Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].CCN(CC)CC.NCCS(O)(=O)=[O:43].Cl>CN1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([OH:43])[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: NCCS(=O)(=O)O
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Agent: CN1CCCC1
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1cc(F)ccc1-c1nc(O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 26.6 %

Procedure:
To a solution of 8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-methanesulfonyl-8H-pyrido[2,3-d]pyrimidin-7-one (223 mg, 0.5 mmol) in N-methylpyrollidine (5 mL) was added Et3N (0.1 mL) followed by 2-aminoethanesulfonic acid (200 mg, 1.5 mmol, 3 eq) and the reaction mixture was heated to 50° for 12 h. 1 M aq HCl was then added dropwise till pH 3. The reaction mixture was then extracted with EtOAc (2×20 mL). Organic layers were combined, washed with satd aq NaCl, dried (MgSO4), filtered and solvent was evaporated. The yellow residue was then purified by flash chromatography to give an oily product, which was then recrystalized from methanol:H2O (3:1) to afford 51 mg of pure 8-(2,6-difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-hydroxy-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR (CDCl3): δ 2.24 (s, 3H), 6.31 (d, 1H, J=9.8 Hz), 7.02 (m, 5H). 7.23 (m, 1H), 7.352 (m, 1H), LC MS (m/e)=384.2 (MH+). Rt=1.65 min.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:22])[CH:10]=[N+:11]([O-])[C:12]=2[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:7]1=[O:23]>C(OC(=O)C)(=O)C>[C:16]([O:18][C:10]1[N:11]=[C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:13]2[CH2:14][CH2:15][N:6]([CH2:5][C:4]3[CH:24]=[CH:25][C:26]([F:27])=[C:2]([Cl:1])[CH:3]=3)[C:7](=[O:23])[C:8]=2[C:9]=1[O:22][C:9](=[O:22])[CH3:8])(=[O:17])[CH3:12]
Reactant: CCOC(=O)c1c2c(c(O)c[n+]1[O-])C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1nc(OC(C)=O)c(OC(C)=O)c2c1CCN(Cc1ccc(F)c(Cl)c1)C2=O

Procedure:
A solution of ethyl 6-(3-chloro-4-fluorobenzyl)-4-hydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate 2-oxide (23 g, 58 mmol) in acetic anhydride (400 mL) was heated under nitrogen at 100° C. for one hour. The product mixture was concentrated under vacuum to the title bisacetate and was used in the following step without further purification.
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[Cl:5][C:6]1[C:7]([OH:15])=[N:8][O:9][C:10]=1[CH2:11][S:12][CH2:13][CH3:14]>C1C=CC=CC=1>[Cl:5][C:6]1[C:7](=[O:15])[N:8]([C:1]([Cl:4])=[O:2])[O:9][C:10]=1[CH2:11][S:12][CH2:13][CH3:14]
Reactant: O=C(Cl)Cl
Reactant: CCSCc1onc(O)c1Cl
Solvent: c1ccccc1
Product: CCSCc1on(C(=O)Cl)c(=O)c1Cl
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of 0.5 ml of phosgene in 5 ml of benzene was added to 581 mg of 4-chloro-3-hydroxy-5-ethylthiomethylisoxazole, and then the mixture was stirred at room temperature for 5 hours, after which the solvent and excess phosgene were distilled off, to produce 4-chloro-2-chlorocarbonyl-5-ethylthiomethyl-4-isoxazolin-3-one. This was dissolved, without purification, in 30 ml of benzene and an equimolar mixture of the calculated amount of dimethylamine with triethylamine in 5 ml of benzene was added, with stirring, at room temperature. The mixture was stirred for a further 30 minutes and then washed, in turn, with 0.1N sulphuric acid (twice, 10 ml each time) and then water (3 times, 10 ml each time). The benzene layer was dried over anhydrous sodium sulphate, and the solvent was distilled off. The residue was purified by column chromatography through silica gel, eluted with a 25:1 by volume mixture of benzene and acetone. The solvent was distilled from the eluate, to give 661 mg (yield 83.2%) of the title compound in the form of an oil having a refractive index, nD22 =1.5454.
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[C:11]([N:20](S(C2C=CC(C(C)(C)C)=CC=2)(=O)=O)[S:21]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([CH3:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[N:10]([CH3:47])[N:9]=1)(=O)C.[OH-].[Na+]>C(O)C>[C:30]([C:27]1[CH:26]=[CH:25][C:24]([S:21]([NH:20][C:11]2[N:10]([CH3:47])[N:9]=[C:8]([O:7][CH2:6][CH2:5][OH:4])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)(=[O:22])=[O:23])=[CH:29][CH:28]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(=O)OCCOc1nn(C)c(N(S(=O)(=O)c2ccc(C(C)(C)C)cc2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(-c2c(OCCO)nn(C)c2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reaction time: 16 h
Yield: 48 %

Procedure:
To 2-{[5-(bis {[4-(tert-butyl)phenyl]sulfonyl}amino)-1-methyl-4-(4-methylphenyl)-1H-pyrazol-3-yl]oxy}ethyl acetate (Preparation 4) (80 mg) in ethanol (20 ml) at room temperature was added 2M sodium hydroxide (2 ml) and the mixture was stirred for 16 hrs. The mixture was reduced in volume to 10 ml by rotary evaporation, diluted with water (50 ml) and extracted with ethyl acetate (2×50 ml). The organic fraction was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica (10 g) eluted with dichloromethane to yield the title compound as a white solid (25 mg).
Reaction SMILES: [C-:1]#[N:2].[K+].Br[CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:20][CH3:21])=[C:10]([S:12]([NH:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])=[O:13])[CH:11]=1>CS(C)=O>[C:1]([CH2:5][C:6]1[CH:7]=[CH:8][C:9]([O:20][CH3:21])=[C:10]([S:12]([NH:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])=[O:13])[CH:11]=1)#[N:2]
Reactant: COc1ccc(CBr)cc1S(=O)(=O)NC(C)(C)C
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(CC#N)cc1S(=O)(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.7 %

Procedure:
A mixture of 1.63 g potassium cyanide and 8 g of the compound from Example 1 in 50 ml of DMSO was stirred at room temperature overnight. The solution became darker in color with time, going from orange to purple to black. After being stirred overnight the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), filtered and the solvent evaporated. The residual red oil was eluted through a dry silica column with 20% ethyl acetate--80% dichloromethane. The product band was isolated to give 3.0 g solid m.p. 146°-147° C.;
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].CO[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[C:25]3[C:20](=[CH:21][C:22]([Br:26])=[CH:23][CH:24]=3)[NH:19][N:18]=2)[CH2:13][CH2:12]1)=O.O>C1COCC1>[Br:26][C:22]1[CH:21]=[C:20]2[C:25]([C:17]([CH:14]3[CH2:15][CH2:16][N:11]([CH3:9])[CH2:12][CH2:13]3)=[N:18][NH:19]2)=[CH:24][CH:23]=1
Reactant: COC(=O)N1CCC(c2n[nH]c3cc(Br)ccc23)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCC(c2n[nH]c3cc(Br)ccc23)CC1
Yield: 55.3 %

Procedure:
To a stirred suspension of LiAlH4 (6.2 g, 0.083 mol of a 50-55% oil dispersion) in THF (175 ml), under nitrogen, was added, dropwise, 4-(6-bromo-1H-indazol-3-yl)piperidine-1-carboxylic acid methyl ester (28.1 g, 0.083 mol) of Example 106 (a). The reaction was refluxed for 1 hour, cooled in an ice bath, and water was added. The reaction was filtered and the filtrate was concentrated to yield 13.5 g of a solid. The solid was recrystallized from toluene to yield 10.2 g (42%) of a solid, mp 203°-205° C. An analytical sample was obtained by chromatography of a 3.4 g sample on a preparative HPLC (silica gel column) utilizing CH2Cl2 --CH3OH--(C2H5)2NH (95:4:1) as eluent. After evaporation of the appropriate fractions there remained 2.8 g of 6-bromo-3-(1-methyl-4-piperidinyl)-1H-indazole, mp 205°-207° C.
Reaction SMILES: [N+](C1C=CC(C([O:10][C@H:11]2[CH2:19][C:18]3[C:13](=[CH:14][C:15]([O:20][CH3:21])=[CH:16][CH:17]=3)[C@H:12]2[N:22]=[N+:23]=[N-:24])=O)=CC=1)([O-])=O.C[O-].[Na+]>CO.C(Cl)Cl>[N:22]([C@@H:12]1[C:13]2[C:18](=[CH:17][CH:16]=[C:15]([O:20][CH3:21])[CH:14]=2)[CH2:19][C@@H:11]1[OH:10])=[N+:23]=[N-:24]
Reactant: COc1ccc2c(c1)[C@@H](N=[N+]=[N-])[C@@H](OC(=O)c1ccc([N+](=O)[O-])cc1)C2
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COc1ccc2c(c1)[C@@H](N=[N+]=[N-])[C@@H](O)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
Step AC (4): To a solution of (1R,2S)-1-azido-6-methoxy-2,3-dihydro-1H-inden-2-yl 4-nitrobenzoate (248 mg) from Step AC (3) in methanol (2.8 mL) and DCM (2.4 mL) was added sodium methoxide (114 mg), and the reaction mixture was stirred at rt for 30 min. the solvents were removed in vacuo, and water was added. The aqueous layer was separated, and the aqueous layer was extracted with EtOAc (×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated in vacuo, and the residue was purified by preparative TLC eluting with 30% EtOAc/70% hexanes to give (1R,2S)-1-azido-6-methoxy-2,3-dihydro-1H-inden-2-ol compound as a white solid (100 mg). 1H NMR (400 MHz, CDCl3) δ 7.15 (1H, d), 6.91 (1H, d), 6.87 (1H, dd), 4.72 (1H, d), 4.57 (1H, t), 3.80 (3H, s), 3.09 (1H, dd), and 2.84 (1H, dd). The ee of this product was 86% by chiral HPLC (chircel OJ-H column, 4.6×250 mm, 5 μm; mobile phase: 5% ethanol in CO2; flow rate: 2.0 mL/min). Retention time of the title compound: 10.04 min; Retention time of the other enantiomer: 7.38 min.
Reaction SMILES: O[C:2]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[C:34]([OH:39])[CH:33]=2)(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19].C1(C)C=CC(S(O)(=O)=O)=CC=1>ClC(Cl)C>[C:18]([C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:31][C:32]2[CH:33]=[C:34]([OH:39])[C:35]([CH3:38])=[CH:36][C:37]=2[C:2]2([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[NH:4][C:3]2=[O:11])(=[O:30])=[O:29])=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1ccc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1O
Reactant: O=C1Nc2ccccc2C1(O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(Cl)Cl
Product: Cc1cc(C2(c3ccccc3)C(=O)Nc3ccccc32)c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1O
Temperature: 25 °C
Yield: 89.4 %

Procedure:
As another non-limiting example, 4-tert-butyl-N-[5-hydroxy-4-methyl-2-(2-oxo-3-phenyl-2,3-dihydro-1H-indol-3-yl)-phenyl]-benzenesulfonamide (compound 1430) was synthesized by adding dropwise 4-tert-butyl-benzenesulfonyl chloride (8 g, 34 mmol) in 5 mL dichloromethane to a stirring solution of 5-Amino-2-methyl-phenol (4 g, 32 mmol) in 20 mL pyridine and letting the mixture spin overnight at room temperature. The resulting mixture was concentrated in vacuo and the product was purified by column chromatography to yield 8 g (78%) of 4-tert-butyl-N-(3-hydroxy-4-methyl-phenyl)-benzenesulfonamide. A mixture of 3-hydroxy-3-phenyl-1,3-dihydro-indol-2-one (3.9 g, 17 mmol), 4-tert-butyl-N-(3-hydroxy-4-methyl-phenyl)-benzenesulfonamide (7 g, 22 mmol) and p-toluenesulfonic acid (6.5 g, 32 mmol) in dichloroethane was refluxed for 12 hours. The resulting mixture was cooled to room temperature to yield a colorless solid. The solid was filtered and purified using column chromatography to yield 8 g (88%) of the desired product (compound 1430).
Reaction SMILES: [CH3:1][N:2]([CH3:27])[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[S:8][C:9](=[CH:13][C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]3)=[CH:16][CH:15]=2)[C:10](=[O:12])[N:11]=1.[NH2:28][CH2:29][C@H:30]([OH:39])[CH2:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH3:27][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][NH:6][C:7]1[S:8][C:9](=[CH:13][C:14]2[CH:15]=[CH:16][C:17]([N:20]3[CH2:25][CH2:24][CH:23]([NH:28][CH2:29][C@H:30]([OH:39])[CH2:31][O:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:22][CH2:21]3)=[CH:18][CH:19]=2)[C:10](=[O:12])[N:11]=1
Reactant: CN(C)CCCNC1=NC(=O)C(=Cc2ccc(N3CCC(=O)CC3)cc2)S1
Reactant: NC[C@H](O)COc1ccccc1
Product: CN(C)CCCNC1=NC(=O)C(=Cc2ccc(N3CCC(NC[C@H](O)COc4ccccc4)CC3)cc2)S1

Procedure:
The title compound was prepared from 1-{4-[2-(3-dimethylamino-propylamino)-4-oxo-4H-thiazol-5-ylidenemethyl]-phenyl}-piperidin-4-one (which was obtained in Intermediate 33) and (2S)-1-amino-3-phenoxy-propan-2-ol (which was obtained in Intermediate 3) according to the procedure of Example 1 as a yellowish solid; mp 166-168° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ1.20-1.40 (m, 10 H), 1.60-1.80 (m, 2 H), 1.80-2.00 (m, 2 H), 2.19 (s, 6 H), 2.25 (t, J=6.8 Hz, 2 H), 2.55-3.00(m, 5 H), 3.50-4.05(m, 7 H), 6.65-6.95(m, 3 H), 7.02 (d, J=9.0 Hz, 2 H), 7.20-7.30 (m, 2 H), 7.40 (d, J=9.0 Hz, 2 H), 7.48 (s, 1 H); MS (ES) m/z: 269.6 (M+2H)2+, 100%), 538.1(MH+, 10%); HRMS Calcd. for C29H40N5O3S (MH): 538.2852. Found 538.2885.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[N:12]([CH:13]=1)[CH2:11][CH2:10][C:9]1[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=1[C:7]2=[O:18])(=[O:3])N.S(=O)(=O)(O)[OH:20].N([O-])=O.[Na+]>O>[O:18]=[C:7]1[C:8]2[CH:17]=[CH:16][CH:15]=[CH:14][C:9]=2[CH2:10][CH2:11][N:12]2[CH:13]=[C:4]([C:1]([OH:20])=[O:3])[CH:5]=[C:6]12
Reactant: O=S(=O)(O)O
Reactant: NC(=O)c1cc2n(c1)CCc1ccccc1C2=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc2n(c1)CCc1ccccc1C2=O
Yield: 89 %

Procedure:
To 2-carbamoyl-6,11-dihydro-pyrrolo[2,1-b][3]-benzazepine-11-one (27 g., 0.112 moles) in 300 ml. of 50% sulfuric acid maintained at 50° C., was added slowly 25 g. of sodium nitrite in 75 ml. of water. At the end of the addition, the solid was filtered, washed with water and air-dried to yield 6,11-dihydro-11-oxo-pyrrolo[2,1-b][3]-benzazepine-2-carboxylic acid (24 g., 89%), m.p. 287°-290° C.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[N:12]=2)[CH:4]=1)[CH3:2].[C:19]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)(=[O:21])[CH3:20]>>[C:19]([N:22]1[CH2:27][CH2:26][N:25]([CH2:17][C:13]2[N:12]=[C:11]([C:5]3[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=3[CH3:10])[CH:16]=[CH:15][CH:14]=2)[CH2:24][CH2:23]1)(=[O:21])[CH3:20]
Reactant: CCc1cc(-c2cccc(C=O)n2)c(C)[nH]c1=O
Reactant: CC(=O)N1CCNCC1
Product: CCc1cc(-c2cccc(CN3CCN(C(C)=O)CC3)n2)c(C)[nH]c1=O

Procedure:
5′-Ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[2,3′]bipyridinyl-6-carbaldehyde prepared in accordance with PREPARATION 11 is reacted with 4-acetylpiperazine as described in Method A, Example 123 to give the title compound. MS: m/e=355 (M+H).
Reaction SMILES: [Br:1]Br.[CH3:3][N:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[C:5]1=[O:14]>C(O)(=O)C>[Br:1][C:12]1[C:11]2[C:6](=[CH:7][N:8]=[CH:9][CH:10]=2)[C:5](=[O:14])[N:4]([CH3:3])[CH:13]=1
Reactant: BrBr
Reactant: Cn1ccc2ccncc2c1=O
Solvent: CC(=O)O
Product: Cn1cc(Br)c2ccncc2c1=O
Temperature: 15 °C
Reaction time: 1 h
Yield: 27.4 %

Procedure:
Bromine (1.1 g, 6.87 mmol) in acetic acid (10 mL) was added dropwise to 2-methyl-2,7-naphthyridin-1-one (1.1 g, 6.87 mmol) in acetic acid (60 mL) at 10-15° C. After stirring at 15° C. for 1 h, the mixture was concentrated under vacuum. Purification by silica gel chromatography (DCM: MeOH=50:1 to 10:1) gave the title compound (0.45 g, 27.4%) as a yellow solid. 1H NMR (CDCl3, 400 MHz) δ 9.61 (1H, s), 8.86-8.85 (1H, d, J=5.6 Hz), 7.62-7.60 (1H, d, J=5.6 Hz), 7.56 (1H, s), 3.63 (3H, s).
Reaction SMILES: [CH3:1][C:2]1[C:7]([NH2:8])=[CH:6][CH:5]=[C:4]([S:9]([CH3:12])(=[O:11])=[O:10])[N:3]=1.Cl[C:14]1[C:19]2[O:20][CH2:21][CH2:22][N:23]([CH:24]3[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]3)[C:18]=2[N:17]=[CH:16][N:15]=1>>[CH3:1][C:2]1[C:7]([NH:8][C:14]2[C:19]3[O:20][CH2:21][CH2:22][N:23]([CH:24]4[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH2:25]4)[C:18]=3[N:17]=[CH:16][N:15]=2)=[CH:6][CH:5]=[C:4]([S:9]([CH3:12])(=[O:11])=[O:10])[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCOc3c(Cl)ncnc32)CC1
Reactant: Cc1nc(S(C)(=O)=O)ccc1N
Product: Cc1nc(S(C)(=O)=O)ccc1Nc1ncnc2c1OCCN2C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
By the procedure described in Example 3, with the exception that 2-methyl-6-(methylsulfonyl)pyridin-3-amine was used instead of 2-fluoro-4-(methylsulfonyl)-aniline, tert-butyl 4-(4-chloro-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate from Example 3C was converted into Example 123. 1H NMR (500 MHz, CDCl3) δ ppm 1.45 (s, 9 H) 1.55-1.65 (m, 2 H) 1.66-1.72 (m, 2 H) 2.61 (s, 3 H) 2.82-2.90 (m, 2 H) 3.15 (s, 3 H) 3.45-3.48 (m, 2 H) 4.25-4.28 (m, 4 H) 4.79-4.88 (m, 1 H) 6.86-7.00 (m, 1 H) 7.91 (d, J=8.25 Hz, 1 H) 8.06 (s, 1 H) 8.91 (m, 1 H) LRMS (ESI): 505.3 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][N:14]2[C:18]([CH2:19][OH:20])=[CH:17][N:16]=[C:15]2[S:21][CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)C1C=CC=CC=1.O.C(=O)(O)[O-].[Na+]>FC(F)(F)C(O)=O>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][N:14]2[C:18]([CH2:19][OH:20])=[CH:17][N:16]=[C:15]2[S:21][CH2:22][CH2:23][CH3:24])=[CH:25][CH:26]=1
Reactant: CCCSc1ncc(CO)n1Cc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCCSc1ncc(CO)n1Cc1ccc(O)cc1
Yield: 26.5 %

Procedure:
A solution of 1.40 g of 1-(4-benzyloxybenzyl)-2-propylthio-5-hydroxymethylimidazole in 15 mL of trifluoroacetic acid was refluxed for 0.25 hour. After cooling, the reaction was poured into water containing an excess of sodium bicarbonate, and the resulting emulsion was extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Column chromatography on silica gel (elution: 0-5% methanol/chloroform) afforded 0.28 g of 1-(4-hydroxybenzyl)-2-propylthio-5-hydroxymethylimidazole; NMR (200 MHz, DMSO-d6): δ9.41 (s, 1h); 6.88 (s, 1h); 6.79 (A2B2, 4H); 5.14 (t, 1h); 5.07 (s, 2H); 4.33 (d, 2H); 2.89 (t, 2H); 1.54 (sext., 2H); 0.88 (t, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4]([C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1Cl)(=[O:6])=[O:5].[NH2:17][CH2:18][CH2:19][NH2:20]>>[OH:1][CH2:2][CH2:3][S:4]([C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[CH:9][C:8]=1[NH:17][CH2:18][CH2:19][NH2:20])(=[O:6])=[O:5]
Reactant: NCCN
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)CCO)c1
Product: NCCNc1ccc([N+](=O)[O-])cc1S(=O)(=O)CCO
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.5 %

Procedure:
132.85 g of 2-chloro-5-nitrophenyl hydroxyethyl sulfone are added at 65°-70° C. with stirring to 250 g of 1,2-diaminoethane in the course of 15 minutes, and the mixture is stirred at this temperature for a further 15 minutes. The reaction mixture is then allowed to cool down to room temperature with stirring and is poured onto 1 l of ice-water, and the product is isolated by filtration. This gives 139.6 g (2-β-aminoethylamino)-5-nitrophenyl hydroxyethyl sulfone having a melting point of 147° C. and a purity of >98%, which corresponds to a yield of 94.5% of theory, relative to starting 2-chloro-5-nitrophenyl hydroxyethyl sulfone.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]1([C:16]2[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH2:25]([O:27][C:28](=[O:37])[C@@:29]([CH3:36])([C:32]([NH:34][CH3:35])=[O:33])[NH:30][CH3:31])[CH3:26].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[CH2:25]([O:27][C:28](=[O:37])[C:29]([N:30]([CH3:31])[C:20]([C:19]1[CH:23]=[CH:24][C:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:17][CH:18]=1)=[O:21])([CH3:36])[C:32]([NH:34][CH3:35])=[O:33])[CH3:26]
Reactant: CCOC(=O)[C@](C)(NC)C(=O)NC
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C(C)(C(=O)NC)N(C)C(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.9 %

Procedure:
DIPEA (1.0 mL) and 4-phenylbenzoyl chloride (0.50 g) were added in this order to a chloroform (10 mL) solution of O-ethyl-N,N2,2-trimethyl-3-oxoserinamide (Intermediate 9-1, 0.69 g), and the mixture was stirred for 5 hours at room temperature. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, whereafter the desiccant was filtered out, and the solvent was distilled off under reduced pressure. The resulting residue was purified by OH type silica gel chromatography (gradient elution with hexane/ethyl acetate=60/40→25/75) to obtain 4-{[1-ethoxy-2-methyl-3-(methylamino)-1,3-dioxopropan-2-yl](methyl)carbamoyl}biphenyl (colorless oil) (0.79 g, 66%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:13]CC1C2SC3C(=CC=CC=3)C(=O)C=2C(NCCN(CC)CC)=CC=1.O.[OH-].[Na+]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH2:13])(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCN(CC)CCNc1ccc(CN)c2sc3ccccc3c(=O)c12
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: NS(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3,4-dichlorobenzenesulfonyl chloride (1.84 g, 7.5 mmol) in 35 mL of dry pyridine was added 2.5 g (7 mmol) of 4-(aminomethyl)-1-[[2-(diethylamino)ethyl]amino]-thioxanthen-9-one (prepared by the method described in Example 4) under nitrogen and the reaction mixture was stirred at room temperature for 15 min. and then was allowed to stand for approximately 72 hours. The reaction mixture was poured into 75 mL of water containing 0.75 g of NaOH, and extracted into chloroform. The organic layer was washed with water (2x) and brine, and dried over sodium sulfate. Chloroform was removed in vacuo, the residue was recrystallized from ethanol to afford 1.24 g of N-[[1-[[2-(diethylamino)]ethyl]amino]-9-oxothioxanthen-4-yl]methyl]-3,4-dichlorobenzenesulfonamide, m.p. 95° C. (dec.). The free base was dissolved in methanol and treated with methanesulfonic acid in methanol to afford the methanesulfonate·1/2 hydrate, m.p. 55° C. (dec.).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH:9]([C:13]([F:26])([F:25])[C:14]([N:16]([F:24])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[CH2:8][CH2:7]2)([O-])=O>C1COCC1.CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH:9]([C:13]([F:26])([F:25])[C:14]([N:16]([F:24])[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:15])[CH2:8][CH2:7]2
Reactant: O=C(N(F)Cc1ccccc1)C(F)(F)C1CCc2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc2c(c1)CCC2C(F)(F)C(=O)N(F)Cc1ccccc1
Reaction time: 1 h

Procedure:
To a stirred solution of 2-(5-nitroindanyl)-N-(phenylmethyl)trifluoroacetamide (1.17g, 3.21 mmol) in THF/MeOH (100 ml, 1:1) was added a catalytic amount of 10% Pd/C. The mixture was hydrogenated at 50 psi for 1 hr, filtered through celite, and concentrated to give 2-(5-aminoindanyl)-N-(phenylmethyl)trifluoroacetamide which was homogeneous by TLC and used immediately in step (f).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.[C:13]([Si:17]([CH3:24])([CH3:23])[O:18][CH2:19][C@@H:20]1[CH2:22][O:21]1)([CH3:16])([CH3:15])[CH3:14]>>[C:13]([Si:17]([CH3:24])([CH3:23])[O:18][CH2:19][C@@H:20]([OH:21])[CH2:22][NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1)([CH3:14])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1CO1
Reactant: Nc1ccc2c(c1)NC(=O)CO2
Product: CC(C)(C)[Si](C)(C)OC[C@@H](O)CNc1ccc2c(c1)NC(=O)CO2

Procedure:
Starting from 6-amino-4H-benzo[1,4]oxazin-3-one and tert-butyl-dimethyl-((S)-1-oxiranylmethoxy)-silane and using a procedure analogous to that of Example 201, step 201.ii, the title compound was obtained as a pale brown foam (5.2 g, 66% yield).