Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[Cl:10].[Na+].[CH3:12][S:13]([O-:15])=[O:14].O>CS(C)=O>[Cl:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[S:13]([CH3:12])(=[O:15])=[O:14])[CH:6]=[O:7]
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Reactant: CS(=O)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CS(=O)(=O)c1ccc(C=O)cc1Cl
Temperature: 90 °C

Procedure:
To a solution containing 1.0 g of 4,3-dichlorobenzaldehyde in 45 ml of DMSO was added 1.93 g of methanesulfinicacid sodium salt with stirring at 90° C. The solution was stirred for 6 hours at 90° C. and then poured into water. Sodiumhydrogencarbonate was added and the product was extracted with ethyl acetate. The extract was evaporated to dryness in vacuo. The residue was triturated with 2-propanol, yield 1.06 g. 1H-NMR (DMSO-d6,400 MHz): 3.45 (s, 3 H, CH3), 8.09-8.27 (m, 3 H, Ar), 10.01 (d, 1 H, CHO).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[CH:12]=[C:13]([OH:15])[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[Cl:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>>[CH3:1][O:2][C:3](=[O:26])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:20][CH:21]=2)[CH:12]=[C:13]([O:15][C:31]2[CH:32]=[CH:33][C:28]([Cl:27])=[CH:29][CH:30]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COC(=O)C(CC(C)C)c1cc(O)cc(-c2ccc(C(F)(F)F)cc2)c1
Product: COC(=O)C(CC(C)C)c1cc(Oc2ccc(Cl)cc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Yield: 35 %

Procedure:
The title compound was prepared in 35% yield from 2-(5-hydroxy-4′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester (prepared in Example 15, step (f)) and 4-chlorobenzene boronic acid under the conditions described in Example 15, step (g).
Reaction SMILES: [I:1][C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[N:4]([CH3:17])[C:3]=1[C:18]([OH:20])=O.[N:21]1([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH2:26][CH2:25][CH:24]([OH:27])[CH2:23][CH2:22]1>>[OH:27][CH:24]1[CH2:23][CH2:22][N:21]([CH:28]2[CH2:33][CH2:32][N:31]([C:18]([C:3]3[N:4]([CH3:17])[C:5]([C:7]4[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:15])[F:16])[CH:8]=4)=[N:6][C:2]=3[I:1])=[O:20])[CH2:30][CH2:29]2)[CH2:26][CH2:25]1
Reactant: OC1CCN(C2CCNCC2)CC1
Reactant: Cn1c(-c2cccc(C(F)(F)F)c2)nc(I)c1C(=O)O
Product: Cn1c(-c2cccc(C(F)(F)F)c2)nc(I)c1C(=O)N1CCC(N2CCC(O)CC2)CC1

Procedure:
In analogy to the procedure described for example 2, 5-iodo-3-methyl-2-(3-trifluoromethyl-phenyl)-3H-imidazole-4-carboxylic acid (example 36) was coupled with [1,4′]bipiperidinyl-4-ol to give the title compound as light red solid. MS: 563.2 (MH+).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[F:29][C:30]1[CH:38]=[CH:37][C:36]2[C:35](=O)[CH2:34][CH2:33][C:32]=2[C:31]=1[C:40]#[N:41].[NH4+].[Cl-]>C1COCC1>[F:29][C:30]1[CH:38]=[CH:37][C:36]2[C:35](=[CH:2][O:3][CH3:4])[CH2:34][CH2:33][C:32]=2[C:31]=1[C:40]#[N:41]
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: N#Cc1c(F)ccc2c1CCC2=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC=C1CCc2c1ccc(F)c2C#N

Procedure:
To a suspension of (METHOXYMETHYL)TRIPHENYLPHOSPHONIUM CHLORIDE (1.3 g, 3.8 mmol) in THF (15 ml) was dropped n-Butyl Lithium (3.85 ml, 3.85 mmol) at −20° C. The mixture was stirred for 20 minutes before a THF solution of 5-Fluoro-1-oxo-2,3-dihydro-1H-indene-4-carbonitrile (450 mg, 2.6 mmol) was added into the reaction. TLC showed some green color spot right away. The reaction was then poured into NH4Cl, extracted with EtOAc, and flashed through silica gel. LC-MS (1E, m/z): 204 [M+1]+.
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([C:24](=[O:36])[N:25]([CH2:31][CH2:32][C:33](=[O:35])[NH2:34])[CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>ClCCl>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[C:33]([CH2:32][CH2:31][N:25]([CH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1)[C:24](=[O:36])[C:19]1[CH:18]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:22]=[C:21]([Cl:23])[CH:20]=1)(=[O:35])[NH2:34]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCC(N)=O)C2CCCC2)c1)c1ccncc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)CCN(C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1)C1CCCC1
Reaction time: 2 h

Procedure:
A solution of (2-{3-[(2-carbamoyl-ethyl)-cyclopentyl-carbamoyl]-5-chloro-phenoxy}-ethyl)-pyridin-4-yl-carbamic acid tert-butyl ester (0.074 g) in a mixture of dichloromethane (1 ml) and trifluoroacetic acid (1 ml) was stored at room temperature for 2 h and then concentrated under reduced pressure to give the title compound (0.060 g) as a colourless gum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:19])([CH3:18])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)=[C:4]([O:20]C)[CH:3]=1.[NH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[CH:26][C:27](=[O:33])[NH:28]2.B(Br)(Br)Br>>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5]([C:8]([CH3:18])([CH3:19])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]2[NH:22][C:23]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=2[CH:25]=[CH:26][C:27](=[O:33])[NH:28]3)=[C:4]([OH:20])[CH:3]=1
Reactant: COc1cc(Cl)ccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Reactant: Nc1cccc2[nH]c(=O)ccc12
Agent: BrB(Br)Br
Product: CC1(C)CC(O)(C(F)(F)F)C(Nc2cccc3[nH]c(=O)ccc23)c2cc(Cl)cc(O)c21
Yield: 1.4 %

Procedure:
Analogously to Example 2, the corresponding imine is produced starting from 1.0 g of 4-(4-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 492 mg of 5-aminoquinolin-2(1H)-one. 20 mg of the title compound is obtained by reaction of 300 mg of the imine with 3.2 ml of BBr3 (1N in dichloromethane).
Reaction SMILES: [Cl:1]CCl.[OH:4][C:5]1[C:10]([C:11]([OH:13])=O)=[CH:9][N:8]=[CH:7][CH:6]=1.S(Cl)(Cl)=O>C(N(CC)CC)C>[OH:4][C:5]1[C:10]([C:11]([Cl:1])=[O:13])=[CH:9][N:8]=[CH:7][CH:6]=1
Reactant: ClCCl
Reactant: O=C(O)c1cnccc1O
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: O=C(Cl)c1cnccc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 80 ml. of dichloromethane solution containing 9.8 g. of 4-hydroxynicotinic acid and 10 ml. of triethylamine was added dropwise 7 ml. of thionyl chloride with stirring under ice-cooling over a period of 20 minutes and the mixture was stirred for 2 hours at room temperature. The crystals thus formed were recovered by filtration, washed with a small amount of dichloromethane, and then dried to provide 4-hydroxynicotinoyl chloride.
Reaction SMILES: [CH2:1]([N:8]1[C@H:12]([C:13](O)=[O:14])[CH2:11][CH2:10][C@@H:9]1[C:16]([OH:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C.[CH3:26][NH2:27]>>[CH3:26][NH:27][C:13]([C@H:12]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C@@H:9]([C:16]([OH:18])=[O:17])[CH2:10][CH2:11]1)=[O:14]
Reactant: CN
Reactant: O=C(O)[C@H]1CC[C@@H](C(=O)O)N1Cc1ccccc1
Solvent: CC(=O)OC(C)=O
Product: CNC(=O)[C@@H]1CC[C@H](C(=O)O)N1Cc1ccccc1
Reaction time: 0.33 h

Procedure:
Cis-N-benzylpyrrolidine-2,5-dicarboxylic acid (41.3 g, 0.166 mole) and acetic anhydride (206.5 ml) were heated carefully together to 100°C; the solid gradually dissolved, and the mixture assumed a dark brown color. In typical experiments, solution was complete in 10-30 minutes, depending on the state of subdivision of the starting material. Heating time was minimized. Just before the last solid dissolved, the excess acetic anhydride was removed in vacuo, and the brown oily residue of crude cis-N-benzylpyrrolidine-2,5-dicarboxylic acid anhydride was taken up in 400 ml benzene. Anhydrous methylamine (0.33 mole as 9.9% solution in benzene) was added in two portions, and the mixture was heated on the steam bath for 45 minutes. After cooling, the crude cis-5-(N-methylcarbamyl)-1-benzylpyrrolidine-2-carboxylic acid (35.8 g) was collected by filtration, washed with benzene and recrystallized from ethanol. Yield: 31.4 g (72%), melting point 190°-192°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.[CH2:12]([O:14][C:15](=[O:26])[CH2:16][NH:17][C:18](=[O:25])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])[CH3:13]>>[CH2:12]([O:14][C:15](=[O:26])[CH2:16][NH:17][C:18](=[O:25])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:7](=[O:9])[C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=1)[CH3:13]
Reactant: CCOC(=O)CNC(=O)CCCCCN
Reactant: COc1ccc(C(=O)O)cc1
Product: CCOC(=O)CNC(=O)CCCCCNC(=O)c1ccc(OC)cc1

Procedure:
By working analogously to what described in example 2 and by using 4-methoxybenzoic acid (33 mmoles) and N-(6-aminohexanoyl)glycine ethyl ester (39.5 mmoles), prepared as described in example 3, N-[6-[(4-methoxybenzoyl)amino]hexanoyl]glycine ethyl ester was obtained as a crude product, used as such in the subsequent reactions.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.[C:9]1([C:15]([CH:17](Cl)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(N(CC)CC)C.C(O)C>[Cl:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:15](=[O:16])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: O=C(c1ccccc1)C(Cl)c1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(c1ccccc1)C(c1ccccc1)n1cc(Cl)cnc1=O
Yield: 40.3 %

Procedure:
A solution of 5-chloropyrimidin-2-one (406 mg) and desyl chloride (2-chloro-2-phenyl acetophenone) (692 mg) in triethylamine (1 ml) and ethanol (20 ml) was stirred at ambient temperature for one hour, then heated at reflux for 11/2 hours. After evaporation of solvents, the residue was dissolved in ethyl acetate (150 ml). The solution was washed with water (100 ml), dried (MgSO4) and evaporated to a foam which was crystallised from ethyl acetate to give the title pyrimidinone (393 mg,); m.p. 145°-146°; λmaxEtOH 230 nm (ε 15960), 250 nm (ε 15000), 335 nm (ε 4700), λinf 262.5 nm (ε 8400), 269 n, (ε 4420).
Reaction SMILES: C([Li])CCC.[CH2:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH3:7].[CH:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[C:15]1([CH:14]([OH:21])[CH:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH3:7])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=Cc1ccccc1
Reactant: CCc1ccccn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(c1ccccn1)C(O)c1ccccc1
Temperature: -60 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
n-Butyllithium (2.5 M, 15.0 mL, 36.0 mmol) is added drop wise to a solution of 2-ethylpyridine (4.1 mL, 36.0 mmol) in THF (56 mL) at −40° C. The resulting dark red solution is kept at −30° C. to −20° C. for 1 hour and then cooled to −60° C. A solution of benzaldehyde (3.7 mL, 36.0 mmol) in THF (10 mL) is added drop wise. The reaction mixture is allowed to warm up to 0° C. for 1 hour and then quenched with aqueous NH4Cl solution. The mixture is separated and the aqueous phase is extracted with ethyl acetate (2×50 mL). The extracts are combined, dried, concentrated and purified by column chromatography (hexane/ethyl acetate 10:1 to 1:1) to give 2 (7.0 g, 91%) as a yellow oil. This mixture contained two diastereoisomers (3:1). 1H NMR (300 MHz, CDCl3) for the major isomer: δ 1.14 (d, J=7.2 Hz, 3H), 2.98 (q, J=6.9 Hz, 1H), 4.70-4.75 (m, 1H), 5.13-5.16 (m, 1H), 6.80-7.39 (m, 8H), 8.34 (d, J=4.8 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=3[O:33][CH3:34])(=[O:25])=[O:24])=[C:16]([O:35][CH3:36])[CH:15]=2)=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CO[C:39]1C=CC(C)=C[C:40]=1S(Cl)(=O)=O>>[CH2:39]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=3[O:33][CH3:34])(=[O:25])=[O:24])=[C:16]([O:35][CH3:36])[CH:15]=2)=[O:13])=[CH:10][C:2]=1[F:1])[CH3:40]
Reactant: COc1ccc(C)cc1S(=O)(=O)Cl
Reactant: COc1ccc(C)cc1S(=O)(=O)N1CCc2c(OC)cc(C(=O)Nc3ccc(C(=O)O)c(F)c3)cc21
Product: CCOC(=O)c1ccc(NC(=O)c2cc(OC)c3c(c2)N(S(=O)(=O)c2cc(C)ccc2OC)CC3)cc1F

Procedure:
2-Fluoro-4-{[4-methoxy-1-(2-methoxy-5-methyl-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid, m/z (ES+): 515.37 (M+H+.), was prepared in analogy to example 14, steps 1 to 6. Step 5 was performed using 2-methoxy-5-methyl-benzenesulfonyl chloride and yielded 2-fluoro-4-{[4-methoxy-1-(2-methoxy-5-methyl-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 6.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9](N(OC)C)=[O:10])([CH3:4])([CH3:3])[CH3:2].[CH3:22][Mg+].[Br-]>C1COCC1>[C:1]([O:5][C:6](=[O:21])[NH:7][C@@H:8]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:9](=[O:10])[CH3:22])([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)[C@@H](NC(=O)OC(C)(C)C)c1ccccc1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=O)[C@@H](NC(=O)OC(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At 0° C., to a solution of (S)-tert-butyl(2-(methoxy(methyl)amino)-2-oxo-1-phenylethyl)carbamate (0.9 g, 3.06 mmol) in anhydrous THF (15 mL), was added MeMgBr (3M solution in Et2O, 2.0 mL, 6.1 mmol) and resultant mixture was allowed to warm and stirred at ambient temperature. After 2 hrs, the reaction was carefully quenched with saturated aqueous NH4Cl solution (10 mL), and the organic contents were extracted with CH2Cl2 (3×25 mL). The volatiles were removed under reduced pressure to afford (S)-tert-butyl(2-oxo-1-phenylpropyl)carbamate. The compound obtained is pure and no further purification is necessary. 1H NMR (300 MHz, CDCl3) δ 7.40-7.33 (m, 5H), 5.88 (bs, 1H), 5.28 (bs, 1H), 2.08 (s, 3H), 1.41 (s, 9H).
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:9][C:10]([F:30])([F:29])[O:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([N:21]2[CH2:26][CH2:25][CH:24]([O:27][NH2:28])[CH2:23][CH2:22]2)(=[O:20])=[O:19])=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:6]([O:5][C:3](=[O:4])[C:2]([NH:28][O:27][CH:24]1[CH2:23][CH2:22][N:21]([S:18]([C:15]2[CH:14]=[CH:13][C:12]([O:11][C:10]([F:30])([F:9])[F:29])=[CH:17][CH:16]=2)(=[O:19])=[O:20])[CH2:26][CH2:25]1)=[O:8])[CH3:7]
Reactant: CCOC(=O)C(=O)Cl
Reactant: NOC1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C(=O)NOC1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl chlorooxoacetate (0.145 ml, 1.30 mmol) was added to a solution of O-(1-(4-(trifluoromethoxy)phenylsulfonyl)piperidin-4-yl)hydroxylamine (390 mg, 1.15 mmol) and triethylamine (0.246 ml, 1.76 mmol) in CH2Cl2 (8 ml) and stirred at room temperature for 2 hours. The reaction mixture was diluted with CH2Cl2 and washed with aqueous NaHCO3 solution (10 ml) and concentrated in vacuo to give crude product of N-[1-(4-trifluoromethoxybenzenesulfonyl)piperidin-4-yloxy]oxalamic acid ethyl ester.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:42])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH2:35][C:36](N(OC)C)=[O:37])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][N:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].[CH3:43][Mg]Br.Cl>O1CCCC1>[O:42]=[C:17]1[C:16]([CH2:15][C:12]2[CH:11]=[CH:10][C:9]([C:4]3[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:14][CH:13]=2)=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]2[N:25]=[CH:26][N:27]=[C:19]2[N:18]1[C@H:28]1[CH2:33][CH2:32][C@H:31]([O:34][CH2:35][C:36](=[O:37])[CH3:43])[CH2:30][CH2:29]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)N(C)OC)CC2)c2ncnn12
Reactant: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(C)=O)CC2)c2ncnn12
Temperature: 70 °C
Reaction time: 3 h

Procedure:
2-[(trans-4-{6-[(2′-Cyanobiphenyl-4-yl)methyl]-5-oxo-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]-N-methoxy-N-methylacetamide (0.75 g) was dissolved in tetrahydrofuran (10 mL), and methylmagnesium bromide (1.0 M tetrahydrofuran solution, 4 mL) was added at room temperature. The reaction mixture was warmed to 70° C. and stirred for 3 hr. 1 N Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.48 g, 69%).
Reaction SMILES: Br[C:2]1[C:3]([F:17])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[CH:5]2.C(N(CC)CC)C.[C:25]([CH:27]1[CH2:29][CH2:28]1)#[CH:26]>C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH:27]1([C:25]#[C:26][C:2]2[C:3]([F:17])=[C:4]3[C:8](=[CH:9][CH:10]=2)[N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[N:6]=[CH:5]3)[CH2:29][CH2:28]1
Reactant: Fc1c(Br)ccc2c1cnn2C1CCCCO1
Reactant: C#CC1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Fc1c(C#CC2CC2)ccc2c1cnn2C1CCCCO1
Temperature: 120 °C
Yield: 56.4 %

Procedure:
In a high pressure tube, a mixture of 5-bromo-4-fluoro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (8.0 g, 26.8 mmol; Intermediate 21), PdCl2(PPh3)2 (3.7 g, 5.35 mmol), CuI (1.0 g, 5.35 mmol), and triethylamine (30 mL) was deoxygenated with three cycles of vacuum/nitrogen. Ethynylcyclopropane (8.9 g, 134 mmol) was added under N2 atmosphere. The tube was sealed and the reaction mixture was heated at 120° C. for 63 hours. Upon completion, the reaction mixture was diluted with ethyl acetate and filtered through Celite. The filtrate was concentrated in vacuo and the residue was purified by column chromatography on silica gel (0˜10% ethyl acetate in petroleum ether) affording the title compound (4.3 g). 1H NMR (400 MHz, DMSO-d6): δ 8.25 (s, 1H), 7.55 (d, 1H), 7.40 (dd, 1H), 5.88 (dd, 1H), 3.88-3.85 (m, 1H), 3.76-3.73 (m, 2H), 2.43-2.33 (m, 1H), 2.05-1.95 (m, 2H), 1.76-1.72 (m, 1H), 1.62-1.56 (m, 3H), 0.93-0.89 (m, 2H), 0.79-0.74 (m, 2H); LCMS: 285 (M+H)+.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5]2([CH2:11][S:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]2=3)[CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.Br[CH2:26][CH2:27][CH2:28][CH:29]([C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[CH:43]=1)[CH2:30][N:31]([CH3:41])[S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)(=[O:34])=[O:33]>C(#N)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:48][C:44]1[CH:43]=[C:42]([CH:29]([CH2:28][CH2:27][CH2:26][N:2]2[CH2:7][CH2:6][C:5]3([CH2:11][S:10][C:9]4[CH:12]=[CH:13][CH:14]=[CH:15][C:8]3=4)[CH2:4][CH2:3]2)[CH2:30][N:31]([CH3:41])[S:32]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)(=[O:34])=[O:33])[CH:47]=[CH:46][CH:45]=1
Reactant: CN(CC(CCCBr)c1cccc(Cl)c1)S(=O)(=O)c1ccccc1
Reactant: c1ccc2c(c1)SCC21CCNCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CN(CC(CCCN1CCC2(CC1)CSc1ccccc12)c1cccc(Cl)c1)S(=O)(=O)c1ccccc1
Temperature: 52 °C
Reaction time: 48 h
Yield: 42.7 %

Procedure:
Spiro(benzo[b] thiophene-3(2H),4'-piperidine) hydrochloride (16.5 mg, 0.068 mmol) and N,N-diisopropylethylamine (0.036 mL, 27 mg, 0.21 mmol) were added to a solution of N-(5-bromo-2-(3-chlorophenyl)pentyl)-N-methylbenzenesulfonamide (24.6 mg, 0.057 mmol) in 0.30 mL of acetonitrile, and the mixture was heated in an oil bath at 52° C. After 2 days, tetrabutylammonium iodide (5.5 mg, 0.011 mmol) was added and the reaction was continued for an additional 24 h. Without work-up, the reaction mixture was purified by preparative TLC. Elution with 30% ethyl acetate in dichloromethane gave 13.5 mg the title compound. 1NMR (400 MHz, CD3OD): δ 7.74 (d, 2H, J=8 Hz), 7.64 (tt, 1H, J=8, 1 Hz), 7.57 (t, 2H, J=8 Hz), 7.33-7.22 (m, 3H), 7.18 (d, 1H, J=8 Hz), 7.13-7.01 (m, 4H), 3.32-3.25 (m, 3H), 3.11 (dd, 1H, J=13, 8 Hz), 3.00-2.84 (m, 3H), 2.61 (s, 3H), 2.48-2.35 (m, 2H), 2.21 (bq, 2H, J=12 Hz), 1.99 (tt, 2H, J=13, 4 Hz), 1.84-1.75 (m, 3H), 1.67-1.56 (m, 1H), 1.52-1.34 (m, 2H). Mass spectrum (ESI): m/z=555 (M+1).
Reaction SMILES: O.O[CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14](=[O:16])[CH3:15])[CH2:4][CH2:5][CH3:6].Cl.[H][H]>[Pd].C(O)C>[CH2:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14](=[O:16])[CH3:15])[CH2:4][CH2:5][CH3:6]
Reactant: [H][H]
Reactant: CCCC(O)c1ccccc1NC(C)=O
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCCCc1ccccc1NC(C)=O
Yield: 94 %

Procedure:
A suspension of 10% (w/w) palladium on carbon (7.8 g, wet with an additional 50% by weight of water) in absolute ethanol (625 ml) containing N-[2-(1-hydroxybutyl)phenyl]acetamide (156 g) was prepared, and concentrated hydrochloric acid (3.2 ml) was added. The mixture was shaken under a positive pressure of about 345,000 Pascals (50 pounds per square inch gauge reading) of hydrogen gas. When hydrogen uptake had ceased (in about 24 hours), the mixture was filtered through diatomaceous earth, and the filtrate was concentrated at reduced pressure to afford 135.3 grams (94% yield) of the title compound as a white solid, m.p. 96.5°-99.5°. This material was used in step (f) without further purification.
Reaction SMILES: C([N:4]1[C:8]2=[N:9][C:10](Br)=[CH:11][CH:12]=[C:7]2[C:6]([C:14]#[N:15])=[CH:5]1)(=O)C.C(N(CC)CC)C.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[Cl:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1B(O)O>O1CCOCC1>[Cl:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1[C:10]1[N:9]=[C:8]2[NH:4][CH:5]=[C:6]([C:14]#[N:15])[C:7]2=[CH:12][CH:11]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: CC(=O)n1cc(C#N)c2ccc(Br)nc21
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: N#Cc1c[nH]c2nc(-c3ccccc3Cl)ccc12
Temperature: 100 °C
Reaction time: 8 h
Yield: 59.1 %

Procedure:
In a 100 mL round-bottomed flask, 1-acetyl-6-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (250 mg, 947 μmol, Eq: 1.00), triethylamine (575 mg, 792 μl, 5.68 mmol, Eq: 6) and X-PHOS (181 mg, 379 μmol, Eq: 0.40) were combined with dioxane (25.0 ml) to give a colorless solution. [1,1′-bis(diphenylphosphino)ferrocene]dichloropaladium(II) (173 mg, 237 μmol, Eq: 0.25) and 2-chlorophenylboronic acid (296 mg, 1.89 mmol) were added and the resultant mixture was degassed for 5 minutes under Nitrogen. The reaction mixture was heated to 100° C. and stirred overnight. The reaction mixture was poured into 50 mL H2O and extracted with EtOAc (3×50 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 40 g, 20% to 30% EtOAc in hexanes) to give 6-(2-chlorophenyl)-1H-pyrrolo[2,3-b]pyridine-3-carbonitrile (142 mg, 59%).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([CH:8]=[CH:9][C:10]#[N:11])=[CH:6][CH:5]=1)(O)=[O:2].S(Cl)([Cl:16])=O.C1(C)C=CC=CC=1>CN(C)C=O>[Cl:16][C:1]([C:4]1[CH:13]=[CH:12][C:7]([CH:8]=[CH:9][C:10]#[N:11])=[CH:6][CH:5]=1)=[O:2]
Reactant: O=S(Cl)Cl
Reactant: N#CC=Cc1ccc(C(=O)O)cc1
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: N#CC=Cc1ccc(C(=O)Cl)cc1
Yield: 48.4 %

Procedure:
14.3 g (83 mmols) of 4-carboxycinnamonitrile, 11.9 g (100 mmols) of thionyl chloride, 100 ml of toluene and 0.18 ml of N,N-dimethylformamide are boiled under reflux for 15 minutes and then evaporated. Recrystallising the residue twice from carbon tetrachloride gives 7.7 g (48% of theory) of 4-chloroformylcinnamonitrile in the form of yellow crystals; melting point 161.0° C.