Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.Cl.[O:16]([NH2:18])[CH3:17].C(=O)(O)[O-].[Na+]>C1COCC1.O>[C:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][C:2](=[N:18][O:16][CH3:17])[CH2:3][CH2:4]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: CON
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CON=C1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.17 h
Yield: 92.5 %

Procedure:
A solution of tert-butyl 4-oxo-1-piperidinecarboxylate (2.0 g) and methoxylamine hydrochloride (2.93 g) in THF (66 mL) was treated with sodium bicarbonate (2.95 g) dissolved in water (20 mL). The biphasic mixture was stirred vigorously for 10 minutes, diluted with water, and extracted with ethyl acetate (×3). The combined extracts were dried over magnesium sulfate, filtered and concentrated to afford 2.12 g of the title compound, which was used without further purification. 1H NMR (CDCl3, 300 MHz) δ ppm 1.49 (s, 9H), 2.34 (t, 2H, J=6.07 Hz), 2.57 (t, 2H, J=6.07 Hz), 3.51 (t, 2H, J=6.07 Hz), 3.56 (t, 2H, J=6.07 Hz), 3.85 (s, 3H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C:13]1[CH:14]=[C:15]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][OH:28])=[C:23]([CH2:29][OH:30])[CH:22]=2)[CH:16]=[CH:17][C:18]=1[CH2:19][OH:20].C(N(CC)CC)C>ClCCl.ClCCl.CS(C)=O>[C:21]1([C:15]2[CH:16]=[CH:17][C:18]([CH:19]=[O:20])=[C:13]([CH:12]=[O:11])[CH:14]=2)[CH:26]=[CH:25][C:24]([CH:27]=[O:28])=[C:23]([CH:29]=[O:30])[CH:22]=1
Reactant: OCc1ccc(-c2ccc(CO)c(CO)c2)cc1CO
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=Cc1ccc(-c2ccc(C=O)c(C=O)c2)cc1C=O
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 26 %

Procedure:
To a solution of oxalyl chloride 2M in dichloromethane (DCM) (2.8 mL, 5.6 mmol, 4.4 molar equivalents) cooled to −78° C. is added dropwise a solution of dimethylsulfoxyde (DMSO) (0.8 mL, 11.1 mmol, 8.8 molar equivalents) in DCM (10 ml). The solution is stirred at −78° C. for 5 min and 3,3′,4,4′-tetra(hydroxymethyl)-1,1′-biphenyl 1c (0.22 g, 1.3 mmol, 1.0 molar equivalent) dissolved in a mixture of DCM-DMSO (1 ml-2 ml) is added dropwise. The solution is stirred for 1 h at −78° C. and triethylamine (6 mL) is slowly added at −78° C. The reaction mixture is stirred 10 minutes at −78° C. and slowly warmed up to room temperature. Ice-cold water (30 ml) is added to the reaction mixture and the aqueous layer extracted with DCM (3×30 ml). The organic fractions are combined, dried over magnesium sulfate, filtered and concentrated in vacuum to give a brown oil. Purification by column chromatography on silica gel (eluent: hexane-ethyl acetate 6/4) gave the title compound as an off-white powder (90 mg, 42%). 1H NMR (300.13 MHz, CDCl3) δ (ppm) 8.02 (dd, J1=8.1, J2=1.8 Hz, 2H) 8.14 (d, J=8.1 Hz, 2H) 8.28 (d, J=1.8 Hz, 2H) 10.58 (s, 2H) 10.68 (s, 2H).
Reaction SMILES: C[S:2](Cl)(=[O:4])=[O:3].[NH:6]1[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([N:21]3[CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22]3)=[O:20])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1.N[C:31]1C=C2C(=[CH:38][CH:39]=1)CN(C(NC1C=CC(C(=O)NCCC)=CC=1)=O)C2>>[CH:39]([S:2]([N:6]1[CH2:7][CH:8]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([N:21]3[CH2:22][C:23]4[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:29]3)=[O:20])=[CH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:4])=[O:3])([CH3:38])[CH3:31]
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(N)cc3C2)cc1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(Nc1ccc(C2=CCNCC2)cc1)N1Cc2ccccc2C1
Product: CC(C)S(=O)(=O)N1CC=C(c2ccc(NC(=O)N3Cc4ccccc4C3)cc2)CC1

Procedure:
The title compound was prepared as described in Example 283, substituting propane-2-sulfonyl chloride for methanesulfonyl chloride and N-[4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl]-1,3-dihydro-2H-isoindole-2-carboxamide for 5-amino-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.38-8.40 (m, 1H), 7.56-7.59 (m, 2H), 7.29-7.38 (m, 6H), 6.11-6.14 (m, 1H), 4.76-4.80 (m, 4H), 3.93-3.96 (m, 2H), 3.49 (t, J=5.5 Hz, 2H), 3.35-3.45 (m, 1H), 2.47-2.51 (m, 2H), 1.24 (d, J=6.9 Hz, 6H); MS (ESI(−)) m/e 424 (M−H)−.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([C:15](OCC)=[O:16])[S:13][CH:14]=2)=[CH:6][CH:5]=1.O.[NH2:23][NH2:24]>CO>[F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([C:15]([NH:23][NH2:24])=[O:16])[S:13][CH:14]=2)=[CH:6][CH:5]=1
Reactant: NN
Reactant: CCOC(=O)c1nc(-c2ccc(OC(F)(F)F)cc2)cs1
Solvent: CO
Solvent: O
Product: NNC(=O)c1nc(-c2ccc(OC(F)(F)F)cc2)cs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.5 %

Procedure:
To a solution of ethyl 4-(4-(trifluoromethoxy)phenyl)thiazole-2-carboxylate (10.0 g, 31.5 mmol) in MeOH (80 mL) was added hydrazine hydrate (1.95 g, 33.1 mmol; 85%) dropwise over 15 minutes, and the resulting mixture was stirred for a further 16 h at RT. The mixture was then concentrated under reduced pressure to half volume, and H2O (30 mL) was added. A white solid precipitated, was filtered, washed with H2O (3×30 mL) and dried to afford the title compound as a white solid (9.6 g, 100%). MS (ES+) C11H8F3N3O2S requires: 303. found: 304[M+H]+.
Reaction SMILES: [O:1]([C:8]1[N:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([C:24](O)=[O:25])=[CH:16]1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[O:1]([C:8]1[N:13]=[CH:12][C:11]([NH:14][C:24]([C:17]2[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[NH:15][CH:16]=2)=[O:25])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(Oc2ccccc2)nc1
Reactant: O=C(O)c1c[nH]c2ccccc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Oc2ccccc2)nc1)c1c[nH]c2ccccc12
Temperature: 60 °C
Reaction time: 8 h
Yield: 17 %

Procedure:
The 6-phenoxypyridine-3-amine (200 mg, 1.07 mmol) and indole-3-carboxylic acid (200 mg, 1.07 mmol) were dissolved in DMF (5 ml), DCC (200 mg, 1.07 mmol) was added to the solution, and then the mixture was stirred at 60° C. for 8 hours. After the reaction was completed, the product was washed and filtered to yield a target compound as a white solid (60 mg, 17%) by chromatography (methanol:dichloromethane=1:30).
Reaction SMILES: C(O[CH:6](N(C)C)[N:7]([CH3:9])[CH3:8])(C)(C)C.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[C:21]2[C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[C:33]([CH3:40])[CH:32]=2)=[CH:16][CH:15]=1>CN(C=O)C>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=[C:21]2[C:31]2[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[C:33](/[CH:40]=[CH:6]/[N:7]([CH3:9])[CH3:8])[CH:32]=2)=[CH:16][CH:15]=1
Reactant: Cc1cc(-c2nc3ccccc3c(=O)n2-c2ccc(Br)cc2)ccc1[N+](=O)[O-]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Solvent: CN(C)C=O
Product: CN(C)/C=C/c1cc(-c2nc3ccccc3c(=O)n2-c2ccc(Br)cc2)ccc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 2 h
Yield: 95.4 %

Procedure:
tert-Butoxybis(dimethylamino)methane (2.0 mL, 9.60 mmol) was added to a solution of 3-(4-bromophenyl)-2-(3-methyl-4-nitrophenyl)quinazolin-4(3H)-one (1.4 g, 3.20 mmol) in DMF (30 mL). Stirring at 60° C. for 2 hours and concentrating in vacuo afforded (E)-3-(4-bromophenyl)-2-(3-(2-(dimethylamino)vinyl)-4-nitrophenyl)quinazolin-4(3H)-one (1.5 g, quantitative).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH:8]=[C:9]([N:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1)[C:10]1[CH:32]=[CH:31][C:13]([C:14]([O:16][C@@H:17]([CH2:19]OS(C2C=CC(C)=CC=2)(=O)=O)[CH3:18])=[O:15])=[CH:12][CH:11]=1.[Br-:38].[Li+]>CN(C=O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH:8]=[C:9]([N:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1)[C:10]1[CH:32]=[CH:31][C:13]([C:14]([O:16][C@@H:17]([CH2:19][Br:38])[CH3:18])=[O:15])=[CH:12][CH:11]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H](C)OC(=O)c2ccc(C(=N)N3CCCC3)cc2)cc1
Reactant: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: C[C@H](CBr)OC(=O)c1ccc(C(=N)N2CCCC2)cc1
Temperature: 50 °C
Reaction time: 48 h

Procedure:
(2R)-3-{[(4-methylphenyl)sulfonyl]oxy}-2-propyl 4-[imino(pyrrolidin-1-yl)methyl]benzoate trifluoroacetate (45.1 mg, 0.083 mmol) obtained in Step 1 was dissolved in DMF (2 ml), lithium bromide (72 mg, 0.83 mmol) was added thereto, and the mixture was stirred at 50° C. for 2 days. The solvent was evaporated under reduced pressure, and the obtained residue was purified by reversed-phase HPLC in the same manner as in Step 4 of Example 1 to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([N+:14]([O-])=O)[CH:6]=1.Cl.[NH2:26][CH2:27][C:28]#N.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O>[Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[C:7]([NH:14][CH2:28][C:27]#[N:26])[CH:6]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1[N+](=O)[O-]
Reactant: N#CCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: N#CCNc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Yield: 15.4 %

Procedure:
Into a flask equipped with a reflux condenser, magnetic stirrer, nitrogen inlet and heating mantle, there was added 4-(2-chloro-4-(trifluoromethyl)-phenoxy)-1,2-dinitrobenzene (5 gm, 0.014 mol), aminoacetonitrile hydrochloride (5.1 gm, 0.055 mol), anhydrous potassium carbonate (7.4 gm, 0.053 formula weight) and 50 ml of dioxane. The solution was sirred and refluxed overnight, cooled and poured into water. Following ether extraction, the organic layer was dried and evaporated to a residue. The residual material was chromatographed over silica gel using 15% acetone and 85% hexane as the eluant to yield 800 mg of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5](C(Cl)=O)=[CH:4][N:3]=1.[CH3:11][Mg]I.C([O:16][CH2:17][CH3:18])C>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:17]([OH:16])([CH3:18])[CH3:11])=[CH:9][CH:10]=1
Reactant: CCOCC
Reactant: C[Mg]I
Reactant: O=C(Cl)c1ccc(Cl)nc1
Product: CC(C)(O)c1ccc(Cl)nc1

Procedure:
A solution of 6-chloronicotinoyl chloride (38.037 g, 216 mmol, Eq: 1.00) in anhydrous diethyl ether (200 ml) was added dropwise to a stirred 3 M methylmagnesium iodide solution (158 ml, 475 mmol, Eq: 2.2) at room temperature. After the addition the reaction mixture was refluxed for 3 hours. Reaction was quenched by pouring it to a stirred mixture of ice/200 ml acetic acid; sodium bicarbonate was added until pH 8; extracted with diethyl ether; washed with brine; dried over sodium sulfate; filtered; concentrated to give a yellow solid (30.15 g, 0.175 mol)
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:64]([CH3:67])[CH2:65][CH3:66])[C@H:26]([O:62][CH3:63])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:60][CH3:61])[C@@H:36]([CH3:59])[C:37](=[O:58])[NH:38][C@@H:39]([C:47]1[O:48][C:49]([C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)=[N:50][N:51]=1)[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH:11]([CH3:13])[CH3:12].O=[CH:69][CH2:70][CH2:71][C:72]([OH:74])=[O:73].C([BH3-])#N.[Na+].O1CCOCC1>O1CCOCC1.O>[C:72]([CH2:71][CH2:70][CH2:69][N:9]([CH3:8])[C@H:10]([C:14]([NH:16][C@H:17]([C:21]([N:23]([C@@H:25]([C@@H:64]([CH3:67])[CH2:65][CH3:66])[C@H:26]([O:62][CH3:63])[CH2:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[C@H:35]([O:60][CH3:61])[C@@H:36]([CH3:59])[C:37](=[O:58])[NH:38][C@@H:39]([C:47]1[O:48][C:49]([C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=2)=[N:50][N:51]=1)[CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)=[O:29])[CH3:24])=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH:11]([CH3:12])[CH3:13])([OH:74])=[O:73]
Reactant: O=CCCC(=O)O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](Cc1ccccc1)c1nnc(-c2ccccc2)o1)OC)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)C)C(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@H](Cc1ccccc1)c1nnc(-c2ccccc2)o1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C

Procedure:
17.1 mg (18 μmol) of N-methyl-L-valyl-N-[(3R,4S,5S)-3-methoxy-1-{(2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-oxo-3-{[(1R)-2-phenyl-1-(5-phenyl-1,3,4-oxadiazol-2-yl)ethyl]amino}propyl]pyrrolidin-1-yl}-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide trifluoroacetate were dissolved in 1.1 ml of dioxane/water and, analogously to the preparation of Intermediate 61, reacted with 15% aqueous solution of 4-oxobutanoic acid in the presence of sodium cyanoborohydride. After lyophilization from dioxane, 14.8 mg (89% of theory) of the title compound were obtained in the form of a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:11][CH:12]([C:17]([F:20])([F:19])[F:18])[C:13]([F:16])([F:15])[F:14])=[N:4][CH:5]=[C:6]([N+:8]([O-])=O)[CH:7]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[N:4][C:3]=1[O:11][CH:12]([C:13]([F:14])([F:15])[F:16])[C:17]([F:20])([F:19])[F:18]
Reactant: O=[N+]([O-])c1cnc(OC(C(F)(F)F)C(F)(F)F)c(Cl)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cnc(OC(C(F)(F)F)C(F)(F)F)c(Cl)c1
Temperature: 25 °C
Yield: 85.9 %

Procedure:
3-Chloro-2-(1,1,1,3,3,3-hexafluoropropan-2-yloxy)-5-nitropyridine (Preparation 255, 2.55 g, 7.9 mmol), ammonium chloride (2.50 g, 46.7 mmol) and iron powder (1.70 g, 30.4 mmol) were suspended in a mixture of ethanol (10 mL) and water (3 mL). The suspension was heated for 3 hours under reflux then allowed to cool to room temperature. The reaction mixture was filtered on a Celite™ pad and the pad was washed with ethanol. The filtrate was concentrated in vacuo and the crude residue was partitioned between water and ethyl acetate. The aqueous layer was separated and extracted by ethyl acetate (2×25 mL). Organic layers were combined, dried over magnesium sulfate and concentrated in vacuo. The crude residue was purified by silica gel chromatography eluting with 50% diethyl ether in heptane to afford the title compound as a light yellow oil (2.0 g, 87%).
Reaction SMILES: C([NH:9][C:10]([NH:12][CH:13]1[C:22]2[N:21]=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=2[CH2:16][CH2:15][CH2:14]1)=[S:11])(=O)C1C=CC=CC=1.[OH-].[Na+].Cl>>[C:10]([NH:12][CH:13]1[C:22]2[N:21]=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=2[CH2:16][CH2:15][CH2:14]1)(=[S:11])[NH2:9]
Reactant: Cc1cnc2c(c1)CCCC2NC(=S)NC(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cnc2c(c1)CCCC2NC(N)=S
Yield: 98 %

Procedure:
8-Benzoylthiocarbamoylamino-3-methyl-5,6,7,8-tetrahydroquinoline (6 g.) was treated with a 10% sodium hydroxide solution (24 ml.) and the mixture heated on a steam bath for 15 minutes. The cooled reaction mixture was adjusted to pH 1.0 with conc. HCl, filtered to remove benzoic acid and the filtrate adjusted to pH 10.0 with aqueous ammonia. The resultant solid was recrystallised from ethanol to give the hydrate of the title compound as colourless needles (4 g.).m.p. 114° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:12])([CH3:11])[CH2:9][CH3:10])[CH:5]=[CH:4][C:3]=1[OH:13].[CH2:14]([CH:16]1[O:18][CH2:17]1)Cl>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:12])([CH3:11])[CH2:9][CH3:10])[CH:5]=[CH:4][C:3]=1[O:13][CH2:14][CH:16]1[CH2:17][O:18]1
Reactant: CCC(C)(C)c1ccc(O)c(Cl)c1
Reactant: ClCC1CO1
Product: CCC(C)(C)c1ccc(OCC2CO2)c(Cl)c1

Procedure:
The title compound was prepared from 2-chloro-4-(1,1-dimethyl-propyl)-phenol and epichlorohydrin employing the procedures as set forth in Step 1 of Example 2.
Reaction SMILES: [C:1]1(C([O-])=O)(C)[CH2:6][CH2:5][CH:4]([CH:7](C)[CH3:8])[CH:3](O)[CH2:2]1.[Na+].CN(C)CCN(C)C>>[CH2:6]=[CH:1][CH:2]=[CH2:3].[CH2:8]=[CH:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: CC(C)C1CCC(C)(C(=O)[O-])CC1O
Agent: CN(C)CCN(C)C
Agent: [Na+]
Product: C=CC=C
Product: C=Cc1ccccc1

Procedure:
The procedure described in Example 1 was utilized in this example except that 1 mL of 1 M solution of sodium alkoxide (NaOR), i.e., sodium mentholate, in hexanes and 1 mL of 1 M solution of N,N,N′,N′-tetramethylethylene diamine (TMEDA) in hexanes were added to the catalyst system (BaTHFA/MgR2) making the molar ratio (BaTHFA/MgR2/NaOR/TMEDA) 1:3:1:1. The styrene-butadiene produced was determined to have a glass transition temperature (Tg) at −77° C. and a melting temperature (Tm) at +8° C. The Mooney viscosity (ML-4) at 100° C. was 89. The GPC measurements indicated that the polymer has a number average molecular weight (Mn) of 284,600 g/mol and a weight average molecular weight (Mw) of 350,800 g/mol. The polydispersity (Mw/Mn) of the resulting polymer was 1.23. Carbon-13 NMR analysis showed a trans 1,4 polybutadiene content of 74.20%, cis 1,4 polybutadiene content of 19.80%, a 1,2 polybutadiene content of 6%, and a polystyrene content of 18%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[C:13]([NH2:18])=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[H-].[Na+].Cl[CH2:22][CH2:23][S:24](Cl)(=[O:26])=[O:25].O>C1COCC1.CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[C:13]3=[N:18][S:24](=[O:26])(=[O:25])[CH2:23][CH2:22][N:14]3[CH:15]=[CH:16][CH:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CC(C)Oc1ccc(-c2cccnc2N)cc1Cl
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CC(C)Oc1ccc(C2=CC=CN3CCS(=O)(=O)N=C23)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-(3-chloro-4-isopropoxyphenyl)pyridin-2-amine (770 mg) in THF (dry) (10 mL) was added to a suspension of NaH (60%, 586 mg) and 2-chloroethanesulfonyl chloride (0.919 mL) in THF (dry) (10 mL) at 0° C. The mixture was stirred at room temperature overnight. Water and hexane were added to give a white precipitate. The precipitate was collected by filtration, washed with water and EtOAc and crystallized from THF-IPE to give the title compound (600 mg) as a white solid.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[N:11]=[C:12]([C:14]1[N:19]=[C:18]([C:20](=O)[CH3:21])[CH:17]=[CH:16][CH:15]=1)[CH3:13])([CH3:3])[CH3:2].[CH:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[NH2:32])([CH3:25])[CH3:24]>C1(C)C=CC=CC=1>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:5]=1[N:11]=[C:12]([C:14]1[CH:15]=[CH:16][CH:17]=[C:18]([C:20](=[N:32][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[CH:23]([CH3:25])[CH3:24])[CH3:21])[N:19]=1)[CH3:13])([CH3:3])[CH3:2]
Reactant: CC(=O)c1cccc(C(C)=Nc2c(C)cccc2C(C)C)n1
Reactant: CC(C)c1ccccc1N
Solvent: Cc1ccccc1
Product: CC(=Nc1ccccc1C(C)C)c1cccc(C(C)=Nc2c(C)cccc2C(C)C)n1

Procedure:
4.0 g (0.0135 mol) of 1-{6-[1-(2-isopropyl-6-methyl-phenylimino)-ethyl]-pyridin-2-yl}-ethanone 15, 2.76 g (0.0204 mol) of 2-Isopropyl-phenylamine 9 (4.0 g, 0.0135 mol), 100 g of fresh molecular sieves, and 100 ml of toluene were kept at 100° C. for 3 days under a flow of nitrogen. The solvent was removed in a rotary evaporator and the residue was recrystallized from 10 ml of ethanol. The yield of (2-Isopropyl-6-methyl-phenyl)-(1-{6-[1-(2-isopropyl-phenylimino)-ethyl]-pyridin-2-yl}-ethylidene)-amine 16 was 4.83 g (87%) as a yellow solid. 13C NMR (500 MHz, CD2Cl2, TMS (selected signals)), δ 166.9 (C═N), 166.2 (C═N).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:15][C:16]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([F:27])[CH:25]=3)[NH:20][C:19]=2[CH3:28])=[O:17])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])#[N:2].C(=O)([O-])[O-].[K+].[K+].[C:35]([O:38][CH2:39][CH2:40]Br)(=[O:37])[CH3:36].CN(C)C=O>O>[C:35]([O:38][CH2:39][CH2:40][N:20]1[C:21]2[C:26](=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:18]([C:16]([NH:15][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:3]([C:1]#[N:2])[CH:4]=2)=[O:17])=[C:19]1[CH3:28])(=[O:37])[CH3:36]
Reactant: Cc1[nH]c2ccc(F)cc2c1C(=O)Nc1ccc(OCC(C)(C)C)c(C#N)c1
Reactant: CC(=O)OCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCCn1c(C)c(C(=O)Nc2ccc(OCC(C)(C)C)c(C#N)c2)c2cc(F)ccc21
Temperature: 40 °C
Reaction time: 3 h
Yield: 30.6 %

Procedure:
N-(3-Cyano-4-neopentyloxyphenyl)-5-fluoro-2-methyl-1H-indole-3-carboxamide ¼ hydrate (0.8 g) obtained in Example 9,. potassium carbonate (0.2 g) and 2-bromoethyl acetate (0.4 g) were added to dimethylformamide (5 ml) and the mixture was stirred at 40° C. for 3 hr. Then the reaction mixture was treated with water and the oganic layer was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was separated and purified by silica gel column chromatography (mobile phase: chloroform) to give the title compound (0.3 g). melting point: 124-125° C.
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]1[O:10][C:11]1[CH:21]=[CH:20][C:14]2[C:15]([CH2:18]O)=[CH:16][O:17][C:13]=2[CH:12]=1.O=S(Cl)[Cl:24]>C(Cl)Cl>[Cl:24][CH2:18][C:15]1[C:14]2[CH:20]=[CH:21][C:11]([O:10][C:2]3[S:1][C:9]4[C:4]([N:3]=3)=[N:5][CH:6]=[CH:7][CH:8]=4)=[CH:12][C:13]=2[O:17][CH:16]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1coc2cc(Oc3nc4ncccc4s3)ccc12
Solvent: ClCCl
Product: ClCc1coc2cc(Oc3nc4ncccc4s3)ccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
To a solution of [6-(thiazolo[4,5-b]pyridin-2-yloxy)-benzofuran-3-yl]-methanol (1.0 g, 3.4 mmol) in DCM (34 mL) was added SOCl2 (0.49 mL, 0.83 g, 7.0 mmol) and the reaction mixture was stirred (rt, 2 h). The reaction mixture was filtered to afford the hydrochloride salt of the title compound as a yellow solid (1.0 g, 84%). MS (ESI): mass calcd. for C15H9ClN2O2S, 316.01; m/z found, 317.0 [M+H]+. 1H NMR (400 MHz, CD3OD): 8.93 (dd, J=8.1, 1.4, 1H), 8.69 (dd, J=5.9, 1.4, 1H), 8.02 (s, 1H), 7.90 (d, J=8.5, 1H), 7.81-7.75 (m, 2H), 7.45 (dd, J=8.5, 2.2, 1H), 4.90 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[N+:12]([O-])=O)[N:8]([C:15](=[O:23])[CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)[CH2:7][CH2:6]2.O.O.[Sn](Cl)Cl.Cl>C(O)C.CC(N(C)C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[NH2:12])[N:8]([C:15](=[O:23])[CH2:16][N:17]1[CH2:18][CH2:19][O:20][CH2:21][CH2:22]1)[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C(=O)CN1CCOCC1)CC2
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc2c(cc1N)N(C(=O)CN1CCOCC1)CC2
Reaction time: 8 h

Procedure:
To a solution of 5-(methyloxy)-1-(4-morpholinylacetyl)-6-nitro-2,3-dihydro-1H-indole (0.56 g, 1.74 mmol) in absolute ethanol (100 mL) and DMA (20 mL) was added tin(II)chloride dihydrate (2.36 g, 10.45 mmol) and 1M HCl (1.0 mL). After overnight stirring, reaction was quenched with excess saturated NaHCO3 solution, stirred for one hr, filtered through celite which was and rinsed with methanol. After organic solvent removal, the aqueous layers were extracted with dichloromethane (2×200 mL), the combined organic layers were adsorbed to silica gel and purified by column chromatography (DCM to 5% MeOH/DCM+0.1% NH4OH) to afford 5-(methyloxy)-1-(4-morpholinylacetyl)-2,3-dihydro-1H-indol-6-amine. ESIMS (M+H)+=292.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:4]2[CH:10]=[N:9][CH:8]=[C:5]2[S:6][CH:7]=1.[CH:11](O)=[O:12].C(OC(=O)C)(=O)C.C(=O)([O-])O.[Na+]>ClCCl>[CH:11]([NH:1][CH2:2][C:3]1[N:4]2[CH:10]=[N:9][CH:8]=[C:5]2[S:6][CH:7]=1)=[O:12]
Reactant: O=CO
Reactant: NCc1csc2cncn12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: O=CNCc1csc2cncn12
Yield: 87 %

Procedure:
0.33 g of the above-obtained 3-aminomethylimidazo[5,1-b]-thiazole was dissolved in 10 ml of dichloromethane. To this solution, a mixture which had been prepared in advance by reacting 0.5 ml of formic acid with 0.5 ml of acetic anhydride at 50° C. for 10 minutes was added with stirring, and the resulting mixture was stirred at room temperature for an additional one hour. To the reaction solution was added 20 ml of a saturated aqueous solution of sodium hydrogencarbonate, and the organic layer was separated. The aqueous layer was extracted with dichloromethane (10 ml×2). The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated to dryness under reduced pressure to give 0.338 g (yield 87%) of the title compound.