Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:44]=[CH:43][C:8]([C:9]([NH:11][C@@H:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[N:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:31][CH:30]=4)=[CH:25][N:24]=3)=[CH:19][CH:18]=2)[C:13](O)=[O:14])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:45][S:46]([NH2:49])(=[O:48])=[O:47].C(Cl)CCl>CN(C1C=CN=CC=1)C.CN(C=O)C.CC(=O)OCC>[C:1]([C:5]1[CH:44]=[CH:43][C:8]([C:9]([NH:11][C@@H:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[N:28]=[CH:27][C:26]([C:29]4[CH:30]=[CH:31][C:32]([O:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:33][CH:34]=4)=[CH:25][N:24]=3)=[CH:19][CH:18]=2)[C:13]([NH:49][S:46]([CH3:45])(=[O:48])=[O:47])=[O:14])=[O:10])=[CH:7][CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CS(N)(=O)=O
Reactant: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)cc4)C(=O)O)cc3)nc2)cc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCCCCCCOc1ccc(-c2cnc(-c3ccc(C[C@H](NC(=O)c4ccc(C(C)(C)C)cc4)C(=O)NS(C)(=O)=O)cc3)nc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
To a solution of (S)-2-(4-(tert-butyl)benzamido)-3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)propanoic acid Compound 85 (78.0 mg, 0.13 mmol), methanesulfonamide (20.0 mg, 0.21 mmol), and DMAP (16.1 mg, 0.13 mmol) in DMF (1.5 mL) was added EDC (40.3 mg, 0.21 mmol) and the solution stirred overnight at room temperature. The reaction mixture was diluted in EA (50 mL), washed with aqueous saturated sodium bicarbonate (2×20 mL) and brine (20 mL). The organic layer was dried over MgSO4, filtered, and the solvent removed under reduced pressure. The crude product was purified by chromatography (hexane/EA) to afford 36 mg (40%) of (S)-4-(tert-butyl)-N-(3-(4-(5-(4-(heptyloxy)phenyl)pyrimidin-2-yl)phenyl)-1-(methylsulfonamido)-1-oxopropan-2-yl)benzamide, Compound 299 as a colorless solid. LCMS-ESI (m/z) calculated for C38H46N4O5S: 670.3. found 671.3 [M+H]+, tR=11.01 min (Method 10).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][N:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[F:23])[NH2:19].C(=O)(O)[O-].[Na+]>C(O)C.[Cl-].[Na+].O>[Cl:15][C:16]1[CH:17]=[C:18]([NH:19][C:2]2[C:11]3[C:6](=[CH:7][N:8]=[C:9]([F:12])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:13]#[N:14])[CH:20]=[CH:21][C:22]=1[F:23]
Reactant: N#Cc1cnc2cnc(F)cc2c1Cl
Reactant: Nc1ccc(F)c(Cl)c1
Agent: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(F)c(Cl)c1
Yield: 83.6 %

Procedure:
To 600 mg of 4-chloro-6-fluoro-[1.7]naphthyridine-3-carbonitrile in 15 mL of absolute ethanol was added 500 mg of 3-chloro-4-fluoroaniline. After refluxing the reaction under an inert atmosphere for 2 hours, the reaction mixture was poured into a mixture of brine and saturated aqueous sodium bicarbonate and the resultant crystals were filtered and washed with water. The product was then recrystallized from chloroform/hexanes. Drying in vacuo yielded 765 mg (83%) of 4-(3-chloro-4-fluoro-phenylamino)-6-fluoro-[1.7]naphthyridine-3-carbonitrile as yellow needles: melting point 108-111° C.; mass spectrum (m/e): M+H 316.8.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:22])[C:10]([NH:12][N:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]([O:20]C)=O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:23]1([NH2:26])[CH2:25][CH2:24]1>>[CH:23]1([NH:26][C:18]([C:14]2[N:13]([NH:12][C:10](=[O:11])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:22])[CH:17]=[CH:16][CH:15]=2)=[O:20])[CH2:25][CH2:24]1
Reactant: NC1CC1
Reactant: COC(=O)c1cccn1NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nn1cccc1C(=O)NC1CC1

Procedure:
Same procedure as described in preparation 133a was used from (S)-methyl 1-(2-(tert-butoxycarbonylamino)propanamido)-1H-pyrrole-2-carboxylate (900 mg, 80% purity, 2.28 mmols) and cyclopropanamine (0.48 ml, 6.86 mmols). After 3.5 h stirring at 80° C. the title compound was obtained (589 mg, 77%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[CH2:28](I)[CH3:29].O>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][CH:22]=2)[CH2:28][CH3:29])=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(OCCCNc2ccc(Cl)cc2)cc1
Reactant: CCI
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CCCOc1ccc(C(=O)OC)cc1)c1ccc(Cl)cc1
Temperature: 100 °C
Reaction time: 11 h

Procedure:
Methyl 4-[3-[N-(4-chlorophenyl)amino]propoxy]benzoate (1.2 g) and sodium bicarbonate (1.58 g) were dissolved and suspended in DMF (10 ml), and ethyl iodide (1.52 ml) was added thereto. The mixture was heated with stirring at 100° C. for 11 hours, and cooled. Water and ethyl acetate were added thereto and the mixture was separated into layers. The organic layer was washed with water 3 times, and concentrated under reduced pressure to give the oily desired product (1.38 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[C:25]([C:29]1[CH:38]=[C:37]2[C:32]([C:33](=[O:55])[N:34]([C:39]3[CH:44]=[CH:43][CH:42]=[C:41](B4OC(C)(C)C(C)(C)O4)[C:40]=3[CH3:54])[CH:35]=[N:36]2)=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:25]([C:29]1[CH:38]=[C:37]2[C:32]([C:33](=[O:55])[N:34]([C:39]3[CH:44]=[CH:43][CH:42]=[C:41]([C:2]4[CH:3]=[C:4]([NH:10][C:11]5[CH:16]=[CH:15][C:14]([C:17]([N:19]6[CH2:24][CH2:23][O:22][CH2:21][CH2:20]6)=[O:18])=[CH:13][N:12]=5)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=4)[C:40]=3[CH3:54])[CH:35]=[N:36]2)=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: Cc1c(B2OC(C)(C)C(C)(C)O2)cccc1-n1cnc2cc(C(C)(C)C)ccc2c1=O
Reactant: Cn1nc(Cl)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1c(-c2cc(Nc3ccc(C(=O)N4CCOCC4)cn3)c(=O)n(C)n2)cccc1-n1cnc2cc(C(C)(C)C)ccc2c1=O
Yield: 27.5 %

Procedure:
A solution of 6-Chloro-2-methyl-4-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-2H-pyridazin-3-one (56 mg, 0.16 mmol), 7-tert-Butyl-3-[2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-3H-quinazolin-4-one (68 mg, 0.16 mmol), tetrakis(triphenylphosphine)palladium(0) (19 mg, 0.016 mmol), and sodium carbonate (52 mg, 0.49 mmol) in 2 mL 1,2-dimethoxyethane and 1 mL water was heated on the microwave synthesizer at 170° C. for 12.5 minutes. The resulting mixture was partitioned between ethylacetate and water. The ethylacetate layer was washed with brine, dried over anhydrous MgSO4, concentrated in vacuo, and purified by preparative TLC (10% MeOH/CH2Cl2) to yield 7-tert-Butyl-3-(2-methyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-3H-quinazolin-4-one (26.4 mg, 0.044 mmol). MS (ESI) 606 (M+H)+.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[C:14]2[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=2[C:12]2[C:7](=[C:8]3[CH:27]=[CH:26][CH:25]=[CH:24][C:9]3=[N:10][C:11]=2Cl)[N:6]=1.[CH3:28][OH:29]>>[CH3:1][O:2][C:5]1[C:14]2[CH:15]=[C:16]([O:21][CH3:22])[C:17]([O:19][CH3:20])=[CH:18][C:13]=2[C:12]2[C:7](=[C:8]3[CH:27]=[CH:26][CH:25]=[CH:24][C:9]3=[N:10][C:11]=2[O:29][CH3:28])[N:6]=1
Reactant: CO
Reactant: C[O-]
Reactant: COc1cc2c(Cl)nc3c4ccccc4nc(Cl)c3c2cc1OC
Agent: [Na+]
Product: COc1cc2c(OC)nc3c4ccccc4nc(OC)c3c2cc1OC
Temperature: 25 °C

Procedure:
Sodium methoxide (63 mg, 1.17 mmol) and 33 (70 mg, 0.2 mmol) were mixed in methanol (10 mL). The mixture was heated to reflux for 10 h. The reaction mixture was cooled to room temperature and ice-cold water (10 mL) was added. The precipitated white amorphous solid (50 mg, 71%) was collected by filtration: mp 173-175° C. IR (KBr) 1650, 1610, 1590, 1515 cm−1; 1H NMR (500 MHz, DMSO-d6) δ 8.80 (d, J=7.2 Hz, 1 H), 8.57 (s, 1 H), 7.78 (d, J=7.8 Hz, 1 H), 7.70 (t, J=7.3 Hz, 1 H), 7.59-7.45 (m, 2 H), 4.24 (s, 3 H), 4.19 (s, 3 H), 3.95 (s, 3 H), 3.91 (s, 3 H); 13C NMR (126 MHz, CDCl3) δ 160.78, 159.51, 153.11, 149.48, 146.29, 143.82, 129.96, 129.49, 126.60, 124.42, 124.34, 123.50, 114.22, 107.61, 105.68, 103.90, 55.82, 55.72, 54.24, 53.95; positive ESIMS m/z (rel intensity) 351 (MH+, 100). Anal. Calcd for C20H18N2O4.0.6H2O: C, 66.51; H, 5.36; N, 7.76. Found: C, 66.41; H, 5.08; N, 7.54.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:9][CH2:8][C@H:7]([OH:10])[CH2:6]1)(=[O:3])[CH3:2].[CH3:11][S:12](Cl)(=[O:14])=[O:13].C(N(CC)CC)C>COC(C)(C)C>[CH3:11][S:12]([O:10][C@@H:7]1[CH2:8][CH2:9][C@H:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:6]1)(=[O:14])=[O:13]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)O[C@@H]1CC[C@H](O)C1
Solvent: COC(C)(C)C
Solvent: CCN(CC)CC
Product: CC(=O)O[C@H]1CC[C@@H](OS(C)(=O)=O)C1
Temperature: -8 °C
Yield: 95.8 %

Procedure:
Dissolve (1S,3R)-cis-3-acetoxy-cyclopentanol (9.75 g, 67.6 mmol, prepared in example 23) in tert-butyl methyl ether (80 mL, anhydrous) and cool to -8° C. with stirring. Add methanesulfonyl chloride (5.7 mL, 73.6 mmol, mesyl chloride) over 5 minutes, followed by dropwise addition of triethylamine (11.4 mL, 81.2 mL), over about 30 minutes, maintaining the temperature below -2° C. The ice bath is then removed and the mixture is stirred for 2 hours. The mixture is poured into a water/brine mixture (50 mL/50 mL). The layers are separated and the aqueous layer extracted with tert-butyl methyl ether (100 mL). The organic layer and extract is combined, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide the title compound (14.4 g) as a yellow oil; 1H NMR (CDCl3) δ 8 5.1 (m, 2 H), 3.02 (s, 3 H), 2.41 (m, 1 H), 2.05 (s, 3 H), 2.0 (m, 5 H).
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:10]O)=[N:4][CH:5]=[C:6]([CH3:9])[C:7]=1[CH3:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:32]>ClCCl>[Br:32][CH2:10][C:3]1[C:2]([CH3:1])=[C:7]([CH3:8])[C:6]([CH3:9])=[CH:5][N:4]=1
Reactant: BrC(Br)(Br)Br
Reactant: Cc1cnc(CO)c(C)c1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cnc(CBr)c(C)c1C

Procedure:
The compound was obtained from reacting (3,4,5-trimethyl-pyridin-2-yl)-methanol with triphenyl phosphine and carbon tetrabromide in dichloromethane as described in the general procedure 2.5. HPLC Rt: 3.979 min. 1H-NMR (CDCl3): δ 8.18 (s, 1H), 4.63 (s, 2H), 2.35 (s, 3H), 2.48 (s, 3H), 2.24 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH3:12])[S:9][C:10]=1[NH2:11])=[O:5])[CH3:2].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.Br[C:56]1[CH:57]=[N:58][CH:59]=[CH:60][CH:61]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([CH3:12])[S:9][C:10]=1[NH:11][C:56]1[CH:57]=[N:58][CH:59]=[CH:60][CH:61]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(C)sc1N
Reactant: Brc1cccnc1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(C)sc1Nc1cccnc1
Yield: 63.3 %

Procedure:
A Schlenck flask was charged with 5-amino-2-methyl-thiazole-4-carboxylic acid ethyl ester (0.33 g, 1.80 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (0.15 g, 0.26 mmol) and palladium dibenzylideneacetone (Pd2dba3)-chloroform complex (0.08 g, 0.08 mmol). Degassed dioxane (6.00 ml) was added, followed by 3-bromopyridine (0.23 g, 1.50 mmol). The flask was subjected to 5 cycles of evacuation and backfiring with argon. The reaction mixture was then transferred under argon to a microwave vial containing cesium carbonate (0.84 g, 2.60 mmol). The vial was then irradiated in a microwave oven at 150° C. for 10 min. The mixture was diluted with THF and the solids filtered, washing with THF. The filtrate was evaporated and the residue purified by flash chromatography (ethyl acetate/methanol) to yield 2-methyl-5-(pyridin-3-ylamino)-thiazole-4-carboxylic acid ethyl ester (0.25 g, 65%) as a light yellow solid, MS (ISP): m/e=264.1 (M+H+).
Reaction SMILES: C[O:2][CH:3]=[CH:4][C:5]1[C:6]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]2=[O:17])=[N:7][CH:8]=[CH:9][CH:10]=1>C(O)=O.O>[O:17]=[C:12]1[CH2:13][CH2:14][CH2:15][CH2:16][N:11]1[C:6]1[C:5]([CH2:4][CH:3]=[O:2])=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: COC=Cc1cccnc1N1CCCCC1=O
Solvent: O
Solvent: O=CO
Product: O=CCc1cccnc1N1CCCCC1=O
Temperature: 50 °C

Procedure:
1-[3-(2-Methoxyethenyl)pyridin-2-yl]piperidin-2-one a4-2 (0.340 g, 1.464 mmol, 1 eq) is dissolved in a mixture of formic acid and water (10 ml/0.5 ml). The reaction mixture is heated at 50° C. overnight. The solvent is removed under reduced pressure to afford crude [2-(2-oxopiperidin-1-yl)pyridin-3-yl]acetaldehyde a4-3 which is used in the next step without any further purification.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[N:10]1.O.[OH-].[Na+]>C(Cl)Cl>[CH3:15][C:11]1[CH:12]=[C:13]([CH3:14])[N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[OH:2])[N:10]=1
Reactant: COc1ccccc1-n1nc(C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C)n(-c2ccccc2O)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78.4 %

Procedure:
3.88 g of 1-(2-methoxyphenyl)-3,5-dimethyl-1H-pyrazol was dissolved in 40 ml of methylene chloride, and 32 ml of 1 M solution of borontribromide in methylene chloride was added and stirred at room temperature for 1.5 hours. The reaction mixture was added to 150 ml of water, neutralized with 1N-sodium hydroxide and extracted with 150 ml of ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure, and purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to yield 2.83 g of the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6](Cl)[C:5]([Cl:10])=[C:4](Cl)[C:3]=1[Cl:12].C1(O)C=CC=CC=1.[H][H]>[Pd].O.[Ta]>[Cl:10][C:5]1[CH:6]=[C:7]([CH:2]=[C:3]([Cl:12])[CH:4]=1)[NH2:8]
Reactant: Nc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Reactant: [H][H]
Agent: [Pd]
Agent: [Ta]
Solvent: Oc1ccccc1
Solvent: O
Product: Nc1cc(Cl)cc(Cl)c1

Procedure:
131 parts of a mixture of 2,3,4,5- and 2,3,5,6-tetrachloroaniline and pentachloroaniline in the ratio of 38:60:2 percent by weight and 200 parts of phenol are reacted with hydrogen over 20 parts of a 1% strength palladium/charcoal catalyst and a maximum pressure of 50 bar and at 170° C. in a tantalum autoclave, in the course of 10 hours, while stirring. After the autoclave has been cooled and the pressure released, the reaction mixture is diluted with 500 parts of water and separated off from the catalyst, and after the addition of toluene, the mixture is rendered alkaline with sodium hydroxide solution. The solution of 3,5-dichloroaniline in toluene, obtained by separation of the layers, is distilled. Yield: 90 g (=98%) of a 99% strength 3,5-dichloroaniline. The phenol can be recovered from the aqueous phase by acidifying the latter and extracting it by shaking with toluene. It was possible to re-use the catalyst 20 times without it losing any of its activity.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]2[C:5]([NH:6][C:7]3[C:12]([S:13]2)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[C:4]2[CH:16]=[CH:17][CH:18]=[CH:19][C:3]=12.Cl[C:21]([O:23][CH:24]([Cl:26])[CH3:25])=[O:22]>O1CCCC1>[OH:1][C:2]1[CH:15]=[C:14]2[C:5]([N:6]([C:21]([O:23][CH:24]([Cl:26])[CH3:25])=[O:22])[C:7]3[C:12]([S:13]2)=[CH:11][CH:10]=[CH:9][CH:8]=3)=[C:4]2[CH:16]=[CH:17][CH:18]=[CH:19][C:3]=12
Reactant: CC(Cl)OC(=O)Cl
Reactant: Oc1cc2c(c3ccccc13)Nc1ccccc1S2
Solvent: C1CCOC1
Product: CC(Cl)OC(=O)N1c2ccccc2Sc2cc(O)c3ccccc3c21
Yield: 57.1 %

Procedure:
A mixture of 5-hydroxy-12H-benzo[a]phenothiazine (5 g) and α-chloroethyl chloroformate (10 g) in tetrahydrofuran (20 ml) was refluxed for 9 hours, then the volatile components were evaporated away and the residue chromatographed on a column of silica gel, eluting with a 1:9 ethyl acetate-hexane mixture to afford the title compound (4 g) as an oil.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[C:27]([Cl:28])=[C:26]([CH3:29])[S:25][C:16]=2[N:17]=[C:18]([C:20]2[O:24][N:23]=[CH:22][CH:21]=2)[N:19]=1>>[O:24]1[C:20]([C:18]2[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:1][O:2][C:3]=4[CH:4]=3)[C:15]3[C:27]([Cl:28])=[C:26]([CH3:29])[S:25][C:16]=3[N:17]=2)=[CH:21][CH:22]=[N:23]1
Reactant: Cc1sc2nc(-c3ccno3)nc(Cl)c2c1Cl
Reactant: NCCc1ccc2c(c1)OCO2
Product: Cc1sc2nc(-c3ccno3)nc(NCCc3ccc4c(c3)OCO4)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(isoxazol-5-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-(3,4-methylenedioxyphenethylamino)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[O:3]1.N1CCCC1C(O)=O.[Br:19][C:20]1[S:21][C:22]([CH:25]=O)=[CH:23][N:24]=1.[CH3:27][S:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[C:34]2[C:38]=1[NH:37][CH:36]=[CH:35]2>C(#N)C>[Br:19][C:20]1[S:21][C:22]([CH:25]([C:35]2[C:34]3[C:38](=[C:30]([CH2:29][S:28][CH3:27])[CH:31]=[CH:32][CH:33]=3)[NH:37][CH:36]=2)[CH:6]2[C:7](=[O:8])[O:9][C:2]([CH3:10])([CH3:1])[O:3][C:4]2=[O:5])=[CH:23][N:24]=1
Reactant: O=Cc1cnc(Br)s1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CSCc1cccc2cc[nH]c12
Agent: O=C(O)C1CCCN1
Solvent: CC#N
Product: CSCc1cccc2c(C(c3cnc(Br)s3)C3C(=O)OC(C)(C)OC3=O)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.02 g (7.08 mmol) of Meldrum's acid, 0.04 g (0.34 mmol) of D,L-proline and 1.36 g (7.08 mmol) of 2-bromo-5-formylthiazole were successively added to a solution of 1.30 g (6.75 mmol) of the compound from Example 8A in 50 ml of acetonitrile. The reaction mixture was stirred at RT overnight and then the solvent was removed in vacuo. Purification of the residue by flash chromatography on silica gel (mobile phase: dichloromethane/methanol 95/5) resulted in 3.58 g (81% purity, 87% of theory) of the title compound.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11]([F:12])=[CH:10][C:9]([NH:13]C(OC(C)(C)C)=O)=[CH:8][C:7]=1[Cl:21])(=[O:3])[CH3:2].C[Si](I)(C)C>CC#N>[C:1]([O:4][CH2:5][C:6]1[C:11]([F:12])=[CH:10][C:9]([NH2:13])=[CH:8][C:7]=1[Cl:21])(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(F)cc(NC(=O)OC(C)(C)C)cc1Cl
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: CC(=O)OCc1c(F)cc(N)cc1Cl
Reaction time: 0.25 h

Procedure:
To a solution of 4-(tert-butoxycarbonylamino)-2-chloro-6-fluorobenzyl acetate (8.5 g, 24 mmol) in CH3CN (300 mL) was added trimethylsilyl iodide (4.12 mL, 28 mmol) at 0° C. under N2. After stirring 15 min, the reaction mixture was quenched with 5% Na2S2O3 (10 mL) in ice-bath, concentrated in vacuo, and extracted with EtOAc. The combined extracts were washed with H2O and brine successively, dried over anhyd MgSO4, concentrated and purified by column chromatography (Hex/DCM=1:1) to afford 4-amino-2-chloro-6-fluorobenzyl acetate as yellow solid. 1H NMR (400 MHz, CDCl3) δ 6.55-6.49 (m, 1H), 6.33-6.27 (m, 1H), 5.15 (d, 2H), 3.97 (d, 2H), 2.07 (s, 3H).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5]O.[Br-:11].[Br-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CO>[CH3:1][S:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][Br:11]
Reactant: CSc1ccccc1CO
Reactant: [Br-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Product: CSc1ccccc1CBr
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.4 %

Procedure:
To a solution of 400 mg (2.59 mmol) of 2-methylthio-benzylalcohol in 8 mL of methanol was added 1.42 g (3.37 mmol) of triphenylphosphine dibromide and stirred at room temperature for 18 h. The mixture was concentrated and purified by silica gel flash chromatography, eluting with 2% ethyl acetate/hexane to give 289 mg of the title compound. NMR (CDCl3): δ 2.50 (s, 3H), 4.63 (s, 2H), 7.13 (m, 1H), 7.27 (m, 2H), 7.34 (d, 1).
Reaction SMILES: [Cl:1][C:2]1[C:3](OS(O)(=O)=O)=[C:4]2[C:9](=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[NH:8][C:7](=[O:16])[C:6]([C:17](=[O:21])[CH:18]([CH3:20])[CH3:19])=[C:5]2C.[CH2:28]([O:30][CH:31]([O:35][CH2:36][CH3:37])[CH2:32][CH2:33][NH2:34])[CH3:29]>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([C:12]([F:15])([F:13])[F:14])[CH:11]=1)[NH:8][C:7](=[O:16])[C:6]([C:17](=[O:21])[CH:18]([CH3:19])[CH3:20])=[C:5]2[NH:34][CH2:33][CH2:32][CH:31]([O:35][CH2:36][CH3:37])[O:30][CH2:28][CH3:29]
Reactant: Cc1c(C(=O)C(C)C)c(=O)[nH]c2c(C(F)(F)F)cc(Cl)c(OS(=O)(=O)O)c12
Reactant: CCOC(CCN)OCC
Product: CCOC(CCNc1c(C(=O)C(C)C)c(=O)[nH]c2c(C(F)(F)F)cc(Cl)cc12)OCC
Yield: 72.4 %

Procedure:
6-Chloro-3-isobutyryl-4-methylsulfoxy-8-trifluoromethyl-2-quinolinone (379 mg, 1 mmol) and 3,3-diethoxypropylamine (147 mg, 1 mmol) were used and the reaction was carried out as in the above process of example 1 to obtain the desired product (335 mg, yield: 78%).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[C:10]([CH3:12])[C:9]([OH:13])=[C:8]([CH3:14])[CH:7]=2)=[CH:2]1.CO>O1CCCC1.[C].[Pd]>[CH3:12][C:10]1[CH:11]=[C:6]([CH:3]2[CH2:4][CH2:5][O:1][CH2:2]2)[CH:7]=[C:8]([CH3:14])[C:9]=1[OH:13]
Reactant: Cc1cc(-c2ccoc2)cc(C)c1O
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(C2CCOC2)cc(C)c1O
Reaction time: 18 h
Yield: 52 %

Procedure:
4-(furan-3-yl)-2,6-dimethylphenol (Compound 6-5) (110 mg, 0.74 mmol) were dissolved in tetrahydrofuran:methanol=1 mL:1 mL. Palladium carbon (15 mg, 15%) was added thereto, followed by stirring under hydrogen balloon for 18 hours. After the completion of the reaction, the reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure to obtain 2,6-dimethyl-4-(tetrahydrofuran-3-yl)phenol (74 mg, 72%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[N:13]1[CH2:17][CH2:16][CH:15](OS(C)(=O)=O)[CH2:14]1.[H-].[Na+].[SH:25][CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32].C(Cl)(Cl)Cl>CN(C=O)C.[Cl-].[Na+].O>[CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[N:13]1[CH2:17][CH2:16][CH:15]([S:25][CH2:26][CH2:27][NH:28][C:29](=[O:35])[O:30][C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:14]1
Reactant: CC(C)(C)OC(=O)NCCS
Reactant: COc1ccc2nccc(N3CCC(OS(C)(=O)=O)C3)c2n1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1ccc2nccc(N3CCC(SCCNC(=O)OC(C)(C)C)C3)c2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 77.9 %

Procedure:
To a solution of methanesulfonic acid 1-(6-methoxy-[1,5]naphthyridin-4-yl)-pyrrolidin-3-yl ester (650 mg, 2 mmol, prepared as Example 2b) in DMF (3 mL) was added NaH (89 mg, 2.2 mmol, 65% in mineral oil) followed by 1,1-dimethylethyl (2-mercaptoethyl)carbamate (0.373 mL, 2.2 mmol). The resulting mixture was stirred at 25° C. for 12 h and then diluted with brine. Chloroform was used the extracted the aqueous solution. The organic fractions were pooled, concentrated and purified with column chromatography (silica, 10% MeOH in CDCl3 (1% NH4OH)) to afford the title compound as an off-white solid (630 mg, 78%): LC/MS m/z 405 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[N:3]=1.Cl[C:18]1[N:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=1[N+:25]([O-:27])=[O:26]>>[CH3:24][C:22]1[N:23]=[C:18]([N:14]2[CH2:13][CH2:12][C:11](=[CH:10][C:9]#[C:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[N:3]=3)[CH2:16][CH2:15]2)[C:19]([N+:25]([O-:27])=[O:26])=[CH:20][CH:21]=1
Reactant: Cc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: Cc1cccc(C#CC=C2CCNCC2)n1
Product: Cc1cccc(C#CC=C2CCN(c3nc(C)ccc3[N+](=O)[O-])CC2)n1
Yield: 54.8 %

Procedure:
A well homogenised mixture of the Compound of Example 3 (23 mg, 0.11 mmol) and 6-chloro-5-nitro-2-picoline (26.2 mg, 0.15 mmol) was stirred at 120° C. for 0.5 h. The reaction crude was purified by flash chromatography (EtOAc—Petroleum Ether gradient from 3:7 to 4:6) affording the title product (21 mg).