Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH2:29][CH:30]4[CH2:32][O:31]4)=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][CH:17]=2)[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:7]=1[CH3:8].FC(F)(F)C(O)=[O:36].[OH-].[Na+].O>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH2:29][CH:30]([OH:31])[CH2:32][OH:36])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][CH:17]=2)[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:7]=1[CH3:8]
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccccc3)ccnc2cc1OCC1CO1
Reactant: O=C(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccccc3)ccnc2cc1OCC(O)CO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
4-(5,6-Dimethyl-2-phenyl-pyridin-3-yloxy)-6-methoxy-7-oxiranylmethoxy-quinoline (compound 334) (130 mg) was dissolved in methylene chloride (2 ml) to prepare a solution which was then brought to 0° C. Trifluoroacetic acid (1 ml) was added to the solution, and the mixture was stirred at 0° C. for 30 min and was then stirred at room temperature for 3 hr. The reaction solution was brought to 0° C., was stirred, and was made alkaline by the addition of a 10% aqueous sodium hydroxide solution. Water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (89 mg, yield 66%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1.[CH:11]([O:14][C:15]([NH:17][C@@H:18]([C:22]([S:25][CH:26]([CH3:28])[CH3:27])([CH3:24])[CH3:23])[C:19](O)=[O:20])=[O:16])([CH3:13])[CH3:12]>>[CH3:2][O:3][C:4]([C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:19](=[O:20])[C@@H:18]([NH:17][C:15]([O:14][CH:11]([CH3:13])[CH3:12])=[O:16])[C:22]([S:25][CH:26]([CH3:28])[CH3:27])([CH3:23])[CH3:24])=[O:10]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: CC(C)OC(=O)N[C@H](C(=O)O)C(C)(C)SC(C)C
Agent: Cl
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)OC(C)C)C(C)(C)SC(C)C
Yield: 88.2 %

Procedure:
Reaction of 0.54 g of (L)-proline methyl ester hydrochloride and 0.89 g of 2-(R)-isopropoxycarbonylamino-3-isopropylsulfanyl-3-methyl-butyric acid according to the procedure described for example 91b afforded 1.10 g (88%) of the title compound as a colorless oil. (+)-APCI-MS: 389 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]#[CH:14])[CH:6]=[CH:7][C:8]=1[O:9][C:10](=[O:12])[CH3:11].[Cl:15][C:16]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:17]=1[CH2:18][SH:19].[Na]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][C:10](=[O:12])[CH3:11])/[CH:13]=[CH:14]\[CH:18]([S:19][CH:18](/[CH:14]=[CH:13]\[C:5]1[CH:6]=[CH:7][C:8]([O:9][C:10](=[O:12])[CH3:11])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:17]1[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:16]=1[Cl:15])[C:17]1[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:16]=1[Cl:15]
Reactant: COc1ccc(CS)c(Cl)c1
Reactant: C#Cc1ccc(OC(C)=O)c(OC)c1
Agent: [Na]
Product: COc1ccc(C(/C=C\c2ccc(OC(C)=O)c(OC)c2)SC(/C=C\c2ccc(OC(C)=O)c(OC)c2)c2ccc(OC)cc2Cl)c(Cl)c1

Procedure:
A solution of 3-methoxy-4-acetoxyphenylacetylene (0.02 mol), 2-chloro-4-methoxybenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) is subjected to the General Procedure to form (Z)-3-methoxy-4-acetoxystyryl-2-chloro-4-methoxybenzylsulfide. The title compound is obtained following oxidation of the sulfide, according to the General Procedure.
Reaction SMILES: [OH:1][CH2:2][P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].[H-].[Na+].Cl[CH:14]=[C:15]([CH3:17])[CH3:16].O>C1COCC1>[CH3:16][C:15](=[CH2:14])[CH2:17][O:1][CH2:2][P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6]
Reactant: CCOP(=O)(CO)OCC
Reactant: CC(C)=CCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=C(C)COCP(=O)(OCC)OCC
Reaction time: 1 h

Procedure:
Diethyl hydroxymethylphosphonate (3 g, 17.8 mmol, 1 eq) is dissolved in 50 ml of THF to which sodium hydride (0.43 g, 17.8 mmol, 1 eq) is added. 1-chloro-2-methylpropene (1.62 g, 17.8 mmol, 1 eq) is then added. After one hour under magnetic stirring, at ambient temperature and in a nitrogen atmosphere, hydrolysis is performed with 100 ml of water. Extraction is performed with ether (3×50 ml). The organic phases are collected, washed with 100 ml of a saturated sodium chloride solution and dried on sodium sulphate. After evaporation of the solvent, the residual oil obtained is purified by silica gel chromatography (Eluent=ethyl acetate).
Reaction SMILES: [CH2:1]([CH:4]1[NH:8][S:7](=[O:10])(=[O:9])[NH:6][C:5]1=[O:11])[CH2:2][CH3:3].[C:12]1([CH2:18]Br)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:12]1([CH2:18][N:6]2[C:5](=[O:11])[CH:4]([CH2:1][CH2:2][CH3:3])[NH:8][S:7]2(=[O:9])=[O:10])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: CCCC1NS(=O)(=O)NC1=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: Cc1ccccc1
Product: CCCC1NS(=O)(=O)N(Cc2ccccc2)C1=O
Yield: 39.2 %

Procedure:
To a mixture of 4-propyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (5.0 g, 28.25 mmol) suspended in 150 ml of toluene was added phenylmethyl bromide (5.32 g, 31.03 mmol) and tetrabutylammonium bromide (0.9 g, 0.28 mmol). The resulting mixture was refluxed for 19 hours, cooled, filtered, and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography to afford 2.97 g (39%) of 2-phenylmethyl-4-propyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula IX: R1 =H; R2 =propyl) as a solid, m.p., 63.5°-65.5° C.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([C:6]([C:8]2[CH:32]=[CH:31][C:11]([O:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C@H:25]([O:29][CH3:30])[C:26]([OH:28])=[O:27])=[CH:20][CH:19]=3)=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.[NH2:35][OH:36]>C(O)C>[F:1][C:2]1[CH:34]=[CH:33][C:5]([C:6](=[N:35][OH:36])[C:8]2[CH:32]=[CH:31][C:11]([O:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C@H:25]([O:29][CH3:30])[C:26]([OH:28])=[O:27])=[CH:20][CH:19]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CO[C@@H](Cc1ccc(C#CCCCOc2ccc(C(=O)c3ccc(F)cc3)cc2)cc1)C(=O)O
Reactant: NO
Solvent: CCO
Product: CO[C@@H](Cc1ccc(C#CCCCOc2ccc(C(=NO)c3ccc(F)cc3)cc2)cc1)C(=O)O
Reaction time: 8 h

Procedure:
(2S)-3-(4-{5-[4-(4-Fluoro-benzoyl)-phenoxy]-pent-1-ynyl}-phenyl)-2-methoxy-propionic acid from Example 25 (1 eq) was mixed with Hydroxylamine chlorydrate (4 eq), pyrydine (10 eq) and Ethanol (2 ml) and the mixture reaction was stirred overnight. The ethanol was evaporated under vacuo and HCl 0.5% was added to the residue to pH=3. Extracted with Ethyl Acetate and concentrated to give the title product as a mixture of two oximes. MS(ES) for C28H26FNO5 [M+H]+: 476.2, [M−H]−: 474.2.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[CH:10]=[N:11][CH:12]=[C:13]([Cl:16])[C:14]=1Cl.C(N(CC)CC)C>CN1C(=O)CCC1>[Cl:16][C:13]1[CH:12]=[N:11][CH:10]=[C:9]([Cl:8])[C:14]=1[N:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: Clc1cncc(Cl)c1Cl
Reactant: CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: CN1CCN(c2c(Cl)cncc2Cl)CC1
Yield: 66.2 %

Procedure:
General procedure C was followed using N-methylpiperazine (27 mg, 0.27 mmol), 3,4,5-trichloropyridine (50 mg, 0.27 mmol), triethylamine (0.76 μL, 0.54 mmol) and NMP (1.5 mL). The crude product was purified by flash column chromatography on silica gel (hexane/EtOAc, 1:1) to furnish the title compound as a colourless oil (44 mg, 65%), umax (CHCl3)/cm−1 2942, 2849, 2803, 1558, 1449, 1289, 1151; m/z (ESI) C10H14Cl2N3 requires 246.0559, found [M+H]+ 246.0560.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][C:9](=O)[CH2:8][CH2:7]2.[CH2:13]([NH:16][CH2:17][CH2:18][CH3:19])[CH2:14][CH3:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([N:16]([CH2:17][CH2:18][CH3:19])[CH2:13][CH2:14][CH3:15])[CH2:8][CH2:7]2
Reactant: O=C1CCc2cccc(Br)c2C1
Reactant: CCCNCCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCN(CCC)C1=Cc2c(Br)cccc2CC1

Procedure:
To a solution of 8-bromo-2-tetralone (3.0 gm, 13.3 mMol) in toluene (25 mL) were added di-n-propylamine (3.5 mL, 26 mMol) and p-toluenesulfonic acid (100 mg, 0.52 mMol). The reaction was heated to reflux, water being collected in a Dean-Stark trap. After four hours the reaction was concentrated in vacuo to give 8-bromo2-dipropylamino-3,4-dihydronaphthalene as a dark liquid which was immediately dissolved in methanol (50 mL) and acetic acid (5 mL). To this solution was then added sodium borohydride (2.0 gm, 52.9 mMol), and the mixture was stirred 18 hours at room temperature.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:17][C:18]([CH3:24])([CH3:23])[C:19]([O:21][CH3:22])=[O:20])=[CH:4][CH:3]=1.Br[CH2:28][C:29]1[N:34]=[C:33]2[CH:35]=[CH:36][O:37][C:32]2=[CH:31][CH:30]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:28][C:29]4[N:34]=[C:33]5[CH:35]=[CH:36][O:37][C:32]5=[CH:31][CH:30]=4)=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH2:17][C:18]([CH3:24])([CH3:23])[C:19]([O:21][CH3:22])=[O:20])=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(C)Cc1cc2cc(O)ccc2n1Cc1ccc(Cl)cc1
Reactant: BrCc1ccc2occc2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)C(C)(C)Cc1cc2cc(OCc3ccc4occc4n3)ccc2n1Cc1ccc(Cl)cc1

Procedure:
A solution of 440 mg(1.18 mmol) of methyl 3-[1-(4-chlorobenzyl) -5-hydroxyindol-2-yl]-2,2-dimethylpropanoate, 5(bromomethyl)furo[3,2-b]pyridine (274 mg (1.3 mmol) from Step 3), and 772 mg (2.4 mmol) of Cs2CO3 in 6 mL of acetonitrile was stirred at r.t. for 18 hr. The reaction was diluted with aqueous NH4OAc 25% w/v (50 mL) and the mixture was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The resulting residue was purified by chromatography on silica gel eluted with 25-30 % EtOAc in hexane to give the title compound as a colorless gum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH3:14])=[N:12][NH:11][C:10](=O)[C:9]=2[C:16]2[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=2[F:23])=[CH:4][CH:3]=1.P(Cl)(Cl)([Cl:26])=O>>[Cl:26][C:10]1[N:11]=[N:12][C:13]([CH3:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:9]=1[C:16]1[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=1[F:23]
Reactant: Cc1n[nH]c(=O)c(-c2c(F)cccc2F)c1-c1ccc(Cl)cc1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1nnc(Cl)c(-c2c(F)cccc2F)c1-c1ccc(Cl)cc1
Temperature: 110 °C
Reaction time: 4 h

Procedure:
7.61 g of 5-(4-chlorophenyl)-4-(2,6-difluoropheyl)-6-methyl-2H-pyridazin-3-one and 40 ml of phosphorus oxychloride were mixed and stirred at 110° C. for 4 hours. There action mixture was allowed to cool down to room temperature and concentrated under reduced pressure. To the residue was added ethyl acetate and ice water, and was separated to two layer. The organic layer was washed sequentially with water and saturated brine, and dried over anhydrous sodium sulfate, then, concentrated under reduced pressure, to obtain 8.52 g of 3-chloro-5-(4-chlorophenyl)-4-(2,6-difluorophenyl)-6-methyl pyridazine (hereinafter, referred to as compound (xiv) of the present invention).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH:7](O)[CH2:6][CH2:5]2.N1C=CC=CC=1.C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH:6]=[CH:5]2
Reactant: OC1CCc2cc(Br)ccc21
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Brc1ccc2c(c1)C=CC2
Yield: 46.4 %

Procedure:
A 1 L three-neck round bottom flask equipped with a condenser, magnetic stir bar, nitrogen inlet, and a thermometer was charged with 5-bromo-1-indanol (56.5 g, 0.265 mol), toluene (300 mL), pyridine (250 mL, 3.1 mol), and p-toluenesulfonyl chloride (55.3 g, 0.29 mol). The mixture was stirred and heated to reflux while dehydration progress was followed by GC. After 7 hours at reflux the dark colored reaction mixture was cooled, quenched by pouring over ice-water (700 mL) containing HCl (12M, 200 mL) and extracted several times with diethyl ether (3×250 mL). The combined diethyl ether extracts were washed repeatedly with water, 5% sodium bicarbonate (aqueous), and water then dried over anhydrous magnesium sulfate. Evaporation of diethyl ether followed by vacuum distillation (80° C./0.5 mm Hg) gave 5-bromoindene (24.0 g, 99+% purity by GC) as a colorless oil. 1HNMR (CD2Cl2, 500 MHz) δ7.59 (br s, 1H); 7.38 (dd, JAB=1.5, 8 Hz, 1H), 7.26 (d, JAB=8 Hz, 1H); 6.84 (m, 1H); 6.56 (m, 1H); 3.39 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][CH:7]([C:12]([O:14][CH3:15])=[O:13])[C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.Br[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]([O:30][CH2:31][CH3:32])[O:27][CH2:28][CH3:29])=[CH:22][CH:21]=1.[H-].[Na+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([CH:26]([O:27][CH2:28][CH3:29])[O:30][CH2:31][CH3:32])=[CH:24][CH:25]=2)([C:8]([O:10][CH3:11])=[O:9])[C:12]([O:14][CH3:15])=[O:13])=[CH:16][CH:17]=1
Reactant: COC(=O)C(Cc1ccc(Br)cc1)C(=O)OC
Reactant: CCOC(OCC)c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(OCC)c1ccc(CC(Cc2ccc(Br)cc2)(C(=O)OC)C(=O)OC)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A solution of dimethyl 2-(4-bromobenzyl)malonate (4.2 g), 1-(bromomethyl)-4-(diethoxymethyl)benzene (4 g) in DMF (50 mL) was treated with NaH (0.8 g, 60% in mineral oil). The mixture was stirred for 2 h at 60° C., and then quenched with 100 mL of 50% saturated NH4Cl. The product was extracted with 200 mL of 2:1 hexane/EtOAc. The extract was dried over Na2SO4 and concentrated, and dried under vacuum to give the title compound which was used without further purification.
Reaction SMILES: [Na].[C:2]([O:10]CC)(=[O:9])[CH2:3][C:4]([O:6]CC)=[O:5].CS(O[CH2:18][CH2:19][CH2:20][CH2:21][C:22]#[CH:23])(=O)=O.O>C(O)C>[CH2:23]([CH:3]([C:4]([OH:6])=[O:5])[C:2]([OH:10])=[O:9])[CH2:22][CH2:21][CH2:20][C:19]#[CH:18]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: C#CCCCCOS(C)(=O)=O
Agent: [Na]
Solvent: CCO
Solvent: O
Product: C#CCCCCC(C(=O)O)C(=O)O
Reaction time: 0.5 h

Procedure:
Sodium (1.2 g) was dissolved in dry ethanol (200 ml). Diethyl malonate (7.8 ml) was added and the mixture was stirred for 30 minutes and hex-5-ynyl methanesulphonate (9.0 g) was added. The mixture was stirred and refluxed for 1 hour. The mixture was cooled and the volume was reduced in vacuo. The mixture was poured into water and the aqueous mixture was extracted with diethyl ether. The ethereal extracts were washed with water and dried over anhydrous magnesium sulphate. The solvent was removed in vacuo. The crude ester was added to a solution of aqueous sodium hydroxide solution (100 ml of 15% solution) and methanol (50 ml) and the mixture was stirred at 20° for 24 hours. The mixture was extracted with diethyl ether. The aqueous alkaline phase was acidified with hydrochloric acid and the mixture was extracted with diethyl ether. The ethereal extracts were dried over anhydrous magnesium sulphate. The solvent was removed in vacuo. 2-(Hex-5-ynyl)malonic acid was obtained as a colourless solid (4.5 g) and was used without further purification.
Reaction SMILES: [CH:1](O)=[O:2].C(OC(=O)C)(=O)C.[Br:11][C:12]1[CH:13]=[CH:14][C:15]2[NH:22][CH2:21][CH2:20][CH2:19][C:18]([C:23]([O:25][CH3:26])=[O:24])=[CH:17][C:16]=2[CH:27]=1>C1COCC1>[Br:11][C:12]1[CH:13]=[CH:14][C:15]2[N:22]([CH:1]=[O:2])[CH2:21][CH2:20][CH2:19][C:18]([C:23]([O:25][CH3:26])=[O:24])=[CH:17][C:16]=2[CH:27]=1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2NCCC1
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C1=Cc2cc(Br)ccc2N(C=O)CCC1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
Formic acid (5.96 ml) was added to acetic anhydride (12.2 ml) at 0° C. and then the mixture was stirred under nitrogen atmosphere at 55° C. for 2 hours. After cooling to 0° C., THF (150 ml) was added, and further a solution of methyl 8-bromo-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxylate (8.5 g) in THF (100 ml) was added dropwise under nitrogen atmosphere. The mixture was returned to room temperature and stirred for 5 hours, after which the solvent was distilled off under reduced pressure. The reaction material was diluted with ethyl acetate, followed by washing with saturated sodium bicarbonate, water and saturated brine. The resultant was dried with magnesium sulfate, after which the solvent was distilled off under reduced pressure, and the resulting residue was washed with hexane to give methyl 8-bromo-1-formyl-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxylate (8.3 g) as colorless crystals.
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.CON(C)[C:35](=[O:43])[C:36]1[CH:41]=[CH:40][C:39]([CH3:42])=[N:38][CH:37]=1>C1COCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([N:8]([C:7]2[C:2]([C:35]([C:36]3[CH:37]=[N:38][C:39]([CH3:42])=[CH:40][CH:41]=3)=[O:43])=[N:3][CH:4]=[C:5]([Cl:26])[CH:6]=2)[CH2:23][O:24][CH3:25])(=[O:11])=[O:10])=[CH:13][C:14]=1[C:19]([F:22])([F:21])[F:20]
Reactant: CON(C)C(=O)c1ccc(C)nc1
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C(=O)c1ccc(C)nc1)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 33.7 %

Procedure:
To a solution of N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (90 mg, 0.2 mmol) in 2.0 mL of THF under nitrogen atmosphere at −78° C. was added drop-wise 0.3 mL (0.6 mmol) of isopropylmagnesium chloride. The mixture was then stirred for 10 min at −78° C. followed by warming to room temperature and stirred at that temperature for 30 min. The mixture was cooled to 0° C. (ice water) and a solution of N-methoxy-6, N-dimethyl-nicotinamide (72 mg, 0.4 mmol) in 1 mL of THF was added. The mixture was stirred at room temperature for 3 hours, quenched with 1M HCl and neutralized with 1M NaOH until pH was 9. The mixture was extracted with ethyl acetate, dried and concentrated. The residue was purified by flash column (silica gel, 50% ethyl acetate in hexane) to afford 36 mg of 4-chloro-N-[5-chloro-2-(6-methyl-pyridine-3-carbonyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide as an off white solid. MS: (M+H)/z=534.0.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12](=[O:18])[N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[CH3:19][NH2:20]>>[NH2:1][C:2]1[CH:11]=[C:10]([C:12]([N:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[O:18])[CH:9]=[CH:8][C:3]=1[C:4]([NH:20][CH3:19])=[O:6]
Reactant: CN
Reactant: CCN(CC)C(=O)c1ccc(C(=O)OC)c(N)c1
Product: CCN(CC)C(=O)c1ccc(C(=O)NC)c(N)c1
Temperature: 90 °C
Reaction time: 24 h
Yield: 69.8 %

Procedure:
In an autoclave a mixture of methyl 2-amino-4-(diethylcarbamoyl)benzoate (490 mg, 1.96 mmol) and methylamine solution (33% in ethanol; 25 ml, 200 mmol) was stirred for 24 hrs at 90° C. The reaction mixture was concentrated. The crude product was purified by silica gel chromatography using EtOAc as eluent, providing the title compound as white solid (341 mg, 70%).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)([O-])[O-].[K+].[K+].Br[CH2:16][C:17]1[C:21]([CH2:22]Br)=[CH:20][S:19][CH:18]=1>CN(C)C=O>[CH:18]1[S:19][CH:20]=[C:21]2[CH2:22][N:2]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:16][C:17]=12
Reactant: BrCc1cscc1CBr
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1Cc2cscc2C1
Temperature: 5 °C
Reaction time: 67 h
Yield: 22.2 %

Procedure:
13.18 g (0.0945 mol) of ethyl aminoacetate hydrochloride, 33.8 g (0.245 mol) of potassium carbonate and 60 ml of dimethylformamide are introduced, under argon, into a 250 ml round-bottomed flask. The mixture is cooled to 5° C. and 8.5 g (0.0315 mol) of 3,4bis(bromomethyl)thiophene in solution in 30 ml of dimethylformamide are added over 25 minutes. This mixture is stirred at room temperature for 67 h. The mixture is poured into 500 ml of ice-cold water and extracted 3 times with ether. The organic phases are washed 3 times with water, combined, dried, filtered and then concentrated under reduced pressure. There are obtained 1.57 g (0.007 mol) of product (yield 24%).
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]1[N:10]=[C:9]([C:11](OC)=[O:12])[O:8][N:7]=1)[CH2:2][CH3:3].[BH4-].[Na+]>CO>[CH2:1]([O:4][CH2:5][C:6]1[N:10]=[C:9]([CH2:11][OH:12])[O:8][N:7]=1)[CH2:2][CH3:3]
Reactant: CCCOCc1noc(C(=O)OC)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCOCc1noc(CO)n1
Reaction time: 0.25 h

Procedure:
To a solution of methyl 3-(propoxymethyl)-1,2,4-oxadiazole-5-carboxylate (2.05 g) in MeOH is added sodium borohydride (386 mg) at −10° C. and the mixture is stirred for 15 min at this temperature. The reaction mixture is quenched with ice, stirred for 20 min and extracted with EtOAc three times. The combined organic phases are dried over sodium sulfate and concentrated under reduced pressure. The resulting residue is purified by flash column chromatography (silica gel) to give the title compound as a solid.
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15](B2OC(C)(C)C(C)(C)O2)[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[C:6]([CH3:12])=[N:7][C:8]([CH3:11])=[CH:9][CH:10]=1.C([O-])(O)=O.[Na+].Br[C:32]1[CH:37]=[CH:36][N:35]([CH2:38][CH2:39][CH2:40][CH3:41])[C:34](=[O:42])[C:33]=1[C:43]#[N:44]>O1CCOCC1.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>[CH2:38]([N:35]1[CH:36]=[CH:37][C:32]([C:15]2[CH:14]=[CH:13][C:3]([O:4][C:5]3[C:6]([CH3:12])=[N:7][C:8]([CH3:11])=[CH:9][CH:10]=3)=[C:2]([F:1])[CH:16]=2)=[C:33]([C:43]#[N:44])[C:34]1=[O:42])[CH2:39][CH2:40][CH3:41]
Reactant: CCCCn1ccc(Br)c(C#N)c1=O
Reactant: Cc1ccc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2F)c(C)n1
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: [Na+]
Solvent: C1COCCO1
Product: CCCCn1ccc(-c2ccc(Oc3ccc(C)nc3C)c(F)c2)c(C#N)c1=O
Yield: 51.7 %

Procedure:
To a solution of intermediate 12 (2 mmol) in 1,4-dioxane (6 ml) and a saturated solution of NaHCO3 (6 ml) was added intermediate 6 (0.51 g, 2 mmol). The resulting solution was degassed using a stream of nitrogen and to this was added Pd(PPh3)4 (0.231 mg, 0.2 mmol). The reaction was then microwaved in a sealed tube at 150° C. for 10 minutes. The resulting cooled reaction mixture was filtered through a pad of diatomaceous earth and concentrated in vacuo. The crude reaction mixture was then purified by column chromatography (silica gel; DCM to DCM/MeOH up to 3% as eluent). The desired fractions were collected and evaporated in vacuo to yield compound 2 (0.405 g, 52%).