Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:45]=[CH:46][CH:47]=1)[CH2:6][N:7]1[C:11]([CH3:12])=[C:10]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[CH:23]=[N:24][C:25]([N:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)=[CH:26][CH:27]=4)[CH:20]=3)[N:15]([S:34]([C:37]3[CH:43]=[CH:42][C:40]([CH3:41])=[CH:39][CH:38]=3)(=[O:36])=[O:35])[CH:14]=2)[C:9]([CH3:44])=[N:8]1.[CH3:48][C@H:49]1[CH2:51][O:50]1.CCN(C(C)C)C(C)C>C(O)C>[F:2][C:3]1[CH:4]=[C:5]([CH:45]=[CH:46][CH:47]=1)[CH2:6][N:7]1[C:11]([CH3:12])=[C:10]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[CH:27]=[CH:26][C:25]([N:28]5[CH2:33][CH2:32][N:31]([CH2:48][C@@H:49]([OH:50])[CH3:51])[CH2:30][CH2:29]5)=[N:24][CH:23]=4)[CH:20]=3)[N:15]([S:34]([C:37]3[CH:38]=[CH:39][C:40]([CH3:41])=[CH:42][CH:43]=3)(=[O:36])=[O:35])[CH:14]=2)[C:9]([CH3:44])=[N:8]1
Reactant: C[C@H]1CO1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(N5CCNCC5)nc4)cnc32)cc1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)nc4)cnc32)cc1
Yield: 81.7 %

Procedure:
Using similar reaction conditions as described in step-i of example-82A, 3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-5-(6-(piperazin-1-yl)pyridin-3-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine hydrochloride (186 mg. 0.277 mmol) was alkylated using (S)-2-methyloxirane (32 mg, 0.554 mmol), DIPEA (72 mg, 0.554 mmol) and ethanol (4 mL) to get 157 mg (82% yield) of the titled compound. MS: m/z=694.2 (M+1).
Reaction SMILES: [Cl:1][SiH:2]([CH2:4][SiH:5]([Cl:7])[Cl:6])[Cl:3].[CH2:8]=[CH:9][CH2:10][CH2:11][CH2:12][CH3:13]>C(O)(C)C.[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[CH2:8]([Si:2]([CH2:4][Si:5]([Cl:7])([Cl:6])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])([Cl:3])[Cl:1])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: Cl[SiH](Cl)C[SiH](Cl)Cl
Reactant: C=CCCCC
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: [H+]
Solvent: CC(C)O
Product: CCCCCC[Si](Cl)(Cl)C[Si](Cl)(Cl)CCCCCC
Yield: 72.6 %

Procedure:
In the same apparatus and procedures as EXAMPLE 1, 8 g(0.04 mole) of bisdichlorosilylmethane, 12.7 g (0.15 mole) of 1-hexene and 120 μl of 1% chloroplatinic acid solution in isopropanol were placed and reacted for 2 hours at reflux under the dry nitrogen atmosphere. Vacuum distillation of the reaction products gave 11.1 g (118°-120° C./0.05 mmHg) of bis(hexyldichlorosilyl)methane in 72.6% yield.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:7]([N:21]2[CH2:32][CH2:31][N:30]3[C:23](=[CH:24][C:25]4[CH2:26][C:27]([CH3:34])([CH3:33])[CH2:28][C:29]=43)[C:22]2=[O:35])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16](Br)[C:15](=[O:19])[N:14]([CH3:20])[CH:13]=1)(=[O:3])[CH3:2].Cl.[CH3:37][C:38]1[S:42][N:41]=[C:40]([NH2:43])[CH:39]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:21]2[CH2:32][CH2:31][N:30]3[C:23](=[CH:24][C:25]4[CH2:26][C:27]([CH3:34])([CH3:33])[CH2:28][C:29]=43)[C:22]2=[O:35])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:43][C:40]2[CH:39]=[C:38]([CH3:37])[S:42][N:41]=2)[C:15](=[O:19])[N:14]([CH3:20])[CH:13]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(-c2cc(Br)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Reactant: Cc1cc(N)ns1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)OCc1c(-c2cc(Nc3cc(C)sn3)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 110 °C
Yield: 31.2 %

Procedure:
A 25-mL sealed tube was charged with [4-(5-bromo-1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-2-{4,4-dimethyl-9-oxo-1,10-diazatricyclo[6.4.0.02,6]dodeca-2(6),7-dien-10-yl}pyridin-3-yl]methyl acetate 273a (150 mg, 0.28 mmol), 5-methylisothiazol-3-amine hydrochloride (55 mg, 0.33 mmol), Cs2CO3 (183 mg, 0.56 mmol), Pd2(dba)3 (27 mg, 0.030 mmol), XantPhos (35 mg, 0.060 mmol), and dioxane (10 mL). After three cycles of vacuum/argon flush, the mixture was heated at 110° C. under microwave irradiation for 0.5 hour. It was the cooled to room temperature and evaporated under reduced pressure. The residue was purified by silica-gel column eluting with 20:1 methylene chloride/methanol to afford 310a as a yellow solid (50 mg, 31%). MS-ESI: [M+H]+ 573.2.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:6][CH2:5][C@H:4]1[CH2:7][OH:8].C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)(Cl)Cl>[CH3:16][S:17]([O:1][CH2:2][C@@H:3]1[CH2:6][CH2:5][C@H:4]1[CH2:7][O:8][S:17]([CH3:16])(=[O:19])=[O:18])(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: OC[C@@H]1CC[C@H]1CO
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)OC[C@@H]1CC[C@H]1COS(C)(=O)=O
Yield: 92.7 %

Procedure:
To a solution of the compound (18) (8.50 g; 0.0733 mol) and triethylamine (22.20 g; 0.22 mol) in chloroform (100 ml), methanesulfonyl chloride (16.79 g; 0.147 mol) is dropwise added under ice-cooling, and the resultant mixture is stirred for 7 hours at room temperature. The reaction mixture is washed with water, dried and concentrated under reduced pressure to give trans-1,2-bis(methanesulfonyloxymethyl)cyclobutane (19) (18.50 g). m.p., 60° to 62° C. (crystallized from ether).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=3[Cl:23])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[O:24]1[CH2:28][CH2:27][NH:26][C:25]1=[O:29]>>[Cl:23][C:17]1[CH:18]=[C:19]([Cl:22])[CH:20]=[CH:21][C:16]=1[N:13]1[CH2:14][CH2:15][N:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:26]3[CH2:27][CH2:28][O:24][C:25]3=[O:29])=[CH:3][CH:4]=2)=[O:9])[CH2:11][CH2:12]1
Reactant: O=C1NCCO1
Reactant: O=C(c1ccc(Br)cc1)N1CCN(c2ccc(Cl)cc2Cl)CC1
Product: O=C(c1ccc(N2CCOC2=O)cc1)N1CCN(c2ccc(Cl)cc2Cl)CC1
Yield: 58.6 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromophenyl)[4-(2,4-dichlorophenyl)piperazin-1-yl]methanone (828 mg) described in Preparation Example 19 and oxazolidin-2-one (174 mg), the title compound (492 mg) was obtained.
Reaction SMILES: [Cl:1]Cl.[CH2:3]([CH2:7][C@H:8]([NH2:12])[C:9]([OH:11])=[O:10])[CH2:4][CH2:5][NH2:6].[ClH:13]>Cl>[ClH:1].[ClH:1].[Cl:13][CH:3]([CH2:4][CH2:5][NH2:6])[CH2:7][C@@H:8]([C:9]([OH:11])=[O:10])[NH2:12]
Reactant: ClCl
Reactant: NCCCC[C@H](N)C(=O)O
Agent: Cl
Product: NCCC(Cl)C[C@H](N)C(=O)O
Temperature: 7 °C

Procedure:
Chlorine was bubbled trough a solution of L(+)-lysine monohydrochloride (150 g, 821 mmol) in HCl (36%) at 70° C. The mixture was irradiated with a medium pressure mercury lamp while stirring. After 2 h the reaction mixture was cooled to 7° C. and a seed crystal was added to induce crystallization. After one hour the resulting crystals were filtered off and the crude product was triturated twice with MeOH. The crystals were collected to afford 4.1 as a white solid. Yield: 12.6 g, 49.7 mmol, 6%. 1H-NMR (300 MHz, DMSO-d6) δ 8.81 (br s, αNH3, 3H), 8.43 (br s, εNH3, 3H), 4.48 (m, γCH, 1H), 3.96 (br s, αCH, 1H), 2.94 (m, εCH2, 2H), 2.31 (m, βCH2+δCH, total 3H), 2.04 (m, δCH, 1H). 13C-NMR (75 MHz, DMSO-d6) δ 169.9 (C═O), 56.6 (γCH), 49.6 (αCH), 38.4 (εCH2), 36.1 (βCH2), 35.1 (δCH2). LC-MS program 3: Rt=1.05 min, MS ES+ (amu): 180.94 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8]O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.N1C=CN=C1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[I:34]I>O1CCCC1>[I:34][CH2:8][CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCC1CCCCC1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: ICCC1CCCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79 %

Procedure:
Into a 250-mL 3-necked round-bottom flask was placed 2-cyclohexylethan-1-ol (3 g, 23.40 mmol, 1.00 equiv), imidazole (2 g, 29.41 mmol, 1.26 equiv), PPh3 (8 g, 30.50 mmol, 1.30 equiv), tetrahydrofuran (60 mL) and I2 (7.7 g, 30.31 mmol, 1.30 equiv). The resulting solution was stirred for 4 h at room temperature. The reaction was then quenched by the addition of 100 mL of sodium bicarbonate (sat.). The resulting solution was extracted with 2×100 mL of ethyl acetate and the organic layers combined and concentrated under vacuum. The residue was applied onto a silica gel column with petroleum ether. Purification afforded 4.4 g (79%) of (2-iodoethyl)cyclohexane as a colorless oil.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]2[N:19]3[C:14]([C:15]([NH2:20])=[N:16][CH:17]=[N:18]3)=[C:13]([C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:23][CH:22]=3)[N:12]=2)[CH2:7][CH2:6]1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3].C([O-])(O)=O.[Na+]>C1COCC1>[NH2:20][C:15]1[C:14]2=[C:13]([C:21]3[CH:22]=[CH:23][C:24]([O:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:25][CH:26]=3)[N:12]=[C:11]([C@H:8]3[CH2:7][CH2:6][C@H:5]([CH2:3][OH:2])[CH2:10][CH2:9]3)[N:19]2[N:18]=[CH:17][N:16]=1
Reactant: COC(=O)[C@H]1CC[C@H](c2nc(-c3ccc(Oc4ccccc4)cc3)c3c(N)ncnn32)CC1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Nc1ncnn2c1c(-c1ccc(Oc3ccccc3)cc1)nc2[C@H]1CC[C@H](CO)CC1
Temperature: 25 °C

Procedure:
To a stirred solution of trans-4-[4-amino-5-(4-phenoxy-phenyl)-imidazo[5,1-f][1,2,4]triazin-7-yl]-cyclohexanecarboxylic acid methyl ester (105.0 mg, 0.2368 mmol) in THF (7 mL) was added solution of LiAlH4 in THF (1.0 M, 1.0 mL) at −78° C. The solution was allowed to warm to rt. Sat. aq. NaHCO3 (10 mL) was added to the reaction mixture, and the THF was removed in vacuo. DCM was added, and the mixture was transferred to a separatory funnel. The organic layer was extracted with sat. aq. NaHCO3, washed with brine, dried with magnesium sulfate, filtered and concentrated in vacuo to afford the title compound as an off-white solid. MS (ES+): m/z 416.09 (100) [MH+]. HPLC tR=3.12 min (OpenLynx, polar—5 min).
Reaction SMILES: Br[N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=O.Br[C:10]1[CH:14]=[CH:13][NH:12][C:11]=1Br>>[NH:12]1[CH:13]=[CH:14][CH:10]=[C:11]1[CH:4]1[CH2:3][NH:2][C:6](=[O:7])[CH2:5]1
Reactant: O=C1CCC(=O)N1Br
Reactant: Brc1cc[nH]c1Br
Product: O=C1CC(c2ccc[nH]2)CN1

Procedure:
Alternatively, using the same experimental procedure and 2 equiv. of N-Bromo-succinimide, dibromopyrrole 237 can be obtained.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[F:21].[CH2:22]1[CH2:27][O:26][CH:25]=[CH:24][CH2:23]1.CS(O)(=O)=O.C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH:25]2[CH2:24][CH2:23][CH2:22][CH2:27][O:26]2)=[CH:4][C:3]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[F:21]
Reactant: O=[N+]([O-])c1ccc(Oc2cc3cn[nH]c3cc2Br)c(F)c1
Reactant: C1=COCCC1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(Oc2cc3cnn(C4CCCCO4)c3cc2Br)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.8 %

Procedure:
To a solution of 6-bromo-5-(2-fluoro-4-nitrophenoxy)-1H-indazole (5.0 g, 14.2 mmol) in THF (50 mL) is added DHP (2.4 g, 28.5 mmol) and CH3SO3H (1.0 g, 10.4 mmol). The resulting mixture is stirred at RT for 1 hour. Then EtOAc and aqueous NaHCO3 solutions are added. The organic phase is separated, dried over anhydrous MgSO4, filtered and concentrated. The residue is purified by silica gel column chromatography eluting with PE:EtOAc (5:1) to give the desired product (5.5 g, 89.0% yield). MS (m/z): 436.0 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5](I)=[N:6][CH:7]=1.[C]=O.[C:18]([O:21][CH2:22][CH3:23])(=[O:20])C.C(N(CC)CC)C>C(O)C.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].ClCCl.[Pd](Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([O:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:5]([C:18]([O:21][CH2:22][CH3:23])=[O:20])=[N:6][CH:7]=1
Reactant: CCOC(=O)COc1cc(Cl)cnc1I
Reactant: CCOC(C)=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [C]=O
Solvent: ClCCl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)COc1cc(Cl)cnc1C(=O)OCC
Yield: 89.9 %

Procedure:
Ethyl 2-(5-chloro-2-iodopyridin-3-yloxy)acetate (16.5 g, 48.3 mmol) was carbonylated with 20 bar carbon monoxide in the presence of bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane adduct (1.66 g, 2.03 mmol) in a mixture of ethanol, ethyl acetate and triethylamine at 70° C. for 20 h. The crude reaction mixture was extracted with ethyl acetate and water, the organic layer was dried over sodium sulfate. Removal of the solvent in vacuum left a dark brown oil, which was purified by silica gel column chromatography with n-heptane/ethyl acetate to give the ethyl 5-chloro-3-(2-ethoxy-2-oxoethoxy)picolinate (12.5 g, 43.4 mmol, 89.9% yield) as a light red solid. MS (ISP): m/z=287.9 [(M+H)+] and 290.1 [(M+2+H)+].
Reaction SMILES: [N:1]1([C:6](=O)[CH2:7][CH:8]2[CH2:16][CH2:15][CH2:14][C:13]3[N:12](S(C4C=CC(C)=CC=4)(=O)=O)[CH:11]=[CH:10][C:9]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[N:1]1([CH2:6][CH2:7][CH:8]2[CH2:16][CH2:15][CH2:14][C:13]3[NH:12][CH:11]=[CH:10][C:9]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2CCCC3CC(=O)N2CCCC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1cc2c([nH]1)CCCC2CCN1CCCC1

Procedure:
Pyrrolidin-1-yl-2-[1-(toluene-4-sulfonyl)-4,5,6,7-tetrahydro-1H-indol-4-yl]-ethanone (840 mg) was reduced using lithium aluminum hydride (4 eq.) in THF (80 mL) at reflux for 5 hours to give 480 mg of mainly 4-(2-pyrrolidin-1-yl-ethyl) 4,5,6,7-tetrahydro-1H-indole as an oil.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:41]=[CH:40][C:25]([O:26][C:27]2[CH:39]=[CH:38][C:30]([O:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=O)=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([O:47][C:48](=[O:55])[C@H:49]([C@H:51]([CH2:53][CH3:54])[CH3:52])[NH2:50])(C)(C)C>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:39]=[CH:38][C:30]([O:31][CH2:32][CH2:33][CH2:34][C:35]([NH:50][C@H:49]([C:48]([OH:55])=[O:47])[C@H:51]([CH2:53][CH3:54])[CH3:52])=[O:37])=[CH:29][CH:28]=2)=[CH:40][CH:41]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC[C@H](C)[C@H](N)C(=O)OC(C)(C)C
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCC(=O)O)cc2)cc1
Agent: Cl
Product: CC[C@H](C)[C@H](NC(=O)CCCOc1ccc(Oc2ccc(CN(Cc3ccccc3)c3cccc(NS(C)(=O)=O)c3C)cc2)cc1)C(=O)O

Procedure:
The product from Example 233 and L-isoleucine tert-butyl ester hydrochloride were processed as described in Example 251A and 258B to provide the titled compound. 1H NMR (500 MHz, DMSO-d6) δ12.06-12.82 (br.s, 1 H), 8.94 (s, 1 H), 7.99 (d, 1 H), 7.23 (m, 7 H), 6.87-7.09 (m, 7 H), 6.82 (d, 2 H), 4.19 (dd, 1 H), 4.04 (s, 2 H), 4.00 (s, 2 H), 3.93 (m, 2 H), 2.91 (s, 3 H), 2.38 (s, 3 H), 2.33 (m, 2 H), 1.92 (m, 2 H), 1.76 (m, 1 H), 1.40 (m, 1 H), 1.18 (m, 1 H), 0.83 (m, 6 H); MS (ESI+) m/z 688 (M+H)+.
Reaction SMILES: [C:1]1([C:7](=[C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]2=[O:18])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:20][C:21]([O:23][CH3:24])=[O:22].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:24][O:23][C:21](=[O:22])[CH2:20][N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9](=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH3:8])[C:10]1=[O:18]
Reactant: COC(=O)CBr
Reactant: CC(=C1C(=O)Nc2ccccc21)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)C(=C(C)c2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
3-(1-Phenyl-ethylidene)-1,3-dihydro-indol-2-one (294 mg, 1 mmol) was dissolved in anhydrous DMF, then methyl bromoacetate (184 mg, 1.2 mmol) was added. Finally, Cs2CO3 (488 mg, 1.5 mmol) was added in one portion. The mixture was stirred at room temperature overnight. The reaction was monitored by HPLC. When the reaction was finished, the solvent was removed under reduced pressure. The residue was separated by flash chromatography column (gradient elution, 5-10% ethyl acetate in petroleum ether) to give [2-oxo-3-(1-phenyl-ethylidene)-2,3-dihydro-indol-1-yl]-acetic acid methyl ester as yellow powder (230 mg, 75%). MS calcd. for C19H17NO3 307, obsd. (ESI+) [(M+1)+] 308.1.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[CH:14]1[C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([CH3:24])[NH:17][C:16]([CH2:25][O:26][CH2:27][C:28]#[CH:29])=[C:15]1[C:30]([O:32][CH2:33][CH3:34])=[O:31].[C:35](=[O:37])=[O:36]>CCCCCC.O1CCCC1>[Cl:6][C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[CH:14]1[C:19]([C:20]([O:22][CH3:23])=[O:21])=[C:18]([CH3:24])[NH:17][C:16]([CH2:25][O:26][CH2:27][C:28]#[C:29][C:35]([OH:37])=[O:36])=[C:15]1[C:30]([O:32][CH2:33][CH3:34])=[O:31]
Reactant: C#CCOCC1=C(C(=O)OCC)C(c2cccc(Cl)c2Cl)C(C(=O)OC)=C(C)N1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)C1=C(COCC#CC(=O)O)NC(C)=C(C(=O)OC)C1c1cccc(Cl)c1Cl
Reaction time: 2 h

Procedure:
A 1.6M solution of n-butyllithium in hexane (45 ml) was added dropwise to a solution of 1-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl]methoxy}-2-propyne (132 g) in tetrahydrofuran (1 l.) keeping the temperature below -40°. The mixture was stirred at -60° for 2 hours and then carbon dioxide gas was passed through the solution for 30 minutes with cooling in an acetone/solid carbon dioxide bath. The mixture was allowed to warm to 0° while the passage of carbon dioxide gas was continued and then it was quenched with water (1 l.) and the layers separated. The aqueous layer was extracted into ether (500 ml) and the combined organic layers were washed with water, diluted with dichloromethane, washed with 1M HCl, dried over MgSO4 and evaporated. The residue was triturated with methanol and the resulting solid collected, washed with cold (-20°) methanol and dried to give 4-{[4-(2,3-dichlorophenyl)-3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyrid-2-yl]methoxy}but-2-ynoic acid, (83.7 g), m.p. 150°-152°.
Reaction SMILES: [C:1]1([S:7]([CH2:9]P(=O)(OCC)OCC)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].[Cl:24][C:25]1[CH:26]=[C:27]([C:32](=O)[C:33]([F:36])([F:35])[F:34])[CH:28]=[C:29]([Cl:31])[CH:30]=1>C1(C)C=CC=CC=1>[C:1]1([S:7]([CH:9]=[C:32]([C:27]2[CH:28]=[C:29]([Cl:31])[CH:30]=[C:25]([Cl:24])[CH:26]=2)[C:33]([F:36])([F:35])[F:34])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: CCOP(=O)(CS(=O)c1ccccc1)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=S(C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 93 %

Procedure:
Diethyl [(phenylsulfinyl)methyl]phosphonate (5.00 g, 96% purity, 17.4 mmol) was dissolved in toluene (20 mL) and cooled to 0° C. To the solution potassium tert-butoxide (2.05 g, 18.2 mmol) was added in one portion. This solution was added over 45 minutes to a solution of 1-(3,5-Dichlorophenyl)-2,2,2-trifluoroethanone (4.26 g, 99% purity, 17.4 mmol) in toluene at 0° C. The reaction mixture was stirred for additional 15 minutes at 0° C. and then warmed to room temperature over 30 minutes. The solution was poured onto hydrochloric acid (3.6%) and the phases were separated. The aqueous phase was extracted with toluene and the combined organic phases were washed with water, dried over sodium sulfate and the solvents evaporated. 2-(3,5-dichlorophenyl)-3,3,3-trifluoroprop-1-en-1-yl phenyl sulfoxide was obtained (6.26 g, 94% purity, 93% yield, E/Z=38/62).
Reaction SMILES: C(Cl)(Cl)=O.[NH2:5][C:6]1[CH:10]=[C:9]([Cl:11])[S:8][C:7]=1[S:12]([NH:15][C:16]([NH:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])=S)(=[O:14])=[O:13].C(N(CC)CC)C>O1CCCC1>[Cl:11][C:9]1[S:8][C:7]2[S:12](=[O:14])(=[O:13])[N:15]=[C:16]([NH:18][CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[NH:5][C:6]=2[CH:10]=1
Reactant: CC(C)CCNC(=S)NS(=O)(=O)c1sc(Cl)cc1N
Agent: O=C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)CCNC1=NS(=O)(=O)c2sc(Cl)cc2N1
Temperature: 0 °C
Yield: 29.4 %

Procedure:
Phosgene (0.242 ml, 20% in toluene) was added dropwise to a solution of N-(3-amino-5-chloro-2-thienylsulfonyl)-N′-(3-methylbutyl)thiourea (0.153 g, 0.42 mmol) and dry triethylamine (0.118 ml, 0.85 mmol) in dry tetrahydrofuran (3 ml) with stirring at 0° C. The mixture was stirred for 2 h at 0° C., and evaporated to dryness. Crystallisation was obtained from ethyl acetate, and the precipitate was isolated by filtration, washed with water and dried affording 38 mg (27%) of the title compound. mp 230-231.5° C., 1H-NMR (DMSO-d6): δ0.90 (d, 6H, 2×CH3), 1.40 (q, 2H, CH2),1.60 (m, 1H, CH), 3.20 (q, 2H, CH2), 7.05 (s, 1H, H-5), 7.25 (br s, 1H, NH), 10.95 (s, 1H, NH). MS: M/e 307(M+).
Reaction SMILES: C[O-].[Na+].Cl[C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]([Cl:14])[N:6]=1.[Cl-].[NH4+].[C:17](OCC)(=[O:19])C>C1COCC1>[Cl:14][C:7]1[N:6]=[C:5]([O:19][CH3:17])[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=1
Reactant: CCOC(C)=O
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Agent: C[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 13 h

Procedure:
Sodium methoxide (2.8 g) was added to a solution of 2,6-dichloro-3-nitropyridine (10 g) in THF (100 mL) at 0° C., and the reaction solution was stirred at room temperature for 13 hours. A saturated ammonium chloride solution and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 6.49 g of the title compound. The property value of the compound is as follows.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1(C(/[N:24]=[CH:25]/[C:26]([O:28][CH2:29][CH3:30])=[O:27])C2C=CC=CC=2)C=CC=CC=1.[O:31]1[CH2:35][CH2:34][CH:33]([C:36]([Cl:38])=[O:37])[CH2:32]1.Cl>O1CCCC1>[ClH:38].[NH2:24][CH:25]([C:36](=[O:37])[CH:33]1[CH2:34][CH2:35][O:31][CH2:32]1)[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)/C=N/C(c1ccccc1)c1ccccc1
Reactant: O=C(Cl)C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(N)C(=O)C1CCOC1
Reaction time: 0.5 h

Procedure:
Lithium bis(trimethysilyl)amide (1 M solution in tetrahydrofuran, 288 mL, 0.288 mol) was added drop-wise to a solution of ethyl (2E)-[(diphenylmethyl)imino]ethanoate (70 g, 0.26 mol) in tetrahydrofuran (1 L) at −70° C. The reaction mixture was stirred for 30 minutes, and the resulting suspension was transferred via cannula into a solution of tetrahydrofuran-3-carbonyl chloride (35.7 g, 0.26 mol) in tetrahydrofuran (200 mL) at −70° C. The reaction mixture was stirred at room temperature for 2 hours, at which time aqueous hydrochloric acid (2 M, 260 mL) was added. After the reaction mixture had stirred for 15 minutes, the tetrahydrofuran was removed in vacuo, and the aqueous residue was washed with ethyl acetate (4×200 mL). The aqueous layer was freeze-dried, affording the product as a light yellow solid. Yield: 40 g, 0.20 mol, 77%.