Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrBr.O=[C:4]([CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:8][CH:7]=1.[N:17]1[CH:22]=[CH:21][N:20]=[CH:19][C:18]=1[NH:23][C:24]([NH2:26])=[S:25]>O1CCOCC1>[CH3:16][C:4]1[N:26]=[C:24]([NH:23][C:18]2[CH:19]=[N:20][CH:21]=[CH:22][N:17]=2)[S:25][C:5]=1[C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:8][CH:7]=1
Reactant: NC(=S)Nc1cnccn1
Reactant: CC(=O)Cc1ccc(S(N)(=O)=O)cc1
Agent: BrBr
Solvent: C1COCCO1
Product: Cc1nc(Nc2cnccn2)sc1-c1ccc(S(N)(=O)=O)cc1
Temperature: 60 °C
Yield: 28.1 %

Procedure:
Bromine (0.017 ml, 0.33 mmol) is added dropwise to a stirred solution of 4-(2-oxo-propyl)-benzenesulfonamide (prepared as described in European patent specification EP 91749 A2) (0.087 g, 4.1 mmol) in dioxan (10 ml) at 0° C. After 30 minutes the solvent is removed and the crude product is dissolved in ethanol (4.0 ml). Pyrazin-2-yl-thiourea (0.063 g, 0.41 mmol) is added and the stirred reaction mixture is heated at 60° C. for 3 hours. The solvent is removed and the residue is triturated with ethyl acetate to give the title compound as a pale orange solid (0.040 g). MH+ (AP+):
Reaction SMILES: [C:1](#[N:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[Sn](Cl)(Cl)Cl.[C:14]([O:20][CH2:21][CH3:22])(=[O:19])[CH2:15][C:16]([CH3:18])=[O:17].C([O-])(O)=O.[Na+]>C1C=CC=CC=1>[CH2:21]([O:20][C:14](=[O:19])[C:15](=[C:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:16](=[O:17])[CH3:18])[CH3:22]
Reactant: N#Cc1ccccc1
Reactant: CCOC(=O)CC(C)=O
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: CCOC(=O)C(C(C)=O)=C(N)c1ccccc1
Yield: 45.4 %

Procedure:
To a solution of the benzonitrile (40 g, 388.3 mmol) in benzene (600 mL) were added SnCl4 (44.75 mL, 388.3 mmol) and ethyl acetoacetate (49.1 mL, 388.3 mmol) at r.t. with stirring. The mixture was stirred at r.t. for 40 min, and was then refluxed with stirring for 2 h. After cooling to r.t. sat. NaHCO3 solution (200 mL) was added, and the mixture extracted with EtOAc (4×200 mL). The combined organic phases were washed with sat. aq. NaCl solution and water, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel. Elution with 5-33% EtOAc/CH2Cl2 gave the title compound as a white solid (41.1 g): MS (m/z) 234.3 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[CH2:10])[CH:3]=1.[C:18]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:23]=CC=C[CH:19]=1.C(O)(C)C.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:18]([CH3:23])[CH3:19])=[C:4]([C:9]([C:11]2[CH:12]=[CH:13][C:14]([CH3:17])=[CH:15][CH:16]=2)=[CH2:10])[CH:3]=1
Reactant: C=C(c1ccc(C)cc1)c1cc(Br)ccc1O
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Solvent: CC(C)O
Product: C=C(c1ccc(C)cc1)c1cc(Br)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 22.5 h

Procedure:
To a cold solution (0° C.) of 125 mg (0.4 mmol) of 4-bromo-2-[(1-p-tolyl)vinyl]phenol (Compound R) in 5 mL of tetrahydrofuran was added 125 mg (0.5 mmol) of triphenylphosphine and 0.04 mL (31 mg, 0.5 mmol) of isopropanol followed by 0.07 mL (82 mg, 0.5 mmol) of diethylazodicarboxylate. The dark yellow solution was removed from the ice bath, allowed to warm to ambient temperature on its own and stirred overnight (22.5 hours). The reaction mixture was concentrated in vacuo to a gummy yellow solid. Purification by flash chromatography (silica, 1% ethyl acetate in hexane) gave the title compound as a yellow oil.
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][C:5]([S:9]([NH:12][CH3:13])(=[O:11])=[O:10])=[C:4]([F:14])[CH:3]=1.[C:15]([C:17]1[N:21]([CH3:22])[C:20](B(O)O)=[CH:19][CH:18]=1)#[N:16].[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>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]>[C:15]([C:17]1[N:21]([CH3:22])[C:20]([C:2]2[C:7]([F:8])=[CH:6][C:5]([S:9]([NH:12][CH3:13])(=[O:11])=[O:10])=[C:4]([F:14])[CH:3]=2)=[CH:19][CH:18]=1)#[N:16]
Reactant: Cn1c(C#N)ccc1B(O)O
Reactant: CNS(=O)(=O)c1cc(F)c(Br)cc1F
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CNS(=O)(=O)c1cc(F)c(-c2ccc(C#N)n2C)cc1F
Reaction time: 16 h
Yield: 15.4 %

Procedure:
According to general procedure B, 4-bromo-2,5-difluoro-N-methylbenzenesulfonamide (143 mg, 0.5 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (90 mg, 0.60 mmol), potassium fluoride (96 mg, 1.65 mmol), and tris(dibenzylideneacetone)dipalladium (12 mg, 0.013 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.3 mL) was added. Tri-t-butylphosphine (75 μL, 0.026 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. Purification afforded 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-2,5-difluoro-N-methylbenzenesulfonamide (24 mg). HPLC purity 87.6% at 210-370 nm, 8.4 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min. HRMS: calcd for C13H11F2N3O2S−H+, 310.04673; found (ESI-FTMS, [M−H]−1), 310.04692
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[N:13]1[CH2:22][C:21]2[C:16](=[N:17][C:18](S(C)=O)=[N:19][CH:20]=2)[N:15]([CH2:26][CH3:27])[C:14]1=[O:28].[NH2:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][OH:35]>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[N:13]1[CH2:22][C:21]2[C:16](=[N:17][C:18]([NH:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][OH:35])=[N:19][CH:20]=2)[N:15]([CH2:26][CH3:27])[C:14]1=[O:28]
Reactant: CCN1C(=O)N(c2c(F)c(OC)cc(OC)c2F)Cc2cnc(S(C)=O)nc21
Reactant: NCCOCCO
Product: CCN1C(=O)N(c2c(F)c(OC)cc(OC)c2F)Cc2cnc(NCCOCCO)nc21
Yield: 91.1 %

Procedure:
3-(2,6-Difluoro-3,5-dimethoxy-phenyl)-1-ethyl-7-[2-(2-hydroxy-ethoxy)-ethylamino]-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one was prepared as described in Example 2 using 0.50 g (1.21 mmol) of 3-(2,6-difluoro-3,5-dimethoxy-phenyl)-1-ethyl-7-methylsulfinyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one and 0.36 mL (3.64 mmol) of 2-(2-aminoethoxy)ethanol. The crude product was purified using medium-pressure chromatography eluting with 20:1 dichloromethane/methanol to give 0.50 g (91%) of the title compound: mp 159° C.–160° C. MS (APCI) (m+1)/z 454.1.
Reaction SMILES: [CH2:1]([N:3](C(=O)C1C=CC(O)=CC=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[C@@H:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].[N:38]1([C:46](=O)[CH2:47]Cl)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[N:38]1([CH2:46][CH2:47][O:10][C:8]2[CH:9]=[CH:4][C:5]([CH2:12][CH2:2][CH2:1][NH:3][C:4]3[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=3[C@@H:12]3[CH2:21][CH2:20][C:19]4[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=4[CH2:13]3)=[CH:6][CH:7]=2)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=C(CCl)N1CCCCCCC1
Product: COc1ccc([C@@H]2CCc3cc(O)ccc3C2)c(NCCCc2ccc(OCCN3CCCCCCC3)cc2)c1
Yield: 88.7 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and 1-azocan-1-yl-2-chloroethanone (15 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (9.6 mg) was obtained.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[CH:5]([S:7]([CH:10]=[CH2:11])(=[O:9])=[O:8])=[CH2:6].[NH2:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1>ClC1C=CC=CC=1.C(Cl)Cl.O.CO>[O:8]=[S:7]1(=[O:9])[CH2:10][CH2:11][N:12]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[CH2:6][CH2:5]1
Reactant: C=CS(=O)(=O)C=C
Reactant: N#Cc1ccc(N)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Solvent: ClCCl
Solvent: O
Product: N#Cc1ccc(N2CCS(=O)(=O)CC2)cc1
Temperature: 130 °C
Reaction time: 90 h
Yield: 30.5 %

Procedure:
Aluminium trichloride (1.13 g, 8.46 mmol) was suspended in chlorobenzene (50 ml) at 0° C. Divinyl sulfone (850 μl, 8.46 mmol) was added followed by 4-aminobenzonitrile (1.0 g, 8.46 mmol). The mixture was allowed to reach room temperature and was then stirred at 130° C. for 90 hours. The reaction was cooled and diluted with CH2Cl2 (200 ml), water (150 ml) and MeOH (50 ml) before filtration. Filtered liquid was separated and the aqueous phase was extracted with CH2Cl2 (50 ml). Combined organics were dried over MgSO4 and evaporated. The crude product was purified by flash chromatography using pet.ether/EtOAc (1:1→0:1) as eluent to give 610 mg (30%) of the title compound as pale solids.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12](/[C:15](/[CH3:19])=[CH:16]/[CH2:17][OH:18])=[CH:11][CH:10]=2)[CH:5]=[C:6]([Br:8])[CH:7]=1.[CH2:20]([O:22][C@@H:23]([CH2:29][C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:21]>>[Br:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12](/[C:15](/[CH3:19])=[CH:16]/[CH2:17][O:18][C:33]3[CH:32]=[CH:31][C:30]([CH2:29][C@H:23]([O:22][CH2:20][CH3:21])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:35][CH:34]=3)=[CH:13][CH:14]=2)[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: C/C(=C\CO)c1ccc(-c2cc(Br)cc(Br)c2)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3cc(Br)cc(Br)c3)cc2)cc1)OCC
Yield: 84 %

Procedure:
The title compound (177 mg, 83%) was prepared as a colourless gum from (E)-3-(3′,5′-dibromo-biphenyl-4-yl)-but-2-en-1-ol (135 mg, 0.35 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (90 mg, 0.38 mmol) by a procedure analogous to that described in example 52c.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][C@@H:4]([CH3:8])[NH:3]1.Cl[C:10]1[N:11]([CH2:33][CH:34]2[CH2:36][CH2:35]2)[C:12]2[C:17]([N:18]=1)=[C:16]([N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[N:15]=[C:14]([C:25]1[C:26]([CH3:32])=[N:27][C:28]([NH2:31])=[N:29][CH:30]=1)[N:13]=2>CN1CCCC1=O>[CH:34]1([CH2:33][N:11]2[C:10]([N:6]3[CH2:5][C@H:4]([CH3:8])[NH:3][C@H:2]([CH3:1])[CH2:7]3)=[N:18][C:17]3[C:12]2=[N:13][C:14]([C:25]2[C:26]([CH3:32])=[N:27][C:28]([NH2:31])=[N:29][CH:30]=2)=[N:15][C:16]=3[N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH2:35][CH2:36]1
Reactant: C[C@@H]1CNC[C@H](C)N1
Reactant: Cc1nc(N)ncc1-c1nc(N2CCOCC2)c2nc(Cl)n(CC3CC3)c2n1
Solvent: CN1CCCC1=O
Product: Cc1nc(N)ncc1-c1nc(N2CCOCC2)c2nc(N3C[C@@H](C)N[C@@H](C)C3)n(CC3CC3)c2n1
Temperature: 150 °C
Reaction time: 4 h
Yield: 75.2 %

Procedure:
cis-2,6-Dimethylpiperazine (114 mg, 1.0 mmol) and N-methylpyrrolidone (1 ml) were added to 5-[8-chloro-9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purin-2-yl]-4-methylpyrimidin-2-amine (100 mg, 0.25 mmol) and the resulting mixture was stirred at 150° C. for 4 hours. The reaction mixture was partitioned with ethyl acetate and water and the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by preparative HPLC (column, NOMURA Develosil Combi-RP-5; mobile phase, acetonitrile/water/formic acid) to give the title compound (90 mg, 75%) as a light brown solid.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([CH2:11][CH2:12][CH2:13]I)[CH2:8][C:9]#[N:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:21].[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:36](=[CH:37][CH:38]=1)[CH2:35][C:29]1([CH2:34][CH2:33][CH2:32][CH2:31][NH:30]1)[CH2:28][CH2:27]2.C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[ClH:21].[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:36](=[CH:37][CH:38]=1)[CH2:35][C:29]1([CH2:34][CH2:33][CH2:32][CH2:31][N:30]1[CH2:13][CH2:12][CH2:11][C:7]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:8][C:9]#[N:10])[CH2:28][CH2:27]2
Reactant: COc1ccc2c(c1)CCC1(CCCCN1)C2
Reactant: N#CCC(CCCI)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)CCC1(CCCCN1CCCC(CC#N)(c1ccccc1)c1ccccc1)C2
Yield: 34 %

Procedure:
3,3-Diphenyl-6-iodohexanenitrile (1.5 g), 3,4-dihydro-6-methoxyspiro[naphthalene-2(1H),2'-piperidine]hydrochloride (1.39 g), triethylamine (0.53 g), and potassium carbonate (0.72 g) were stirred in acetonitrile (25 ml) at 70° C. overnight. The insoluble matter in the reaction mixture was filtered off and the filtrate was concentrated to dryness. The group was purified by silica gel column chromatography to provide the hydrochloride salt of the title compound (0.7 g) as light-yellow powder.
Reaction SMILES: [Na+].[I-:2].[CH3:3][O:4]/[C:5](/[CH2:12]Cl)=[CH:6]\[C:7]([O:9][CH2:10][CH3:11])=[O:8]>CC(C)=O>[CH3:3][O:4]/[C:5](/[CH2:12][I:2])=[CH:6]\[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)/C=C(/CCl)OC
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOC(=O)/C=C(/CI)OC
Reaction time: 20 h
Yield: 99.6 %

Procedure:
Fifteen grams (0.1 mol) of NaI was added to a solution of 3.58 g (0.02 mol) of ethyl 3-methoxy-4-chlorocrotonate in 150 mL of acetone. The solution was stirred vigorously for 20 h in a flask protected from light and standard workup yielded 5.38 g (100%) of ethyl 3-methoxy-4-iodocrotonate as an amber liquid: VPC (6 ft 5% SF96 on 60-80 mesh chromosorb G; 160° C.; 60 cm3 /min He flow) tR =4.0 min; NMR (CDCl3)δ1.31 (t, 3H, J=7 Hz, COOCCH3), 3.73 (s, 3H, OCH3), 4.24 (q, 2H, J=7 Hz, COOCH2C), 4.48 (s, 2H, CH2I), 5.13 (s, 1H, CH).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:11])=[N:7][NH:8]2)=[CH:4][C:3]=1[CH:12]=O.[NH2:14][C:15]([CH:19]([F:21])[F:20])=[CH:16][C:17]#[N:18]>C(O)(=O)C.C1COCC1>[F:20][CH:19]([F:21])[C:15]1[NH:14][C:15]([CH:19]([F:21])[F:20])=[C:16]([C:17]#[N:18])[CH:12]([C:3]2[CH:4]=[C:5]3[C:9](=[CH:10][C:2]=2[F:1])[NH:8][N:7]=[C:6]3[CH3:11])[C:16]=1[C:17]#[N:18]
Reactant: N#CC=C(N)C(F)F
Reactant: Cc1n[nH]c2cc(F)c(C=O)cc12
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1n[nH]c2cc(F)c(C3C(C#N)=C(C(F)F)NC(C(F)F)=C3C#N)cc12

Procedure:
A solution of 100 mg (0.56 mmol) 6-fluoro-3-methyl-1H-indazole-5-carbaldehyde (Example 3A) and 146 mg (1.24 mmol) 3-amino-4,4-difluorobut-2-enenitrile [obtainable by Thorpe reaction of acetonitrile with 2,2-difluoroacetonitrile, cf. Org. React. 15, 1 (1967), ibid. 31, 1 (1984)] in acetic acid (0.54 ml) containing powdered 4 Å molecular sieve was heated to reflux temperature for 5 h. After cooling, the reaction mixture was diluted with THF and filtered. The filtrate was directly purified by preparative RP-HPLC (acetonitrile/water+0.1% TFA gradient) yielding 136 mg (64% of th.) of the title compound.
Reaction SMILES: C([Li])CCC.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13](P(=O)(OCC)OCC)[O:14]CC)=[CH:9][CH:8]=1.[CH3:25][N:26]1[C:30]([CH:31]=O)=[CH:29][N:28]=[CH:27]1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>CCCCCC.O1CCCC1.O>[CH3:25][N:26]1[C:30]([CH2:31][C:13]([C:10]2[CH:9]=[CH:8][C:7]([Br:6])=[CH:12][CH:11]=2)=[O:14])=[CH:29][N:28]=[CH:27]1
Reactant: Cn1cncc1C=O
Reactant: CCOC(c1ccc(Br)cc1)P(=O)(OCC)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cn1cncc1CC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.9 %

Procedure:
Butyl lithium (2.4M, 11 ml) in hexane was added over a period of 5 minutes to a solution of diethyl 4-bromophenyl-ethoxymethylphosphonate (10.11 g, 30 mmol) in tetrahydrofuran (150 ml) at 78° C. under an atmosphere of nitrogen. After 10 minutes stirring, a solution of N-methyl 5-imidazolecarboxaldehyde (2.2 g) in tetrahydrofuran (80 ml) was added and the reaction mixture was allowed to warm slowly to room temperature. Water (200 ml) and concentrated hydrochloric acid (25 ml) were added and the reaction mixture was refluxed for 4 hours and then cooled to room temperature. The reaction mixture was then neutralised with anhydrous sodium carbonate and the tetrahydrofuran evaporated. The residue was extracted with ethyl acetate (3×300 ml) and the combined organic extract was then washed with saturated sodium chloride solution, dried and concentrated by evaporating off the solvent. Flash chromatography of the residue on silica gel using 9:1 chloroform:methanol as eluant gave 4-bromophenyl 1-methyl-5-imidazolylmethyl ketone (4.9 g) as a white solid, m.pt. 109° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9](Br)[S:8][CH:7]=1)=[O:5])[CH3:2].C([Sn](CCCC)(CCCC)[C:17]1[CH:21]=[CH:20][S:19][CH:18]=1)CCC>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:17]2[CH:21]=[CH:20][S:19][CH:18]=2)[S:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccsc1
Reactant: CCOC(=O)c1csc(Br)c1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)c1csc(-c2ccsc2)c1
Yield: 44.7 %

Procedure:
The same reaction as in Referential Example 37 was carried out except using 380 mg of 5-bromo-3-thiophenecarboxylic acid ethyl ester [see J. Am. Chem. Soc., 26, 2446 (1954)], 730 mg of tributyl(3-thienyl)stannane and 10 mg of tetrakis(triphenylphosphine) palladium to give 172 mg (yield 51%) of 5-(3-thienyl)-3-thiophenecarboxylic acid ethyl ester.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH3:14])[CH:8]=[CH:7]2)([OH:3])=[O:2].OS(O)(=O)=O.[CH3:20]O>>[C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH3:14])[CH:8]=[CH:7]2)([O:3][CH3:20])=[O:2]
Reactant: CO
Reactant: Cc1ccc2cc(C(=O)O)ccc2n1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc2nc(C)ccc2c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 6-carboxy-2-methyl quinoline in MeOH (600 ml) was added concentrated H2SO4 and stirred for 3 days at room temperature. The reaction mixture was evaporated and the residue was diluted with H2O (250 ml) and ethyl acetate (250 ml), and transferred to a separatory funnel. A solution of saturated sodium bicarbonate in water (1 L) was added and extraction with ethyl acetate afforded a purple solid which was chromatographed on column of flash silica gel using hexane-ethyl acetate (2:1) as eluant to provide the title compound as a yellow solid: m.p. 98-101° C.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH2:6][C:7]1[CH:8]=[N:9][C:10]([Br:13])=[CH:11][CH:12]=1)C.[BH4-].[Li+].O>C1COCC1>[Br:13][C:10]1[N:9]=[CH:8][C:7]([CH2:6][CH2:5][CH2:4][OH:3])=[CH:12][CH:11]=1
Reactant: CCOC(=O)CCc1ccc(Br)nc1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCCCc1ccc(Br)nc1

Procedure:
Under argon, 560 mg (2.17 mmol) of 3-(6-bromopyridin-3-yl)propionic acid ethyl ester and 94.6 mg (4.34 mmol) of lithium borohydride were stirred in 40 ml of THF at 40° C. for 3 h. After cooling, the mixture was cautiously hydrolyzed with water, the precipitate was filtered off with suction, and the filtrate was concentrated and admixed with water and ethyl acetate. The organic phase was separated, washed with water and concentrated. Yield: 450 mg (96%).
Reaction SMILES: [C:1]([N:4]1[C:46]2[C:41](=[CH:42][CH:43]=[C:44]([Cl:47])[CH:45]=2)[C:6]2([CH:11]([C:12]3[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=3[O:19][C:20]([CH2:30][CH3:31])([CH2:28][CH3:29])[C:21]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[O:22])[CH2:10][C:9](=O)[NH:8][CH:7]2[C:33]2[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=2[CH3:40])[C:5]1=[O:48])(=[O:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:58])=CC=1>C1(C)C=CC=CC=1>[C:1]([N:4]1[C:46]2[C:41](=[CH:42][CH:43]=[C:44]([Cl:47])[CH:45]=2)[C:6]2([CH:11]([C:12]3[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=3[O:19][C:20]([CH2:30][CH3:31])([CH2:28][CH3:29])[C:21]([NH:23][S:24]([CH3:27])(=[O:25])=[O:26])=[O:22])[CH2:10][C:9](=[S:58])[NH:8][CH:7]2[C:33]2[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=2[CH3:40])[C:5]1=[O:48])(=[O:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)N(C(C)=O)c1cc(Cl)ccc12)C(=O)NS(C)(=O)=O
Solvent: Cc1ccccc1
Product: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=S)NC(c2cc(F)ccc2C)C12C(=O)N(C(C)=O)c1cc(Cl)ccc12)C(=O)NS(C)(=O)=O
Temperature: 125 °C
Yield: 29.2 %

Procedure:
A mixture of chiral (2′S, 3S, 4′R)-1-acetyl-6-chloro-4′-[5-chloro-2-(2-methanesulfonylamino-1,1-diethyl-2-oxo-ethoxy)-phenyl]-2′-(5-fluoro-2-methyl-phenyl)-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (50 mg, 0.07 mmol) and Lawesson's Reagent (56 mg, 0.126 mmol) in toluene (5 mL) was heated at 125° C. for 1.5 h. The mixture was purified by flash column chromatography to give the title compound as white solid (15 mg).
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][N:14]1[C:18]([S:19]([C:22]2[CH:27]=[CH:26][C:25](C)=[CH:24][CH:23]=2)(=O)=O)=[N:17][N:16]=[N:15]1)(OC(C)(C)C)=O.C1C=CC(S)=CC=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[C:22]1([S:19][C:18]2[N:14]([CH2:13][C@@H:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)[N:15]=[N:16][N:17]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Cc1ccc(S(=O)(=O)c2nnnn2C[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CC#N
Product: c1ccc(Sc2nnnn2C[C@@H]2CCCN2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 135.4 %

Procedure:
The mixture of 2 (6.0 g, 14.7 mmol), phenylthiol (6.5 g, 58.8 mmol) and K2CO3 (4.5 g, 41.1 mmol) in CH3CN (74 ml) was stirred for 2 days at room temperature. The reaction mixture was filtered through a pad of Celite and then concentrated in vacuo. The crude was purified by silica gel column with (Hexane:EtOAc=1:1) as an eluant to give 3 (5.2 g, 97%) as an colorless oil. [α]D −29.2 (c 1.34, CHCl3). 1H NMR (400 MHz, CD3OD, −20° C., rotamers 1:1): δ 1.30 & 1.42 (s, 9H), 1.73 & 2.01 (m, 4H) 3.40 & 3.45 (m, 13.2 Hz, 2H), 4.23 & 4.25 (m, 1H), 4.38 & 4.58 (m, 2H), 7.42 & 7.46 (m, 3H) 7.56 & 7.60 (m, 2H); 13C NMR (CDCl3, 75 MHz): δ 21.2, 23.6, 28.5, 46.5, 49.7, 50.4, 56.7, 60.5, 80.7, 128.1, 129.9, 133.1, 153.5, 154.9; IR (film): 2975, 1693, 1391, 1167, 688 cm−1; MS: (ESI) [M+1]+ 361.2
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]2[CH:16]=[C:15]3[C:11]([CH2:12][CH2:13][C:14]3=O)=[CH:10][CH:9]=2)[C:4]([CH3:18])=[N:3]1.[CH3:19][NH:20][CH3:21].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:19][N:20]([CH3:21])[CH:14]1[C:15]2[C:11](=[CH:10][CH:9]=[C:8]([C:5]3[C:4]([CH3:18])=[N:3][N:2]([CH3:1])[C:6]=3[CH3:7])[CH:16]=2)[CH2:12][CH2:13]1
Reactant: CNC
Reactant: Cc1nn(C)c(C)c1-c1ccc2c(c1)C(=O)CC2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1nn(C)c(C)c1-c1ccc2c(c1)C(N(C)C)CC2
Temperature: 120 °C

Procedure:
(Method 1): 6-(1,3,5-Trimethyl-1H-pyrazol-4-yl)-indan-1-one (0.20 mmol), dimethyl-amine (2.31 mmol) and acetic acid (0.020 mmol) were mixed in 3 ml of MeOH in a process vial, which was sealed with a septum. Sodium cyanoborohydride (0.47 mmol) was added under argon atmosphere. The suspension was subjected to microwave irradiating conditions (CEM Discover® equipped with a CEM Explorer® automated reaction handling module). The reaction mixture was heated for 1 h at 120° C. and then cooled. The crude was evaporated to dryness and then suspended in water. The product was extracted with CH2Cl2 and washed with water. The CH2Cl2 extract was dried with anhydrous Na2SO4, filtered and evaporated to dryness to give the crude product dimethyl-[6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-indan-1-yl]-amine. The crude was purified by flash column chromatography (CH2Cl2-MeOH as eluents) by using a CombiFlash Companion™ system to yield the base of the title compound. The obtained product was diluted in ethyl acetate (5 mL) and a solution of hydrogen chloride 2,0 M in diethylether was added. The resulting precipitate was filtered and dried under vacuum to yield the title compound dimethyl-[6-(1,3,5-trimethyl-1H-pyrazol-4-yl)-indan-1-yl]-amine dihydrochloride (83%). MS [MH]+=270.