Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:15][C@:14]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH3:34])=[C:28]([F:35])[CH:27]=3)[CH:19]=2)([O:16][CH3:17])[C@H:13]([OH:36])[C@@H:12]([OH:37])[C@@H:11]1[OH:38])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].[CH2:41](Br)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CN(C)C=O>[CH2:41]([O:38][C@H:11]1[C@H:12]([O:37][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([O:36][CH2:14][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@:14]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH3:34])=[C:28]([F:35])[CH:27]=3)[CH:19]=2)([O:16][CH3:17])[O:15][C@@H:10]1[CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: BrCc1ccccc1
Reactant: CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O)[C@H](O)[C@H]3O)ccc2Cl)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc(Cc2cc([C@]3(OC)O[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)cc1F
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 199.6 %

Procedure:
(2S,3R,4S,5S,6R)-6-[(tert-butyl(dimethyl)silyl)oxymethyl]-2-[4-chloro-3-[(4-ethoxy-3-fluoro-phenyl)methyl]phenyl]-2-methoxy-tetrahydropyran-3,4,5-triol 4g (7.14 g, 12.5 mmol) was dissolved in 100 mL N,N-dimethyl formamide, followed by addition of 60% NaH (2.5 g, 62.5 mmol) in an ice bath. The reaction mixture was warmed and stirred for 40 minutes at room temperature. The mixture was stirred for 16 hours after benzyl bromide (7.5 mL, 62.5 mmol) was added. Thereafter, the reaction mixture was concentrated under reduced pressure after 20 mL methanol were added. The residue was dissolved in 200 mL ethyl acetate and 50 mL water and partitioned. The aqueous phase was extracted with ethyl acetate (50 mL). The organic extracts were washed with water (50 mL), then saturated sodium chloride (50 mL), combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain the title compound [[(2R,3R,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[(4-ethoxy-3-fluoro-phenyl)methyl]phenyl]-6-methoxy-tetrahydropyran-2-yl]methoxy]tert-butyl-dimethylsilane 4h (10.5 g, yellow grease), yield: 99.8%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:14])([CH3:13])[C:9]([O:11]C)=[O:10])=[CH:4][C:3]=1[F:15].[OH-].[K+]>CCO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:14])[C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[F:15]
Reactant: COC(=O)C(C)(C)c1ccc(Cl)c(F)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C(=O)O)c1ccc(Cl)c(F)c1
Yield: 95.6 %

Procedure:
A solution of methyl 2-(4-chloro-3-fluorophenyl)-2-methylpropanoate (2.94 g, 12.7 mmol) and KOH (7.15 g, 127 mmol) in EtOH (90 mL) and water (30 mL) was stirred at 150° C. in a sealed vessel for 3 hours. The solution was concentrated in vacuo, diluted with 10% HCl (aq) (150 mL), and extracted with EtOAc (2×100 mL). The combined organic layers were washed with water (2×100 mL) and then with brine (75 mL). The organic layer was dried over MgSO4, concentrated, and dried in vacuo to give 2-(4-chloro-3-fluorophenyl)-2-methylpropanoic acid (2.63 g). MS m/e=217.3 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][C:12]([F:16])([F:15])[CH2:11][CH2:10]1)(C)(C)C.[ClH:18].CC(O)=O>>[ClH:18].[F:15][C:12]1([F:16])[CH2:13][CH2:14][CH:9]([CH2:8][NH2:7])[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)NCC1CCC(F)(F)CC1
Agent: Cl
Solvent: CC(=O)O
Product: NCC1CCC(F)(F)CC1

Procedure:
tert-Butyl[(4,4-difluorocyclohexyl)methyl]carbamate (505 mg, 2.03 mmol) was stirred in 5 mL of 1M HCl/AcOH at rt for 2 h. The solvent was evaporated. The residue washed with ether, filtered and dried. Yield: 330 mg (88%); 1H NMR (400 MHz, CD3OD) δ 1.28-1.40 (m, 2 H), 1.71-1.82 (m, 2 H), 1.84 (d, J=3.12 Hz, 2 H), 1.86-1.89 (m, 1 H), 2.03-2.15 (m, 2 H), 2.85 (d, J=7.03 Hz, 2 H).
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Cl)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([OH:28])[CH:25]=[CH:26][CH:27]=1>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([O:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([O:21][CH3:20])[CH:23]=2)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Cl)c2ccccc2c1O
Reactant: COc1cccc(O)c1
Product: CCCCOC(=O)c1nc(Oc2cccc(OC)c2)c2ccccc2c1O

Procedure:
Synthesized from 1-chloro-4-hydroxy-isoquinoline-3-carboxylic acid butyl ester and 3-methoxy phenol in analogy to Example D-20 d); MS-(+)-ion: M+1=368.1.
Reaction SMILES: Cl.[CH2:2]([N:5]([CH:7]1[CH2:10][CH2:9][CH2:8]1)[NH2:6])[CH:3]=[CH2:4].[CH3:11][O:12][C:13]([CH:15]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][C:16]1=O)=[O:14].C([O-])(=O)C.[Na+].C([BH3-])#N.[Na+]>CO>[CH3:11][O:12][C:13]([CH:15]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[NH:6][N:5]([CH2:2][CH:3]=[CH2:4])[CH:7]1[CH2:10][CH2:9][CH2:8]1)=[O:14]
Reactant: COC(=O)C1CCCCCC1=O
Reactant: C=CCN(N)C1CCC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [BH3-]C#N
Solvent: CO
Product: C=CCN(NC1CCCCCC1C(=O)OC)C1CCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N′-Allyl-N′-cyclobutyl-hydrazine hydrochloride (2.01 g, 12.37 mmol) was dissolved in methanol (40 mL). 2-Oxo-cycloheptanecarboxylic acid methyl ester (1.93 mL, 12.37 mmol), sodium acetate (2.04 g, 24.74 mmol), sodium cyanoborohydride (1.55 g, 24.74 mmol) and 4 Å molecular sieves (2.80 g) were added sequentially. The reaction was stirred at 25° C. for 18 h before it was quenched via the addition of saturated aqueous sodium bicarbonate solution (30 mL). The mixture was extracted with ethyl acetate (3×40 mL). The organic layers were combined, dried over magnesium sulfate, filtered and concentrated in vacuo to afford the crude product, 2-(N′-allyl-N′-cyclobutyl-hydrazino)-cycloheptanecarboxylic acid methyl ester, as a yellow oil. The residue was used directly in the next step. LC-MS (ESI) calcd for C16H28N2O2 280.41, found 281.2 [M+H+].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][N:12]([CH3:14])[C:11](=[N:15][C:16]#[N:17])[N:10]([CH3:18])[CH2:9]2)=[CH:4][C:3]=1[C:19]1[CH2:24][CH2:23][C:22]([CH3:26])([CH3:25])[CH2:21][CH:20]=1.[C:27]([C:29]1[N:30]=[C:31]([C:42](O)=[O:43])[N:32]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[CH:33]=1)#[N:28].C1(C2C=C(C3CC(=O)NC(=O)C3)C=CC=2NC(C2NC=C(C#N)N=2)=O)CCCCC=1>>[C:16]([N:15]=[C:11]1[N:12]([CH3:14])[CH2:13][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:42]([C:31]3[N:32]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[CH:33]=[C:29]([C:27]#[N:28])[N:30]=3)=[O:43])=[C:3]([C:19]3[CH2:24][CH2:23][C:22]([CH3:26])([CH3:25])[CH2:21][CH:20]=3)[CH:4]=2)[CH2:9][N:10]1[CH3:18])#[N:17]
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)O
Reactant: CN1CC(c2ccc(N)c(C3=CCC(C)(C)CC3)c2)CN(C)C1=NC#N
Agent: N#Cc1c[nH]c(C(=O)Nc2ccc(C3CC(=O)NC(=O)C3)cc2C2=CCCCC2)n1
Product: CN1CC(c2ccc(NC(=O)c3nc(C#N)cn3COCC[Si](C)(C)C)c(C3=CCC(C)(C)CC3)c2)CN(C)C1=NC#N

Procedure:
5-[4-Amino-3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-1,3-dimethyl-tetrahydro-pyrimidin-2-ylidene-cyanamide (as prepared in the previous step) was coupled to 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid, potassium salt (as prepared in Example 1) as described in Example 1, step (1) to obtain the title compound: Mass spectrum (ESI, m/z): Calcd. for C32H44N8O2Si, 601.3 (M+H). found 601.3.
Reaction SMILES: [NH:1]([C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[CH2:2][C:3]([OH:5])=O.C(N1CCOCC1)C.[CH2:24]([O:28][C:29](=[O:37])[NH:30][CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)[CH2:25][CH2:26][CH3:27].[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O>CN(C=O)C.C(OCC)(=O)C>[CH2:24]([O:28][C:29](=[O:37])[NH:30][CH:31]1[CH2:36][CH2:35][N:34]([C:3](=[O:5])[CH2:2][NH:1][C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH2:33][CH2:32]1)[CH2:25][CH2:26][CH3:27]
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Reactant: CCCCOC(=O)NC1CCNCC1
Agent: CCN1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCOC(=O)NC1CCN(C(=O)CNC(=O)OCc2ccccc2)CC1
Reaction time: 12 h

Procedure:
To a solution of 150 mg Z-Gly-OH in 5 ml DMF were added 0.4 ml N-ethylmorpholine, 144 mg piperidin-4-yl-carbamic acid butyl ester and 236 mg TOTU. After stirring for 12 h it was diluted with ethyl acetate and subsequently washed with aqueous LiCl (4%), saturated NaHCO3 and 0.1 M HCl. The crude product thus obtained after evaporation of the solvent was directly used in the next step. Yield: 287 mg.
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[CH:15]([NH2:18])([CH3:17])[CH3:16].N1C=CC=CC=1>ClCCl>[CH:15]([NH:18][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3])([CH3:17])[CH3:16]
Reactant: CC(C)N
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)NS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Temperature: 25 °C
Reaction time: 4 h
Yield: 45.5 %

Procedure:
A suspension of 3 g of 5-chlorosulfonyl-2-oxindole, 1.15 g of isopropylamine and 1.2 mL of pyridine in 50 mL of dichloromethane was stirred at room temperature for 4 hours at which time a white solid was present. The solid was collected by vacuum filtration, slurry-washed with hot ethanol, cooled, collected by vacuum filtration and vacuum dried at 40° C. to give 1.5 g (45%) of 5-isopropylaminosulfonyl-2-oxindole.
Reaction SMILES: [Br-].[C:2]([C:5]1[CH:6]=[N+:7]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[CH:8]=[CH:9][C:10]=1[CH2:11][CH:12]1[CH2:20][C:19]2[C:14](=[CH:15][C:16]([O:23][CH3:24])=[C:17]([O:21][CH3:22])[CH:18]=2)[C:13]1=[O:25])(=[O:4])[CH3:3].C1C(C(N)=O)=CN(CC2C=CC=CC=2)C=C1>>[C:2]([C:5]1[CH:10]([CH2:11][CH:12]2[CH2:20][C:19]3[C:14](=[CH:15][C:16]([O:23][CH3:24])=[C:17]([O:21][CH3:22])[CH:18]=3)[C:13]2=[O:25])[CH:9]=[CH:8][N:7]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[CH3:33])[CH:6]=1)(=[O:4])[CH3:3]
Reactant: COc1cc2c(cc1OC)C(=O)C(Cc1cc[n+](Cc3ccccc3C)cc1C(C)=O)C2
Agent: NC(=O)C1=CN(Cc2ccccc2)C=CC1
Agent: [Br-]
Product: COc1cc2c(cc1OC)C(=O)C(CC1C=CN(Cc3ccccc3C)C=C1C(C)=O)C2

Procedure:
The title compound 169 is prepared according to the procedure reported in Example 39.1 with compound 142 (7 4.2 mg, 0.15 mmol) and BNAH (35 mg, 1 equiv) as reactants. Yellow solid. (Yield 32.3 mg, 50%).
Reaction SMILES: [C:1]1([CH3:27])[CH:6]=[CH:5][C:4]([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][C:18]([C:19]4[CH:20]=[C:21]([CH2:25]O)[CH:22]=[CH:23][CH:24]=4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])=[CH:3][CH:2]=1.S(Cl)([Cl:30])=O>ClCCl>[Cl:30][CH2:25][C:21]1[CH:20]=[C:19]([C:18]2[CH:17]=[CH:16][N:15]=[C:14]3[N:10]([S:7]([C:4]4[CH:5]=[CH:6][C:1]([CH3:27])=[CH:2][CH:3]=4)(=[O:9])=[O:8])[CH:11]=[CH:12][C:13]=23)[CH:24]=[CH:23][CH:22]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cccc(CO)c4)ccnc32)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3c(-c4cccc(CCl)c4)ccnc32)cc1
Yield: 99.3 %

Procedure:
To a solution of (G) (0.25 g, 0.66 mmol) in dichloromethane (5 mL) was added thionyl chloride (0.5 mL, 6.9 mmol) at RT. The solution was allowed to stir until complete as judged by HPLC (1 hour). The solvent was removed under reduced pressure to afford 0.26 g of (H) (99% yield) as a white solid. FIA MS expected for C21H17ClN2O2S: m/e 396.07, found: 396.8 ES+. The material was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[CH:7]=[N:8]O)([O-])=O.[P:13](=[O:17])([OH:16])([OH:15])[OH:14].[H][H]>[Pt].C(O)C(C)C>[P:13](=[O:14])([OH:17])([OH:16])[OH:15].[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[CH2:7][NH2:8]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccc(C=NO)c1
Agent: [Pt]
Agent: O=P(O)(O)O
Solvent: CC(C)CO
Product: NCc1cccc(N)c1
Reaction time: 18 h
Yield: 86.1 %

Procedure:
33.2 g (0.2 mol) of this m-nitrobenzaldoxime, 70 g (0.35 mol) of a 50% aqueous solution of phosphoric acid, 0.3 g of a 10% Pt-C catalyst and 300 ml of isobutanol were charged into a hermetically sealed glass container and vigorously stirred while charging hydrogen. Reaction was continued at temperatures of 25° to 30° C. for 18 hours and 23 l of hydrogen was absorbed. The reaction mixture from which crystals deposited was filtered and 54.8 g of crude m-aminobenzylamine phosphoric acid salt (yield 86.1%) was obtained. This crude m-aminobenzylamine phosphoric acid salt was recrystallized from a 50% methanol-water solution and pure m-aminobenzylamine phosphoric acid salt of white and flaky crystals was obtained. M.P. 210°-213° C.
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:17]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][N:9]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCCc1ccccc1
Reactant: Cc1ccc(NN=C(c2ccccc2)c2ccccc2)cc1
Product: Cc1ccc(N(CCc2ccccc2)N=C(c2ccccc2)c2ccccc2)cc1

Procedure:
General procedure B was used to convert 1-(diphenylmethylene)-2-p-tolylhydrazine (200 mg, 0.69 mmol; Example 36A) and 2-bromoethylbenzene (210 mg, 0.69 mmol; Aldrich) to the title compound: MS (DCI/NH3) m/z 391 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][N:24]([CH3:31])[CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)=[O:15])=[CH:7][C:6]=2[CH:32]=1.B([O-])([O-])O[C:35]1[CH:40]=[CH:39][C:38]([N:41]([CH2:44][CH2:45][O:46][CH2:47][CH3:48])[CH2:42][CH3:43])=[CH:37][CH:36]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.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>[CH2:47]([O:46][CH2:45][CH2:44][N:41]([C:38]1[CH:37]=[CH:36][C:35]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH2:23][N:24]([CH3:31])[CH:25]5[CH2:26][CH2:27][O:28][CH2:29][CH2:30]5)=[CH:21][CH:22]=4)=[O:15])=[CH:7][C:6]=3[CH:32]=2)=[CH:40][CH:39]=1)[CH2:42][CH3:43])[CH3:48]
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3S(=O)(=O)CC2)cc1)C1CCOCC1
Reactant: CCOCCN(CC)c1ccc(OB([O-])[O-])cc1
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: O
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOCCN(CC)c1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
Under argon atmosphere, a mixture of 7-bromo-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (300 mg), 4-[N-(2-ethoxyethyl)-N-ethylamino]phenyl borate (410 mg) and potassium carbonate (400 mg) in toluene/ethanol/water (10/1/1 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (50 mg), and the mixture was refluxed for 8 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (ethanol/ethyl acetate=1:3) to give crystals, which were recrystallized from ethanol to give yellow crystals of 7-[4-[N-(2-ethoxyethyl)-N-ethylamino]phenyl]-N-[4-[[N-methyl-N-(tetrahydropyran-4-yl)amino]methyl]phenyl]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxamide (Compound 69) (260 mg).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][CH2:24][CH:25]2OCCCO2)=[CH:18][CH:17]=1.[O:31]1[CH2:35][C:34](=[O:36])[NH:33][C:32]1=[O:37].N1CCCCC1>C(O)(=O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][CH2:23][CH2:24][CH:25]=[C:35]2[O:31][C:32](=[O:37])[NH:33][C:34]2=[O:36])=[CH:20][CH:21]=1
Reactant: O=C1COC(=O)N1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCCC2OCCCO2)cc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(CCCC=C2OC(=O)NC2=O)cc1
Yield: 25.9 %

Procedure:
A mixture of 2-[3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propyl]-1,3-dioxane (2.0 g), 2,4-oxazolidinedione (0.99 g), piperidine (0.21 g) and acetic acid (50 ml) was heated for 24 hours under reflux. The reaction mixture was concentrated under reduced pressure, to which was added ethyl acetate. The ethyl acetate layer was washed with an aqueous solution of sodium hydrogencarbonate, 2N HCl and water, successively, which was then dried (MgSO4), followed by concentration. The concentrate was purified by means of a silica gel column chromatography. From the fractions eluted with chloroform - ethyl acetate (5:1), 5-[4-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]butylidene]-2,4-oxazolidinedione (0.55 g, 26%) was obtained. Recrystallization from ethyl ether-methanol gave colorless needles, m.p.152-153° C.
Reaction SMILES: C([C:3]([C:10]([N:12]([CH3:14])[CH3:13])=[O:11])=[CH:4][CH:5]=[CH:6][N:7](C)[CH3:8])#N.[ClH:15]>ClCCCl>[CH3:13][N:12]([CH3:14])[C:10]([C:3]1[C:8]([Cl:15])=[N:7][CH:6]=[CH:5][CH:4]=1)=[O:11]
Reactant: CN(C)C=CC=C(C#N)C(=O)N(C)C
Reactant: Cl
Solvent: ClCCCl
Product: CN(C)C(=O)c1cccnc1Cl
Temperature: 50 °C
Reaction time: 6 h
Yield: 72 %

Procedure:
The 1-cyano-1-dimethylaminocarbonyl-4-dimethylamino-1,3-butadiene (14.5 g, 0.075 mol) obtained in (a) above was dissolved in 1,2-dichloroethane (150 ml) and the resulting solution heated to 50° C. The solution was then stirred whilst hydrogen chloride gas was introduced. After a few minutes, a thick mass of crystals formed in the solution which later dispersed to leave a deep red solution. After about 6 hours, no more starting material could be detected. Nitrogen was then introduced to blow the excess hydrogen chloride gas out of the solution and the solution was then extracted with water (4×100 ml). The organic phase was then dried over sodium sulphate and reduced in a vacuum. The residue was then stirred in petroleum ether, filtered off under suction and dried to give 10 g 2-chloropyridine-3-carboxylic acid N,N-dimethylamide as pale yellowish crystals, m.pt. 70°-71° C. Yield: 72% of the theoretical.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][C:13]=1OS(C(F)(F)F)(=O)=O)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1B(O)O)#[N:23].C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>O1CCCC1.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].O>[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:13]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[O:2][CH3:1])#[N:23]
Reactant: CCOC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(OC)c1
Reactant: N#Cc1ccccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(-c2ccccc2C#N)c(OC)c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 4.7 %

Procedure:
A suspension of ethyl 3-methoxy-4-{[(trifluoromethyl)sulfonyl]oxy}benzoate (7.0 g), (2-cyanophenyl)boronic acid (5.9 g), Pd(dppf)2Cl2 (0.50 g) and 2M aqueous cesium carbonate solution (20 mL) in tetrahydrofuran (60 mL) was stirred under an argon atmosphere at 70° C. for 3 hr. The mixture was allowed to cool, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.28 g, 5%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:13][CH:12]=1)(=[O:10])=[O:9].[CH3:23]I>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]([CH3:23])[S:8]([C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:15][CH:16]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(NCCCCCO)c1ccc(-c2ccccc2)cc1
Reactant: CI
Product: CN(CCCCCO)S(=O)(=O)c1ccc(-c2ccccc2)cc1

Procedure:
Using a method analogous to that described in Example 4, with biphenyl-4-sulfonic acid-(5-hydroxypentyl)-amide and methyl iodide, the title compound was obtained. δC (CDCl3, 62.9 MHz): 22.7, 27.4, 32.2, 34.7, 50.0, 62.7, 127.4, 127.9, 128.5, 129.1, 136.0, 139.3 and 145.4.
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:40])[CH2:25][CH2:26][N:27]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28][CH2:29][C:30]([OH:32])=[O:31])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[B-](F)(F)(F)F.CN(C(O[N:64]1[C:69](=[O:70])[CH2:68][CH2:67][C:65]1=[O:66])=[N+](C)C)C>C1COCC1>[C:1]([O:5][C:6](=[O:41])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:40])[CH2:25][CH2:26][N:27]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28][CH2:29][C:30]([O:32][N:64]1[C:69](=[O:70])[CH2:68][CH2:67][C:65]1=[O:66])=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCNC(=O)CCN(CCC(=O)O)C(=O)OC(C)(C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCNC(=O)CCN(CCC(=O)ON1C(=O)CCC1=O)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
17-{3-[tert-Butoxycarbonyl (2-carboxyethyl)amino]propionylamino}heptadecanoic acid tert-butyl ester (0.122 g, 0.2 mmol) was dissolved in THF (5 mL). DIEA (39 ul) was added and the mixture was cooled to 0° C. TSTU (66 mg, 0.22 mmol) was added. The mixture was stirred at 0° C. for 30 min, then for 16 h at RT. The mixture was concentrated under vacuum. AcOEt (15 mL) and the solution was washed with 0.2 N HCl (5 ml) and sat. NaCl (5 ml), dried over MgSO4, and dried under vacuum. The residue was purified by flash chromatography (silica) eluting with AcOEt/heptane (9:1) and AcOEt. The appropriate fractiones were pooled and concentrated under vacuum to yield 58 mg.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[F:13][C:14]([F:28])([F:27])[C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][C:23]([NH:25][NH2:26])=[O:24])[CH:18]=[CH:19][CH:20]=1>O1CCCC1>[F:13][C:14]([F:27])([F:28])[C:15]1[CH:16]=[C:17]([CH2:21][CH2:22][C:23]([NH:25][NH:26][C:10]([C:7]2[CH:8]=[CH:9][C:4]3[N:3]=[CH:2][S:1][C:5]=3[CH:6]=2)=[O:12])=[O:24])[CH:18]=[CH:19][CH:20]=1
Reactant: NNC(=O)CCc1cccc(C(F)(F)F)c1
Reactant: O=C(O)c1ccc2ncsc2c1
Solvent: C1CCOC1
Product: O=C(CCc1cccc(C(F)(F)F)c1)NNC(=O)c1ccc2ncsc2c1
Reaction time: 1 h
Yield: 66.6 %

Procedure:
To a solution of benzothiazole-6-carboxylic acid (358 mg, 2.00 mmol) in tetrahydrofuran (10 mL) was added N,N′-carbonyldiimidazole (341 mg, 2.10 mmol) at room temperature, and the resulting mixture was stirred for 1 hr. To this reaction mixture was added 3-[3-(trifluoromethyl)phenyl]propanohydrazide (557 mg, 2.40 mmol), and the mixture was further stirred at room temperature for 24 hr. The reaction mixture was concentrated under reduced pressure, and ethyl acetate was added to the residue. The precipitate was collected by filtration, purified by basic silica gel column chromatography (tetrahydrofuran) and recrystallized from hexane/tetrahydrofuran to give the title compound (524 mg, yield 67%) as colorless crystals.