Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][C@H:12]([CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][C@H:16]2[CH3:21])[N:11]([CH2:22][C:23]([N:25]2[C:33]3[C:28](=[N:29][CH:30]=[C:31]([CH2:34][C:35]4[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=4)[CH:32]=3)[C:27]([CH3:43])([CH3:42])[CH2:26]2)=[O:24])[CH2:10][C@H:9]1[CH3:44])=O)(C)(C)C.Cl>C(OCC)(=O)C.O1CCOCC1>[F:41][C:38]1[CH:39]=[CH:40][C:35]([CH2:34][C:31]2[CH:32]=[C:33]3[N:25]([C:23](=[O:24])[CH2:22][N:11]4[CH2:10][C@@H:9]([CH3:44])[NH:8][CH2:13][C@@H:12]4[CH2:14][N:15]4[CH2:20][CH2:19][O:18][CH2:17][C@H:16]4[CH3:21])[CH2:26][C:27]([CH3:43])([CH3:42])[C:28]3=[N:29][CH:30]=2)=[CH:36][CH:37]=1
Reactant: C[C@@H]1COCCN1C[C@H]1CN(C(=O)OC(C)(C)C)[C@H](C)CN1CC(=O)N1CC(C)(C)c2ncc(Cc3ccc(F)cc3)cc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C[C@@H]1CN(CC(=O)N2CC(C)(C)c3ncc(Cc4ccc(F)cc4)cc32)[C@@H](CN2CCOC[C@H]2C)CN1
Reaction time: 18 h
Yield: 87.9 %

Procedure:
To a vigorously stirred solution of (2R,5S)-4-{2-[6-(4-fluoro-benzyl)-3,3-dimethyl-2,3-dihydro-pyrrolo[3,2-b]pyridin-1-yl]-2-oxo-ethyl}-2-methyl-5-((R)-3-methyl-morpholin-4-ylmethyl)-piperazine-1-carboxylic acid tert-butyl ester (11.3 g, 18.5 mmol) in ethyl acetate (100 mL) at 20° C. was added a solution of HCl in dioxan (100 mL) and stirring was continued for 18 h. The resulting fine yellow precipitate was collected by filtration and dried in vacuo. This material was suspended in water (200 mL) and extracted with EtOAc (200 mL). The organic phase was washed with 0.1 M aqueous HCl (50 mL) and the combined aqueous extracts were cooled in an ice bath and basified by the dropwise addition of 5 M aqueous NaOH. Resulting mixture was extracted with DCM (4×60 mL) and the combined extracts were dried (Na2SO4) and evaporated in vacuo to give the title compound (8.29 g) as a colourless foam. 1H NMR and MS data were consistent with those obtained above for Example 262. IR vC═O 1685 cm−1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].[CH3:11][O:12][C:13](=[O:18])[CH:14]=[CH:15]OC.CC(C)([O-])C.[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.C(OC)(C)(C)C>[CH3:11][O:12][C:13](=[O:18])[CH2:14][CH:15]=[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])[C:9]#[N:10]
Reactant: COC=CC(=O)OC
Reactant: N#CCc1ccccc1Br
Agent: CC(C)(C)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: COC(=O)CC=C(C#N)c1ccccc1Br
Temperature: 25 °C
Yield: 99.5 %

Procedure:
A solution of 2-bromo-phenylacetonitrile (6.62 mL, 51.0 mmol) and methyl-3-methoxyacrylate (5.32 mL, 49.5 mmol) in tetrahydrofuran (10 ml) was added to a suspension of sodium tert-butoxide (5.05 g, 51.0 mmol) in tetrahydrofuran (70 mL) at 0° C. over 10 minutes under a stream of nitrogen. The reaction mixture was warmed to room temperature and after 15 minutes diluted with methyl tert-butyl ether (240 mL). To the mixture was added 0.2 N aqueous citric acid until the aqueous layer had a pH of 2 (80 mL). The organic layer was separated and washed with a saturated aqueous solution of sodium chloride (2×80 mL), dried over anhydrous sodium sulfate, filtered through a pad of Celite and silica (4:1) and concentrated in vacuo to provide 4-(2-bromo-phenyl)-4-cyano-but-3-enoic acid methyl ester as a pale yellow oil (13.8 g, 96%). Major isomer 1H NMR (400 MHz, CDCl3) δ 7.59 (dd, 1H, J=7.6, 1.2), 7.57–719 (m, 3H), 6.71 (t, 1H, J=7.1), 3.71 (s, 3H), 3.61 (d, 2H, J=7.1); 13C NMR (100 MHz, CDCl3) δ 169.7, 144.4, 133.7, 131.4, 131.1, 128.3, 122.5, 118.1, 117.3, 115.3, 52.7, 36.6; IR (ATR, neat) 1737, 1434, 1319, 1199, 1171, 1026, 755 cm−1. Minor isomer 1H NMR (400 MHz, CDCl3) δ 7.61 (dd, 1H, J=7.6, 1.0), 7.57–7.19 (m, 3H), 6.9 (t, 1H, J=7.5), 3.64 (s, 3H), 3.06 (d, 2H, J=7.5).
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[CH2:8][CH2:9][N:10]2[C:14](=[CH:15][C:16](SC3C=CC=CC=3)=[O:17])[CH2:13][S:12][C:11]=12)=[O:6])([CH3:3])[CH3:2].[NH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>O1CCCC1.FC(F)(F)C([O-])=O.[Ag+]>[CH:1]([O:4][C:5]([C:7]1[CH2:8][CH2:9][N:10]2[C:14](=[CH:15][C:16]([N:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:17])[CH2:13][S:12][C:11]=12)=[O:6])([CH3:2])[CH3:3]
Reactant: C1CCNCC1
Reactant: CC(C)OC(=O)C1=C2SCC(=CC(=O)Sc3ccccc3)N2CC1
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)OC(=O)C1=C2SCC(=CC(=O)N3CCCCC3)N2CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 69.8 %

Procedure:
1.0 g of S-phenyl (7-isopropoxycarbonyl-2,3,5,6-tetrahydropyrrolo[2,1-b]thiazol-3-ylidene)thioacetate and 1.2 g of piperidine were suspended in 40 ml of tetrahydrofuran and 740 mg of silver trifluoroacetate was added thereto under stirring at room temperature. After 2 hours, the insoluble matters were filtered off and the filtrate was concentrated. The residue was purified by silica gel column chromatography and recrystallized from ethanol. Thus 0.65 g of the title compound was obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7](OC2C=C3C(=CC=2)OC(C2C=CC=CC=2)CC3)=[N:8][CH:9]=1)([O-:3])=[O:2].[F:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[CH:35]1[CH2:44][CH2:43][C:42]2[C:37](=[CH:38][CH:39]=[C:40]([OH:45])[CH:41]=2)[O:36]1>>[F:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1[CH:35]1[CH2:44][CH2:43][C:42]2[C:37](=[CH:38][CH:39]=[C:40]([O:45][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=3)[CH:41]=2)[O:36]1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: Oc1ccc2c(c1)CCC(c1cc(F)ccc1F)O2
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2cc(F)ccc2F)O3)nc1

Procedure:
2-[2-(2,5-Difluorophenyl)chroman-6-yloxy]-5-nitropyridine was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 100 mg of 2-(2,5-difluorophenyl)chroman-6-ol. The product was recrystallised from 2-propanol. 1H NMR (400 MHz, CDCl3) δ: 9.07 (dd, 1H, J 2.8, 0.4 Hz), 8.47 (dd, 1H, J 9.1, 2.8 Hz), 7.26 (m, 1H), 7.05-6.91 (m, 6H), 5.35 (dd, 1H, J 10.3, 1.5 Hz), 3.04 (ddd, 1H, J −16.9, 11.7, 6.0 Hz), 2.82 (ddd, 1H, J −16.9, 5.2, 3.0 Hz), 2.29 (m, 1H), 2.01 (m, 1H).
Reaction SMILES: [CH:1]1([CH:4]([O:16][CH3:17])[C:5]2[O:6][C:7]3[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][C:8]=3[CH:9]=2)[CH2:3][CH2:2]1.[Br:18]N1C(=O)CCC1=O>C(#N)C>[Br:18][C:10]1[C:8]2[CH:9]=[C:5]([CH:4]([CH:1]3[CH2:2][CH2:3]3)[O:16][CH3:17])[O:6][C:7]=2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=1
Reactant: COc1cccc2cc(C(OC)C3CC3)oc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: COc1ccc(Br)c2cc(C(OC)C3CC3)oc12

Procedure:
Prepared from 2-(cyclopropyl-methoxy-methyl)-7-methoxybenzofuran (3.12 g) and N-bromosuccinimide (2.4 g) in acetonitrile (45 ml). The title compound was obtained as an orange gum (3.49 g).
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].Cl.[CH3:15][O:16][C:17](=[O:23])[C@H:18]([CH:20]([CH3:22])[CH3:21])[NH2:19].CN1CCOCC1>C(Cl)Cl>[CH3:15][O:16][C:17](=[O:23])[C@H:18]([CH:20]([CH3:22])[CH3:21])[NH:19][C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)[C@@H](N)C(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)[C@@H](NC(=O)Oc1ccc([N+](=O)[O-])cc1)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 66.1 g (0.328 mol) of 4-nitrophenyl chloroformate in 1.2 liters of CH2Cl2 was cooled to 0° C. and treated with L-valine methyl ester hydrochloride. The resulting mixture was treated slowly, with stirring, with 68.9 ml (0.626 mol) of 4-methylmorpholine. The resulting solution was allowed to slowly warm to ambient temperature and was stirred overnight. After washing with 3 portions of 10% aqueous NaHCO3, the solution was dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel chromatography by eluting with chloroform to provide the desired compound. 1H NMR (DMSO-d6) δ 0.94 (d, J=7 Hz, 3H), 0.95 (d, J=7 Hz, 3 H), 2.12 (octet, J=7 Hz, 1H), 3.69 (s, 3H), 4.01 (dd, J=8, 6 Hz, 1H), 7.41 (dt, J=9, 3 Hz, 2H), 8.27 (dr, J=9, 3 Hz, 2H), 8.53 (d, J=8 Hz, 1H). Mass spectrum: (M+NH4)+ =314.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[Cl:16][C:17]1[C:18]([O:27][C:28]2[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=2)=[N:19][CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1.[CH:38]1[CH:43]=[C:42]([OH:44])[CH:41]=[C:40]([CH:45]([OH:48])[CH2:46][NH2:47])[CH:39]=1>>[Cl:16][C:17]1[C:18]([O:27][C:28]2[CH:33]=[CH:32][C:31]([S:34]([NH:2][C:3]3[CH:8]=[CH:7][C:6]([N:9]4[CH2:14][CH2:13][CH:12]([NH:47][CH2:46][CH:45]([OH:48])[C:40]5[CH:39]=[CH:38][CH:43]=[C:42]([OH:44])[CH:41]=5)[CH2:11][CH2:10]4)=[CH:5][CH:4]=3)(=[O:36])=[O:35])=[CH:30][CH:29]=2)=[N:19][CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1
Reactant: Nc1ccc(N2CCC(=O)CC2)cc1
Reactant: NCC(O)c1cccc(O)c1
Reactant: O=S(=O)(Cl)c1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1
Agent: Cl
Product: O=S(=O)(Nc1ccc(N2CCC(NCC(O)c3cccc(O)c3)CC2)cc1)c1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1

Procedure:
The title compound was prepared from 1-(4-aminophenyl)-4-piperidone hydrochloride (which was obtained in Example 224), 4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)benzenesulfonyl chloride, and DL-norphenylephrine according to the procedure of Example 346; MS (ES) m/z: 663.2 (MH+).
Reaction SMILES: [OH:1][C:2]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14](O)=[O:15])=[CH:11][CH:12]=2)[N:7]([C:17]2[CH:21]=[CH:20][S:19][CH:18]=2)[N:6]=1)([CH3:4])[CH3:3].Cl.Cl.[CH3:24][C:25]1[N:29]=[C:28]([C@H:30]([NH2:32])[CH3:31])[O:27][N:26]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[OH:1][C:2]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH:32][C@@H:30]([C:28]3[O:27][N:26]=[C:25]([CH3:24])[N:29]=3)[CH3:31])=[O:15])=[CH:11][CH:12]=2)[N:7]([C:17]2[CH:21]=[CH:20][S:19][CH:18]=2)[N:6]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(O)c1nn(-c2ccsc2)c2cc(C(=O)O)ccc12
Reactant: Cc1noc([C@@H](C)N)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1noc([C@@H](C)NC(=O)c2ccc3c(C(C)(C)O)nn(-c4ccsc4)c3c2)n1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 89.8 %

Procedure:
3-(2-Hydroxypropan-2-yl)-1-(thiophen-3-yl)-1H-indazole-6-carboxylic acid (457.8 mg, 1.514 mmol), (1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethanamine bis-hydrochloride (374.3 mg, 1.871 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (600.2 mg, 3.13 mmol), 1-hydroxy-7-azabenzotriazole (105.3 mg, 0.774 mmol), and N-methylmorpholine (670 μl, 6.09 mmol) were dissolved in N,N-dimethylformamide (15 mL) at 25° C. The reaction mixture was heated to 50° C. and allowed to stir for 10 min. The reaction was stopped, quenched by addition of water (ca 1 mL) and trifluoroacetic acid (ca 1 mL). The reaction mixture was purified directly by preparative HPLC (reverse phase (C-18)), eluting with acetonitrile/water 0.1% trifluoracetic acid, to give the title compound (559.5 mg, 1.360 mmol, 90% yield) as a white solid. FIRMS: [M+1]=412.1452. 1H NMR (400 MHz, CDCl3): δ 8.22 (s, 1H); 8.06 (d, J=8.5 Hz, 1H); 7.54 (dd, J=8.5, 1.4 Hz, 1H); 7.52-7.46 (m, 2H); 6.89 (d, J=7.7 Hz, 1H); 5.65-5.56 (m, 1H); 2.83 (s, 1H); 2.40 (s, 3H); 1.81 (s, 6H); 1.73 (d, J=7.1 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])[CH3:3].C([Li])CCC.[CH2:20]1[O:22][CH2:21]1.O>O1CCCC1>[OH:22][CH2:21][CH2:20][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[S:6]([NH:5][C:2]([CH3:1])([CH3:3])[CH3:4])(=[O:8])=[O:7]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1
Reactant: C1CO1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1ccccc1CCO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of N-(1,1-dimethylethyl)benzenesulfonamide (40.0 g) in 550 ml dry tetrahydrofuran was cooled to 0° and 250 ml of 1.6M n-butyllithium added dropwise at 0°. After the addition of one equivalent of base, the solution turned yellow. After stirring for 2 hours at room temperature, the resulting suspension was cooled to 0° and 13 ml of ethylene oxide added dropwise. After stirring for 3.5 hours at room temperature, the homogeneous yellow solution was poured into water. The product was extracted with ether and dried (Na2SO4). Concentration gave a yellow oil which was purified by column chromatography [400 g silica gel, ether/hexane (1:1) followed by ethyl acetate]. Pure 2-(2-hydroxyethyl)-N-(1,1-dimethylethyl)benzenesulfonamide was obtained as a colorless oil which solidified after several days; m.p. 43°-45°.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]([CH3:17])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH:7]([C:12](O)=[O:13])[C:6]=2[C:15]=1[CH3:16].B.CSC.CO>O1CCCC1>[OH:1][C:2]1[C:3]([CH3:18])=[C:4]([CH3:17])[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH:7]([CH2:12][OH:13])[C:6]=2[C:15]=1[CH3:16]
Reactant: Cc1c(C)c2c(c(C)c1O)C(C(=O)O)C(C)(C)O2
Agent: B
Solvent: C1CCOC1
Solvent: CO
Solvent: CSC
Product: Cc1c(C)c2c(c(C)c1O)C(CO)C(C)(C)O2
Yield: 0.1 %

Procedure:
To a stirred solution of 58.82 g (0,235 mol) of 2,3-dihydro-5-hydroxy-2,2,4,6,7-pentamethyl-1-benzofuran-3-carboxylic acid (see Example 1) in 500 ml of dry tetrahydrofuran is added dropwise over 30 minutes 50 ml of 10M borane-methyl sulfide and the resulting mixture is stirred at reflux temperature for 7 hours. After cooling, 120 ml of methanol is added carefully and the resulting solution is evaporated to dryness. The residue is taken up in ethyl acetate and the solution is washed with 2N hydrochloric acid, water, a sodium bicarbonate solution, and brine, and is dried over anhydrous sodium sulfate. Filtration and evaporation of solvent gives an oil that crystallizes from ethyl acetate/heptane to give 37.85 g of the title compound, m.p. 89°-90° C. Elemental analysis, IR, UV, and 1H-NMR spectra confirm the structure. A second crop of 12.60 g is obtained, raising the yield to 91%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]([F:12])([F:11])[F:10])=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1O[C:20](=[S:28])OC1C=CC=CN=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]=[C:20]=[S:28])[C:3]=1[C:9]([F:10])([F:11])[F:12]
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Reactant: Nc1cccc(Cl)c1C(F)(F)F
Solvent: C1CCOC1
Product: FC(F)(F)c1c(Cl)cccc1N=C=S

Procedure:
Prepared analogously to example 192a from 3-chloro-2-trifluoromethyl-phenylamine, thiocarbonic acid O,O-dipyridin-2-yl ester and TEA in THF.
Reaction SMILES: [C:1]([OH:6])(=O)[C:2]#[C:3][CH3:4].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:22][C:23]1[CH:24]=[C:25]2[C:30](=[CH:31][CH:32]=1)[N:29]=[CH:28][C:27]([C:33]#[N:34])=[C:26]2[NH:35][C:36]1[CH:41]=[CH:40][C:39]([S:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[C:38]([Cl:49])[CH:37]=1>C1COCC1.CN(C=O)C>[Cl:49][C:38]1[CH:37]=[C:36]([NH:35][C:26]2[C:25]3[C:30](=[CH:31][CH:32]=[C:23]([NH:22][C:1](=[O:6])[C:2]#[C:3][CH3:4])[CH:24]=3)[N:29]=[CH:28][C:27]=2[C:33]#[N:34])[CH:41]=[CH:40][C:39]=1[S:42][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1ccc(Sc2ccccc2)c(Cl)c1
Reactant: CC#CC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC#CC(=O)Nc1ccc2ncc(C#N)c(Nc3ccc(Sc4ccccc4)c(Cl)c3)c2c1
Reaction time: 0.17 h
Yield: 24.4 %

Procedure:
Dissolved 314 mg (3.72 mmol) 2-butynoic acid in 40 ml THF under N2. Chilled to 0° and added 409 μl (3.72 mmol) N-methylmorpholine and 485 μl (3.72 mmol) isobutyl chloroformate and stirred for 10 minutes. Added dropwise a solution that was prepared by dissolving 1.00 g (2.48 mmol) 6-amino-4-[(3-chloro-4-thiophenoxyphenyl)amino]-3-quinolinecarbonitrile in 2.0 ml hot DMF and adding 20 ml THF. Stirred mixture for minutes at 0° and 25° C. overnight. To drive reaction to completion, added 1.24 mmol of the mixed anhydride (104 mg acid, 136 μl NMM, and 161 μl isobutyl chloroformate) in 15 ml THF. Stirred overnight. Stripped solvent, dried in vacuo. Recrystallized from ethyl acetate, dried in vacuo, giving 284 mg of yellow-orange solid: mass spectrum (electrospray m/e): M+H=469.2, 471.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C:14](=[O:25])[CH2:15][S:16]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[C:14](=[O:25])[CH2:15][S:16]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[O:17])=[CH:4][CH:3]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:30])[CH3:27]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(=O)CS(=O)Cc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(=O)CS(=O)Cc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2-phenylmethanesulfinyl-ethanone and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=2)[CH2:15][CH2:14]1.[C:32]1([NH:38]N)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:38][C:32]2[C:37]([C:9]=1[CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]1)=[CH:36][CH:35]=[CH:34][CH:33]=2
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3Br)CC2)c1
Reactant: NNc1ccccc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccccc4Br)[nH]c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(2-bromophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and phenylhydrazine: ESMS m/e: 557.9 (M+H)+.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1S.Br[CH2:12][CH3:13].O[O:15][S:16]([O-:18])=O.[K+]>CN(C=O)C.O>[Br:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:16]([CH2:12][CH3:13])(=[O:18])=[O:15]
Reactant: Sc1ccccc1Br
Reactant: O=S([O-])OO
Reactant: CCBr
Agent: [H-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCS(=O)(=O)c1ccccc1Br
Temperature: 30 °C
Reaction time: 14 h
Yield: 73.8 %

Procedure:
To a suspension of NaH (135 mg, 3.40 mmol, 60% in mineral oil) in anhydrous DMF (5 mL) was added 2-bromobenzenethiol (580 mg, 3.10 mmol) drop-wise at rt. After the resultant mixture was stirred at 20° Celsius for 10 min, bromoethane (670 mg, 6.10 mmol) was slowly added into the mixture. The reaction mixture was stirred at 30° Celsius for 14 hours in an oil bath. The reaction was diluted with water (60 mL) and extracted with petroleum ether (20 mL×2). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to dryness. The residue was dissolved in a mixture of methanol (10 mL) and water (15 mL) then treated with oxone (10 g, 15 mmol) portion-wise. The reaction mixture was stirred at 80° Celsius for 16 hours. The mixture was cooled to rt and the methanol removed. The remaining aqueous mixture was further diluted with water (50 mL) and extracted with DCM (20 mL×2). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, concentrated to dryness and purified by FCC to give the title compound (570 mg, 75%). 1H NMR (300 MHz, CDCl3) δ 8.18-8.12 (m, 1H), 7.76 (dd, J=7.8, 1.5, 1H), 7.52-7.43 (m, 2H), 3.46 (q, J=7.5, 2H), 1.26 (t, J=7.5, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])[C:21]([Cl:37])=[CH:20][N:19]=1>>[Cl:37][C:21]1[C:22]([NH:24][C:25]2[C:34]([O:35][CH3:36])=[CH:33][CH:32]=[CH:31][C:26]=2[C:27]([NH:29][CH3:30])=[O:28])=[N:23][C:18]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:19][CH:20]=1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Reactant: CNC(=O)c1cccc(OC)c1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1cccc(OC)c1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl

Procedure:
2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-3-methoxy-N-methyl-benzamide was prepared from 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-methoxy-N-methyl-benzamide in an analogous manner to Example 313c. Product isolated as a yellow foam (64 mg, 37%). LCMS (m/e) 511 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.05 (s, 1H), 7.71 (s, 1H), 7.33-7.27 (m, 1H), 7.19 (d 1H, J=7.7 Hz), 7.13 (s, 1H), 7.10-7.04 (m, 2H), 6.89 (d, 1H, J=8.1 Hz), 6.85 (s, 1H), 6.04-5.96 (m, 1H), 3.84 (s, 3H), 3.55 (t, 2H, J=5.7 Hz), 3.39 (s, 3H), 2.90-2.84 (m, 2H), 2.79-2.63 (m, 8H), 2.75 (d, 3H, J=4.1 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](B(O)O)[S:5][CH:6]=1.[O:10]1[CH2:15][CH2:14][O:13][C:12]2[CH:16]=[C:17]([CH2:20][N:21]3[CH:26]=[C:25](I)[CH:24]=[CH:23][C:22]3=[O:28])[CH:18]=[CH:19][C:11]1=2.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[O:10]1[CH2:15][CH2:14][O:13][C:12]2[CH:16]=[C:17]([CH2:20][N:21]3[CH:26]=[C:25]([C:4]4[S:5][CH:6]=[C:2]([CH3:1])[CH:3]=4)[CH:24]=[CH:23][C:22]3=[O:28])[CH:18]=[CH:19][C:11]1=2
Reactant: Cc1csc(B(O)O)c1
Reactant: O=c1ccc(I)cn1Cc1ccc2c(c1)OCCO2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Cc1csc(-c2ccc(=O)n(Cc3ccc4c(c3)OCCO4)c2)c1
Reaction time: 0.07 h
Yield: 61.2 %

Procedure:
A 10-mL CEM vial was swept with Ar, and charged with Fibrecat 1029 (0.034 g, 0.0092 mmol), 4-methylthiophen-2-ylboronic acid (0.052 g, 0.37 mmol), a stirbar, 1-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-5-iodopyridin-2(1H)-one (0.0340 g, 0.092 mmol) dissolved in 1 mL dry dioxane, and sodium carbonate (0.092 ml, 0.18 mmol). The Argon line was removed and the vial quickly sealed. The slurry was irradiated to 120° C. (100 W, powermax=on, ramp time=2 min, to 65° C., then from 2-7 minutes, 200 W, temp=120° C., held for 5 minutes). The solution was diluted with 5 mL DCM and loaded onto an unbuffered, 10 mL Varian Chem elute CE 1005 (PN 12198007) and extracted with DCM (3×30 mL). The combined extracts were concentrated in vacuo. The sample was purified using a 19×150 mm Waters Xterra Prep C18 OBD column (100 Å pore diameter, 5 μm particle size, spherical shape, PN 186002381; Gradient: 0→5 min@20 mL/min, 25% B; 5.0→35 min@20 mL/min, linear gradient to 55% B; 35→45@20 mL/min, isocratic at 55% B, 45→55 min@20 mL/min, step to 100% B; 55→60 min@20 mL/min, step to 25% B; 60 min end). A=10.7 mM NH4 HCO3 in water, B=ACN. A band that eluted from 25.2-26.4 minutes was isolated. The solvent was removed in vacuo to afford 1-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-5-(4-methylthiophen-2-yl)pyridin-2(1H)-one (0.0191 g, 61% yield). MS (ESI pos. ion) m/z (MH+): 340; calcd for C19H17NO3S+H+=340.1). 1H NMR (400 MHz, CDCl3) δ ppm 2.24 (d, J=1.08 Hz, 3 H) 4.23 (s, 4 H) 5.05 (s, 2 H) 6.63 (d, J=9.49 Hz, 1 H) 6.77 (t, J=1.08 Hz, 1H) 6.81-6.86 (m, 3 H) 6.84 (dd, J=2.45, 0.98 Hz, 1 H) 7.46 (d, J=2.54 Hz, 1 H) 7.53 (dd, J=9.49, 2.64 Hz, 1 H). 13C NMR (101 MHz, CDCl3) δ ppm 15.75 (s, 1 C) 51.64 (s, 1 C) 64.29 (s, 2 C) 114.82 (s, 1 C) 117.12 (s, 1 C) 117.67 (s, 1 C) 119.28 (s, 1 C) 121.20 (s, 1 C) 121.32 (s, 1 C) 124.90 (s, 1 C) 129.29 (s, 1 C) 133.15 (s, 1 C) 138.48 (s, 1 C) 138.66 (s, 1 C) 139.09 (s, 1 C) 143.48 (s, 1 C) 143.71 (s, 1 C) 161.65 (s, 1 C).