Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[CH2:5][N:6]1[CH2:10][CH2:9][CH2:8][C:7]1=[O:11].CNC1CCCCC1NC.[C:25]([C:29]1[CH:33]=[C:32]([NH2:34])[NH:31][N:30]=1)([CH3:28])([CH3:27])[CH3:26].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.[Cu]I>[NH2:34][C:32]1[N:31]([C:2]2[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=2)[CH2:5][N:6]2[CH2:10][CH2:9][CH2:8][C:7]2=[O:11])[N:30]=[C:29]([C:25]([CH3:28])([CH3:27])[CH3:26])[CH:33]=1
Reactant: O=C1CCCN1Cc1cccc(I)c1
Reactant: CC(C)(C)c1cc(N)[nH]n1
Agent: [Cu]I
Agent: CNC1CCCCC1NC
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(N)n(-c2cccc(CN3CCCC3=O)c2)n1
Temperature: 110 °C

Procedure:
To a solution of 1-(3-iodobenzyl)pyrrolidin-2-one (5.49 g, 16.8 mmol) in toluene (20 mL) was added N1,N2-dimethylcyclohexane-1,2-diamine (530 μL, 3.40 mmol), 3-(tert-butyl)-1H-pyrazol-5-amine (2.57 g, 18.5 mmol), potassium carbonate (4.64 g, 33.5 mmol) and copper(I) iodide (160 mg, 0.839 mmol), and the reaction mixture was heated to 110° C. for 3 days. The mixture was cooled to RT and was partitioned between water (50 mL) and EtOAc (100 mL). The organic phase was separated and was washed with water (4×50 mL) and then dried and evaporated in vacuo. The residue was purified by flash column chromatography (SiO2, 120 g, 0-50% EtOAc in isohexane, gradient elution) to afford the title compound, Intermediate A16, as a black gum (1.64 g, 30%); Rt 1.43 min (Method 2, acidic); m/z 313 (M+H)+, (ES+).
Reaction SMILES: [CH3:1][S-:2].[Na+].Br[CH2:5][CH2:6][N:7]1[C:20](=[O:21])[C:19]2[C:18](=[O:22])[C:17]3[CH:16]=[CH:15][C:14]([Cl:23])=[CH:13][C:12]=3[NH:11][C:10]=2[C:9]([OH:24])=[N:8]1>CN(C)C=O>[Cl:23][C:14]1[CH:15]=[CH:16][C:17]2[C:18](=[O:22])[C:19]3[C:20](=[O:21])[N:7]([CH2:6][CH2:5][S:2][CH3:1])[N:8]=[C:9]([OH:24])[C:10]=3[NH:11][C:12]=2[CH:13]=1
Reactant: C[S-]
Reactant: O=c1c2ccc(Cl)cc2[nH]c2c(O)nn(CCBr)c(=O)c12
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCCn1nc(O)c2[nH]c3cc(Cl)ccc3c(=O)c2c1=O
Reaction time: 1 h
Yield: 91 %

Procedure:
To a suspension of sodium thiomethoxide (230 mg, 3.2 mM) in dimethylformamide (20 mL), was added in one portion 2-(2-bromoethyl)-7-chloro-4-hydroxy-1,2,5,10-tetrahydropyridazino-[4,5-b]quinoline-1,10-dione (0.4 g, 1.08 mM, prepared in Example 4a. of docket No. 37811) as a dry powder. This mixture was warmed to gentle reflux for aboutthree hours. At this point the heat was removed and the reaction mixture was poured into ice cold 1.2N HCl (l00 mL) and stirred about one hour. Theresulting precipitate was vacuum filtered and washed with water and ether, then vacuum dried at 50° C. to yield 330 mg (91%) of the title compound as an off white powder. mp=275°-277° C.; MS: 338(M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:29])=[C:9](B(O)O)[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=3)[C:11]=2[C:24]=1[CH3:25])=[O:5].Br[C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][N:34]=1>>[CH:21]([C:18]1[CH:19]=[CH:20][C:15]([CH:12]2[C:11]3[C:24]([CH3:25])=[C:7]([NH:6][C:4](=[O:5])[CH2:3][C:2]([CH3:31])([CH3:30])[CH3:1])[C:8]([CH3:29])=[C:9]([C:33]4[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][N:34]=4)[C:10]=3[O:14][CH2:13]2)=[CH:16][CH:17]=1)([CH3:23])[CH3:22]
Reactant: Cc1ccc(Br)nc1
Reactant: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1B(O)O)OCC2c1ccc(C(C)C)cc1
Product: Cc1ccc(-c2c(C)c(NC(=O)CC(C)(C)C)c(C)c3c2OCC3c2ccc(C(C)C)cc2)nc1
Yield: 67 %

Procedure:
Using (5-((3,3-dimethylbutanoyl)amino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl)boronic acid obtained in Example 116 and 2-bromo-5-methylpyridine, the title compound was obtained in the same manner as in Example 107. Yield: 67%. Melting point: 228-229° C. (ethyl acetate-hexane).
Reaction SMILES: [CH3:1][C:2]1[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[CH:9][C:3]=1[O:4][CH2:5][C:6](O)=[O:7]>CCCCCC>[CH3:14][C:10]1[C:9]2[C:6](=[O:7])[CH2:5][O:4][C:3]=2[C:2]([CH3:1])=[C:12]([CH3:13])[CH:11]=1
Reactant: Cc1cc(C)c(C)c(OCC(=O)O)c1
Solvent: CCCCCC
Product: Cc1cc(C)c2c(c1C)OCC2=O
Yield: 75 %

Procedure:
Using (2,3,5-trimethylphenoxy)acetic acid obtained in Reference Example 158, the title compound was synthesized in the same manner as in Reference Example 41. Yield 75%. Melting point: 92-93° C. (hexane).
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][NH2:21]>C1COCC1.C1(C)C=CC=CC=1>[NH:21]1[C:2]2=[C:10]([C:11]([O:13][CH3:14])=[O:12])[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]2[CH2:18][CH2:19][CH2:20]1
Reactant: COC(=O)c1c(Cl)[nH]c2ccccc12
Reactant: NCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)c1c2n(c3ccccc13)CCCN2
Reaction time: 0.33 h

Procedure:
A solution of methyl 2-chloroindole-3-carboxylate (D11a, 1.5 g, 0.0071 mole) in THF (30 ml) under argon was treated with sodium hydride (215 mg of 80% oil dispersion, 0.0071 mole) and stirred for 20 minutes. The resulting solution was treated with a solution of 3-bromopropylamine (0.0093 mole) in toluene (15 ml) and a white gelatinous precipitate formed. This mixture was diluted with more THF (30 ml) and heated under reflux for 18 h, then concentrated in vacuo and the residue shaken well with ethyl acetate (40 ml) and 10% Na2CO3 solution (30 ml). The organic layer was separated, dried (Na2SO4) and concentrated in vacuo to leave a beige solid. This was chromatographed on silica gel eluting with ether/60-80 petrol (1:1) to afford unreacted starting material (600 mg) and the title compound (D18) as a white solid (110 mg, 6%).
Reaction SMILES: [F:1][C:2]1[C:14]([NH:15][NH2:16])=[CH:13][C:5]2[N:6]([CH:10]([CH3:12])[CH3:11])[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.[OH:17][N:18]=[C:19]1[CH2:24][CH2:23][CH2:22][CH:21]=[C:20]1N1CCOCC1.C(O)(=O)C.O>C(O)C>[CH:10]([N:6]1[C:5]2[CH:13]=[C:14]([N:15]3[N+:18]([O-:17])=[C:19]4[CH2:24][CH2:23][CH2:22][CH2:21][C:20]4=[N:16]3)[C:2]([F:1])=[CH:3][C:4]=2[S:8][C:7]1=[O:9])([CH3:12])[CH3:11]
Reactant: CC(C)n1c(=O)sc2cc(F)c(NN)cc21
Reactant: ON=C1CCCC=C1N1CCOCC1
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CC(C)n1c(=O)sc2cc(F)c(-n3nc4c([n+]3[O-])CCCC4)cc21
Yield: 43.8 %

Procedure:
6-Fluoro-3-(1-methylethyl)-2(3H)-benzothiazolon5-ylhydrazine (1.11 g) and 4-(3-hydroxyimino-1-cyclohexen2-yl)morpholine (0.90 g) were dissolved in ethanol (20 ml), a catalytic amount of acetic acid was added thereto, and the resultant mixture was heated under reflux for 3 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The extract was distilled under reduced pressure to remove the solvent and combined with a mixture of 15% aqueous pyridine (30 ml), tetrahydrofuran (20 ml) and cupric sulfate pentahydrate (2.2 g), followed by refluxing for 2 hours. After cooling, water and ethyl acetate were added to the reaction mixture. The organic layer was separated from the water layer, washed with dilute hydrochloric acid, dried and concentrated. The residue was crystallized from ether to give 2-[3-isopropyl6-fluoro-2(3H)-benzothiazolon-5-yl]-4, 5, 6, 7-tetrahydro-2H-benzotriazole-1-oxide (Compound No. 3; 0.7 g). m.p., 92.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2O)=[N:13][C:14]=1[CH2:15][CH3:16].Br[C:31]1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2CC)=N[C:36]=1CC>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH2:28][CH3:29])[C:12]([NH:17][C@@H:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:20][C@@H:19]2[CH2:31][CH3:36])=[N:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2CC)c(CC)nc1Br
Reactant: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1O
Product: CCc1nc(-c2ccc(Cl)cc2Cl)c(CC)nc1N[C@@H]1c2ccccc2C[C@@H]1CC

Procedure:
Following the procedure for the preparation of (1R,2S)-1-{[5-(2,4-dichlorophenyl)-3,6-diethylpyrazin-2-yl]amino}-2,3-dihydro-1H-inden-2-ol but substituting (+/−)-5-bromo-3,6-diethyl-N-[cis-2-ethyl-2,3-dihydro-1H-inden-1-yl]pyrazin-2-amine and making non-critical variations provided the title compound as a light yellow semi-solid. IR (liq.) 3452, 2965, 2934, 2874, 1589, 1566, 1551, 1495, 1470, 1392, 1377, 1203, 1175, 1101, 752 cm−1; OAMS supporting ions at: ESI+ 439.8; HRMS (FAB) calcd for C25H27CL2N3+H1 440.1660, found 440.1648. Anal. Calcd for C25H27Cl2N3: C, 68.18; H, 6.18; N, 9.54. Found: C, 68.33; H, 6.36; N, 9.30.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20](OCC)=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:26][C@@H:27]([OH:30])[CH2:28][NH2:29]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:25])=[C:14]([C:20]([NH:29][CH2:28][C@H:27]([OH:30])[CH3:26])=[O:21])[C:15](=[O:19])[NH:16]3)=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O
Reactant: C[C@@H](O)CN
Product: C[C@@H](O)CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2[nH]c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and R-(−)-1-amino-2-propanol employing methods similar to those described in Example 2 and was obtained as a white solid: 1H NMR (d6-DMSO) tautomers are observed δ 11.81 (1H, t, J=5.7), 10.81 (1H, br s), 10.10 (1H, br s), 8.18 (0.58H, s), 8.15 (0.42H, s), 7.36-7.23 (3H, m), 7.15-7.08 (2H, m), 4,74 (1H, t, J=4.4 Hz), 3.98 (2H, s), 3.75-3.65 (1H, m), 3.26-3.15 (2H, m), 1.06 (3H, m); HRMS calcd for C19H18FN3O4+H+: 372.1360. Found 372.1367.
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([NH2:15])=[N:8][C:9]([S:12][CH2:13][CH3:14])=[N:10][CH:11]=1)=[O:5].Br[C:18]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[CH:20][C:19]=1[O:26][CH3:27]>>[NH2:15][C:7]1[C:6]([C:4]([C:18]2[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[CH:20][C:19]=2[O:26][CH3:27])=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH2:13][CH3:14])[N:8]=1
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Reactant: COc1cccc(OC)c1Br
Product: CCSc1ncc(C(=O)c2c(OC)cccc2OC)c(N)n1

Procedure:
The same procedure as described in Example 47 was used, starting from 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methyl-amide (Example 1) and 2-bromo-3-methoxyanisole (Aldrich), to give (4-amino-2-ethylsulfanyl-pyrimidin-5-yl)-(2,6-dimethoxy-phenyl)-methanone as a white solid. MS (M+H)+, 320.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4](/[CH:10]=[C:11](\[C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)/[C:12]#[N:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].C([NH:33][C@H:34]([C:38]([NH2:40])=[O:39])[C@@H:35]([CH3:37])[OH:36])(OC(C)(C)C)=O.[ClH:41].O1CCOCC1.C(OCC)C>ClCCl>[NH2:1][C:2]1[CH:3]=[C:4](/[CH:10]=[C:11](\[C:14]2[CH:15]=[C:16]([O:24][CH3:25])[C:17]([O:22][CH3:23])=[C:18]([O:20][CH3:21])[CH:19]=2)/[C:12]#[N:13])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[ClH:41].[NH2:33][C@H:34]([C:38]([NH2:40])=[O:39])[C@@H:35]([CH3:37])[OH:36]
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(N)=O
Agent: COc1ccc(/C=C(/C#N)c2cc(OC)c(OC)c(OC)c2)cc1N
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCOCC
Product: C[C@@H](O)[C@H](N)C(N)=O

Procedure:
(E)-3-(3-Amino-4-methoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-prop-2-enenitrile-Boc-L-threonineamide (810 mg, 1.95 mmols) were dissolved in 10 ml of dichloromethane, and 5 ml of a solution of 4-M hydrochloric acid and dioxane were added thereto. The mixture was reacted at 60° C. for 3 hours. One-hundred milliliters of diethyl ether were added thereto, and the mixture was filtered. The resulting powder was purified twice through medium-pressure liquid chromatography (ODS, mixture of water and acetonitrile at a ratio of 75:25), and was dissolved in a small amount of methanol. A mixture of acetonitrile and ethyl acetate was added thereto, and the precipitate was collected by filtration to obtain 290 mg (0.607 mmols) of the final product in a yield of 31%.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.N#N.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH:22]1[C:27]([C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29])=[C:26]([CH3:34])[N:25]([CH2:35][CH3:36])[C:24]2[CH2:37][O:38][C:39](=[O:40])[C:23]1=2.BrBr.C1CCCCC=1.C1C[O:52]CC1>>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH:22]1[C:27]([C:28]([O:30][CH:31]([CH3:33])[CH3:32])=[O:29])=[C:26]([CH3:34])[N:25]([CH2:35][CH3:36])[C:24]2[CH:37]([OH:52])[O:38][C:39](=[O:40])[C:23]1=2
Reactant: CCN1C(C)=C(C(=O)OC(C)C)C(c2ccccc2Cl)C2=C1COC2=O
Reactant: C1CCOC1
Agent: BrBr
Agent: N#N
Agent: [Li]CCCC
Solvent: C1=CCCCC1
Solvent: CC(C)NC(C)C
Product: CCN1C(C)=C(C(=O)OC(C)C)C(c2ccccc2Cl)C2=C1C(O)OC2=O
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
60 mmol of diisopropylamine in 100 ml of analytical grade tetrahydrofuran are initially taken. 50 mmol of butyllithium are added at a temperature of 0°C., under a stream of N2. Thereafter, the mixture is cooled to -78° C. and a solution of 50 mmol of isopropyl 4-(2-chlorophenyl)-1-ethyl-2-methyl-5-oxo-1,4,5,7-tetrahydrofuro[3,4-b]pyridine3-carboxylate (dissolved in THF) is added dropwise. The mixture is stirred for 15 minutes at -78° C., and this solution is pumped, with the aid of nitrogen, into a solution of 50 mmol of Br2 and 50 ml of THF, and immediately thereafter 50 mmol of cyclohexene are added and the mixture is allowed to warm up to room temperature and is evaporated down, the residue is dissolved in DMSO, and H2O is added until the mixture starts to become cloudy. The mixture is left to stand for 12 hours, and the product is precipitated with H2O, filtered off under suction and separated with 9:1 CHCl3 /MeOH over silica gel.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH2:30][C:31]#[C:32][CH2:33][CH3:34])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.CO.[OH-].[Na+]>C1COCC1>[Br:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][N:9]2[CH2:10][CH2:11][C:6]([S:20]([C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:30][C:31]#[C:32][CH2:33][CH3:34])=[CH:27][CH:28]=3)(=[O:22])=[O:21])([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)=[CH:18][CH:17]=1
Reactant: CCC#CCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccc(Br)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCC#CCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccc(Br)cc3)CC2)cc1

Procedure:
1-(4-Bromo-benzyl)-4-(4-pent-2-ynyloxy-benzenesulfonyl)-piperdine-4-carboxylic acid was prepared starting from 1-(4-bromo-benzyl)-4-(4-pent-2-ynyloxy-benzenesulfonyl)-piperdine-4-carboxylic acid ethyl ester (2.64 g 4.8 mmol) dissolved in THF:methanol (100:50 ml) and 10 N NaOH (10 ml). The resulting reaction mixture was worked up as outlined in Example 1 (Step 7). Yield 1.6 g (65%); off white solid; mp 217° C.; MS: 521.9 (M+H)+.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[S:20][C:19]([C:21]([O:23]C)=[O:22])=[CH:18][C:9]=3[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C=O)C.CCOCC.O>[CH2:27]([N:10]1[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:8]2[S:20][C:19]([C:21]([OH:23])=[O:22])=[CH:18][C:9]1=2)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)c1cc2[nH]c(-c3ccccc3)c(C3CCCCC3)c2s1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: O=C(O)c1cc2c(s1)c(C1CCCCC1)c(-c1ccccc1)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22 %

Procedure:
A solution (0.15 M) of methyl 6-cyclohexyl-5-phenyl-4H-thieno[3,2-b]pyrrole-2-carboxylate in DMF at 0° C. was treated with NaH (3.5 eq., 60% dispersion in mineral oil), and the suspension was stirred at RT for 30 min then it was treated with benzyl bromide (2.5 eq.). The reaction mixture was stirred at RT for 3 h then it was diluted with Et2O and water then the layers were separated and the aqueous phase was extracted with AcOEt. The combined organic phase was dried and concentrated giving a residue that was purified by flash chromatography on silica gel (1:10 MeOH/DCM) affording the title compound (22%) as a solid.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH2:5][C:6]1[N:10]=[CH:9][NH:8][N:7]=1.[B:16]1(B2OCC(C)(C)CO2)[O:21]CC(C)(C)C[O:17]1.C([O-])(=O)C.[K+]>CS(C)=O>[CH3:15][O:14][C:13]1[CH:12]=[CH:11][C:4]([CH2:5][C:6]2[N:10]=[CH:9][NH:8][N:7]=2)=[CH:3][C:2]=1[B:16]([OH:21])[OH:17]
Reactant: CC1(C)COB(B2OCC(C)(C)CO2)OC1
Reactant: COc1ccc(Cc2nc[nH]n2)cc1I
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(Cc2nc[nH]n2)cc1B(O)O
Temperature: 80 °C

Procedure:
A mixture of 3-(3-iodo-4-methoxybenzyl)-1H-1,2,4-triazole (Step B) (397 mg, 1.260 mmol), bis(neopentyl glycolato)diboron (342 mg, 1.512 mmol), potassium acetate (495 mg, 5.04 mmol), and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (51.4 mg, 0.063 mmol) in DMSO (10 ml) was degassed flushing with nitrogen and heated at 80° C. overnight. The reaction was diluted with ethyl acetate and washed with water followed by brine, dried over sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to afford the crude title product that was used without further purification. Mass spectrum (ESI) 234.3 (M+1).
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:7]=[C:8]([C:14]([OH:16])=[O:15])[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:28]=[N:29][NH:30][CH:31]=2)O1.C(=O)(O)[O-].[Na+].O.C(#N)C>C(OCC)(=O)C.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>[NH:29]1[CH:28]=[C:27]([C:2]2[CH:18]=[CH:17][C:5]3[C:6]4[N:7]=[C:8]([C:14]([OH:16])=[O:15])[S:9][C:10]=4[CH2:11][CH2:12][O:13][C:4]=3[CH:3]=2)[CH:31]=[N:30]1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
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: CCOC(C)=O
Solvent: CC#N
Product: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Temperature: 150 °C
Yield: 104.2 %

Procedure:
To a degassed solution of 8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (1.40 g, 4.29 mmol), 4,4,5,5-Tetramethyl-2-(1H-pyrazol-4-yl)-1,3,2-dioxaborolane (1.0 g, 5.0 mmol), 2 M Sodium bicarbonate in water (6.0 mL, 10.0 mmol) and acetonitrile (8.0 mL, 200 mmol) in a microwave vial was added Tetrakis(triphenylphosphine)palladium(0) (0.499 g, 0.432 mmol). The vial was heated on the Emrys microwave at 150° C. for 20 minutes. Cooled to room temperature and diluted with ethyl acetate, the precipitate was filtered off, washed with ethyl acetate and water and dried under vacuum to give 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (1.4 g, 103% yield).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH2:6]([O:8][C:9]([C:11]1[C:15]([CH3:16])=[CH:14][NH:13][C:12]=1[CH3:17])=[O:10])[CH3:7].CN(C)[CH:20]=[O:21]>>[CH2:6]([O:8][C:9]([C:11]1[C:15]([CH3:16])=[C:14]([CH:20]=[O:21])[NH:13][C:12]=1[CH3:17])=[O:10])[CH3:7]
Reactant: CCOC(=O)c1c(C)c[nH]c1C
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1c(C)[nH]c(C=O)c1C
Temperature: 0 °C

Procedure:
Into a 5-L four necked round-bottomed flask equipped with a mechanical stirrer, a thermometer pocket, addition funnel, air condenser and a nitrogen bubbler was charged dimethyl formamide (1.05 L). The solvent was cooled to 0° C. To this chilled solvent, phosphorous oxychloride (0.434 L) was charged at below 5° C. After addition, the temperature of the reaction mixture was slowly brought to 25-30° C. Then a solution of 2,4-dimethyl-1H-pyrrole-3-carboxylic acid ethyl ester (III) (0.7 Kg; 4.2 mole) dissolved in dimethyl formamide (1.05 L) was added drop-wise into the flask at 25-30° C. After addition, the temperature of the reaction mixture was brought to 50° C. and maintained for 2-3 hours. The reaction was monitored by TLC. After maintenance, the reaction mixture was cooled to 25-30° C. and quenched in a carboy containing ice-water. The pH of the solution was then adjusted to 12-13 using aq. KOH solution. After pH adjustment, the solution was stirred at 25-30° C. and filtered and washed with water. The product was dried in a hot air oven at 60° C.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:5]=1[CH:6]([OH:8])[CH3:7].[F:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19](F)[C:16]=1[C:17]#[N:18]>CN(C=O)C>[F:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:5]=1[CH:6]([O:8][C:19]1[CH:20]=[CH:21][CH:22]=[C:15]([F:14])[C:16]=1[C:17]#[N:18])[CH3:7]
Reactant: N#Cc1c(F)cccc1F
Reactant: CC(O)c1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(Oc1cccc(F)c1C#N)c1c(F)cccc1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.3 %

Procedure:
To a cold (ice water) suspension of sodium hydride (409 mg; 10 mmol) in anhydrous DMF (4 mL) is added a solution of 2,6-difluoro-alpha-methylbenzyl alcohol (1.63 g; 10 mmol) in anhydrous DMF (5 mL) over 10 minutes. After allowing to room temperature over 1 hour, this solution is added to a cold (ice water) stirred solution of 2,6-difluorobenzonitrile (1.53 g; 11 mmol) in anhydrous DMF (6 mL), and allowed to room temperature over 2.5 hours. The reaction mixture is poured into ice water with vigorous stirring and the resulting solid is filtered, washed with water, and dried under vacuum at 40° C. overnight to give 1.92 grams of 2-[1-(2,6-difluorophenyl)-ethoxy]-6-fluorobenzonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH2:14]Br.[H-].[Na+].CC(O)C>CS(C)=O.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2([C:7]#[N:8])[CH2:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1
Reactant: BrCCCBr
Reactant: N#CCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Solvent: CS(C)=O
Product: N#CC1(c2ccc(Cl)cc2)CCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 4-chlorobenzyl cyanide (10 g) and 1,3-dibromopropane (7.5 ml) in dry dimethyl sulphoxide (12 ml) was added dropwise under nitrogen to a stirred mixture of sodium hydride (3.6 g) dispersed in mineral oil (3,6 g) and dimethylsulphoxide (70 ml) at a temperature in the range 30° to 35° C. The mixture was stirred at room temperature for two hours and then propan-2-ol (10 ml) and water (150 ml) were added dropwise. The mixture was filtered through a diatomaceous earth sold under the Registered Trade Mark CELITE and the solid residue washed with ether. The filtrate was extracted with ether and the ether phases combined, washed with water, dried and evaporated. 1-(4-chlorophenyl)-1-cyclobutanecarbonitrile (b.p. 116°-120° at 0.6 mm Hg) was isolated by distillation. This method is a modification of that described by Butler and Pollatz (J.Org.Chem., Vol. 36, No. 9, 1971, p. 1308).