Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(CN)O.C(=O)([O-])[O-].[K+].[K+].[F:11][C:12]1[C:20]([F:21])=[C:19]2[C:15]([C:16]([NH:30]C(=O)CCC)=[N:17][N:18]2[CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])=[CH:14][C:13]=1[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CN(C)C=O>[F:11][C:12]1[C:20]([F:21])=[C:19]2[C:15]([C:16]([NH2:30])=[N:17][N:18]2[CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])=[CH:14][C:13]=1[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2c(F)c(F)c(-c3ccccc3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: NCCO
Product: C[Si](C)(C)CCOCn1nc(N)c2cc(-c3ccccc3)c(F)c(F)c21
Yield: 23.7 %

Procedure:
1.1 cm3 of ethanolamine and then 1.50 g of potassium carbonate are added to 1.6 g of N-[6,7-difluoro-5-phenyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]-butanamide described above, in 50 cm3 of dimethylformamide, and the mixture is refluxed for one week. The reaction medium is concentrated to dryness under reduced pressure and taken up in 150 cm3 of ethyl acetate and 75 cm3 of water. The organic phase is separated out after settling of the phases and washed successively with twice 75 cm3 of water and 50 cm3 of brine. The organic phase is dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa; 50° C.). The crude oil obtained is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 4 cm), eluting with a cyclohexane/ethyl acetate mixture (80/20 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). After drying (90 Pa; 45° C.), 0.32 g of 6,7-difluoro-5-phenyl-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazole-3-amine is obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[S:10][C:9](S(C)(=O)=O)=[N:8][C:6]=2[N:7]=1.[CH3:21][N:22]1[CH2:27][CH2:26][CH:25]([NH:28][CH3:29])[CH2:24][CH2:23]1>C(N(CC)CC)C>[Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[S:10][C:9]([N:28]([CH3:29])[CH:25]3[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]3)=[N:8][C:6]=2[N:7]=1
Reactant: CS(=O)(=O)c1nc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CNC1CCN(C)CC1
Solvent: CCN(CC)CC
Product: CN1CCC(N(C)c2nc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
Alternatively, 5-chloro-2-(methylsulfonyl)-7-morpholinothiazolo[4,5-d]pyrimidine was reacted with 1-methyl-4-(methylamino)piperidine, without triethylamine, via General Procedure C, to give crude 5-chloro-N-methyl-N-(1-methylpiperidin-4-yl)-7-morpholinothiazolo[4,5-d]pyrimidin-2-amine, which was then reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine via General Procedure C again to give 144 after purification by silica gel chromatography. MS (Q1) 441 (M+)
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:9][CH2:8]1.[NH3:24]>CO>[CH2:16]([O:15][CH2:14][CH2:13][N:10]1[CH2:11][CH2:12][CH:7]([CH2:6][CH2:5][CH2:4][C:3]([NH2:24])=[O:2])[CH2:8][CH2:9]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)CCCC1CCN(CCOCc2ccccc2)CC1
Reactant: N
Solvent: CO
Product: NC(=O)CCCC1CCN(CCOCc2ccccc2)CC1
Temperature: 50 °C
Reaction time: 72 h
Yield: 78 %

Procedure:
Compound 3a (1.30 g, 4.0 mmol) was dissolved in 7 N NH3 in methanol (25 mL) in a sealed tube. The resulting solution was stirred at 50° C. for 3 days. After that the solvent was removed under vacuum and the residue was purified by Flash™ chromatography (BIOTAGE, Inc) (9.5:0.45:0.05 dichloromethane/methanol/concentrated ammonium hydroxide, v/v) to provide 4a (0.93 g, 78%) as a white solid. 1H NMR (300 MHz, CD3OD) δ 1.27 (m, 5H), 1.65 (m, 4H), 2.11 (m, 4H), 2.65 (m, 2H), 2.96 (d, 2H), 3.62 (m, 2H), 4.51 (s, 2H), 7.37 (m, 5H). m/z (ESI): 305 [C18H28N2O2+H]+.
Reaction SMILES: [C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH3:12])=[CH:8][C:7]([CH2:13][CH2:14][CH:15]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH3:12])=[CH:8][C:7]([CH2:13][CH2:14][CH2:15][N:27]2[CH2:26][CH2:25][N:24]([C:21]3[CH:20]=[CH:19][C:18]([Cl:17])=[CH:23][CH:22]=3)[CH2:29][CH2:28]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: CCCc1cc(CCC=O)nn1C(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3ccc(Cl)cc3)CC2)nn1C(C)(C)C

Procedure:
62 mg (63%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-propyl-1H-pyrazol-3-yl)propanal (50 mg, 0.225 mmol), 1-(4-chlorophenyl)piperazine (0.034 mg, 0.225 mmol), DIPEA (0.060 mL, 0338 mmol) and NaBH(OAc)3 (143 mg, 0.675 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9](Cl)=[O:10])[CH2:6]1.[CH3:16][NH2:17]>O1CCCC1.O>[Cl:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[O:4][CH:5]1[CH2:8][N:7]([C:9]([NH:17][CH3:16])=[O:10])[CH2:6]1
Reactant: O=C(Cl)N1CC(Oc2ccccc2Cl)C1
Reactant: CN
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)N1CC(Oc2ccccc2Cl)C1
Reaction time: 16 h

Procedure:
A stirred solution of 4.5 g (0.018 mol) of 3-(2-chlorophenoxy)-1-azetidinecarbonyl chloride in 20 ml of tetrahydrofuran was treated with 4 ml (0.05 mol) of 40% aqueous monomethylamine and stirred for 16 h. The reaction mixture was diluted with 200 ml of water and the precipitated product collected by filtration (4.3 g). The crude product was recrystallized from benzene/ligroin yielding 3.9 g (90.0%) of fine white crystals, mp 129.5°-131.5° C.
Reaction SMILES: O[C:2]1[C:11]2[C:10](=[O:12])[C:9]([O:13][CH3:14])=[CH:8][C:7](=[O:15])[C:6]=2[C:5]([OH:16])=[C:4]2[C:17](=[O:37])[C@:18]3([C:32]4[C:31]([OH:33])=[C:30]5[C:25]([CH:26]=[C:27]([CH:35]=O)[NH:28][C:29]5=[O:34])=[CH:24][C:23]=4[CH2:22][CH2:21]3)[C:19](=[O:20])[C:3]=12.[Cl-].[OH:39][NH3+:40].N1C=CC=CC=1.[OH2:47]>CN(C=O)C>[OH:47][C:2]1[C:11]2[C:10](=[O:12])[C:9]([O:13][CH3:14])=[CH:8][C:7](=[O:15])[C:6]=2[C:5]([OH:16])=[C:4]2[C:17](=[O:37])[C@:18]3([C:32]4[C:31]([OH:33])=[C:30]5[C:25]([CH:26]=[C:27]([CH:35]=[N:40][OH:39])[NH:28][C:29]5=[O:34])=[CH:24][C:23]=4[CH2:22][CH2:21]3)[C:19](=[O:20])[C:3]=12
Reactant: COC1=CC(=O)c2c(O)c3c(c(O)c2C1=O)C(=O)[C@]1(CCc2cc4cc(C=O)[nH]c(=O)c4c(O)c21)C3=O
Reactant: O
Reactant: [NH3+]O
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COC1=CC(=O)c2c(O)c3c(c(O)c2C1=O)C(=O)[C@]1(CCc2cc4cc(C=NO)[nH]c(=O)c4c(O)c21)C3=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ten (10) mg (19.4 μmol) fredericamycin aldehyde (4) are dissolved in 2 mL DMF. After addition of 3.1 mg (44.6 μmol) hydroxylammonium chloride, 3.2 μl pyridine are added. Stirring for 2 h at room temperature. The reaction mixture is added to 50 ml water and extracted 3 times with ethyl acetate. After drying and concentration, a deep red amorphous crystal powder was left (HPLC clean).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:41])[CH2:9][CH2:10][N:11]([CH3:40])[C:12](=[O:39])[CH2:13][N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([O:25]C)=[O:24])[CH:21]=2)[C:16]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[C:15]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Cl>O1CCOCC1.O.CO>[C:1]([O:5][C:6]([N:8]([CH3:41])[CH2:9][CH2:10][N:11]([CH3:40])[C:12](=[O:39])[CH2:13][N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:23]([OH:25])=[O:24])[CH:21]=2)[C:16]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[C:15]1[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3)n(CC(=O)N(C)CCN(C)C(=O)OC(C)(C)C)c2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: CN(CCN(C)C(=O)OC(C)(C)C)C(=O)Cn1c(-c2ccccc2)c(C2CCCCC2)c2ccc(C(=O)O)cc21
Temperature: 60 °C
Reaction time: 4 h

Procedure:
The crude methyl 1-{2-[{2-[(tert-butoxycarbonyl)(methyl)amino]ethyl}(methyl)amino]-2-oxoethyl}-3-cyclohexyl-2-phenyl-1H-indole-6-carboxylate in dioxane/H2O/MeOH solution (1:1:1; 0.06 M) was treated with an aqueous solution of KOH (5N) (3 eq). The solution was stirred at 60° C. for 4 h. The volume of the solution was reduced in vacuo, and the mixture acidified with HCl (1N) before extracting with EtOAc (2×). The combined organic fractions were washed with brine, before being dried over Na2SO4, filtered and concentrated in vacuo. The crude was then used in the next step without any further purification. (ES+) m/z 548 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[N:12]1[CH:17]=[CH:16][C:15]([CH2:18][NH:19][C:20]([C:22]2[C:26]([CH3:27])=[C:25]([CH:28]=O)[NH:24][C:23]=2[CH3:30])=[O:21])=[CH:14][CH:13]=1>>[N:12]1[CH:13]=[CH:14][C:15]([CH2:18][NH:19][C:20]([C:22]2[C:26]([CH3:27])=[C:25]([CH:28]=[C:5]3[C:4]4[C:8](=[CH:9][CH:10]=[C:2]([Br:1])[CH:3]=4)[NH:7][C:6]3=[O:11])[NH:24][C:23]=2[CH3:30])=[O:21])=[CH:16][CH:17]=1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCc1ccncc1
Reactant: O=C1Cc2cc(Br)ccc2N1
Product: Cc1[nH]c(C=C2C(=O)Nc3ccc(Br)cc32)c(C)c1C(=O)NCc1ccncc1
Yield: 4 %

Procedure:
5-Bromo-1,3-dihydroindol-2-one (170 mg, 0.8 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (pyridin-4-ylmethyl)amide (200 mg) to give 14 mg (4%) of the title compound as a yellow solid.
Reaction SMILES: C([O-])(=O)C.[CH:5]1([NH3+:8])[CH2:7][CH2:6]1.C([O:11][C:12](=O)[CH2:13][S:14][C:15]#[N:16])C>>[CH:5]1([NH:8][C:15]2[S:14][CH2:13][C:12](=[O:11])[N:16]=2)[CH2:7][CH2:6]1
Reactant: CCOC(=O)CSC#N
Reactant: [NH3+]C1CC1
Agent: CC(=O)[O-]
Product: O=C1CSC(NC2CC2)=N1
Temperature: 90 °C
Reaction time: 8 h
Yield: 36.6 %

Procedure:
A solution of ethyl chloroacetate (20 g, 0.16 mol) and potassium thiocyanate (12.7 g, 0.13 mol) in ethanol (100 ml) was refluxed for 3 h. The solution was filtered and concentrated under reduced pressure to afford 18.7 g of thiocyanato-acetic acid ethyl ester (97%). A mixture of cyclopropylammonium acetate (0.50 g, 4.27 mmol) and thiocyanato-acetic acid ethyl ester (0.62 g, 4.27 mmol) was heated to 90° C. for 3 h, and left at rt overnight. The reaction mixture was partitioned between 6N HCl and dichloromethane. The layers were separated. The aqueous layer was made basic by the addition of 6N ammonium hydroxide, and then concentrated to dryness. The crude was triturated with dichloromethane and the solution separated from the solid by filtration. This solution was dried over sodium sulfate and concentrated to dryness. The crude was purified on a silica gel column with 100% ethyl acetate to afford 2-cyclopropylamino-thiazol-4-one (244 mg, 37%).
Reaction SMILES: [CH:1]1(N=C=NC2CCCCC2)CCCCC1.[Br:16][CH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[CH:20][C:19]=1[N+:27]([O-:29])=[O:28].CN(CC1C=CN=CC=1)C>ClCCl.ClCCl.CO>[CH3:1][O:23][C:22](=[O:24])[C:21]1[CH:25]=[CH:26][C:18]([CH2:17][Br:16])=[C:19]([N+:27]([O-:29])=[O:28])[CH:20]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)c1ccc(CBr)c([N+](=O)[O-])c1
Agent: CN(C)Cc1ccncc1
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccc(CBr)c([N+](=O)[O-])c1
Reaction time: 6 h

Procedure:
A solution of dicyclohexylcarbodiimide (DCC, 0.95 g, 4.61 mmol, 1.2 equiv) in 10 mL of dichloromethane (DCM) was added dropwise to a stirred mixture of 4-bromomethyl-3-nitro-benzoic acid 1 (1.0 g, 3.84 mmol, 1.0 equiv) and 4-dimethylaminomethylpyridine (DMAP) (0.020 g, 0.19 mmol, 0.05 equiv) in 10 mL of dichloromethane-methanol (10%) at room temperature. The mixture was stirred for 6 hours to obtain 4-bromomethyl-3-nitro-benzoic acid methyl ester 2. Dicyclohexyl urea (DCU) thus obtained was removed by filtration and the solvent in the filtered solution was removed under vacuum. The residue was purified by column chromatography using hexane-ethyl acetate (15%) as an eluant to give ester 2 as a light yellow oil.
Reaction SMILES: C1C2C(=CC=CC=2)C[N:2]1[CH2:10][CH2:11][C:12]1[CH:13]=[C:14]([NH:22][C:23]([CH:25]2[CH2:34][C:33]3[CH:32]=[C:31]([O:35][C:36]4[CH:41]=[CH:40][N:39]=[C:38]([C:42]([NH:44][CH3:45])=[O:43])[CH:37]=4)[CH:30]=[CH:29][C:28]=3[CH2:27][CH2:26]2)=[O:24])[CH:15]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:17]=1.C(N)CN>CCOC(C)=O.O>[NH2:2][CH2:10][CH2:11][C:12]1[CH:13]=[C:14]([NH:22][C:23]([CH:25]2[CH2:34][C:33]3[CH:32]=[C:31]([O:35][C:36]4[CH:41]=[CH:40][N:39]=[C:38]([C:42]([NH:44][CH3:45])=[O:43])[CH:37]=4)[CH:30]=[CH:29][C:28]=3[CH2:27][CH2:26]2)=[O:24])[CH:15]=[C:16]([C:18]([F:21])([F:19])[F:20])[CH:17]=1
Reactant: CNC(=O)c1cc(Oc2ccc3c(c2)CC(C(=O)Nc2cc(CCN4Cc5ccccc5C4)cc(C(F)(F)F)c2)CC3)ccn1
Solvent: NCCN
Solvent: O
Solvent: CCOC(C)=O
Product: CNC(=O)c1cc(Oc2ccc3c(c2)CC(C(=O)Nc2cc(CCN)cc(C(F)(F)F)c2)CC3)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 106.9 %

Procedure:
A solution of 4-{[7-({[3-[2-(1,3-dihydro-2H-isoindol-2-yl)ethyl]-5-(trifluoromethyl)phenyl]amino}carbonyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}-N-methylpyridine-2-carboxamide (0.158 g, 0.25 mmol) and ethane-1,2-diamine (2 mL) was allowed to stir at rt overnight. The reaction mixture was diluted with EtOAc and water. The solution was extracted with EtOAc. The combined organic solutions were washed with brine and concentrated to give a white solid. The residue was purified by column chromatography to give 4-{[7-({[3-(2-aminoethyl)-5-(trifluoromethyl)phenyl]-amino}carbonyl)-5,6,7,8-tetrahydronaphthalen-2-yl]oxy}-N-methylpyridine-2-carboxamide (I-47, 137 mg, 29%) as the formate salt. 1H NMR (300 MHz, CD3OD): δ 8.44 (d, 1H), 8.42 (s, 1H), 7.91 (s, 1H), 7.78 (s, 1H), 7.51 (s, 1H), 7.34 (s, 1H), 7.24-7.21 (m, 1H), 7.07-7.04 (m, 1H), 6.92-6.89 (m, 1H), 3.24-3.19 (m, 2H), 3.10-2.78 (m, 9H), 2.56-2.13 (m, 1H), and 2.03-1.84 (m, 2H).
Reaction SMILES: C[Mg]Br.[C:4]1(C)C=CC=CC=1.[CH2:11]([O:13][P:14]([N:19]1[CH:25]2[CH:20]1[CH2:21][CH2:22][N:23]([C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[CH2:24]2)([O:16][CH2:17][CH3:18])=[O:15])[CH3:12].O>C1COCC1>[CH2:11]([O:13][P:14]([NH:19][C@H:25]1[C@H:20]([CH3:4])[CH2:21][CH2:22][N:23]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:24]1)([O:16][CH2:17][CH3:18])=[O:15])[CH3:12]
Reactant: Cc1ccccc1
Reactant: CCOP(=O)(OCC)N1C2CCN(C(=O)OCc3ccccc3)CC21
Agent: C[Mg]Br
Solvent: O
Solvent: C1CCOC1
Product: CCOP(=O)(N[C@@H]1CN(C(=O)OCc2ccccc2)CC[C@H]1C)OCC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 48 %

Procedure:
To a suspension of Cu(I)I (0.10 g, 0.54 mmol) in THF (20 mL) was slowly added 1.40M methylmagnesium bromide (15.5 mL, 21.7 mmol) in 3:1 toluene:THF at −30° C. After stirring at that temperature for 15 minutes, a solution of benzyl 7-(diethoxyphosphoryl)-3,7-diazabicyclo[4.1.0]heptane-3-carboxylate (2.00 g, 5.43 mmol, Example H, Step D) in THF (10 mL) was added at −30° C. The mixture was then slowly warmed to 0° C. in 2 hours and stirred at 0° C. for 2 hours. Water (20 mL) was added and extracted with ethyl acetate (2×30 mL), washed with brine, dried (sodium sulfate) and concentrated in vacuo. The residue obtained was purified by flash chromatography on silica gel (ethyl acetate) to give trans-benzyl 3-(diethoxyphosphorylamino)-4-methylpiperidine-1-carboxylate (1.00 g, 48%) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[S:17][C:10]=12.FC1C=C(NC(=O)CC(NC2C=CC=CC=2OC)=O)C=CC=1OC1C=CN=C2C=C(C3N(C)C=CN=3)SC=12.COC1C=CC=CC=1NC(=O)CC(O)=O.[CH3:78][CH:79]([C:83](=[O:91])[NH:84][C:85]1[CH:90]=[CH:89][CH:88]=[CH:87][CH:86]=1)[C:80](O)=[O:81]>>[F:1][C:2]1[CH:3]=[C:4]([NH:24][C:80](=[O:81])[CH:79]([CH3:78])[C:83]([NH:84][C:85]2[CH:86]=[CH:87][CH:88]=[CH:89][CH:90]=2)=[O:91])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[S:17][C:10]=12
Reactant: Cn1ccnc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Reactant: CC(C(=O)O)C(=O)Nc1ccccc1
Agent: COc1ccccc1NC(=O)CC(=O)Nc1ccc(Oc2ccnc3cc(-c4nccn4C)sc23)c(F)c1
Agent: COc1ccccc1NC(=O)CC(=O)O
Product: CC(C(=O)Nc1ccccc1)C(=O)Nc1ccc(Oc2ccnc3cc(-c4nccn4C)sc23)c(F)c1

Procedure:
Starting from the amine 9 and following the procedure described above for compound 28a (example 8, step 2) but substituting acid 27 for the acid 37, title compound 38 was obtained as a white solid (20% yield). 1H NMR (d6-DMSO) δ (ppm): 10.99 (s, 1H), 10.51 (s, 1H), 8.64 (d. 1H), 8.25 (s, 1H), 7.94 (s, 1H), 7.80 (s, 1H), 7.65 (d, 2H) 7.57-7.48 (m, 2H), 7.28 (t, 2H), 7.03 (t, 1H), 6.88 (d, 1H), 4.08 (s, 3H), 1.18 (s, 3H). MS (m/z): 516.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH:13][C@@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]([O:22]C)=[O:21])[CH2:16][C@@H:15]1[NH:24][C:25]([C:27]1[S:28][C:29]3[CH2:30][N:31]([CH3:36])[CH2:32][CH2:33][C:34]=3[N:35]=1)=[O:26])=[O:12])=[CH:5]2.[OH-].[Li+].Cl>O1CCCC1.O>[ClH:1].[C:20]([C@H:17]1[CH2:18][CH2:19][C@@H:14]([NH:13][C:11]([C:6]2[NH:7][C:8]3[C:4]([CH:5]=2)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)=[O:12])[C@@H:15]([NH:24][C:25]([C:27]2[S:28][C:29]3[CH2:30][N:31]([CH3:36])[CH2:32][CH2:33][C:34]=3[N:35]=2)=[O:26])[CH2:16]1)([OH:22])=[O:21]
Reactant: COC(=O)[C@H]1CC[C@@H](NC(=O)c2cc3cc(Cl)ccc3[nH]2)[C@@H](NC(=O)c2nc3c(s2)CN(C)CC3)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCc2nc(C(=O)N[C@H]3C[C@@H](C(=O)O)CC[C@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 149.2 %

Procedure:
(1R*,2S*,4S*)-N1-[(5-Chloroindol-2-yl)carbonyl]-4-methoxycarbonyl-N2-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexane-diamine (180 mg) was dissolved in a mixed solvent of tetrahydrofuran (8 ml) and water (2 ml), and lithium hydroxide (17 mg) was added to stir the mixture at room temperature for 45 minutes. After adding 1N hydrochloric acid, the reaction mixture was concentrated under reduced pressure, a small amount of water was added to the residue, and solids deposited were collected by filtration to obtain the title compound (140 mg) as a pale yellow solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:12]#[N:13])[C:7](=O)[NH:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].CN(C)C1C=CC=CC=1.O=P(Cl)(Cl)[Cl:25].[OH-].[Na+]>ClC1C=CC=CC=1>[C:1]([C:4]1[C:9]([CH3:10])=[N:8][C:7]([Cl:25])=[C:6]([C:12]#[N:13])[CH:5]=1)(=[O:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)c1cc(C#N)c(=O)[nH]c1C
Agent: [Na+]
Agent: [OH-]
Solvent: Clc1ccccc1
Solvent: CN(C)c1ccccc1
Product: CC(=O)c1cc(C#N)c(Cl)nc1C
Temperature: 100 °C

Procedure:
35 g (0.2 mol) of 5-acetyl-3-cyano-6-methyl-2-pyridone* are suspended in 400 ml of chlorobenzene, 24.2 g (0.2 mol) of N,N-dimethylaniline are added, and 37 g (0.24 mol) of POCl3 are added dropwise. The mixture is then heated at 100° C. for three hours. After cooling, the mixture is cautiously poured onto water, neutralization with dilute sodium hydroxide solution is carried out, the organic phase is separated off, and the aqueous phase is again extracted with CHCl3. The combined extracts are dried with Na2SO4 and evaporated. The residue is purified by filtration through silica gel, using CH2Cl2 /ethyl acetate as eluent.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:20])=[C:6]([C@:8]2([CH3:19])[C:13]([F:15])([F:14])[C:12]([CH3:17])([CH3:16])[O:11][C:10]([NH2:18])=[N:9]2)[CH:7]=1.[F:21][C:22]([F:33])([F:32])[C:23]1[CH:24]=[N:25][C:26]([C:29](O)=[O:30])=[N:27][CH:28]=1>>[NH2:18][C:10]1[O:11][C:12]([CH3:16])([CH3:17])[C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:29]([C:26]3[N:25]=[CH:24][C:23]([C:22]([F:32])([F:21])[F:33])=[CH:28][N:27]=3)=[O:30])[CH:3]=[CH:4][C:5]=2[F:20])([CH3:19])[N:9]=1
Reactant: CC1(C)OC(N)=N[C@](C)(c2cc(N)ccc2F)C1(F)F
Reactant: O=C(O)c1ncc(C(F)(F)F)cn1
Product: CC1(C)OC(N)=N[C@](C)(c2cc(NC(=O)c3ncc(C(F)(F)F)cn3)ccc2F)C1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4,6,6-trimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-2) and 5-trifluoromethyl-pyrimidine-2-carboxylic acid following procedure I yielded the title compound as a white foam. MS (ISP): m/z=462.2 [M+H]+.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].Cl.[NH2:7][CH:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[O:10][CH2:9]1.C(N(CC)CC)C>O1CCCC1>[Cl:1][CH2:2][C:3]([NH:7][CH:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[O:10][CH2:9]1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: NC1COc2ccccc2C1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CCl)NC1COc2ccccc2C1=O
Reaction time: 1 h
Yield: 28.1 %

Procedure:
Chloroacetyl chloride (41.6 g, 368 mmol) was added to a solution of 3-amino-chroman-4-one hydrochloride (67 g, 335 mmol) and triethylamine (102 g, 1.01 mol) in tetrahydrofuran (700 ml) and the mixture was stirred for one hour. The solution was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; 5-10% methanol in chloroform) to afford 2-chloro-N-(4-oxo-chroman-3-yl)-acetamide (22.6 g, 94.3 mmol, 28%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([OH:21])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23](=[O:27])[N:24]([CH3:26])[CH3:25].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:36][C:37]1[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=1.O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:36][C:37]4[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:4][C:3]=1[NH:22][C:23](=[O:27])[N:24]([CH3:26])[CH3:25]
Reactant: ClCc1ccncc1
Reactant: COc1cc2c(Oc3ccc(NC(=O)N(C)C)c(Cl)c3)ncnc2cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(Oc3ccc(NC(=O)N(C)C)c(Cl)c3)ncnc2cc1OCc1ccncc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 60 %

Procedure:
A starting compound (N′-{2-chloro-4-[(7-hydroxy-6-methoxy-4-quinazolinyl)oxy]phenyl}-N,N-dimethylurea, 50 mg), potassium carbonate (138 mg), and 4-chloromethylpyridine hydrochloride (49 mg) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was purified by HPLC by development with chloroform/methanol to give 37 mg (yield 60%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[CH2:9]Br.[C:11]([O-:14])(=[O:13])[CH3:12].[K+]>CN(C)C=O>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[C:3]=1[CH2:9][O:14][C:11](=[O:13])[CH3:12]
Reactant: CC(=O)[O-]
Reactant: BrCc1c(Br)cccc1Br
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)OCc1c(Br)cccc1Br
Temperature: 70 °C
Yield: 61.1 %

Procedure:
To 1,3-Dibromo-2-bromomethyl-benzene (3.35 g, 10.2 mmol) was added potassium acetate (4.00 g, 40.8 mmol) and 25 mL N,N-dimethylformamide. This was heated at 70° C. for 20 minutes. The resulting mixture was partitioned between water and ethyl acetate. The ethyl acetate layer was washed with water, washed with brine, dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by flash chromatography (gradient elution 0 to 5% ethyl acetate hexanes) to yield Acetic acid 2,6-dibromo-benzyl ester (1.92 g, 6.23 mmol). 1HNMR (300 MHz, CDCl3) δ 2.12 (s, 3H), 5.42 (s, 2H), 7.08 (t, J=8 Hz, 1H), and 7.58 (d, J=8 Hz, 2H).