH2:30][CH2:31][CH3:32])[C:7]=2[Cl:20])[C:2]=1[Cl:1])[CH2:30][CH2:31][CH3:32]
Reactant: O=S(=O)(Oc1ccc2c(Cl)c(OS(=O)(=O)C(F)(F)F)ccc2c1Cl)C(F)(F)F
Reactant: C#Cc1sccc1CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CCCCc1ccsc1C#Cc1ccc2c(Cl)c(C#Cc3sccc3CCCC)ccc2c1Cl
Yield: 32.7 %

Procedure:
1.46 g (2.96 mmol) of [1,5-dichloro-6-(trifluoromethylsulfonyloxy)-2-naphthyl]trifluoro-methanesulfonate (17) and 1.46 g (8.89 mmol) of 3-butyl-2-ethynylthiophene (18) are dissolved in 1.25 ml of dry triethylamine and 30 ml of dry THF. To the reaction mixture are added 208 mg (0.30 mmol) of Pd(PPh3)2Cl2 and 113 mg (0.59 mmol) of copper(I) iodide. The mixture is heated under reflux for 20 h. 3 ml of water and 3 ml of 1N HCl solution are added thereto, the phases are separated and the aqueous phase is extracted three times with 25 ml of DCM. The combined organic phases are dried over sodium sulfate. After the solvents have been distilled off, the residue is recrystallized from hexane/chloroform to obtain 505 mg (33%) of product. 1H NMR (CDCl3): 8.22 ppm (d, 2H), 7.68 (d, 2H), 7.27 (d, 2H), 6.94 (d, 2H), 2.88 (dd, 4H), 1.70 (m, 4H), 1.42 (qa, 4H), 0.96 (t, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[I:14]I.C(Cl)(Cl)Cl>CC(O)=O.CCOC(C)=O.[Hg](OC(C)=O)OC(C)=O>[N+:1]([C:4]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[C:7]([I:14])[C:5]=1[NH2:6])([O-:3])=[O:2]
Reactant: II
Reactant: Nc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: CC(=O)O[Hg]OC(C)=O
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Nc1c(I)cc([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 12 h
Yield: 81.3 %

Procedure:
To a solution of 2,4-dinitroaniline (3.0 g, 16 mmol) and Hg(OAc)2 (6.8 g, 21 mmol) in 40 ml of AcOH was added 5.0 g (19 mmol) of I2 in 100 ml of AcOH dropwise and reaction mixture was stirred for 12 h. The reaction mixture was concentrated in vacuo, yielding a dark residue which was diluted with EtOAc and washed with aqueous NaHCO3. Organic layer was dried over MgSO4 and concentrated in vacuo to produce dark residue which was subjected to column chromatography (CHCl3, neat) to provide 4.1 g (13 mmol, 81%) of 2,4-dinitro-6-iodoaniline.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:24][C@H:23]([CH2:25][O:26]C(=O)C)[C@@H:18]([O:19]C(=O)C)[C@H:13]3[O:14]C(=O)C)[C:6]=2[N:7]=1.C([O-])([O-])=O.[K+].[K+].CC(O)=O>CO>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:10][C:9](=[O:11])[N:8]([C@@H:12]3[O:24][C@H:23]([CH2:25][OH:26])[C@@H:18]([OH:19])[C@H:13]3[OH:14])[C:6]=2[N:7]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2c(=O)sc3cnc(N)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CO
Product: Nc1ncc2sc(=O)n([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
To a solution of 89 (0.52 g, 1.22 mmol) in MeOH (20 mL) was added K2CO3 (25 mg, 0.18 mmol). The reaction was stirred at room temperature overnight, then neutralized with AcOH (21 μL, 0.36 mmol). The resulting mixture was stirred at room temperature for additional 30 min, concentrated, and triturated with H2O (2 ml) to afford 0.33 g of compound 90 (89%) as a white solid: mp 220° C. (Dec); 1H (400 MHz, d6-DMSO) δ 8.34 (s, 1H), 6.85 (s, 2H), 5.90 (d, J=4.8 Hz, 1H), 5.31 (d, J=5.6 Hz, 1H), 4.98 (d, J=5.6 Hz, 1H), 4.81 (q, J=5.2 Hz, 1H), 4.67 (t, J=6.0 Hz, 1H), 4.11 (q, J=5.2 Hz, 1H), 3.77 (dd, J=10.8, 4.8 Hz, 1H), 3.58 (m, 1H), 3.44 (m, 1H); MS (+)-ES [M+H]+ m/z 301.1. Elemental Analysis calc'd for C10H12N4O5S.0.3 H2O: C, 39.29; H, 4.15; N, 18.33; S 10.49. Found: C, 39.51; H, 4.18; N, 17.95; S, 10.27.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:9]=[C:10]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:11]3[N:16]=[C:15]([CH2:17][CH:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)[S:14][C:12]=3[N:13]=2)[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=2[N:4]=1)[CH3:2].Cl[C:35]([C:37]([O:40][C:41](=[O:43])[CH3:42])([CH3:39])[CH3:38])=[O:36].CCN(CC)CC>C(Cl)Cl>[CH2:1]([C:3]1[N:7]([C:8]2[N:9]=[C:10]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[C:11]3[N:16]=[C:15]([CH2:17][CH:18]4[CH2:19][CH2:20][N:21]([C:35](=[O:36])[C:37]([O:40][C:41](=[O:43])[CH3:42])([CH3:39])[CH3:38])[CH2:22][CH2:23]4)[S:14][C:12]=3[N:13]=2)[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=2[N:4]=1)[CH3:2]
Reactant: CC(=O)OC(C)(C)C(=O)Cl
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCNCC3)sc2n1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCN(C(=O)C(C)(C)OC(C)=O)CC3)sc2n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5-(2-ethylbenzoimidazol-1-yl)-7-morpholin-4-yl-2-piperidin-4-ylmethylthiazolo[5,4-d]pyrimidine (96 mg, 0.21 mmol), acetic acid 1-chlorocarbonyl-1-methylethyl ester (40 μL, 0.28 mmol) and NEt3 (40 μL, 0.31 mmol) in DCM (1 mL) was allowed to stir at r.t. for 30 min then concentrated in vacuo. The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH affording Acetic acid 2-{4-[5-(2-ethylbenzoimidazol-1-yl)-7-morpholin-4-ylthiazolo[5,4-d]pyrimidin-2-ylmethyl]piperidin-1-yl}-1,1-dimethyl-2-oxoethyl ester. LCMS (method A): RT 3.19 min [M+H]+ 592.2
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C(N(CC)CC)C.Cl>CS(C)=O>[O:1]=[CH:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:9])([CH3:8])[CH3:10]
Reactant: CC(C)(C)OC(=O)NCCO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)NCC=O
Reaction time: 1 h
Yield: 65.8 %

Procedure:
To a mixed solution of tert-butyl (2-hydroxyethyl)carbamate (10.0 g) in dimethyl sulfoxide (50 mL) and triethylamine (12.3 g) was added sulfur trioxide pyridine complex (15.0 g) under ice-cooling, and the mixture was stirred for 1 hr. The reaction mixture was further stirred at room temperature for 3 hr, 1 mol/L hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layers were washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=17:3→13:7) to give the title compound as a pale-yellow oil (yield 6.50 g, 66%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:12]2[CH2:15][CH2:14][C:13]2([CH3:19])[C:16]([OH:18])=O)=[O:11])[CH:5]=[C:6]([CH3:8])[CH:7]=1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[CH3:31][O:32][C:33](=[O:44])[CH2:34][NH:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:31][O:32][C:33](=[O:44])[CH2:34][N:35]([CH2:36][C:37]1[CH:38]=[CH:39][C:40]([Cl:43])=[CH:41][CH:42]=1)[C:16]([C:13]1([CH3:19])[CH2:14][CH2:15][N:12]1[C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[CH:3]=1)=[O:18]
Reactant: Cc1cc(C)cc(CC(=O)N2CCC2(C)C(=O)O)c1
Reactant: COC(=O)CNCc1ccc(Cl)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)CN(Cc1ccc(Cl)cc1)C(=O)C1(C)CCN1C(=O)Cc1cc(C)cc(C)c1
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-[2-(3,5-dimethyl-phenyl)-acetyl]-2-methyl-azetidine-2-carboxylic acid, Intermediate 119 (1 eq.) in DCM under nitrogen, was added DMF (0.01 eq.) then oxalyl chloride (2 eq.). The solution was stirred at 20° C. for 30 min, then cooled to 0° C. A solution of (4-Chloro-benzylamino)-acetic acid methyl ester (1.5 eq.) and either TEA or DIPEA (2 to 7 eq.) in DCM was then added to the previous mixture. The solution was stirred at 0° C. for 1 h then at 20° C. until completion (1 h). The reaction was quenched with a saturated aqueous solution of NaHCO3 and extracted three times with DCM. The organic layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (elution with heptane/EtOAc: 1/0 to 1/1) to afford ((4-chloro-benzyl)-{1-[2-(3,5-dimethyl-phenyl)-acetyl]-2-methyl-azetidine-2-carbonyl}-amino)-acetic acid methyl ester.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[C:12]([F:15])([F:14])[F:13])[NH:5][CH:4]=[C:3]1[C:16]([OH:18])=O.[CH:19]12[N:25]([C:26]3[N:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[C:29]([NH2:36])=[CH:28][CH:27]=3)[CH:22]([CH2:23][CH2:24]1)[CH2:21][CH2:20]2.N1C=CC=CC=1>CC1CCCO1.C(OCC)(=O)C>[CH:22]12[N:25]([C:26]3[N:31]=[C:30]([C:32]([F:35])([F:33])[F:34])[C:29]([NH:36][C:16]([C:3]4[C:2](=[O:1])[C:11]5[C:6](=[CH:7][CH:8]=[CH:9][C:10]=5[C:12]([F:13])([F:14])[F:15])[NH:5][CH:4]=4)=[O:18])=[CH:28][CH:27]=3)[CH:19]([CH2:20][CH2:21]1)[CH2:24][CH2:23]2
Reactant: O=C(O)c1c[nH]c2cccc(C(F)(F)F)c2c1=O
Reactant: Nc1ccc(N2C3CCC2CC3)nc1C(F)(F)F
Solvent: CC1CCCO1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C(Nc1ccc(N2C3CCC2CC3)nc1C(F)(F)F)c1c[nH]c2cccc(C(F)(F)F)c2c1=O
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 71 %

Procedure:
To a solution of 4-oxo-5-(trifluoromethyl)-1H-quinoline-3-carboxylic acid (100 mg, 0.3889 mmol) and 6-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(trifluoromethyl)pyridin-3-amine (110.1 mg, 0.4278 mmol) in 2-methyltetrahydrofuran (1.0 mL) was added propyl phosphonic acid cyclic anhydride (50% solution in ethyl acetate, 495.0 μL, 0.7778 mmol) and pyridine (61.52 mg, 62.90 μL, 0.7778 mmol). The reaction was capped and heated at 60° C. for 16 h. The reaction was cooled to room temperature, diluted with ethyl acetate (10 mL) and quenched with saturated Na2CO3 solution (6 mL). After stirring for 20 min the organic layer was separated, dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (0-20% ethyl acetate in dichloromethane) provided N-(6-(7-azabicyclo[2.2.1]heptan-7-yl)-2-(trifluoromethyl)pyridin-3-yl)-4-oxo-5-(trifluoromethyl)-1,4-dihydroquinoline-3-carboxamide (137 mg, 71% yield). LC/MS m/z 497.5 [M+H]+, retention time 1.92 min (RP—C18, 10-99% CH3CN/0.05% TFA over 3 min).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([C:12]1[CH:13]=[N:14][C:15]2[C:20]([C:21]=1[OH:22])=[CH:19][C:18]([O:23][CH3:24])=[CH:17][CH:16]=2)[CH:10]=[CH2:11].CO>ClCCl>[Br:1][CH2:11][CH:10]1[O:22][C:21]2[C:20]3[CH:19]=[C:18]([O:23][CH3:24])[CH:17]=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[CH2:9]1
Reactant: C=CCc1cnc2ccc(OC)cc2c1O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2ncc3c(c2c1)OC(CBr)C3
Temperature: 10 °C
Reaction time: 1 h
Yield: 73.2 %

Procedure:
N-Bromosuccinimide (1.19 g, 6.69 mmol, 1.2 eq) is added at 10° C. to a stirred solution of 3-allyl-6-methoxy-quinolin-4-ol (1.20 g, 5.57 mmol, 1.0 eq) in dichloromethane (120 mL) and the resulting mixture is stirred at 10° C. for 1 hour. The reaction mixture is then successively washed with water (50 mL) and brine (20 mL), dried over sodium sulfate, filtered and concentrated to give a crude product that is purified by column chromatography (silica gel, eluent: dichloromethane:methanol, 80:1, v/v) to afford 2-bromomethyl-8-methoxy-2,3-dihydro-furo[3,2-c]quinoline as a light yellow solid (1.2 g, 73% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][O:13][CH3:14])[CH2:6][NH2:7].[C:15](Cl)(Cl)=[S:16].C(N(CC)CC)C>C(OCC)(=O)C>[N:7]([CH2:6][C:5]1[CH:8]=[CH:9][C:10]([O:11][CH2:12][O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=1)=[C:15]=[S:16]
Reactant: S=C(Cl)Cl
Reactant: COCOc1ccc(CN)cc1OC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COCOc1ccc(CN=C=S)cc1OC

Procedure:
A solution of 3-methoxy-4-methoxymethoxybenzylamine (5.3 g, 26.9 mmol) in ethyl acetate (50 mL) was added, via an addition funnel) to a solution of thiophosgene (2.15 mL, 28.2 mmol) and triethylamine (7.87 mL, 56.5 mmol) in ethyl acetate (30 mL) at 0° C. The resultant solution was stirred at ambient temperature overnight. The solution was washed with saturated aqueous sodium bicarbonate and dried over sodium sulfate. The solvent was evaporated in vacuo, and the residue was purified by flash chromatography on silica gel eluted with ethyl acetate/hexanes (1/9 to 3/7) to give the product, 4-isothiocyanatomethyl-2-methoxy-1-methoxymethoxy-benzene, as a waxy tan solid, 4.9 g (76%). 1H NMR (CDCl3): δ 3.51 (s, 3H), 3.91 (s, 3H), 4.64 (s, 2H), 5.23 (s, 2H), 6.83 (m, 2H) and 7.14 (d, J=8 Hz).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH2:6].[N+](C1C=CC([O:16][C:17](=O)[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[NH:25][C:26]2[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:33])=CC=1)([O-])=O>C(Cl)Cl.CO>[ClH:32].[NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:17](=[O:16])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][C:26]1[C:31]([Cl:32])=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:33]
Reactant: NCCCCN
Reactant: O=C(Cc1ccccc1Nc1c(Cl)cccc1Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CO
Product: Cl
Product: NCCCCNC(=O)Cc1ccccc1Nc1c(Cl)cccc1Cl

Procedure:
1,4-diaminobutane and 2-{2-[(2,6-dichlorophenyl)-amino]-phenyl}-acetic acid p-nitrophenyl ester are allowed to react for 8 hours at room temperature in methylene chloride/methanol (1:1). The reaction solution is then concentrated by evaporation in vacuo, the residue is taken up in tetrahydrofuran and the whole is extracted by shaking with 2N hydrochloric acid. The aqueous phase is extracted three times with diethyl ether to remove nitrophenol and is then saturated with NaCl and extracted with tetrahydrofuran. The organic phase is dried with Na2SO4 and concentrated by evaporation. The residue is triturated with diethyl ether and yields a crystalline powder which is recrystallised from ethyl acetate. 2-{2-[(2,6-dichlorophenyl)-amino]-phenyl}-acetic acid 4-aminobutylamide hydrochloride is obtained in the form of its ethyl acetate solvate; m.p. 137°-140°; Rf =0.177 (CHCl3 :methanol:concentrated aqueous ammonia solution=10:10:0.1).
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]([CH:6]1[CH2:9][N:8]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:20][C@@H:19]([CH2:21]CS([O-])(=O)=O)[O:18][C:17]3=[O:27])=[CH:12][C:11]=2[F:28])[CH2:7]1)[CH3:5].[N-:29]=[N+:30]=[N-:31].[Na+].CO.C(Cl)(Cl)Cl.S([O-])(=O)(=O)C>CN(C)C=O>[F:1][CH2:2][CH2:3][N:4]([CH:6]1[CH2:9][N:8]([C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH2:20][C@H:19]([CH2:21][N:29]=[N+:30]=[N-:31])[O:18][C:17]3=[O:27])=[CH:12][C:11]=2[F:28])[CH2:7]1)[CH3:5]
Reactant: [N-]=[N+]=[N-]
Reactant: CN(CCF)C1CN(c2ccc(N3C[C@@H](CCS(=O)(=O)[O-])OC3=O)cc2F)C1
Agent: CS(=O)(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CN(CCF)C1CN(c2ccc(N3C[C@H](CN=[N+]=[N-])OC3=O)cc2F)C1
Temperature: 65 °C
Reaction time: 3 h
Yield: 85.9 %

Procedure:
A solution of (R)-[[3-[4-[3-[N-(2-fluoroethyl)-N-methylamino]-1-azetidinyl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]methanesulfonate (1.65 g, 3.94 mmol) in dry N,N-dimethylformamide (15 mL) was treated with solid sodium azide (0.768 g, 11.8 mmol). The reaction mixture was then heated to 65° C. under a nitrogen atmosphere. After 3 h, TLC analysis (5% methanol/chloroform) revealed a small amount of starting mesylate still remained. An additional portion of sodium azide (0.256 g, 3.94 mmol) was added and the reaction mixture heated at 65° C. for 1 h. The reaction mixture was cooled to ambient temperature, filtered and concentrated under reduced pressure. The residue was chromatographed over silica gel (100 g), eluting with a gradient of 1-4% methanol/chloroform, to afford, after concentration of appropriate fractions, 1.24 g (86%) of the title compound as an off-white solid with mp 60°-63° C. and MS(EI) 366 (M+).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([O:31][CH3:32])=[C:6]2[C:10]([C:11](=[O:30])[C:12]([N:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[CH2:15]3)=[O:13])=[CH:9][NH:8][C:7]=12.C([Sn](CCCC)(CCCC)[C:38]1[CH:42]=[C:41]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[NH:40][N:39]=1)CCC>O1CCOCC1.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>[CH3:32][O:31][C:5]1[CH:4]=[N:3][C:2]([C:38]2[CH:42]=[C:41]([C:43]([O:45][CH2:46][CH3:47])=[O:44])[NH:40][N:39]=2)=[C:7]2[NH:8][CH:9]=[C:10]([C:11](=[O:30])[C:12](=[O:13])[N:14]3[CH2:23][CH2:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)[CH2:15]3)[C:6]=12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C(=O)OCC)[nH]n1
Reactant: COc1cnc(Br)c2[nH]cc(C(=O)C(=O)N3CCc4c(cccc4-c4ccccn4)C3)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(-c2ncc(OC)c3c(C(=O)C(=O)N4CCc5c(cccc5-c5ccccn5)C4)c[nH]c23)n[nH]1
Temperature: 110 °C
Yield: 30.4 %

Procedure:
To a sealable rb flask containing 1-(7-bromo-4-methoxy-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(5-(pyridin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)ethane-1,2-dione (0.5 g, 1.018 mmol) and ethyl 3-(tributylstannyl)-1H-pyrazole-5-carboxylate (0.480 g, 1.119 mmol) in 1,4-dioxane (2 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.235 g, 0.204 mmol). The flask was flushed with N2, sealed, and heated to 110° C. After heating the mixture for 17 h, the mixture was cooled to rt. The crude LC/MS showed no starting material remained and the mass for the expected product was present. The crude mixture was diluted with MeOH and was passed through a plug of CELITE® to remove solids. The CELITE® was washed with MeOH, and the organic solution was concentrated under reduced pressure. The residue was diluted with MeOH and ether was added slowly to the mixture. The product that formed was collected by filtration and washed with MeOH. The mother liquor was concentrated under reduced pressure. A second recrystallization was performed using hot MeOH and Et2O. The expected product, ethyl 3-(4-methoxy-3-(2-oxo-2-(5-(pyridin-2-yl)-3,4-dihydroisoquinolin-2(1H)-yl)acetyl)-1H-pyrrolo[2,3-c]pyridin-7-yl)-1H-pyrazole-5-carboxylate (0.17 g, 0.309 mmol, 30.3% yield), was isolated as a light-brown solid and was used in the next step although impurities were still apparent by 1H NMR. LC/MS: m/z 551.18 (M+H)+, 1.778 min (method 1). 1H NMR (500 MHz, DMSO-d6) δ ppm 14.04-14.50 (m, 1H) 11.90-12.88 (m, 1H) 8.58-8.76 (m, 1H) 7.81-8.28 (m, 3H) 7.14-7.67 (m, 6H) 4.29-4.96 (m, 4H) 3.53-3.89 (m, 5H) 2.79-3.06 (m, 2H) 1.36 (t, J=7.02 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:30].C(OC([NH:47][CH:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)=O)(C)(C)C.[CH3:54][S:55](Cl)(=[O:57])=[O:56]>>[F:35][C:34]([F:37])([F:36])[C:32]1[CH:31]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:38])[F:39])[CH:33]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][NH:11][C:10]2[N:15]=[C:16]([N:51]3[CH2:52][CH2:53][CH:48]([NH:47][S:55]([CH3:54])(=[O:57])=[O:56])[CH2:49][CH2:50]3)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[CH3:25])[C:9]=2[C:8]1=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Cc1ccccc1-c1nc(S(C)(=O)=O)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Product: Cc1ccccc1-c1nc(N2CCC(NS(C)(=O)=O)CC2)nc2c1C(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)CCCN2
Yield: 45 %

Procedure:
In a similar manner to Example 24, 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-(methylsulfonyl)-5-oxopyrimido[4,5-b][1,5]diazocine (Compound of Reference Example 19; 85.9 mg), 4-(t-butoxycarbonylamino)piperidine (36.1 mg) and methanesulfonylchloride (0.04 mL) were reacted to obtain 6-[3,5-bis(trifluoromethyl)benzyl]-5,6,7,8,9,10-hexahydro-4-(2-methylphenyl)-2-[4-(methylsulfonylamino)piperidine-1-yl]-5-oxopyrimido[4,5-b][1,5]diazocine (45.2 mg, 45%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([Cl:11])[CH:3]=1.ClC(OC(=O)C(C)C)=O.CN1CCOCC1.[BH4-].[Na+]>O1CCCC1.O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[C:4]([Cl:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Br)cc1Cl
Agent: CC(C)C(=O)OC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: OCc1ccc(Br)cc1Cl
Temperature: -15 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
4-Bromo-2-chlorobenzoic acid (14, 92.0 g, 0.39 mol) was dissolved in dry tetrahydrofuran (920 mL) and cooled to −15° C. Isobutyryl choroformate (51.0 mL, 0.39 mol) was added followed by N-methylmorpholine (43.5 mL, 0.39 mol). The resulting mixture was stirred for 10 minutes at −15° C., cooled to −25° C. and the precipitated N-methylmorpholine hydrochloride salt was filtered off. The filtrate was warmed to −5° C. and a solution of sodium borohydride (22.19 g, 0.586 mol) in water (190 mL) was added dropwise to the mixture keeping the temperature below 0° C. After stirring for 1 h at 0° C., the volatiles were evaporated, and the residue was diluted with water (500 mL) and dichloromethane (450 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (150 mL). The combined organic layers were washed with water (150 mL), dried over sodium sulfate and evaporated. The product (86.1 g, 0.39 mol, 99%) was obtained as a white crystalline solid.