Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[S:34][C:15]3[N:16]=[C:17]([C:26]4[CH:27]=[N:28][CH:29]=[C:30]([CH:33]=4)[CH:31]=[O:32])[N:18]=[C:19]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)[C:14]=3[CH:13]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O.C(Cl)Cl>ClCCCl>[O:23]1[CH2:24][CH2:25][N:20]([C:19]2[C:14]3[CH:13]=[C:12]([CH2:11][N:8]4[CH2:7][CH2:6][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:10][CH2:9]4)[S:34][C:15]=3[N:16]=[C:17]([C:26]3[CH:33]=[C:30]([CH2:31][OH:32])[CH:29]=[N:28][CH:27]=3)[N:18]=2)[CH2:21][CH2:22]1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(-c4cncc(C=O)c4)nc3s2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(Cc2cc3c(N4CCOCC4)nc(-c4cncc(CO)c4)nc3s2)CC1
Reaction time: 4 h
Yield: 38.8 %

Procedure:
5-(6-((4-(Methylsulfonyl)piperazin-1-yl)methyl)-4-morpholinothieno[2,3-d]pyrimidin-2-yl)nicotinaldehyde (95 mg) and sodium triacetoxyborohydride (55 mg) in dry 1,2-dichloroethane (10 mL) was heated at 40° C. overnight. A further portion of sodium triacetoxyborohydride (49 mg) was then added and heating continued for another 4 h. Water/CH2Cl2 work up then purification on silica yielded 232 (37 mg). NMR (CDCl3): 2.65-2.67 (m, 4H, 2×CH2), 2.80 (s, 3H, CH3), 3.27-3.30 (m, 4H, 2×CH2), 3.82 (s, 2H, CH2), 3.88-3.91 (m, 4H, 2×CH2), 3.97-4.0 (m, 4H, 2×CH2), 4.84 (s, 2H, CH2), 7.17 (s, H, ArH), 8.67 (s, H, ArH), 8.69 (s, H, ArH), 9.55 (s, H, ArH). MS: (ESI+): MH+ 505.18
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([CH:12]([CH3:27])[N:13]([S:16]([C:19]4[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=4)(=[O:18])=[O:17])[C:14]=2[CH:15]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3.C1CCCCC=1.B(Br)(Br)Br.CO>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:11]([CH:12]([CH3:27])[N:13]([S:16]([C:19]4[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=4)(=[O:18])=[O:17])[C:14]=2[CH:15]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: COc1ccc(S(=O)(=O)N2c3cc(F)ccc3-c3ccccc3C2C)cc1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Solvent: CO
Solvent: ClCCl
Product: CC1c2ccccc2-c2ccc(F)cc2N1S(=O)(=O)c1ccc(O)cc1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 30.7 %

Procedure:
To a stirred slurry of 3-fluoro-5-[(4-methoxyphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridine (262 mg, 0.68 mmol) in cyclohexene (1.38 mL, 14 mmol) under an inert atmosphere of nitrogen was added a 1 M solution of boron tribromide in dichloromethane (4.1 mL). The progress of the reaction was monitored by thin-layered chromatography and after 2.5 hours the reaction was deemed complete. The reaction contents were cooled to 0° C. and methanol was added slowly. The volatile components were removed in vacuo and the crude residue was purified by preparative liquid chromatography on a Biotage® 40 Mi column of prepacked silica gel (90 g), eluting with a gradient of 30%-50% methyl tert-butyl ether in hexane, to afford the title compound (77 mg, 30%) as a solid, m.p. 162-165° C.;
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[N:10]([O-])=[O:11].[Na+]>C(O)C.O>[CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[C:7]=1[N:10]=[O:11]
Reactant: Cc1cc(C)cc(O)c1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc(O)cc(C)c1N=O
Temperature: 0 °C
Yield: 71.6 %

Procedure:
750 ml of concentrated HClare added to a solution of 3,5-dimethyl phenol (80.6 g) in 750 ml of 95% ethyl alcohol. The mixture is cooled to 0° C. in an ice/methanol bath. While maintaining the temperature of the reaction mixture below 5° C. a solution of NaNO2 (69.0 g) in 150 ml of H2O is added dropwise to the reaction mixture. The mixture is stirred at 0° C. for more than an hour and then poured into 9 liters of water. The aqueous mixture is filtered to give a yellow solid which is recrystallized from hot methanol and filtered to give 71.45 grams of a yellow solid, M.P. 180°-181° C. (dec).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][N:8]([CH3:19])[CH2:9][CH2:10][O:11][C:12]1[C:17]([OH:18])=[CH:16][CH:15]=[CH:14][N:13]=1.C1(=O)O[CH2:23][CH2:22][O:21]1>CS(C)=O>[CH3:7][N:8]([CH3:19])[CH2:9][CH2:10][O:11][C:12]1[C:17]([O:18][CH2:23][CH2:22][OH:21])=[CH:16][CH:15]=[CH:14][N:13]=1
Reactant: CN(C)CCOc1ncccc1O
Reactant: O=C1OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CN(C)CCOc1ncccc1OCCO
Temperature: 58 °C

Procedure:
DMSO (17 L) and potassium carbonate (8.2 kg) were charged to the 100 L-glasslined reactor. The mixture was heated to 58° C. while stirring. 2-(2-Dimethylaminoethoxy)pyridin-3-ol (4.11 kg) was charged to the reactor during 25 minutes (gas evolution). The mixture was heated to 117° C. before the prepared ethylene carbonate solution was added through the manhood in portions. After 1 L ethylene carbonate solution was added IP-HPLC was taken to ensure that the title compound had started to form. The total addition of ethylene carbonate solution was made during 1 h 35 minutes. Temperature after the addition was 124° C. A HPLC sample was taken from the reaction mixture 10 minutes after finished addition. It showed 95% conversion to product. The reaction-mixture was allowed to cool to 70° C. before water (45 L) and sodium chloride (4.06 kg) was charged to the reactor. The mixture was then stirred for 20 minutes at 70° C. before cooled to RT. Ethyl acetate (137 L) was charged into a 328 L glass-lined reactor. The water mixture was transferred from the 100 L reactor to the 328 L reactor. The mixture was stirred for 25 minutes before the mechanical stirrer was turned off. After allowing the phases to separate for 40 minutes, the water-phase (65 L) was discharged. The mixture was heated to reflux and 102 L of ethyl acetate was distilled off. Toluene (72 L) was added and the mixture was heated to reflux again and 61 L of toluene/ethyl acetate was distilled off. The reaction mixture was then cooled to RT. The title compound was never isolated; it was directly used in Example 2C.
Reaction SMILES: [CH:1]([S:4]([N:7]1[C:11]2[CH:12]=[C:13]([C:16]3[N:17]=[C:18]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)[NH:19][C:20]=3[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH2:33])(=[O:6])=[O:5])([CH3:3])[CH3:2].[CH2:34](N(CC)CC)[CH3:35].ICC>CN(C)C=O>[CH:1]([S:4]([N:7]1[C:11]2[CH:12]=[C:13]([C:16]3[N:17]=[C:18]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:34][CH3:35])[CH2:29][CH2:28]4)[NH:19][C:20]=3[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH2:33])(=[O:5])=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)S(=O)(=O)n1c(N)nc2ccc(-c3nc(C4CCNCC4)[nH]c3-c3ccccc3)cc21
Reactant: CCN(CC)CC
Solvent: CCI
Solvent: CN(C)C=O
Product: CCN1CCC(c2nc(-c3ccc4nc(N)n(S(=O)(=O)C(C)C)c4c3)c(-c3ccccc3)[nH]2)CC1
Yield: 76 %

Procedure:
Stir a mixture of 1-isopropylsulfonyl-2-amino-6-(2-(piperidin-4-yl)-5-(phenyl)-imidazol-4-yl)-benzimidazole (0.574 g, 1.23 mmol), triethylamine (3.1 mmol), and iodoethane (1.54 mmol) in anhydrous dimethylformamide (5 mL) at room temperature for 6 hours. Partition the mixture between ethyl acetate and water. Extract the aqueous layer with ethyl acetate (3 times). Wash the combined organic layers sequentially with cold water (5 times) and saturated aqueous sodium chloride, dry over sodium sulfate, and concentrate under reduced pressure. Subject the residue to silica gel chromatography to provide the title compound in 76% yield. MS(ES+): m/z=493.2 (M+H)+
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]2[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.C([Li])CCC.[B:17](OC)([O:20]C)[O:18]C>O1CCCC1.CCCCCC>[CH:9]1([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([B:17]([OH:20])[OH:18])=[CH:3][CH:4]=2)[CH2:11][CH2:10]1
Reactant: Brc1ccc(CC2CC2)cc1
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: OB(O)c1ccc(CC2CC2)cc1
Temperature: -70 °C

Procedure:
1-Bromo-4-(cyclopropylmethyl)benzene (2.11 g) was dissolved in anhydrous tetrahydrofuran (20 ml) and cooled to -70° C. under an argon atmosphere. A 1.25M solution of n-butyl lithium in hexane (8.8 ml) was added at such a rate that the temperature did not exceed -65° C. with stirring, which was maintained for a further 30 minutes. Trimethyl borate was added slowly keeping the temperature below -60° C. and the reaction mixture was stirred for a further 1.5 hours at -70° C. After warming to -5° C., the reaction was quenched by the addition of a saturated aqueous solution of ammonium chloride (50 ml) and the organic phase was separated. The aqueous layer was extacted with ethyl acetate (2×30 ml) and combined organic phases were dried (MgSO4) and evaporated to give 4-(cyclopropylmethyl)phenylboronic acid (1.52 g); 1H NMR (d6 -DMSO): 0.2 (d, 2 H), 0.5 (d, 2 H), 0.9-1.07 (m, 1 H), 2.5 (partly obscured by DMSO), 7.2 (d, 2 H), 7.7 (d, 2 H); mass spectrum (-ve ESP) 175 (M-H)-.
Reaction SMILES: ClC1C=CC([N+]([O-])=O)=CC=1S([O-])=O.[Na+].[OH:15][CH2:16][CH2:17][S:18]([C:21]1[CH:26]=[CH:25][C:24](Cl)=[C:23]([N+:28]([O-])=O)[CH:22]=1)(=[O:20])=[O:19].P([O-])([O-])([O-])=O.[H][H]>O>[OH:15][CH2:16][CH2:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH2:28])[CH:22]=1)(=[O:19])=[O:20]
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)CCO)ccc1Cl
Reactant: [H][H]
Agent: O=P([O-])([O-])[O-]
Agent: O=[N+]([O-])c1ccc(Cl)c(S(=O)[O-])c1
Agent: [Na+]
Solvent: O
Product: Nc1cccc(S(=O)(=O)CCO)c1
Temperature: 85 °C

Procedure:
102.6 g of moist paste of 2-chloro-5-nitrophenyl 2-hydroxyethyl sulphone from Example 1 [or an equimolar amount of 4-chloro-3-nitrophenyl 2-hydoxyethyl sulphone] are stirred into 250 ml of water and 50 ml of the phosphate buffer solution described under Example 2. A small amount of a nonionic emulsifier and 5 g of palladium-oncharcoal catalyst are added. Hydrogenation with hydrogen is then carried out in an autoclave at 70° C. and approximately 40 bar. The reduction is monitored by chromatography. After the hydrogenation, and after releasing the pressure and flushing the reactor, the product is heated to 85° C. and clarified via a pressure filter. The filter is cooled to 0° C. and the crystalline 3-aminophenyl 2-hydroxyethyl sulphone is isolated by filtration. 53 g of single-substance product are obtained after drying.
Reaction SMILES: C[O:2][C:3](=[O:18])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:7][CH:6]=1.Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29][CH3:30])=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+].Cl>CCOC(C)=O.C(#N)C>[CH2:27]([C:24]1[CH:23]=[CH:22][C:21]([CH2:20][N:13]([S:14]([CH3:17])(=[O:16])=[O:15])[CH2:12][CH2:11][C:8]2[CH:9]=[CH:10][C:5]([CH2:4][C:3]([OH:2])=[O:18])=[CH:6][CH:7]=2)=[CH:26][CH:25]=1)[CH2:28][CH2:29][CH3:30]
Reactant: COC(=O)Cc1ccc(CCNS(C)(=O)=O)cc1
Reactant: CCCCc1ccc(CBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCCc1ccc(CN(CCc2ccc(CC(=O)O)cc2)S(C)(=O)=O)cc1

Procedure:
A mixture of [4-[2-methanesulfonylamino-ethyl]-phenyl]-acetic acid methyl ester (38 mg, 0.14 mmol), 1-bromomethyl-4-butylbenzene (35 mg, 0.15 mmol), K2CO3 (25 mg, 0.182 mmol) and acetonitrile was heated at reflux for 1 h. Aqueous HCl (2 mL, 1N) and EtOAc (30 mL) were added to the reaction. The organic solution was dried with MgSO4, filtered, and concentrated in vacuo. The product was purified by flash chromatography (30% EtOAc/hexanes) to afford the title compound of Step A. 1H NMR (400 MHz, CDCl3) δ 7.28-7.05 (m, 8H), 4.37 (s, 2H), 3.65 (s, 3H), 3.58 (s, 2H), 3.26 (t, 2H), 2.77 (t, 2H), 2.69 (s, 3H), 2.60 (t, 2H), 1.59 (m, 2H), 1.37 (m, 2H), 0.94 (t, 3H).
Reaction SMILES: O=S(Cl)Cl.[NH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([C:15]([F:18])([F:17])[F:16])[CH:7]=1.[CH3:19]O>>[NH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:12][CH3:19])=[O:11])=[C:8]([C:15]([F:16])([F:17])[F:18])[CH:7]=1
Reactant: CO
Reactant: Nc1ccc(C(=O)O)c(C(F)(F)F)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(N)cc1C(F)(F)F
Yield: 64 %

Procedure:
SOCl2 (1.1 mL, 14.62 mmol, 1 equiv.) was added to a solution of 4-amino-2-trifluoromethylbenzoic acid (3 g, 14.62 mmol, 1 equiv.) in 40 mL of MeOH and the reaction mixture was refluxed overnight. Solvent was removed in vacuo and the residue was taken into EtOAc and washed with sat. NaHCO3 (×2), brine and dried over MgSO4, and concentrated to give 2.06 g (Yield=64%) of product as a clear oil.
Reaction SMILES: Cl.[CH3:2][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH:8]1[CH2:12][CH2:11][NH:10][CH2:9]1.F[C:14]1[CH:15]=[CH:16][C:17]([N+:21]([O-:23])=[O:22])=[C:18]([CH3:20])[CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH3:2][CH:3]1[CH2:7][CH2:6][CH2:5][N:4]1[CH:8]1[CH2:12][CH2:11][N:10]([C:14]2[CH:15]=[CH:16][C:17]([N+:21]([O-:23])=[O:22])=[C:18]([CH3:20])[CH:19]=2)[CH2:9]1
Reactant: CC1CCCN1C1CCNC1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1[N+](=O)[O-]
Temperature: 85 °C

Procedure:
2-Methyl-[1,3′]bipyrrolidinyl hydrochloride (Intermediate (ii) obtained above, 5.3 g, 21.6 mmol, 1.12 equiv.) was dissolved in anhydrous DMSO (30 mL). To this solution was added 5-fluoro-2-nitrotoluene (3.00 g, 18.78 mmol, 1 equiv.), followed by powdered potassium carbonate (8.9 g, 65 mmol). The suspension was heated on an oil bath to 85° C. for 4 h when the starting material was consumed as determined by TLC (5% MeOH in DCM) and LC/MS. To the suspension were added 20 mL of water and 50 mL of DCM. The two layers were separated, and the aqueous layer was extracted with DCM (20 mL×2). The combined DCM extracts were washed with sodium bicarbonate (20 mL), and brine (15 mL×2), dried (anhydrous potassium carbonate), filtered, and concentrated in vacuo. The crude product was purified on a silica gel column, eluted with 5% MeOH in DCM to get the title compound as a yellow solid after drying, 5.47 g (100%). MS: 290 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]=[C:10]([CH2:21][CH2:22][CH2:23]O)[C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=O)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:31][NH2:32]>ClCCl.CN(C1C=CN=CC=1)C.C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]=[C:10]2[CH2:21][CH2:22][CH2:23][N:32]([CH3:31])[C:11]2=[N:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1
Reactant: CN
Reactant: Cc1ccc(NC(=O)C(=CSc2ccc(F)cc2)CCCO)cc1
Agent: CN(C)c1ccncc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1ccc(N=C2C(=CSc3ccc(F)cc3)CCCN2C)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
687 mg (1.99 mmol) of 2-{[(4-fluorophenyl)sulphanyl]methylene}-5-hydroxy-N-(4-methylphenyl)-pentanamide (prepared by the method described in WO 2010/070910) are dissolved in 25 ml of dichloromethane, and 828 mg (3.98 mmol) of phosphorus pentachloride are added. After 12 h of stirring at room temperature, all volatile components are removed under reduced pressure and the residue is suspended in 9 ml of triethylamine. 36.4 mg (0.297 mmol) of DMAP and 4.97 ml of 2M methanamine in THF are added to the reaction mixture. The mixture is stirred in a CEM microwave at 80° C. for 60 min (divided into three microwave vessels). The reaction mixture is diluted with water and extracted with ethyl acetate, and the organic phase is washed with saturated aqueous sodium chloride solution and dried over sodium sulphate. Purification of the residue by column chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate) gives 7.6 mg of N-(3-{[(4-fluorophenyl)sulphanyl]methylene}-1-methylpiperidin-2-ylidene)-4-methylaniline.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([O:16]C)=[O:15])[C:5]2[CH:6]=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[CH3:18][S:19]([O-:21])=[O:20].[Na+].CNCCNC>CS(C)=O>[CH:11]([N:8]1[C:9]2[CH:10]=[C:2]([S:19]([CH3:18])(=[O:21])=[O:20])[CH:3]=[C:4]([C:14]([OH:16])=[O:15])[C:5]=2[CH:6]=[CH:7]1)([CH3:13])[CH3:12]
Reactant: COC(=O)c1cc(Br)cc2c1ccn2C(C)C
Reactant: CS(=O)[O-]
Agent: CNCCNC
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)n1ccc2c(C(=O)O)cc(S(C)(=O)=O)cc21
Temperature: 165 °C
Yield: 9.2 %

Procedure:
To a 10-mL microwave tube were added methyl 6-bromo-1-(1-methylethyl)-1H-indole-4-carboxylate (160 mg, 0.540 mmol), sodium methanesulfinate (80 mg, 0.702 mmol), DMSO (2 mL), and N,N′-dimethyl-1,2-ethanediamine (6.19 mg, 0.070 mmol), and the mixture was degassed for 5 min by bubbling N2. Copper(I) trifluoromethanesulfonate benzene complex (25.6 mg, 0.043 mmol) was added and the mixture was heated to 165° C. for 2 h with stirring. The mixture was filtered and the DMSO solution was purified using reverse-phase HPLC to give 14 mg of product as white solid. 1H NMR (400 MHz, DMSO-d6) ppm 1.51 (d, J=4.00 Hz, 6H), 4.90-5.11 (m, 1H), 7.13 (d, J=3.03 Hz, 1H), 7.98-8.08 (m, 1H), 8.15-8.23 (m, 1H), 8.32-8.46 (m, 1H), 13.19 (br. s., 1H). MS: (M+H)+=281.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=O)=[CH:5][CH:4]=1.[H-].[Na+].O1C2C=CC(C(C3C=C(OC)C=C(OC)C=3)=[CH:32][C:33]#[N:34])=CC=2OCC1>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:32][C:33]#[N:34])=[CH:5][CH:4]=1
Reactant: COc1cc(OC)cc(C(=CC#N)c2ccc3c(c2)OCCO3)c1
Reactant: COc1ccc(C(=O)c2ccc(OC)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C(=CC#N)c2ccc(OC)cc2)cc1
Yield: 69 %

Procedure:
Bis-(4-methoxy-phenyl)-methanone (2.42 g, 10 mmol), cyano-methylphosphonic acid diethyl ester (1.6 ml, 10 mmol) in anhydrous THF (10 ml), and sodium hydride (0.48 g, 10 mmol) were treated in the same manner as described above for the synthesis of 3-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-3-(3,5-dimethoxyphenyl)acrylonitrile. The crude material was purified by flash column chromatography to give 3,3-bis-(4-methoxy-phenyl)-acrylonitrile as a solid (1.84 g, 69%): 1H NMR (CDCl3) δ 7.39 (d, J=8.7 Hz, 1H, Ar), 7.25 (d, J=8.7 Hz, 1H, Ar), 6.95 (d,j=8.7 Hz, 1H, Ar), 6.88 (d, J=8.7 Hz, 1H, Ar), 5.54 (s, 1H, CH), 3.86, 3.83 (2s, 6H, CH3); 13C NMR (CDCl3) δ 162.3, 161.4, 160.9, 131.7, 131.3, 130.1, 129.5, 118.7, 113.9, 113.8, 91.5, 55.4, 55.3; Anal. Calcd. For C17H15NO2: C, 76.94; H, 5.70; N, 5.27. Found: C, 76.83; H, 5.64; N, 5.17.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11](=[O:30])[N:12]([CH2:14][CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([CH:27]=[CH:28][CH:29]=2)[O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:13]=1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[CH:10][C:11](=[O:30])[N:12]([CH2:14][CH2:15][CH2:16][C:17]2[CH:18]=[C:19]([CH:27]=[CH:28][CH:29]=2)[O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:13]=1
Reactant: CCOC(=O)COc1cccc(CCCn2cc(-c3ccccc3Br)ccc2=O)c1
Reactant: COc1ccccc1B(O)O
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: Cc1ccccc1
Solvent: O
Product: CCOC(=O)COc1cccc(CCCn2cc(-c3ccccc3-c3ccccc3OC)ccc2=O)c1
Temperature: 98 °C
Reaction time: 30 h
Yield: 30.2 %

Procedure:
A mixture of ethyl (3-{3-[5-(2-bromophenyl)-2-oxopyridin-1(2H)-yl]propyl}phenoxy)acetate (235 mg), (2-methoxyphenyl)boronic acid (114 mg), Na2CO3(159 mg), Pd(PPh3)4 (29 mg) in toluene (8 mL) and water (4 mL) was stirred under N2 gas atmosphere at 98° C. for 30 hours and cooled to ambient temperature. The reaction mixture was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. The aqueous layer of the reaction mixture was acidified with 1M HCl aqueous solution and extracted with EtOAc and the organic layer was washed with brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. The filtrate and the residue of the first extract was combined and evaporated in vacuo. The residue was dissolved in EtOH (20 mL). To the solution was added concentrated H2SO4 (1.5 mL) at ambient temperature and refluxed for 1 hour. The reaction mixture was cooled to ambient temperature, neutralized with saturated NaHCO3 aqueous solution and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered and evaporated in vacuo. The residue was purified by silica gel column chromatography (n-hexane:EtOAc=60:40) to afford ethyl (3-{3-[5-(2′-methoxybiphenyl-2-yl)-2-oxopyridin-1(2H)-yl]propyl}phenoxy)acetate (75 mg) as a colorless oil.
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].C(O[B:10]1[O:14][C:13]([CH3:16])([CH3:15])[C:12]([CH3:18])([CH3:17])[O:11]1)(C)C.[C-]#[C-].[Li+].[Li+].Cl.[CH2:24]1[CH2:28]O[CH2:26][CH2:25]1>>[CH3:16][C:13]1([CH3:15])[C:12]([CH3:17])([CH3:18])[O:11][B:10]([C:5]#[C:4][C:3]2[CH:2]=[CH:26][CH:25]=[CH:24][CH:28]=2)[O:14]1
Reactant: [Li]CCCC
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: C1CCOC1
Agent: Cl
Agent: [C-]#[C-]
Agent: [Li+]
Product: CC1(C)OB(C#Cc2ccccc2)OC1(C)C
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a stirred solution of IId′ (10 mL, 91 mmol) in dry THF (50 mL) at −78° C. was added n-BuLi (2.5 M in n-hexane, 40 mL, 100 mmol). Another flask was charged with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (18.7 mL, 91 mmol) in dry THF (100 mL) under argon atmosphere, and the reaction mixture was cooled to −78° C. The lithium acetylide from the first flask, which was cooled to −78° C., was slowly added to the second by a double-ended needle. The mixture was stirred at −78° C. for 2 hours, after which anhydrous HCl (105 mmol) was added. Then, reaction mixture was warmed to room temperature. After removal of the precipitated LiCl by filtration and removal of solvents under reduced pressure, the residue was purified by distillation (185-200° C./15 mbar) to afford IIId (16.05 g, 76%) as a colourless oil.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([N:5]2[C:9]([C:10]3[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=3[C:20]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:21]=3[CH:22]=[CH:23][C:24]([S:30]([NH:33][C:34]3[S:35][CH:36]=[CH:37][N:38]=3)(=[O:32])=[O:31])=[CH:25]4)=[CH:8][CH:7]=[N:6]2)[CH2:2]1.Cl[CH2:40]CCl.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CC(O)=O>[CH3:40][N:1]1[CH2:2][CH:3]([N:5]2[C:9]([C:10]3[CH:15]=[C:14]([C:16]([F:19])([F:17])[F:18])[CH:13]=[CH:12][C:11]=3[C:20]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:21]=3[CH:22]=[CH:23][C:24]([S:30]([NH:33][C:34]3[S:35][CH:36]=[CH:37][N:38]=3)(=[O:31])=[O:32])=[CH:25]4)=[CH:8][CH:7]=[N:6]2)[CH2:4]1
Reactant: ClCCCl
Reactant: O=S(=O)(Nc1nccs1)c1ccc2c(-c3ccc(C(F)(F)F)cc3-c3ccnn3C3CNC3)cccc2c1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CN1CC(n2nccc2-c2cc(C(F)(F)F)ccc2-c2cccc3cc(S(=O)(=O)Nc4nccs4)ccc23)C1
Reaction time: 0.03 h

Procedure:
A flask was charged with 5-(2-(1-(azetidin-3-yl)-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)naphthalene-2-sulfonamide (26.25 mg, 0.047 mmol), DCE (1 mL), AcOH (0.05 mL), and formaldehyde (37% aq.) (10.55 μl, 0.142 mmol). The mixture was stirred for 2 min, then sodium triacetoxyborohydride (20.03 mg, 0.094 mmol) was added in one portion. The resulting mixture was stirred for 3 h, then concentrated. The residue was dissolve in MeOH, and this solution was loaded onto a 500 mg SCX-2 ion exchange column (Biotage AB, Uppsala, SE). The column was eluted with methanol, then with 2N ammonia in methanol. The basic fraction was concentrated to afford 5-(2-(1-(1-methylazetidin-3-yl)-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)naphthalene-2-sulfonamide (23.53 mg, 0.041 mmol) as a beige-solid. 1H NMR (400 MHz, DMSO-d6) δ ppm=8.40 (s, 1H), 8.09 (d, J=7.9 Hz, 1H), 8.00 (d, J=6.9 Hz, 1H), 7.82 (s, 1H), 7.74 (d, J=8.4 Hz, 2H), 7.62-7.51 (m, 2H), 7.39 (d, J=6.8 Hz, 1H), 7.29 (s, 1H), 7.15 (d, J=4.1 Hz, 1H), 6.71 (d, J=4.0 Hz, 1H), 5.99 (s, 1H), 4.59 (td, J=7.3, 14.2 Hz, 1H), 3.66-3.59 (m, 1H), 3.33 (t, J=7.0 Hz, 1H), 3.09-2.95 (m, 2H), 2.27 (s, 3H). m/z (ESI) 570.2 (M+H)+.