Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([CH:7]=[C:8]([C:18]#[N:19])[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:3][CH:2]=1.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O)C>CN(C)C=O>[C:1]1([CH:20]=[CH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:2]=[CH:3][C:4]([CH:7]=[C:8]([C:18]#[N:19])[S:9]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])=[CH:5][CH:6]=1
Reactant: O=Cc1ccccc1
Reactant: Cc1ccc(C=C(C#N)S(=O)(=O)c2ccccc2)cc1
Solvent: CCO
Solvent: CN(C)C=O
Product: N#CC(=Cc1ccc(C=Cc2ccccc2)cc1)S(=O)(=O)c1ccccc1
Yield: 63 %

Procedure:
12.48 g (20 mmole) of the triphenylphosphonium bromide of Example 1 c) were dissolved in 200 ml of absolute dimethylformamide at 70° C, by stirring and under an atmosphere of nitrogen. After the mixture had cooled to 30° to 35° C, 2.24 g (20 mmole) of potassium-tert. butylate were introduced and the whole was stirred again for 5 minutes. The solution of 2.12 g (20 mmole) of benzaldehyde in 20 ml of absolute dimethylformamide was added dropwise within 10 minutes to the violet solution and the whole was further heated for 4 hours to 100° C under an atmosphere of nitrogen. After cooling, the potassium bromide separated was filtered off with suction and the dimethylformamide was eliminated by destillation on a rotary vaporator and under a vacuum produced by a water jet. The residue was combined with 200 ml of hot ethanol. After cooling, 4.65 g of weakly yellow crystals of 1-(stilbene-4-yl)-2-cyano-2-phenylsulfonylethylene having a melting point of 179° to 183° C (corresponding to a yield of 63% of the theory), were obtained. ##STR17##
Reaction SMILES: CO[C:3]([C@H:5]1[NH:18][C:17](=[S:19])[CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:11](=[O:20])[C:10]2[C:21]([CH3:28])=[C:22]([O:26][CH3:27])[CH:23]=[C:24]([OH:25])[C:9]=2[CH2:8][S:7][CH2:6]1)=[O:4].[NH2:29][CH2:30][CH2:31][CH2:32][OH:33]>CO.C(OCC)(=O)C>[OH:33][CH2:32][CH2:31][CH2:30][NH:29][C:3]([C@H:5]1[NH:18][C:17](=[S:19])[CH2:16][CH2:15][CH2:14][CH2:13][O:12][C:11](=[O:20])[C:10]2[C:21]([CH3:28])=[C:22]([O:26][CH3:27])[CH:23]=[C:24]([OH:25])[C:9]=2[CH2:8][S:7][CH2:6]1)=[O:4]
Reactant: NCCCO
Reactant: COC(=O)[C@@H]1CSCc2c(O)cc(OC)c(C)c2C(=O)OCCCCC(=S)N1
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(O)c2c(c1C)C(=O)OCCCCC(=S)N[C@H](C(=O)NCCCO)CSC2
Temperature: 50 °C

Procedure:
A solution of 43 mg of the product of Example 23 in a mixture of 0.5 ml of methanol and 0.5 ml of 3-amino-propanol was heated to 50° C. 20 min. The mixture was diluted with ethyl acetate and washed with 1N hydrochloric acid and water. The organic layer was dried over sodium sulfate and evaporated in vacuo and the solid residue was recrystallized from ethyl acetate/hexane to afford 12 mg (R)-16-hydroxy-14-methoxy-13-methyl-12-oxo-6-thioxo-1,3,4,5,6,7,8,9,10,12-decahydro-11,2,5-benzoxathiaazacyclotetradecine-4-carboxylic acid 3-hydroxy-propylamide as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH2:10][N:9]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:7]3[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:6]=3[N:5]2[CH:23]=1.[Cl-].CC(=[NH2+])C.[CH3:29][N:30]([CH3:33])[CH:31]=O>>[CH3:29][N:30]([CH2:33][C:23]1[N:5]2[C:6]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:7]=3[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])=[N:9][CH2:10][C:4]2=[N:3][C:2]=1[CH3:1])[CH3:31]
Reactant: CN(C)C=O
Reactant: Cc1cn2c(n1)CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2
Agent: CC(C)=[NH2+]
Agent: [Cl-]
Product: Cc1nc2n(c1CN(C)C)-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 1, 6.844 (20 mmol) of 2-methyl-8-chloro-6-(o-chlorophenyl)-4H-imidazo[1,2-a]-[1,4]benzodiazepine is treated with 40.0 mmol of dimethylmethylene ammonium chloride in dimethylformamide during 2 hours at 100° C. The reaction mixture is quenched on ice, neutralized with 10% aqueous sodium hydroxide and chromatographed over silica gel with 1 l. fractions of 3% methanol/97% chloroform solutions to give 1-(dimethylamino)methyl-2-methyl-8-chloro-6-(o-chlorophenyl)-4H-imidazo[1,2-a][1,4]benzodiazepine of melting point 191°-194° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[C:13]([C:18](O)=[O:19])=[C:12]([Cl:21])[N:11]3[CH:22]=2)[CH:5]=[CH:6][CH:7]=1.BrC1C=C(C2N=C3C=C(C)C(C(=O)[C:40]([O:42][CH3:43])=[O:41])=C(Cl)N3C=2)C=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]3[C:15]([CH3:16])=[C:14]([CH3:17])[C:13]([C:18](=[O:19])[C:40]([O:42][CH3:43])=[O:41])=[C:12]([Cl:21])[N:11]3[CH:22]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(=O)c1c(C)cc2nc(-c3cccc(Br)c3)cn2c1Cl
Reactant: Cc1c(C(=O)O)c(Cl)n2cc(-c3cccc(Br)c3)nc2c1C
Product: COC(=O)C(=O)c1c(C)c(C)c2nc(-c3cccc(Br)c3)cn2c1Cl

Procedure:
Prepared from 2-(3-bromophenyl)-5-chloro-7,8-dimethylimidazo[1,2-a]pyridine-6-carboxylic acid following the same procedure as methyl 2-(2-(3-bromophenyl)-5-chloro-7-methylimidazo[1,2-a]pyridin-6-yl)-2-oxoacetate. LCMS (ESI, M+1): 420.85.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][OH:15])[O:11][C:10]2=[O:16])[CH:5]=[CH:6][C:7]=1[I:8].C(N(CC)C(C)C)(C)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][C@H:12]([CH2:14][O:15][S:27]([CH3:26])(=[O:29])=[O:28])[O:11][C:10]2=[O:16])[CH:5]=[CH:6][C:7]=1[I:8]
Reactant: O=C1O[C@@H](CO)CN1c1ccc(I)c(F)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 87.3 %

Procedure:
A solution of (5R)-3-(3-fluoro-4-iodophenyl)-5-hydroxymethyl-oxazolidin-2-one (1019, 269.6 g, 0.8 mol) in methylene chloride (CH2Cl2, 1200 mL) was treated with N,N-diisopropylethylamine (Hunig's base, DIEA, 206.8 g, 279 mL, 1.6 mol, 2.0 equiv) at 25° C., and the resulting mixture was cooled down to 0-5° C. before methanesulfonyl chloride (MsCl, 109.97 g, 74.3 mL, 0.96 mol, 1.2 equiv) was dropwise introduced into the reaction mixture at 0-5° C. under N2. The resulting reaction mixture was subsequently stirred at 0-5° C. for 1 h and then gradually warmed up to room temperature for 4 h under N2. When TLC and HPLC/MS showed that the reaction was complete, the reaction mixture was quenched with H2O (500 mL). The resulting mixture was then stirred at room temperature for 30 min. before being concentrated in vacuo to remove methylene chloride. When almost all of methylene chloride was removed in vacuo, the residue was then treated with H2O (1000 mL). The resulting slurry was stirred at room temperature for an additional 1 h. The solids were then collected by filtration, washed with H2O (2×500 mL), and dried in vacuo at 40° C. for 24 h to afford the crude, desired (5R)-methanesulfonic acid 3-(3-fluoro-4-iodophenyl)-2-oxo-oxazolidin-5-ylmethyl ester (1020, 290.0 g, 332.0 g theoretical, 87.3%) as off-white powders, which was found to be essentially pure and was directly used in the subsequent reactions without further purifications. For 1020: 1H NMR (300 MHz, DMSO-d6) δ 3.26 (s, 3H, OSO2CH3), 3.83 (dd, 1H, J=6.4, 9.2 Hz), 4.19 (t, 1H, J=5.4 Hz), 4.44-4.54 (m, 2H), 5.01-5.06 (m, 1H), 7.22 (dd, 1H, J=2.4, 8.7 Hz), 7.56 (dd, 1H, J=2.4, 8.7 Hz), 7.84 (dd, 1H, J=7.5, 8.7 Hz); C11H11FINO5S, LCMS (EI) m/e 416 (M++H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([OH:6])=O.O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[Cl:26][C:27]1[CH:28]=[C:29]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:52][CH3:53])=[CH:42][C:43]=3[O:45][CH2:46][C@H:47]3[CH2:51][CH2:50][CH2:49][NH:48]3)[N:38]=[CH:37][N:36]=2)[CH:30]=[CH:31][C:32]=1[F:33]>C(Cl)Cl>[Cl:26][C:27]1[CH:28]=[C:29]([NH:34][C:35]2[C:44]3[C:39](=[CH:40][C:41]([O:52][CH3:53])=[CH:42][C:43]=3[O:45][CH2:46][C@H:47]3[CH2:51][CH2:50][CH2:49][N:48]3[C:4](=[O:6])[CH2:3][O:2][CH3:1])[N:38]=[CH:37][N:36]=2)[CH:30]=[CH:31][C:32]=1[F:33]
Reactant: COCC(=O)O
Reactant: COc1cc(OC[C@H]2CCCN2)c2c(Nc3ccc(F)c(Cl)c3)ncnc2c1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: COCC(=O)N1CCC[C@@H]1COc1cc(OC)cc2ncnc(Nc3ccc(F)c(Cl)c3)c12
Reaction time: 1 h
Yield: 82.3 %

Procedure:
Methoxyacetic acid (27 mg) and 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (103 mg) were added sequentially, each in one portion, to a stirred mixture of N-(3-chloro-4-fluorophenyl)-7-methoxy-5-[(2R)-pyrrolidin-2-ylmethoxy]-quinazolin-4-amine (100 mg) in DCM (2 ml) at room temperature. The reaction mixture was stirred for 1 hour and then diluted with DCM (10 ml) and washed with saturated aqueous sodium hydrogen carbonate. The organic layer was dried (MgSO4) and concentrated in vacuo to leave a yellow solid, which was triturated with 1:1 ether/hexanes and filtered to give the title compound as a white solid (97 mg, 82%); NMR Spectrum (DMSO-d6) 9.90 (br s, 1H), 8.40 (s, 1H), 8.15 (m, 1H), 7.65 (m, 1H), 7.40 (m, 1H), 6.80 (m, 2H), 4.60 (m, 1H), 4.50 (m, 1H), 4.25 (m, 1H), 4.0 (m, 3H), 3.95 (s, 3H), 3.50 (m, 21), 3.20 (m, 2H), 2.0-1.85 (m, 4H); Mass spectrum MH+ 475.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[C:12]3[N:16]([C:17]=2[CH:18]=O)[C:15]2[CH2:20][CH2:21][CH2:22][CH2:23][C:14]=2[S:13]3)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:24]([NH:32][NH2:33])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[N:27][CH:26]=1.[OH-].[K+].O>CO>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]2[N:11]=[C:12]3[N:16]([C:17]=2[CH:18]=[N:33][NH:32][C:24]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)=[O:31])[C:15]2[CH2:20][CH2:21][CH2:22][CH2:23][C:14]=2[S:13]3)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NNC(=O)c1cccnc1
Reactant: O=Cc1c(-c2cccc([N+](=O)[O-])c2)nc2sc3c(n12)CCCC3
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(NN=Cc1c(-c2cccc([N+](=O)[O-])c2)nc2sc3c(n12)CCCC3)c1cccnc1

Procedure:
Next, 0.33 g of 5,6,7,8-tetrahydro-2-(3-nitrophenyl)-3-formylimidazo[2,1-b]benzothiazol, 0.15 g of nicotinohydrazide, and 0.1 g of potassium hydroxide were heated and stirred in 20 ml of methanol at 90° C. for 1.5 hours. After cooling, water was added and the desired substance was obtained in an amount of 0.21 g (yield of 46.7%).
Reaction SMILES: [CH3:1][N:2]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[C:3]([C:5]1[C:10]([N:11]([S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:28])([F:27])[F:26])[CH:19]=2)(=[O:17])=[O:16])COC)=[CH:9][C:8]([Cl:29])=[CH:7][N:6]=1)=[O:4].Cl>O.O1CCOCC1>[CH3:1][N:2]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[C:3]([C:5]1[C:10]([NH:11][S:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([C:25]([F:28])([F:26])[F:27])[CH:19]=2)(=[O:17])=[O:16])=[CH:9][C:8]([Cl:29])=[CH:7][N:6]=1)=[O:4]
Reactant: COCN(c1cc(Cl)cnc1C(=O)N(C)c1ccc(F)cc1)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CN(C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1ccc(F)cc1

Procedure:
5-Chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carboxylic acid N-methyl-N-(4-fluorophenyl)amide (141 mg, 0.258 mmol) was magnetically stirred in water (1.0 mL) and 4N HCl in dioxane (2.5 mL) and heated at 85° C. (oil bath) for 7 h. LCMS indicated complete reaction; the reaction was concentrated and the residue was neutralized (pH 7) with aqueous sodium bicarbonate and extracted with EtOAc (3×80 mL). The extracts were dried (MgSO4), filtered, and chromatographed on silica gel using ethyl acetate-hexane gradient (0:100 to 50:50) to provide 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid N-methyl-N-(4-fluorophenyl)amide. MS m/z 522.1 (M+H).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:18]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19]>C1COCC1>[C:21]([O:20][C:18]([N:25]1[CH2:30][CH2:29][N:28]([S:7]([C:5]2[S:6][C:2]([Br:1])=[CH:3][CH:4]=2)(=[O:9])=[O:8])[CH2:27][CH2:26]1)=[O:19])([CH3:24])([CH3:22])[CH3:23]
Reactant: O=S(=O)(Cl)c1ccc(Br)s1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(Br)s2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.9 %

Procedure:
To a stirred solution of commercially available 5-bromo-thiophene-2-sulfonyl chloride (1.0 g, 3.82 mmol) in THF (8 ml) was added at room temperature triethylamine (0.59 ml, 4.21 mmol), the mixture was cooled (ice-water) and a solution of commercially available 1-BOC-piperazine (2.14 g, 11.5 mmol) in THF (8 ml) was added drop wise. The reaction mixture was stirred at room temperature for 16 h and evaporated. The crude product was further purified by flash chromatography (ethyl acetate/heptane) and subsequent crystallization from dichloromethane/hexane to yield the title compound (1.35 g, 86%) as a white solid. MS (ISP) 413.2 [(M+H)+], mp 127° C.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31]([N:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[O:32])[CH2:25]4)[N:18]=[N:19][C:20]=3[C:21]([NH2:23])=[O:22])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH:39](O)=[O:40].CCN(C(C)C)C(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:39]([N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31]([N:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[O:32])[CH2:25]4)[N:18]=[N:19][C:20]=3[C:21]([NH2:23])=[O:22])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1)=[O:40]
Reactant: NC(=O)c1nnc(N2CCC[C@@H](NC(=O)N3CCCCC3)C2)nc1Nc1ccc(C2CCNCC2)cc1
Reactant: O=CO
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)c1nnc(N2CCC[C@@H](NC(=O)N3CCCCC3)C2)nc1Nc1ccc(C2CCN(C=O)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-5-(4-(Piperidin-4-yl)phenylamino)-3-(3-(piperidine-1-carboxamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide hydrochloride (494) (60 mg, 0.11 mmol) was dissolved in 3 mL DMF. To it were added formic acid (25 mg, 0.55 mmol), DIEA (200 μL, 1.10 mmol) and then PyBOP (115 mg, 0.22 mmol). The mixture was stirred at RT for 1 hour, quenched with 0.3 mL TFA, and directly subjected to reverse phase prep HPLC to isolate the title compound, (R)-5-(4-(1-formylpiperidin-4-yl)phenylamino)-3-(3-(piperidine-1-carboxamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide (496), as HCl salt (37 mg). LC-MS (ESI): m/z (M+1) 536.2. UV: λ=261, 329, 337 nm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]2[N:9]=[CH:8][NH:7][C:6]=2[CH:10]=1.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.CS(O)(=O)=O>O1CCCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]2[N:9]=[CH:8][N:7]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][O:12]3)[C:6]=2[CH:10]=1
Reactant: C1=COCCC1
Reactant: Cc1cc(Br)cc2[nH]cnc12
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(Br)cc2c1ncn2C1CCCCO1
Temperature: 75 °C
Yield: 92.5 %

Procedure:
6-Bromo-4-methyl-1H-benzo[d]imidazole (1.02 g, 4.83 mmol) was dissolved in tetrahydrofuran (10 mL) at room temperature with stirring under nitrogen. 3,4-Dihydro-2H-pyran (3.5 mL, 38.4 mmol) and methanesulfonic acid (0.032 mL, 0.48 mmol) were added and the resulting mixture heated at 75° C. for 49 h. The resulting mixture was cooled to room temperature, diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine. The organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure. Flash chromatography (50-100% ethyl acetate in hexanes) gave the desired product (1.32 g, 4.47 mmol, 93% yield) as a light yellow solid. MS (ESI) m/z 295.1 [M]+, 297.3 [M+2]+.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:4]=1[CH2:5][Zn+].[CH2:12]([N:19]1[CH2:24][CH:23]([C:25]2[CH:30]=[CH:29][C:28](Br)=[CH:27][CH:26]=2)[O:22][CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1COCC1.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>[CH2:12]([N:19]1[CH2:20][CH2:21][O:22][CH:23]([C:25]2[CH:30]=[CH:29][C:28]([CH2:5][C:4]3[C:3]([Cl:2])=[CH:10][CH:9]=[CH:8][C:7]=3[Cl:11])=[CH:27][CH:26]=2)[CH2:24]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Brc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Reactant: Clc1cccc(Cl)c1C[Zn+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Product: Clc1cccc(Cl)c1Cc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
To a mixture of 2,6-dichlorobenzylzinc chloride (7.95 mL; 0.50 mol/l in THF; 3.97 mmol) and tetrakis(triphenylphosphine)palladium(0) (83.48 mg; 0.07 mmol) in THF (25 mL) was added 4-benzyl-6-(4-bromo-phenyl)-morpholine (1.20 g; 3.61 mmol). The resulting mixture was stirred at RT for 2 hours, and subsequently heated under reflux, for 2 h. After cooling to RT the mixture was concentrated in vacuo. The residue was partitioned between 5% aqueous NaHCO3 and EtOAc. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O:hexanes 1:1) to afford 4-benzyl-2-[4-(2,6-dichloro-benzyl)-phenyl]-morpholine (1.40 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[Br:12])[NH:8][C:7](=[O:13])[C:6](=[O:14])[NH:5]2.[N+:15]([O-])([O-:17])=[O:16].[K+]>OS(O)(=O)=O>[N+:15]([C:10]1[C:11]([Br:12])=[C:2]([Br:1])[CH:3]=[C:4]2[C:9]=1[NH:8][C:7](=[O:13])[C:6](=[O:14])[NH:5]2)([O-:17])=[O:16]
Reactant: O=c1[nH]c2cc(Br)c(Br)cc2[nH]c1=O
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=c1[nH]c2cc(Br)c(Br)c([N+](=O)[O-])c2[nH]c1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 75.8 %

Procedure:
The procedure of Cheeseman, G. W. H., J. Chem Soc. 1170 (1962) was adapted. To a stirred suspension of 6,7-dibromo-1,4-dihydro-2,3-quinoxalinedione (576 mg, 1.8 mMol) in concentrated H2SO4 (6 mL) at 0° C. for 30 min. was added KNO3 (220 mg, 2.18 mMol, Baker) in one portion. The mixture was stirred at 0° C. for 3 h then at room temperature for one day. The color of mixture was changed from red to yellow brown. Then it was poured into ice (60 g) resulting in the separation of a bright yellow precipitate, which was collected by filtration and washed with distilled water (2×2 mL) followed by ethanol (2×1 mL) to get 498 mg of crude 5-nitro-6,7-dibromo-1,4-dihydro-2,3-quinoxalinedione (76%, contains minor impurities by NMR). Crystallization from DMSO/H2O gave pure 5-nitro-6,7-dibromo-1,4-dihydro-2,3-quinoxalinedione as bright yellow microcrystals; mp: 352°-354° C. (dec.). IR (KBr, cm-1): 3387; 3256; 1756; 1700; 1537. NMR (1H, DMSO-d6): δ 7.475 (s, 1H); 12.217 (s, 1H); 12.265 (s, 1H). HRMS: calcd for C8H3N3O4Br2 (M+) m/z: 362.8489; found: 362.8509.
Reaction SMILES: [Cl:1][C:2]1[S:9][C:8]2[CH:7]=[C:6]([C:10]([NH:12][C@@H:13]3[CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C@H:14]3[N:22]([C:24](=[O:27])[CH2:25]Cl)[CH3:23])=[O:11])[NH:5][C:4]=2[C:3]=1[Cl:28].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>C(Cl)Cl>[Cl:1][C:2]1[S:9][C:8]2[CH:7]=[C:6]([C:10]([NH:12][C@H:13]3[CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C@@H:14]3[N:22]([CH3:23])[C:24](=[O:27])[CH2:25][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[O:11])[NH:5][C:4]=2[C:3]=1[Cl:28]
Reactant: C1COCCN1
Reactant: CN(C(=O)CCl)[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Solvent: ClCCl
Product: CN(C(=O)CN1CCOCC1)[C@H]1c2ccccc2C[C@@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Temperature: 25 °C
Reaction time: 20 h
Yield: 0.9 %

Procedure:
2,3-Dichloro-N-{(1R,2R)-1-[(chloroacetyl)(methyl)amino]-2,3-dihydro-1H-inden-2-yl}4H-thieno[3,2-b]pyrrole-5-carboxamide (Method 10, 100 mg, 0.22 mol) and morpholine (100 mg, 12.6 mmol) were dissolved in DCM, stirred at ambient temperature for 20 hours and the volatiles removed by evaporation under reduced pressure. EtOAc (10 mL) was added and the mixture washed with water (2×5 mL), brine (5 mL), dried (MgSO4) and the volatiles removed by evaporation under reduced pressure to give the title compound (60 mg, 54%) as a buff coloured powder.
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=2)=[N:6][N:7]([CH:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17]C(C)(C)C)=[O:16])[CH2:11][CH:10]2[C:22]#[N:23])[CH:8]=1)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:4]1[C:5]([NH:24][C:25]2[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=2)=[N:6][N:7]([CH:9]2[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=[O:16])[CH2:11][CH:10]2[C:22]#[N:23])[CH:8]=1)(=[O:3])[NH2:2]
Reactant: CC(C)(C)OC(=O)C1CCC(n2cc(C(N)=O)c(Nc3ccc(Cl)cc3)n2)C(C#N)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#CC1CC(C(=O)O)CCC1n1cc(C(N)=O)c(Nc2ccc(Cl)cc2)n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (1S,3S,4S and 1R,3R,4R)-t-butyl 4-[4-carbamoyl-3-[(4-chlorophenyl)amino]-1H-pyrazol-1-yl]-3-cyanocyclohexane-1-carboxylate (500 mg, 1.1 mmol) in DCM (4 mL) was added TFA (2 mL) at 0° C. The resulting solution was stirred at ambient temperature for 16 hours and then concentrated in vacuo to afford the title compound as an off-white solid, which was used directly without further purification. 1H NMR (400 MHz, CD3OD) δ 8.14 (s, 1H), 7.58-7.53 (m, 2H), 7.26-7.21 (m, 2H), 4.32-4.30 (m, 1H), 3.50-3.46 (m, 1H), 2.58-2.48 (m, 2H), 2.33-2.15 (m, 3H), 1.98-1.88 (m, 1H), 1.77-1.64 (m, 1H). MS ESI: [M+H]+ m/z 388.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7]([N+:11]([O-])=O)=[CH:8][C:9]=1[Cl:10])[CH:5]=[O:6]>C(O)C.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+2]>[Cl:1][C:2]1[CH:3]=[C:4]([C:7]([NH2:11])=[CH:8][C:9]=1[Cl:10])[CH:5]=[O:6]
Reactant: O=Cc1cc(Cl)c(Cl)cc1[N+](=O)[O-]
Agent: [Fe+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Solvent: O
Product: Nc1cc(Cl)c(Cl)cc1C=O
Yield: 86.8 %

Procedure:
3,4-Dichloro-6-nitrobenzaldehyde (4.40 g, 20 mmol) was dissolved in 50% aqueous ethanol (200 ml) at 50°-60° C. and the solution was added to a solution of iron(II) sulfate heptahydrate (27.8 g, 100 mmol) in water (200 ml) at 90° C. Concentrated (25%) aqueous ammonia (50 ml) was added in several portions with intensive stirring while the temperature was kept close to the boiling point. The mixture was refluxed for 5-10 min. and cooled. The precipitate was filtered off and washed with ethanol. The filtrate was concentrated in vacuo until most of the ethanol was removed. The resulting precipitate was collected, washed with water and dried in vacuo at 40°-50° C. to give 3.3 g of 3,4-dichloro-6-aminobenzaldehyde.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][C@@H:10]2[CH2:15][CH2:14][C@@H:13]([CH3:16])[N:12](CC3C=CC(OC)=CC=3)[CH2:11]2)=[N:6][CH:7]=1.C(N(CC)CC)C.ClC(OC(Cl)C)=O.ClC(OCCCl)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][C@@H:10]2[CH2:15][CH2:14][C@@H:13]([CH3:16])[NH:12][CH2:11]2)=[N:6][CH:7]=1
Reactant: COc1ccc(CN2C[C@H](C#Cc3ccc(F)cn3)CC[C@H]2C)cc1
Agent: CC(Cl)OC(=O)Cl
Agent: O=C(Cl)OCCCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1CC[C@@H](C#Cc2ccc(F)cn2)CN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-fluoro-2-{[(3S,6R)-1-(4-methoxybenzyl)-6-methylpiperidin-3-yl]ethynyl}pyridine (276 mg, 0.82 mmol) and triethylamine (0.23 mL, 1.6 mmol) in CH2Cl2 (5 mL) was cooled at 0° C. and treated with 1-chloroethyl chloroformate (0.18 mL, 1.6 mmol) and allowed to warm to ambient temperature. After stirring overnight, additional triethylamine (0.20 mL) and chloroethyl chloroformate (0.15 mL) was added and the reaction stirred overnight again. The reaction was quenched by addition of 1N NaOH. The layers were separated and the aqueous phase was extracted with CH2Cl2. The organics were washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was taken up in MeOH and heated at reflux for 2 h. The reaction was concentrated in vacuo. The crude material was purified by silica gel flash chromatography eluting with 0-10% MeOH in CH2Cl2 to provide 5-fluoro-2-{[(3S,6R)-6-methylpiperidin-3-yl]ethynyl}pyridine as an orange solid which gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 219.3 for M+H+.