Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[CH:10]=[CH:11][CH:12]2[OH:20])[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([O:21][CH2:22][CH2:23][CH2:24][O:25][NH:26][C:27](=[O:35])[C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=1)[CH:4]=[CH:5]2.C(=O)(O)[O-].[Na+].[C:41](Cl)(Cl)=[S:42]>C(Cl)Cl>[O:1]1[CH:13]2[C@@:14]34[CH2:16][CH2:17][N:18]([CH3:19])[C@@H:8]([C@@H:9]3[CH:10]=[CH:11][CH:12]2[OH:20])[CH2:7][C:6]2=[C:15]4[C:2]1=[C:3]([O:21][CH2:22][CH2:23][CH2:24][O:25][NH:26][C:27](=[O:35])[C:28]1[CH:29]=[CH:30][C:31]([N:34]=[C:41]=[S:42])=[CH:32][CH:33]=1)[CH:4]=[CH:5]2
Reactant: S=C(Cl)Cl
Reactant: CN1CC[C@]23c4c5ccc(OCCCONC(=O)c6ccc(N)cc6)c4OC2C(O)C=C[C@H]3[C@H]1C5
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CN1CC[C@]23c4c5ccc(OCCCONC(=O)c6ccc(N=C=S)cc6)c4OC2C(O)C=C[C@H]3[C@H]1C5
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.2 %

Procedure:
A stirred solution of 0.5 g (1.1 mmol) of N-[3-[(7,8-Didehydro-4,5-epoxy-6-hydroxy-17-methylmorphinan-3-yl)oxy]propoxy]-4-aminobenzamide in 10 ml of methylene chloride was treated with 0.5 g of solid anhydrous sodium bicarbonate followed by 150 ul (1.9 mmol) of thiophosgene and stirred at room temperature for 30 minutes. The solvent was removed in vacuo and the residue was chromatographed on 150 g of silica gel using 15% methanol-chloroform to give 230 mg of N-[3-[(7,8-Didehydro-4,5-epoxy-6-hydroxy-17-methylmorphinan-3-yl)oxy]propoxy]-4-isothiocyanatobenzamide as an amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][CH:9]([N:12]([CH2:17][CH2:18][CH3:19])[C:13](=[O:16])[CH2:14][CH3:15])[CH2:8][CH2:7]2.[N+:20](C)([O-:22])=[O:21]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:20]([O-:22])=[O:21])=[C:6]2[C:11]=1[CH2:10][CH:9]([N:12]([CH2:17][CH2:18][CH3:19])[C:13](=[O:16])[CH2:14][CH3:15])[CH2:8][CH2:7]2
Reactant: CCCN(C(=O)CC)C1CCc2cccc(Cl)c2C1
Reactant: C[N+](=O)[O-]
Product: CCCN(C(=O)CC)C1CCc2c([N+](=O)[O-])ccc(Cl)c2C1
Temperature: 0 °C
Yield: 31 %

Procedure:
To an ice-cold solution of compound 6(12.5 g, 44.5 mmol) in nitromethane (100 ml) was added (dropwise) "nitrating acid" (32.6 ml) (see synthesis of compound 3) until all starting material was consumed (monitored with gas chromatography after basification of analytical samples and extraction with Et2O). Ice-water/Et2O was added, shaken and extracted one additional time (Et2O). The combined organic extracts were dried (Na2SO4), filtered and the solvent was evaporated (12.5 g, 87%). The resulting residue was chromatographed using flash chromatography on a silica column, using petroleum ether/E2O (1:2) as eluant, yielding 4.5 g (31%) of 8-chloro-5-nitro-2-(N-n-propyl-N-propionylamino)tetralin (7a) and 3.5 g (24% of 8-chloro-7-nitro-2-(N-n-propyl-N-propionylamino)tetralin (7b). Unseparated material could be recycled in second chromatography.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][N:9]=[CH:8][C:7]=2[N+:12]([O-])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H][H]>O1CCOCC1.[C].[Pd]>[NH2:12][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:6]=1[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=[N+]([O-])c1cnccc1N1CCCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Product: Nc1cnccc1N1CCCC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.7 %

Procedure:
4-pyrrolidine-1-yl-3-nitropyridine (2.10 g, 10.9 mmol) was dissolved in 40 ml of 1,4-dioxane. After the atmosphere was replaced with nitrogen, 0.42 g of 10% palladium-carbon was added thereto. After the atmosphere was replaced with hydrogen, hydrogen addition was conducted with stirring at room temperature for about 15 hours. Palladium-carbon was removed by filtraton and the filtered cake was washed with 1,4-dioxane. The filtrate and the washings were combined and then concentrated to obtain 1.61 of a brown liquid (yield: 90.7%).
Reaction SMILES: P([O-])([O-])([O-])=[O:2].[OH:6][C@H:7]([CH2:59][CH2:60][C:61]1[CH:66]=[CH:65][C:64]([F:67])=[CH:63][CH:62]=1)[CH2:8][C:9](SCCNC(=O)CCNC(=O)[C@H](O)C(C)(C)COP(O)(=O)OP(O)(=O)OC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H](O)[C@@H]1OP(O)(O)=O)=[O:10]>>[OH:6][CH:7]([CH2:59][CH2:60][C:61]1[CH:66]=[CH:65][C:64]([F:67])=[CH:63][CH:62]=1)[CH2:8][C:9]([OH:10])=[O:2]
Reactant: CC(C)(COP(=O)(O)OP(=O)(O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](O)[C@@H]1OP(=O)(O)O)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C[C@H](O)CCc1ccc(F)cc1
Reactant: O=P([O-])([O-])[O-]
Product: O=C(O)CC(O)CCc1ccc(F)cc1

Procedure:
Ten parts of the above described immobilized enzyme was suspended in 480 parts of a 0.1M phosphate buffer (pH 7.0), then 10 parts of (R)-3-hydroxy-5-(4-fluorophenyl)valeryl CoA (prepared by a method described in Eur. J. Biochem., 250, 432–439 (1997) after obtaining 3-hydroxy-5-(4-fluorophenyl)valeric acid by hydrolyzing 3-hydroxyphenylvaleric acid ester obtained by a Reformatsky reaction) and one part of bovine serum albumin (Sigma) were added to the suspension and moderately shaken for one and a half hours at 30° C. After the reaction was completed, centrifugation was performed for 10 minutes at 10,000×g to recover the pellet.
Reaction SMILES: [CH3:1][N:2]([CH:4](OC)OC)[CH3:3].[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][C:14](=[O:19])[CH2:13]2.O>C1COCC1>[CH3:1][N:2](/[CH:4]=[C:13]1/[C:14](=[O:19])[NH:15][C:16]2[C:12]/1=[CH:11][C:10]([F:9])=[CH:18][CH:17]=2)[CH3:3]
Reactant: COC(OC)N(C)C
Reactant: O=C1Cc2cc(F)ccc2N1
Solvent: O
Solvent: C1CCOC1
Product: CN(C)/C=C1/C(=O)Nc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
DMF-DMA (3.15 g, 26.4 mmol) was added into a solution of 5-fluoroindolin-2-one LXXXVIII (2.0 g, 13.2 mmol) in dry THF. The reaction mixture was stirred at rt for 4 hr before being poured into water and extracted by EtOAc. The organic layer was separated and dried by Na2SO4, and concentrated to give (E)-3-((dimethylamino)methylene)-5-fluoroindolin-2-one LXXXVIX.
Reaction SMILES: [CH2:1]([C:4]1[C:13]([OH:14])=[C:12]([CH2:15][CH:16]=[CH2:17])[CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][C:8](=[O:24])[N:9]2[CH2:18][C:19](OCC)=[O:20])[CH:2]=[CH2:3].O.[NH3:26]>CO>[C:19]([CH2:18][N:9]1[C:10]2[C:5](=[C:4]([CH2:1][CH:2]=[CH2:3])[C:13]([OH:14])=[C:12]([CH2:15][CH:16]=[CH2:17])[CH:11]=2)[CH2:6][CH2:7][C:8]1=[O:24])(=[O:20])[NH2:26]
Reactant: C=CCc1cc2c(c(CC=C)c1O)CCC(=O)N2CC(=O)OCC
Reactant: N
Solvent: O
Solvent: CO
Product: C=CCc1cc2c(c(CC=C)c1O)CCC(=O)N2CC(N)=O
Yield: 80 %

Procedure:
1.65 Grams of 5,7-diallyl-1-(ethoxy-carbonylmethyl)-3,4-dihydro-6-hydroxy-2(1H)-quinolinone obtained in Example 57 was dissolved in 50 ml of methanol, then 20 ml of 25% ammonia water thereto, the reaction mixture was stirred for 24 hours. Then the reaction mixture was concentrated under reduced pressure. The concentrate was extracted with chloroform, washed with water, dried, then concentrated again under reduced pressure. Thus obtained crude crystals were subjected to purification by passing it through a silica gel column and by using methylene chloridemethanol (50:1) as the eluent, there was obtained 1.2 g (80%) of 1-(carbamoylmethyl)-5,7-diallyl-3,4-dihydro-6-hydroxy-2(1H)-quinolinone.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl[C:13]1[N:18]=[C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:16]=[CH:15][N:14]=1.Cl>O1CCOCC1>[S:8]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[NH:1][C:13]1[N:18]=[C:17]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:26]2[CH2:27][CH2:28][O:29][CH2:30][CH2:31]2)[CH:16]=[CH:15][N:14]=1)(=[O:9])(=[O:10])[NH2:11]
Reactant: Clc1nccc(Nc2ccccc2N2CCOCC2)n1
Reactant: Nc1cccc(S(N)(=O)=O)c1
Agent: Cl
Solvent: C1COCCO1
Product: NS(=O)(=O)c1cccc(Nc2nccc(Nc3ccccc3N3CCOCC3)n2)c1
Temperature: 100 °C
Yield: 84.2 %

Procedure:
To 3-aminobenzenesulphonamide (172 mg, 1.0 m.mol) in 1,4-dioxane (8 ml) was added 2-Chloro-4-[(2-Morpholino)anilino]pyrimidine (290 mgs, 1 m.mol) and hydrogen chloride (4.0M solution in 1,4-dioxane, 50 μl). The mixture was heated at 100° C. for 60 hrs. The reaction mixture was cooled, the resulting solid filtered, washed with 1,4-dixane and dried (in vacuo at 48° C.) to give pale brown solid (358 mg). Rt 5.88; MS (M+H)+: 427.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[S:11][C:10]=2[CH2:24][CH3:25])O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:28])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:28][CH:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:9]1[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[S:11][C:10]=1[CH2:24][CH3:25]
Reactant: O=S(Cl)Cl
Reactant: CCc1sc(-c2ccc(C(F)(F)F)cc2)cc1C(O)C1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCc1sc(-c2ccc(C(F)(F)F)cc2)cc1C(Cl)C1CCCCC1
Temperature: 100 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a solution of cyclohexyl{2-ethyl-5-[4-(trifluoromethyl)phenyl]thiophen-3-yl}methanol (2.29 g) synthesized in Example 69 (7) in toluene (25 mL) was added thionyl chloride (907 μL), and the mixture was stirred at 100° C. for 1 hr. The reaction mixture was cooled to 0° C., saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4, volume ratio) to give the title compound (2.08 g, 86%) as a pale-brown solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:41])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37]C)=[O:36])=[CH:33][N:32]=2)=[O:29])[CH:5]=[CH:6][CH:7]=1.[Br-].[Al+3].[Br-].[Br-].CSC>C(Cl)Cl>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([C@@:12]2([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[NH:10][C@@H:9]([C:28]([NH:30][C:31]3[CH:40]=[CH:39][C:34]([C:35]([OH:37])=[O:36])=[CH:33][N:32]=3)=[O:29])[C@@H:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:41])=[C:16]([F:22])[CH:17]=1
Reactant: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)nc1
Agent: [Al+3]
Agent: [Br-]
Solvent: ClCCl
Solvent: CSC
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(=O)O)cn2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 50 mL round-bottomed flask, methyl 6-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)nicotinate (25 mg, 41.6 μmol, Eq: 1.00) was dissolved in methylene chloride (8 ml) to give a colorless solution. Aluminum bromide (66.5 mg, 249 μmol, Eq: 6) and dimethyl sulfide (25.8 mg, 30.7 μl, 416 μmol, Eq: 10) were added and the mixture was stirred at rt for overnight. The solvent was removed and the residue was suspended in 3 ml of acetonitrile, 3 ml of water was added and the mixture was extracted with ethyl acetate (3×8 ml). The extracts were combined and dried with sodium sulfate. Removal of solvent at reduced pressure gave a yellow solid, 30 mg.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH3:12])=[CH:8][C:9]=2Br)[CH:4]=[CH:3]1.C([Li])(C)(C)C.[C:18](OC)(=[O:23])[C:19]([O:21][CH3:22])=[O:20]>C1COCC1>[CH3:22][O:21][C:19](=[O:20])[C:18]([C:9]1[CH:8]=[C:7]([CH3:12])[CH:6]=[C:5]2[C:10]=1[N:2]([CH3:1])[CH:3]=[CH:4]2)=[O:23]
Reactant: COC(=O)C(=O)OC
Reactant: Cc1cc(Br)c2c(ccn2C)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COC(=O)C(=O)c1cc(C)cc2ccn(C)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.3 %

Procedure:
A solution of 1,5-dimethyl-7-bromoindole (4.27 g, 19.05 mmol) in THF (130 mL) was cooled to −78° C. and a solution of tert-butyl lithium in pentanes (1.7 M, 24.6 mL, 41.8 mmol) added dropwise over 30 min. After 30 min at −78° C., the mixture was treated with dimethyl oxalate (5.62 g, 47.6 mmol) in one portion. After 15 min, the mixture was allowed to warm to room temperature and stirred 4 h. The reaction mixture was quenched with water, extracted with ethyl acetate, and the extracts washed with brine, dried (Na2SO4) and concentrated. Flash chromatography (EtOAc/hexanes) afforded the title compound (4.2 g, 95%) as bright yellow oil. 1H NMR (400 MHz, CDCl3) δ 2.46 (s, 3H), 3.85 (s, 3H), 4.01 (s, 3H), 6.51 (dd, J1=1.17 Hz, J2=3.13 Hz, 1 H), 7.06 (d, J=3.13 Hz, 1H), 7.36 (s, 1H), 7.69 (s, 1H); MS (ES, m/z): C13H13NO3: 232.19 (M++1).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][N:15]=[C:16]=[O:17]>C1(C)C=CC=CC=1>[CH3:14][NH:15][C:16]([N:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:17]
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: CN=C=O
Solvent: Cc1ccccc1
Product: CNC(=O)N(c1ccccc1)c1ccccc1
Temperature: 100 °C
Yield: 480 %

Procedure:
0.5 mole of diphenylamine was taken together with 0.53 mole of methyl isocyanate and 0,6 g of di-n-butyl phosphate in 150 ml of toluene. The mixture was heated at 100° C. for 10 hours, with stirring. After cooling to room temperature, the N-methyl-N',N'-diphenylurea formed was filtered off wtih suction. The filtrate was made up to 150 ml with toluene, and 0.5 mole of diphenylamine and 0.53 mole of methyl isocyanate were added. The mixture was heated again at 100° C. for 10 hours, with stirring, and then cooled to room temperature. Recycling of the filtrate and subsequent addition of in each case 0.5 mole of diphenylamine and 0.53 mole of methyl isocyanate was repeated a further three times. After these five reactions with only a single addition of catalyst, 2.4 moles of N-methyl-N',N'-diphenylurea were obtained. The urea was washed with in each case 100 ml of cold toluene after each reaction. Melting point: 170°/yield: 96% of theory.
Reaction SMILES: [CH2:1]([C:3]1[N:12]([CH2:13][CH2:14][CH3:15])[C:11](=[O:16])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2].C([O-])(=O)C.[Na+].[Br:22]Br.O>C(O)(=O)C>[Br:22][CH:1]([C:3]1[N:12]([CH2:13][CH2:14][CH3:15])[C:11](=[O:16])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2]
Reactant: BrBr
Reactant: CCCn1c(CC)nc2ccccc2c1=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCCn1c(C(C)Br)nc2ccccc2c1=O
Yield: 92.3 %

Procedure:
To a solution of 2-ethyl-3-propyl-3H-quinazolin-4-one (125 mg, 0.58 mmol) and sodium acetate (48 mg, 0.58 mmol) in glacial acetic acid (1 mL) cooled in an ice bath was added dropwise a solution of bromine (29.8 μL, 0.58 mmol) in glacial acetic acid (0.5 mL). After addition was complete the reaction was heated to reflux for 2 hours. Water was then added to the solution and the mixture extracted with dichloromethane. The organic layer was then washed with 10% sodium bisulfite solution, water and then dried over magnesium sulfate, filtered and concentrated to yield the product as a brown oil (158 mg, 92%). 1H NMR (CDCl3) δ 1.05 (t, 3H, J=7.3 Hz), 1.66 (m, 1H), 1.91 (m, 1H), 2.19 (d, 3H, J=6.3 Hz), 3.89 (m, 1H,), 4.53 (m, 1H,), 5.04 (q, 1H, J=6.6 Hz), 7.49 (t, 1H, J=7.3 Hz), 7.73 (m, 2H), 8.27 (d, 1H, J=8.4 Hz).
Reaction SMILES: C([C@H]1CSC(=O)N1[C:14]([C@@H:16]([C@@H:29]([OH:46])[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[C:42]([F:44])[CH:41]=[C:40]([F:45])[CH:39]=2)=[CH:34][CH:33]=1)[CH2:17][N:18]1[C:23](=[O:24])[C:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=2[N:20]=[N:19]1)=[O:15])C1C=CC=CC=1.[OH:47]O.O.[OH-].[Li+]>O1CCCC1.O.O>[F:45][C:40]1[CH:39]=[C:38]([C:35]2[CH:34]=[CH:33][C:32]([CH2:31][CH2:30][C@@H:29]([OH:46])[C@H:16]([CH2:17][N:18]3[C:23](=[O:24])[C:22]4[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=4[N:20]=[N:19]3)[C:14]([OH:15])=[O:47])=[CH:37][CH:36]=2)[CH:43]=[C:42]([F:44])[CH:41]=1
Reactant: OO
Reactant: O=C1SC[C@H](Cc2ccccc2)N1C(=O)[C@H](Cn1nnc2ccccc2c1=O)[C@@H](O)CCc1ccc(-c2cc(F)cc(F)c2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)[C@@H](Cn1nnc2ccccc2c1=O)[C@H](O)CCc1ccc(-c2cc(F)cc(F)c2)cc1
Temperature: 0 °C

Procedure:
To a stirred solution of the compound obtained from step f above (0.2 g) in tetrahydrofuran:water (3:1, 10 mL) aqueous hydrogen peroxide solution (30%, 0.16 mL) was added at 0° C., followed by the addition of lithium hydroxide monohydrate (19.53 mg) in water (2 mL). The reaction mixture was stirred at 0° C. until the completion of the hydrolysis. The reaction mixture was concentrated and the residue was extracted with ethyl acetate. The aqueous layer was acidified with sodium hydrogen sulphate and extracted with ethyl acetate. The combined layers were washed with water and brine and dried over anhydrous sodium sulphate. The solvents were evaporated under reduced pressure, and the crude residue was purified by silica gel flash column chromatography using 10% methanol in dichloromethane as eluant to afford the title compound (0.090 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C@H:7]2[N:8](C(C3C=CC=CC=3)C)[CH2:9][C@H:4]([O:5][C:6]2=[O:18])[CH2:3]1.[H][H]>[Pd].CO>[CH3:1][C:2]1([CH3:19])[C@H:7]2[NH:8][CH2:9][C@H:4]([O:5][C:6]2=[O:18])[CH2:3]1
Reactant: [H][H]
Reactant: CC(c1ccccc1)N1C[C@H]2CC(C)(C)[C@@H]1C(=O)O2
Agent: [Pd]
Solvent: CO
Product: CC1(C)C[C@@H]2CN[C@H]1C(=O)O2
Yield: 94.8 %

Procedure:
To a small Parr shaker bottle was added of (1R,4R)-8,8-Dimethyl-5-(1-phenyl-ethyl)-2-oxa-5-aza-bicyclo[2.2.2]octan-3-one (compound of formula XXXV, 1.04 g, 4.01 mmol), methanol (50 ml) and 0.12 g of 10% Palladium on charcoal. The mixture was shaken under about 50 psi of hydrogen for about 19 hours. The mixture was filtered and concentrated, affording 0.59 g of (1R,4R)-8,8-dimethyl-2-oxa-5-aza-bicyclo[2.2.2]octan-3-one (compound of formula XXXVI) as a filmy solid.
Reaction SMILES: [F:1][C:2]1[C:19]([NH:20][NH2:21])=[CH:18][C:5]2[N:6]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.C([O:24][C:25]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][C:28]1=O)=O)C.[O-]CC.[Na+]>C(O)C>[F:1][C:2]1[C:19]([N:20]2[C:25](=[O:24])[CH:27]3[C:28]([CH2:29][CH2:30][CH2:31][CH2:32]3)=[N:21]2)=[CH:18][C:5]2[N:6]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: NNc1cc2c(cc1F)OCC(=O)N2Cc1ccccn1
Reactant: CCOC(=O)C1CCCCC1=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C1COc2cc(F)c(N3N=C4CCCCC4C3=O)cc2N1Cc1ccccn1
Yield: 60.8 %

Procedure:
A mixture of 7-fluoro-6-hydrazino-4-(pyridin-2-ylmethyl)-2H-1,4-benzoxazin-3(4H)-one (1.49 g), 2-ethoxycarbonyl-cyclohexanone (0.9 g) and ethanol (20 ml) was admixed with a catalytic amount of sodium ethoxide, and heated under reflux for 5 hours. The reaction mixture was distilled to remove the ethanol therefrom, admixed with toluene (30 ml), heated under reflux for 10 minutes, cooled to a temperature of 0° to 10° C., and filtered. The solid portion thus obtained was washed with n-hexane, and dried, so that the aimed compound, i.e. 7-fluoro-6-(3,3a,4,5,6,7-hexahydro-2H-indazole-3-on-2-yl)-4-(pyridin-2-ylmethyl)-2H-1,4-benzoxazin-3(4H)-one (1.24 g) was obtained. m.p. 216°-219° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:9][CH3:10])[C:3]=1[O:11][CH2:12][O:13][CH3:14].C(=O)([O-])[O-].[K+].[K+].[CH2:21](I)[CH3:22]>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:21][CH3:22])=[C:4]([O:9][CH3:10])[C:3]=1[O:11][CH2:12][O:13][CH3:14]
Reactant: COCOc1c(Br)ccc(O)c1OC
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1ccc(Br)c(OCOC)c1OC
Temperature: 70 °C
Yield: 79.1 %

Procedure:
To a stirring solution of 4-bromo-2-methoxy-3-(methoxymethoxy)phenol (600 mg, 2.28 mmol) in acetonitrile (20 mL) was added potassium carbonate (944 mg, 6.84 mmol) and ethyl iodide (711 mg, 4.56 mmol) and the resultant reaction mixture was heated to 70° C. for 3 h. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-7% ethyl acetate in pet ether) to afford 1-Bromo-4-ethoxy-3-methoxy-2-(methoxymethoxy)benzene as a solid (525 mg, 79%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]3([CH3:26])[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:10][C:9]=2[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][S:34]([C:37]3[CH:41]=[CH:40][O:39][CH:38]=3)(=[O:36])=[O:35])[C:28]=2[F:42])[CH:5]=[CH:4][N:3]=1.[CH3:43][Zn]C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O1CCOCC1>[F:42][C:28]1[C:29]([NH:33][S:34]([C:37]2[CH:41]=[CH:40][O:39][CH:38]=2)(=[O:36])=[O:35])=[CH:30][CH:31]=[CH:32][C:27]=1[C:9]1[N:10]=[C:11]([C:13]2([CH3:26])[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[S:12][C:8]=1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:43])[N:7]=1
Reactant: C[Zn]C
Reactant: CC(C)(C)OC(=O)N1CCC(C)(c2nc(-c3cccc(NS(=O)(=O)c4ccoc4)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1nccc(-c2sc(C3(C)CCN(C(=O)OC(C)(C)C)CC3)nc2-c2cccc(NS(=O)(=O)c3ccoc3)c2F)n1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
1,1-dimethylethyl 4-(5-(2-chloro-4-pyrimidinyl)-4-{2-fluoro-3-[(3-furanylsulfonyl)amino]phenyl}-1,3-thiazol-2-yl)-4-methyl-1-piperidinecarboxylate (130 mg, 0.205 mmol) was dissolved into 1,4-dioxane (3 mL) and the solution was degassed for 10 min. PdCl2(dppf)-CH2Cl2 adduct (8.37 mg, 10.25 μmol) and dimethylzinc (0.205 mL, 0.410 mmol) were added the reaction mixture. The reaction mixture was stirred at 80° C. for 1 h. The reaction was quenched with methanol (3 mL) and water (10 mL) and extracted with EtOAc (3×). The extract was dried over Na2SO4, filtered, and concentrated. The residue was purified using column chromatography (40% to 100% EtOAc/hexane) to the title compound (100 mg). MS (ESI): 557.7 [M+1]+.
Reaction SMILES: [O:1]=[S:2]1(=[O:35])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[C:28]([C:30](=[NH:33])[NH:31][OH:32])[CH:27]=[CH:26][C:25]=4[CH3:34])=[CH:20][CH:19]=3)=[O:17])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[CH:36]1([C:39](Cl)=O)[CH2:38][CH2:37]1>>[O:35]=[S:2]1(=[O:1])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[CH:19]=[CH:20][C:21]([C:24]4[CH:29]=[C:28]([C:30]5[N:33]=[C:39]([CH:36]6[CH2:38][CH2:37]6)[O:32][N:31]=5)[CH:27]=[CH:26][C:25]=4[CH3:34])=[CH:22][CH:23]=3)=[O:17])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1
Reactant: Cc1ccc(C(=N)NO)cc1-c1ccc(C(=O)Nc2ccc(CN3CCS(=O)(=O)CC3)cc2)cc1
Reactant: O=C(Cl)C1CC1
Product: Cc1ccc(-c2noc(C3CC3)n2)cc1-c1ccc(C(=O)Nc2ccc(CN3CCS(=O)(=O)CC3)cc2)cc1

Procedure:
5′-(N-Hydroxycarbamimidoyl)-2′-methyl-biphenyl-4-carboxylic acid [4-(1,1-dioxo-1lambda*6*-thiomorpholin-4-ylmethyl)-phenyl]-amide (50 mg) and cyclopropylcarbonyl chloride (0.02 ml) was heated in a microwave at 150 C for 40 min. The solvent was then evaporated and the residue purified on silica gel. Gradient elution with 0-30% 20:8:1 CH2Cl2/EtOH/NH3 in CH2Cl2 gave the title compound as a white solid (24 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].[OH:27][CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([N:33]2[CH2:34][CH2:35][N:30]([CH2:29][CH2:28][OH:27])[CH2:31][CH2:32]2)=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: OCCN1CCNCC1
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(C(=O)N2CCN(CCO)CC2)cc1Cl

Procedure:
50 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to N-(2-hydroxyethyl)piperazine via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(4-(2-hydroxyethyl)piperazine-1-carbonyl)benzamide. MS (Q1) 499 (M)+.