Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[C:19]([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])=[O:10])[S:6][CH:7]=1.[CH3:26][O:27][C:28](=[O:35])[CH2:29][CH2:30][S:31](Cl)(=[O:33])=[O:32]>>[CH3:26][O:27][C:28](=[O:35])[CH2:29][CH2:30][S:31](=[O:33])(=[O:32])[NH:1][CH2:2][C:3]1[N:4]=[C:5]([NH:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:13]=2[C:19]([CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:20])=[O:10])[S:6][CH:7]=1
Reactant: Cc1ccc(NC(=O)Nc2nc(CN)cs2)c(C(=O)C2CCCC2)c1
Reactant: COC(=O)CCS(=O)(=O)Cl
Product: COC(=O)CCS(=O)(=O)NCc1csc(NC(=O)Nc2ccc(C)cc2C(=O)C2CCCC2)n1
Yield: 91.2 %

Procedure:
3-({2-[3-(2-Cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-ylmethyl}-sulfamoyl)-propionic acid metyl ester (116 mg, 91%) was prepared from 1-(4-aminomethyl-thiazol-2-yl)-3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-urea (90 mg, 0.25 mmol) and 3-chlorosulfonyl-propionic acid methyl ester (47 mg, 0.25 mmol) following the general procedure T.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([CH3:14])(C(OCC)=O)[C:6]=1[CH2:7][CH3:8].[CH:15](=O)[CH2:16][CH3:17]>>[CH3:1][C:2]1[NH:3][C:4]([CH2:15][CH2:16][CH3:17])=[C:5]([CH3:14])[C:6]=1[CH2:7][CH3:8]
Reactant: CCC=O
Reactant: CCOC(=O)C1(C)C=NC(C)=C1CC
Product: CCCc1[nH]c(C)c(CC)c1C

Procedure:
2,4-Dimethyl-3-ethyl-4-carbethoxy-pyrrole was reductively alkylated with propionaldehyde to yield 2,4-dimethyl-3-ethyl-5-n-propylpyrrole. ##STR102##
Reaction SMILES: Cl.[NH2:2][OH:3].C(N(CC)CC)C.[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]2[C:30]3[C:31]([C:35]([O:37][CH3:38])=[S:36])=[CH:32][CH:33]=[CH:34][C:29]=3[N:28]=[C:27]2[CH2:39][CH2:40][CH3:41])=[CH:21][CH:20]=1)#[N:12].O1CCCC1>CS(C)=O>[OH:3][NH:2][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:26]2[C:30]3[C:31]([C:35]([O:37][CH3:38])=[S:36])=[CH:32][CH:33]=[CH:34][C:29]=3[N:28]=[C:27]2[CH2:39][CH2:40][CH3:41])=[CH:21][CH:20]=1)=[NH:12]
Reactant: CCCc1nc2cccc(C(=S)OC)c2n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: NO
Agent: Cl
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCCc1nc2cccc(C(=S)OC)c2n1Cc1ccc(-c2ccccc2C(=N)NO)cc1
Reaction time: 0.5 h
Yield: 75.4 %

Procedure:
To a solution of hydroxylamine hydrochloride (20.85 g) in DMSO (200 ml) was added triethylamine (3.9 g) and the mixture was stirred for 30 minutes at room temperatures. To the reaction mixture was added the compound (16 g) obtained in Example (34c), and the mixture was stirred for 60 hours at 70° C. To the resultant mixture was added tetrahydrofuran (100 ml). After removal of crystalline precipitate by filtration, the filtrate was concentrated to dryness. The residue was partitioned between water (1.2 liter) and ethyl acetate (350 ml), and the upper layer was washed with water (70 ml×3). Ethyl acetate was evaporated under reduced pressure, and to the residue was added methanol (70 ml). Resulting crystalline precipitate was filtered off. The filtrate was concentrated to dryness under reduced pressure to give the title compound as a pale yellow syrup (13.0 g, 76%).
Reaction SMILES: [CH2:1]([Li])CCC.[C:6]([C:8]1([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:13][CH2:12][CH:11]([CH:14]2[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)#[CH:7].IC.CN1CCCN(C)C1=O>CCCCCC.C1COCC1>[CH2:25]([C:8]1([C:6]#[C:7][CH3:1])[CH2:9][CH2:10][CH:11]([CH:14]2[CH2:19][CH2:18][CH:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:16][CH2:15]2)[CH2:12][CH2:13]1)[CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: C#CC1(CCCCC)CCC(C2CCC(CCCCC)CC2)CC1
Reactant: [Li]CCCC
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC#CC1(CCCCC)CCC(C2CCC(CCCCC)CC2)CC1
Reaction time: 0.25 h

Procedure:
9.66 ml of a 15% solution of n-butyllithium in hexane are added dropwise at −70° C. to 4.80 g of 4-ethynyl-4,4′-dipentylbicyclohexyl in 40 ml of THF, and the mixture is stirred for 15 minutes. A solution of 0.99 ml of iodomethane and 1.914 ml of 1,3-dimethyltetrahydro-2-pyrimidinone in 10 ml of THF is subsequently added dropwise to the reaction solution at this temperature, and the cooling is removed. Conventional work-up gives 4,4′-dipentyl-4-prop-1-ynylbicyclohexyl (C 35 N 35.4 I, Δε−1.54, Δn 0.01).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5](B(O)O)=[C:4]([O:12][C@H:13]([CH2:15][CH:16]=[CH2:17])[CH3:14])[CH:3]=1.[CH2:18]([O:21][C:22]1([CH3:55])[CH2:27][CH2:26][N:25]([C:28]2[N:33]3[CH:34]=[C:35]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39](Br)[CH:38]=4)[N:36]=[C:32]3[CH:31]=[C:30]([CH3:44])[C:29]=2[C@H:45]([O:50][C:51]([CH3:54])([CH3:53])[CH3:52])[C:46]([O:48][CH3:49])=[O:47])[CH2:24][CH2:23]1)[CH:19]=[CH2:20].C(OC1(C)CCN(C2N3C=C(C4C=C(C5C=CC(F)=CC=5O[C@H](CC=C)C)C=CC=4)N=C3C=C(C)C=2[C@H](OC(C)(C)C)C(OC)=O)CC1)C=C>>[C:51]([O:50][C@@H:45]([C:29]1[C:30]([CH3:44])=[CH:31][C:32]2[N:33]([CH:34]=[C:35]([C:37]3[CH:38]=[CH:39][CH:40]=[C:41]([C:5]4[CH:6]=[C:7]([F:8])[C:2]([F:1])=[CH:3][C:4]=4[O:12][C@H:13]([CH2:15][CH:16]=[CH2:17])[CH3:14])[CH:42]=3)[N:36]=2)[C:28]=1[N:25]1[CH2:24][CH2:23][C:22]([CH3:55])([O:21][CH2:18][CH:19]=[CH2:20])[CH2:27][CH2:26]1)[C:46]([O:48][CH3:49])=[O:47])([CH3:52])([CH3:53])[CH3:54]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(Br)c4)cn23)CC1
Reactant: C=CC[C@H](C)Oc1cc(F)c(F)cc1B(O)O
Agent: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(-c5ccc(F)cc5O[C@@H](C)CC=C)c4)cn23)CC1
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(-c5cc(F)c(F)cc5O[C@@H](C)CC=C)c4)cn23)CC1
Yield: 72 %

Procedure:
Prepared in 72% yield from (S)-(4,5-difluoro-2-(pent-4-en-2-yloxy)phenyl)boronic acid and (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate following the procedure for (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(4′-fluoro-2′-((S)-pent-4-en-2-yloxy)-[1,1′-biphenyl]-3-yl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate. 1H NMR (400 MHz, CDCl3) δ 8.07-7.88 (m, 3H), 7.51-7.38 (m, 3H), 7.32 (br. s., 1H), 6.92-6.74 (m, 1H), 6.14-6.00 (m, 2H), 5.80-5.65 (m, 1H), 5.51-5.40 (m, 1H), 5.12-4.97 (m, 3H), 4.28-4.17 (m, 1H), 4.05-3.95 (m, 3H), 3.86-3.77 (m, 1H), 3.69 (s, 3H), 3.07-2.97 (m, 1H), 2.79-2.65 (m, 1H), 2.47 (s, 3H), 2.41-2.30 (m, 1H), 2.29-2.18 (m, 1H), 2.04-1.92 (m, 2H), 1.88-1.68 (m, 2H), 1.33 (s, 3H), 1.27 (s, 9H), 1.19 (d, J=6.0 Hz, 3H); 19F NMR (376 MHz, CDCl3) δ −137.17-−137.33 (d, J=23 Hz, 1F), −147.78-−147.92 (d, J=23 Hz, 1F); LCMS (ESI, M+1): 702.25.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[F:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1>>[F:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:2]2[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=2[C:4]#[N:5])=[CH:15][CH:14]=1
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: Oc1ccc(F)cc1
Product: N#Cc1cc(C=O)ccc1Oc1ccc(F)cc1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 2-fluoro-5-formylbenzonitrile and 4-fluorophenol.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[CH:5][CH:4]=1)=O.[S:19]1[CH:23]=[C:22]([CH2:24][CH2:25][NH2:26])[C:21]2[CH:27]=[CH:28][CH:29]=[CH:30][C:20]1=2>>[S:19]1[CH:23]=[C:22]([CH2:24][CH2:25][NH:26][CH2:1][C:3]2[CH:18]=[CH:17][C:6]([O:7][C:8]3[CH:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=3)=[CH:5][CH:4]=2)[C:21]2[CH:27]=[CH:28][CH:29]=[CH:30][C:20]1=2
Reactant: NCCc1csc2ccccc12
Reactant: NC(=O)c1ccc(Oc2ccc(C=O)cc2)cn1
Product: NC(=O)c1ccc(Oc2ccc(CNCCc3csc4ccccc34)cc2)cn1
Yield: 50.2 %

Procedure:
Using a method similar to Example 405, a reaction of 5-(4-formylphenoxy)pyridine-2-carboxamide (Example 388, Part D) (0.0366 g, 0.151 mmol) and 2-benzo[b]thiophen-3-ylethylamine (0.0295 g, 0.166 mmol) gives the title compound (0.0306 g, 50.2%): TOF MS ES+ 404.1 (M+H)+, HRMS calcd for C23H22N3O2S 404.1433 (M+H)+, found 404.1423, time 0.39 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=8.9 min. 100% purity.
Reaction SMILES: [CH2:1]([C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]=1[C:14]1[N:15]=[CH:16][NH:17][CH:18]=1)[CH3:2].F[C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=1>>[CH2:1]([C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4]=1[C:14]1[N:15]=[CH:16][N:17]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH:18]=1)[CH3:2]
Reactant: CCc1onc(-c2ccccc2)c1-c1c[nH]cn1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: CCc1onc(-c2ccccc2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)cn1
Yield: 30 %

Procedure:
As described for Example 30 e), 5-ethyl-4-(1H-imidazol-4-yl)-3-phenyl-isoxazole (100 mg, 0.43 mmol) was converted using 1-fluoro-4-nitro-benzene instead of 4-fluoroacetophenone to the title compound (45 mg, 30%) which was obtained as a white solid. MS: m/e=347.1 [M+H]+.
Reaction SMILES: Cl.C([O:6][C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[S:25][C:24]3[C:19](=[N:20][CH:21]=[CH:22][C:23]=3[Cl:26])[CH:18]=2)=[O:16])[CH2:11][CH2:10]1)=O)(C)(C)C.[CH3:27]O>>[Cl:26][C:23]1[CH:22]=[CH:21][N:20]=[C:19]2[CH:18]=[C:17]([C:15]([N:12]3[CH2:13][CH2:14][N:9]([C:7](=[O:6])[CH3:27])[CH2:10][CH2:11]3)=[O:16])[S:25][C:24]=12
Reactant: CO
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc3nccc(Cl)c3s2)CC1
Agent: Cl
Product: CC(=O)N1CCN(C(=O)c2cc3nccc(Cl)c3s2)CC1
Reaction time: 0.25 h

Procedure:
HCl (gas) was bubbled through a solution of 4-(7-chloro-thieno[3,2-b]pyridine-2-carbonyl)-piperazine-1-carboxylic acid tert-butyl ester (270 mg, 0.71 mmol) in MeOH (5 mL). After 15 min, TLC showed the reaction to be complete. The resulting HCl salt was obtained as a yellow oil (199 mg, 99%) after the solvent was removed under pressure. The title compound was prepared from the resulting HCl salt and acetyl chloride by a procedure analogous to Example 70A. MS: 325 (MH+); HPLC Rf: 3.62; HPLC purity: 95%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:24])[C:11]([C:17]1[CH:18]=[CH:19][C:20](=[O:23])[NH:21][CH:22]=1)([OH:16])[C:12]([F:15])([F:14])[F:13].[C:25]([O-])([O-])=O.[K+].[K+].IC.CCOC(C)=O>CN(C)C(=O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([CH3:24])[C:11]([C:17]1[CH:18]=[CH:19][C:20](=[O:23])[N:21]([CH3:25])[CH:22]=1)([OH:16])[C:12]([F:14])([F:15])[F:13]
Reactant: COc1ccc(C(C)C(O)(c2ccc(=O)[nH]c2)C(F)(F)F)c(Cl)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CI
Product: COc1ccc(C(C)C(O)(c2ccc(=O)n(C)c2)C(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 108.8 %

Procedure:
To a solution of 5-[2-(2-chloro-4-methoxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1H-pyridin-2-one (Example 194, 100 mg) in N,N-dimethylacetamide (1.5 ml) were added powdered K2CO3 (42 mg) and iodomethane (41 mg). The mixture was stirred at room temperature for 3 days. EtOAc and water were added and the mixture was extracted with EtOAc. The organic phase was dried (MgSO4), filtered and concentrated to dryness. The product was purified by chromatography (SiO2, cyclohexane/EtOAc 1:1=>0:1) to give the title compound (113 mg, contains 10.7 mass-% of N,N-dimethylacetamide) as a light yellow oil. MS (m/e)=376.1 [M+H+].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](OS(C(F)(F)F)(=O)=O)=[C:7]([O:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:21]=2[CH2:29][S:30][CH2:31][C:32]([F:35])([F:34])[F:33])[CH:6]=1.[CH3:37]B1OB(C)OB(C)O1.C(=O)([O-])[O-].[K+].[K+]>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>[CH3:1][O:2][C:3](=[O:36])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:37])=[C:7]([O:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][C:21]=2[CH2:29][S:30][CH2:31][C:32]([F:35])([F:33])[F:34])[CH:6]=1
Reactant: CB1OB(C)OB(C)O1
Reactant: COC(=O)Cc1ccc(OS(=O)(=O)C(F)(F)F)c(Oc2ccc([N+](=O)[O-])cc2CSCC(F)(F)F)c1
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: [K+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)Cc1ccc(C)c(Oc2ccc([N+](=O)[O-])cc2CSCC(F)(F)F)c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
{3-[4-Nitro-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]-4-trifluoromethanesulfonyloxy-phenyl}-acetic acid methyl ester (0.20 g, 0.35 mmol), trimethylboroxine (0.07 mL, 0.53 mmol), potassium carbonate (0.123 g, 0.89 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.041 g, 0.035 mmol) were combined in DME:H2O (2:1; 4 mL) and degassed with N2 for 8 minutes. The reaction was stirred at 90° C. for 2 hours, and then worked up with EtOAc and 10% aqueous HCl. The residue was purified by silica gel chromatography to give {4-methyl-3-[4-nitro-2-(2,2,2-trifluoro-ethylsulfanylmethyl)-phenoxy]phenyl}-acetic acid methyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([O:12][N:13]=[C:14]([C:18]2[N:19]=[C:20]([NH:23][C:24]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[S:21][CH:22]=2)[C:15]([OH:17])=O)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:43][CH:44]1[C:51](=[O:52])[N:50]2[CH:45]1[S:46](=[O:82])[CH2:47][C:48]([CH:69]=[CH:70][O:71][S:72]([C:75]1[CH:81]=[CH:80][C:78]([CH3:79])=[CH:77][CH:76]=1)(=[O:74])=[O:73])=[C:49]2[C:53]([O:55][CH:56]([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)=[O:54].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:56]([O:55][C:53]([C:49]1[N:50]2[CH:45]([S:46](=[O:82])[CH2:47][C:48]=1[CH:69]=[CH:70][O:71][S:72]([C:75]1[CH:76]=[CH:77][C:78]([CH3:79])=[CH:80][CH:81]=1)(=[O:73])=[O:74])[CH:44]([NH:43][C:15](=[O:17])[C:14](=[N:13][O:12][C:8]1([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:11][CH2:10][CH2:9]1)[C:18]1[N:19]=[C:20]([NH:23][C:24]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[S:21][CH:22]=1)[C:51]2=[O:52])=[O:54])([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[C:57]1[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=1
Reactant: Cc1ccc(S(=O)(=O)OC=CC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(N)C3S(=O)C2)cc1
Reactant: CC(C)(C)OC(=O)C1(ON=C(C(=O)O)c2csc(NC(c3ccccc3)(c3ccccc3)c3ccccc3)n2)CCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC=CC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)C(=NOC4(C(=O)OC(C)(C)C)CCC4)c4csc(NC(c5ccccc5)(c5ccccc5)c5ccccc5)n4)C3S(=O)C2)cc1
Temperature: 5 °C
Reaction time: 4 h

Procedure:
The syn isomer of 2-(1-t-butoxycarbonylcyclobutoxyimino)-2-(2-tritylaminothiazol-4-yl)-acetic acid prepared according to Belgian Patent 876,541 (4.42 g) and 4-dimethylaminopyridine (0.25 g) are added to a solution of the E form of 7-amino-2-benzhydryloxycarbonyl-8-oxo-3-(2-tosyloxyvinyl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-5-oxide (product 7d) (4.34 g) in methylene chloride (50 cc). The mixture is cooled to 5° C. and a solution of N,N'-dicyclohexylcarbodiimide (1.69 g) in methylene chloride (30 cc) is added dropwise in the course of 10 minutes. The temperature is left to rise, the mixture is stirred for 4 hours at 20° C. and concentrated to dryness at 20° C. under 20 mm Hg (2.7 kPa) and the residue is taken up in ethyl acetate (200 cc). The solution is washed with water (2×100 cc), 0.1 N hydrochloric acid (100 cc), a saturated aqueous solution of sodium bicarbonate (100 cc) and water (100 cc), dried over sodium sulphate and filtered and the filtrate is concentrated to dryness at 25° C. under 20 mm Hg (2.7 kPa). The residue is chromatographed on a column of Merck silica gel (0.06-0.2) (180 g) (diameter of the column: 3 cm, height: 60 cm). Elution is carried out with a 70/30 (by volume) cyclohexane/ethyl acetate mixture (1 liter), 60 cc fractions being collected. Fractions 6 to 10 are concentrated to dryness at 20° C. under 20 mm Hg (2.7 kPa) and this yields a product (7a) (2.7 g) in the form of a cream-coloured powder.
Reaction SMILES: C1(C(C2C=CC=CC=2)=[N:8][CH:9]([P:17]([CH:22]([N:30]=C(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:21])[O:18]CC)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)C=CC=CC=1.[BrH:50]>C(O)(=O)C>[BrH:50].[NH2:8][CH:9]([P:17]([CH:22]([NH2:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:18])[OH:21])[CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOP(=O)(C(Cc1ccccc1)N=C(c1ccccc1)c1ccccc1)C(Cc1ccccc1)N=C(c1ccccc1)c1ccccc1
Agent: Br
Solvent: CC(=O)O
Product: NC(Cc1ccccc1)P(=O)(O)C(N)Cc1ccccc1
Yield: 94 %

Procedure:
A solution of the bis-alkylated phosphinate 5 (205 mg; 0.31 mmol) in 30% strength hydrogen bromide in glacial acetic acid (11 ml) is heated to a temperature of 55°-65° C. for 25 minutes. The phosphinic acid hydrobromide 15 (136 mg, 94% of theory) is obtained after evaporating the reaction solution under reduced pressure and repeated coevaporation with methanol and toluene.
Reaction SMILES: [C:1]([O:12][CH2:13][C@@H:14]([O:44][C:45](=[O:55])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54])[CH2:15][S:16][CH2:17][C@H:18]([NH:26][C:27]([O:29][CH2:30][CH:31]1[C:43]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[C:37]2[C:32]1=[CH:33][CH:34]=[CH:35][CH:36]=2)=[O:28])[C:19]([O:21]C(C)(C)C)=[O:20])(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(O[C@H](COC(=O)CCCCCCCCCCC)CSC[C@@H](C(O)=O)NC(=O)OCC1C2C=CC=CC=2C2C1=CC=CC=2)(=O)CCCCCCCCCCC>>[C:45]([O:44][C@H:14]([CH2:13][O:12][C:1](=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:15][S:16][CH2:17][C@@H:18]([C:19]([OH:21])=[O:20])[NH:26][C:27](=[O:28])[O:29][CH2:30][CH:31]1[C:43]2[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=2[C:37]2[C:32]1=[CH:33][CH:34]=[CH:35][CH:36]=2)(=[O:55])[CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH3:54]
Reactant: CCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OC(C)(C)C)OC(=O)CCCCCCCCC
Agent: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OC(=O)CCCCCCCCCCC
Product: CCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)OC(=O)CCCCCCCCC

Procedure:
The product was prepared from (R)-3-((R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-tert-butoxy-3-oxopropylthio)propane-1,2-diyl bis(decanoate) by following the procedure described for compound 6.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([N:12]=[C:13]=[O:14])[CH2:4][CH2:3]1.[N-:15]=C=S.Cl.O=C1C2C(=CC=CC=2)C(N)CC1>>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]([NH:12][C:13]([NH2:15])=[O:14])[CH2:4][CH2:3]1
Reactant: O=C=NC1CCC(=O)c2ccccc21
Reactant: [N-]=C=S
Agent: Cl
Agent: NC1CCC(=O)c2ccccc21
Product: NC(=O)NC1CCC(=O)c2ccccc21

Procedure:
The following formula I 1,2,3,4-tetrahydro-4-oxo-1-naphthylurea compounds are prepared by reacting 1,2,3,4-tetrahydro-4-oxo-1-naphthylisocyanate or isothiocyanate with the appropriately substituted amines, or by reacting 1,2,3,4-tetrahydro-4-oxo-1-naphthylamine hydrochloride with the appropriately substituted isocyanates, isothiocyanates or carbamoyl chlorides by the process of Example 6. The compounds obtained are listed in Table I below.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]=1[OH:20])[C:8](=[N:15][OH:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:25](Cl)(=[O:29])[CH2:26][CH2:27][CH3:28]>>[C:25]([O:16][N:15]=[C:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:7]1[CH:17]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:19]([OH:20])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=1)(=[O:29])[CH2:26][CH2:27][CH3:28]
Reactant: CCCC(=O)Cl
Reactant: CC(C)(C)c1cc(C(=NO)c2ccccc2)cc(C(C)(C)C)c1O
Product: CCCC(=O)ON=C(c1ccccc1)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
3,5-di-t-butyl-4-hydroxybenzophenone oxime and butyryl chloride were treated in the same way as in Example 3 to give 3,5-di-t-butyl-4-hydroxybenzophenone O-butyryloxime.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11][CH3:12].O.O.O.O.O.O.O.O.O.[S-2:22].[Na+].[Na+]>C(O)C.O>[CH3:12][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[SH:22]
Reactant: COc1cc([N+](=O)[O-])ccc1Cl
Reactant: [S-2]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1cc([N+](=O)[O-])ccc1S
Temperature: 100 °C

Procedure:
To a suspension of 2-chloro-5-nitroanisole (1.00 g; 5.33 mmol) in 10 mL of ethanol at rt was added a solution of sodium sulfide nonahydrate (1.30 g; 5.41 mmol) in 1.4 mL of water and 0.8 mL of ethanol in three portions over 3 minutes. The resulting suspension was heated at 100° C. for 10 min. The suspension was cooled and concentrated under reduced pressure to a dark solid which was used immediately in the next step. HPLC 2.23 min retention time; LCMS (ES): m/z 186 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[C:6]([C@H:12]([O:14][CH2:15][C:16]3([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[CH3:13])[CH:7]=[C:8]([Br:11])[CH:9]=2)[NH:4][N:3]=1.C=O.[C:31]([BH3-])#N.[Na+].O>C(#N)C.C(O)(=O)C>[Br:1][C:2]1[C:10]2[C:5](=[C:6]([C@H:12]([O:14][CH2:15][C:16]3([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[CH2:21][CH2:20][N:19]([CH3:31])[CH2:18][CH2:17]3)[CH3:13])[CH:7]=[C:8]([Br:11])[CH:9]=2)[NH:4][N:3]=1
Reactant: C[C@@H](OCC1(c2ccc(F)cc2)CCNCC1)c1cc(Br)cc2c(Br)n[nH]c12
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CC(=O)O
Product: C[C@@H](OCC1(c2ccc(F)cc2)CCN(C)CC1)c1cc(Br)cc2c(Br)n[nH]c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-3,5-Dibromo-7-(1-((4-(4-fluorophenyl)piperidin-4-yl)methoxy)ethyl)-1H-indazole (77 mg, 0.15 mmol) was dissolved in acetonitrile (1 mL) and treated with formalin (50 μL) and sodium cyanoborohydride (9.5 mg, 0.15 mmol) and one drop of acetic acid. The reaction was stirred at room temperature for 1 h. The reaction was poured into water and extracted with diethyl ether. The aqueous was made basic by addition of 4 M sodium hydroxide and extracted with diethyl ether. The ethereal was combined, washed with brine, dried over magnesium sulfate, and concentrated. The resulting residue was dissolved in 20% trifluoroacetic acid in dichloromethane and stirred at room temperature for 5 min. The solution was concentrated, loaded onto a strong cation exchange cartridge in methanol, and the cartridge washed with several volumes of methanol which were discarded. The product was eluted with 2M ammonia in methanol and concentrated to give 41 mg (52%). 1H-NMR (CDCl3, 500 MHz) δ 10.09 (bs, 1H), 7.62 (d, J=1.5 Hz, 1H), 7.24 (dd, J=8.9 Hz, 5.2, 2H), 7.13 (d, J=1.5 Hz, 1H), 7.05 (dd, J=8.9, 8.5 Hz, 2H), 4.49 (q, J=6.7 Hz, 1H), 3.39 (d, J=8.9 Hz, 1H), 3.25 (d, J=8.9 Hz, 1H), 2.59 (m, 2H), 1.85-2.30 (m, 9H), 1.40 (d, J=6.7 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ ppm 161.6 (d, J=246 Hz), 137.2, 128.7, 128.63, 128.57, 127.68, 125.3, 121.7, 121.6, 115.7, 115.5, 114.3, 78.9, 77.9, 51.9, 51.7, 46.1, 40.3, 32.6, 32.3, 22.1.