Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][N:14]([CH2:30][C:31]1[N:32]=[N:33][C:34]2[C:39]([CH:40]=1)=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:15]([C:17]1[CH:27]=[C:26]([O:28][CH3:29])[C:20]2[O:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=2[CH:18]=1)=[O:16])=O)(C)(C)C.FC(F)(F)C(O)=O.ClCCl.ClCCl.[C:54]1(=O)[CH2:57]C[CH2:55]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[N:33]1[C:34]2[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:40]=[C:31]([CH2:30][N:14]([CH2:13][C@@H:9]2[CH2:10][CH2:11][CH2:12][N:8]2[CH:6]2[CH2:57][CH2:54][CH2:55]2)[C:15]([C:17]2[CH:27]=[C:26]([O:28][CH3:29])[C:20]3[O:21][C:22]([CH3:25])([CH3:24])[O:23][C:19]=3[CH:18]=2)=[O:16])[N:32]=1
Reactant: COc1cc(C(=O)N(Cc2cc3ccccc3nn2)C[C@@H]2CCCN2C(=O)OC(C)(C)C)cc2c1OC(C)(C)O2
Reactant: O=C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C(=O)N(Cc2cc3ccccc3nn2)C[C@@H]2CCCN2C2CCC2)cc2c1OC(C)(C)O2

Procedure:
Experimental conditions analogous to Example 1, from 172 mg (0.31 mmol) of (S)-2-{[cinnolin-3-ylmethyl-(7-methoxy-2,2-dimethyl-benzo[1,3]dioxole-5-carbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester and 3 mL 10% trifluoroacetic acid/dichloromethane. The crude deprotected material was submitted to reductive amination reaction in 5 mL dichloromethane using 108 mg (1.55 mmol) of cyclobutanone and 329 mg (1.55 mmol) sodium triacetoxyborohydride. The reaction mixture was purified using flash chromatography elution with 0-10% methanol in dichloromethane, gave 47 mg of pale yellow solid as the free base. LC-MSD, m/z for C29H34N4O4 [M+H]+: 503.7. 1H NMR (400 MHz, CDCl3): δ 1.6-2.5 (m, 16 H), 2.8-2.9 (m, 1 H), 3.5-3.8 (m, 3 H), 3.8 (s, 3 H), 3.9-4.0 (m, 2 H), 5.1-5.3 (m, 2 H), 6.8 (bs, 1 H), 7.2 (bs, 1 H), 7.7-7.9 (m, 4 H), 8.4-8.5 (m, 1 H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:4][CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1.[Cl:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26].C(OC1C(=O)C=C(CNS(C2C=CC=CC=2)(=O)=O)OC=1)C1C=CC=CC=1>>[CH2:11]([O:10][C:6]1[C:7](=[O:9])[CH:8]=[C:3]([CH2:2][NH:1][S:25]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[Cl:18])(=[O:27])=[O:26])[O:4][CH:5]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1cc(=O)c(OCc2ccccc2)co1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Agent: O=c1cc(CNS(=O)(=O)c2ccccc2)occ1OCc1ccccc1
Product: O=c1cc(CNS(=O)(=O)c2ccccc2Cl)occ1OCc1ccccc1
Yield: 59.2 %

Procedure:
N-(5-Benzyloxy-4-oxo-4H-pyran-2-ylmethyl)-2-chloro-benzenesulfonamide (7-03) (26.0 g, 59.19%) was synthesized as a light brown solid from 2-aminomethyl-5-benzyloxy-pyran-4-one (5) (25.0 g, 108.2 mmol) and 2-chloro-benzenesulfonyl chloride (6-03) (27.2 g, 129.87 mmol) following the procedure described for N-(5-benzyloxy-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (7-01).
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].C([Li])CCC.[CH:13]1([CH2:19][C:20]([CH3:26])([CH3:25])[C:21](OC)=[O:22])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[Cl-].[NH4+]>C1COCC1>[CH:13]1([CH2:19][C:20]([CH3:26])([CH3:25])[C:21](=[O:22])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COP(C)(=O)OC
Reactant: COC(=O)C(C)(C)CC1CCCCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COP(=O)(CC(=O)C(C)(C)CC1CCCCC1)OC
Reaction time: 0.5 h
Yield: 54 %

Procedure:
To a solution of dimethyl methylphosphonate (6.6 ml, 60.5 mmol) in 100 ml of anhydrous THF was added dropwise n-butyl lithium (1.59N, 38.1 ml, 60.5 mmol) at -78° C. under argon atmosphere, and the mixture was stirred for 30 minutes. Then, methyl 3-cyclohexyl-2,2-dimethylpropionate (5.00 g, 25.2 mmol) was added dropwise and the mixture was stirred at -78° C. for 20 minutes and then at room temperature for 2 hours. An aqueous saturated solution of ammonium chloride was added to the reaction mixture. The mixture was extracted with ethyl acetate (50 ml×4) and then the combined ethyl acetate layers were washed with water (50 ml) and brine (50 ml), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography (silica gel, ethyl acetate) to yield a pure product of dimethyl 4-cyclohexyl-3,3-dimethyl-2-oxobutylphosphonate (3.9491 g, 13.6 mmol, 54.0%). This compound was assigned the structure by the following data:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]=[C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]2=[O:19])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][CH2:28][CH2:29][Cl:30]>CN(C=O)C>[Cl:30][CH2:29][CH2:28][CH2:27][O:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]=[C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11]2=[O:19])=[CH:4][CH:3]=1
Reactant: O=C1Nc2ccccc2C1=CNc1ccc(O)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1Nc2ccccc2C1=CNc1ccc(OCCCCl)cc1
Temperature: 40 °C
Yield: 58 %

Procedure:
A solution of 3-[(4-hydroxy-phenylamino)-methylene]-1,3-dihydro-indol-2-one (0.945 g, 3.75 mmol) in 20 mL DMF is treated with potassium carbonate (777 mg, 1.5 equiv.) and 1-bromo-3-chloropropane (1.1 equiv.). The reaction mixture is heated to 40° C. for 3 h. The reaction mixture is partitioned between EtOAc and water. The organic layer is collected and washed sequentially with H2O (1×), saturated aqueous NaHCO3 solution (1×), and brine (1×). The organic phase was dried and concentrated to give an oil. The oil was purified by preparative chromatography (silica gel; 1:1 EtOAc:hexane) to give the named compound as a yellow solid (711 mg, 58%).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([OH:15])=O)[N:10]=[C:9]([C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[CH:8]=2)=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CN1CCOCC1.[CH3:52][S:53]([CH:56]1[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1)(=[O:55])=[O:54]>CC(N(C)C)=O>[F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][C:7]2[N:11]([CH2:12][C:13]([N:59]3[CH2:60][CH2:61][CH:56]([S:53]([CH3:52])(=[O:55])=[O:54])[CH2:57][CH2:58]3)=[O:15])[N:10]=[C:9]([C:16]3[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=3)[CH:8]=2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)C1CCNCC1
Reactant: O=C(O)Cn1nc(-c2ccncc2)cc1Cc1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: CN1CCOCC1
Product: CS(=O)(=O)C1CCN(C(=O)Cn2nc(-c3ccncc3)cc2Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of [5-(4-fluorobenzyl)-3-pyridin-4-yl-1H-pyrazol-1-yl]acetic acid (150 mg, 0.48 mmol) in DMA (3 mL) at room temperature was added HOBt (72 mg, 0.53 mmol), EDCI (102 mg, 0.53 mmol), NMM (0.13 mL, 1.20 mmol) and 4-(methylsulfonyl)piperidine (117 mg, 0.72 mmol) and the mixture sonicated to a fine suspension and stirred for 18 hours at room temperature. The volatiles were removed under high vacuum and the residue partitioned between EtOAc (70 mL) and water (25 mL). The aqueous layer was removed and the organics washed with NaHCO3 (30 mL), brine (30 mL), dried over MgSO4, filtered and stripped to yield the title compound as an off-white solid, 144 mg, 66%. 1H NMR (400 MHz, DMSO-D6) δ ppm 8.46-8.56 (2 H, m), 7.60-7.71 (2 H, m), 7.25-7.37 (2 H, m), 7.07-7.19 (2 H, m), 6.53 (1 H, s), 5.10-5.41 (2 H, m), 4.40 (1 H, d, J=13.14 Hz), 3.97-4.15 (1 H, m), 3.95 (2 H, s), 3.34-3.49 (1 H, m), 3.12 (1 H, t, J=12.00 Hz), 2.96 (3 H, s), 2.64 (1 H, t, J=11.62 Hz), 2.06 (2 H, d, J=12.88 Hz), 1.59-1.79 (1 H, m), 1.36-1.54 (1 H, m); m/z (APCI+) for C23H25N4O3F 457.1 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([F:16])[CH:10]=2)=[N:6][CH:7]=1.C([Mg]Cl)(C)C.[I:22]I.[NH4+].[Cl-]>O1CCCC1.CCOC(C)=O>[F:16][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[F:15])[O:8][C:5]1[CH:4]=[CH:3][C:2]([I:22])=[CH:7][N:6]=1
Reactant: II
Reactant: Fc1ccc(Oc2ccc(Br)cn2)cc1F
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Fc1ccc(Oc2ccc(I)cn2)cc1F
Temperature: 20 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
To a solution of 5-bromo-2-(3,4-difluorophenoxy)pyridine (19 g, 66.4 mmol) in tetrahydrofuran (THF) (200 mL) was added isopropylmagnesium chloride (66.4 mL, 66.4 mmol). The reaction mixture was stirred at 20° C. for 2 hr, and then I2 (16.86 g, 66.4 mmol) was added, The reaction mixture was stirred at 20° C. for another 4 hr, then saturated aqueous NH4Cl solution (200 ml) and EtOAc (200 ml) were added, the organic layer was separated, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography eluting with Hex/EtOAc (20:1). The collected fractions provided 2-(3,4-difluorophenoxy)-5-iodopyridine (22 g, 61.7%).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][O:9][C:10]1[C:11]([CH3:56])=[C:12]2[C:17](=[C:18]([CH3:21])[C:19]=1[CH3:20])[O:16][C:15]([CH2:23][O:24][C:25]1[CH:54]=[CH:53][C:28]([CH2:29][C:30]3([CH2:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[S:34][C:33](=[O:35])[N:32]([CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:31]3=[O:44])=[CH:27][CH:26]=1)([CH3:22])[CH2:14][C:13]2=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:58][OH:59].N1C=CC=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.CO>[C:1]([O:5][C:6]([CH2:8][O:9][C:10]1[C:11]([CH3:56])=[C:12]2[C:17](=[C:18]([CH3:21])[C:19]=1[CH3:20])[O:16][C:15]([CH2:23][O:24][C:25]1[CH:54]=[CH:53][C:28]([CH2:29][C:30]3([CH2:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[S:34][C:33](=[O:35])[N:32]([CH2:36][C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])[C:31]3=[O:44])=[CH:27][CH:26]=1)([CH3:22])[CH2:14][C:13]2=[N:58][OH:59])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NO
Reactant: Cc1c(C)c2c(c(C)c1OCC(=O)OC(C)(C)C)C(=O)CC(C)(COc1ccc(CC3(CC(=O)OC(C)(C)C)SC(=O)N(CC(=O)OC(C)(C)C)C3=O)cc1)O2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1c(C)c2c(c(C)c1OCC(=O)OC(C)(C)C)C(=NO)CC(C)(COc1ccc(CC3(CC(=O)OC(C)(C)C)SC(=O)N(CC(=O)OC(C)(C)C)C3=O)cc1)O2
Reaction time: 120 h

Procedure:
A mixture of 350 mg of di-t-butyl α,α'-{5-[4-(6-t-butoxycarbonylmethoxy-2,5,7,8-tetramethyl -4-oxochroman-2-ylmethoxy)benzyl]-2,4-dioxothiazolidine-3,5-diyl}diacetate (prepared as described in Example 50), 122 mg of hydroxylamine hydrochloride, 122 mg of pyridine and 4 ml of methanol was allowed to stand at 25°-+° C. for 5 days. Ethyl acetate and an aqueous solution of potassium carbonate were added to the mixture, and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was subjected to silica gel column chromatography (eluted with a 20:1 by volume mixture of benzene and ethyl acetate) to obtain the title compound.
Reaction SMILES: S([O:11][C@H:12]1[CH2:36][CH2:35][C@@:34]2([CH3:37])[C:14](=[CH:15][CH2:16][C@@H:17]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:38])[C@H:18]3[CH2:19][CH2:20][C@@H:21]2[C@H:22]([CH3:29])[CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:13]1)(C1C=CC(C)=CC=1)(=O)=O.[CH2:39](O)[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][OH:45].O1CCOCC1>CCCCCC>[OH:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][O:11][C@@H:12]1[CH2:36][CH2:35][C@@:34]2([CH3:37])[C:14](=[CH:15][CH2:16][C@@H:17]3[C@@H:33]2[CH2:32][CH2:31][C@@:30]2([CH3:38])[C@H:18]3[CH2:19][CH2:20][C@@H:21]2[C@H:22]([CH3:29])[CH2:23][CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:13]1
Reactant: OCCCCCCO
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CC[C@@]3(C)C(=CC[C@H]4[C@@H]5CC[C@H]([C@H](C)CCCC(C)C)[C@@]5(C)CC[C@@H]43)C2)cc1
Solvent: CCCCCC
Solvent: C1COCCO1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@H](OCCCCCCO)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 52 %

Procedure:
Using the procedure of Davis, J. Chem. Soc. 178-181 (1962), cholesterol tosylate and 1,6-hexanediol were condensed in refluxing dioxane to provide 52% yield of the title ether as colorless plates from hexane, m.p. 79.5°-81° C.; [α]D25 -28.1°±0.5° C.; IR 3500-3200 (OH), 1100 and 1080 cm-1 (ether); NMR (CDCL3): δ2.8-3.3 (br, 1H, H-1), 3.3-3.75 (2t,4H), 5.4 m, 1H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[O:1]=[C:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COC(=O)[C@@H]1CC(=O)CN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 85.9 %

Procedure:
A solution of (2S,4R)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (10 g, 40.8 mmol) in DCM (100 mL) was cooled to 0° C., then treated portion wise with Dess-Martin periodinane (17.29 g, 40.8 mmol) over 20 min. The reaction was maintained at 0° C. for 1 h, and then the cold bath was removed. After another 3 h at room temperature, the reaction was treated with 300 mL of 1:1 sat. aq. Na2SO3:sat. aq. NaHCO3. The reaction was stirred vigorously overnight at room temperature, then the layers were separated. The organics were washed with water and brine, then dried over magnesium sulfate and concentrated. The resulting mixture was slurried in DCM (20 mL) then filtered over Celite. The organics were concentrated. The crude oil was further purified by direct filtration from grained solids to provide (S)-1-tert-butyl 2-methyl 4-oxopyrrolidine-1,2-dicarboxylate (8.53 g, 87% yield). LCMS (m/z): 244.3 (MH+), 0.42 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH-:9].[O:10]=[C:11]1[C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([C:24](O)=O)[C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][CH:16]=2.C(=O)([O-])O.[Na+]>C(O)(=O)C.O>[CH3:8][C:4]1[C:3]2[N:9]=[C:24]([C:19]3[C:18]4[C:17]5[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=5)[C:11](=[O:10])[C:23]=4[CH:22]=[CH:21][CH:20]=3)[NH:1][C:2]=2[CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cccc(N)c1[NH-]
Reactant: O=C(O)c1cccc2c1-c1ccccc1C2=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cccc2[nH]c(-c3cccc4c3-c3ccccc3C4=O)nc12

Procedure:
The procedure used in Example 68 is followed. In a 250 ml round-bottomed flask under an argon atmosphere, reflux, for 6 hours, a suspension of 5 g of (2-amino-6-methylphenyl)amide of 9-oxo-9H-fluorene-4-carboxylic acid, obtained in the previous stage, in 100 ml of acetic acid. After cooling, bring to dryness under reduced pressure. Take the residue up in 25 ml of water then bring to pH=8 by addition of a saturated aqueous solution of sodium hydrogen carbonate. The precipitate that formed is filtered off, washed with water, and made into a paste with diisopropyl ether, and in this way, we obtain 4.7 g of 4-(4-methyl-1H-benzimidazol-2-yl)-9H-fluoren-9-one, in the form of an orange powder, which is used as it is in the following stage, with the following characteristics:
Reaction SMILES: [C:1]([CH2:3][C:4](O)=[O:5])#[N:2].[CH:7]1([NH:10][C:11]([NH2:13])=[O:12])[CH2:9][CH2:8]1>C(OC(=O)C)(=O)C>[NH2:2][C:1]1[N:10]([CH:7]2[CH2:9][CH2:8]2)[C:11](=[O:12])[NH:13][C:4](=[O:5])[CH:3]=1
Reactant: N#CCC(=O)O
Reactant: NC(=O)NC1CC1
Solvent: CC(=O)OC(C)=O
Product: Nc1cc(=O)[nH]c(=O)n1C1CC1
Reaction time: 2 h

Procedure:
To a solution of 64 g (0.75 mol) cyanoacetic acid and 250 ml of acetic anhydride was added 70 g (0.7 mol) of cyclopropylurea. The solution was stirred at 60°-70° C. for 2 hours. After cooling white crystals were filtered off and washed with ethanol. Yield 76.7 g (66%) (I). This was suspended in 200 ml of hot water and 55 ml of 5N NaOH was added in portions so the solution the whole time was basic. The reaction mixture was refluxed for 20 minutes and then neutralized with 5N HCl. After cooling, white crystals were filtered off. Yield 31.7 g (42%) (II) NMR.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([CH3:20])([CH3:19])[CH2:10][C:11]([C:15]([F:18])([F:17])[F:16])([OH:14])[CH2:12][OH:13].ClCCl.CS(C)=O.[Cl-].[NH4+]>CC(OC)(C)C.C(N(CC)CC)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]([CH3:20])([CH3:19])[CH2:10][C:11]([OH:14])([C:15]([F:16])([F:17])[F:18])[CH:12]=[O:13]
Reactant: CC(C)(CC(O)(CO)C(F)(F)F)c1cc(F)ccc1F
Agent: [Cl-]
Agent: [NH4+]
Solvent: COC(C)(C)C
Solvent: ClCCl
Solvent: CS(C)=O
Product: CC(C)(CC(O)(C=O)C(F)(F)F)c1cc(F)ccc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
800 mg (2.8 mmol) of 4-(2,5-difluorophenyl)-4-methyl-2-trifluoromethyl-pentane-1,2-diol is introduced into 20 ml of dichloromethane, and at 0° C., 9.5 ml of DMSO and 1.95 ml of triethylamine are added. The solution is slowly mixed with 1.34 g (8.4 mmol) of SO3-pyridine complex, and it is stirred for 2 hours at 0° C. The mixture is dispersed between saturated ammonium chloride solution and MTBE, the phases are separated, and the aqueous phase is extracted with MTBE. The combined organic phases are washed with water and saturated NaCl solution and dried with NaSO4. It is concentrated by evaporation and chromatographed on silica gel with hexane/ethyl acetate (30%). 710 mg of the desired product is obtained.
Reaction SMILES: [C:1]([C:3]1[C:4]([F:14])=[C:5]([CH:9]=[C:10]([F:13])[C:11]=1[F:12])[C:6](F)=[O:7])#[N:2].[Cl-].[Al+3].[Cl-].[Cl-].[Si](Cl)(Cl)(Cl)[Cl:20]>>[C:1]([C:3]1[C:4]([F:14])=[C:5]([CH:9]=[C:10]([F:13])[C:11]=1[F:12])[C:6]([Cl:20])=[O:7])#[N:2]
Reactant: Cl[Si](Cl)(Cl)Cl
Reactant: N#Cc1c(F)c(F)cc(C(=O)F)c1F
Agent: [Al+3]
Agent: [Cl-]
Product: N#Cc1c(F)c(F)cc(C(=O)Cl)c1F

Procedure:
76.6 g of 3-cyano-2,4,5-trifluoro-benzoyl fluoride were initially introduced together with 1 g of anhydrous aluminium chloride at 60-65° C., and 25 g of silicon tetrachloride were then added dropwise at the rate of gas evolution. After the evolution of gas at 65° C. had ceased, the mixture was distilled under reduced pressure. In the boiling range from 120-122° C./14 mbar, 73.2 g of 3-cyano-2,4,5-trifluoro-benzoyl chloride passed over.
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([S:7]([NH:10][CH:11]([CH2:16][CH:17]=[CH2:18])[C:12]([O:14][CH3:15])=[O:13])(=[O:9])=[O:8])=[CH:3][CH:2]=1.O.ClC1C=CC=C(C(OO)=[O:34])C=1>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:1]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:6]=[CH:5][C:4]([S:7]([NH:10][CH:11]([CH2:16][CH:17]2[O:34][CH2:18]2)[C:12]([O:14][CH3:15])=[O:13])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCC(NS(=O)(=O)c1ccc(-c2ccccc2)cc1)C(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(CC1CO1)NS(=O)(=O)c1ccc(-c2ccccc2)cc1
Reaction time: 8 h

Procedure:
To a solution of methyl 2-[[(1,1′-biphenyl)-4-yl]sulfonyl]amino-4-pentenoate 16a (2.0 g, 5.8 mmol) in CH2Cl2 (15 mL), NaHCO3 (0.58 g, 7 mmol) and water (10 mL) at 0° C., is added slowly m-chloroperbenzoic acid (3.3 g, 11.6 mmol, 57-86%). The reaction mixture is stirred overnight. The resulting mixture is diluted with aqueous NaHCO3, and the mixture is extracted three times with CH2Cl2. The combined CH2Cl2 layers are washed with NaHCO3, brine, dried over MgSO4 and concentrated to an oil which is purified by column chromatography eluting with EtOAc/hexane (4:6) to give the desired product as a mixture of two isomers (ratio 2:3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]2[CH2:7][NH:8][CH2:9][CH2:10][S:11][C:5]=2[CH:4]=1.Cl[C:15]1[CH:24]=[C:23]([Cl:25])[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH3:26])[CH:21]=2)[N:16]=1>C(O)CCC>[Cl:25][C:23]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([CH3:26])[CH:21]=2)[N:16]=[C:15]([N:8]2[CH2:7][C:6]3[CH:12]=[CH:13][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[S:11][CH2:10][CH2:9]2)[CH:24]=1
Reactant: Cc1ccc2nc(Cl)cc(Cl)c2c1
Reactant: COc1ccc2c(c1)SCCNC2
Solvent: CCCCO
Product: COc1ccc2c(c1)SCCN(c1cc(Cl)c3cc(C)ccc3n1)C2
Temperature: 160 °C
Reaction time: 2.5 h
Yield: 49.7 %

Procedure:
A mixture of 8-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine (0.63 g, 3.2 mmol), 2,4-dichloro-6-methylquinoline (0.68 g, 3.2 mmol) and n-butanol (4 mL) was heated with stirring in a 5 mL of microwave process vial for 2.5 hours at 160° C. under microwave irradiation. The solvent was removed by concentration in vacuo. The residue was dissolved in a mixture solvent of ethanol and dichloromethane and then concentrated in vacuo to remove dichloromethane. The formed precipitate was collected by filtration, which was washed with diethyl ether and petroleum ether, dried in vacuo to afford 0.59 g of the product as a pale white solid (yield was 50%). MS obsd. (ESI+) [(M+H)+] 371.
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[S:4][C:3]=1[CH3:11].[CH2:12]([CH:14]([C:17]1[C:18]2[N:19]([C:24](I)=[C:25]([CH3:27])[N:26]=2)[N:20]=[C:21]([CH3:23])[CH:22]=1)[CH2:15][CH3:16])[CH3:13]>C1COCC1.[Zn]>[CH2:12]([CH:14]([C:17]1[C:18]2[N:19]([C:24]([C:2]3[C:10]4[C:5](=[N:6][CH:7]=[CH:8][CH:9]=4)[S:4][C:3]=3[CH3:11])=[C:25]([CH3:27])[N:26]=2)[N:20]=[C:21]([CH3:23])[CH:22]=1)[CH2:15][CH3:16])[CH3:13]
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Reactant: Cc1sc2ncccc2c1Br
Agent: [Zn]
Solvent: C1CCOC1
Product: CCC(CC)c1cc(C)nn2c(-c3c(C)sc4ncccc34)c(C)nc12
Temperature: 100 °C
Yield: 10.4 %

Procedure:
382 mg of 3-Bromo-2-methyl-thieno[2,3-b]pyridine (1.67 mmol) is placed into the vial with 2.5 ml of Reiki Zn, suspension in THF (1.75 mmol) and capped and heated at 100° C. for 2 h. The excess Zinc is allowed to settle down and the solution is transferred to the vial containing 200 mg of 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.58 mmol) and 41 mg of PdCl2(pddf) (0.05 mmol) in 3 ml of dry THF. The vial is capped with a Teflon cap and heated at 80° C. for 2 days. The reaction mixture is quenched with sat. NH4Cl and extracted by CH2Cl2, dried over Na2SO4 and evaporated. The crude product is applied onto a silica-gel chromatography column (Hexane:AcOEt=8:1) to give 22 mg of the title compound. Yield 4%. mass spectrum (m/e): 365 (M+1).
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][CH2:7][C:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]=2[NH:4][C:3]1=[O:13].[H-].[Na+].Br[CH2:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>CN(C)C=O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:21]([O:20][C:18]([CH2:17][N:4]1[C:5]2[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=2[CH2:7][CH2:8][CH:2]([NH:1][CH2:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[C:3]1=[O:13])=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NC1CCc2ccccc2NC1=O
Reactant: O=C(CBr)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [H-]
Solvent: CN(C)C=O
Product: O=C(CNC1CCc2ccccc2N(CC(=O)OCc2ccccc2)C1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of 3-amino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (5.0 g, 0.028 mol) in dimethylformamide (100 ml) was added under a nitrogen atmosphere to a stirred suspension of sodium hydride [prepared from the 60% mineral oil dispersion (1.2 g) by washing with petroleum ether (3×150)] in dimethylformamide (400 ml) to which tetrabutylammonium bromide (10.9 g, 0.031 mol) had been added. The reaction mixture was maintained at 50° for 15 minuites, then a solution of benzyl bromoacetate (7.2 g, 0.031 mol) in dimethylformamide (25 ml) was added. The reaction mixture was stirred for an additional 18 hours at 50°, then cooled to room temperature, and the dimethylformamide removed under high vacuum. The residue was stirred with toluene/dichloromethane (1:1, 500 ml) to precipitate inorganic salts. After filtration, the solution was evaporated under reduced pressure, and the residue chromatographed on silica gel (200 g). Elution with 0-15% ethyl acetate in toluene gave 1-benzyloxycarbonylmethyl-3-benzyloxycarbonylmethylamino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one as the first fraction. Further elution gave 3-benzyloxycarbonylamino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one, m.p. 124°-127° C. and 3-amino-1-benzyloxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (see example 1).