Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][NH:13]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:18]1([CH2:24][O:25][C:26]2[CH:31]=[CH:30][C:29](Br)=[CH:28][CH:27]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O>O1CCOCC1>[C:1]1([CH2:7][O:8][C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH:11]=[CH:12][N:13]3[C:29]2[CH:30]=[CH:31][C:26]([O:25][CH2:24][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:27][CH:28]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Brc1ccc(OCc2ccccc2)cc1
Reactant: c1ccc(COc2cccc3[nH]ccc23)cc1
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: c1ccc(COc2ccc(-n3ccc4c(OCc5ccccc5)cccc43)cc2)cc1
Temperature: 100 °C
Yield: 16 %

Procedure:
4-[(phenylmethyl)oxy]-1H-indole (504 mg, 2.26 mmoL), 4-bromophenyl phenylmethyl ether (580 mg, 1.88 mmoL), K3PO4 (998 mg, 4.7 mmoL) and L-Proline (43.3 mg, 0.376 mmoL) were dissolved in 1,4-Dioxane (4 mL) in a microwave vial and degassed by sonication under a flow of argon. To this was added CuI (18 mg, 0.094 mmoL) and the solution was heated to 100° C. in the microwave reactor. After 5 hours a second portion of CuI (48 mg, 0.252 mmoL) and L-Proline (40 mg, 0.347 mmoL) were added and the mixture heated for 2 more hours. The reaction mixture was filtered through a pad of celite and concentrated. The residue was partitioned between ethyl acetate (100 mL)/water (100 mL), the phases were separated and the aqueous phase re-extracted with ethyl acetate (100 mL). The combined organic phases were washed with brine (2×50 mL) then water (50 mL) and finally dried over MgSO4. The crude product was purified by flash chromatography (Biotage SP4) eluting with a gradient of 0 to 30% Et2O in hexane to give the title compound (D24), (143 mg).
Reaction SMILES: S(Cl)([Cl:3])=O.N1C=CC=CC=1.[CH2:11]([C:18]1[O:19][CH:20]=[C:21]([CH2:23]O)[CH:22]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1(C)C=CC=CC=1>[CH2:11]([C:18]1[O:19][CH:20]=[C:21]([CH2:23][Cl:3])[CH:22]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCc1coc(Cc2ccccc2)c1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: ClCc1coc(Cc2ccccc2)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A solution of 13 g of thionyl chloride in toluene was added dropwise over 15 minutes to a mixture of 15.8 g pyridine and 18.8 g 2-benzyl-4-hydroxymethylfuran, in toluene, at a temperature of 0°-5° C. The mixture was slowly warmed to 80° C. and stirred for 11/2 hours and then cooled in an ice-bath, poured into ice and filtered. The resulting solution was extracted with diethyl ether, washed with water and then with sodium bicarbonate solution, and dried over magnesium sulphate. The solution was then stripped of solvent, yielding a brown oil, which was chromatographed over silica gel using toluene as eluent to give 2-benzyl-4-chloromethylfuran (1A) as a brown oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH2:12])([CH3:11])[CH3:10])=[CH:5][CH:4]=1.[Cl:13][CH2:14][CH2:15][CH2:16][C:17](Cl)=[O:18].C(N(CC)CC)C>ClCCl>[Cl:13][CH2:14][CH2:15][CH2:16][C:17]([NH:12][C:9]([C:6]1[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=1)([CH3:10])[CH3:11])=[O:18]
Reactant: O=C(Cl)CCCCl
Reactant: CC(C)(N)c1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(NC(=O)CCCCl)c1ccc(Cl)cc1

Procedure:
In a similar manner to Example 52b, 1-(4-chlorophenyl)-1-methylethylamine hydrochloride (2.5 g) was treated with 4-chlorobutyryl chloride (1.7 g) in dichloromethane (30 ml) containing triethylamine (3.4 ml) to give 4-chloro-N-[1-(4-chlorophenyl)-1-methylethyl]butyramide which was used directly in part (b) below.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:20]2[CH:19]=[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:17]3[C:27](=[O:31])[NH:28][C:29](=[O:30])[C:16]=3[C:15]=2[C:14]2[CH:13]=[C:12]([OH:32])[CH:11]=[CH:10][C:9]1=2)(=O)=O.[CH3:33][NH:34][CH3:35]>>[CH3:33][N:34]([CH3:35])[CH2:6][CH2:7][N:8]1[C:20]2[CH:19]=[C:18]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:17]3[C:27](=[O:31])[NH:28][C:29](=[O:30])[C:16]=3[C:15]=2[C:14]2[CH:13]=[C:12]([OH:32])[CH:11]=[CH:10][C:9]1=2
Reactant: CNC
Reactant: CS(=O)(=O)OCCn1c2ccc(O)cc2c2c3c(c(-c4ccccc4)cc21)C(=O)NC3=O
Product: CN(C)CCn1c2ccc(O)cc2c2c3c(c(-c4ccccc4)cc21)C(=O)NC3=O
Yield: 48 %

Procedure:
Mesylate (205) prepared as described in example 174 (70 mg, 0.16 mmol) was reacted with aqueous dimethylamine solution according to the procedure described in example 179 to give amine (209) (30 mg, 48%) as a yellow powder, mp 283–286° C. 1H NMR δ [(CD3)2SO] 11.05 (br s, 1H), 9.33 (s, 1H), 8.41 (d, J=2.4 Hz, 1H), 7.77 (s, 1H), 7.65 (m, 2H), 7.54 (d, J=8.8 Hz, 1H), 7.46 (m, 3H), 7.12 (dd, J=8.8, 2.4 Hz, 1H), 4.55 (t, J=6.5 Hz, 2H), 2.62 (t, J=6.5 Hz, 2H), 2.19 (s, 6H). Found: C, 71.92; H, 5.16; N, 10.55. C24H21N3O3 requires: C, 72.17; H, 5.30; N, 10.52.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH:20]2[CH2:22][CH2:21]2)=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[N:7][CH:8]=1.[CH2:23]([O:25][C:26](=[O:42])[C:27]([O:30][C:31]1[CH:36]=[CH:35][C:34]([S:37]C(=O)C)=[CH:33][C:32]=1[CH3:41])([CH3:29])[CH3:28])[CH3:24].CO.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[CH2:23]([O:25][C:26](=[O:42])[C:27]([O:30][C:31]1[CH:36]=[CH:35][C:34]([S:37][CH2:2][C:3]2[C:4]([CH:20]3[CH2:22][CH2:21]3)=[N:5][C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=3)=[N:7][CH:8]=2)=[CH:33][C:32]=1[CH3:41])([CH3:28])[CH3:29])[CH3:24]
Reactant: FC(F)(F)Oc1ccc(-c2ncc(CCl)c(C3CC3)n2)cc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(SC(C)=O)cc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: CC#N
Product: CCOC(=O)C(C)(C)Oc1ccc(SCc2cnc(-c3ccc(OC(F)(F)F)cc3)nc2C2CC2)cc1C
Temperature: 25 °C
Reaction time: 27 h
Yield: 78.3 %

Procedure:
0.399 g (1.2 mmol) of 5-Chloromethyl-4-cyclopropyl-2-(4-trifluoromethoxy-phenyl)-pyrimidine (example 150D]) and 0.300 g (1.0 mmol) of 2-(4-acetylsulfanyl-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (example 142C]) were dissolved in 2.0 ml of acetonitrile and 0.08 ml of MeOH and treated with 0.462 g (1.4 mmol) of Cs2CO3. After vigorous stirring for 27 h at ambient temperature and filtration, the solvent was evaporated and the residue redissolved in dichloromethane and filtered again and evaporated. Purification by flash chromatography (SiO2, dichloromethane/n-heptane 1:2 to 4:1 and then AcOEt) afforded 0.428 g of the title compound as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([CH3:23])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:12][C:11]=2[Cl:22])[C:6]=1[CH:7]=[O:8].[BH4-].[Na+].O>C(O)C>[Cl:1][C:2]1[N:3]=[C:4]([CH3:23])[N:5]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])=[CH:12][C:11]=2[Cl:22])[C:6]=1[CH2:7][OH:8]
Reactant: CCCCCOc1ccc(Cn2c(C)nc(Cl)c2C=O)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCCOc1ccc(Cn2c(C)nc(Cl)c2CO)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74.4 %

Procedure:
4-Chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-2-methyl-1H-imidazole-5-carbaldehyde (1.05 g) was dissolved in ethanol (10 ml), and sodium borohydride (168 mg) was added under ice-cooling. The mixture was stirred at room temperature for 3 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the residue was added hexane (10 ml) and the precipitated crystals were collected by filtration and dried by heating under reduced pressure to give 4-chloro-1-(2-chloro-4-(1-pentyloxy)benzyl)-5-hydroxymethyl-2-methyl-1H-imidazole (786 mg) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C@H:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:18](=[O:22])[CH2:19][CH2:20][CH3:21])[CH2:13]2)[C:3]=1[C:4]#[N:5].[S:23](Cl)(=[O:26])(=[O:25])[NH2:24]>CC(N(C)C)=O>[S:23]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][C@H:12]2[CH2:17][CH2:16][CH2:15][N:14]([C:18](=[O:22])[CH2:19][CH2:20][CH3:21])[CH2:13]2)[C:3]=1[C:4]#[N:5])(=[O:26])(=[O:25])[NH2:24]
Reactant: NS(=O)(=O)Cl
Reactant: CCCC(=O)N1CCC[C@H](COc2cccc(N)c2C#N)C1
Solvent: CC(=O)N(C)C
Product: CCCC(=O)N1CCC[C@H](COc2cccc(NS(N)(=O)=O)c2C#N)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.8 %

Procedure:
To a solution of (S)-2-amino-6-((1-butyrylpiperidin-3-yl)methoxy)benzonitrile (Example 1b, 9.2 g, 30.53 mmol) in DMA (60 mL) was added sulfamoyl chloride (Example 1f, 10.54 g, 91.58 mmol) at room temperature under nitrogen. The reaction mixture was stirred at room temperature under nitrogen overnight then concentrated under reduced pressure, diluted with EtOAc, successively washed with NaHCO3, water and brine, dried over Na2SO4, filtered and the solvent was removed under reduced pressure to give the title compound as colorless gel (9.5 g) in 82% yield. MS 381 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](=O)[CH3:14])[CH3:2].N1CCC[C@H]1C(O)=O.[NH2:25][C:26]1[C:31]([CH:32]=O)=[CH:30][CH:29]=[CH:28][N:27]=1>CCO>[CH2:1]([O:3][C:4](=[O:16])[CH:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:14]=[CH:32][C:31]2[C:26](=[N:27][CH:28]=[CH:29][CH:30]=2)[N:25]=1)[CH3:2]
Reactant: CCOC(=O)C=CCCCCCCC(C)=O
Reactant: Nc1ncccc1C=O
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CCO
Product: CCOC(=O)C=CCCCCCCc1ccc2cccnc2n1
Temperature: 110 °C

Procedure:
A mixture of 28-3 (4.1 g, 18.3 mmol), proline (2.7 g, 23.8 mmol), and 1-3 (2.9 g, 23.8 mmol ) in 50 mL EtOH was heated at 110° C. for 24 hr. The reaction mixture was concentrated and purified by silica gel chromatography (EtOAc, 100%) to afford the desired product 28-4 as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([NH:6][CH2:7][C:8]([O:10]CC)=O)=[CH:4][C:3]=1[F:15].[O-:16][C:17]#[N:18].[K+]>C(O)(=O)C.O>[Br:1][C:2]1[CH:14]=[CH:13][C:5]([N:6]2[CH2:7][C:8](=[O:10])[NH:18][C:17]2=[O:16])=[CH:4][C:3]=1[F:15]
Reactant: N#C[O-]
Reactant: CCOC(=O)CNc1ccc(Br)c(F)c1
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: O=C1CN(c2ccc(Br)c(F)c2)C(=O)N1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of ethyl 2-(4-bromo-3-fluoro-anilino)acetate (86 g, 0.31 mol) in acetic acid (1.5 L) and water (100 mL) was added a solution of potassium cyanate (50 g, 0.6 mol) in water (200 mL). The reaction mixture was stirred at room temperature for 12 h and then evaporated to dryness. Then 1.5 L of 25% HCl was added to the residue and the mixture was heated to reflux for 3 h. After cooling to room temperature, the solid was filtered and dried to give the title compound. LC-MS: calculated for C9H6BrFN2O2 271.96 observed m/e: 273.35 (M+H)+ (Rt 3.44/6.5 min).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([C:9]1[CH:27]=[CH:26][C:12]([CH2:13][CH2:14][NH:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[CH:11][CH:10]=1)(=[O:8])[CH2:6][CH3:7].C(N(CC)CC)C>C(Cl)Cl>[C:5]([C:9]1[CH:27]=[CH:26][C:12]([CH2:13][CH2:14][N:15]([C:1](=[O:3])[CH3:2])[S:16]([C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)(=[O:17])=[O:18])=[CH:11][CH:10]=1)(=[O:8])[CH2:6][CH3:7]
Reactant: CCC(=O)c1ccc(CCNS(=O)(=O)c2ccc(Cl)cc2)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)c1ccc(CCN(C(C)=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 3.57 g. (45.5 mmole) acetyl chloride in 50 ml. methylene chloride is slowly added dropwise to an ice-cold mixture of 16.0 g. (45.5 mmole) 4-chlorobenzenesulphonic acid-(4-propionylphenethylamide), 5.1 ml. (50 mmole) triethylamine and 200 ml. methylene chloride. The reaction mixture is then stirred for 3 hours at ambient temperature, extracted with 2N hydrochloric acid and several times with water, dried with anhydrous sodium sulphate and evaporated. After chromatography with silica gel/toluene +ethyl acetate (12:1 v/v), there are obtained 10.2 g. (57% of theory) of the desired product; m.p. 91°-92° C. (after recrystallisation from heptane +toluene).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH:14]=O)=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[N:16]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][N:19]2[CH2:18][CH2:17][N:16]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=Cc1ccccc1-c1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2-c2ccc(Cl)cc2)CC1

Procedure:
4′-Chlorobiphenyl-2-carbaldehyde (EXAMPLE 27C) (4.1 g), tert-butyl piperazine-1-carboxylate (4.23 g), and sodium triacetoxyborohydride (5.61 g) in CH2Cl2 (60 mL) were combined stirred for 24 hours. The reaction was quenched with methanol and poured into ether. The solution was washed with water and brine, concentrated, and chromatographed on silica gel with 2-25% ethyl acetate/hexanes.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:38]=[CH:37][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([N:27](CCCCCC)[C:28]([NH2:30])=[O:29])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.[F:39][C:40]1[CH:50]=[CH:49][C:43]([O:44][CH2:45][C@@H:46]2[CH2:48][O:47]2)=[CH:42][CH:41]=1>>[F:39][C:40]1[CH:50]=[CH:49][C:43]([O:44][CH2:45][C@@H:46]([OH:47])[CH2:48][NH:4][CH2:5][CH2:6][C:7]2[CH:38]=[CH:37][C:10]([NH:11][CH:12]3[CH2:17][CH2:16][N:15]([S:18]([C:21]4[CH:22]=[CH:23][C:24]([NH:27][C:28]([NH:30][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[O:29])=[CH:25][CH:26]=4)(=[O:19])=[O:20])[CH2:14][CH2:13]3)=[CH:9][CH:8]=2)=[CH:42][CH:41]=1
Reactant: Fc1ccc(OC[C@@H]2CO2)cc1
Reactant: CCCCCCN(C(N)=O)c1ccc(S(=O)(=O)N2CCC(Nc3ccc(CCN)cc3)CC2)cc1
Solvent: O=CO
Product: CCCCCCNC(=O)Nc1ccc(S(=O)(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(F)cc4)cc3)CC2)cc1
Yield: 63.6 %

Procedure:
N-[4-({4-[4-(2-Aminoethyl)anilino]-1-piperidinyl}sulfonyl)phenyl]-N-hexylurea formate (0.20 g 0.365 mmol) was reacted with (2S)-2-[(4-fluorophenoxy)methyl]oxirane (0.061 mL, 0.365 mmol) according to Procedure G to give the title compound (0.078 g, 0.116 mmol).
Reaction SMILES: [Cl:1][C:2]1[C:21](I)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[F:23][C:24]1[CH:25]=[N:26][CH:27]=[C:28](B(O)O)[CH:29]=1>>[Cl:1][C:2]1[C:21]([C:28]2[CH:27]=[N:26][CH:25]=[C:24]([F:23])[CH:29]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1
Reactant: OB(O)c1cncc(F)c1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(I)c1
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2cncc(F)c2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 247.1 using 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-iodonicotinamide (Stage 247.2) and 3-Fluoropyridine-5-boronic acid pinacolester (80° C. instead of 90° C.) to afford a white solid. UPLC-MS (Condition 3) tR=1.17 min, m/z=428.0/429.9 [M+H]+.
Reaction SMILES: [Cu][C:2]#[N:3].[ClH:4].[CH3:5][N:6]1[CH2:10][CH2:9][CH2:8][C:7]1=O>CCOCC>[ClH:4].[C:2]([C:8]1[CH:7]=[C:8]2[C:7](=[CH:10][CH:9]=1)[CH2:5][NH:6][CH2:10][CH2:9]2)#[N:3]
Reactant: CN1CCCC1=O
Reactant: N#C[Cu]
Agent: Cl
Solvent: CCOCC
Product: N#Cc1ccc2c(c1)CCNC2
Yield: 85 %

Procedure:
As an alternative procedure to that contained within Description 1, a solution of 6-bromo-1,2,3,4-tetrahydroisoquinoline hydrochloride (6.0 g, 24 mmol) and triethylamine (7.4 ml, 5.36 g, 53 mmol) in dichloromethane (100 ml) was treated with trifluoroacetic anhydride (3.7 ml, 5.54 g, 26.4 mmol) with ice cooling. Mixture was stirred at 20° C. for 1.5 h. then partitioned between saturated aqueous NaHCO3 (250 ml) and dichloromethane (3×50 ml). Combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give a solid (8.3 g). A mixture of the latter with copper (I) cyanide (5.1 g, 56.6 mmol) in 1-methyl-2-pyrrolidinone (100 ml) was heated at reflux under argon for 4 h, then cooled and partitioned between water (300 ml), 0.880 aqueous ammonia (100 ml) and dichloromethane (5×200 ml). Combined organic extracts were dried (Na2SO4) and evaporated in vacuo to give an oil. The latter was dissolved in ether and treated with ethereal HCl to give the title compound (4.47 g, 85%) as a colourless solid.
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[C:7]1([CH:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[NH:15][CH2:14]2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C1C=CC=CC=1>[Br:1][CH:2]([CH3:6])[C:3]([N:15]1[C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:13]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:14]1)=[O:4]
Reactant: c1ccc(C2CNc3ccccc32)cc1
Reactant: CC(Br)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(Br)C(=O)N1CC(c2ccccc2)c2ccccc21
Yield: 96.6 %

Procedure:
A solution of 3.0 g of 2-bromopropionylchloride in 5 ml of benzene was added dropwise at 10° C. to a mixture of 3.0 g of 3-phenylindoline, 3.0 ml of triethylamine in 30 ml of dry benzene. The mixture was then washed with water, the benzene layer dried over sodium sulfate and the solvent removed in vacuo at room temperature to leave 4.9 g of the desired N-(2-bromopropionyl)-3-phenylindoline as a resin.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([C:18]2[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:19]=2[O:26]C2CCCCO2)[C:11](=[O:12])[N:10]([CH3:13])[C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=2[S:7]1.O1CCCC1.[CH3:38][SH:39].[Na]>C(O)C>[OH:26][C:19]1[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:18]=1[C:6]1([CH2:5][CH2:4][CH2:3][CH2:2][S:39][CH3:38])[C:11](=[O:12])[N:10]([CH3:13])[C:9]2[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=2[S:7]1
Reactant: COc1ccc(OC2CCCCO2)c(C2(CCCCBr)Sc3ccccc3N(C)C2=O)c1
Reactant: CS
Agent: [Na]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(O)c(C2(CCCCSC)Sc3ccccc3N(C)C2=O)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 77.3 %

Procedure:
To a stirred solution of 2-(4-bromobutyl)-2-[5-methoxy-2-(tetrahydropyran-2-yloxy)phenyl]-4-methyl-3-oxo-2H-1,4-benzothiazine (4.9 g, compound No. 34) in ethanol (25 ml), 20-25% aqueous sodium methyl mercaptan solution (16.6 ml) is added. Ethanol (15 ml) and tetrahydrofuran (20 ml) are added to the mixture. The mixture is stirred for 45 minutes at room temperature, and concentrated in vacuo. 2N Hydrochloric acid (50 ml), tetrahydrofuran (25 ml) and ethanol (25 ml) are added to the residue dissolved in tetrahydrofuran (50 ml), and the mixture is stirred for 45 minutes at room temperature. The reaction mixture is poured into a mixture of ethyl acetate and water. The organic layer is washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate and concentrated in vacuo. The separated crystals are collected by filtration to give 3.0 g (77.3%) of the titled compound.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH2:4][CH2:3]1.[H][H]>CO.[Pd]>[CH3:1][CH:2]1[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)[CH2:6][CH2:7]1
Reactant: [H][H]
Reactant: CC1CCN(CCOc2ccc([N+](=O)[O-])cc2)CC1
Agent: [Pd]
Solvent: CO
Product: CC1CCN(CCOc2ccc(N)cc2)CC1

Procedure:
A reaction mixture of 680 mg (2.57 mmol) of 4-methyl-1-[2-(4-nitrophenoxy)ethyl]piperidine and 80 mg palladium (10% on charcoal) in 10 mL of methanol is hydrogenated at ambient temperature and 3 bar hydrogen for 4.5 hours. The catalyst is suction filtered and the filtrate is evaporated down. Yield: 540 mg (90% of theory); C14H22N2O (M=234.34); calc.: molecular ion peak (M+H)+: 235; found: molecular ion peak (M+H)+: 235; Rf value: 0.33 (silica gel, dichloromethane/methanol/ammonia (90:10:0.1)).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:29]O>S(=O)(=O)(O)O.C(OCC)C>[C:1]1([C:7]2[N:8]=[C:9]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28][CH3:29])=[O:27])[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CCCCCCCCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Reactant: CO
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: COC(=O)CCCCCCCCc1nc(-c2ccccc2)c(-c2ccccc2)o1
Reaction time: 2 h
Yield: 96 %

Procedure:
A mixture of 4,5-diphenyl-2-oxazole nonanoic acid (800 mg, 2 mmol), methanol (2 mL) and concentrated sulfuric acid (2 drops) was heated to reflux. After 2 hours, the solvent was evaporated and the residue partitioned between CH2Cl2 and water. The organic phase was separated, washed with saturated NaHCO3 solution, dried over sodium sulfate and concentrated in vacuo to leave an oil. Chromatography on a column of silica gel using a mixture of hexanes and diethyl ether (4:1) as eluent gave methyl 4,5-diphenyl-2-oxazolenonanoate (800 mg, 96%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([OH:31])=[C:27]([CH3:32])[CH:26]=1>>[Cl:23][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:31][C:28]2[CH:29]=[CH:30][C:25]([Cl:24])=[CH:26][C:27]=2[CH3:32])=[N:3][CH:4]=1
Reactant: Cc1cc(Cl)ccc1O
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cl)cc1
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Oc2ccc(Cl)cc2C)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from methyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 48) and 4-chloro-2-methylphenol: 1H-NMR (CDCl3) δ 8.57 (1H, d, J=2.6 Hz), 8.14 (1H, d, J=7.6 Hz), 8.11 (1H, d, J=2.6 Hz), 8.01 (2H, d, J=8.2 Hz), 7.43 (2H, d, J=8.2 Hz), 7.31 (1H, d, J=2.4 Hz), 7.27 (1H, dd, J=8.6, 2.4 Hz), 7.04 (1H, d, J=8.6 Hz), 5.36 (1H, dq, J=7.6, 7.1 Hz), 3.91 (3H, s), 2.11 (3H, s), 1.60 (3H, d, J=7.1 Hz); MS (ESI) m/z 459 (M+H)+, 457 (M−H)−.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13](B(O)O)[CH:12]=1.C([O-])([O-])=O.[Na+].[Na+].O>COCCOC.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>[N+:8]([C:4]1[CH:3]=[C:2]([C:13]2[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=2)[CH:7]=[CH:6][CH:5]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccc(I)c1
Reactant: OB(O)c1cccnc1
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: O
Solvent: COCCOC
Product: O=[N+]([O-])c1cccc(-c2cccnc2)c1
Reaction time: 0.08 h
Yield: 78.5 %

Procedure:
To a degassed solution of 1-iodo-3-nitrobenzene (0.35 g, 1.4 mmol) in DME (5 mL) was added Pd(PPh3)4 (0.08 g, 10% mol). After stirring for 5 min, 3-pyridylboronic acid (0.2 g, 1.65 mmol) and 2M Na2CO3 (1 mL) solution were added. After refluxing for 16 h under an Ar atmosphere, the reaction mixture was poured into H2O (15 mL) and extracted with EtOAc (2×30 mL). The combined organic extracts were washed with brine, dried (Na2SO4), concentrated and purified via column chromatography to yield 3-(3-nitrophenyl)pyridine (0.22 g, 78%) as a white solid. 1H NMR (CDCl3): δ 8.94 (brs, 1H), 8.73 (brs, 1H), 8.48 (t, J=1.6 Hz, 1H), 8.32-8.29 (m, 1H), 7.98-7.93 (m, 2H), 7.72-7.68 (m, 1H), 7.48 (brs, 1H); Exact mass: 200.0, Found: 201.0 (M+1)+.