Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:42])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:39]=[CH:38][C:34]([C:35]([OH:37])=[O:36])=[CH:33][C:32]=2[O:40][CH3:41])=[O:29])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:49][O:50][CH2:51][CH2:52][N:53]([CH2:60][CH2:61][O:62][CH3:63])[C:54](=[O:59])[O:55][CH:56](Cl)[CH3:57]>CN(C)C=O.C(OCC)(=O)C>[CH3:63][O:62][CH2:61][CH2:60][N:53]([CH2:52][CH2:51][O:50][CH3:49])[C:54]([O:55][CH:56]([O:36][C:35](=[O:37])[C:34]1[CH:38]=[CH:39][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:42])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]2)=[O:29])=[C:32]([O:40][CH3:41])[CH:33]=1)[CH3:57])=[O:59]
Reactant: COCCN(CCOC)C(=O)OC(C)Cl
Reactant: COc1cc(C(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCN(CCOC)C(=O)OC(C)OC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)c(OC)c1
Reaction time: 0.17 h
Yield: 63.3 %

Procedure:
To a solution of chiral 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoic acid (US20100152190A1, 200 mg, 0.324 mmol) in dimethylformamide (8 mL) was added cesium carbonate (846 mg, 2.6 mmol). After stirring for 10 min, a solution of the above freshly made 1-chloroethyl bis(2-methoxyethyl)carbamate (510 mg, 2.13 mmol) in dimethylformamide (3 mL) was added. The reaction mixture was allowed to stir at room temperature overnight. This reaction mixture was taken up in ethyl acetate, washed with water, brine and concentrated to dryness. The crude material was purified by flash chromatography (hexane/ethyl acetate, 90/10 to 10/90) to give 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 1-[bis-(2-methoxy-ethyl)-carbamoyloxy]-ethyl ester as a white solid (168 mg, 63% yield). LCMS (ES+) m/z calcd. for C40H47Cl2F2N4O8 [(M+H)+]: 819, found: 819.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7](Cl)[S:8][C:4]=2[CH:3]=1.Cl.[NH:13]1[CH2:18][CH2:17][CH2:16][C@H:15]([OH:19])[CH2:14]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([N:13]3[CH2:18][CH2:17][CH2:16][C@H:15]([OH:19])[CH2:14]3)[S:8][C:4]=2[CH:3]=1
Reactant: Clc1nc2ccc(Br)cc2s1
Reactant: O[C@H]1CCCNC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O[C@H]1CCCN(c2nc3ccc(Br)cc3s2)C1
Temperature: 150 °C

Procedure:
A mixture of 6-bromo-2-chlorobenzo[d]thiazole (1.0 g, 4.0 mmol) and (S)-piperidin-3-ol hydrochloride (0.609 g, 4.43 mmol), and N,N-diisopropylethylamine (3.51 mL, 0.02012 mole) in N,N-dimethylformamide (2.0 mL) was heated to 150° C. under microwave irradiation for 15 minutes. The reaction mixture was transferred to a 100 mL round bottom flask (methanol rinse) and volatiles were removed under reduced pressure. The residue was partitioned between CHCl3 and saturated aqueous sodium carbonate. The organic layer was dried over MgSO4. Drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The crude material was purified by column chromatography on an Analogix IntelliFlash-280 (Analogix SF15-12g, 100% CHCl3 to 60:40 CHCl3/ethyl acetate). Fractions containing product were combined and concentrated under reduced pressure to provide (S)-1-(6-bromobenzo[d]thiazol-2-yl)piperidin-3-ol.
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[C:5](O)(=[O:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>C(O)C>[OH:2][CH2:1][CH2:3][NH:4][C:5](=[O:23])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCCCCCCC(=O)O
Reactant: NCCO
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCC(=O)NCCO
Temperature: 135 °C
Reaction time: 5 h

Procedure:
To a solution of 24.4 g (0.4 mole) ethanolamine in 500 ml ethanol at 60° C. was added 85.2 g (0.3 mole) stearic acid. The ethanol was distilled off until the pot temperature reached 100° C., at which time 300 ml toluene was added, and the water was distilled off as an azeotrope. After 5 hours at 110° C., 6 ml water was recovered in the Stark & Dean trap. Some toluene was removed to raise the pot temperature to 135° C. After an additional 4 hours, another 7 ml water was trapped. The title product (38.5 g) that crystallized on cooling had a melting point of 96°-99° C.
Reaction SMILES: [ClH:1].[C:2]([N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([C:11]([OH:13])=[O:12])[CH2:6]1)(=[NH:4])[NH2:3].[C:14]1(O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[ClH:1].[C:2]([N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([C:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:12])[CH2:6]1)(=[NH:3])[NH2:4]
Reactant: Oc1ccccc1
Reactant: N=C(N)N1CCCC(C(=O)O)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Product: N=C(N)N1CCCC(C(=O)Oc2ccccc2)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 73.2 %

Procedure:
A mixture of 3 g of 1-amidino-3-piperidinecarboxylic acid hydrochloride, 1.4 g of phenol, 3 g of dicyclohexylcarbodiimide and 40 ml of dry pyridine was stirred at room temperature for 2 days. After removal of any insoluble materials, the solvent was removed under reduced pressure to give a light yellow oil. The oil was washed twice with ethyl acetate to give white powder. The powder was washed with dry ether and dried under reduced pressure to obtain 3 g of phenyl 1-amidino-3-piperidinecarboxylate hydrochloride as hygroscopic white powder having a melting point of 54° to 60° C.
Reaction SMILES: [CH:1]1[C:17]2[CH2:16][C@H:15]3[N:18]([CH2:20][CH2:21][C@@:7]45[C@H:14]3[CH:13]=[CH:12][C@H:10]([OH:11])[C@@H:8]4[O:9][C:5]([C:6]=25)=[C:3]([OH:4])[CH:2]=1)[CH3:19].[C:22](=O)([O-])[O-].[K+].[K+].O>[Cl-].C[N+](C)(C)C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:19][N:18]1[C@@H:15]2[CH2:16][C:17]3[CH:1]=[CH:2][C:3]([O:4][CH3:22])=[C:5]4[O:9][C@H:8]5[C@@H:10]([OH:11])[CH:12]=[CH:13][C@@H:14]2[C@:7]5([C:6]=34)[CH2:21][CH2:20]1
Reactant: O=C([O-])[O-]
Reactant: CN1CC[C@]23c4c5ccc(O)c4O[C@H]2[C@@H](O)C=C[C@H]3[C@H]1C5
Agent: C[N+](C)(C)c1ccccc1
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1ccc2c3c1O[C@H]1[C@@H](O)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Yield: 95.6 %

Procedure:
Morphine of 89.0% purity 320 parts (1 mole part), potassium carbonate 552 parts (4 moles part), water 65 parts and trimethylphenylammonium chloride 188 parts (1.1 moles part) are heated under stirring in toluene (4000 parts) at 45° to 120° C. for 2 to 8 hrs. to yield 296 parts codeine (95.6% yield after workup as in Example 1.
Reaction SMILES: CO[C:3]([CH:5]1[C:10]2[S:11][CH:12]=[CH:13][C:9]=2[S:8](=[O:15])(=[O:14])[N:7]([CH3:16])[C:6]1=[O:17])=[O:4].[NH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>C1(C)C(C)=CC=CC=1>[CH3:16][N:7]1[C:6](=[O:17])[CH:5]([C:3](=[O:4])[NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[C:10]2[S:11][CH:12]=[CH:13][C:9]=2[S:8]1(=[O:14])=[O:15]
Reactant: Nc1ccccn1
Reactant: COC(=O)C1C(=O)N(C)S(=O)(=O)c2ccsc21
Solvent: Cc1ccccc1C
Product: CN1C(=O)C(C(=O)Nc2ccccn2)c2sccc2S1(=O)=O

Procedure:
0.3 G. of 3,4-dihydro-4-methoxycarbonyl-2-methyl-3-oxo-2H-thieno[2,3-e]1,2-thiazine 1,1-dioxide and 0.13 g. of 2-aminopyridine are dissolved in 30 ml. of absolute xylene and the solution is heated for 1 hour under reflux. After cooling, the crystals are removed by filtration and recrystallized from glacial acetic acid. 3,4-Dihydro-2-methyl-3-oxo-4-(2-pyridyl-carbamoyl)-2H-thieno[2,3-e]1,2-thiazine 1,1-dioxide, melting point 255° C. to 256° C. (decomposition), is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]4[CH2:15][CH2:16][CH:11]([CH2:12][CH2:13]4)[C:7]=3[NH:8][C:9]=2[CH:10]=1.[CH3:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]=[CH2:25])=[CH:20][N:19]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:14]4[CH2:15][CH2:16][CH:11]([CH2:12][CH2:13]4)[C:7]=3[N:8]([CH2:25][CH2:24][C:21]3[CH:20]=[N:19][C:18]([CH3:17])=[CH:23][CH:22]=3)[C:9]=2[CH:10]=1
Reactant: Cc1ccc2c3c([nH]c2c1)C1CCN3CC1
Reactant: C=Cc1ccc(C)nc1
Product: Cc1ccc2c3c(n(CCc4ccc(C)nc4)c2c1)C1CCN3CC1

Procedure:
The coupling of 7-methyl-2,3,4,5-tetrahydro-1,4-ethanopyrido[3,2-b]indole (110 mg, 0.52 mmol; Example 217) and 2-methyl-5-vinylpyridine (93 mg, 0.78 mmol; prepared as described in International Publication No. WO 2001017968) was performed according to the procedure described in Example 106A to provide the title compound: 1H NMR (500 MHz, methanol-d4) δ ppm 0.88-1.03 (m, 2H), 1.71-1.82 (m, 2H), 2.38 (s, 3H), 2.41-2.48 (m, 2H), 2.44 (s, 3H), 3.07-3.17 (m, 5H), 4.42 (t, J=6.3 Hz, 2H), 6.89 (d, J=8.2 Hz, 1H), 7.07 (d, J=7.9 Hz, 1H), 7.16 (s, 1H), 7.25 (dd, J=7.9, 2.1 Hz, 1H), 7.44 (d, J=7.9 Hz, 1H), 7.77 (d, J=1.8 Hz, 1H); MS (DCI) m/z 332 (M+H)+.
Reaction SMILES: [O:1]([CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[NH:15][C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1)[Si](C(C)(C)C)(C)C.[CH3:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=1.[K+].[Br-]>>[OH:1][CH2:9][CH2:10][CH:11]1[C:16](=[O:17])[N:15]([CH2:22][C:23]2[CH:30]=[CH:29][C:26]([CH3:27])=[CH:25][CH:24]=2)[C:14]2[CH:18]=[CH:19][CH:20]=[CH:21][C:13]=2[O:12]1
Reactant: CC(C)(C)[Si](C)(C)OCCC1Oc2ccccc2NC1=O
Reactant: Cc1ccc(CCl)cc1
Agent: [Br-]
Agent: [K+]
Product: Cc1ccc(CN2C(=O)C(CCO)Oc3ccccc32)cc1

Procedure:
Prepared from 2-(2-tert-butyldimethylsiloxyethyl)-3,4-dihydro-3-oxo-2H-1,4-benzoxazine by Methods F and G alkylating with 4-methylbenzyl chloride, in 50% overall yield. This material was crystallized from ether to afford a white solid, mp 92°-94° C.; IR (KBr) 3496, 1659, 1503, 1405, 1304, 1283, 1248, 1063, 801 cm-1 ; 1H NMR (CDCl3) δ2.18-2.36 (m, 5H), 3.91 (q, J=5.7, 2H), 4.83 (dd, J=7.4, 5.7, 1H), 5.12 (s, 2H), 6.90-7.00 (m, 4H), 7.13 (s, 4H); MH+ at m/z=298; Anal. Calc'd for C18H19NO3 : C, 72.71; H, 6.44; N, 4.71. Found: C, 72.71; H, 6.48; N, 4.65.
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:8]1[CH:13]=[CH:12][N:11]=[C:10]([S:14][CH3:15])[N:9]=1)[C:5](=O)[CH3:6].C([O-])([O-])=O.[K+].[K+].Cl.[NH2:24][C:25]([NH2:27])=[NH:26]>CN(C=O)C>[CH3:6][C:5]1[C:4]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([S:14][CH3:15])[N:9]=2)=[CH:3][N:24]=[C:25]([NH2:27])[N:26]=1
Reactant: N=C(N)N
Reactant: CSc1nccc(C(=CN(C)C)C(C)=O)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSc1nccc(-c2cnc(N)nc2C)n1
Temperature: 120 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
To a solution of 4-Dimethylamino-3-(2-methylsulfanyl-pyrimidin-4-yl)-but-3-en-2-one (18) (1.02 g, 4.30 mmol) in DMF (14 mL) was added K2CO3 (1.782 g, 12.89 mmol) and Guanidine HCl (0.616 g, 6.45 mmol) and the resulting suspension was stirred at 120° C. for 1 hour. The DMF was evaporated and the crude residue partitioned between water and ethyl acetate. The organic layer was washed with water and brine, dried with sodium sulfate, and concentrated. The crude residue was purified by flash chromatography with a gradient of 1-12% MeOH in DCM to give the desired product as a light yellow solid (800 mg, 80%). MS (ES+): m/z=234.3/235.4 (100/20) [MH+]. HPLC: tR=1.01 minutes over 3 minutes. Purity: 70% [HPLC (LC/MS) at 220 nm].
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:13][Si:14]([CH3:21])([CH3:20])[CH2:15][CH2:16][O:17][CH2:18]Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:18][O:17][CH2:16][CH2:15][Si:14]([CH3:21])([CH3:20])[CH3:13])[C:5]2=[N:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Brc1cnc2[nH]cnc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cnc2cc(Br)cnc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 6-bromo-3H-imidazo[4,5-b]pyridine (1.0 g) in THF (20 mL) at 0° C. was added sodium hydride (187 mg) and the reaction stirred at 0° C. for 1 h. Then, 2-(trimethylsilyl)ethoxymethyl chloride (0.94 mL) was added and the reaction stirred at room temperature for 16 h. The reaction was quenched with water (20 mL) and extracted into ethyl acetate (2×20 mL). The combined organics were washed with aqueous brine solution (2×20 mL), dried (MgSO4), reduced in vacuo and purified by column chromatography to give 6-bromo-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridine.
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:10]=2)=[CH:4][CH:3]=1.O.[NH2:22][NH2:23]>CC(O)C>[NH:22]([C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]([C:15]3[CH:16]=[N:17][N:18]([CH3:20])[CH:19]=3)[CH:10]=2)=[CH:4][CH:3]=1)[NH2:23]
Reactant: NN
Reactant: Cn1cc(-c2cc(Oc3ccc(F)nc3)ccn2)cn1
Solvent: O
Solvent: CC(C)O
Product: Cn1cc(-c2cc(Oc3ccc(NN)nc3)ccn2)cn1
Temperature: 80 °C
Reaction time: 12 h
Yield: 87.1 %

Procedure:
4-((6-Fluoropyridin-3-yl)oxy)-2-(1-methyl-1H-pyrazol-4-yl)pyridine (0.99 g, 3.66 mmol) was dissolved in 2-propanol (7.3 mL) in a screw-cap reaction vessel. Hydrazine hydrate (64%) (0.9 mL, 18.3 mmol) was added, the vessel was sealed, and the reaction mixture was stirred at 80° C. for 12 h. The mixture was partitioned between sat. aqueous NaHCO3 (aq) (30 mL) and EtOAc (30 mL). The organic phase was collected and the aqueous phase was extracted with EtOAc (4×30 mL). The combined organics were dried (Na2SO4) and concentrated in vacuo to afford 4-((6-hydrazinylpyridin-3-yl)oxy)-2-(1-methyl-1H-pyrazol-4-yl)pyridine (0.9 g, 87%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 9.29 (s, 1H), 8.33 (d, J=5.7 Hz, 1H), 8.23 (s, 1H), 8.00 (d, J=2.9 Hz, 1H), 7.93 (s, 1H), 7.48 (dd, J=9.0, 2.9 Hz, 1H), 7.16 (d, J=2.4 Hz, 1H), 7.12 (d, J=9.0 Hz, 1H), 6.62 (dd, J=5.7, 2.4 Hz, 1H), 4.10 (d, J=4.5 Hz, 2H), 3.84 (s, 3H); MS (ESI) m/z: 283.1 (M+H+).
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[S:8][C:9]3[C:14]([N:15]=2)=[CH:13][CH:12]=[C:11]([O:16][C:17]2[CH:18]=[C:19]([NH:24]C(=O)OCC4C=CC=CC=4)[CH:20]=[CH:21][C:22]=2[CH3:23])[N:10]=3)=[O:5])[CH2:3][CH2:2]1.CN1CCCC1=O.C([O-])=O.[NH4+]>C(O)C.[C].[Pd]>[NH2:24][C:19]1[CH:20]=[CH:21][C:22]([CH3:23])=[C:17]([CH:18]=1)[O:16][C:11]1[N:10]=[C:9]2[S:8][C:7]([NH:6][C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:5])=[N:15][C:14]2=[CH:13][CH:12]=1
Reactant: Cc1ccc(NC(=O)OCc2ccccc2)cc1Oc1ccc2nc(NC(=O)C3CC3)sc2n1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CN1CCCC1=O
Solvent: CCO
Product: Cc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)sc2n1
Temperature: 25 °C
Reaction time: 120 h
Yield: 70.7 %

Procedure:
To a solution of benzyl [3-({2-[(cyclopropylcarbonyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}oxy)-4-methylphenyl]carbamate (14.4 g, 30.3 mmol) produced in Example 33(v) in ethanol (300 mL)/1-methylpyrrolidin-2-one (100 mL) were added 10% palladium carbon (27.3 g, 25.7 mmol) and ammonium formate (61.9 g, 909 mmol), and the mixture was stirred at room temperature for 5 days under a hydrogen atmosphere (1 atm). The insoluble material was filtered off through a celite pad, and the filtrate was concentrated under reduced pressure. To the obtained solution in 1-methylpyrrolidin-2-one was added water (300 ml), and the precipitated solid was collected by filtration and washed with water (500 mL). The solid collected by filtration was dissolved in a mixture of tetrahydrofuran (800 mL)/ethyl acetate (800 mL), washed with saturated brine (2×400 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was washed successively with a mixture of tetrahydrofuran (10 mL)/diisopropyl ether (10 mL) and diisopropyl ether (40 mL) to give the title compound (7.29 g, 71%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][CH2:11]2)=[CH:7][C:6]=1[NH2:14].[CH3:20][S:21](Cl)(=[O:23])=[O:22]>N1C=CC=CC=1>[F:1][C:2]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:13]=[C:12]2[C:8]([CH2:9][CH2:10][CH2:11]2)=[CH:7][C:6]=1[NH:14][S:21]([CH3:20])(=[O:23])=[O:22]
Reactant: Nc1cc2c(cc1Oc1ccc(F)cc1F)CCC2
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1cc2c(cc1Oc1ccc(F)cc1F)CCC2
Reaction time: 3 h

Procedure:
At 0° C., 13.1 g of 6-(2,4-difluorophenoxy)-5-indanylamine in 60 ml of pyridine was combined with 4.0 ml of methanesulfonyl chloride. After 3 hours at 0° C. and 16 hours at 20° C., the mixture was concentrated, the residue was taken up in chloroform, the solution was washed with 1N hydrochloric acid, and concentrated. Recrystallization of the residue from ethanol yielded 8.1 g of N-[6-(2,4-difluorophenoxy)-5-indanyl]methanesulfonamide, mp 85°-87° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([N:9]([CH3:11])[NH2:10])[N:3]=1.[C:12](OC)(=[O:16])[C:13]([CH3:15])=O>CO>[NH2:8][C:6]1[C:5]2[C:12](=[O:16])[C:13]([CH3:15])=[N:10][N:9]([CH3:11])[C:4]=2[N:3]=[C:2]([NH2:1])[N:7]=1
Reactant: CN(N)c1cc(N)nc(N)n1
Reactant: COC(=O)C(C)=O
Solvent: CO
Product: Cc1nn(C)c2nc(N)nc(N)c2c1=O
Reaction time: 5 h
Yield: 76 %

Procedure:
To a refluxing solution of 2,4-diamino-6-(1-methylhydrazino)-pyrimidine (500 mg) in anhydrous methanol (15 ml) was added methyl pyruvate (496 mg) over a five minute period. Reflux was continued for 5 hours after which time the solid which had separated was collected by suction filtration of the hot mixture, washed with methanol, and dried under vacuum at 70° C. to yield tan crystals of 5,7-diamino-1,3-dimethylpyrimido [4,5-c]pyridazin-4(1H)-one (508 mg; 76% of theoretical yield; M.P.>275° C.)
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:21]#[C:22][CH2:23][OH:24])=[CH:15][C:14]=3[O:25][CH3:26])=[O:9])=[CH:4][CH:3]=1>C(OCC)C.CCCCCC.[Pd]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([CH2:21][CH2:22][CH2:23][OH:24])=[CH:15][C:14]=3[O:25][CH3:26])=[O:9])=[CH:27][CH:28]=1
Reactant: COc1cc(C#CCO)cc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc12
Agent: [Pd]
Solvent: CCCCCC
Solvent: CCOCC
Product: COc1cc(CCCO)cc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc12
Yield: 62.6 %

Procedure:
N-(4-Chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-8-methoxy-3-quinolinecarboxamide (397 mg) from Example No. 118 is dissolved in methanol/dichloromethane (1/1, 80 mL) and palladium on carbon (5%, 80 mg) are --added. The mixture is placed under a hydrogen atmosphere (23 psi) for 1 h, filtered through celite, and concentrated. The crude product is purified by column chromatography (dichloromethane/methanol, 50/1 to 20/1) to afford 251 mg (63%) of the title compound as a white solid.
Reaction SMILES: [NH2:1][CH:2]([C:19]([N:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:20])[CH2:3][NH:4][C:5]([CH:7]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH2:9][CH2:8]1)=[O:6].[CH:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[C:37](Cl)=[O:38]>>[N:21]1([C:19]([CH:2]([NH:1][C:37]([C:28]2[CH:29]=[CH:30][C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:27]=2)=[O:38])[CH2:3][NH:4][C:5]([CH:7]2[CH2:8][CH2:9][N:10]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[CH2:11][CH2:12]2)=[O:6])=[O:20])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1
Reactant: NC(CNC(=O)C1CCN(c2ccncc2)CC1)C(=O)N1CCCCC1
Reactant: O=C(Cl)c1ccc2ccccc2c1
Product: O=C(NC(CNC(=O)C1CCN(c2ccncc2)CC1)C(=O)N1CCCCC1)c1ccc2ccccc2c1
Yield: 85 %

Procedure:
Using an analogous procedure to that described in Example 2, N-[2-amino-2-(piperidinocarbonyl)ethyl]-1-(4-pyridyl)piperidine-4-carboxamide was reacted with naphthalene-2-carbonyl chloride to give N-{1-(piperidinocarbonyl)-2-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]-ethyl}naphthalene-2-carboxamide in 85% yield;
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][C@H:10]([CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:11][OH:12].[Cl:22][CH2:23][C:24](Cl)=[O:25]>C(Cl)Cl>[CH2:15]([O:14][CH2:13][C@@H:10]([NH:9][C:24](=[O:25])[CH2:23][Cl:22])[CH2:11][OH:12])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)CCl
Reactant: N[C@@H](CO)COCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)N[C@@H](CO)COCc1ccccc1
Temperature: 0 °C

Procedure:
Add triethylamine (7.0 mL, 50.6 mmol) to a RT slurry of (S)-2-amino-3-benzyloxy-propan-1-ol hydrochloride (5 g, 23.0 mmol) in CH2Cl2 (75 mL). Stir until all the solid dissolves and then cool to 0° C. Add chloroacetylchloride (2.0 mL, 25.3 mmol). Stir 1 h and add more TEA (960 μL, 6.9 mmol) and chloroacetylchloride (549 μL, 6.9 mmol) to consume all the starting amine with continued stirring for 2 h. Pour into a separatory funnel containing 1 N HCl (200 mL) and extract with CH2Cl2 (2×250 mL). Wash the combined organic extracts with brine (200 mL), dry over Na2SO4, and concentrate to give crude N—((S)-1-benzyloxymethyl-2-hydroxy-ethyl)-2-chloro-acetamide. Dissolve this intermediate in THF (75 mL), cool to 0° C., and treat with NaH (1.1 g, 27.6 mmol). Stir 6 h at 0° C. to form the NH morpholinone. Add additional NaH 1.1 g (27.6 mmol) followed by MeI (3.6 mL, 57.5 mmol). Stir at 0° C. for 30 min and then pour into a separatory funnel containing 0.1 M HCl (200 mL). Extract with EtOAc (2×250 mL). Wash the combined organic extracts with brine (200 mL), dry over Na2SO4, filter, and concentrate to give the crude methylated product. Purify via silica gel chromatography using a gradient of 0-100% EtOAc/hexanes to yield 1.3 g (24%, 3 steps) of the title compound. MS/ES m/z 236.1 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].FC(F)(F)S(O[C:13]1[C:14]([N+:33]([O-:35])=[O:34])=[CH:15][C:16]2[O:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[C:18]([C:28](=[O:31])[NH:29][CH3:30])[C:17]=2[CH:32]=1)(=O)=O.[CH2:38]([O:40][C:41]([C:43]1[CH:44]=[C:45](B(O)O)[CH:46]=[CH:47][CH:48]=1)=[O:42])[CH3:39].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.O>[F:27][C:24]1[CH:23]=[CH:22][C:21]([C:19]2[O:20][C:16]3[CH:15]=[C:14]([N+:33]([O-:35])=[O:34])[C:13]([C:47]4[CH:48]=[C:43]([CH:44]=[CH:45][CH:46]=4)[C:41]([O:40][CH2:38][CH3:39])=[O:42])=[CH:32][C:17]=3[C:18]=2[C:28](=[O:31])[NH:29][CH3:30])=[CH:26][CH:25]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(OS(=O)(=O)C(F)(F)F)cc12
Reactant: CCOC(=O)c1cccc(B(O)O)c1
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cccc(-c2cc3c(C(=O)NC)c(-c4ccc(F)cc4)oc3cc2[N+](=O)[O-])c1
Temperature: 90 °C
Yield: 84.9 %

Procedure:
Cesium carbonate (1.69 g, 5.19 mmol) was added to Pd(Ph3P)4 (250 mg, 0.216 mmol), 2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-nitrobenzofuran-5-yl trifluoromethanesulfonate (2.00 g, 4.33 mmol), 3-(ethoxycarbonyl)phenylboronic acid (1.01 g, 5.19 mmol). Dioxane (36 mL) and water (7 mL) was added at rt and the mixture was degassed 3×. The reaction was heated to 90° C. overnight. It was allowed to cool. The mixture was diluted with EtOAc and washed with 1M HCl, and sat NaCl. The organic phase was dried over Na2SO4, Tilt and concentrated. The crude solid was triturated with DCM to give the titled compound (1.70 g, 85%). 1H NMR (400 MHz, DMSO-d6) δδ ppm 8.55-8.61 (1H, m), 8.54 (1H, s), 8.00-8.09 (3H, m), 7.95 (1H, s), 7.73 (1H, s), 7.61-7.70 (2H, m), 7.45 (2H, t, J=8.91 Hz), 4.35 (2H, q, J=7.19 Hz), 2.83 (3H, d, J=4.52 Hz), 1.34 (3H, t, J=7.03 Hz). LC-MS retention time: 1.62 min; m/z (MH+): 463. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters XBridge 5u C18 4.6×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 5 ml/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where solvent A was 5% acetonitrile/95% H2O/10 mM ammonium acetate and solvent B was 5% H2O/95% acetonitrile/10 mM ammonium acetate. MS data was determined using a Micromass Platform for LC in electrospray mode.