Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH2:11][CH:12]=C)[C:3]=1[OH:14].C[OH:16]>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([CH2:11][CH2:12][OH:16])[C:3]=1[OH:14]
Reactant: C=CCc1cc([N+](=O)[O-])cc(Br)c1O
Reactant: CO
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Br)c(O)c(CCO)c1

Procedure:
2-Bromo-6-prop-2-enyl-4-nitrophenol (5.8 g) was dissolved in dichloromethane (30 ml) and methanol (30 ml) and the resulting solution was cooled to -78° C. Ozone was bubbled through the solution until a faint blue coloration was observed and all starting material had reacted. The solution was purged with nitrogen, sodium borohydride (850 g) was added and the solution was allowed to come to room temperature. The solvent was evaporated and the residue was dispersed between ethyl acetate and HCl (1N). The ethyl acetate layer was washed with water, brine, dried (MgSO4) and concentrated. The residue was purified on silica using 2% methanol in dichloromethane as eluent to afford the title compound as a white solid (4 g). 1H NMR (360 MHz, CDCl3) δ 3.03 (2H, t, J=5.4 Hz), 4.06 (2H, t, J=5.5 Hz), 8.01 (1H, d, J=2.6 Hz), 8.35 (1H, d, J=2.6 Hz).
Reaction SMILES: [H-].[Na+].[C:3]1([CH3:17])[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[CH2:15][OH:16].[F:18][C:19]([F:33])([F:32])[C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:23]Br>CCCCCC.CN(C)C=O>[F:18][C:19]([F:32])([F:33])[C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([C:28]([F:31])([F:29])[F:30])[CH:27]=1)[CH2:23][O:16][CH2:15][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][C:9]=1[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH3:17]
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: Cc1ccccc1-c1ccncc1CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: Cc1ccccc1-c1ccncc1COCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (89.1 mg, 2.04 mmol, 1.1 eq) was washed twice with n-hexane under argon and suspended in 1 ml dimethyl formamide. (4-o-Tolyl-pyridin-3-yl)-methanol (370 mg, 1.86 mmol), dissolved in 4 ml dimethyl formamide, was added dropwise and the mixture was stirred 1 h at room temperature. 3,5-Bis(trifluoromethyl)benzyl bromide (627 mg, 2.04 mmol, 1 eq), dissolved in 2 ml dimethyl formamide, was added and the mixture was stirred 2.5 h at room temperature.
Reaction SMILES: Cl.Cl.Cl.[CH3:4][O:5][C:6]1[CH:7]=[C:8]([NH:18][C:19]2[S:20][C:21]3[CH2:22][NH:23][CH2:24][CH2:25][C:26]=3[N:27]=2)[CH:9]=[CH:10][C:11]=1[N:12]1[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]1.[CH3:28][O:29][CH2:30][C:31](O)=[O:32]>>[CH3:28][O:29][CH2:30][C:31]([N:23]1[CH2:24][CH2:25][C:26]2[N:27]=[C:19]([NH:18][C:8]3[CH:9]=[CH:10][C:11]([N:12]4[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]4)=[C:6]([O:5][CH3:4])[CH:7]=3)[S:20][C:21]=2[CH2:22]1)=[O:32]
Reactant: COc1cc(Nc2nc3c(s2)CNCC3)ccc1-n1cnc(C)c1
Reactant: COCC(=O)O
Agent: Cl
Product: COCC(=O)N1CCc2nc(Nc3ccc(-n4cnc(C)c4)c(OC)c3)sc2C1

Procedure:
The title compound was prepared in analogy to example 53 from 90 mg (0.2 mmol) [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-(4,5,6,7-tetrahydro-thiazolo[5,4-c]pyridin-2-yl)-amine trihydrochloride and 20 mg (0.22 mmol) methoxyacetic acid yielding 46 mg (56%) 2-methoxy-1-{2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl}-ethanone as a light yellow solid. MS ISP (m/e): 414.2 (100) (M+H)+. 1H NMR (DMSO-D6, 250 MHz): δ (ppm)=10.32 (s, 1H), 7.65 (s, 1H), 7.48 (s, 1H), 7.29 (d, 1H), 7.24 (d, 1H), 7.02 (s, 1H), 4.54 (br s, 2H), 4.20 & 4.14 (s, 2H), 3.78 (s, 3H), 3.78 & 3.68 (m, 2H), 3.32 (s, 3H), 2.73-2.60 (m, 2H), 2.14 (s, 3H).
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH:11]=O)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[N+:13]([C:16]1[CH:25]=[CH:24][C:19]2[O:20][CH2:21][CH2:22][NH:23][C:18]=2[CH:17]=1)([O-:15])=[O:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCCl>[CH3:1][N:2]([CH2:10][CH2:11][N:23]1[CH2:22][CH2:21][O:20][C:19]2[CH:24]=[CH:25][C:16]([N+:13]([O-:15])=[O:14])=[CH:17][C:18]1=2)[C:3](=[O:9])[O:4][C:5]([CH3:6])([CH3:7])[CH3:8]
Reactant: CN(CC=O)C(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc2c(c1)NCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CN(CCN1CCOc2ccc([N+](=O)[O-])cc21)C(=O)OC(C)(C)C
Reaction time: 18 h

Procedure:
To an oven dried, argon purged flask fitted with a magnetic stirbar was added tert-butyl methyl(2-oxoethyl)carbamate (0.135 g, 0.777 mmol), and DCE (10 mL). At this time, stirring began, and 6-nitro-3,4-dihydro-2H-benzo[b][1,4]oxazine (0.10 g, 0.555 mmol) was added, followed by acetic acid (0.064 mL, 1.110 mmol) and sodium triacetoxyborohydride (0.294 g, 1.388 mmol). The resulting mixture stirred overnight at room temperature. After 18 hours, the reaction was quenched by the addition of saturated NaHCO3 (10 mL) and extracted with CH2Cl2. The aqueous layer was extracted further, and the combined organics were washed with brine, dried (Na2SO4), and concentrated. The crude product was combined with the product of a second reaction (prepared in accordance with the above procedure, with the omission of acetic acid). The combined products were purified on silica gel eluting with 50-70% EtOAc/hexanes to yield the title compound as a yellow residue (130 mg, 34.7%). 1H NMR (DMSO-d6) δ 7.58-7.37 (m, 2H), 6.92-6.80 (m, 1H), 4.25 (t, 2H, J=4.2 Hz), 3.58-3.36 (m, 6H), 2.87-2.74 (m, 3H), 1.27, 1.18 (2×s, 9H); ESI-MS (m/z, %): 360 (MNa+, 100).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][C:11]=1[N+:19]([O-:21])=[O:20].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:14](=[O:15])[C:13]2[CH:17]=[CH:18][C:10]([Cl:9])=[C:11]([N+:19]([O-:21])=[O:20])[CH:12]=2)=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(Br)cc1)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 4-bromoaniline (2.58 g 14.99 mmol) in dry CH2Cl2 (100 mL) was treated with 4-chloro-3-nitrobenzoyl chloride (3.60 g, 17.99 mmol) and N,N-diisopropyl-ethylamine (3.14 mL, 17.99 mmol), and the resulting mixture stirred at room temperature for 17 hours. The solvent was concentrated under vacuum giving the title compound and the residue taken up in ethyl acetate (100 mL) and washed with water and brine. The organic extract was dried over Na2SO4, filtered and concentrated under vacuum giving the title compound as a tan solid (5.132 g, 14.45 mmol, 96%).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][NH:29][C:30]([CH2:32][N:33]([S:41]([CH3:44])(=[O:43])=[O:42])[C:34]1[CH:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=1)=[O:31]>>[CH3:28][NH:29][C:30]([CH2:32][N:33]([C:34]1[CH:35]=[CH:36][C:37]([NH:40]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:38][CH:39]=1)[S:41]([CH3:44])(=[O:43])=[O:42])=[O:31]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Reactant: CNC(=O)CN(c1ccc(N)cc1)S(C)(=O)=O
Product: CNC(=O)CN(c1ccc(N/C(=C2\C(=O)Nc3cc(C(=O)OC)ccc32)c2ccccc2)cc1)S(C)(=O)=O

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and N-methylaminocarbonylmethyl-N-methylsulphonyl-p-phenylenediamine Rf value: 0.5 (silica gel, methylene chloride/methanol=10:1) C27H26N4O6S
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:21]([C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH:30]2[O:42][CH2:43][C:44]2[CH:45]=[CH:46][C:47]3[O:52][CH2:51][C:50](=[O:53])[N:49]([CH2:54][CH2:55][CH2:56][O:57][CH3:58])[C:48]=3[CH:59]=2)=[CH:25][CH:24]=1)=[O:22].C(=O)([O-])O.[Na+]>ClCCl>[CH3:58][O:57][CH2:56][CH2:55][CH2:54][N:49]1[C:48]2[CH:59]=[C:44]([CH2:43][O:42][CH:30]3[CH:29]([C:26]4[CH:27]=[CH:28][C:23]([C:21]([N:10]5[CH2:11][CH2:12][CH:7]([C:1]6[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=6)[CH2:8][CH2:9]5)=[O:22])=[CH:24][CH:25]=4)[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31]3)[CH:45]=[CH:46][C:47]=2[O:52][CH2:51][C:50]1=[O:53]
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(C(=O)Cl)cc3)cc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(C(=O)N4CCC(c5ccccc5)CC4)cc3)cc21
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
A solution of 0.122 g of 4-phenylpiperidine in 2 ml of dichloromethane is admixed with 0.101 ml of triethylamine. The reaction solution is cooled to 0° and a solution of tert-butyl 4-(4-chlorocarbonylphenyl)-3-[4-(3-methoxypropyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate in 4 ml of dichloromethane is added dropwise. The reaction mixture is stirred at 0° C. over 40 minutes and subsequently poured onto 25 ml of saturated sodium hydrogencarbonate solution. The mixture is extracted with 80 ml of dichloromethane, the phases are separated and the organic phase is washed with 40 ml each of water and brine, dried over sodium sulphate, filtered and concentrated. The residue is purified by means of flash chromatography (SiO2 60F). The title compound is obtained as a colourless oil. Rf=0.20 (3:1 EtOAc-heptane); Rt=5.44.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7]([N:10]2[C:14]([C:15]3[C:16]([F:21])=[N:17][CH:18]=[CH:19][CH:20]=3)=[C:13]([F:22])[C:12]([CH2:23][N:24](C)[C:25](=O)OC(C)(C)C)=[CH:11]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.C(OCC)(=O)C.[ClH:39]>C(OCC)(=O)C.CC(O)C>[ClH:39].[Br:1][C:2]1[S:6][C:5]([S:7]([N:10]2[C:14]([C:15]3[C:16]([F:21])=[N:17][CH:18]=[CH:19][CH:20]=3)=[C:13]([F:22])[C:12]([CH2:23][NH:24][CH3:25])=[CH:11]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2ccc(Br)s2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CNCc1cn(S(=O)(=O)c2ccc(Br)s2)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 55 %

Procedure:
To a solution of tert-butyl {[1-[(5-bromo-2-thienyl)sulfonyl]-4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (248 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethyl acetate-ethanol to give the title compound as a white solid (yield 121 mg, 55%).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[CH2:13]([SH:16])[CH2:14][SH:15].B(F)(F)F.CCOCC>C(Cl)Cl>[S:15]1[C:2]2([CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]2)[S:16][CH2:13][CH2:14]1
Reactant: SCCS
Reactant: CCOC(=O)C1CCC(=O)CC1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)C1CCC2(CC1)SCCS2
Temperature: 27.5 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
To a stirred solution of ethyl 4-oxocyclohexane carboxylate (5 g, 29.41 mmol) and ethane-1,2-dithiol (4.14 g, 44.11 mmol) in DCM (25 mL) was added BF3.Et2O (4.17 g, 29.41 mmol) at 0° C. and the reaction mixture was allowed to stir at 20-35° C. for 2 h. Then the reaction mixture was rotary evaporated under vacuum to get residue which was purified by column chromatography using mixture of 5% ethyl acetate/hexane as an eluent to get the desired compound as a yellow liquid (5.4 g, 75%); 1H NMR (400 MHz, DMSO-d6) δ 4.05 (q, J=7.4 Hz, 2H), 3.34-3.26 (m, 4H), 2.42-2.34 (m, 1H), 2.10-2.02 (m, 2H), 1.96-1.84 (m, 4H), 1.66-1.54 (m, 2H), 1.17 (t, J=7.3 Hz, 3H).
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10](=[O:15])/[C:11](/[CH3:14])=[CH:12]/[CH3:13])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1(C)C=CC=CC=1.[CH3:33][Si:34]([CH3:41])([CH3:40])[CH2:35][CH2:36][O:37][CH2:38]Cl>>[CH:1]([C@@H:4]1[CH2:8][O:7][C:6](=[O:9])[N:5]1[C:10](=[O:15])[C@@:11]([CH3:14])([CH2:38][O:37][CH2:36][CH2:35][Si:34]([CH3:41])([CH3:40])[CH3:33])[CH:12]=[CH2:13])([CH3:3])[CH3:2]
Reactant: C/C=C(\C)C(=O)N1C(=O)OC[C@H]1C(C)C
Reactant: C[Si](C)(C)CCOCCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=C[C@](C)(COCC[Si](C)(C)C)C(=O)N1C(=O)OC[C@H]1C(C)C
Temperature: -78 °C
Reaction time: 0.58 h
Yield: 73.2 %

Procedure:
Residual moisture in (R)-4-isopropyl-3-((E)-2-methyl-but-2-enoyl)-oxazolidin-2-one (458.9 mg, 2.172 mmol) was removed by azeotroping with anhydrous toluene. A cooled (−78° C.) solution of dried (R)-4-isopropyl-3-((E)-2-methyl-but-2-enoyl)-oxazolidin-2-one in anhydrous toluene (10 mL) was treated dropwise with a solution of sodium bis(trimethylsily)amide in toluene (0.6 M, 5.4 mL, 3.258 mmol). After stirring the yellow solution at −78° C. for 35 min, 2-(trimethylsilyl)ethoxymethyl chloride (1.1 mL, 6.516 mmol) was added. After stirring at 0° C. for 3.5 h, the reaction was quenched with saturated ammonium chloride. The aqueous layer was extracted with dichloromethane (2×). The organics were combined, filtered through a phase separator and the volatiles were removed in vacuo. The residue was purified by silica gel chromatography using a 50 g Isolute cartridge eluted with a continuous gradient of iso-hexanes/ethyl acetate 1:0 to 9:1 to afford the title compound (543.3 mg, 73%) as a colourless oil and as a 5:1 mixture of diastereoisomers. 1H NMR (300 MHz, CDCl3) δ 0.01 (s, 9H), 0.77-0.99 (m, 8H), 1.49 (s, 3H), 2.36 (d of heptet, J=6.9, 3.8 Hz, 1H), 3.42-3.60 (m, 3H), 4.15-4.31 (m, 3H), 4.49-4.57 (m, 1H), 5.00 (d, J=17.6 Hz, 1H), 5.10 (d, J=10.7, 1H), 6.19 (dd, J=17.8, 10.7 Hz, 1H). LCMS (m/z) 364.1 [M+Na], Tr=3.32 min.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH3:17])[C:11](=[O:12])[NH:10][C@@H:9]2[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]2[O:7]1)=[O:5])[CH3:2].[H-].[Na+].[CH3:20]I>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1([CH3:17])[C:11](=[O:12])[N:10]([CH3:20])[C@@H:9]2[CH2:13][CH2:14][CH2:15][CH2:16][C@H:8]2[O:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(C)O[C@@H]2CCCC[C@H]2NC1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1(C)O[C@@H]2CCCC[C@H]2N(C)C1=O
Yield: 62.5 %

Procedure:
To a solution of trans-ethyl-2-methyl-3-oxo-octahydro-2H-1,4-benzoxazine-2-carboxylate (483 mg, 2 mmoles) in anhydrous toluene (10 ml), NaH (96 mg, 4 mmoles) and methyl iodide (710 mg, 5 mmoles) were added and the mixture was heated for 30 minutes at reflux temperature. After the completion of the reaction, the toluene solution was washed with 1N HCl (10 ml), 1N NaOH (10 ml) and a saturated NaCl solution (10 ml). The solution was dried over MgSO4 and the solvent was evaporated. Thus there were obtained 319 mg (62%) of a yellow product, which was purified by column chromatography (silica gel; chloroform/methanol=9:1). Thus there were obtained 246 mg (48%) of the title compound in the form of a viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.O.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>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:18]2[CH:19]=[CH:20][C:15]([C:14]([NH:13][CH2:12][CH2:11][C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=4)[NH:7][CH:6]=3)=[O:22])=[CH:16][CH:17]=2)=[CH:26][CH:25]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(I)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: O
Solvent: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(-c2ccc(Cl)cc2)cc1
Yield: 40.3 %

Procedure:
4′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-iodobenzamide (0.075 g; 0.176 mmol), 4-chlorophenylboronic acid (0.029 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.029 g (40%) of 4′-chloro-N-(2-(5-chloro-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide as a white solid.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][C:18]=2[Cl:19])[C:15](=[O:20])[NH:14][CH:13]=[CH:12]3)[CH2:4][CH2:3]1.[CH2:21]([O:23][C:24](=[O:27])[CH:25]=O)[CH3:22].C([BH3-])#N.[Na+]>CO>[CH2:21]([O:23][C:24](=[O:27])[CH2:25][NH:1][C@H:2]1[CH2:3][CH2:4][C@@H:5]([O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][C:18]=2[Cl:19])[C:15](=[O:20])[NH:14][CH:13]=[CH:12]3)[CH2:6][CH2:7]1)[CH3:22]
Reactant: N[C@H]1CC[C@@H](Oc2cc3cc[nH]c(=O)c3cc2Cl)CC1
Reactant: CCOC(=O)C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)CN[C@H]1CC[C@@H](Oc2cc3cc[nH]c(=O)c3cc2Cl)CC1
Temperature: 60 °C

Procedure:
300 mg (0.91 mmol) of 6-cis-(4-amino-cyclohexyloxy)-7-chloro-2H-isoquinolin-1-one (12) were dissolved in 20 ml of methanol and treated with 258 mg (1.14 mmol) glyoxylic acid ethyl ester following the general method for reductive amination reactions. To achieve complete conversion, additional 5.0 equivalents of glyoxylic acid ethyl ester and 0.5 equivalents sodium cyano borohydride were added portionwise over 34 h and the temperature was increased to 60° C. after 5 h reaction time until the reaction went to completion. After filtration, the reaction solution was evaporated. The residue was dissolved in dichloromethane, washed with 1 N NaOH and saturated NaCl-solution, dried over MgSO4 and evaporated. The so obtained crude product was used in the next reaction without further purification. Rt=0.81 min (Method C). Detected mass: 365.4 (M+H+, methyl ester, because methanol was used as solvent), 0.87 min. (Method C). Detected mass: 379.4 (M+H+, ethyl ester, title compound).
Reaction SMILES: C(OP([CH2:9][C:10]#[N:11])(=O)OCC)C.[H-].[Na+].[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=O)[CH3:23])=[CH:18][CH:17]=1>COCCOC.C(OCC)C>[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([CH3:23])=[CH:9][C:10]#[N:11])=[CH:18][CH:17]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: COc1ccc(C(C)=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: COCCOC
Product: COc1ccc(C(C)=CC#N)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Diethylcyanomethylphosphonate (85 g) is added dropwise to a stirred suspension of sodium hydride (19.2 g) in 1,2-dimethoxyethane (400 ml) under nitrogen. The solution is cooled in an ice bath and a solution of paramethoxyacetophenone (48 g) in 1,2-dimethoxyethane (80 ml) is added dropwise. The reaction mixture is stirred at RT for three hours and diluted with diethyl ether, washed, dried, filtered and evaporated in vacuo affording the desired product as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[S:13])[NH:11][N:10]=[N:9]2)=[C:4]([F:14])[CH:3]=1.Br[CH2:16][CH3:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.C(OCC)C>[CH2:16]([S:13][C:12]1[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[F:14])[N:9]=[N:10][N:11]=1)[CH3:17]
Reactant: Fc1cc(Cl)ccc1-n1nn[nH]c1=S
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: CCSc1nnnn1-c1ccc(Cl)cc1F
Yield: 81.4 %

Procedure:
A solution of 1.75 g (0.0076 mole) of 1-(4-chloro-2-fluorophenyl)-1,4-dihydro-5H-tetrazol-5-thione, 0.57 ml (0.0076 mole) of bromoethane, and 1.6 g (0.012 mole) of potassium carbonate in 8 ml of acetone was stirred at room temperature for seven hours. The solvent was evaporated from the reaction mixture under reduced pressure leaving a residue. This residue was dissolved in diethyl ether and the organic solution was washed with water. The washed organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to yield 1.6 g of (1-(4-chloro-2-fluorophenyl)-1H-tetrazol-5-yl) ethyl sulfide as a solid, m.p. 76°-79° C.
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][O:5][C:6](=[O:24])[C:7]1[C:12]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[F:21])=[C:11]([F:22])[C:10](Cl)=[N:9][CH:8]=1.CO>C1COCC1>[CH3:4][O:5][C:6](=[O:24])[C:7]1[C:12]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[F:21])=[C:11]([F:22])[C:10]([O:2][CH3:1])=[N:9][CH:8]=1
Reactant: C[O-]
Reactant: COC(=O)c1cnc(Cl)c(F)c1Nc1ccc(Br)cc1F
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cnc(OC)c(F)c1Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Sodium methoxide (2.20 g, 40.8 mmol) was slowly added to a stirred solution of 4-(4-bromo-2-fluorophenylamino)-6-chloro-5-fluoro-nicotinic acid methyl ester in 4:1 MeOH:THF (20 mL) at 0° C. The reaction mixture was warmed to room temperature, stirred for 17 hours and then warmed to 40° C. and stirred for 5 hours. After cooling to room temperature, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic extracts were dried (MgSO4) and concentrated under reduced pressure. The desired product, contaminated with some starting material, was carried forward without purification.
Reaction SMILES: O[CH2:2][C:3]1[CH:12]=[N:11][C:10]2[N:9]3[CH2:13][CH2:14][O:15][CH2:16][CH:8]3[C:7](=[O:17])[NH:6][C:5]=2[CH:4]=1.[I-].C(C[P+](C)(C)C)#N.C(N(C(C)C)C(C)C)C.[N:35]1([C:41]2[CH:48]=[CH:47][C:44]([C:45]#[N:46])=[CH:43][N:42]=2)[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>C(#N)CC>[O:17]=[C:7]1[NH:6][C:5]2[CH:4]=[C:3]([CH2:2][N:38]3[CH2:39][CH2:40][N:35]([C:41]4[CH:48]=[CH:47][C:44]([C:45]#[N:46])=[CH:43][N:42]=4)[CH2:36][CH2:37]3)[CH:12]=[N:11][C:10]=2[N:9]2[CH2:13][CH2:14][O:15][CH2:16][CH:8]12
Reactant: N#Cc1ccc(N2CCNCC2)nc1
Reactant: O=C1Nc2cc(CO)cnc2N2CCOCC12
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCC#N
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)C3COCCN43)CC2)nc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
3-(hydroxymethyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[4,3-a]pyrido[3,2-e]pyrazin-6(5H)-one (70.0 mg, 0.298 mmol) was suspended in propionitrile (0.74 mL) and (cyanomethyl)trimethylphosphonium iodide (87.0 mg, 0.357 mmol) was added followed by N-ethyl-N-isopropylpropan-2-amine (115 ul, 0.893 mmol). To the stirred mixture was then added 6-(piperazin-1-yl)nicotinonitrile (56.0 mg, 0.298 mmol). The reaction was heated to 90° C. with stirring for 16 h. The reaction was cooled to room temperature and left to sit 48 h. The precipitate was filtered off, washed with methanol (5 mL) and dried in vacuum to afford the title compound (72.5 mg, 60.1%) as a white solid. 1H NMR (CHLOROFORM-d) δ: 8.41 (d, J=1.8 Hz, 1H), 8.20 (br. s., 1H), 7.80 (d, J=2.0 Hz, 1H), 7.61 (dd, J=9.0, 2.4 Hz, 1H), 6.99 (br. s., 1H), 6.59 (d, J=9.1 Hz, 1H), 4.42 (dd, J=11.5, 3.7 Hz, 1H), 4.26 (dd, J=13.3, 1.6 Hz, 1H), 3.95-4.12 (m, 2H), 3.58-3.80 (m, 6H), 3.45 (s, 2H), 2.92-3.08 (m, 1H), 2.53 (br. s., 4H). [M+H] calc'd for C21H23N7O2, 406. found, 406.