Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH:10]([OH:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[CH3:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:17](O)=[O:18]>>[CH3:13][C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:17]([N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]([OH:12])[CH2:11][CH:2]1[CH3:1])=[O:18]
Reactant: CC1CC(O)c2ccccc2N1
Reactant: Cc1ccc(C(=O)O)cc1C
Product: Cc1ccc(C(=O)N2c3ccccc3C(O)CC2C)cc1C
Yield: 62.5 %

Procedure:
Starting with 2-methyl-1,2,3,4-tetrahydro-4-quinolinol (1.00 g, 6.12 mmol) synthesized in the published manner and 3,4-dimethylbenzoic acid (1.20 g, 7.96 mmol), the same procedure as shown in Reference Example 19 was repeated to give the titled compound (1.13 g, yield: 48%) as an oil. (cis:trans=1:1)
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([CH2:14][OH:15])=[CH:11][S:12][CH:13]=2)=[CH:5][CH:4]=1)[CH3:2].C(C1C=CC(C2C=C(C(F)(F)F)SC=2CO[C:35]2[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][C:43]([O:45]CC)=[O:44])=[C:37]([F:48])[C:36]=2[F:49])=CC=1)C>>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:10]([CH2:14][O:15][C:35]3[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][C:43]([OH:45])=[O:44])=[C:37]([F:48])[C:36]=3[F:49])=[CH:11][S:12][CH:13]=2)=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(-c2cscc2CO)cc1
Reactant: CCOC(=O)CCc1ccc(OCc2sc(C(F)(F)F)cc2-c2ccc(CC)cc2)c(F)c1F
Product: CCc1ccc(-c2cscc2COc2ccc(CCC(=O)O)c(F)c2F)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 216 by coupling of (4-(4-ethylphenyl)thiophen-3-yl)methanol and ethyl 3-(4-hydroxy-2,3-difluoro phenyl) propanoate followed by hydrolysis of ethyl 3-(4-((3-(4-ethylphenyl)-5-(trifluoromethyl)thiophen-2-yl)methoxy)-2,3-difluorophenyl)propanoate to afford the desired product as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 7.52 (s, 1H), 7.42 (m, 2H), 7.28 (m, 3H), 6.80 (m, 1H), 6.62 (m, 1H), 5.02 (s, 2H), 2.95 (t, J=5.5 Hz, 2H), 2.68 (m, 4H), 1.25 (t, J=6.5 Hz, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[CH2:17]([O:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][OH:1])=[CH:5][CH:6]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCCc1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: OCCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(2-hydroxy-ethyl)-phenol (50 g, 0.36 mol) in ethanol (400 ml) is added potassium carbonate (75 g, 0.54 mol, 1.5 eq) and benzyl bromide (47.2 ml, 0.39 mol, 1.1 eq), the reaction mixture is stirred at room temperature overnight. The reaction mixture is then filtered off trough celite and concentrated under vacuum. 2-(4-Benzyloxy-phenyl)-ethanol is isolated after crystallization with diethyl ether (82.6 g, 95%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]Cl)=[C:6]([C:12]([Cl:15])([Cl:14])[Cl:13])[CH:5]=1)([O-:3])=[O:2].[CH3:16][CH:17]([SH:19])[CH3:18]>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10][S:19][CH:17]([CH3:18])[CH3:16])=[C:6]([C:12]([Cl:15])([Cl:14])[Cl:13])[CH:5]=1)([O-:3])=[O:2]
Reactant: CC(C)S
Reactant: O=[N+]([O-])c1ccc(SCl)c(C(Cl)(Cl)Cl)c1
Product: CC(C)SSc1ccc([N+](=O)[O-])cc1C(Cl)(Cl)Cl
Yield: 92.3 %

Procedure:
As in Example 1, 61 g of 4-nitro-2-trichloromethylbenzenesulfenyl chloride is reacted with 15 g of 2 -propylmercaptan. There is obtained 63 g (91% of theory) of (4-nitro-2-trichloromethylphenyl)-isopropyl disulfide.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:6]=[CH:7][CH:8]=1.Cl.[C:38]1([C:44]2([C:50]([NH2:52])=[O:51])[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[F:1][C:2]([F:35])([F:36])[C:3]1[CH:4]=[C:5]([C:9]2([CH2:28][CH2:29][N:47]3[CH2:46][CH2:45][C:44]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)([C:50]([NH2:52])=[O:51])[CH2:49][CH2:48]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3cccc(C(F)(F)F)c3)C2)cc(OC)c1OC
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Agent: Cl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3cccc(C(F)(F)F)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.3 using 2-[3-(3-trifluoromethyl-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (8 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (12 mmol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][C:14]([CH3:17])([OH:16])[CH3:15])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH3:18][O:19][C:20]([NH:22][C:23](=NC(OC)=O)OC)=[O:21].C(O)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:16][C:14]([CH3:17])([CH3:15])[CH2:13][N:12]1[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=[C:23]1[NH:22][C:20](=[O:21])[O:19][CH3:18]
Reactant: COC(=O)N=C(NC(=O)OC)OC
Reactant: CC(C)(O)CNc1c(N)cnc2ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)Nc1nc2cnc3ccccc3c2n1CC(C)(C)O

Procedure:
A mixture of 1-[(3-amino-4-quinolinyl)amino]-2-methyl-2-propanol (1.0 g, 4.3 mmol), 1,3-dimethoxycarbonyl-O-methylisourea (prepared according to the general method of Viswanathan, N. Indian Patent No. 168,784, 1.64 g, 8.64 mmol), acetic acid (1.3 g, 22 mmol), and p-toluenesulfonic acid (0.82 g, 4.3 mmol) in methanol (20 mL) was heated at reflux for 16 hours. The volatiles were removed under reduced pressure, and the residue was dissolved in chloroform (100 mL). The solution was washed sequentially with water (100 mL), aqueous sodium carbonate (100 mL of 4% w/w), water (100 mL), and brine (100 mL) and then concentrated under reduced pressure. The residue was purified by automated flash chromatography (40+M silica cartridge, eluting with 0% to 25% CMA in chloroform) followed by recrystallization from acetonitrile to provide 0.64 g of methyl [1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]carbamate as a white solid, mp 225° C.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[F:26][C:27]([F:40])([F:39])[S:28]([C:31]1[CH:32]=[C:33]([NH:37]N)[CH:34]=[CH:35][CH:36]=1)(=[O:30])=[O:29]>>[F:39][C:27]([F:26])([F:40])[S:28]([C:31]1[CH:32]=[C:33]([N:37]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:2]2)[CH:34]=[CH:35][CH:36]=1)(=[O:29])=[O:30]
Reactant: NNc1cccc(S(=O)(=O)C(F)(F)F)c1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Product: O=c1ccn(-c2cccc(OC(F)(F)F)c2)nc1-c1ccnn1-c1cccc(S(=O)(=O)C(F)(F)F)c1

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and (3-trifluoromethanesulfonyl-phenyl)-hydrazine according to the method described for example 91. MS: M=531.1 (M+H)+
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([NH:6][C:7](=[O:9])[CH3:8])=[N:2]1.C[C:11]([CH3:14])([O-:13])[CH3:12].[Na+].[Cl-].[Li+]>CN(C=O)C>[CH3:12][C:11]1([CH3:14])[O:13][C@H:11]([CH2:14][N:1]2[CH:5]=[CH:4][C:3]([NH:6][C:7](=[O:9])[CH3:8])=[N:2]2)[CH2:12][O:13]1
Reactant: CC(=O)Nc1cc[nH]n1
Reactant: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [Li+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1
Temperature: 100 °C
Reaction time: 5 h
Yield: 279.4 %

Procedure:
A 3 L flask was charged with 200.0 g (1.60 mol) of N-(1H-pyrazol-3-yl)-acetamide and 1 L of anhydrous DMF. To the agitated suspension was added 173.8 g (1.75 mol) of sodium tert-butoxide in one portion. To the mixture was added 82.0 g (1.91 mol) of lithium chloride in one portion. To the mixture was added 267 g (1.75 mol) of (S)-(−)-4-(chloromethyl)-2,2-dimethyl-1,3-dimethyl-1,3-dioxolane in one portion. The mixture was agitated at 100° C. for 5 h. To the resulted mixture was added additional 31.6 g (0.32 mol) of sodium tert-butoxide and followed by 48.5 g (0.32 mol) of (S)-(−)-4-(chloromethyl)-2,2-dimethyl-1,3-dimethyl-1,3-dioxolane. The mixture was agitated at 100° C. for additional 5 h. To the resulted mixture was added additional 31.6 g (0.32 mol) of sodium tert-butoxide and followed by 48.5 g (0.32 mol) of (S)-(−)-4-(chloromethyl)-2,2-dimethyl-1,3-dimethyl-1,3-dioxolane. The mixture was agitated at 100° C. for 16 h. Then the mixture was cooled to 60° C. and concentrated under reduced pressure (60-25 mbar, 60° C.) to remove 720 g of the solvents. To the residue was added 1.6 L of water. The resulting solution was extracted with 3.2 L of dichloromethane (DCM). The combined organic phases were washed with 1.6 L of 20 wt % sodium chloride solution, and concentrated by distillation in vacuo (30-40° C. (batch)/P<−100 mbar), giving 585 g (316 g after corrected with wt %, 82.8% yield) of N-[1-((R)-2,2-Dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-acetamide as a red-brown oil which was used in the subsequent step directly without further processing. 1H-NMR (400 MHz, d6-DMSO): δ 10.37 (s, 1H), 7.57 (s, 1H), 6.44 (s, 1H), 4.33-4.36 (m, 1H), 4.08-4.11 (m, 2H), 3.98-4.02 (m, 1H), 3.71-3.75 (m, 1H), 1.98 (s, 3H), 1.31 (s, 3H), 1.26 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[CH:22]=[CH:23][C:24]2[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26][C:25]=2[CH:32]=1.C(O)(C)C>Cl>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:20][C:21]2[CH:22]=[CH:23][C:24]3[CH2:30][CH2:29][C:28](=[O:31])[CH2:27][CH2:26][C:25]=3[CH:32]=2)=[N:3][CH:4]=1
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Reactant: Nc1ccc2c(c1)CCC(=O)CC2
Agent: Cl
Solvent: CC(C)O
Product: CNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCC(=O)CC3)ncc1Cl
Yield: 43.6 %

Procedure:
Into a microwave vial was placed 2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (50 mg, 0.0002 mol) and 2-amino-5,6,8,9-tetrahydro-benzocyclohepten-7-one (38 mg, 0.00022 mol) in isopropyl alcohol (5 mL, 0.06 mol) with 4 M HCl (3 drops). The mixture was subjected microwaves at 130° C. for 10 minutes. Trace starting materials were present so the reaction mixture was resubjected to the same microwave conditions. The resulting solid was collected by filtration and washed with cold methylene chloride and dried in a vacuum oven at 50° C. overnight to give 38 mg (50%) of an off-white solid 2-[5-Chloro-2-(7-oxo-6,7,8,9-tetrahydro-5H-benzocyclo-hepten-2-ylamino)-pyrimidin-4-ylamino]-N-methyl-benzamide. MP: 262-269° C.; 1HNMR (400 MHz, DMSO-d6) δ 11.63 (s, 1H), 9.50 (s, 1H), 8.78 (d, 1H, J=5.3 Hz), 8.69 (d, 1H, J=8.08 Hz), 8.24 (s, 1H), 7.76 (d, 1H, J=7.58), 7.59 (s, 1H), 7.48 (t, 1H, J=7.58 Hz), 7.42 (d, 1H, J=7.58), 7.17 (t, 1H, J=8 Hz), 2.77-2.85 (m, 8H), 2.5 (d, 3H); MS (m/e) 436 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:16]1[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[N:20][CH:21]=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:16]2[CH:21]=[N:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc([N+](=O)[O-])nc2)CC1

Procedure:
A mixture of 4-amino-piperidine-1-carboxylic acid tert-butyl ester (500 mg; 2.5 mmol), 5-bromo-2-nitro-pyridine (406 mg; 2.0 mmol), Tris(dibenzylideneacetone)dipalladium (36 mg; 0.04 mmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (75 mg; 0.12 mmol), and sodium tert-butoxide (280 mg; 3.00 mmol) is suspended in toluene (5 mL) and is irradiated in a mono-mode microwave oven for 30 minutes at 120° C. The mixture is then concentrated under reduced pressure and the crude residue is purified by column chromatography on silica gel (dichloromethane:ethyl acetate 1:0 and then 4:1). The desired product is obtained with 78% purity (200 mg; 0.62 mmol).
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([CH3:22])([CH3:21])[CH2:6][CH2:7][CH2:8][S:9][CH2:10][S:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:20])([CH3:19])[C:16]([OH:18])=[O:17])C.[OH-].[Na+]>C(O)C.O>[CH3:21][C:5]([CH3:22])([CH2:6][CH2:7][CH2:8][S:9][CH2:10][S:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:20])([CH3:19])[C:16]([OH:18])=[O:17])[C:4]([OH:23])=[O:3]
Reactant: CCOC(=O)C(C)(C)CCCSCSCCCC(C)(C)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(CCCSCSCCCC(C)(C)C(=O)O)C(=O)O
Yield: 47.2 %

Procedure:
A solution of 2,2,12,12-tetramethyl-6,8-dithiatridecane-1,13-dioic acid ethyl ester (7.16 g, 18.25 mmol) and sodium hydroxide (3.13 g, 76 mmol) in ethanol (40 mL) and deionized water (4 mL) was heated to reflux for 2 h. The ethanol was evaporated and the residue dissolved in water (30 mL) and extracted with diethyl ether (20 mL). The aqueous layer was acidified with 2 N hydrochloric acid to pH 2 and extracted with diethyl ether (2×20 mL). The combined organic layers were washed with saturated sodium chloride solution (15 mL), dried over MgSO4, and concentrated to give the crude product (4.79 g) as an oil, which solidified on standing. Recrystallization (hexanes/ethyl acetate=2/1) yielded 2,2,12,12-tetramethyl-6,8-dithiatridecane-1,13-dioic acid (2.9 g, 47%) as nice white needles. Mp.: 72.0-72.5° C.). 1H NMR (300 MHz, CDCl3/TMS): d (ppm): 11.55 (br, 2H), 3.65 (s, 2H), 2.62 (t, J=6.8 Hz, 4H), 1.70-1.51 (m, 8H), 1.21 (s, 12H). 13C NMR (75 MHz, CDCl3/TMS): d (ppm): 184.76, 41.99, 39.54, 35.20, 31.07, 24.87, 24.54. HRMS (HR, LSIMS, gly): Calcd. for C15H29O4S2 (MH+): 337.1507, found 337.1508. Anal. (C15H28O4S2) calcd. (found): C, 53.54 (53.38); H, 8.39 (8.26); S, 19.06 (19.29).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[C:10](=[N:12]/[S:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])/[CH3:11])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].CCC(C)[BH-](C(C)CC)C(C)CC.[Li+]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C@H:10]([NH:12][S:13]([C:15]([CH3:16])([CH3:18])[CH3:17])=[O:14])[CH3:11])[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: C/C(=N\S(=O)C(C)(C)C)c1ccc(C#N)c(Br)c1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@@H](NS(=O)C(C)(C)C)c1ccc(C#N)c(Br)c1
Reaction time: 0.17 h

Procedure:
To a solution of 38-1 (500 mg, 1.5 mmol) in THF (4 mL) at −78 C was added L-Selectride (3.1 mL, 3.1 mmol, 1M). After 10 minutes, the reaction was diluted in EtOAc, washed with saturated sodium bicarbonate, dried over sodium sulfate, filtered and concentrated. Purification by reverse phase chromatography (1-100%, 0.1% TFA in H2O/Acetonitrile) gave desired product. MS (M+H)+: observed=329.0/331.0, calculated=329.3/331.3.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:16](C1C=C(C=CC=1)C(Br)Br)C1C=CC=CC=1.C1N2CN3CN(C2)CN1C3.Cl>C(O)C.C(O)(=O)C>[O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrC(Br)c1cccc(Oc2ccccc2)c1
Reactant: ClCc1cccc(Oc2ccccc2)c1
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: O=Cc1cccc(Oc2ccccc2)c1

Procedure:
A process according to claim 1, wherein the mixture of m-phenoxybenzyl bromide (II) and m-phenoxybenzal bromide (X = bromine) is reacted with 1 to 2 molar equivalents of hexamethylenetetramine in hot aqueous ethanol or hot aqueous acetic acid and hydrolyzing the mixture with dilute hydrochloric acid to yield m-phenoxybenzaldehyde (I).
Reaction SMILES: Cl[C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([O:14][CH3:15])[C:3]=1[CH:4]=[O:5].CC1(C)C(C)(C)OB([C:24]2[CH:25]=[CH:26][C:27]([C:30]([NH:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:31])=[N:28][CH:29]=2)O1.COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:4]([C:3]1[C:6]([O:14][CH3:15])=[CH:7][C:8]([C:10]([F:13])([F:12])[F:11])=[CH:9][C:2]=1[C:24]1[CH:25]=[CH:26][C:27]([C:30]([NH:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:31])=[N:28][CH:29]=1)=[O:5]
Reactant: COc1cc(C(F)(F)F)cc(Cl)c1C=O
Reactant: CCOC(=O)CCNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)cc(OC)c2C=O)cn1
Temperature: 90 °C

Procedure:
2-Chloro-6-methoxy-4-(trifluoromethyl)benzaldehyde (272.1 mg, 1.14 mmol), ethyl 3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamido)propanoate (516.2 mg, 1.48 mmol), SPhos (140.5 mg, 0.34 mmol), Pd(OAc)2 (38.4 mg, 0.17 mmol) and K3PO4 (726.3 mg, 3.42 mmol) were dissolved in wet PhMe (8 mL) and the resulting mixture was heated to 90° C. After 16 h the resulting mixture was diluted with water and extracted with EtOAc. The combined organic extracts were dried (Na2SO4), concentrated, and purified via column chromatography to yield the title compound.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([I:33])=[CH:29][C:28]=2[F:34])=[C:4]([CH:12]=[C:13](/[CH:16]=[N:17]/[O:18][CH2:19][CH2:20][CH2:21][C:22](=[O:25])NC)[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6].ClC(Cl)C(O)=O>C(Cl)Cl>[F:1][C:2]1[C:3]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([I:33])=[CH:29][C:28]=2[F:34])=[C:4]([CH:12]=[C:13]([CH2:16][N:17]2[C:22](=[O:25])[CH2:21][CH2:20][CH2:19][O:18]2)[C:14]=1[F:15])[C:5]([NH:7][O:8][CH2:9][CH2:10][OH:11])=[O:6]
Reactant: CNC(=O)CCCO/N=C/c1cc(C(=O)NOCCO)c(Nc2ccc(I)cc2F)c(F)c1F
Agent: O=C(O)C(Cl)Cl
Solvent: ClCCl
Product: O=C(NOCCO)c1cc(CN2OCCCC2=O)c(F)c(F)c1Nc1ccc(I)cc1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.8 %

Procedure:
(E)-3,4-Difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-[(3-methylcarbamoyl-propoxyimino)-methyl]-benzamide (8.0 g, 13.5 mmol) obtained in Step C of Example 28 was suspended in methylene chloride (240 ml), and borane-pyridine complex (5.45 ml, 53.8 mmol) and dichloroacetic acid (6.65 ml, 80.8 mmol) were added thereto at room temperature. The reaction mixture was stirred at room temperature for 15 hours, and dichloromethane was removed under reduced pressure with a rotary evaporator. The residue was diluted with 1,2-dichloroethane (240 ml), and the mixture was stirred at 60° C. for 8 hours, and filtered. The residue obtained by concentrating the filtrate was diluted with ethyl acetate (800 ml), and washed sequentially with water (400 ml), saturated aqueous sodium bicarbonate (400 ml), and saturated brine (400 ml). The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CH2Cl2/MeOH (25:1)) to give 3,4-difluoro-2-(2-fluoro-4-iodo-phenylamino)-N-(2-hydroxy-ethoxy)-5-(3-oxo-[1,2]oxazinan-2-ylmethyl)-benzamide (Compound G-1, 6.93 g, 91% yield).
Reaction SMILES: [CH:1]([O:14][C:15]1[C:16]2[C:34](=[O:35])[N:33]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[CH2:32][C:17]=2[C:18]([O:25]CC[Si](C)(C)C)=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(N(CC)CC)C>C1COCC1>[CH:1]([O:14][C:15]1[C:16]2[C:34](=[O:35])[N:33]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([F:43])=[CH:39][CH:38]=3)[CH2:32][C:17]=2[C:18]([OH:25])=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2)([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[Si](C)(C)CCOc1c2c(c(OC(c3ccccc3)c3ccccc3)c3ncccc13)C(=O)N(Cc1ccc(F)cc1)C2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1c2c(c(O)c3cccnc3c2OC(c2ccccc2)c2ccccc2)CN1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the compound 44 (350.0 mg, 0.592 mmol) in anhydrous THF (20 mL), was added tetrabutylammonium fluoride (1M in THF, 651 μl, 0.651 mmol) and triethylamine (330 μl, 2.37 mmol). The reaction mixture turned to red and was stirred at room temperature under nitrogen for 1 hour. The reaction forming 45 was monitored by TLC (EtOAc/Hexane=3/7).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl[CH2:29][C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1.C(N(CC)CC)C>CN(C=O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][N:25]([CH2:29][C:30]4[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=4)[CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: ClCc1cccnc1
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCN(Cc4cccnc4)CC3)c2[N+](=O)[O-])cc1

Procedure:
Compound A2 (0.12 mmol, 50 mg), 3-chloromethyl-pyridine (0.12 mmol, 20 mg) and triethylamine (0.63 mmol, 88 μL) were dissolved in DMF and microwaved at 80° C. for 10 minutes. The reaction mixture was quenched with water and extracted with ethyl acetate. Removal of organic solvent in vacuo provided Compound A6 pure as a yellow solid (39 mg, 66%). 1H NMR (400 MHz, CDCl3) δ (ppm): 10.09 (s, 1H), 8.45 (m, 2H), 8.33 (s, 1H), 7.90 (d, 2H), 7.78 (d, 2H), 7.65 (m, 1H), 7.21 (m, 1H), 5.41 (heptet, 1H), 3.52 (m, 2H), 3.01 (s, 3H), 2.65 (m, 2H), 2.47 (m, 2H), 1.98 (m, 2H), 1.94 (m, 2H). LCMS (ESI), m/z 484.3 (M+H+, 100%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:21]4[C:22]([F:27])=[N:23][CH:24]=[CH:25][CH:26]=4)[CH:13]=3)[O:8][C:5]2=[N:6][CH:7]=1.CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:66][C:67]1([CH3:73])[O:72][CH2:71][CH2:70][NH:69][CH2:68]1>[Cl-].[NH4+].O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:66][C:67]1([CH3:73])[CH2:68][N:69]([C:2]2[CH:3]=[C:4]3[C@:15]4([CH2:19][O:18][C:17]([NH2:20])=[N:16]4)[C:14]4[C:9](=[CH:10][CH:11]=[C:12]([C:21]5[C:22]([F:27])=[N:23][CH:24]=[CH:25][CH:26]=5)[CH:13]=4)[O:8][C:5]3=[N:6][CH:7]=2)[CH2:70][CH2:71][O:72]1
Reactant: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3F)ccc1Oc1ncc(Br)cc12
Reactant: CC1(C)CNCCO1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: O
Product: CC1(C)CN(c2cnc3c(c2)[C@]2(COC(N)=N2)c2cc(-c4cccnc4F)ccc2O3)CCO1

Procedure:
A vial was charged with (S)-3-bromo-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (110 mg, 0.257 mmol), DavePhos (12.16 mg, 0.031 mmol), and tris(dibenzylideneacetone)dipalladium(0) (11.79 mg, 0.013 mmol). The vessel was flushed with Ar(g), then lithium bis(trimethylsilyl)amide (772 μL, 0.772 mmol) (1.0 M solution in THF) and 2,2-dimethylmorpholine (61.8 μL, 0.515 mmol) were added in sequence. The vial was sealed and placed in a 75° C. oil bath for two hours. The mixture was diluted with saturated aq. ammonium chloride solution (20 mL) and water (10 mL). The mixture was extracted with DCM (3×20 mL), leaving behind a dark oily solid. The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was chromatographed on an 24-g Redi-Sep Gold column with 0-70% of a 90:10:1 mix of DCM/MeOH/NH4OH in DCM to give (S)-3-(2,2-dimethylmorpholino)-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine as a yellow solid.