Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[C:4]([C:6]1[CH:11]=[CH:10][C:9](B(O)O)=[CH:8][CH:7]=1)=[O:5])[CH3:2].Br[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]2)=[CH:20][CH:19]=1>>[CH2:1]([N:3]([CH2:15][CH3:16])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH:26]3[CH2:27][CH2:28][N:29]([C:32]([O:34][CH:35]([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:31]3)=[CH:22][CH:23]=2)=[CH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CC(C)OC(=O)N1CCC(COc2ccc(Br)cc2)CC1
Reactant: CCN(CC)C(=O)c1ccc(B(O)O)cc1
Product: CCN(CC)C(=O)c1ccc(-c2ccc(OCC3CCN(C(=O)OC(C)C)CC3)cc2)cc1
Yield: 43.1 %

Procedure:
The title compound (39 mg, 34%) was prepared from {4-[(diethylamino)carbonyl]phenyl}boronic acid (44 mg, 0.2 mmol) and 1-methylethyl 4-{[(4-bromophenyl)oxy]methyl}-1-piperidinecarboxylate (prepared as in Example 9, Step 2, 71 mg, 0.2 mmol) in a manner similar to Example 21, Step 3, and worked up in a manner similar to Example 9, Step 3. 1H NMR (400 MHz, CDCl3): δ 7.56 (d, 2H, J=8.4 Hz), 7.52 (d, 2H, J=8.8 Hz), 7.41 (d, 2H, J=8.2 Hz), 6.96 (d, 2H, J=8.8 Hz), 4.97-4.86 (m, 1H), 4.21 (bs, 2H), 3.84 (d, 2H, J=6.4 Hz), 3.56 (bs, 2H), 3.32 (bs, 2H), 2.84-2.74 (m, 2H), 2.05-1.95 (m, 1H), 1.90-1.80 (m, 2H), 1.38-1.06 (m, 14H); LRMS (ESI), m/z 453 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:12]3[N:13]=[CH:14][C:15]([CH2:16][OH:17])=[C:11]3[N:10]=[CH:9][CH:8]=2)[CH:2]=1.Cl.[CH3:19]O>>[CH3:19][O:17][CH2:16][C:15]1[CH:14]=[N:13][N:12]2[C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)=[CH:8][CH:9]=[N:10][C:11]=12
Reactant: CO
Reactant: OCc1cnn2c(-c3cccnc3)ccnc12
Agent: Cl
Product: COCc1cnn2c(-c3cccnc3)ccnc12

Procedure:
To a mixture of 0.01 mole of 7-(3-pyridyl)pyrazolo-[1,5-a]pyrimidine-3-methanol in 50 ml. of methanol is added anhydrous hydrochloric acid in 10 ml. of methanol. The mixture is heated on a steam bath for 3 hours and the solvent removed. The residue is partitioned between dichloromethane and aqueous sodium bicarbonate. The dichloromethane solution is dried over magnesium sulfate, concentrated and diluted with hexane to give the product of the example.
Reaction SMILES: [C:1]([NH:9][CH2:10][CH:11]1[C:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:19][CH2:18][CH2:17][C:12]21[O:16][CH2:15][CH2:14][O:13]2)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[CH2:1]([NH:9][CH2:10][CH:11]1[C:20]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:19][CH2:18][CH2:17][C:12]21[O:13][CH2:14][CH2:15][O:16]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCC1C2(CCCC1(c1ccccc1)c1ccccc1)OCCO2)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(CNCC2C3(CCCC2(c2ccccc2)c2ccccc2)OCCO3)cc1
Yield: 84.2 %

Procedure:
A solution of (RS)-6-benzamidomethyl-7,7-diphenyl-1,4-dioxaspiro[4.5]decane (8.1 g) in anhydrous tetrahydrofuran (150 cc) is added dropwise, in the course of 1 hour 30 minutes and while the temperature of the reaction mixture is maintained at +5° C., to a suspension, cooled to +5° C. of lithium aluminum hydride (1.9 g) in anhydrous tetrahydrofuran (60 cc), and the mixture is then brought to reflux for 24 hours. The reaction mixture is then cooled to +5° C., treated with distilled water (2.1 cc), then with 5N aqueous sodium hydroxide solution (1.9 cc) and then with distilled water (5.8 cc), filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is chromatographed on a column of silica gel with a slight excess pressure of nitrogen (0.04-0.063 mm, diameter 5 cm, height 29 cm), eluting with ethyl acetate and collecting 120-cc fractions. Fractions 3 to 12 are combined and concentrated to dryness under reduced pressure (2.7 kPa). (RS)-6-Benzylaminomethyl-7,7-diphenyl-1,4-dioxaspiro[4.5]decane (6.6 g) is obtained in the form of a yellow oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]CS([O-])(=O)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:17][C:18]1[S:19][C:20]2[CH2:21][CH2:22][NH:23][CH2:24][CH2:25][C:26]=2[N:27]=1>C(Cl)(Cl)Cl>[NH2:17][C:18]1[S:19][C:20]2[CH2:21][CH2:22][N:23]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:24][CH2:25][C:26]=2[N:27]=1
Reactant: O=S(=O)([O-])CCCCCCc1ccccc1
Reactant: Nc1nc2c(s1)CCNCC2
Solvent: ClC(Cl)Cl
Product: Nc1nc2c(s1)CCN(CCCCCc1ccccc1)CC2
Yield: 19 %

Procedure:
Prepared from 5-phenyl-1-pentyl-mesylate and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6H- thiazolo[5,4-d]azepine in chloroform. Yield: 19% of theory, Melting point: 102°-105° C. (petroleum ether).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[NH:9][N:10]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:11]3[C:16]=2[CH2:15][C:14]([C:17]([OH:19])=O)=[CH:13][CH:12]=3)[CH:5]=[CH:4][N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:63][C:64]1[CH:80]=[CH:79][CH:78]=[CH:77][C:65]=1[CH2:66][C:67]1([CH2:74][O:75][CH3:76])[CH2:72][CH2:71][CH2:70][N:69]([NH2:73])[CH2:68]1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[F:63][C:64]1[CH:80]=[CH:79][CH:78]=[CH:77][C:65]=1[CH2:66][C:67]1([CH2:74][O:75][CH3:76])[CH2:72][CH2:71][CH2:70][N:69]([NH:73][C:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[N:10]([C:20]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:9]=[C:8]3[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)=[O:19])[CH2:68]1
Reactant: Cc1cc(C2=C3CC(C(=O)O)=CC=C3N(C(c3ccccc3)(c3ccccc3)c3ccccc3)N2)ccn1
Reactant: COCC1(Cc2ccccc2F)CCCN(N)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCC1(Cc2ccccc2F)CCCN(NC(=O)c2ccc3c(c2)c(-c2ccnc(C)c2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Reaction time: 1 h

Procedure:
In a flask, 3-(2-methylpyridin-4-yl)-1-trityl-4H-indazole-5-carboxylic acid (271 mg, 0.546 mmol), HATU (256 mg, 0.67 mmol) and 3-(2-fluorobenzyl)-3-(methoxymethyl)piperidin-1-amine (122 mg, 0.42 mmol) was dissolved in dimethylformamide (2 mL). Diisopropylethylamine (0.366 mL, 2.1 mmol) was added to the reaction. The reaction was allowed to stir for an additional 1 h. Upon completion, the reaction was quenched with water (10 mL). The water layer was extracted with ethyl acetate (20 mL) three times. The organic fractions were combined, dried with sodium sulfate, and concentrated to yield the crude product. The crude product was progressed to the next step without further purification.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[C:11]([S-:13])#[N:12].[K+]>C(O)C.O>[S:13]([CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4])[C:11]#[N:12]
Reactant: N#C[S-]
Reactant: O=C(CCl)c1ccccc1
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CSCC(=O)c1ccccc1
Temperature: 50 °C
Reaction time: 0.17 h

Procedure:
150 g of ω-chloroacetophenone are dissolved at 50° C. in 1000 ml of ethanol, followed by the addition of a solution of 102 g of KSCN in 40 ml of water. After stirring for 10 minutes at 50° C., the ω-thiocyano acetophenone formed is precipitated with water.
Reaction SMILES: [CH3:1][N:2]([CH3:29])[C:3](=[O:28])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2([O:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[O:13])[CH:6]=1.C(N(CC)C(C)C)(C)C.Cl[C:40]1[C:41]2[C:48]([CH3:49])=[CH:47][NH:46][C:42]=2[N:43]=[CH:44][N:45]=1>C(O)(C)C>[CH3:1][N:2]([CH3:29])[C:3](=[O:28])[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2([O:20][CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:19][CH2:18][N:17]([C:40]3[C:41]4[C:48]([CH3:49])=[CH:47][NH:46][C:42]=4[N:43]=[CH:44][N:45]=3)[CH2:16][CH2:15]2)=[O:13])[CH:6]=1
Reactant: CN(C)C(=O)Oc1cccc(NC(=O)C2(OCc3ccccc3)CCNCC2)c1
Reactant: Cc1c[nH]c2ncnc(Cl)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1c[nH]c2ncnc(N3CCC(OCc4ccccc4)(C(=O)Nc4cccc(OC(=O)N(C)C)c4)CC3)c12
Temperature: 110 °C

Procedure:
To a solution of 3-(4-(benzyloxy)piperidine-4-carboxamido)phenyl dimethylcarbamate, from step E, and N,N-diisopropylethylamine (0.7 mL, 4.02 mmol) in isopropanol (1.6 mL) was added 4-chloro-5-methyl-7H-pyrrolo[2,3-d]pyrimidine (135 mg, 0.804 mmol). The reaction mixture was heated to 110° C. in a sealed high-pressure vial for 17 hours, during which time the mixture became homogenous. The reaction was concentrated under vacuum, and half of the material was purified by prep HPLC (30×100 mm C18 column, 20-100% acetonitrile:water (10 mM ammonium acetate), 15 min, 45 mL/min) to afford the title compound (33.4 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:18])([CH3:17])[C:3]([O:5][C:6]1[CH:11]([OH:12])[NH:10][CH:9]=[N:8][C:7]=1[C:13]([O:15][CH3:16])=[O:14])=[O:4].[CH2:19](Br)[CH:20]=[CH2:21].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1>[CH2:21]([N:10]1[C:11](=[O:12])[C:6]([O:5][C:3](=[O:4])[C:2]([CH3:18])([CH3:17])[CH3:1])=[C:7]([C:13]([O:15][CH3:16])=[O:14])[N:8]=[CH:9]1)[CH:20]=[CH2:19]
Reactant: COC(=O)C1=C(OC(=O)C(C)(C)C)C(O)NC=N1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: C=CCn1cnc(C(=O)OC)c(OC(=O)C(C)(C)C)c1=O

Procedure:
Methyl 5-[(2,2-dimethylpropanoyl)oxy]-6-hydroxy-1,6-dihydropyrimidine-4-carboxylate (see Example 4, Step 3) was dissolved in THF, then allyl bromide (2 eq.) and Cs2CO3 (2 eq.) were added. The reaction mixture was refluxed for 2 h, then evaporated. The residue was diluted with EtOAc, washed with 1N HCl, dried (Na2SO4) and the solvent evaporated. The product was-purified by flash chromatography on silica gel eluting with a gradient of petroleum ether/EtOAc.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:17]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26]CC)=[O:25])[CH3:18])=[CH:4][C:5]([O:15][CH3:16])=[C:6]([CH:14]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[OH-].[Na+].Cl.C(OCC)(=O)C>C(O)C>[C:10]([O:9][C:7]([C:6]1[C:5]([O:15][CH3:16])=[CH:4][C:3]([N:17]([CH3:18])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[C:2]([Cl:1])[CH:14]=1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CCOC(=O)CCCCCN(C)c1cc(OC)c(C(=O)OC(C)(C)C)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc(N(C)CCCCCC(=O)O)c(Cl)cc1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 102 %

Procedure:
The compound (200 mg, 0.48 mmol) obtained in Example 99c was dissolved in ethanol (4 mL), a 1 N aqueous sodium hydroxide solution (1.00 mL, 1.00 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, a 1 N aqueous hydrochloric acid solution (1.00 mL, 1.00 mmol) was added to the reaction mixture under ice cooling, and ethyl acetate was further added to separate the layers. The resulting organic layer was separated, washed with saturated sodium chloride solution, and then dried with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give crude 6-{[4-(tert-butoxycarbonyl)-2-chloro-5-methoxyphenyl](methyl)amino}hexanoic acid (189 mg).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1>>[Cl:11][C:4]1[N:3]=[C:2]([NH:18][CH2:17][C:16]2[CH:19]=[CH:20][C:13]([F:12])=[CH:14][CH:15]=2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: NCc1ccc(F)cc1
Product: O=[N+]([O-])c1ccc(Cl)nc1NCc1ccc(F)cc1
Yield: 65 %

Procedure:
In accordance with the same procedures as in Preparation 7, except for using 2,6-dichloro-3-nitropyridine and 4-fluorobenzylamine, the titled compound was obtained as yellow solid. (Yield: 65%)
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[C:15]([NH:22][CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>>[CH3:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([N:26]2[CH2:25][CH2:24][CH:23]([NH:22][C:15](=[O:16])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])[CH2:28][CH2:27]2)=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1)(=[O:10])=[O:9]
Reactant: CS(=O)(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(S(C)(=O)=O)cc2[N+](=O)[O-])CC1

Procedure:
Method 1 was followed using 1-fluoro-4-(methylsulfonyl)-2-nitrobenzene (1.0 eq), 4-(N-Boc-amino) piperidine (1.1 eq), and TEA (2.0 eq) at 55° C. for 24 hours yielding tert-butyl 1-(4-(methylsulfonyl)-2-nitrophenyl)piperidin-4-ylcarbamate. LCMS (m/z): 400.1 (MH+); LC Rt=2.83 min.
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=2[S:5][C:6]=1[CH:7]([OH:11])[C:8]([OH:10])=[O:9].S(=O)(=O)(O)O.[CH3:21]O>>[Br:1][C:2]1[C:3]2[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=2[S:5][C:6]=1[CH:7]([OH:11])[C:8]([O:10][CH3:21])=[O:9]
Reactant: O=C(O)C(O)c1sc2ccccc2c1Br
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C(O)c1sc2ccccc2c1Br
Yield: 91 %

Procedure:
A solution of (3-bromo-benzo[b]thiophen-2-yl)-hydroxy-acetic acid (21b) (590 mg, 2.05 mmol) and sulfuric acid (500 μL) in methanol (10 mL) was refluxed for 1 hour. The reaction mixture was then concentrated in vacuo and the residue was diluted with ethyl acetate (20 mL). The organic layer was washed with water (2×20 mL), a saturated solution of sodium bicarbonate (20 mL), brine (20 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure to afford the desired ester (21c) as a orange solid (560 mg, 1.86 mmol, 91%) without further purification.
Reaction SMILES: [S:1]1[C:5]([NH:6][S:7]([C:10]2[CH:11]=[CH:12][C:13]3[N:18]([C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=4[C:29]4[CH2:34][CH2:33][N:32](C(OC(C)(C)C)=O)[CH2:31][CH:30]=4)[CH2:17][CH2:16][O:15][C:14]=3[CH:42]=2)(=[O:9])=[O:8])=[N:4][CH:3]=[N:2]1>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH:32]1[CH2:31][CH:30]=[C:29]([C:20]2[CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=[CH:24][C:19]=2[N:18]2[CH2:17][CH2:16][O:15][C:14]3[CH:42]=[C:10]([S:7]([NH:6][C:5]4[S:1][N:2]=[CH:3][N:4]=4)(=[O:9])=[O:8])[CH:11]=[CH:12][C:13]2=3)[CH2:34][CH2:33]1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc(C(F)(F)F)ccc2N2CCOc3cc(S(=O)(=O)Nc4ncns4)ccc32)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1ncns1)c1ccc2c(c1)OCCN2c1ccc(C(F)(F)F)cc1C1=CCNCC1
Reaction time: 0.08 h

Procedure:
Tert-butyl 4-(2-(7-(N-(1,2,4-thiadiazol-5-yl)sulfamoyl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)-5-(trifluoromethyl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate (EXAMPLE 5, 30 mg) was diluted with 0.5 mL of DCM and TFA (0.5 mL) was added. After 5 minutes, complete conversion to the desired deprotected product was observed. The material was concentrated under a vacuum and purified via reverse-phase HPLC (Column: Phenomenex 150×30 mm, 5 micron, C18 column; 0.1% TFA in CH3CN/H2O, gradient 25% to 90% over 20 min) to yield 4-(2-(1,2,3,6-tetrahydropyridin-4-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.39 (m, J=17.50 Hz, 2 H) 3.19 (m, J=12.90 Hz, 2 H) 3.59 (m, J=3.80 Hz, 2 H) 3.65-3.71 (m, 2 H) 4.30 (m, J=4.90 Hz, 2 H) 5.88 (s, 1 H) 6.48 (d, J=8.41 Hz, 1 H) 7.11-7.19 (m, 2 H) 7.59 (d, J=8.12 Hz, 1 H) 7.63 (d, J=2.05 Hz, 1 H) 7.76 (dd, J=8.41, 1.66 Hz, 1 H) 8.39 (s, 1 H) 8.77 (br. s., 2 H). m/z (ESI) 524.0 (M+H)+.
Reaction SMILES: [C:1]([C@@:8]([NH2:23])([CH2:12][S:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)C(O)=O)([O:3][C:4](C)(C)C)=[O:2]>CO>[CH3:4][O:3][C:1](=[O:2])[C@@H:8]([NH2:23])[CH2:12][S:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1
Reactant: COc1ccc(CSC[C@@](N)(C(=O)O)C(=O)OC(C)(C)C)cc1
Solvent: CO
Product: COC(=O)[C@@H](N)CSCc1ccc(OC)cc1

Procedure:
(R)-2-BOC-amino-3-(4-methoxy-benzylsulfanyl)-propionic acid prepared in Step B of Preparation 27 and methanol were reacted according to the same procedure as Preparation 30 to give the title compound.
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[CH:7][C:8]([O:19][CH2:20][CH:21]([OH:28])[CH2:22][NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[C:9]([CH:18]=1)[C:10]([CH2:12][CH2:13][C:14](OC)=[O:15])=O)(=O)C.O.[NH2:30][NH2:31]>>[NH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:19][CH2:20][CH:21]([OH:28])[CH2:22][NH:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[C:9]([C:10]2[CH2:12][CH2:13][C:14](=[O:15])[NH:30][N:31]=2)[CH:18]=1
Reactant: NN
Reactant: COC(=O)CCC(=O)c1cc(NC(C)=O)ccc1OCC(O)CNC(C)(C)C
Solvent: O
Product: CC(C)(C)NCC(O)COc1ccc(N)cc1C1=NNC(=O)CC1

Procedure:
Methyl 3-[5-acetamido-2-(3-t-butylamino-2-hydroxypropoxy)benzoyl]propionate was hydrolysed by aqueous acid and the solution was neutralised and evaporated to dryness. 3-[5-Amino-2-(3-t-butylamino-2-hydroxypropoxy)benzoyl]propionic acid was extracted from the residue with hot ethanol and the combined extracts were evaporated to give the crude acid, which was cyclised by hydrazine hydrate as in Example 2(iv) to give 6-[5-amino-2-(3-t-butylamino-2-hydroxypropoxy)phenyl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[C:12]=1[NH:13][CH3:14])[C:6]([O:8]C)=[O:7].[OH-].[Li+].Cl>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([N+:15]([O-:17])=[O:16])[C:12]=1[NH:13][CH3:14])[C:6]([OH:8])=[O:7]
Reactant: CNc1c(OC)cc(C(=O)OC)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CNc1c(OC)cc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 19 h
Yield: 86 %

Procedure:
To a solution of methyl 3-methoxy-4-(methylamino)-5-nitrobenzoate (13.69 g, 57.0 mmol) in tetrahydrofuran (THF) (100 mL) and water (50.0 mL) was added a single portion of lithium hydroxide (4.09 g, 171 mmol). The resulting suspension was stirred for 19 hr at room temperature. The reaction was acidified with aq. 2N HCl (˜50 mL), until pH reached ˜4. The resultant suspension was filtered and the orange solid dried on the high vacuum line overnight to give the title compound as an orange solid (11.09 g).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Br:7][C:8]1[C:9]([O:18][CH3:19])=[C:10]([C:14]([F:17])=[CH:15][CH:16]=1)[C:11](O)=[O:12].C[N:21](C=O)C>C(Cl)Cl>[Br:7][C:8]1[C:9]([O:18][CH3:19])=[C:10]([C:14]([F:17])=[CH:15][CH:16]=1)[C:11]([NH2:21])=[O:12]
Reactant: CN(C)C=O
Reactant: COc1c(Br)ccc(F)c1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1c(Br)ccc(F)c1C(N)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Oxalyl chloride (15 mL) was added dropwise at 0° C. to a suspension of 3-bromo-6-fluoro-2-methoxybenzoic acid (15 g, 60 mmol) in 100 mL of DCM with 0.5 mL of DMF. The mixture was stirred at 25° C. for 2 hours and the clear solution was concentrated to dryness under reduced pressure. The residue dissolved in 60 mL of anhydrous acetonitrile was added to 600 mL of aqueous NH3.H2O at 0° C. and stirred for 2 hours, then filtered to give 3-bromo-6-fluoro-2-methoxybenzamide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)=[N:14][NH:13][C:12](=[O:24])[CH:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl[CH2:26][CH:27]1[CH2:29][CH2:28]1>>[CH:27]1([CH2:26][N:13]2[C:12](=[O:24])[CH:11]=[C:10]([C:4]3[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=3)[C:15]([C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)=[N:14]2)[CH2:29][CH2:28]1
Reactant: COc1ccc(-c2n[nH]c(=O)cc2-c2ccc(OC)c(F)c2)cc1
Reactant: ClCC1CC1
Product: COc1ccc(-c2nn(CC3CC3)c(=O)cc2-c2ccc(OC)c(F)c2)cc1
Yield: 93.8 %

Procedure:
Using 5-(3-fluoro-4-methoxyphenyl)-6-(4-methoxyphenyl)-2H-pyridazin-3-one and (chloromethyl)cyclopropane as starting materials, the procedures of Example 146 were repeated likewise, whereby the title compound was obtained in a yield of 93.8%.
Reaction SMILES: C([O:4][CH2:5][CH2:6][NH:7][C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]2[N:20]([CH3:21])[C:19](=[O:22])[CH2:18][N:17]=[C:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[C:15]=2[C:30]=1[Cl:31])=[O:9])(=O)C.C[O-].[Na+].C(O)(=O)C>CO>[Cl:31][C:30]1[C:15]2[C:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])=[N:17][CH2:18][C:19](=[O:22])[N:20]([CH3:21])[C:14]=2[CH:13]=[CH:12][C:11]=1[NH:10][C:8]([NH:7][CH2:6][CH2:5][OH:4])=[O:9]
Reactant: CC(=O)OCCNC(=O)Nc1ccc2c(c1Cl)C(c1ccccc1F)=NCC(=O)N2C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CN1C(=O)CN=C(c2ccccc2F)c2c1ccc(NC(=O)NCCO)c2Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
600 mg of 2-[3-[6-chloro-5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]ureido]ethyl acetate dissolved in 35 ml of absolute methanol are treated with 830 mg of sodium methylate and stirred at room temperature for 1 hour. The mixture is buffered with a small amount of acetic acid and concentrated. The residue is treated with methylene chloride/10% sodium bicarbonate solution, the aqueous solution is extracted with methylene chloride and the organic solution is dried over sodium sulphate, filtered and concentrated. The residue is purified on a 30 g silica gel column with ethyl acetate/methanol (10:1) as the eluting agent and crystallised from ethanol/ether. There is obtained 1-[6-chloro-5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]-3-(2-hydroxyethyl)urea which, according to the melting point, mixed melting point and IR spectrum, is identical with a sample prepared in another manner (see Example 13).
Reaction SMILES: O1CCOCC1.Br[C:8]1[C:12]([CH3:14])([CH3:13])[O:11]/[C:10](=[C:15]2/[C:16](=[O:25])[NH:17][C:18]3[C:23]/2=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)/[CH:9]=1.[CH:26]([C:28]1[S:32][CH:31]=[C:30](B(O)O)[CH:29]=1)=[O:27].C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[F:24][C:20]1[CH:19]=[C:18]2[C:23](/[C:15](=[C:10]3/[CH:9]=[C:8]([C:30]4[CH:29]=[C:28]([CH:26]=[O:27])[S:32][CH:31]=4)[C:12]([CH3:14])([CH3:13])[O:11]/3)/[C:16](=[O:25])[NH:17]2)=[CH:22][CH:21]=1
Reactant: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1Br
Reactant: O=Cc1cc(B(O)O)cs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)O/C(=C2/C(=O)Nc3cc(F)ccc32)C=C1c1csc(C=O)c1
Temperature: 80 °C

Procedure:
To 30 mL of 1,4-dioxane were added (3E)-3-(4-bromo-5,5-dimethylfuran-2(5H)-ylidene)-6-fluoro-1,3-dihydro-2H-indol-2-one (600 mg, 1.85 mmol), 5-formylthiophene-3-boronic acid (348 mg, 2.23 mmol), PdCl2(PPh3)2 (60 mg, 0.085 mmol), 1M Na2CO3 aqueous solution (7.4 mL, 7.4 mmol). The mixture was heated at 80° C. under N2 for 3.5 hours, cooled to room temperature and poured into 200 mL of water. The mixture was extracted with EtOAc (3×80 mL). The organic layers were combined, washed with brine (50 mL), dried over Na2SO4, and concentrated to give the crude product, which was purified through silica gel column with 1-5% MeOH/CHCl3 to give 4-[(5E)-5-(6-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)-2,2-dimethyl-2,5-dihydrofuran-3-yl]thiophene-2-carbaldehyde as brown solid. Yield: 458 mg, 70%.