Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]([CH3:21])[CH2:3][C:4]1([C:17](OC)=[O:18])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:28].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>CO>[CH3:21][CH:2]1[CH2:3][C:4]2([CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]2)[C:17](=[O:18])[NH:28]1
Reactant: COC(=O)C1(CC(C)=O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CO
Product: CC1CC2(CCN(C(=O)OC(C)(C)C)CC2)C(=O)N1
Temperature: 80 °C

Procedure:
1-tert-Butyl 4-methyl 4-(2-oxopropyl)piperidine-1,4-dicarboxylate (1.15 g, 3.84 mmol) in methanol (25 mL) was treated with ammonium acetate (3.85 g, 49.9 mmol), sodium cyanoborohydride (0.681 g, 10.83 mmol) and magnesium sulfate (2.54 g, 21.1 mmol). The mixture was heated at 80° C. in a sealed tube for 12 hours. The reaction mixture was filtered through a pad of CELITE® and the filter cake was washed with methanol. The filtrates were then concentrated and the residue was purified by column chromatography eluting with 0-10% methanol/ethyl acetate to afford the title compound. LC-MS (IE, m/z): 291.27 (M+23)+
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[NH:7][CH:8]1[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.F[B-](F)(F)F.[N:23]#[O+:24]>C(#N)C>[C:1]([O:5][C:6](=[O:11])[N:7]([N:23]=[O:24])[CH:8]1[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CC1
Reactant: N#[O+]
Agent: F[B-](F)(F)F
Solvent: c1ccncc1
Solvent: CC#N
Product: CC(C)(C)OC(=O)N(N=O)C1CC1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 26.4 %

Procedure:
A solution of cyclopropyl-carbamic acid tert-butyl ester (4.8 g, 30.5 mmol) and pyridine (5.9 mL, 73 mmol) in acetonitrile (75 mL) was cooled to approximately −25° C. in a carbon tetrachloride/dry ice bath. Nitrosonium tetrafluoroborate (4.7 g, 40.2 mmol) was added over a period of 20 min. The cooling bath was removed and the reaction mixture was stirred in an ice-bath at 0° C. for 2.5 h. Water (100 mL) and ethyl acetate (500 mL) were added and the organic layer was washed with water (100 mL), 2 M aqueous HCl (50 mL) and brine (100 mL), dried (magnesium sulfate), filtered, evaporated, and purified in two batches using an ISCO 120 g column, eluting with 10-30% ethyl acetate, to give N-nitroso-N-cyclopropyl-carbamic acid tert-butyl ester (1.5 g, 26%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[C:10]([CH:13]2[O:18][CH2:17][CH2:16][NH:15][CH2:14]2)[NH:11][CH:12]=1.[Cl:19][C:20]1[CH:25]=[C:24](Cl)[N:23]=[C:22]([NH2:27])[N:21]=1.CCN(C(C)C)C(C)C>C(O)C>[Cl:19][C:20]1[CH:25]=[C:24]([N:15]2[CH2:16][CH2:17][O:18][CH:13]([C:10]3[NH:11][CH:12]=[C:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[N:9]=3)[CH2:14]2)[N:23]=[C:22]([NH2:27])[N:21]=1
Reactant: Nc1nc(Cl)cc(Cl)n1
Reactant: Clc1ccccc1-c1c[nH]c(C2CNCCO2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Nc1nc(Cl)cc(N2CCOC(c3nc(-c4ccccc4Cl)c[nH]3)C2)n1
Yield: 30.7 %

Procedure:
A solution of 2-[4-(2-chlorophenyl)-1H-imidazol-2-yl]morpholine (250 mg, 0.833 mmol), 4,6-dichloro-2-pyrimidinamine (137 mg, 0.833 mmol) and Hunig's base (0.36 mL, 2.08 mmol) in ethanol (80 mL) was heated at 85° C. for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated. The resulting residue was purified by silica gel chromatography using 50% EtOAc in petroleum ether to afford the title compound (100 mg) as a white solid. LC-MS (ES) m/z=391, 393 [M+H]+.
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12]C)=[O:11].[OH-].[Li+].Cl>O1CCOCC1.O>[F:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: COC(=O)CCCCCCCCF
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)CCCCCCCCF
Temperature: 25 °C
Yield: 80 %

Procedure:
A solution of methyl 9-fluorononanoate (17.1 g, 90 mmol) in 1,4-dioxane (45 mL) was treated drop-wise with a solution of lithium hydroxide (2.4 g, 100 mmol) in water (15 mL). The reaction mixture was stirred at ambient temperature until no starting material remained by thin layer chromatography. The reaction mixture was acidified to pH 1.0 with 2N hydrochloric acid and extracted with diethyl ether. The combined organic phase was washed with water, dried over anhydrous sodium sulfate, filtered, through a short pad of silica gel, and the filtrate evaporated in vacuo to yield 9-fluorononanoic acid (12.75 g, 72 mmol) as a clear, colorless oil, which solidified on standing in the refrigerator. The product was used without further purification.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([CH:17]([CH3:19])[CH3:18])[C:12]=1[O:13]C(C)C)C(O)=O)[CH3:3].O(C1C=CC(C(O)=O)=CC=1)C1C=CC(C(O)=O)=CC=1>CCOCC>[CH:17]([C:11]1[CH:10]=[CH:6][CH:5]=[C:4]([CH:2]([CH3:3])[CH3:1])[C:12]=1[OH:13])([CH3:19])[CH3:18]
Reactant: CC(C)Oc1c(C(C)C)cc(C(=O)O)cc1C(C)C
Agent: O=C(O)c1ccc(Oc2ccc(C(=O)O)cc2)cc1
Solvent: CCOCC
Product: CC(C)c1cccc(C(C)C)c1O

Procedure:
The process for the preparation of highly pure 2,6-diisopropyl phenol (Formula I), comprises reacting p-hydroxy benzoic acid (Formula II) with an alkylating agent in presence of aq. mineral acid at a temperature in the range of 60-65° C. followed by basification with sodium hydroxide to yield crude 4-hydroxy-3,5-diisopropylbenzoic acid (Formula III) including ether impurity 3,5-di(propan-2-yl)-4-(propan-2-yloxy)benzoic acid of Formula V, dimer impurity, 4,4′-oxydibenzoic acid of Formula IV, and the monoalkylated impurity 4-hydroxy-3-(propan-2-yl)benzoic acid of Formula VI and subsequently (a) washing with toluene at basic pH to remove the ether impurity 3,5-di(propan-2-yl)-4-(propan-2-yloxy)benzoic acid of Formula V; (b) washing with hot water to remove dimer impurity 4,4′-oxydibenzoic acid of Formula IV; (c) washing with methanol-water mixture, to remove monoalkylated impurity 4-hydroxy-3-(propan-2-yl)benzoic acid of Formula VI, followed by decarboxylation of 4-hydroxy-3,5-diisopropylbenzoic acid (Formula III), free from impurities of Formula IV, V and VI, in presence of high boiling solvent and a catalyst at high temperature to yield 2,6-diisopropyl phenol having purity of 99.9% by HPLC. 2,6-diisopropyl phenol thus obtained is substantially free of ether impurity 1,3-di(propan-2-yl)-2-(propan-2-yloxy)benzene of Formula VII and monoalkylated phenol impurity 2-(propan-2-yl) phenol of Formula VIII.
Reaction SMILES: [NH:1]([C:3]([S:5][CH3:6])=[NH:4])[NH2:2].O.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([C:16]([CH:18]=O)=O)[CH:13]=[CH:14][CH:15]=1>>[CH3:6][S:5][C:3]1[N:1]=[N:2][CH:18]=[C:16]([C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH3:8])[CH:11]=2)[N:4]=1
Reactant: CSC(=N)NN
Reactant: COc1cccc(C(=O)C=O)c1
Solvent: O
Product: COc1cccc(-c2cnnc(SC)n2)c1
Yield: 78.7 %

Procedure:
3-(Methylsulfanyl)-5-(3-methoxyphenyl)-1,2,4-triazine (1.01 g, 79%) was prepared from methyl hydrazinecarbimidothioate (0.58 g, 5.50 mmol) and 3-methoxyphenylglyoxal monohydrate (1.00 g, 5.50 mmol) according to the general procedure of Preparation 2.
Reaction SMILES: [C:1]([NH:4][CH:5]([C:16](=O)[CH2:17][CH2:18][C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=1)[CH2:6][C:7]1[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[S:10][CH:11]=1)(=[O:3])[CH3:2].Cl.[NH2:35][OH:36].C([O-])(=O)C.[Na+]>CO>[C:1]([NH:4][CH:5]([C:16](=[N:35][OH:36])[CH2:17][CH2:18][C:19]1[CH:24]=[C:23]([C:25]([F:27])([F:26])[F:28])[CH:22]=[C:21]([C:29]([F:32])([F:31])[F:30])[CH:20]=1)[CH2:6][C:7]1[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[S:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC(Cc1csc2ccccc12)C(=O)CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(=O)NC(Cc1csc2ccccc12)C(CCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)=NO
Reaction time: 16 h

Procedure:
The compound of Example 4 (0.5 g) was dissolved in methanol followed by hydroxylamine hydrochloride (0.220 g) and sodium acetate (0.7 g). The reaction was stirred for 16 hours, the solvent was removed and the residue was dissolved in ethyl acetate (100 ml), washed with water (100 ml), dried (MgSO4), filtered and evaporated to yield an oil which was purified by chromatography on silica using dichloromethane/Et2O (3:1) to yield the title compound isomer A as a white solid, mp=200°-201° C.; found: C, 54.79; H, 4.24; N, 5.19; C23H20F6N2O2S requires C, 54.98; H, 4.01; N, 5.58%. Further elution yielded the title compound isomer B as a white solid, mp=200°-203° C.; found: C, 55.13; H, 4.14; N, 5.45; C23H20F6N2O2S requires C, 54.98; H, 4.01; N, 5.58 %.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][N:12]=2)=[N:8][O:9][CH:10]=1)=[O:5])C.COC(C1C=NC(OCC2C(C3C=CC(Cl)=CC=3)=NOC=2)=CN=1)=O>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:7]2[C:6]([C:4]([OH:5])=[O:3])=[CH:10][O:9][N:8]=2)=[N:12][CH:13]=1
Reactant: CCOC(=O)c1conc1-c1ccc(F)cn1
Agent: COC(=O)c1cnc(OCc2conc2-c2ccc(Cl)cc2)cn1
Product: O=C(O)c1conc1-c1ccc(F)cn1
Yield: 66.7 %

Procedure:
As described for example 112a, 3-(5-fluoro-pyridin-2-yl)-isoxazole-4-carboxylic acid ethyl ester (1.0 g, 4.23 mmol) was converted, instead of 5-[3-(4-chloro-phenyl)-isoxazol-4-ylmethoxy]-pyrazine-2-carboxylic acid methyl ester, to the title compound (587 mg, 67%) which was obtained as a dark brown solid. MS: m/e=207.1 [M−H]−.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([CH:9]2[CH2:12][N:11]([CH:13](C3C=CC=CC=3)[C:14]3C=CC=C[CH:15]=3)[CH2:10]2)[CH:6]=[CH:7][CH:8]=1.NC[C@H]([OH:32])C.C(C1C=CC(C2CN(C(NCC=C)=O)C2)=CC=1)(C)(C)C>>[F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([CH:9]2[CH2:12][N:11]([CH2:13][C@H:14]([OH:32])[CH3:15])[CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: C[C@@H](O)CN
Reactant: FC(F)(F)c1cccc(C2CN(C(c3ccccc3)c3ccccc3)C2)c1
Agent: C=CCNC(=O)N1CC(c2ccc(C(C)(C)C)cc2)C1
Product: C[C@@H](O)CN1CC(c2cccc(C(F)(F)F)c2)C1

Procedure:
This compound was prepared from compound (38) and (R)-1-amino-2-propanol using the procedure described for compound (12). mp. 81-82° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH:12]([CH3:14])[CH3:13])=[C:6]([N+:15]([O-])=O)[CH:5]=1>CO.CCOC(C)=O.[Pd]>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH:12]([CH3:13])[CH3:14])=[C:6]([NH2:15])[CH:5]=1
Reactant: COC(=O)c1ccc(NCC(C)C)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(NCC(C)C)c(N)c1
Yield: 94.4 %

Procedure:
3-Amino-4-isobutylamino-benzoic acid methyl ester (790.0 mg) was prepared by following General Procedure B starting from 4-isobutylamino-3-nitro-benzoic acid methyl ester (950.0 mg) and Pd/C (20% by weight, 190.0 mg) in MeOH:EtOAc (1:1, 10.0 mL). The crude product was used in the next step without further purification.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1)[CH2:3][NH2:4].[C:12](/[CH:16]=[CH:17]/[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](=O)[CH3:26])=[CH:20][CH:19]=1)([O:14][CH3:15])=[O:13]>>[C:12](/[CH:16]=[CH:17]/[C:18]1[CH:19]=[CH:20][C:21]([CH2:24][CH:25]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=2)[CH3:26])=[CH:22][CH:23]=1)([O:14][CH3:15])=[O:13]
Reactant: COC(=O)/C=C/c1ccc(CC(C)=O)cc1
Reactant: NCC(O)c1cccc(F)c1
Product: COC(=O)/C=C/c1ccc(CC(C)NCC(O)c2cccc(F)c2)cc1
Yield: 39.2 %

Procedure:
This was prepared in an identical manner to the compound described in Example 1 using 2-hydroxy-2-(3-fluorophenyl) ethanamine (1.55 g) and 4{(E)-2-carbomethoxyethenyl}phenylpropan-2-one (2.18 g). Elution with 1% methanolchloroform on Kieselgel 60 gave the title compound (1.4 g) m.p. 75°-110° C. (benzene-heptane) as an ~45:55 mixture of diastereoisomers. τ(CDCl3) 8.9 (3H, d, J=6 Hz), 6.9-7.8 (7H, m, 2H disappears with D2O), 6.25 (3H, s), 5.45 (1H, m), 3.6 (1H, d, J=16 Hz), 2.55-3.2 (8H, m), 2.35 (1H, d, J=16 Hz).
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[K+].Cl[CH2:7][C:8]1[CH:9]=[C:10]([C:14](=[O:35])[C:15](=[C:26]2[NH:30][C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[NH:27]2)[C:16]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=2)=[O:17])[CH:11]=[CH:12][CH:13]=1.[Cl-].[NH4+]>CS(C)=O>[C:1]([O:4][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14](=[O:35])[C:15](=[C:26]2[NH:27][C:28]3[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=3[NH:30]2)[C:16]([C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=2)=[O:17])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: O=C(C(C(=O)c1cccc(CCl)c1)=C1Nc2ccccc2N1)c1cc(F)cc(F)c1
Reactant: CC(=O)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CS(C)=O
Product: CC(=O)OCc1cccc(C(=O)C(C(=O)c2cc(F)cc(F)c2)=C2Nc3ccccc3N2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 64.4 %

Procedure:
After adding 35 mg of potassium acetate to 2 ml of DMSO solution containing 100 mg of 1-[3-(chloromethyl)phenyl]-3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)propane-1,3-dione, the mixture was stirred at room temperature for about 2 days. The reaction liquid was mixed with an appropriate amount of saturated ammonium chloride aqueous solution, extracted several times with ethyl acetate, dried with anhydrous magnesium sulfate and concentrated, and then the thus formed residue was purified by a silica gel column chromatography to obtain 90 mg of a yellow oily substance from an ethyl acetate-hexane (1:2) eluate. By crystallizing this from a small amount of ethyl acetate-hexane (1:3) at 0° C., 68 mg (64%) of 3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]benzyl acetate (Reference Example 12-1) was obtained as yellow crystals. FA: 449
Reaction SMILES: [Na].[CH2:2](O)[CH3:3].[C:5]([CH:10]1[CH2:14][CH2:13][CH2:12][C:11]1=[O:15])([O:7][CH2:8][CH3:9])=[O:6].C(I)C>[Cl-].[Na+].O.O>[CH2:2]([C:10]1([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:14][CH2:13][CH2:12][C:11]1=[O:15])[CH3:3]
Reactant: CCOC(=O)C1CCCC1=O
Reactant: CCO
Agent: [Cl-]
Agent: [Na+]
Agent: [Na]
Solvent: CCI
Solvent: O
Product: CCOC(=O)C1(CC)CCCC1=O
Yield: 99 %

Procedure:
In a three-necked flask 5.0 g. of sodium metal was dissolved in 250 ml. of dry ethanol and 31.24 g. (0.20 mole) 2-carboethoxycyclopentanone added. To the resulting yellow solution 18.4 ml. (0.23 mole) ethyl iodide was added dropwise and the mixture heated at reflux for two hours. After cooling, 250 ml. of brine and 50 ml. of water were added and the mixture extracted with ethyl ether (2×100 ml.). After drying (MgSO4) and evaporation of solvent 36.5 g. (99%) of 2-ethyl-2-carboethoxycyclopentanone was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][C:26]([F:29])([F:28])[F:27])[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:31][C:32]([OH:34])=[O:33]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][C:26]([F:27])([F:28])[F:29])[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:31][C:32]([OH:34])=[O:33])=[CH:4][CH:3]=1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC(c2ccccc2OC(F)(F)F)CC1
Reactant: O=C(O)CBr
Product: O=C(O)Cn1cc(C(=O)N2CCC(c3ccccc3OC(F)(F)F)CC2)c2ccc(Cl)cc21

Procedure:
Following general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2-trifluoromethoxy-phenyl)-piperidin-1-yl]-methanone (preparation described herein), with (commercially available) bromo-acetic acid gave the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:18])[N:9]2[CH3:19])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH:26](I)([CH3:28])[CH3:27]>O>[CH:26]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:18])[N:9]2[CH3:19])=[CH:6][CH:7]=1)([CH3:28])[CH3:27]
Reactant: CC(C)I
Reactant: CN1C(=O)c2ccccc2CC1c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CC(C)Oc1ccc(C2Cc3ccccc3C(=O)N2C)cc1

Procedure:
To 20 ml of a solution containing 1.50 g of 3-(4-hydroxyphenyl)-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline, 0.86 g of potassium carbonate and 1.24 ml of isopropyl iodide were added and the resulting mixture was heated to reflux for 21 hours. After allowing the mixture to cool, water was added thereto and the resultant was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography [hexane/ethyl acetate (2/1)] to obtain 1.53 g of 3-(4-isopropyloxyphenyl)-2-methyl-1-oxo-1,2,3,4-tetrahydroisoquinoline.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH:7]=[C:8]2[S:12][C:11](=[S:13])[N:10]([CH2:14][C:15]([OH:17])=[O:16])[C:9]2=[O:18])[O:4][N:3]=1.C(=O)([O-])O.[Na+]>O.[Pd]>[CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][CH:8]2[S:12][C:11](=[S:13])[N:10]([CH2:14][C:15]([OH:17])=[O:16])[C:9]2=[O:18])[O:4][N:3]=1
Reactant: Cc1cc(C=C2SC(=S)N(CC(=O)O)C2=O)on1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: Cc1cc(CC2SC(=S)N(CC(=O)O)C2=O)on1
Yield: 29.8 %

Procedure:
In 100 ml of water were dissolved 2.0 g of 5-(3-methyl-5-isoxazolylmethylene)rhodanine-3-acetic acid and 1.0 g of sodium hydrogencarbonate. To the solution was added 1.0 g of 10% palladium charcoal and the mixture was subjected to a reduction at room temperature and under a hydrogen pressure of 3 atm. After completion of the reaction, the catalyst was removed by filtration. To the filtrate was added dilute hydrochloric acid to adjust the pH to 1. The precipitate was separated by filtration and recrystallized from water, giving 0.6 g of 5-(3-methyl-5-isoxazolylmethyl)rhodanine-3-acetic acid (Compound 1g) having a melting point of 235° to 240° C. (decomposition) in a yield of 30%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5](=[CH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:25])=[CH:12][CH:11]=1)[C:6]([O-:8])=[O:7])[CH3:2].[BH4-].[Na+].[C:29](O)(=O)[CH3:30]>C(O)C>[CH2:1]([O:3][C:4](=[O:26])[CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:25])=[CH:12][CH:11]=1)[C:6]([O:8][CH2:29][CH3:30])=[O:7])[CH3:2]
Reactant: CC(=O)O
Reactant: CCOC(=O)C(=Cc1ccc(OCc2c(Cl)cccc2Cl)cc1)C(=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(Cc1ccc(OCc2c(Cl)cccc2Cl)cc1)C(=O)OCC
Yield: 88 %

Procedure:
T a stirred solution of ethyl[4-(2,6-dichlorobenzyloxy)benzylidene]malonate (8.35 g, 19,2 mmol) in ethanol at 0° C. under argon was added sodium borohydride in small portions. Upon completion of the addition, the reaction mixture was adjusted to pH 6 with acetic acid. The mixture was filtered, concentrated in vacuo then partitioned between ether and water. The organic extract was washed successively with 1N hydrochloric acid, saturated sodium bicarbonate solution, water, brine and dried (MgSO4). Removal of volatiles in vacuo afforded the title compound (7.47 g, 88%).
Reaction SMILES: [CH:1]1([CH2:9][NH2:10])[CH2:6][CH2:5][CH:4]([CH2:7][NH2:8])[CH2:3][CH2:2]1.[CH2:11]1[O:13][CH2:12]1>CO>[OH:13][CH2:12][CH2:11][NH:8][CH2:7][CH:4]1[CH2:5][CH2:6][CH:1]([CH2:9][NH2:10])[CH2:2][CH2:3]1
Reactant: NCC1CCC(CN)CC1
Reactant: C1CO1
Solvent: CO
Product: NCC1CCC(CNCCO)CC1

Procedure:
A solution of 14.2 gm. (0.1 mole) of 1,4-cyclohexanebis(methylamine) in 150 ml. anhydrous methyl alcohol and under an atmosphere of nitrogen is warmed to 45° C.-50° C. In a 20 minute period, there is introduced with good agitation and beneath the liquid surface a total of 1.1 gm. (0.025 mole) of ethylene oxide in gaseous form. The reaction temperature is maintained at 45° C.-50° C. for an additional one-half hour after stopping the addition of ethylene oxide. The methyl alcohol is removed by distillation at atmospheric pressure; excess 1,4-cyclohexanebis(methylamine) is readily separated from the product by fractionation under reduced pressure. Only monoethoxylated compound remained and could be used as such or further purified by distillation at reduced pressure.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][N:5]=1.[CH3:13][N:14]([CH3:18])[CH2:15][CH2:16][OH:17]>O1CCCC1>[N+:10]([C:7]1[CH:8]=[CH:9][C:4]([O:17][CH2:16][CH2:15][N:14]([CH3:18])[CH3:13])=[N:5][CH:6]=1)([O-:12])=[O:11]
Reactant: CN(C)CCO
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a mixture of sodium hydride (189 mg, 4.73 mmol) in anhydrous tetrahydrofuran (2 mL) at 0° C. a solution of 2-chloro-5-nitropyridine (500 mg, 3.16 mmol) and 2-(dimethylamino)ethanol (353 mg, 3.96 mmol) in anhydrous tetrahydrofuran (4 mL) was added dropwise. The reaction was warmed to room temperature and stirred for 16 h. The THF was evaporated, and water (100 mL) and EtOAc (200 mL) were added. The aqueous layer was extracted with EtOAc (200 mL), and the organic layers combined, washed with brine, dried over sodium sulfate and concentrated to give a brown oil. Purification column chromatography on silica gel using 5% methanol/methylene chloride yielded 2-(5-nitropyridin-2-yloxy)-N,N-dimethylethanamine as a light yellow solid (233=mg, 35%). LC/MS (m/z): 212.2 (Ma), Rt 1.28 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=[O:7])=[CH:4][C:3]=1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].[OH-].[Li+]>C1COCC1.O>[C:15]([O:14][C:12]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:2]=1[Cl:1])[C:6]([OH:8])=[O:7])=[O:13])([CH3:18])([CH3:16])[CH3:17]
Reactant: COC(=O)c1ccc(Cl)c(C(=O)OC(C)(C)C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1cc(C(=O)O)ccc1Cl
Reaction time: 18 h
Yield: 91.2 %

Procedure:
3-tert-Butyl 1-methyl 4-chloroisophthalate (0.37 g) in THF (5 mL) was treated with lithium hydroxide (0.17 g) in water (5 mL) and the mixture was stirred for 18 h. The solvent was evaporated. Water and ethyl acetate were added. The aqueous extract was separated and acidified with dilute hydrochloric acid. The product was extracted into ethyl acetate. The solution was dried over sodium sulphate, filtered and the solvent was evaporated to yield the subtitle compound as a white solid (0.32 g).
Reaction SMILES: COC([C:5]1([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:9][CH2:8][C:7]([CH2:11][C:12]([Cl:14])=[CH2:13])([CH3:10])[C:6]1=[O:15])=O.[OH-].[Na+]>CC(O)C.O>[Cl:14][C:12](=[CH2:13])[CH2:11][C:7]1([CH3:10])[CH2:8][CH2:9][CH:5]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:6]1=[O:15]
Reactant: C=C(Cl)CC1(C)CCC(Cc2ccc(Cl)cc2)(C(=O)OC)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: C=C(Cl)CC1(C)CCC(Cc2ccc(Cl)cc2)C1=O
Reaction time: 2.5 h

Procedure:
3-(2-Chloro-2-propenyl)-1-(4-chlorobenzyl)-3-methyl-2-oxocyclopentane carboxylic acid methyl ester (Compound (XIII), R1=(Rb)Xbnb=CH2CCl═CH2, R2═CH3) (2.90 g, 8.16 mmol) was dissolved in i-PrOH (5 ml), and then an aqueous solution of NaOH (0.65 g, 16.3 mmol) dissolved in water (5.4 ml) was added, and stirring under reflux was conducted for 2.5 hours. Water (50 ml) was added, and extraction with hexane (50 ml×2) was conducted. The organic layer was dried over anhydrous sodium sulfate, and concentrated to obtain the desired substance
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12]([NH:14][NH2:15])=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl[C:17]1[N:18]=[N:19][C:20]([C:23]2[CH:24]=[N:25][N:26]([CH3:28])[CH:27]=2)=[CH:21][CH:22]=1.O>C(O)CCC>[CH3:28][N:26]1[CH:27]=[C:23]([C:20]2[CH:21]=[CH:22][C:17]3[N:14]([C:12]([CH2:11][C:7]4[CH:6]=[C:5]5[C:10](=[CH:9][CH:8]=4)[N:1]=[CH:2][CH:3]=[CH:4]5)=[N:19][N:18]=3)[N:15]=2)[CH:24]=[N:25]1
Reactant: Cn1cc(-c2ccc(Cl)nn2)cn1
Reactant: NNC(=O)Cc1ccc2ncccc2c1
Solvent: CCCCO
Solvent: O
Product: Cn1cc(-c2ccc3nnc(Cc4ccc5ncccc5c4)n3n2)cn1
Temperature: 120 °C
Yield: 65 %

Procedure:
Quinolin-6-yl-acetic acid hydrazide (188 mg, 0.93 mmol) and 3-Chloro-6-(1-methyl-1H-pyrazol-4-yl)-pyridazine (202 mg, 0.93 mmol, Example 1: step a) were dissolved in butanol (120 mL). The reaction mixture was heated to 120° C. overnight fitted with water cooled refluxing condenser and argon line. The reaction was concentrated in vacuo followed by HPLC purification (5-65% CH3CN over 40 min) resulting in the title compound as a tan solid (201.6 mg, 65%).